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Lifelong Learning for Cardiovascular Professionals

Vascular

Lifelong Learning for Vascular Professionals

Volume 6 • 2020

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Editor-in-Chief Andrew JS Coats Monash University, Melbourne, Australia and University of Warwick, Coventry, UK

Deputy Editor-in-Chief Giuseppe Rosano Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy; Cardiology Clinical Academic Group, St George’s Hospitals NHS Trust, University of London, UK

Associate Editor Cristiana Vitale Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy

Editorial Board William T Abraham

Frank Edelmann

Francesco Maisano

Ali Ahmed

Julia Grapsa

Theresa A McDonagh

Ohio State University College of Medicine, US Washington DC VA Medical Center, US

John J Atherton

Royal Brisbane and Women’s Hospital, Australia

Michael Böhm

St Bartholomew’s Hospital, King’s College London, UK

Finn Gustafsson

University of Copenhagen, Denmark

Saarland University, Germany

David L Hare

Josip A Borovac

Sivadasanpillai Harikrishnan

University of Split, Croatia

Eugene Braunwald

Harvard Medical School, Boston, MA, US

Javed Butler

University of Mississippi Medical Center, US

Ovidiu Chioncel

University of Medicine Carol Davila, Romania

Alain Cohen-Solal

University of Melbourne, Australia Sree Chitra Tirunal Institute for Medical Sciences and Technology, India

Dipak Kotecha

University of Birmingham, UK

Sean Lal

University Hospital, Zurich King’s College Hospital, UK

Kenneth McDonald

St Vincent’s Hospital, Ireland

Ileana L Piña

Montefiore Einstein Center for Heart and Vascular Care, US

Kian Keong Poh

Department of Cardiology, National University Heart Center, Singapore

Aniket Rali

Baylor College of Medicine, US

Royal Prince Alfred Hospital and the University of Sydney, Australia

Izabella Uchmanowicz

Lars H Lund

Maurizio Volterrani

Paris Diderot University, France

Karolinska Institutet and Karolinska University Hospital, Sweden

Carmine De Pasquale

Alexander Lyon

Flinders University, Australia

Cover image © stock.adobe.com.

Charité University Medicine, Germany

Royal Brompton Hospital, UK

Wroclaw Medical University, Poland IRCCS San Raffaele Pisana, Italy

Yuhui Zhang

Fuwai Hospital and National Center for Cardiovascular Diseases, China

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Published by Radcliffe Cardiology, a division of Radcliffe Medical Media. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK. © 2020 All rights reserved ISSN: 2057–7540 • eISSN: 2057–7559

Established: March 2015 | Volume 6, 2020

Aims and Scope

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• Cardiac Failure Review is an international, English language, peer-reviewed, open access journal that publishes articles continuously on www.CFRjournal.com. • Cardiac Failure Review aims to assist time-pressured physicians to stay abreast of key advances and opinions in heart failure. • Cardiac Failure Review publishes balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Cardiac Failure Review provides comprehensive updates on a range of salient issues to support physicians in developing their knowledge and effectiveness in day-to-day clinical practice.

The journal follows guidance from the International Committee of Medical Journal Editors and the Committee on Publication Ethics. We expect all parties involved in the journal’s publication to follow these guidelines. All authors must declare any conflicts of interest.

Structure and Format • Cardiac Failure Review publishes review articles, expert opinion pieces, guest editorials and letters to the editor. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Editorial Board.

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Online All published manuscripts are free to read at www.CFRjournal.com. They are also available at www.radcliffecardiology.com, along with articles from the other journals in Radcliffe Cardiology’s portfolio – Arrhythmia & Electrophysiology Review, European Cardiology Review, Interventional Cardiology Review and US Cardiology Review.

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Cardiology

Lifelong Learning for Cardiovascular Professionals © RADCLIFFE CARDIOLOGY 2020

Contents

Temporary Mechanical Circulatory Support in Acute Heart Failure Federica Jiritano, Valeria Lo Coco, Matteo Matteucci, Dario Fina, Anne Willers and Roberto Lorusso DOI: https://doi.org/10.15420/cfr.2019.02

Suppression of Tumourigenicity 2 in Heart Failure With Preserved Ejection Fraction Veronika Zach, Felix Lucas BĂ¤hr and Frank Edelmann DOI: https://doi.org/10.15420/cfr.2019.10

The Use of App-based Follow-up of Cardiac Implantable Electronic Devices Paul Richard Roberts and Mohamed Hassan ElRefai DOI: https://doi.org/10.15420/cfr.2019.13

Long-term Outcome of Pulmonary Vein Isolation Versus Amiodarone Therapy in Patients with Coexistent Persistent AF and Congestive Heart Failure Michela Faggioni, Domenico G Della Rocca, Sanghamitra Mohanty, Chintan Trivedi, Ugur Canpolat, Carola Gianni, Amin Al-Ahmad, Rodney Horton, Gerald Joseph Gallinghouse, John David Burkhardt and Andrea Natale DOI: https://doi.org/10.15420/cfr.2019.03

Pulmonary Hypertension in Heart Failure Patients Sriram D Rao, Srinath Adusumalli and Jeremy A Mazurek DOI: https://doi.org/10.15420/cfr.2019.09

Telemonitoring in Heart Failure Management Ivo Planinc, Davor Milicic and Maja Cikes DOI: https://doi.org/10.15420/cfr.2019.12

Telemonitoring for the Management of Patients with Heart Failure Ferdinando Iellamo, Barbara Sposato and Maurizio Volterrani DOI: https://doi.org/10.15420/cfr.2019.20

High-flow Nasal Cannula Oxygenation Revisited in COVID-19 Aniket S Rali, Krishidhar R Nunna, Christopher Howard, James P Herlihy and Kalpalatha K Guntupalli DOI: https://doi.org/10.15420/cfr.2020.06

Cardiovascular Clinical Trials in a Pandemic: Immediate Implications of Coronavirus Disease 2019 Ernest Spitzer, Ben Ren, Jasper J Brugts, Joost Daemen, Eugene McFadden, Jan GP Tijssen and Nicolas M Van Mieghem DOI: https://doi.org/10.15420/cfr.2020.07

Link Between Synovial and Myocardial Inflammation: Conceptual Framework to Explain the Pathogenesis of Heart Failure with Preserved Ejection Fraction in Patients with Systemic Rheumatic Diseases Milton Packer DOI: https://doi.org/10.15420/cfr.2019.23

Artificial Intelligence, Data Sensors and Interconnectivity: Future Opportunities for Heart Failure Patrik Bachtiger, Carla M Plymen, Punam A Pabari, James P Howard, Zachary I Whinnett, Felicia Opoku, Stephen Janering, Aldo A Faisal, Darrel P Francis and Nicholas S Peters DOI: https://doi.org/10.15420/cfr.2019.14

Cardiopulmonary Ultrasonography for Severe Coronavirus Disease 2019 Patients in Prone Position Aniket S Rali, Sergio Trevino, Edward Yang, James P Herlihy and Jose Diaz-Gomez DOI: https://doi.org/10.15420/cfr.2020.12

Apps and Online Platforms for Patients with Heart Failure Nida Ahmed, Sabahat Ahmed and Julia Grapsa DOI: https://doi.org/10.15420/cfr.2019.15

ÂŠ RADCLIFFE CARDIOLOGY 2020

Contents

Mechanisms of Myocardial Injury in Coronavirus Disease 2019 Aniket S Rali, Sagar Ranka, Zubair Shah and Andrew J Sauer DOI: https://doi.org/10.15420/cfr.2020.10

Telemedicine, Artificial Intelligence and Humanisation of Clinical Pathways in Heart Failure Management: Back to the Future and Beyond Domenico D’Amario, Francesco Canonico, Daniele Rodolico, Josip A Borovac, Rocco Vergallo, Rocco Antonio Montone, Mattia Galli, Stefano Migliaro, Attilio Restivo, Massimo Massetti and Filippo Crea DOI: https://doi.org/10.15420/cfr.2019.17

Coronavirus Disease 2019: Where are we and Where are we Going? Intersections Between Coronavirus Disease 2019 and the Heart Emilia D’Elia and Michele Senni DOI: https://doi.org/10.15420/cfr.2020.11

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use Zoltán Papp, Piergiuseppe Agostoni, Julian Alvarez, Dominique Bettex, Stefan Bouchez, Dulce Brito, Vladimir Černý, Josep Comin-Colet, Marisa G Crespo-Leiro, Juan F Delgado, Istvan Édes, Alexander A Eremenko, Dimitrios Farmakis, Francesco Fedele, Cândida Fonseca, Sonja Fruhwald, Massimo Girardis, Fabio Guarracino, Veli-Pekka Harjola, Matthias Heringlake, Antoine Herpain, Leo MA Heunks, Tryggve Husebye, Višnja Ivancan, Kristjan Karason, Sundeep Kaul, Matti Kivikko, Janek Kubica, Josep Masip, Simon Matskeplishvili, Alexandre Mebazaa, Markku S Nieminen, Fabrizio Oliva, Julius-Gyula Papp, John Parissis, Alexander Parkhomenko, Pentti Põder, Gerhard Pölzl, Alexander Reinecke, Sven-Erik Ricksten, Hynek Riha, Alain Rudiger, Toni Sarapohja, Robert HG Schwinger, Wolfgang Toller, Luigi Tritapepe, Carsten Tschöpe, Gerhard Wikström, Dirk von Lewinski, Bojan Vrtovec and Piero Pollesello DOI: https://doi.org/10.15420/cfr.2020.03

Morphine in the Setting of Acute Heart Failure: Do the Risks Outweigh the Benefits? Oren Caspi and Doron Aronson DOI: https://doi.org/10.15420/cfr.2019.22

Cardiac Transthyretin-derived Amyloidosis: An Emerging Target in Heart Failure with Preserved Ejection Fraction? Sebastiaan HC Klaassen, Dirk J van Veldhuisen, Hans LA Nienhuis, Maarten P van den Berg, Bouke PC Hazenberg and Peter van der Meer DOI: https://doi.org/10.15420/cfr.2019.16

Coronavirus Disease 2019 and Heart Failure: A Multiparametric Approach Estefania Oliveros, Yevgeniy Brailovsky, Paul Scully, Evgenia Nikolou, Ronak Rajani and Julia Grapsa DOI: https://doi.org/10.15420/cfr.2020.09

Neprilysin as a Biomarker: Challenges and Opportunities Noemi Pavo, Suriya Prausmüller, Philipp E Bartko, Georg Goliasch and Martin Hülsmann DOI: https://doi.org/10.15420/cfr.2019.21

Transcriptomic Research in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives Sebastian Rosch, Karl-Philipp Rommel, Markus Scholz, Holger Thiele and Philipp Lurz DOI: https://doi.org/10.15420/cfr.2019.19

Congestion and Diuretic Resistance in Acute or Worsening Heart Failure Ingibjörg Kristjánsdóttir, Tonje Thorvaldsen and Lars H Lund DOI: https://doi.org/10.15420/cfr.2019.18

Gone, but not Forgotten Barbara Pisani and Rahul Sharma DOI: https://doi.org/10.15420/cfr.2020.18

Contents

Effects of Exercise Training on Cardiac Function in Heart Failure with Preserved Ejection Fraction Hidekatsu Fukuta DOI: https://doi.org/10.15420/cfr.2020.17

Heart Failure With Mid-range or Recovered Ejection Fraction: Differential Determinants of Transition Davide Margonato, Simone Mazzetti, Renata De Maria, Marco Gorini, Massimo Iacoviello, Aldo P Maggioni and Andrea Mortara DOI: https://doi.org/10.15420/cfr.2020.13

Determinants of Functional Capacity and Quality of Life After Implantation of a Durable Left Ventricular Assist Device Kiran K Mirza and Finn Gustafsson DOI: https://doi.org/10.15420/cfr.2020.15

Corrigendum to: Pulmonary Hypertension in Heart Failure Patients Sriram D Rao, Srinath Adusumalli and Jeremy A Mazurek DOI: https://doi.org/10.15420/cfr.2020.1.1

Sodium–Glucose Co-transporter 2 Inhibitors in Heart Failure: Recent Data and Implications for Practice Giuseppe Rosano, David Quek and Felipe Martínez DOI: https://doi.org/10.15420/cfr.2020.23

Acute Heart Failure in Coronavirus Disease 2019 and the Management of Comedications Chia Siang Kow and Syed Shahzad Hasan DOI: https://doi.org/10.15420/cfr.2020.24

Acute Heart Failure

Temporary Mechanical Circulatory Support in Acute Heart Failure Federica Jiritano,1,2 Valeria Lo Coco,1 Matteo Matteucci,1,3 Dario Fina,1,4 Anne Willers1 and Roberto Lorusso1 1. Cardiothoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; 2. Cardiac Surgery Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy; 3. Department of Cardiac Surgery, Circolo Hospital, University of Insubria, Varese, Italy; 4. University of Milan, IRCCS Policlinico San Donato, Milan, Italy

Abstract Cardiogenic shock (CS) is a challenging syndrome, associated with significant morbidity and mortality. Although pharmacological therapies are successful and can successfully control this acute cardiac illness, some patients remain refractory to drugs. Therefore, a more aggressive treatment strategy is needed. Temporary mechanical circulatory support (TCS) can be used to stabilise patients with decompensated heart failure. In the last two decades, the increased use of TCS has led to several kinds of devices becoming available. However, indications for TCS and device selection are part of a complex process. It is necessary to evaluate the severity of CS, any early and prompt haemodynamic resuscitation, prior TCS, specific patient risk factors, technical limitations and adequacy of resources and training, as well as an assessment of whether care would be futile. This article examines options for commonly used TCS devices, including intra-aortic balloon pumps, a pulsatile percutaneous ventricular assist device (the iVAC), veno-arterial extra-corporeal membrane oxygenation and Impella (Abiomed) and TandemHeart (LivaNova) percutaneous ventricular assist device.

Keywords Temporary mechanical circulation, intra-aortic balloon pump, left ventricular assist device, extra-corporeal membrane oxygenation, acute heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 19 June 2019 Accepted: 27 September 2019 Citation: Cardiac Failure Review 2020;6:e01. DOI: https://doi.org/10.15420/cfr.2019.02 Correspondence: Roberto Lorusso, Cardiothoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, P Debeylaan 26, Maastricht 6220 AZ, the Netherlands. E: roberto.lorusso@mumc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Cardiogenic shock (CS) is a circulatory failure as a consequence of left, right or biventricular dysfunction.1 It leads to critical end-organ hypoperfusion due to primary cardiac dysfunction.1 Therefore, CS is not only a cardiac disease but also a multiorgan dysfunction syndrome involving the entire circulatory system, often complicated by a systemic inflammatory response syndrome.2 The goals of haemodynamic support for patients with CS should be circulatory support, ventricular unloading/support, coronary arteries perfusion and decongestion.3 Unfortunately, pharmacological approaches fail to achieve all the objectives.3 Often drug therapy will solve only one element, but this is at the cost of another.3 For example, although vasopressors sustain haemodynamic status by increasing mean arterial pressure, their use can impair microvascular organ perfusion, increase left ventricular afterload and myocardial work and cause myocardial ischaemia.3 Therefore, in recent decades, more aggressive strategies, such as temporary mechanical circulatory support (TCS), have been investigated to address all the elements to achieve an optimal haemodynamic status. TCS includes a group of devices used generally for less than 30 days to maintain adequate organ perfusion (Table 1).4 TCS counteracts acute circulatory failure, which might also arise after cardiac surgery.4 Moreover, since it was introduced, TCS has been used as a bridge to a

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more definitive therapy.5 The management of CS with TCS has advanced in the past decade.5 The scope of applications has widened, and easily deployable devices are significantly more available.5 High-risk procedures, for example, percutaneous coronary interventions (PCI) and ventricular tachycardia ablation, have also started to involve TCS device use.5 However, indications for TCS and device selection are part of a complex process requiring consideration of the severity of CS, early and prompt haemodynamic resuscitation, specific patient risk factors, technical limitations, adequate resources and training and assessment of the futility of care.6 Early intervention with the most appropriate mechanical circulatory support device may improve outcomes.6 The aim of this review is to provide an overview of the TCS devices currently available for patients with CS.

Temporary Mechanical Circulatory Support Devices The technical features of percutaneous assist devices available are compared in Table 2.

Intra-aortic Balloon Pump The intra-aortic balloon pump (IABP) is the most frequently used form of TCS (Figure 1A).7 Straightforward insertion, ready availability and low

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Temporary Mechanical Circulatory Support in Acute Heart Failure cost have made IAPB use common in the treatment of the acute heart failure.7 When positioned in a timely manner, it can play a critical role in the rescue of patients with acute ischaemic MI.7 However, the benefit of IABP therapy is still being debated, and a considerable gap exists between current guidelines and clinical practice. The Intra-aortic Balloon Counterpulsation in Cardiogenic Shock II (IABP-SHOCK II) trial failed to show that an IABP can improve 30-day and 1-year mortality if used in conjunction with optimal medical therapy and early revascularisation.8,9 Accordingly, the European Society of Cardiology guidelines downgraded IABP use for cardiogenic shock from a class I to a class III B recommendation (Table 2).10–12 In the American Heart Association/American College of Cardiology guidelines, IABP use has been downgraded to a class IIb B recommendation based on registry data.13,14 However, the IABP-SHOCK II trial involved a selected population. Nearly half of the subjects enrolled in the study had experienced resuscitation before IABP implantation, which probably resulted in a poor neurological prognosis for many of them regardless of cardiac disease type, and almost all were supported by a high dose of catecholamine at implantation.8,9 Therefore, questions remain over the role of IABP. Despite these negative results, IABPs may still benefit subgroups of patients.15 There is stronger evidence of the efficacy of IABPs in highrisk PCI, based on a prospective randomised trial that included 300 high-risk PCI patients with severe left ventricular dysfunction and extensive coronary disease.16 Moreover, a recent meta-analysis confirmed that the use of IABP in high-risk PCI caused a significant reduction in long-term, all-cause mortality.17 Furthermore, improved organ function and whole-body perfusion associated with reduced endothelial activation have been shown when IABP is used during cardiopulmonary bypass for coronary artery bypass grafting.18,19 Several studies have reported a significant benefit of combining IABP with venous-arterial extra-corporeal membrane oxygenation (VA ECMO); this configuration, theoretically, can reduce the left ventricular (LV) afterload.20–25 The association of the two devices may have a synergistic effect in the treatment of the acute cardiac failure.20–25 Recently, Wang et al. showed that patients receiving VA ECMO with IABP had greater success in weaning from VA ECMO.26 However, they did not have lower in-hospital mortality rates than those with VA ECMO but without IABP. Combined support devices also facilitated cardiac function recovery in post-cardiotomy patients.27–29 These findings underline that, despite apparent benefits from the combination of the two devices, further investigations are warranted to conclusively prove the actual role in cardiogenic shock patients requiring TCS.

iVAC The IABP drive unit can also be used for another TCS, a pulsatile catheter pump called the iVAC (PulseCath, Figure 1B). The iVAC is a minimally invasive pneumatic circulatory assist device that offers circulatory support of 2.5–3.0 l/min, so is positioned between an IABP and a conventional ventricular assist device (VAD).28 It is implanted through the right axillary artery and it directly unloads the LV by active blood aspiration during systole while it creates pulsatile flow into the ascending aorta in diastole.28 Side-effects from its use are mainly haemolysis, which is usually evident within 2 days of implantation, and platelet consumption caused by shear stress and fragmentation, but both effects are minimal and comparable to side-effects of other pulsatile devices.29 However, the iVAC is easy to implant, and there is

CARDIAC FAILURE REVIEW

Table 1: Indications and Contraindications for Temporary Mechanical Circulatory Support Indications

Contraindications

• CI <1.8 l/min/m2

• Irreversible neurological disease

• CVP >20 mmHg

• Disseminated malignancy

• S ystolic BP <80 mmHg with two inotropes

• Severe peripheral vascular disease

• Signs of distal low perfusion

• Contraindication to anticoagulation

• Thrombocytopenia

• Cardiac arrest • Cardiogenic shock • Post-cardiotomy syndrome (unable to wean from bypass) • A cute MI and related mechanical complications • Acute myocarditis • A cute or chronic decompensated heart failure • A cute rejection post-cardiac transplant with haemodynamic compromise • P rophylactic for high-risk interventions (percutaneous coronary intervention, ventricular tachycardia ablation) • Refractory arrhythmias • B ridge to recovery, bridge to decision, bridge to long-term VAD or transplant BP = blood pressure; CI = cardiac index; CVP = central venous pressure; VAD = ventricular assist device.

no need for additional equipment beyond a standard IABP driver unit and transoesophageal echocardiography apparatus.30 In a prospective pilot study of 14 patients, den Uil et al. reported that the iVAC offered support in high-risk PCI with 100% angiographic success.30 The PULsecath mechanicaL Support Evaluation (PULSE) study (NCT03200990) aims to evaluate iVAC and Impella CP (Abiomed) in patients with severe LV impairment undergoing PCI. However, further research addressing its role in the TCS family is required.

Temporary Ventricular Assist Devices Impella The Impella system (Figure 1C) is a miniaturised, continuous-flow, axial pump in a single pigtail catheter.31 Using the Archimedes screw principle, it pumps blood from the LV to the ascending aorta by rotating a screw-shaped surface inside a small, hollow pipe that traverses the aortic valve.31 It produces a non-pulsatile axial flow, pumping blood from the LV into the ascending aorta.31 The Impella 2.5 is the smallest device, generating up to 2.5 l/min of blood flow, and it is usually delivered via the femoral or axillary artery.31 The largest device in the same family can develop 5 l/min of blood flow, but requires a surgical cut-down, although a novel trans-caval approach has recently been designed.32,33 The Impella CP provides an intermediate level of support of 3.0–4.0 l/min.34 In addition, the Impella Right Percutaneous (Impella RP) is available for the treatment of right heart failure.34 The Impella RP, implanted through the femoral vein, provides right ventricular support. However, it could make the patient dependent on the sedation/paralysis status and the right ventricle filling. The variations of the blood volume filling the right ventricle and patient movement could affect the performance of the device.

Acute Heart Failure Table 2: Comparison of Devices IABP

iVAC

Impella 2.5

Impella 5

Impella RP

VA ECMO

TandemHeart

Bedside implantation

Yes

Pump mechanism

Pneumatic

Axial

Centrifugal

Cannula size

7–8 Fr

17 Fr

Catheter: 9 Fr Pump motor: 12 Fr

Catheter: 9 Fr Pump motor: 21 Fr

Catheter: 11 Fr 18–21 Fr inflow Pump motor: 22 Fr 15–22 Fr outflow

21 Fr inflow 15 Fr outflow

Flow (l/min)

0.5–1.0

2.5

> 4.5

Insertion technique

Percutaneous

Surgical

Percutaneous

Percutaneous Surgical

Percutaneous

Implantation time

+++

Gas exchanger

++++

Metabolic support

++++

Left ventricular support

+++

++++

Right ventricular support

+++

++++

Biventricular support

Circulatory support

+++

++++

Anticoagulation

+++

Haemolysis

+++

Post-implantation management difficulty

+++

++++

Level of evidence (European guidelines)

IIIb

N/A

IABP = intra-aortic balloon pump; N/A = not available; VA ECMO = venous-arterial extracorporeal membrane oxygenation; +,++,+++,++++ = relative qualitative grading concerning: time (implantation time); intensity (anticoagulation, post-implantation management difficulty, gas exchanger, metabolic support, left ventricular support, right ventricular support, biventricular support and circulatory support); and severity (haemolysis).

Micro-axial flow pumps can rapidly reduce ventricular wall stress and myocardial oxygen consumption, increasing antegrade flow and consequently reduce ventricular pressure and volume.35 Higher coronary flow velocities and favourable microvascular resistance response with increasing Impella support levels have been described as well.36 Accordingly, in acute left ventricular failure, especially if caused by myocardial ischaemia, mechanical support with Impella confers several beneficial effects.35,36 A survival rate of 94% at 30 days has been reported by a multicentre, prospective feasibility study, including patients treated by the Impella 5.0 for postcardiotomy CS. 37 Data from the USpella Registry similarly showed that, in patients with CS undergoing PCI, those receiving an Impella before a PCI procedure had lower mortality rates than those in whom the device was implanted only after revascularisation. 38 Moreover, in a retrospective single-centre analysis comparing the outcomes of patients with CS who received the Impella 2.5 or 5.0, the Impella 5.0 group had better 30-day survival. 39 Two small randomised controlled trials, studying the use of the Impella and IABP for patients with CS, have been published.40,41 In the Efficacy Study of LV Assist Device to Treat Patients with Cardiogenic Shock (ISAR-SHOCK) trial, patients with acute MI complicated by CS were randomised to receive the Impella 2.5 or an IABP.40 Compared to the IABP, the Impella group showed a higher cardiac index at 30 minutes after implantation, but no difference in mortality was observed.40 Similarly, in the IMPella versus IABP Reduces mortality in ST-elevation MI (STEMI) patients treated with primary PCI in Severe cardiogenic Shock (IMPRESS) trial, the Impella CP was not associated with better recovery of myocardial function or lower mortality when compared to IABP.41

The introduction of percutaneous micro-axial flow pumps also allowed retrograde trans-aortic unloading of the LV during VA ECMO, providing effective decompression of the left chambers with a less invasive approach than other surgical techniques.42 Animal models originally revealed that the Impella device could decrease LV end-diastolic pressure and pressure-volume area even more than ECMO in an acute failing heart, and its use was associated with a higher successful defibrillation rate.43 Accordingly, in a retrospective multicentre cohort of patients with CS treated with VA ECMO plus an Impella device, Pappalardo et al. reported that their combination resulted in lower inhospital mortality and higher rates of bridging to recovery.44 Finally, Patel et al. recently showed that using an Impella device in addition to a VA ECMO for CS is associated with improved survival and reduced need for inotropic support, without higher complication rates.45 The use of intracardiac micro-axial flow pumps, although less invasive than surgically implanted devices for mechanical support, is not without potential complications. The most commonly reported are limb ischaemia, bleeding and vascular injury, ranging from haematoma, pseudo-aneurysm and arterial-venous fistula to retroperitoneal haemorrhage.46 Mechanical erythrocyte shearing often causes haemolysis as well, which has been observed within the first 24 hours of use in up to 10% of patients.46 The Impella device is positioned in the LV, across the aortic valve plane, so has obvious contraindications, including significant aortic valve disease, the presence of a mechanical aortic valve and LV thrombus.47 The device should not be placed in patients with severe peripheral arterial disease or those who cannot tolerate systemic anticoagulation.31 In patients with a known, pre-existing ventricular septal defect, the worsening of right-to-left shunting and hypoxaemia have to be taken into account as well.31 However, in spite of the contraindications and

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Temporary Mechanical Circulatory Support in Acute Heart Failure Figure 1: Temporary Mechanical Circulatory Support Devices

A: Intra-aortic balloon pump; B: iVAC; C: Impella.

possible complications, since the device gained FDA approval in 2008, an increasing number of patients have been treated with Impella devices worldwide, and this has been supported by more favourable literature evidence.48 Some of the latest preclinical experiences have highlighted the key role of LV unloading, along with a 30-minute coronary reperfusion delay, in limiting ischaemiaâ&#x20AC;&#x201C;reperfusion injury.49,50 This approach may promote myocardial recovery, enhance the activity of kinases, preserve mitochondrial integrity, increase the production of cardioprotective cytokines and favour microcirculatory coronary flow.49,50 In this context, Kapur et al. recently showed there was no difference in infarct size of patients affected by acute MI without CS, when comparing subjects treated traditionally by immediate PCI with those who received acute LV unloading with an Impella device, even before myocardial reperfusion.51 This pilot study may represent a turning point for the progress in cardioprotection against acute myocardial ischaemia, by claiming, for the first time, a delay in coronary reperfusion, and considering LV unloading in this setting as a true priority.

TandemHeart The TandemHeart (LivaNova) system (Figure 2B) is a percutaneous VAD with an extra-corporeal continuous-flow centrifugal pump (flow rates up to 4 l/min at a maximum speed of 7,500 rpm).52 It is a left atriumfemoral artery system.52 Oxygenated blood is withdrawn from the left atrium, which is accessed using a standard trans-septal technique and pumped into the systemic circulation in the femoral artery, thereby bypassing the left heart.52 Right ventricular support can be achieved by placing the inflow cannula in the right atrium and the outflow cannula in the pulmonary artery.52 The need for trans-septal puncture for LV support is a potential limitation to its widespread use.52 Specific contraindications are ventricular septal defect (this could cause right to left shunting and hypoxaemia) and aortic insufficiency.52 The complications are limb ischaemia, tamponade after a transeptal puncture, bleeding, infection and thromboembolism.53,54 Several studies demonstrate an increase in cardiac index and mean arterial pressure with a consequent decrease in pulmonary capillary wedge pressure.55â&#x20AC;&#x201C;60 In 2005, Thiele et al. reported their experience with TandemHeart support in patients with CS after acute MI.58 Patients were randomised to haemodynamic support with either an IABP or the

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TandemHeart.58 Those fitted with the device showed a statistically significant improvement in cardiac output, cardiac power index, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, central venous pressure and serum lactate level.58 On the other hand, there was an increased risk of limb ischaemia and coagulopathy.58 There was no difference in mortality.58

ProtekDuo The ProtekDuo (LivaNova) is a dual-lumen cannula, placed through the internal jugular vein.61 One lumen is for the inflow, draining the right atrium; the second lumen serves as outflow, perfusing the pulmonary artery.61 This percutaneous device was designed specifically for right ventricular support.61 It provides a minimally invasive option because of easy insertion and removal.61 Moreover, the patient can be mobilised.61 Furthermore, an oxygenator can be inserted into the circuit (an ambulatory oxygenator right ventricular assist device or OxyRVAD), which contributes to systemic oxygenation.62

Veno-arterial Extra-corporeal Membrane Oxygenation VA ECMO (Figure 2A) is a form of temporary mechanical circulatory and simultaneous extra-corporeal gas exchange for acute cardiorespiratory failure.63 All VA ECMO circuits consist of a venous (inflow) cannula, a pump, an oxygenator and an arterial (outflow) cannula.63 During ECMO support, deoxygenated blood is drained from the venous circulation, passes through the pump into the oxygenator, where gas exchange occurs, and is then returned oxygenated to the arterial circulation.63 Patients may be cannulated centrally or peripherally.63 Peripheral VA ECMO is commonly applied via the femoral artery and vein, either surgically or percutaneously using the Seldinger technique.63 Central VA ECMO is primarily implemented in the operating room and cannulas are usually secured directly to the large vessels or heart chambers while the chest is open.63 Left atrial VA ECMO involves the trans-septal placement of a venous femoral cannula to simultaneously drain both atria in patients with severe left ventricular systolic dysfunction.64 Left atrial VA ECMO allows the drainage of both atria and decreases pulmonary oedema in patients with severe heart failure.64 In recent years, VA ECMO has become the firstline therapy in the setting of CS unresponsive to standard therapy, since it provides both respiratory and cardiac support, is easy to insert and can stay in place

Acute Heart Failure Figure 2: Temporary Ventricular Assist Devices

A: Extra-corporeal membrane oxygenation; B: TandemHeart.

for several days as a bridge to making a decision, which could be for recovery, transplantation or long-term mechanical support.65â&#x20AC;&#x201C;68 However, despite advances in technology and cannulation strategies over time, the prognosis of patients in refractory CS supported with ECMO remains poor.69 A previous retrospective analysis by Sheu et al., reporting data on 30-day survival in 46 patients with STEMI in profound CS, found a morality rate of 39.1%.70 Furthermore, in the cohort reported by Belle et al., in-hospital mortality was 51.9% in 27 patients with CS.71

ultimately delay cardiac contractility improvement.74 Based on these adverse mechanisms, it is clear that unloading the LV during VA ECMO may provide an actual LV functional rest or reduce complications due to counterflow generated by the temporary mechanical support.75 A variety of LV unloading strategies can be used after peripheral VA ECMO has been started, such as IABP, atrial septostomy, pulmonary artery drainage and percutaneous trans-aortic ventricular assist device implantation.75

As physicians care for an ever-increasing number of patients with refractory CS, we should better understand which patients could benefit from VA ECMO. Patient selection for VA ECMO must take into account the underlying diagnosis, comorbidities and whether there is a viable exit strategy, such as recovery, heart transplantation (HTx) or long-term support.68 Several studies have highlighted the importance of the underlying diagnosis in determining survival. Patients with potentially reversible causes of myocardial injury, such as acute myocarditis, have better survival rates those patients with CS after acute MI or cardiac surgery.67,72,73 In addition to considering the underlying diagnosis, given the importance of multiorgan dysfunction syndrome in determining clinical outcome, the timing of VA ECMO initiation is key. Just as premature use may expose a patient to undue risks and complications, delayed initiation may be medically futile. The ideal window for deployment is after other, less invasive treatments have been considered or exhausted, but before the onset of significant end-organ dysfunction.63

Despite the well-known controversy, IABP remains widely used in combination with VA ECMO.75 Percutaneous approaches using unloading devices, such as Impella equipment, are becoming increasingly used.75 However, the optimal strategy to achieve LV decompression remains unclear.75 Peripheral VA ECMO is also a viable alternative for right ventricular failure caused by a primary dysfunction or as a consequence of a pulmonary disease.63 It can be applied percutaneously at the bedside and the most common configuration is femo-femoral.63 In select cases, it is possible to add a venous cannula in the pulmonary artery to drain the right atrium from two places (VV-VA ECMO).80 These settings increase LV afterload and systemic mean arterial pressure.76 If left ventricular function is impaired, it is often useful to add a second device to decompress the LV.76

Peripheral VA ECMO is a potential option for a refractory cardiogenic shock because it quickly improves haemodynamics, can be initiated outside the operating room and requires a relatively non-invasive procedure.63 However, since it provides retrograde blood flow in the aorta, it may increase LV afterload, leading to an increase in LV pressure and wall stress, which impair myocardial recovery and may

Timing of weaning from ECMO is important to achieve good outcomes from this therapy. At the crux of the decision to wean patients off support is whether adequate myocardial recovery to provide sufficient blood and oxygen delivery to organs to meet metabolic demands has been demonstrated.63 Although there is controversy over the degree of acceptable pharmacological support, data suggest that lower levels of inotropes at the time of weaning are associated with better outcomes.77 If cardiac recovery is unlikely or cannot be achieved despite medical therapy optimisation and recovery of end-organ function, HTx or longterm mechanical support should be considered.78

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Temporary Mechanical Circulatory Support in Acute Heart Failure Decision Management If there are signs of cardiac recovery and sustained optimal peripheral perfusion (such as improved cardiac indices, left ventricular ejection fraction, tricuspid annular plane systolic excursion >12 mm, low lactate levels or low wedge pressure), the patient should be weaned from TCS. However, if there are no signs of improvement in haemodynamic parameters or clinical signs, then durable mechanical circulatory support or the withdrawal of TCS (for patients with permanent neurological damage) should be considered. In recent years, a shortage of donors and long waiting-list times resulted in a progressive increase of the number of patients who are bridged to HTx under mechanical circulatory support. 79 A potential alternative, in suitable candidates, would be transition from TCS to a durable LVAD. This condition has been shown to be characterised by acceptable survival.80 A recent meta‐analysis found favourable survival to discharge rates in such patients, with 19% of patients undergoing TCS transitioned to durable LVAD with in-hospital survival ranging from 60% to 100%.81 Similar results were reported by Barge‐Caballero et al. in their retrospective study.82 Patients on durable mechanical circulatory support can subsequently be electively evaluated for transplantation. Outcomes after transplantation in patients on long‐term, continuous‐ flow LVADs are now similar to those achieved in elective patients transplanted without bridging with mechanical circulatory support.83 The use of mechanical circulatory support bridging to HTx has several advantages. Most importantly, the use of donor organs is minimised. Furthermore, for some patients, remaining on LVAD as a destination therapy may turn out to be preferable to transitioning to HTx, either because of concomitant medical issues or simply because of patient

ebazaa A, Combes A, Van Diepen S, et al. Management of M cardiogenic shock complicating myocardial infarction. Intensive Care Med 2018;44:760–73. https://doi.org/10.1007/s00134-0185214-9; PMID: 29767322. 2. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation 2017;136:e232–68. https://doi.org/10.1161/CIR.0000000000000525; PMID: 28923988. 3. Esposito ML, Kapur NK. Acute mechanical circulatory support for cardiogenic shock: the “door to support” time. F1000Res 2017;6:737. https://doi.org/10.12688/f1000research.11150.1; PMID: 28580136. 4. Kantrowitz A, Tjonneland S, Freed PS, et al. Initial clinical experience with intraaortic balloon pumping on cardiogenic shock. JAMA 1968;203:113–8. https://doi.org/10.1001/ jama.203.2.113; PMID: 5694059. 5. Stretch R, Sauer CM, Yuh DD, et al. National trends in the utilization of short-term mechanical circulatory support: incidence, outcomes, and cost analysis. J Am Coll Cardiol 2014;64:1407–15. https://doi.org/10.1016/j.jacc.2014.07.958; PMID: 25277608. 6. Bellumkonda L, Gul B, Masri SC. Evolving concepts in diagnosis and management of cardiogenic shock. Am J Cardiol 2018;122:1104–10. https://doi.org/10.1016/j. amjcard.2018.05.040; PMID: 30072134. 7. Sandhu A, McCoy LA, Negi SI, et al. Use of mechanical circulatory support in patients undergoing percutaneous coronary intervention: insights from the National Cardiovascular Data Registry. Circulation 2015;132:1243–51. https://doi.org/10.1161/CIRCULATIONAHA.114.014451; PMID: 26286905. 8. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287–96. https://doi.org/10.1056/ NEJMoa1208410; PMID: 22920912. 9. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic Balloon Pump in cardiogenic shock II (IABP-SHOCK II) trial investigators. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABPSHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;382:1638–45. https://doi.org/10.1016/S01406736(13)61783-3; PMID: 24011548. 10. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the

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preference. Finally, some patients may experience cardiac recovery that means the device can be removed and a donor organ is not required after long‐term LVAD support.84 Disadvantages of the bridge-to-bridge approach include the need for repeated surgery and consequent increase in costs. Moreover, the strategy cannot be used in all cases. Transition to a durable LVAD requires adequate right ventricular function to sustain satisfactory circulatory function on the LVAD. TCS as a technology is increasingly being used to maintain or even replace basic biological functions. However, timely TCS withdrawal should be considered if the chances of recovery are extremely poor or if severe complications (mainly neurological) occur. This challenging situation has raised conflicting behaviours among doctors. Recently, some physicians have been increasingly engaged with families in shared decision-making.85 Others think that physicians should have the right to discontinue the TCS over a family’s objection.85 TCS devices increase our ability to push the limits of life and delay death (even if only temporarily), bringing potential ethical complications. Further research and debate are warranted where solutions to this complex ethical dilemma can be propose and agreed upon.

Conclusion Major technological evolution has enabled TCS to take on a larger role in the treatment of acute CS over the last decades. Physicians and surgeons are now equipped with an assortment of TCS devices. These are being used both to treat and prevent circulatory collapse. Moreover, they improve haemodynamics in a large array of clinical situations. The choice of adequate TCS is typically guided by the availability of devices and patient-specific factors and conditions. Given that studies that directly compare TCS devices are lacking, further research is needed to provide better guidance on device selection and placement.

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Acute Heart Failure PMID: 30485466. 27. C hen K, Hou J, Tang H, Hu S. Concurrent initiation of intraaortic balloon pumping with extracorporeal membrane oxygenation reduced in-hospital mortality in postcardiotomy cardiogenic shock. Ann Intensive Care 2019;9:16. https://doi. org10.1186/s13613-019-0496-9; PMID: 30485466. 28. Anastasiadis K, Chalvatzoulis O, Antonitsis P, et al. Left ventricular decompression during peripheral extracorporeal membrane oxygenation support with the use of the novel iVAC pulsatile paracorporeal assist device. Ann Thorac Surg 2011;92:2257–9. https://doi.org/10.1016/j. athoracsur.2011.05.063; PMID: 22115242. 29. Mariani MA, Diephuis JC, Kuipers MJ, et al. Off-pump coronary artery bypass graft surgery with a pulsatile catheter pump for left ventricular dysfunction. Ann Thorac Surg 2007;84:690–2. https://doi.org/10.1016/j.athoracsur.2006.12.016; PMID: 17643674. 30. den Uil CA, Daemen J, Lenzen MJ, et al. Pulsatile iVAC 2L circulatory support in high-risk percutaneous coronary intervention. EuroIntervention 2017;12:1689–96. https://doi. org/10.4244/EIJ-D-16-00371; PMID: 28216471. 31. Rihal CS, Naidu SS, Givertz MM, et al. 2015 SCAI/ACC/HFSA/ STS clinical expert consensus statement on the use of percutaneous mechanical circulatory support devices in cardiovascular care. J Am Coll Cardiol 2015;65:e7–26. https:// doi.org/10.1016/j.jacc.2015.03.036; PMID: 25861963. 32. Gaudard P, Mourad M, Eliet J, et al. Management and outcome of patients supported with Impella 5.0 for refractory cardiogenic shock. Crit Care 2015;19:363. https://doi. org/10.1186/s13054-015-1073-8; PMID: 26453047. 33. Frisoli TM, Guerrero M, O’Neill WW. Mechanical circulatory support with impella to facilitate percutaneous coronary intervention for post-TAVI bilateral coronary obstruction. Catheter Cardiovasc Interv 2016;88:E34–7. https://doi. org/10.1002/ccd.26075; PMID: 26104838. 34. Anderson MB, Goldstein J, Milano C, et al. Benefits of a novel percutaneous ventricular assist device for right heart failure: the prospective RECOVER RIGHT study of the Impella RP device. J Heart Lung Transplant 2015;34:1549–60. https://doi. org/10.1016/j.healun.2015.08.018; PMID: 26681124. 35. Kapur NK, Paruchuri V, Pham DT, et al. Hemodynamic effects of left atrial or left ventricular cannulation for acute circulatory support in a bovine model of left heart injury. ASAIO J 2015;61:301–6. https://doi.org/10.1097/ MAT.0000000000000195; PMID: 25485565. 36. Remmelink M, Sjauw KD, Henriques JPS, et al. Effects of left ventricular unloading by Impella recover LP2.5 on coronary hemodynamics. Catheter Cardiovasc Interv 2007;70:532–7. https://doi.org/10.1002/ccd.21160; PMID: 17896398. 37. Griffith BP, Anderson MB, Samuels LE, et al. The RECOVER I: a multicenter prospective study of Impella 5.0/LD for postcardiotomy circulatory support. 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J Am Coll Cardiol 2008;52:1584–8. https://doi. org/10.1016/j.jacc.2008.05.065; PMID: 19007597. 41. Ouweneel DM, Eriksen E, Sjauw KD, et al. Percutaneous mechanical circulatory support versus intra-aortic balloon pump in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2017;39:278–87. https://doi.org/10.1016/j. jacc.2016.10.022; PMID: 27810347. 42. Koeckert MS, Jorde UP, Naka Y, et al. Impella LP 2.5 for left ventricular unloading during venoarterial extracorporeal membrane oxygenation support. J Card Surg 2011;26:666–8. https://doi.org/10.1111/j.1540-8191.2011.01338.x; PMID: 22122379. 43. Kawashima D, Gojo S, Nishimura T, et al. 2011. Left ventricular mechanical support with Impella provides more ventricular unloading in heart failure than extracorporeal membrane oxygenation. ASAIO J 57:169–76. https://doi.org/10.1097/ MAT.0b013e31820e121c; PMID: 21317769. 44. Pappalardo F, Schulte C, Pieri M, et al. Concomitant implantation of Impella® on top of veno-arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock. Eur J Heart Fail 2017;19:404– 12. https://doi.org/10.1002/ejhf.668; PMID: 27709750. 45. Patel SM, Lipinski J, Al-Kindi SG, et al. Simultaneous venoarterial extracorporeal membrane oxygenation and percutaneous left ventricular decompression therapy with impella is associated with improved outcomes in refractory cardiogenic shock. ASAIO J 2019;65:21–8. https://doi.

org/10.1097/MAT.0000000000000767; PMID: 29489461. 46. L auten A, Engström AE, Jung C, et al. Percutaneous leftventricular support with the Impella-2.5-assist device in acute cardiogenic shock: results of the Impella-EUROSHOCK-registry. Circ Heart Fail 2013;6:23–30. https://doi.org/10.1161/ CIRCHEARTFAILURE.112.967224; PMID: 23212552. 47. Naidu SS. Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support. Circulation 2011;123:533–43. https://doi.org/10.1161/ CIRCULATIONAHA.110.945055; PMID: 21300961. 48. Nalluri N, Patel N, Saouma S, et al. Utilization of the Impella for hemodynamic support during percutaneous intervention and cardiogenic shock: an insight. Expert Rev Med Devices 2017;14:789–804. https://doi.org/10.1080/17434440.2017.1374 849; PMID: 28862481. 49. Kapur NK, Qiao X, Paruchuri V, et al. Mechanical preconditioning with acute circulatory support before reperfusion limits infarct size in acute myocardial infarction. JACC Heart Fail 2015;3:873–82. https://doi.org/10.1016/j.jchf.2015.06.010; PMID: 26541785. 50. Watanabe S, Fish K, Kovacic JC, et al. Left ventricular unloading using an Impella CP improves coronary flow and infarct zone perfusion in ischemic heart failure. J Am Heart Assoc 2018;7: e006462. https://doi.org/10.1161/JAHA.117.006462; PMID: 29514806. 51. Kapur NK, Alkhouli MA, DeMartini TJ, et al. Unloading the left ventricle before reperfusion in patients with anterior ST-segment-elevation myocardial infarction. Circulation 2019;139:337–46. https://doi.org/10.1161/ CIRCULATIONAHA.118.038269; PMID: 30586728. 52. Mandawat A, Rao SV. Percutaneous mechanical circulatory support devices in cardiogenic shock. Circ Cardiovasc Interv 2017;10:e004337. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.004337; PMID: 28500136. 53. John R, Long JW, Massey HT, Griffith BP, et al. Outcomes of a multicenter trial of the levitronix centrimag ventricular assist system for short-term circulatory support. J Thorac Cardiovasc Surg 2011;141:932–9. https://doi.org/10.1016/j. jtcvs.2010.03.046; PMID: 20605026. 54. Rihal C, Naidu S, Givertz M, et al. The 2015 SCAI/ACC/HFSA/ STS clinical expert consensus statement on the use of percutaneous mechanical circulatory support devices in cardiovascular care. J Card Fail 2015;21:499–518. https://doi. org/10.1016/j.jacc.2015.03.036; PMID: 25861963. 55. Cheng J, den Uil C, Hoeks S, et al. Percutaneous left ventricular assist devices vs intra-aortic balloon pump counterpulsation for treatment of cardiogenic shock: a meta-analysis of controlled trials. Eur Heart J 2009;30:2102–8. https://doi. org/10.1093/eurheartj/ehp292; PMID: 19617601. 56. Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8. https://doi. org/10.1016/j.jacc.2008.05.065; PMID: 19007597. 57. Anderson M, Smedira N, Samuels L, et al. Use of AB5000 ventricular assist device in cardiogenic shock after acute myocardial infarction. Ann Thorac Cardiovasc Surg 2010;90:706– 12. https://doi.org/10.1016/j.athoracsur.2010.03.066; PMID: 20732481. 58. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26:1276–83. https://doi.org/10.1093/eurheartj/ ehi161; PMID: 15734771. 59. Sakar K, Kini AS. Percutaneous left ventricular support devices. Cardiol Clin 2010;28:169–84. https://doi.org/10.1016/j. ccl.2009.09.007; PMID: 19962057. 60. Kar B, Gregoric ID, Basra SS, et al. The percutaneous ventricular assist device in severe refractory cardiogenic shock. J Am Coll Cardiol 2011;57:688–96. https://doi. org/10.1016/j.jacc.2010.08.613; PMID: 20950980. 61. Kazui T, Tran PL, Echeverria A, et al. Minimally invasive approach for percutaneous CentriMag right ventricular assist device support using a single PROTEKDuo Cannula. J Cardiothorac Surg 2016;11:123. https://doi.org/10.1186/s13019016-0515-y; PMID: 27487837. 62. Bermudez CA, Lagazzi L, Crespo MM. Prolonged support using a percutaneous OxyRVAD in a patient with end-stage lung disease, pulmonary hypertension, and right cardiac failure. ASAIO J 2016;62:e37–40. https://doi.org/10.1097/ MAT.0000000000000343; PMID: 26771397. 63. Keebler ME, Haddad EV, Choi CW, et al. Venoarterial extracorporeal membrane oxygenation in cardiogenic shock. JACC Heart Fail 2018;6:503–16. https://doi.org/10.1016/j. jchf.2017.11.017; PMID: 29655828. 64. Dulnuan K, Guglin M, Zwischenberger J, Gurley J. Left atrial veno-arterial extracorporeal membrane oxygenation: percutaneous bi-atrial draina ge to avoid pulmonary edema in patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2018;71(11 Suppl):A1358. https://doi.org/10.1016/ S0735-1097(18)31899-0. 65. Abrams D, Combes A, Brodie D. Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. J Am Coll Cardiol 2014;63:2769–78. https://doi.org/10.1016/j.

jacc.2014.03.046; PMID: 24814488. 66. A brams D, Combes A, Brodie D. What’s new in extracorporeal membrane oxygenation for cardiac failure and cardiac arrest in adults? Intensive Care Med 2014;40:609–12. https://doi. org/10.1007/s00134-014-3212-0; PMID: 24474528. 67. Combes A, Leprince P, Luyt CE, et al. Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med 2008;36:1404–11. https://doi.org/10.1097/ CCM.0b013e31816f7cf7; PMID: 18434909. 68. Ziemba EA, John R. Mechanical circulatory support for bridge to decision: which device and when to decide. J Card Surg 2010;25:425–33. https://doi. org/10.1111/j.1540-8191.2010.01038.x; PMID: 20412350. 69. Takayama H, Truby L, Koekort M, et al. Clinical outcome of mechanical circulatory support for refractory cardiogenic shock in the current era. J Heart Lung Transplant 2013;32:106– 11. https://doi.org/10.1016/j.healun.2012.10.005; PMID: 23260710. 70. Sheu JJ, Tsai TH, Lee FY, et al. Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock. Crit Care Med 2010;38:1810– 7. https://doi.org/10.1097/CCM.0b013e3181e8acf7; PMID: 20543669. 71. Belle L, Mangin L, Bonnet H, et al. Emergency extracorporeal membrane oxygenation in a hospital without on-site cardiac surgical facilities. EuroIntervention 2012;8:375–82. https://doi. org/10.4244/EIJV8I3A57; PMID: 22829512. 72. Mirabel M, Luyt CE, Leprince P, et al. Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support. Crit Care Med 2011;39:1029–35. https://doi. org/10.1097/CCM.0b013e31820ead45; PMID: 21336134. 73. Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J 2015;36:2246– 56. https://doi.org/10.1093/eurheartj/ehv194; PMID: 26033984. 74. Bréchot N, Demondion P, Santi F, et al. Intra-aortic balloon pump protects against hydrostatic pulmonary oedema during peripheral venoarterial-extracorporeal membrane oxygenation. Eur Heart J Acute Cardiovasc Care 2018;7:62–9. https://doi.org/10.1177/2048872617711169; PMID: 28574276. 75. Meani P, Gelsomino S, Natour E, et al. Modalities and effects of left ventricle unloading on extracorporeal life support: a review of the current literature. Eur J Heart Fail 2017;19(Suppl 2):84–91. https://doi.org/10.1002/ejhf.850; PMID: 28470925. 76. Napp LC, Kühn C, Hoeper MM. Cannulation strategies for percutaneous extracorporeal membrane oxygenation in adults. Clin Res Cardiol 2016;105:283–96. https://doi. org/10.1007/s00392-015-0941-1; PMID: 26608160. 77. Pappalardo F, Pieri M, Arnaez Corada B, et al. Timing and strategy for weaning from venoarterial ECMO are complex issues. J Cardiothorac Vasc Anesth 2015;29:906–11. https://doi. org/10.1053/j.jvca.2014.12.011; PMID: 25836952. 78. Rousse N, Juthier F, Pinçon C, et al. ECMO as a bridge to decision: Recovery, VAD, or heart transplantation? Int J Cardiol 2015;187:620–7. https://doi.org/10.1016/j.ijcard.2015.03.283; PMID: 25863737. 79. Shah P, Pagani FD, Desai SS, et al. Mechanical circulatory support research network. outcomes of patients receiving temporary circulatory support before durable ventricular assist device. Ann Thorac Surg 2017;103:106–12. https://doi. org/10.1016/j.athoracsur.2016.06.002; PMID: 27577033. 80. Gustafsson F, Rogers JG. Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes. Eur J Heart Fail 2017;19:595–602. https://doi.org/10.1002/ejhf.779; PMID: 28198133. 81. den Uil CA, Akin S, Jewbali LS, et al. Short-term mechanical circulatory support as a bridge to durable left ventricular assist device implantation in refractory cardiogenic shock: a systematic review and meta-analysis. Eur J Cardiothorac Surg 2017;52:14–25. https://doi.org/10.1093/ejcts/ezx088; PMID: 28472406. 82. Barge-Caballero E, Almenar-Bonet L, Gonzalez-Vilchez F, et al. Clinical outcomes of temporary mechanical circulatory support as a direct bridge to heart transplantation: a nationwide Spanish registry. Eur J Heart Fail 2018;20:178–86. https://doi.org/10.1002/ejhf.956; PMID: 28949079. 83. Lund LH, Khush KK, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report – 2017; focus theme: allograft ischemic time. J Heart Lung Transplant 2017;36:1037–46. https://doi.org/10.1016/j.healun.2017.07.019; PMID: 28779893. 84. Chaggar PS, Williams SG, Yonan N, et al. Myocardial recovery with mechanical circulatory support. Eur J Heart Fail 2016;18:1220–7. https://doi.org/10.1002/ejhf.575; PMID: 27297263. 85. Bein T, Brodie D. Understanding ethical decisions for patients on extracorporeal life support. Intensive Care Med 2017;43:1510–1. https://doi.org/10.1007/s00134-017-4781-5; PMID: 28349177.

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Ejection Fraction

Suppression of Tumourigenicity 2 in Heart Failure With Preserved Ejection Fraction Veronika Zach,1,2 Felix Lucas Bähr1,2 and Frank Edelmann1,2,3 1. Department of Internal Medicine and Cardiology, Charité University Medicine Berlin, Germany; 2. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany; 3. Berlin Institute of Health, Berlin, Germany

Abstract Heart failure (HF), with steadily increasing incidence rates and mortality in an ageing population, represents a major challenge. Evidence suggests that more than half of all patients with a diagnosis of HF suffer from HF with preserved ejection fraction (HFpEF). Emerging novel biomarkers to improve and potentially guide the treatment of HFpEF are the subject of discussion. One of these biomarkers is suppression of tumourigenicity 2 (ST2), a member of the interleukin (IL)-1 receptor family, binding to IL-33. Its two main isoforms – soluble ST2 (sST2) and transmembrane ST2 (ST2L) – show opposite effects in cardiovascular diseases. While the ST2L/IL-33 interaction is considered as being cardioprotective, sST2 antagonises this beneficial effect by competing for binding to IL-33. Recent studies show that elevated levels of sST2 are associated with increased mortality in HF with reduced ejection fraction. Nevertheless, the significance of sST2 in HFpEF remains uncertain. This article aims to give an overview of the current evidence on sST2 in HFpEF with an emphasis on prognostic value, clinical association and interaction with HF treatment. The authors conclude that sST2 is a promising biomarker in HFpEF. However, further research is needed to fully understand underlying mechanisms and ultimately assess its full value.

Keywords Heart failure, biomarker, suppression of tumourigenicity 2, heart failure with preserved ejection fraction Disclosure: The authors have no conflicts of interest to declare. Received: 16 August 2019 Accepted: 22 October 2019 Citation: Cardiac Failure Review 2020;6:e02. DOI: https://doi.org/10.15420/cfr.2019.10 Correspondence: Frank Edelmann, Department of Internal Medicine and Cardiology, Charité University Medicine, Campus Virchow-Klinikum, Augustenburger

Platz 1, 13353 Berlin, Germany. E: frank.edelmann@charite.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-

commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a chronic, progressive disease with steadily increasing incidence rates and high morbidity and mortality that represents a major challenge in healthcare worldwide.1–3 The disease is characterised by chronic exacerbations, recurrent hospitalisations and poor prognosis.1,2 Survival rates in HF patients are lower than in patients suffering from some malignant diseases, including breast cancer and prostate cancer.3 Epidemiological data suggest that between a third and more than half of all HF patients suffer from HF with preserved ejection fraction (HFpEF).4,5 For some time, investigators have been discussing an inferior prognosis in HF with reduced ejection fraction (HFrEF) compared with HFpEF.6,7 However, several recent studies suggest that survival rates for patients with HFpEF and patients with HFrEF are similar.4,8–12 With its poor prognosis and prevalence rates that are expected to increase further in an ageing population, new approaches to the diagnostics and treatment of HFpEF are increasingly important.4,5,13 However, there is still a lack of established diagnostic standards and therapies because of unresolved challenges in this complex disease entity. Several studies have evaluated the role of emerging novel biomarkers in this field.14–16 Systemic inflammation, fibrosis and cardiac remodelling are central features in the pathophysiology of HFpEF.17–19 Suppression of tumourigenicity 2 (ST2) – a receptor suggested to

indicate and reflect these complex underlying processes – has therefore been discussed as a promising biomarker.20 The prognostic value of ST2 in HFpEF, as well as its association with clinical features and interaction with HF treatment, are the main subject of this article.

ST2 and its Relationship with Heart Failure The Biology of ST2 ST2 is a member of the interleukin (IL)-1 receptor family.20 First described in 1989 by Tominaga et al., its role as a marker in myocardial injury was initially suggested in 2002 by Weinberg et al.21,22 Four different isoforms of ST2 – with a soluble (sST2) and a transmembrane receptor (ST2L) at the centre of attention – were detected and IL-33 was identified as their ligand.20,23 IL-33 – a cytokine that belongs to the IL-1 family – is released by a multitude of different cell types in different situations, such as during mechanical stress, among others.20,24 ST2L and sST2 promote opposing biological effects by binding to IL33. The ST2L/IL-33 interaction initiates a complex cardioprotective biochemical cascade that counteracts hypertrophic and fibrotic processes and protects cells from apoptosis. However, in times of cardiac damage, cardiomyocytes, fibroblasts and extracardiac cells secrete large amounts of sST2. By competing for the IL-33 binding site, circulating sST2 antagonises those cardioprotective mechanisms and thereby promotes myocardial damage (Figure 1).20,25

Access at: www.CFRjournal.com

Ejection Fraction Figure 1: Schematic Illustration of ST2/IL-33 Interaction

IL-33 IL-33

IL-33

CARDIAC INJURY AND STRESS

IL-33 Increased production of sST2 in cardiac fibroblasts, cardiomyocytes and extracardiac cells

IL-33

sST2 sST2

IL-33 sST2 sST2

sST2

sST2 sST2 sST2 IL-33 Interruption of IL-33/ ST2L binding

CARDIOPROTECTION through IL-33/ST2L interaction -reduction of myocardial fibrosis -prevention of hypertrophy -reduction of apoptosis

ST2L

ST2 is a member of the IL-1 receptor family consisting of two main isoforms – a transmembrane (ST2L) and a soluble receptor (sST2). The cytokine IL-33, known to be its ligand, is produced by many cells (e.g. fibroblasts etc.) in the presence of injury and stress. When IL-33 binds transmembrane ST2L located on different cells (e.g. myocytes, fibroblasts, immune cells), a complex cardioprotective biochemical cascade is launched, leading to a reduction of myocardial fibrosis, prevention of cardiomyocyte hypertrophy and protection from apoptosis. However, in times of cardiac damage and stress cardiac fibroblasts, cardiomyocytes and extracardiac cells produce sST2. By binding IL-33, and therefore competing for the binding site, excessive amounts of sST2 interrupt the cardioprotective interaction of IL-33 and ST2L. IL = interleukin; ST2 = suppression of tumourigenicity 2. Source: Pascual-Figal and Januzzi 2015.20 Reproduced with permission from Elsevier.

Clinical Relevance of sST2 in Cardiovascular Disease and Heart Failure After observing elevated sST2 levels in patients after MI, its clinical value as a biomarker for cardiac stress and mechanical overload was first discussed.22 The marker’s prognostic potential arose after an analysis of sST2 levels in >800 patients with acute ST-elevation MI. A significant association between increased sST2 levels and higher 30day mortality was described.26,27 Furthermore, because myocardial strain, fibrosis and volume overload are common features in the pathophysiology of congestive HF, researchers also suggested a prognostic, as well as a diagnostic, value of sST2 in this disease entity.26,28,29 Analyses of blood samples from the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) HF trial and the Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department (PRIDE) trial found increased levels of sST2 in patients with severe, acute decompensated HF (ADHF) with reduced ejection fraction. In addition, both trials also identified sST2 levels as a predictor of outcome in this disease entity.28–31 Subsequently, the findings of several other studies supported these data and highlighted the role of sST2 as a promising prognostic biomarker in HFrEF.32–35 In view of these findings, many investigators are exploring the potential value of sST2 being integrated into the routine work-up and treatment

of HF patients. Maisel et al. described sST2 as the HbA1c of HF and considered the biomarker capable of depicting a bigger picture of the disease and its underlying mechanisms including inflammatory processes and fibrosis.36 Hence, the measurement of biomarkers indicating myocardial injury and fibrosis was included in the 2017 American College of Cardiology/ American Heart Association/Heart Failure Society of America guidelines for the management of HF as a class IIa recommendation in patients with chronic HF.37 However, the 2016 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic HF do not explicitly recommend the measurement of such biomarkers in routine clinical settings.38 While the promising role of sST2 as a biomarker in HFrEF is supported by increasing evidence, several aspects of this biomarker still remain unclear and call for further investigation. One aspect is that no consensus on a standardised reference interval has been reached. Indeed, different values for European compared with US populations, as well as sex-specific cut-offs, have been described. 36,39–42 Furthermore, data investigating the value of sST2 in HF with mid-range or preserved ejection fraction are sparse and, therefore, its significance as a biomarker in this disease remains uncertain.

CARDIAC FAILURE REVIEW

ST2 in Heart Failure With Preserved Ejection Fraction Figure 2: The Role of Comorbidities and Inflammatory Agents Including sST2 in the Pathophysiology of HFpEF Hypertension

Obesity

COPD

Diabetes

Iron deficiency Systemic proinflammatory state Monocytes PLASMA - sST2 - TNF-alpha - IL-6 - Pentraxin-3

ENDOTHELIAL CELL VCAM and E-selectin

ROS

Migration of monocytes into subendothelium

NO ONOO-

TGF-beta CARDIOMYOCYTE

Fibroblast

Collagen

Myofibroblast

sGC cGMP

Hypertrophy

PKG Common comorbidities, including diabetes, obesity and hypertension, generate a systemic proinflammatory state characterised by increased levels of sST2, TNF-alpha, IL-6 and pentraxin-3. These factors trigger the production of ROS, VCAM and E-selectin in coronary endothelial cells. The accumulation of ROS induces the synthesis of ONOO- and causes a decrease in the supply of NO. The impact of ONOO- and NO on sGC and cGMP in adjoining cardiomyocytes subsequently leads to a reduction in the activity of PKG. The latter, in consequence, activates a complex prohypertrophic cascade resulting in cardiomyocyte hypertrophy. VCAM and E-selectin accumulation, however, sets monocytes in motion that migrate into subendothelium and produce TGF-beta. TGF-beta, in turn, induces the transformation of fibroblasts to myofibroblasts, which then produce collagen. cGMP = cyclic guanosine monophosphate; COPD = chronic obstructive pulmonary disease; HFpEF = preserved ejection fraction; IL = interleukin; NO = nitric oxide; ONOO- = peroxynitrite; PKG = protein kinase G; ROS = reactive oxygen species; sGC = soluble guanylate cyclase; sST2 = soluble suppression of tumourigenicity 2; TGF-beta = transforming growth factor-beta; TNF-alpha = tumour necrosis factor-alpha; VCAM = vascular cell adhesion molecule. Source: Paulus et al. 2013.17 Reproduced with permission from Elsevier.

Systemic Inflammation and Cardiac Remodelling: Pathophysiological Pathways The pathophysiology of HFpEF is complex and not entirely understood. However, it is essential to consider underlying mechanisms to assess the role of biomarkers in this disease. In general, systemic inflammation and microvascular dysfunction, along with cardiomyocyte hypertrophy and fibrosis, are believed to play a key role in the pathophysiology of HFpEF.17,18,43–46 Paulus et al. suggested that some of those cardiac modifications derive from common comorbidities in HFpEF, such as diabetes, obesity, hypertension and physical inactivity. These diseases are considered to induce a state of systemic inflammation with increased levels of sST2 and other inflammatory agents, consequently triggering a complex signalling cascade initiating cardiac remodelling and leading to diastolic myocardial dysfunction (Figure 2).17 Increased levels of sST2 could mark the activation of this pathophysiological pathway. Therefore, researchers expect to gain important information through the collection of sST2 levels in patients with suspected HFpEF. The utility of this biomarker as a diagnostic, therapeutic and prognostic tool in this disease entity is the subject of discussion.

CARDIAC FAILURE REVIEW

Prognostic Value of sST2 Several studies provide evidence of a significant association between increased sST2 levels and outcome in HFpEF. Five predominantly retrospective/post-hoc analyses with cohort sizes ranging from 86 to 200 patients showed increased sST2 levels mostly measured at baseline to significantly correlate with increased mortality, as well as with increased hospitalisation rates at different periods of follow-up.47–51 In contrast, two studies with cohort sizes of 76 and 135 patients delivered contradictory results. Friões et al. reported that there was no significant association between increased sST2 levels and and a composite endpoint of all-cause death or hospital readmission for HF within 6 months, while Moliner et al. reported no association with cardiovascular death or HF-related hospitalisation/all-cause death or HF-related hospitalisation (Table 1).52,53

Association Between sST2, Clinical Parameters and Echocardiographic Measurements In 2011, Shah et al. published results of an investigation of 200 patients presenting to the emergency department with worsening dyspnoea but preserved left ventricular ejection fraction (LVEF).47 At enrolment, sST2 concentrations correlated with elevated levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), myeloperoxidase

Ejection Fraction Table 1: Studies Investigating the Prognostic Value of sST2 in HFpEF Study and Year

Type of Analysis LVEF

Outcome

Shah et al. 201147

200

Post hoc

≥50%

Association between increased baseline sST2 levels and increased 1-year mortality (p=0.001)

Manzano-Fernández et al. 201148

197

Retrospective

≥50%

Association between increased baseline sST2 levels and increased 1-year mortality (p=0.002)

Friões et al. 201552

Retrospective

≥50%

No association between increased sST2 levels measured at discharge after hospitalisation for ADHF and a composite endpoint of all-cause death or hospital readmission for HF within 6 months (p=0.07)

Sanders-van Wijk et al. 201549

100

Post hoc

≥50%

Association between increased baseline sST2 levels and decreased 18-month overall survival and HF hospitalisation-free survival (p=0.002)

Moliner et al. 201853

135

Retrospective

≥50%

No association between increased baseline sST2 levels and cardiovascular death or HF-related hospitalisation (p=0.79) and all-cause death or HF-related hospitalisation (p=0.44; mean follow-up period 4.9 ± 2.8 years)

Najjar et al. 201950

Retrospective

≥45%

Association between increased sST2 levels 4–8 weeks (stable condition) after enrolment and a composite endpoint of death or HF hospitalisation (median follow-up of 522 days; p=0.046)

Sugano et al. 201951

191

Post hoc

≥50%

Association between increased baseline sST2 levels and increased all-cause death and noncardiovascular death (median follow-up 445 days; p=0.002, p=0.003)

ADHF = acute decompensated heart failure; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; LVEF = left ventricular ejection fraction; sST2 = soluble suppression of tumourigenicity 2.

and C-reactive protein (CRP), as well as with decreased estimated glomerular filtration rate (eGFR), previous diagnosis of ADHF and older age. However, sST2 lagged behind NT-proBNP regarding the association with echocardiographic measurements and indices of diastolic dysfunction. In summary, sST2 was not associated with left ventricular (LV) mass and most indices of diastolic dysfunction in patients with an LVEF ≥50%.47 In a study by Manzano-Fernández et al., sST2 levels were measured in 447 patients with ADHF.48 The investigators sought to analyse the association of sST2 with mortality, both in HFrEF and HFpEF. Higher levels of sST2 were associated clinically with more severe HF symptoms in both subgroups. In patients with HFpEF increased baseline levels of sST2 were associated with higher levels of leukocytes, creatinine, eGFR, CRP, NT-proBNP and troponin T. Again, the study failed to provide evidence of a significant association with relevant echocardiographic parameters in HFpEF.48 Zile et al. evaluated data from the Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial. In a group of 301 patients NT-proBNP, matrix metalloproteinase-2, collagen III N-terminal propeptide, galectin-3 and sST2 were measured at baseline and 12 and 36 weeks after randomisation.54 Levels of sST2 were higher than reference values in comparable control groups determined in previous investigations.39,40,54 In line with previous results, there was evidence of an association between higher baseline levels of sST2 and higher levels of NT-proBNP, as well as reduced renal function. In contrast to previous findings, worsening degrees of diastolic dysfunction measured through an increase in E/E’ and left atrial (LA) volume during follow-up were found to be associated with an increase in sST2 values during follow-up. However, only the correlation with LA volume showed statistical significance. Further adjusted multivariate statistical analysis only found female sex, New York Heart Association (NYHA) class and LA volume to significantly correlate with elevated sST2 levels.54 AbouEzzedine et al. analysed serum sST2 levels from 174 patients enrolled in the Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection

Fraction (RELAX) trial.55,56 They found evidence of an association of increased baseline sST2 values with worse clinical signs and symptoms, including pronounced leg oedema, higher jugular venous pressure and again higher classes in the NYHA classification. Elevated sST2 levels were mainly found in patients with comorbidities, while there was no evidence of sST2 being linked to co-factors, such as body size, age or history of HF hospitalisation. In addition, while NT-proBNP levels again correlated strongly with echocardiographic measurements of diastolic dysfunction, sST2 values in this cohort failed to show this phenomenon and were only found to indicate malfunction of the right ventricle. Investigators concluded that sST2 in this setting is to be seen as a marker of systemic inflammation rather than as a measure of diastolic dysfunction.55 This assumption is further supported by recurrent findings reporting increased levels of sST2 in various disease entities, including trauma, sepsis and pulmonary disease.57,58 Nagy et al. investigated the value of sST2 in 86 patients with HFpEF from the Karolinska Rennes study with special interest in its association with echocardiographic parameters.59 SST2 levels were measured in a stable state of disease 4–8 weeks after a patient presented to the hospital with ADHF. Of note, their results showed a significant association between increased ST2 levels and reduced left atrial global strain, as well as reduced RV-function, but not with indices of LV geometrical diameters, LV functional parameters and several other measurements.59 The findings discussed here are depicted in detail in Table 2.47,48,50,51,54,55,59

Comorbidities and sST2 Although common chronic diseases, such as diabetes, arterial hypertension and obesity, play a major role in HFpEF, data in this specific area are scarce. While on the one hand those diseases are frequently observed comorbidities in HFpEF patients, on the other hand their causal potential in HFpEF pathophysiology is debated.17 Even though this dual role suggests a close connection to sST2 values, only two studies (AbouEzzedine et al. and Sugano et al.) evaluated associations between the biomarker and comorbidities in HFpEF. However, the results of these analyses were contradictory.51,55 BMI was the only parameter that was evaluated by almost all investigators. Here again findings diverged, leaving many questions unresolved.47,48,50,51

CARDIAC FAILURE REVIEW

ST2 in Heart Failure With Preserved Ejection Fraction Table 2: Studies Investigating the Association Between sST2 and a Variety of Clinical Features in HFpEF Study

Type of Analysis

LVEF Significant Correlation

No Significant Correlation

Shah et al. 201147

200

Post hoc

≥50%

Association between increased baseline sST2 levels and: • ↑ age (p=0.001) • ↓ eGFR (p=0.002) • ↑ CRP (p<0.001) • ↑ MPO (p=0.004) • ↑ NT-proBNP (p<0.001) • ADHF diagnosis (p=0.001) • ↑ E/E’ (p=0.01)

No association between increased baseline sST2 levels and: • male sex (p=0.8) • BMI (p=0.9) • SBP and DBP (p=0.7 and p=0.6) • African-American (p=0.5) • cTnI (p<0.1) • other echocardiographic indices

Manzano-Fernández 197 et al. 201148

Retrospective

≥50%

Association between increased baseline sST2 levels and: • ↑ leukocytes (p=0.01) • ↑ creatinine (p=0.015) • ↓ eGFR (p=0.01) • ↑ CRP (p<0.001) • ↑ NT-proBNP (p<0.001) • ↑ cTnT (p=0.001)

No association between increased baseline sST2 levels and: • age (p=0.65) • BMI (p=0.94) • SBP and DBP (p=0.47 and p=0.13) • HR (p=0.19) • Hb (p=0.09) • BUN (p=0.08) • LV end-systolic and end-diastolic diameter (p=0.16 and p=0.49) • RV systolic pressure (p=0.08)

Zile et al. 201654

Post hoc (PARAMOUNT)

≥45%

Association between increased baseline sST2 levels and: • ↑ NT-proBNP (p=0.002) • ↓ eGFR (p=0.005) • ↑ galectin-3 (p<0.001) • ↑ LA volume (p<0.001; p=0.02*) • female sex (p<0.001*) • ↑ NYHA class (p=0.002*)

No association between increased baseline sST2 levels and: • SBP (p=0.64) • E/A (p=0.11) • E´ (p=0.31) • E/E´ (p=0.09)

Post hoc (RELAX)

≥50%

Association between increased baseline sST2 levels and: • diabetes (p=0.005†), hypertension (p=0.023†), AF/flutter (p=0.049†), renal dysfunction (p<0.0001†)

No association between increased baseline sST2 levels and: • LV diastolic or systolic function • aldosterone • pro-collagen III N-terminal peptide

301

AbouEzzedine et al. 174 201755

Clinical Features

• treatment with diuretics (p=0.013†) • ↑ NT-proBNP (p<0.0001†) • higher prevalence of jugular venous pressure elevation (p=0.003†) • increased peripheral oedema (p=0.0006†) • ↑ NYHA class (p=0.029†) • higher RV systolic pressure (p=0.016†) and worse RV function (p=0.015†) • • • •

↑ endothelin-1 (p<0.0001†) ↑ CRP (p=0.002†) ↑ C-telopeptide for type 1 collagen (p=0.0004†) ↑ cTnI (p<0.0001†)

Nagy et al. 201859

Retrospective

≥45%

Association between increased sST2 levels 4–8 weeks (stable condition) after enrolment and: • ↓ LA-GS • ↓ RV function • ↑ NYHA class

No association between increased sST2 levels 4–8 weeks (stable condition) after enrolment and: • degree of LA enlargement • indices of LV geometrical diameters • LV systolic functional parameters • measures of LV relaxation and end-diastolic function • indices of AV coupling and systemic vascular function • creatinine • eGFR

Najjar et al. 201950

Retrospective

≥45%

Association between increased sST2 levels 4–8 weeks (stable condition) after enrolment and: • ↑ NT-proBNP (p<0.001) • ↑ NYHA class (p=0.005) • ↑ LAVI (p=0.019)

No association between increased sST2 levels 4–8 weeks (stable condition) after enrolment and: • age (p=0.295)

CARDIAC FAILURE REVIEW

• • • • • •

eGFR (p=0.513) mean arterial pressure (p=0.668) BMI (p=0.301) E/E´ (p=0.248) LVMI (p=0.795) LVEF (p=0.634)

Ejection Fraction Table 2: Cont. Study and Year n

Type of Analysis

LVEF

Sugano et al. 201951

Post hoc (ICAS-HF)

≥50%

191

Clinical Features Significant Correlation

No Significant Correlation

Association between increased baseline sST2 levels and: • male sex (p=0.02) • ↓ BMI (p=0.02) • ↓ albumin (p<0.001) • ↓ Hb (p=0.02) • ↓ potassium (p=0.04) • ↑ CRP (p=0.02) • ↑ pentraxin3 (p<0.001) • ↑ noradrenaline (p=0.005) • ↑ BNP (p<0.001) • ↑ tricuspid regurgitation pressure gradient (p=0.01)

No association between increased baseline sST2 levels and: • age (p=0.20) • body weight (p=0.11) • HR (p=0.35) • comorbidities: AF (p=0.28), coronary artery disease (p=0.19), hypertension (p=0.22), COPD (p=0.51), diabetes (p=0.32) • medications: beta-blocker (p=0.84), ACE inhibitor or ARB (p=0.73), diuretics (p=0.69), aldosterone antagonist (p=0.09), statin (p=0.15) • eGFR (p=0.35) • sodium (p=0.56) • total cholesterol (p=0.63) • HbA1c (p=0.13) • plasma aldosterone (p=0.12) • plasma renin activity (p=0.054) • other echocardiographic indices

*Multivariable analysis adjusted for age, sex, NYHA class, history of AF, diastolic blood pressure, eGFR, log NT-proBNP, E/E’ and LA volume. †Adjusted for sex. ADHF = acute decompensated heart failure; BNP = brain natriuretic peptide; BUN = blood urea nitrogen; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; cTnI = cardiac troponin I; cTnT = cardiac troponin T; DBP = diastolic blood pressure; E’ = mean value of the lateral and septal mitral annular early diastolic velocity; E/A = ratio between early diastolic inflow velocity (E)/inflow velocity due to atrial contraction (A); E/E’ = early diastolic tissue velocity; eGFR = estimated glomerular filtration rate; Hb = haemoglobin; HFpEF = heart failure with preserved ejection fraction; HR = heart rate; LA = left atrium; LA-GS = left atrial global strain; LAVI = left atrial volume index; LV = left ventricle; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; MPO = myeloperoxidase; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association; RV = right ventricle; SBP = systolic blood pressure; sST2 = soluble suppression of tumourigenicity 2.

Heart Failure Treatment and sST2 Beyond the existing evidence of an interaction between sST2 and treatment with beta-blockers, valsartan and spironolactone in patients with HFrEF, there are very limited data investigating the relationship between sST2 levels and the response to different treatment approaches in HFpEF.33,60,61 To date, only the PARAMOUNT investigators have addressed this issue, when they discussed the interaction between sacubitril/valsartan, valsartan and sST2 levels.54 They analysed whether the effectiveness of treatment with LCZ696 could be predicted and measured using sST2 and other biomarkers. At 12 and 36 weeks, neither sST2 nor any of the other biomarkers interacted with the changes in NT-proBNP levels associated with LCZ696 treatment. However, baseline levels of sST2 were associated with the effects of treatment with LCZ696 or valsartan on LA volume after 36 weeks. In patients with sST2 levels below the median of 33 ng/ml at baseline, the change in LA volume after 36 weeks of treatment with LCZ696 was significantly higher when compared to valsartan than in those with baseline sST2 values above the median. In a comparison of baseline levels to post-treatment sST2 levels, sST2 values did not respond significantly to treatment with LCZ696 or valsartan.54 Currently there are no data on the interaction of sST2 and treatment with beta-blockers, mineralocorticoid receptor antagonists, such as spironolactone, diuretics and other commonly used agents in HFpEF.

Conclusion In conclusion, sST2 is a promising novel biomarker, with a significant value as an outcome indicator in HFrEF. In contrast, the existing evidence in HFpEF remains uncertain.

So far, most studies agree on the promising value of sST2 in predicting outcomes in patients with HFpEF. Furthermore, data repeatedly show evidence of an association between increased levels of sST2 and higher NT-proBNP, decreased eGFR, high CRP levels and advanced clinical HF severity. In contrast, most analyses have failed to show a significant correlation with characteristic echocardiographic measurements and indices, which are prerequisites for the diagnosis of HFpEF. Although comorbidities play a bimodal role in HFpEF, there are hardly any data analysing the value of sST2 in, for example, patients with both diabetes and HFpEF. Additional investigations in this area could answer remaining pathophysiological questions. To date, most results on sST2 in HFpEF are derived from retrospective/ post-hoc analyses of acute HF cohorts with limited sample sizes. Thus, prospective data, as well as data evaluating the significance of sST2 in chronic HFpEF, are scarce. Furthermore, interactions between sST2 and commonly used therapeutic agents including, for example, beta blockers, mineralocorticoid receptor antagonists and diuretics have not been investigated sufficiently, but data from the PARAMOUNT trial suggest a potential role of sST2 in the management of the treatment of HFpEF. Future research should therefore focus on the predictive value, clinical associations and impact of sST2 on the response to different therapeutic approaches in HFpEF. Because recent studies suggest that aldosterone inhibits cardioprotective mechanisms promoted through IL-33/ST2L, mineralocorticoid receptor antagonists could be of particular interest. 62

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44. S hah SJ, Lam CSP, Svedlund S, et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J 2018;39:3439–50. https://doi.org/10.1093/eurheartj/ehy531; PMID: 30165580. 45. van Heerebeek L, Borbély A, Niessen HWM, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006;113:1966–73. https://doi.org/10.1161/ CIRCULATIONAHA.105.587519; PMID: 16618817. 46. Mohammed SF, Hussain S, Mirzoyev SA, et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015;131:550–9. https://doi.org/10.1161/ CIRCULATIONAHA.114.009625; PMID: 25552356. 47. Shah KB, Kop WJ, Christenson RH, et al. Prognostic utility of ST2 in patients with acute dyspnea and preserved left ventricular ejection fraction. Clin Chem 2011;57:874–82. https://doi.org/10.1373/clinchem.2010.159277; PMID: 21515743. 48. Manzano-Fernández S, Mueller T, Pascual-Figal D, et al. Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am J Cardiol 2011;107:259–67. https://doi. org/10.1016/j.amjcard.2010.09.011; PMID: 21211603. 49. Sanders-van Wijk S, van Empel V, Davarzani N, et al. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail 2015;17:1006–14. https://doi.org/10.1002/ejhf.414; PMID: 26472682. 50. Najjar E, Faxén UL, Hage C, et al. ST2 in heart failure with preserved and reduced ejection fraction. Scand Cardiovasc J 2019;53:21–7. https://doi.org/10.1080/14017431.2019.158336 3; PMID: 30776920. 51. Sugano A, Seo Y, Ishizu T, et al. Soluble ST2 and brain natriuretic peptide predict different mode of death in patients with heart failure and preserved ejection fraction. J Cardiol 2019;73:326–32. https://doi.org/10.1016/j.jjcc.2018.10.012; PMID: 30580891. 52. F riões F, Lourenço P, Laszczynska O, et al. Prognostic value of sST2 added to BNP in acute heart failure with preserved or reduced ejection fraction. Clin Res Cardiol 2015;104:491– 9. https://doi.org/10.1007/s00392-015-0811-x; PMID: 25586507. 53. Moliner P, Lupón J, Barallat J et al. Bio-profiling and bioprognostication of chronic heart failure with mid-range ejection fraction. Int J Cardiol 2018;257:188–92. https://doi. org/10.1016/j.ijcard.2018.01.119; PMID: 29415801. 54. Zile MR, Jhund PS, Baicu CF, et al. Plasma biomarkers reflecting profibrotic processes in heart failure with a preserved ejection fraction: data from the Prospective Comparison of ARNI with ARB on Management of Heart Failure With Preserved Ejection Fraction study. Circ Heart Fail 2016;9:e002551. https://doi.org/10.1161/ CIRCHEARTFAILURE.115.002551; PMID: 26754625. 55. AbouEzzeddine OF, McKie PM, Dunlay SM, et al. Suppression of tumorigenicity 2 in heart failure with preserved ejection fraction. J Am Heart Assoc 2017;6:e004382. https://doi. org/10.1161/JAHA.116.004382; PMID: 28214792. 56. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268–77. https://doi.org/10.1001/jama.2013.2024; PMID: 23478662. 57. Brunner M, Krenn C, Roth G, et al. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med 2004;30:1468–73. https://doi. org/10.1007/s00134-004-2184-x; PMID: 14991091. 58. Oshikawa K, Kuroiwa K, Tago K, et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med 2001;164:277–81. https://doi.org/10.1164/ajrccm.164.2.2008120; PMID: 11463601. 59. Nagy AI, Hage C, Merkely B, et al. Left atrial rather than left ventricular impaired mechanics are associated with the profibrotic ST2 marker and outcomes in heart failure with preserved ejection fraction. J Intern Med 2018;283:380–91. https://doi.org/10.1111/joim.12723; PMID: 29430747. 60. Gaggin HK, Motiwala S, Bhardwaj A, et al. Soluble concentrations of the interleukin receptor family member ST2 and β-blocker therapy in chronic heart failure. Circ Heart Fail 2013;6:1206–13. https://doi.org/10.1161/ CIRCHEARTFAILURE.113.000457; PMID: 24114865. 61. Maisel A, Xue Y, van Veldhuisen DJ, et al. Effect of spironolactone on 30-day death and heart failure rehospitalization (from the COACH Study). Am J Cardiol 2014;114:737–42. https://doi.org/10.1016/j. amjcard.2014.05.062; PMID: 25129066. 62. Martínez-Martínez E, Cachofeiro V, Rousseau E, et al. Interleukin-33/ST2 system attenuates aldosterone-induced adipogenesis and inflammation. Mol Cell Endocrinol 2015;411:20–7. https://doi.org/10.1016/j.mce.2015.04.007; PMID: 25896545.

Digital Health

The Use of App-based Follow-up of Cardiac Implantable Electronic Devices Paul Richard Roberts and Mohamed Hassan ElRefai University Hospital Southampton NHS Foundation Trust, Southampton, UK

Abstract There has been a steady rise in the number of patients treated with cardiac implantable electrical devices. Remote monitoring and remote follow-up have proven superior to conventional care in the follow-up of these patients and represent the new standard of care. With the widespread availability of smartphones and with more people using them for health queries, app-based remote care offers a promising new digital health solution promoting the shift of follow-up to exception-based assessments. It focuses on patients’ enablement and has shown promising results, but also highlights the need to increase the system’s automaticity to achieve acceptable follow-up adherence rates. MyCareLink Heart is a fully automated app-based system that represents the next generation of app-based monitoring and is currently being evaluated in an international study with promising initial results.

Keywords Remote monitoring, digital health, cardiac implantable electronic devices, enablement, smart technology, mobile app, Bluetooth, m-health, e-health, MyCareLink Smart, MyCareLink Heart Disclosure: PRR has received research funding/speakers fees and consultancy fees from Medtronic. MHER has no conflicts of interest to declare. Received: 11 September 2019 Accepted: 19 November 2019 Citation: Cardiac Failure Review 2020;6:e03. DOI: https://doi.org/10.15420/cfr.2019.13. Correspondence: Paul Roberts, Mailpoint 46, Southampton General Hospital, Southampton SO16 6YD, UK. E: paul.roberts@uhs.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

‘Digital health’ increasingly surrounds us in the clinical environment, although it is not always embraced among all healthcare professionals. Modern technologies and digital appliances have a significant impact on the way we care for patients by offering innovative ways to converge technology, connectivity and people. This should translate into improved care and clinical outcomes.1 The term is often used more broadly to include ‘e-health’, as well as developing areas, such as the use of advanced computer sciences in the fields of big data, genomics and artificial intelligence.

Device follow-up is a mandatory part of the care for patients treated with cardiac implantable electronic devices (CIEDs). These include permanent pacemakers (PPMs), ICDs, cardiac resynchronisation therapy (CRT) pacemakers and CRT defibrillators and implantable loop recorders. After implantation, CIEDs require close monitoring. This is a highly technical and specialised process requiring dedicated structures, equipment and the interaction of several healthcare personnel. It needs to be done in a timely manner to safely and effectively deliver therapy and is guideline driven.7

The WHO has described e-health as the cost-effective and secure use of information and communication technologies in support of health and health-related fields, including healthcare services, health surveillance, health literature, health education, knowledge and research.2 Currently, there is a need to adopt evidence-based practice via research with regard to digital health solutions. This can facilitate reimbursement, promote their use on a wider scale and make them more readily available.

There has been a steady increase in the number of patients with CIEDs. In 2016, a total of 547,586 PPMs, 105,730 ICDs and 87,654 CRTs were implanted worldwide in 53 European Society of Cardiology (ESC) member countries. Between 2007 and 2016 there was an increased rate of implantation of various CIEDs in ESC member countries. Implantation rates for PPM increased from 619 per million inhabitants in 2007 to 742 per million inhabitants in 2016, ICDs from 92 per million inhabitants in 2007 to 133 per million in 2016 and CRTs from 53 per million inhabitants in 2007 to 118 per million in 2016.8 This has imposed a significant burden on the already limited resources arising from their follow-up in outpatient clinics. It is estimated that the number of encounters for CIED follow-up is approximately 2.2 million per year in Europe alone. Therefore, there is a need to organise follow-up of patients with CIEDs efficiently and effectively.7

In the US, 53% of individuals over the age of 65 years have smartphones and 62% use their smartphone for health enquiries.3,4 It has been estimated that 83% of payers and providers believe that consumers need to take more control of their health in a value-based system.5 Mobile wireless technologies for public health – referred to as m-health – have been shown to increase access to health information, services and skills, as well as promoting positive changes in health behaviours to prevent the onset of acute and chronic diseases.6 It is the responsibility of healthcare practitioners to remain up to date with available options to provide appropriate advice and guidance to our patients.

Access at: www.CFRjournal.com

Remote Follow-up and Monitoring of Cardiac Implantable Electronic Devices Traditional follow-up of CIEDs involved patients attending clinics where their devices were interrogated using a wand-based radiofrequency

App-based Follow-up of ICDs (RF) system that communicates with a programmer. The frequency of this depends on the device implanted and the patient’s specific clinical condition. For patients with pacemakers this might mean that they would only be seen once a year. Important clinical diagnostics might, therefore, be missed and the opportunity to intervene lost. A good example of relevant clinical data that can be missed (or at least manifest unacceptable delays before reaching the attention of the responsible healthcare practitioner with traditional follow-up) are clinically relevant but asymptomatic episodes of AF that would require timely intervention. This intervention might include assessing the appropriateness of and starting anticoagulation as per guidelines to minimise the risk for thromboembolic events/strokes. Remote follow-up of CIEDs refers to the process of routine scheduled remote device interrogations, where transmission of data occurs based on pre-specified parameters related to the device functionality and clinical events. These systems usually consist of base units that reside in the patient’s home and communicate with their device either wirelessly or using an RF-based solution. The base unit then transmits the data using either cell services or landline internet connection to the companyspecific remote follow-up system. It is structured to mimic conventional in-clinic checks but provides the opportunity for alert-based interactions and more frequent follow-up with monitoring between scheduled transmissions (remote monitoring).9 While more frequent follow-up and more monitoring may result in an increase in the transmitted data, acting on this increasing generation of data should be driven by guidelines to reduce the risk of overuse of remote monitoring. Remote follow-up offers an opportunity to resolve some of the challenges associated with the delivery of effective CIEDs follow-up by improving clinic efficiency and improving the patient’s adherence to follow-up.10–14 Remote care (RC) has proven superior to conventional monitoring in many aspects. RC in pacemaker patients is associated with increased survival, and patients with high RC adherence have shown 53% greater survival than patients with low RC adherence and 140% greater survival compared with no RC.15 The Pacemaker Remote Follow-up Evaluation and Review (PREFER) study highlighted that the diagnosis of clinical actionable events – namely AF, fast ventricular rates in response to atrial arrhythmias, non-sustained ventricular tachycardia (VT), abnormal device or lead parameters and change in percentage of ventricular pacing – was higher and 26% faster in patients with RC.16 Furthermore, the Evaluate the Benefits of Pacemaker Follow-Up With HomeMonitoring (COMPAS) trial demonstrated that there were 66% fewer hospitalisations as a result of atrial arrhythmias and overall 56% fewer ambulatory visits for the remotely monitored pacemaker recipients.12 This all translates into lower healthcare expenditure in office visits in remotely followed-up PPM patients.17 If the system requires the patient to positively interact with the remote system, then this adds the potential to lose adherence. Several randomised trials have shown that RC is more effective in achieving patients’ adherence as well as timely scheduled follow-up goals. Large cohort analyses of databases have consistently shown improved survival rates in patients undergoing RC.18,19 RC represents the new standard of care for patients with CIEDs, with alert-driven inpatient evaluation replacing routine clinic interrogation. This has been reflected in international guidelines recognising RC as a Class 1 recommendation for certain aspects of CIED follow-up, such as lead function, battery management, reduction in inappropriate shocks from ICDs and the early detection of AF.20

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Challenges to the Adoption of New Digital Health Solutions in Remote Care Physicians Physicians have to provide solutions that ensure the validity and accuracy of the handled data without compromising on its integrity or the quality. Furthermore, any patient data have to be handled securely. This flow of data requires infrastructure changes and revision of traditional workflow and patient pathways. The organisational model needs to be designed to act in a timely fashion to alerts, but recognising that the system does not replace emergency care for unwell patients.

Patients New digital health solutions in RC need to focus on patients’ enablement, a concept that describes patients’ ability to better understand, or cope with, participate in or have a greater responsibility for their own care.21 Patient education is key to success. In order for the new digital health solutions to work, patients need to have an acceptable degree of health, as well as digital literacy. It is important to take the time to explain to patients the expected reaction times with telemedicine, how to react during emergencies and their responsibilities to keep contact information up to date and maintain the function of the equipment and appropriate communications. New digital health solutions need to be able to promote the shift to exception-based assessments, reducing the economic costs for the patients in order to motivate patients to adhere to follow-up requirements and promote engagement with clinical services.

Application-based Remote Monitoring MyCareLink Smart (Medtronic) is a first-generation, application-based remote management system for CIEDs. This is a first of its kind system, with no other comparable applications that will allow for meaningful comparison. Patients who have application-based, RC-enabled CIEDs are given a hand-held reader device and are instructed to download a compatible application on their smartphone/tablet. The RC process involves turning on and placing the reader over the implanted device manually so that the device can be interrogated and data retrieved. The reader then transmits the information via Bluetooth to the application on the patient’s smartphone or tablet, which then sends the information through to the CareLink network via cellular or landline internet connection. The information is then available to the clinical team in the usual manner. This system replaces the conventional transmission unit with a reader and the patient’s smartphone/tablet. The process requires the patient to interrogate their device with the reader. Patients are given a timetable of when to interrogate the device so that the data can be transmitted to the CareLink network (Figure 1). A large retrospective analysis was performed in the US of more than 95,000 patients who were enrolled in the CareLink database, using MyCareLink Smart. The analysis looked into the proportion of patients who adhered to the follow-up transmissions according to the clinic schedule. There were 48,016 patients assigned app-based remote follow-up, and 40,511 (84.4%) of them activated their devices for RC. Adherence analysis was limited to 14,232 patients who activated their RC and had at least 12 months of follow-up after activation. Of these patients, 89% were considered adherent, as per Heart Rhythm Society guidelines, as they had at least one more transmission within 3 months to 1 year after activation. There was no difference in adherence to follow-up in patients having a generator change or a de novo device. There was also no difference between men and women. The high

Digital Health Figure 1: MyCareLink Smart

Manual: Tel A/B only

Pacemaker

Transmission sent from MyCareLink Smart App to CareLink™ Network via cellular or Wi-FI connection

Patient Reader manually interrogates pacemaker

Patient Reader communicates to MyCareLink Smart™ App on smart device (Apple® or Android™) The first generation of app-based follow-up was MyCareLink Smart. This uses a patient reader that manually interrogates the pacemaker in a similar way to previous programmers. This then transmits the pacemaker data via Bluetooth to the patient’s phone, which then transmits the data to CareLink via Wi-Fi connection or data services. Reproduced with permission from Medtronic.

percentages of adherence across all age groups suggest patients’ ability and desire to continue using RC.22 A further retrospective analysis was carried out on 156,426 patients in the US who were enrolled using the CareLink System between January 2012 and December 2016. The aim of the analysis was to assess patients’ compliance to scheduled transmissions in a real-world setting among different age groups. Over a mean follow-up of 3 years, compliance to scheduled remote monitoring since activation was 61.8% and sub-group analysis identified patients ≤60 years old (52.8%; 95% CI [52.1–53.5]) to be less compliant than patients >60 years (62.8%; 95% [CI 62.6–63.1%]). The outcome of this analysis is that less than twothirds of patients are adherent to the follow-up regime at 3 years. This is clinically unacceptable in terms of comprehensive CIED follow-up. The system requires timely manual transmissions using the patient reader and so requires active engagement over the life of the patient and device. It is probable that this is the stage of the pathway that results in reduced engagement because it requires active action from the patient. With this in mind, increasing the automaticity of the system would likely result in more optimal follow-up adherence.23

Next-generation Application-based Remote Monitoring The latest platform of pacemakers developed by Medtronic uses Bluetooth Low Energy to communicate with its programmer. Bluetooth Low Energy is different to the Bluetooth used in household items, such as speakers and hands-free headsets. These devices require high amounts of data transfer at fast rates. Bluetooth Low Energy is slower and for low volumes of data, so is perfectly suited to CIED interrogation. The current drain on the device is, as a consequence, approximately two-thirds of current energy drain used in historic device communication. As most current smartphones/tablets use Bluetooth for communication, this provides the perfect partnership. MyCareLink Heart is a fully automated app-based RC system that communicates with Medtronic pacemakers using Bluetooth Low Energy. The compatible CIED is paired directly and automatically to the

patient’s smartphone/tablet via the application. The patient’s device then transmits the data to CareLink securely via cellular network or landline internet connection. It uses the patient’s phone/tablet as a ‘pass-through’ device with no data being retained on the phone/tablet. Select data can then be passed back to the patient’s device via CareLink and is then visible on the MyCareLink Heart app (Figure 2). This system requires the application to be open in the background on the patient’s device so that communication can occur, allowing passive data transfer, in contrast to active data transfer that requires action from the patient. The schedule of transmissions is directed by the clinic through the CareLink network. If a schedule is due and the patient does not have the application open, then a push notification will be sent to prompt action from the patient. Patients’ interaction with the application provides a platform to prompt their consent on both passive and active transfer of data on an ongoing basis. Device and clinical alerts can be programmed on, so if there are any alerts the physician will receive notification of these outside of the usual follow-up regimen, with regular connectivity between the CIED and the patient’s device. These alerts include events related to lead impedance, low battery voltage, atrial tachycardia (AT)/AF burden, VT episodes, fast V rate during AT/AF, capture management and percentage V pacing. The system has the facility for patients to make an additional transmission if required. To ensure that this facility is not used inappropriately the patient is prompted with “Does your clinic know that you are going to send a transmission?”. Limited data are fed back to the MyCareLink Heart app, including battery longevity, activity levels determined by the accelerometer and the status of the patient’s transmission schedule. The application also allows patients to record vital signs and any symptoms on a daily basis. The data are not transmitted to CareLink but allow a record that the patient can show to their healthcare professional. There are education signposts within the application and also essential details about the patient’s device and leads that can act as their CIED identification card (Figure 3).

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App-based Follow-up of ICDs Figure 2: MyCareLink Heart

SMART PATIENT MONITORING MYCARELINK HEART MOBILE APP

Heart device with BlueSync technology

Patient’s smartphone

Cellular or Wi-Fi

CareLink network

(acts as a pass-through only)

Select pacemaker data**

Use of Bluetooth low energy is designed to minimise battery drain of the pacemaker.1

Enhanced security with data encryption and pacemaker protection1

Upgradeable throughout lifetime of device

Automatic notifications inform patients of transmission status.

*Please visit www.MCLHeart.com for a list of compatible smartphones and tablets. **Content of transmissions and alerts is not visible to the patient

MyCareLink Heart is a mobile application for remote patient monitoring of BlueSync-enabled CIEDs

Medtronic Azure XT DR MRI SureScan Device Manual. M964338A001B. 2016-10-22.

MyCareLink Heart allows the compatible device to automatically communicate, securely via low energy Bluetooth to the patient’s phone. The phone acts a pass-through device and the data goes to the CareLink network via cellular or wi-fi. Selected information can be transmitted back to the patient via the app. CIEDs = cardiac implantable electronic devices. Reproduced with permission from Medtronic.

This next generation of app-based monitoring represents an example of Quantifying Self Hybrid Models (QSHMs), which combine features of patient reported outcomes measures (PROMs) and objective telemonitoring into a system that integrates passive data collection and active patient reporting. They help to overcome the unreliable subjectivity of PROMs and the absolute objectivity of telemonitoring alone. The use of QSHMs promotes patients’ enablement, and initial studies evaluating the impact of QSHMs in chronic disease management have been promising.24 A prospective randomised control trial conducted in Toronto, Canada, examined this in 110 patients with diabetes and uncontrolled systolic hypertension. Patients in the intervention group were provided with a home blood pressure (BP) telemonitoring system that provided selfcare messages on the patients’ smartphones based on the averages of the transmitted readings. Patients in the control group were provided with a home BP monitoring system without the self-care messages. At 12 months, there was a significant reduction in the mean daytime systolic BP (−9.1 mmHg and −1.5 mmHg), and mean daytime diastolic BP (−4.6 mmHg and −1.3 mmHg) in the intervention group compared with the control group, respectively. In addition, 51% of the patients in the intervention group achieved the guideline recommended target BP in comparison to 31% of the control group. There were no significant changes in the number or classes of antihypertensive medications at exit and there was no difference in the number of physicians’ office visits between both groups.25

Expectations and Challenges Patients’ expectations from this technology would be to provide them with more information on the status of their device, in particular battery longevity and status of the scheduled transmissions, which is fed back to them through the application.

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Physicians’ expectations from this new technology would be to provide them with concise, clinically relevant information, promoting efficiency. The main concern would be overuse of this technology because of the increased generation of data. Initial experience with this nextgeneration application showed that after the introduction of notifications prompting patients to acknowledge unscheduled downloads and asking them if their healthcare practitioner was aware of them, most of the time they don’t go through with them, making a high volume of unscheduled downloads by the patients less likely. Another concern that would need to be addressed is healthcare practitioners’ responsibility. With the increased automaticity of the follow-up process with minimal – if any – action required by the patient, it is implied that more responsibility for the device follow-up is shifted from the patient to the healthcare practitioner/physician. This means that guidelines and pathways need to be implemented to react in timely manner to the downloaded data. It is also important to stress the fact that the system does not replace emergency care for unwell patients. This brings another challenge – the time and the cost of patients’ education. It is important to take the time to explain to patients the expected reaction times with this new system. Furthermore, they also need to understand their responsibilities within this new system such as maintaining the function of the equipment and appropriate communications and what to do in case of an emergency. In practice, if implementation of this system proves to promote the shift to the more efficient exception-based follow-up, this would not only reduce the economic cost for the patients under follow-up for implanted devices but also would lower healthcare expenditure because of the reduction in the number of office visits needed to be dedicated to these patients. This has the potential to benefit the population as a whole by freeing up specialists outpatient appointments and reducing waiting times.

Digital Health Figure 3: MyCareLink Heart User Interface

Connectivity Status Green check mark confirms your phone settings are appropriate for your heart device to connect to the app.

My Heart Device Displays battery longevity, implant date, heart device name and serial number, as well as patients’ clinics information.

My Transmissions Has information about transmissions sent from a patient’s heart device to their clinic.

My Vitals Tracking Used to record weight, blood pressure and heart rate measurements – and track these measurements over time.*

My Symptom Journal Used to create a log of symptoms to share with doctor at an in-office visit.*

Physical Activity Has information about a patient’s activity level. The app uses data from patient’s heart device to create daily, weekly and monthly views of physical activity.

Education Provides information about living with a heart device.

My Clinic Provides patients’ clinic information.

*These inputs stay on a patient’s phone; they do not get sent to CareLink.

The user interface as it appears on the patient’s phone. Reproduced with permission from Medtronic.

BlueSync Field Evaluation BlueSync technology is intended to enable more secure automatic wireless RM via the Medtronic CareLink network with security controls implemented to protect the integrity of the device functionality and protecting patient data. BlueSync field evaluation is an observational prospective study that started recruiting patients in April 2018, with 254 patients enrolled and paired with MyCareLink Heart app. This is a global study (NCT03518658) that includes 104 patients in Europe. The primary objective is to measure the percentage of CareLink quarterly scheduled transmissions successfully completed within a reasonable timeframe. Secondary objectives include patient compliance to pre-scheduled CareLink transmissions, patient adoption to remote monitoring with the new application and patients and healthcare practitioners perceived value and user experiences with the application.

Wireless Programming with BlueSync Technology The security of data transmission and communication is always a concern in healthcare environments. Programmers are used in the operating environment at the time of CIED implantation and in the clinic if programming adjustments are required. Currently, there are no facilities in place that allow for remote programming of CIEDs. The programming system is comprised of three components with incorporated tamper-proofing protections: a downloadable software application, a proprietary patient connector for secure connectivity and

2. 3.

WHO. Executive Board: 142nd session. Provisional agenda item 4.4. mHealth: Use of appropriate digital technologies for public health. Geneva: WHO, 2017. https://apps.who.int/gb/ebwha/pdf_files/ EB142/B142_20-en.pdf (accessed 10 February 2020). WHO. Resolution WHA58, page 109. 58th World Health Assembly. Geneva: WHO, 2005. Mobile fact sheet. Pew Research Center. https://www. pewresearch.org/internet/fact-sheet/mobile (accessed 12 June 2019). Smith A. US Smartphone Use in 2015. Pew Research Center. 1

a base unit that communicates with the pacing system analyser. The patient connector and the base unit communicate with the tablet using Bluetooth Classic technology. The patient connector communicates with the implanted device using Bluetooth Low Energy to minimise battery drain of the CIED. The system has rigorous security enhancements with multiple levels of encryption in the device, the programming communicator and the programmer.

Conclusion There has been a steady increase in the number of patients with CIEDs, imposing a significant burden on the already limited resources arising from their follow-up in CIED outpatient clinics. RC offers an opportunity to resolve some of the challenges associated with the delivery of effective follow-up by improving efficiency and patient engagement. Database analyses have consistently shown improved survival rates in patients undergoing RC. They now represent the new standard of care replacing routine clinic interrogation. Current systems require a significant degree of patient interaction to ensure that follow-up schedules are maintained. Remote follow-up requires the physical act of the patient interrogating their CIED using a communicator device. The MyCareLink Heart system increases the automaticity of this concept by seamless Bluetooth communication between the patient’s CIED and their smartphone/tablet. Further prospective studies will evaluate the true value to both patients and healthcare professionals.

April 2015. https://www.pewresearch.org/internet/2015/04/01/ us-smartphone-use-in-2015 (accessed 10 February 2020). Xerox Corporation. New Insights on Value-based Care: Healthcare Attitudes. Xerox, 2016. https://www.baseinc.com/sites/default/ files/imce/u4/healthcare-attitudes-2016.pdf (accessed 10 February 2020). WHO. Executive Board: 139th session. Provisional agenda item 6.6. mHealth – use of mobile wireless technologies for public health. Geneva: WHO, 2016. http://apps.who.int/gb/ebwha/pdf_files/ EB139/B139_8-en.pdf (accessed 10 February 2020).

Boriani G, Auricchio A, Klersy C, et al. Healthcare personnel resource burden related to in-clinic follow-up of cardiovascular implantable electronic devices: a European Heart Rhythm Association and Eucomed joint survey. Europace 2011;13:1166– 73. https://doi.org/10.1093/europace/eur026; PMID: 21345922. Raatikainen MJ, Arnar DO, Merkely B, et al. A decade of information on the use of cardiac implantable electronic devices and interventional electrophysiological procedures in the European Society of Cardiology Countries: 2017 report from the European Heart Rhythm Association. Europace

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App-based Follow-up of ICDs

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2017;19(Suppl 2):ii1–90. https://doi.org/10.1093/europace/ eux258; PMID: 28903470. Burri H. Remote follow-up and continuous remote monitoring, distinguished. Europace 2013;15(Suppl 1):i14–6. https://doi. org/10.1093/europace/eut071; PMID: 23737223. Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverterdefibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010;122:325– 32. https://doi.org/10.1161/CIRCULATIONAHA.110.937409; PMID: 20625110. Varma N, Michalski J, Stambler B, et al. Superiority of automatic remote monitoring compared with in-person evaluation for scheduled ICD follow-up in the TRUST trial-testing execution of the recommendations. Eur Heart J 2014;35:1345–52. https://doi. org/10.1093/eurheartj/ehu066; PMID: 24595864. Mabo P, Victor F, Bazin P, et al. A randomized trial of long-term remote monitoring of pacemaker recipients (the COMPAS trial). Eur Heart J 2012;33:1105–11. https://doi.org/10.1093/ eurheartj/ehr419; PMID: 22127418. Crossley GH, Boyle A, Vitense H, et al. The clinical Evaluation of remote notification to reduce time to clinical Decision (CONNECT) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol 2011;57:1181–9. https://doi.org/10.1016/j.jacc.2010.12.012; PMID: 21255955. Guédon-Moreau L, Lacroix D, Sadoul N, et al. A randomized

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study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial. Eur Heart J 2013;34:605–14. https://doi.org/10.1093/eurheartj/ ehs425; PMID: 23242192. Mittal S, Piccini JP, Fischer A, et al. Increased adherence to remote monitoring is associated with reduced mortality in both pacemaker and defibrillator patients. Heart Rhythm Society 2014 Scientific Sessions, 8 May 2014, San Francisco, CA. Abstract LB01-05. Crossley GH, Chen J, Choucair W, et al. Clinical benefits of remote versus transtelephonic monitoring of implanted pacemakers. J Am Coll Cardiol 2009;54:2012–9. https://doi. org/10.1016/j.jacc.2009.10.001; PMID: 19926006. Ladapo J, Turakhia MP, Ryan MP, et al. Health care utilization and expenditures associated with remote monitoring in patients with implantable cardiac devices. Am J Cardiol 2016;117:1455–62. https://doi.org/10.1016/j. amjcard.2016.02.015; PMID: 26996767. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67. https://doi.org/10.1161/ CIRCULATIONAHA.110.960633; PMID: 21098452. Varma N, Piccini JP, Snell J, et al. The relationship between level of adherence to automatic wireless remote monitoring and survival in pacemaker and deﬁbrillator patients. J Am Coll Cardiol 2015;65:2601–10. https://doi.org/10.1016/j.

jacc.2015.04.033; PMID: 25983008. 20. Slotwiner D, Varma N, Akar JG, et al. HRS expert consensus statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015;12:e69–100. https://doi.org/10.1016/j.hrthm.2015.05.008; PMID: 25981148. 21. Haughney J, Cotton P, Rosen JP, et al. The use of a modification of the patient enablement instrument in asthma. Prim Care Respir J 2007;16:89–92. https://doi.org/10.3132/ pcrj.2007.00014; PMID: 17356786. 22. Tarakji KG, Vives CA, Patel AS, et al. Success of pacemaker remote monitoring using app-based technology: does patient age matter? Pacing Clin Electrophysiol 2018;41:1329– 35. https://doi.org/10.1111/pace.13461; PMID: 30055013. 23. Tarakji K, Zweibel SL, Turakhia MP, et al. Compliance to remote monitoring of pacemakers: A US CareLink analysis. Heart Rhythm 2018;15(5 Suppl):S590–640. Poster B-PO06-040. 24. Appelboom G, Sussman ES, Raphael P, et al. A critical assessment of approaches to outpatient monitoring. Curr Med Res Opin 2014;30:1383–4. https://doi.org/10.1185/03007995.20 14.904774; PMID: 24627950. 25. Logan AG, Irvine MJ, Mclsaac WJ, et al. Effect of home blood pressure telemonitoring with self-care support on uncontrolled systolic hypertension in diabetics. Hypertension 2012;60:51–7. https://doi.org/10.1161/ HYPERTENSIONAHA.111.188409; PMID: 22615116.

Congestive Heart Failure

Long-term Outcome of Pulmonary Vein Isolation Versus Amiodarone Therapy in Patients with Coexistent Persistent AF and Congestive Heart Failure Michela Faggioni,1 Domenico G Della Rocca,2 Sanghamitra Mohanty,2 Chintan Trivedi,2 Ugur Canpolat,2,3 Carola Gianni,2 Amin Al-Ahmad,2 Rodney Horton,2 Gerald Joseph Gallinghouse,2 John David Burkhardt2 and Andrea Natale2,4,5,6,7 1. Department of Medicine, James J Peters Veterans Affairs Medical Center, New York, NY, US; 2. Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, TX, US; 3. Department of Cardiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey; 4. Interventional Electrophysiology, Scripps Clinic, La Jolla, CA, US; 5. Department of Cardiology, MetroHealth Medical Center, School of Medicine, Case Western Reserve University, Cleveland, OH, US; 6. Division of Cardiology, Stanford University, Stanford, CA, US; 7. Atrial Fibrillation and Arrhythmia Center, California Pacific Medical Center, San Francisco, CA, US

Abstract Although pharmacological rhythm control of AF in patients with heart failure with reduced ejection fraction (HFrEF) does not seem to provide any benefit over rate control, catheter ablation of AF has been shown to improve clinical outcomes. These results can be explained with higher success rates of catheter ablation in restoring and maintaining sinus rhythm compared with antiarrhythmic drugs. In addition, pharmacotherapy is not void of side-effects, which are thought to offset its potential antiarrhythmic benefits. Therefore, efforts should be made towards optimisation of ablation techniques for AF in patients with HFrEF.

Keywords AF, catheter ablation, amiodarone, heart failure with reduced ejection fraction, pharmacotherapy Disclosure: AN has received speaker honoraria from Boston Scientific, Biosense Webster, St Jude Medical, Biotronik and Medtronic, and is a consultant for Biosense Webster, St Jude Medical and Janssen. All other authors have no conflicts of interest to declare. Received: 20 June 2019 Accepted: 14 October 2019 Citation: Cardiac Failure Review 2020;6:e04. DOI: https://doi.org/10.15420/cfr.2019.03 Correspondence: Michela Faggioni, Department of Medicine, Rm7A11, James J Peters Veterans Affairs Medical Center, 130 West Kingsbridge Rd, Bronx, NY 10468, US. E: michela.faggioni@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure with reduced ejection fraction (HFrEF) and AF share several predisposing risk factors and often coexist in the same population.1 Although AF can be a marker of worsening heart failure (HF), it can also be a main driver of disease progression. The presence of AF in patients with HFrEF is associated with an increased risk of stroke, re-hospitalisations and all-cause death.2 Therefore, restoration and maintenance of sinus rhythm was initially thought to be preferable in HFrEF patients, in whom atrial systole may play a critical role in left ventricular filling and overall haemodynamics.3–5 Surprisingly, large studies have failed to prove a significant difference in cardiovascular outcomes between rate and rhythm control-based strategies in the HFrEF population.6 This may be due, in part, to the limited choice of antiarrhythmic drugs for pharmacological cardioversion that can be used in HFrEF.5 As a result, current clinical guidelines favour a rate control strategy for patients with AF and HFrEF over rhythm control.7 However, in the past few years the use of catheter ablation for the definitive treatment of AF has been investigated in comparison to medical treatment of AF. An overall benefit with AF ablation seems to be present compared with both pharmacological rhythm and rate control.8 Here, we review the most recent results in the literature comparing catheter ablation with pulmonary vein isolation (PVI) and pharmacological treatment of AF with amiodarone.

Access at: www.CFRjournal.com

Use of Amiodarone in Patients with AF and Heart Failure with Reduced Ejection Fraction Although guidelines still favour a pharmacological rate control approach as first-line therapy in patients with AF, there is a Class IIa recommendation for AV node ablation or rhythm control in patients with chronic HF who remain symptomatic from AF despite a pharmacological rate control strategy.7 Based on the 2014 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines, only two antiarrhythmic medications are recommended for the treatment of AF in HFrEF: dofetilide and amiodarone.7 Other antiarrhythmic drugs, such as Class Ic agents, should be avoided because of their possible proarrhythmic and negative inotropic effects. Although dofetilide seems effective in restoring sinus rhythm and reducing rehospitalisation, it failed to show a mortality benefit, possibly because of proarrhythmic effects in patients with QTc prolongation.5,9 Amiodarone represents the most effective medication for rhythm control and it is by far the most used in HFrEF patients.10 Despite its efficacy, amiodarone is associated with organ toxicity, such as liver failure, thyroid dysfunction and pulmonary fibrosis, which has limited its use, especially as a maintenance therapy.11 In addition, a subanalysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) showed

PVI Versus Amiodarone in AF and CHF that, compared with placebo, amiodarone did not provide a mortality benefit in AF patients with a left ventricular ejection fraction (LVEF) <35% and New York Heart Association (NYHA) Class II/III.12 The trial further suggested an increase in non-cardiac mortality with amiodarone in patients with NYHA Class III HF. These results should be interpreted with caution because they represent a study subanalysis in a selected patient population with HFrEF and NYHA Class III.12 Nevertheless, they raise concerns on the risk–benefit balance of amiodarone use in patients with advanced HF.

Questionnaire, was also improved in the catheter ablation arm.17 Contrary to prior studies on pharmacological rhythm control versus rate control, these trials on catheter ablation did show a significant benefit in maintaining sinus rhythm in HFrEF patients over simple rate control of AF. In addition to advocating for the safety and efficacy of catheter ablation, these results highlight possible limitations of pharmacological rhythm control.

Furthermore, amiodarone failed to show a significant benefit compared with rate control in HFrEF.6 The Atrial Fibrillation and Congestive Heart Failure trial (AF-CHF) was a large multicentre study that randomised 1,376 patients to either rate control or rhythm control, of whom 80% were treated with amiodarone. The main finding of the study was that rhythm control was associated with an increased rate of hospitalisation and had no mortality benefit.6

Evidence on the efficacy of catheter ablation of AF in HFrEF patients compared with pharmacological rhythm control has been increasing in the past few years. Interpretation of such evidence has been difficult because of the heterogeneity of the study populations, the pharmacological treatment strategies used, the methods for the determination of AF reoccurrence, etc. Even the degree of expertise of the centres performing the ablation represents a significant source of variability among trials. Nevertheless, the use of catheter ablation of AF in HFrEF patients seems to be more effective than pharmacological rhythm or rate control with respect to both soft endpoints, such as improved ejection fraction and hard endpoints, such as rehospitalisations and mortality rates.8,18

Clinical Benefits of Catheter Ablation Over Rate Control Strategies Given these limitations of pharmacological rhythm control strategies, attention has been shifted towards catheter ablation for the definitive treatment of AF (Table 1). In 2014, catheter ablation received a Class IIb recommendation from the AHA/ACC/HRS for selected patients requiring rhythm control who were not suitable for or refractory to pharmacological therapy.7 Similarly, the recently updated 2019 guidelines provide a Class IIb recommendation for catheter ablation in patients with symptomatic AF and HFrEF because of its potential benefit in both mortality rate and rehospitalisation for HF.13 These guidelines are based on a handful of trials overall showing improved LVEF and long-term clinical outcomes with catheter ablation of AF in HFrEF patients compared with sole rate or rhythm control.8 These results are somewhat unsurprising, given that AF is the most common cause of tachyarrhythmia-induced cardiomyopathy, and that even short runs of tachycardic AF can trigger an acute decompensation in patients with an already compromised systolic function.14 In the long run, persistent AF can chronically worsen LVEF, a phenomenon that seems to occur even with normal heart rates, likely due to asynchrony and irregular heart rhythm.15 The Comparison of Pulmonary Vein Isolation Versus AV Nodal Ablation With Biventricular Pacing for Patients With Atrial Fibrillation With Congestive Heart Failure (PABA CHF) trial showed that PVI was superior to atrioventricular node ablation with biventricular pacing in patients with HFrEF and uncontrolled AF with regard to improved cardiac function, exercise capacity and quality of life.16 Interestingly, the PABA CHF trial showed that heart rate control with atrioventricular node ablation and pacemaker (PM) implantation is not as effective as AF catheter ablation with restoration of sinus rhythm in improving LVEF, stressing the importance of long-term effective rhythm control over rate control. The results of the PABA CHF trial were confirmed by the Catheter Ablation Versus Medical Treatment of AF in Heart Failure (CAMTAF) trial, a small study on 50 patients with HFrEF randomised to either catheter ablation or pharmacological rate control.17 In that study, a significant improvement in ejection fraction was found at 6 months in the catheter ablation group with an 80% arrhythmia-free survival rate. Quality of life, assessed by means of the Minnesota Living With HF

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Direct Comparison of Catheter Ablation of AF and Pharmacological Rhythm Control

One of the main trials to affect the most recent guidelines on the management of AF is the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial.19 CASTLE-AF tested the use of catheter ablation of AF in patients with HFrEF and symptomatic paroxysmal or persistent AF who were not responding to antiarrhythmic drugs or had significant sideeffects from the medications. Compared with medical treatment, catheter ablation was associated with a significant reduction in the risk of the composite endpoint comprising all-cause death or hospitalisation for worsening HF. Although the primary composite endpoint was mostly driven by reduction in rehospitalisation, a significant improvement in allcause mortality and, in particular, cardiovascular mortality became evident after 3 years of follow-up. Unfortunately, the control arm of CASTLE-AF included a heterogeneous group of patients treated with either rhythm or rate control pharmacological strategies, which complicates the interpretation of the results. The medical treatment was at the discretion of the clinician and, therefore, not standardised. Nevertheless, approximately 55% of the trial population had received amiodarone: in 45–47% of these patients, amiodarone failed to adequately control AF, whereas in 12– 14% unacceptable side-effects from the medication were reported. Interestingly the benefits of catheter ablation were observed regardless of the use of amiodarone.19 Probably the main limitation of the CASTLE-AF trial is the study population itself. By enrolling patients who could not tolerate or failed medical treatment, patients were selected who were likely to benefit from any additional intervention to control AF. Nevertheless, CASTLE-AF represents a critical trial to prove the efficacy of catheter ablation in HFrEF. Furthermore, the findings of CASTLE-AF are not an isolated occurrence. Similar results were obtained in the Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD (AATAC) trial in a broader population of HFrEF patients who did not previously fail medical treatment.20 The AATAC trial is also one of the few randomised studies to compare

Congestive Heart Failure Table 1: Main Trials on Catheter Ablation of AF in Patients With Heart Failure With Reduced Ejection Fraction Trial

Inclusion Criteria

Study Arms

Endpoint

AF AF Results Reoccurrence Determination Method

Limitations

CAMTAF 201417

Persistent AF, symptomatic HF, LVEF <50%

CA (n=26) versus medical rate control (n=24)

Change in LVEF at 6 months, peak oxygen consumption, quality of life

30% for AF (54% including AF and AT) in the CA group

CA associated with greater improvement in LVEF, peak oxygen consumption and quality of life based on Minnesota questionnaire

Small sample size, lack of blinded randomisation, soft endpoint

AATAC 201620

Persistent AF, ICD/ CRT-D, NYHA Class II or III, LVEF <40%

CA (n=101) versus amiodarone (n=102)

Primary: recurrence of AF; secondary: all-cause death and unplanned hospitalisation

30% in the CA PM/ICD group versus 66% interrogation in the amiodarone group

CA was associated with lower rates of AF recurrence, unplanned hospitalisation (relative

Small sample size, lack of blinded randomisation

CA (n=33) versus medical rate control (n=33)

Change in LVEF on repeat MRI at 6 months

44% if off AAD, 25% if on AAD versus 100% in medical rate control arm

CA associated with greater LVEF improvement (18±13% versus 4.4±13%; p<0.0001); LVEF normalised in 58% versus 9% of patients (p=0.0002)

Small sample size, lack of blinded randomisation, no hard outcomes

CA (n=179) versus medical therapy (rate or rhythm control; n=184)

Primary: composite of all-cause death or HF hospitalisation

37% in the CA PM/ICD group versus 78% interrogation in the medical therapy group

CA associated with lower rates of all-cause death (HR 0.53; 95% CI [0.32–0.86], p=0.01), hospitalisations (HR 0.56; 95% CI [0.37–0.83], p=0.004) and CV deaths (HR 0.49; 95% CI [0.29–0.64], p=0.009) versus medical treatment

Small sample size, lack of blinded randomisation, non-standardised medical treatment

CAMERAMRI 201738

Persistent AF, LVEF <45%

CASTLE-AF Symptomatic 201819 paroxysmal or persistent AF, ICD, NYHA Class II–IV, EF <35%

CABANA 201921

Paroxysmal, CA (n=1,108) versus persistent or medical therapy long-standing (rate/rhythm; persistent AF, ≥65 n=1,096) years of age or <65 years of age with ≥1 CVA or CV risk factor, on ≥2 rhythm or rate control drugs

Primary outcome: 49.9% in the CA death, stroke, group versus serious bleeding, 69.5% in the or cardiac arrest; medical therapy secondary group outcome: all-cause death, death or CV hospitalisation and AF recurrence

12-lead ECG and 48-h Holter ECG

Loop recorder in CA arm versus serial Holter in medical therapy arm

risk 0.55; 95% CI [0.39–0.76]) and all-cause mortality

ECG event recorder Non-significant reduction in Lack of blinded for symptomatic the primary composite randomisation, high events endpoint with CA; crossover rate, high significantly lower rates of AF reoccurrence in all-cause death or ablation group, hospitalisations (HR 0.83; choice of primary 95% CI [0.74–0.93]) and AF composite endpoint, reoccurrence (HR 0.52; 95% low event rate in CI [0.45–0.60]) with CA primary endpoint

AAD = antiarrhythmic drugs; AT = atrial tachycardia; CA = catheter ablation; CRT-D = cardiac resynchronisation therapy-defibrillator; CV = cardiovascular; CVA = cerebrovascular accident; EF = ejection fraction; HF = heart failure; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; PM = pacemaker.

catheter ablation with a pharmacological arm comprising 100% amiodarone-treated patients.20 Inclusion criteria for AATAC included HF with an ejection fraction <40% and the presence of dual-chamber ICD or CRT device. Similar to CASTLE-AF, the mandatory presence of an ICD or PM in patients in the AATAC trial allowed for very accurate monitoring of AF reoccurrence during follow-up. The main finding of the AATAC trial was that catheter ablation of AF was superior to amiodarone in achieving freedom from AF at the 2-year follow-up, as determined by PM interrogation. Importantly, catheter ablation of AF was associated with a significant reduction in unplanned hospitalisation for HF and overall mortality compared with amiodarone treatment.20 Most recently the Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial produced similar results on a large population of 2,204 patients with paroxysmal, persistent or long-standing persistent AF.21 Although the rates of the composite primary endpoint of death, stroke, serious bleeding or cardiac arrest did not differ significantly between the catheter ablation and medical treatment (rate or rhythm)

arms, likely because of the heterogeneity of the chosen endpoint components and a paucity of events, the rates of the secondary endpoint of all-cause death or rehospitalisation was again lower in the catheter ablation arm. This result from an intention-to-treat analysis is even more impressive because it occurred despite a 27% crossover rate from the medical treatment to the catheter ablation arm and a much higher AF reoccurrence rate in the catheter ablation arm (49%) compared with previous trials. Interestingly, CABANA also recorded data on symptomatic improvement and quality of life at 12 months. Using both the Atrial Fibrillation Effect on Quality of Life summary score and the Mayo AFSpecific Symptom Inventory frequency score, catheter ablation was found to be associated with significant improvements in symptoms and quality of life compared with the pharmacological arm of the study.22 Similarly, the Catheter Ablation Compared With Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial showed greater improvement in quality of life at 1 year with catheter ablation as measured with the General Health subscale score (Medical Outcomes

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PVI Versus Amiodarone in AF and CHF Study 36-Item Short-Form Health Survey).23 It should be noted that patients’ self-assessment may be biased based on the treatment received. As in all trials on catheter ablations, sham procedures were not performed. Nevertheless, these results further support the safety of catheter ablation and its long-lasting clinical benefit over pharmacological approaches. Interestingly, although most clinical trials used radiofrequency ablation, cryoablation has also been considered. Few reports are available. A recent study on 89 patients, 30 with HFrEF, noted lower success rates for PVI in patients with HF due to difficult cannulation of the right inferior pulmonary vein (PV), possibly because of the enlarged atrium.24 The recurrence of AF at 1 year was approximately 67% in patients with HFrEF after cryoablation.24 Data from randomised studies are not yet available; however, Ablation of Atrial Fibrillation in Heart Failure Patients (CONTRA-HF; NCT03062241), an on-going randomised multicentre trial, is testing the safety and efficacy of cryoablation versus guidelinerecommended medical management in patients with HF. Although CONTRA-HF will not directly compare radiofrequency versus cryoablation in the HFrEF population, it will provide important information on the feasibility of this technique and the arrhythmia-free survival rate compared with optimal pharmacological treatment.

Limitations of Amiodarone for Rhythm Control Although rhythm control with pharmacotherapy does not seem to improve outcomes compared with rate control in patients with concomitant HFrEF and AF, the use of a catheter ablation strategy seems to improve left ventricular haemodynamics and overall outcomes. A possible explanation would be an incomplete efficacy of pharmacological strategies in permanently maintaining sinus rhythm. In the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study, a variety of medications could be used for rhythm control, but amiodarone was used in 62% of patients at some point during the study.25 At 5 years, only 63% of patients in the rhythm control arm were actually in sinus rhythm; this does not account for subclinical episodes of AF that may have occurred between follow-up visits. In addition, approximately 34% of the rate control population actually achieved and seemed to maintain sinus rhythm at 5 years.25 Similarly, in the AF-CHF trial, one of the largest randomised trials to show no benefit of pharmacological rhythm control over rate control in HFrEF patients, approximately 21% of patients in the rhythm control arm crossed over to rate control because of an inability to maintain sinus rhythm. Furthermore, it was estimated that approximately 56% of patients in the rhythm control arm had at least one episode of AF during follow-up.6 This percentage is likely to represent an underestimation, given that reoccurrence of AF was determined only with 12-lead ECGs during the scheduled follow-up appointments or by chart review. A much-needed subanalysis of the AFFIRM trial by the presence or absence of sinus rhythm showed a significant mortality benefit with maintenance of sinus rhythm.10 Most strikingly, antiarrhythmic drugs not only failed to improve survival, but were also associated with increased mortality after adjustment for the presence of sinus rhythm. The authors concluded that any beneficial antiarrhythmic effect of pharmacotherapy is offset by its adverse effects.10 Drug interaction in the setting of polypharmacy and medication noncompliance represent other possible contributors to pharmacological failure in this population.

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Is Pulmonary Vein Isolation the Answer? Although studies in favour of catheter ablation for the treatment of AF in HFrEF are slowly piling up, this approach is not free of limitations. As mentioned previously, what makes catheter ablation more effective than pharmacological rhythm control is essentially twofold: higher efficacy in restoring or maintaining sinus rhythm and avoidance of medication-induced side-effects. However, in the CASTLE-AF trial only 63% of patients in the ablation group remained in sinus rhythm during follow-up.19 Similarly, Jones et al. reported a single-procedure success of 68% at 1-year follow-up; when all patients undergoing a second procedure were included, the 1-year success rate increased to 88%. 26 It is well-known that the recurrence of AF after catheter ablation is highly variable depending on the expertise and volume of procedures at the performing centres. In contrast with other cardiovascular procedures, AF ablation has not yet been standardised: some operators perform only PVI, whereas others pursue more aggressive ablation strategies, involving non-PV triggers. Non-PV triggers can potentially be identified in the left atrial posterior wall, the interatrial septum, mitral and tricuspid periannular regions, the crista terminalis and Eustachian ridge, the left atrial appendage, the coronary sinus or even the inferior vena cava and additional complex fractionated atrial electrograms. 27–29 Although we may be unable to reach a one-size-fits-all approach for AF ablation, it is becoming evident that PVI alone is not sufficient to obtain long-term arrhythmia-free survival in almost 30–40% of patients.30 This is especially critical in the HFrEF population and in those with long-standing AF in whom AF ablation with PVI has a lower success rate than in those without HF or with only paroxysmal AF. HFrEF patients usually exhibit a severely diseased atrial substrate that can harbour a greater number of non-PV foci that ultimately account for the increased rates of AF and atrial tachycardia recurrence after sole PVI. Both reduced ejection fraction and the presence of non-PV triggers identified during the procedure are independent predictors of AF recurrence.31 Not surprisingly, several studies have shown that ablation of non-PV triggers significantly increases arrhythmia-free survival. For example, a subanalysis of the AATAC trial showed that when stratified by procedure type (PVI versus PVI plus non-PV triggers), success rates were significantly higher in patients treated with both PVI and non-PV triggers than those treated with PVI alone or amiodarone (p<0.001).32 Interestingly, when looking at outcomes, no benefit was found with PVI only versus amiodarone, suggesting that the encouraging results of the AATAC trial, in terms of both arrhythmia-free survival and hard outcomes, are driven by definitive restoration of sinus rhythm with aggressive ablation procedures including both PVI and non-PV trigger ablations. In patients with HFrEF, in whom strict sinus maintenance can, indeed, improve outcomes compared with incomplete rhythm control with pharmacotherapy, studies aiming to establish more comprehensive ablation strategies may result in further improvement in clinical outcomes. To this end, stimulation protocols with adenosine and/or isoproterenol after PVI can successfully unmask non-PV triggers and guide further ablations, thus improving procedural outcomes.33 However, standardised stimulation protocols for residual triggers after PVI are also lacking.

Congestive Heart Failure Studies have shown that low doses and/or an incremental infusion of isoproterenol are not very effective in unmasking non-PV triggers, especially when AF ablation is performed under deep sedation or general anaesthesia. Conversely, the use of high doses of isoproterenol while the patient is in sinus rhythm seems to be associated with better yield of non-PV triggers and overall lower likelihood of arrhythmia relapse. 34 In some cases, even in the absence of identifiable non-PV foci, patients with HFrEF could benefit from the empirical ablation of areas, such as the vena cava and the left atrial appendage. 35–37

10.

11.

12.

13.

L ubitz SA, Benjamin EJ, Ellinor PT. Atrial fibrillation in congestive heart failure. Heart Fail Clin 2010;6:187–200. https:// doi.org/10.1016/j.hfc.2009.11.001; PMID: 20347787. Cherian TS, Shrader P, Fonarow GC, et al. Effect of atrial fibrillation on mortality, stroke risk, and quality-of-life scores in patients with heart failure (from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF]). Am J Cardiol 2017;119:1763–9. https://doi.org/10.1016/j. amjcard.2017.02.050; PMID: 28416199. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;351:2373–83. https://doi.org/10.1056/NEJMoa041018; PMID: 15575053. Stulak JM, Dearani JA, Daly RC, et al. Left ventricular dysfunction in atrial fibrillation: restoration of sinus rhythm by the Cox-maze procedure significantly improves systolic function and functional status. Ann Thorac Surg. 2006;82:494– 500. https://doi.org/10.1016/j.athoracsur.2006.03.075; PMID: 16863752. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999;341:857–65. https://doi.org/10.1056/NEJM199909163411201; PMID: 10486417. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–77. https://doi.org/10.1056/NEJMoa0708789; PMID: 18565859. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071–104. https://doi.org/10.1161/ CIR.0000000000000040; PMID: 24682348. Turagam MK, Garg J, Whang W, et al. Catheter ablation of atrial fibrillation in patients with heart failure: a meta-analysis of randomized controlled trials. Ann Intern Med 2019;170:41–50. https://doi.org/10.7326/M18-0992; PMID: 30583296. Baher A, Marrouche NF. Treatment of atrial fibrillation in patients with co-existing heart failure and reduced ejection fraction: time to revisit the management guidelines? Arrhythm Electrophysiol Rev 2018;7:91–4. https://doi.org/10.15420/ aer.2018.17.2; PMID: 29967680. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1509–13. https://doi.org/10.1161/01. CIR.0000121736.16643.11; PMID: 15007003. Park HS, Kim YN. Adverse effects of long-term amiodarone therapy. Korean J Intern Med 2014;29:571–3. https://doi. org/10.3904/kjim.2014.29.5.571; PMID: 25228830. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter–defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. https://doi.org/10.1056/ NEJMoa043399; PMID: 15659722. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation

Conclusion Catheter ablation of AF is more effective in restoring and maintaining sinus rhythm than pharmacological rhythm control with amiodarone. Most importantly, growing evidence suggests that catheter ablation is associated with a significant reduction in HF rehospitalisation and mortality likely because of a more stable, long-term maintenance of sinus rhythm and avoidance of side-effects of antiarrhythmic medications. Further large randomised clinical trials are warranted to confirm these results and to establish appropriate ablation strategies to maximise arrhythmia-free survival in HFrEF patients.

2019;140:e125–51. https://doi.org/10.1016/j. hrthm.2019.01.024; PMID: 30703530. 14. L ee Park K, Anter E. Atrial fibrillation and heart failure: a review of the intersection of two cardiac epidemics. J Atr Fibrillation 2013;6:751. 10.4022/jafib.751; PMID: 28496849. 15. Della Rocca DG, Santini L, Forleo GB, et al. Novel perspectives on arrhythmia-induced cardiomyopathy: pathophysiology, clinical manifestations and an update on invasive management strategies. Cardiol Rev 2015;23:135–41. https:// doi.org/10.1097/CRD.0000000000000040; PMID: 25133468. 16. Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778–85. https://doi.org/10.1056/NEJMoa0708234; PMID: 18946063. 17. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 2014;7:31–8. https://doi.org/10.1161/ CIRCEP.113.000806; PMID: 24382410. 18. Al Halabi S, Qintar M, Hussein A, et al. Catheter ablation for atrial fibrillation in heart failure patients: a meta-analysis of randomized controlled trials. JACC Clin Electrophysiol 2015;1:200–9. https://doi.org/10.1016/j.jacep.2015.02.018; PMID: 26258174. 19. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–27. https://doi.org/10.1056/NEJMoa1707855; PMID: 29385358. 20. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation 2016;133:1637–44. https://doi.org/10.1161/ CIRCULATIONAHA.115.019406; PMID: 27029350. 21. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019;321:1261–74. https://doi.org/10.1001/jama.2019.0693; PMID: 30874766. 22. Mark DB, Anstrom KJ, Sheng S, et al. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019:321;1275–85. https://doi.org/10.1001/jama.2019.0692; PMID: 30874716. 23. Blomstrom-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of catheter ablation vs antiarrhythmic medication on quality of life in patients with atrial fibrillation: the CAPTAF randomized clinical Trial. JAMA 2019;321:1059–68. https://doi.org/10.1001/ jama.2019.0335; PMID: 30874754. 24. Pruszkowska P, Lenarczyk R, Gumprecht J, et al. Cryoballoon ablation of atrial fibrillation in patients with advanced systolic heart failure and cardiac implantable electronic devices. Kardiol Pol 2018;76:1081–8. https://doi.org/10.5603/KP. a2018.0068; PMID: 29528482. 25. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33. https://doi.org/10.1056/ NEJMoa021328; PMID: 12466506. 26. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the

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management of persistent atrial fibrillation in heart failure. Am J Coll Cardiol 2013;61:1894–903. https://doi.org/10.1016/j. jacc.2013.01.069; PMID: 23500267. Santangeli P, Marchlinski FE. Techniques for the provocation, localization, and ablation of non-pulmonary vein triggers for atrial fibrillation. Heart Rhythm 2017;14:1087–96. https://doi. org/10.1016/j.hrthm.2017.02.030; PMID: 28259694. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 2010;122:109–18. https://doi. org/10.1161/CIRCULATIONAHA.109.928903; PMID: 20606120. Hocini M, Shah AJ, Nault I, et al. Localized reentry within the left atrial appendage: arrhythmogenic role in patients undergoing ablation of persistent atrial fibrillation. Heart Rhythm 2011;8:1853–61. https://doi.org/10.1016/j. hrthm.2011.07.013; PMID: 21762673. Hung Y, Lo LW, Lin YJ, et al. Characteristics and long-term catheter ablation outcome in long-standing persistent atrial fibrillation patients with non-pulmonary vein triggers. Int J Cardiol 2017;241:205–11. https://doi.org/10.1016/j. ijcard.2017.04.050; PMID: 28456483. Zhao Y, Di Biase L, Trivedi C, et al. Importance of nonpulmonary vein triggers ablation to achieve long-term freedom from paroxysmal atrial fibrillation in patients with low ejection fraction. Heart Rhythm 2016;13:141–9. https://doi. org/10.1016/j.hrthm.2015.08.029; PMID: 26304713. Di Biase L, Mohanty P, Mohanty S, et al. Pulmonary vein isolation alone is not superior to amiodarone for the treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC randomized trial. Circulation 2015;132:A14766. Elayi CS, Di Biase L, Bai R, et al. Administration of isoproterenol and adenosine to guide supplemental ablation after pulmonary vein antrum isolation. J Cardiovasc Electrophysiol 2013;24:1199– 206. https://doi.org/10.1111/jce.12252; PMID: 24020649. Della Rocca DG, Mohanty S, Trivedi C, et al. Percutaneous treatment of non-paroxysmal atrial fibrillation: a paradigm shift from pulmonary vein to non-pulmonary vein trigger ablation? Arrhythm Electrophysiol Rev 2018;7:256–60. https://doi. org/10.15420/aer.2018.56.2; PMID: 30588313. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial. J Am Coll Cardiol 2016;68:1929–40. https://doi.org/10.1016/j.jacc.2016.07.770; PMID: 27788847. Elayi CS, Fahmy TS, Wazni OM, et al. Left superior vena cava isolation in patients undergoing pulmonary vein antrum isolation: impact on atrial fibrillation recurrence. Heart Rhythm 2006;3:1019–23. https://doi.org/10.1016/j.hrthm.2006.05.024; PMID: 16945794. Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of the superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol 2007;18:1261–6. https://doi. org/10.1111/j.1540-8167.2007.00953.x; PMID: 17850288. Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI study. Am J Coll Cardiol 2017;70:1949–61. https://doi.org/10.1016/j.jacc.2017.08.041; PMID: 28855115.

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Pulmonary Hypertension

Pulmonary Hypertension in Heart Failure Patients Sriram D Rao,1 Srinath Adusumalli2 and Jeremy A Mazurek1,3 1. Advanced Heart Failure/Transplantation Programme, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, US; 2. Department of Medicine, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, US; 3. Pulmonary Hypertension Programme, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, US

Abstract The development of pulmonary hypertension (PH) in patients with heart failure is associated with increased morbidity and mortality. In this article, the authors examine recent changes to the definition of PH in the setting of left heart disease (PH-LHD), and discuss its epidemiology, pathophysiology and prognosis. They also explore the complexities of diagnosing PH-LHD and the current evidence for the use of medical therapies, promising clinical trials and the role of left ventricular assist device and transplantation.

Keywords Pulmonary hypertension, heart failure, pre-capillary, post-capillary, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, pulmonary vasodilators Disclosure: The authors have no conflicts of interest to declare. Received: 12 August 2019 Accepted: 13 December 2019 Citation: Cardiac Failure Review 2020;6:e05. DOI: https://doi.org/10.15420/cfr.2019.09 Correspondence: Jeremy A Mazurek, Advanced Heart Failure/Cardiac Transplantation and Pulmonary Hypertension, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, South Pavilion, 11th Floor, Suite 11–179, 3400 Civic Center Boulevard, Philadelphia, PA 19104, US. E: jeremy.mazurek@pennmedicine.upenn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure (HF) remains one of the most common medical conditions worldwide, placing a continuously growing burden on healthcare providers. Within the HF population itself, the subset of patients who develop pulmonary hypertension (PH-LHD) has been identified as having a significantly higher morbidity and mortality.1 There are limited therapeutic options for PH-LHD and it often complicates the use of standard treatment approaches. This article will focus on PH-LHD as it relates to patients with both HF with reduced ejection fraction (HFrEF) – left ventricular ejection fraction (LVEF) <40% – and HF with preserved ejection fraction (HFpEF) – patients with LVEF >50%.

Definition Previously, PH was defined by a mean pulmonary artery pressure (mPAP) ≥25 mmHg with PH-LHD; with the WHO defining group II PH as mPAP ≥25 mmHg in the setting of a pulmonary artery wedge pressure (PAWP) >15 mmHg.2 There is a continuum of disease comprising PHLHD pathophysiology and several haemodynamic variables have traditionally been incorporated into the definition of PH-LHD to differentiate between these two subgroups. These variables include the diastolic pressure gradient (DPG), which is defined as the difference between the diastolic pulmonary artery pressure and the PAWP; the transpulmonary gradient (TPG), defined as the mPAP–PAWP; and pulmonary vascular resistance (PVR), defined as the TPG divided by the cardiac output. According to the 2015 European Society of Cardiology and the European Respiratory Society guidelines for the diagnosis and treatment of PH, isolated post-capillary PH (IpcPH), is defined as PH-LHD with

DPG <7 mmHg and/or PVR ≤3 Wood units (WU), and represents the majority of PH-LHD, with the predominant causative factor being elevation in left-sided pressures. By comparison, combined post- and pre-capillary PH (CpcPH), the group previously referred to as having out-of-proportion or reactive PH-LHD, with a prevalence of 12–38%, was defined as PH-LHD with DPG ≥7 mmHg and/or PVR >3 WU.2,3 In 2018, the 6th World Symposium on Pulmonary Hypertension recommended changing the definitions of PH, with the goal of identifying patients with earlier stages of PH who could potentially benefit from interventions. This recommendation was to define precapillary PH as mPAP >20 mmHg in the setting of an elevated PVR.4 The rationale for this change was based on previous studies that found a mPAP cut-off of 20 mmHg is two standard deviations above normal mPAP value.5,6 The group also suggested updates to the definitions of PH-LHD; IpcPH was defined as mPAP >20 mmHg, PAWP >15 mmHg and PVR <3 WU. CpcPH was defined as mPAP >20 mmHg, PAWP >15 mmHg and PVR ≥3 WU. The rationale for a change away from DPG to PVR exclusively included concern for the fidelity and interpretation of the DPG measurement.4,5 A summary of these changes is presented in Table 1.

Prevalence, Prognosis and Pathophysiology PH-LHD is remarkably common, accounting for 65–80% of all PH patients, with the prevalence of PH estimated at 40–75% in people with HFrEF, and 36–83% in people with HFpEF.3,7–10 PH is a poor prognostic indicator in all HF patients, with PASP >45 mmHg on echocardiography being associated with increased 5-year mortality, independent of the severity of HF and other comorbidities.11,12

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Pulmonary Hypertension Table 1: Definition of Pulmonary Hypertension Current Guidelines

2018 WHO Update

≥25 mmHg

>20 mmHg

>15 mmHg

Diastolic pressure gradient

<7 mmHg

N/A

Pulmonary vascular resistance

≤3 WU

<3 WU

PH Mean pulmonary artery pressure

Group II PH Pulmonary artery wedge pressure

Isolated Post-capillary PH

Combined Post- and Pre-capillary PH Diastolic pressure gradient

≥7 mmHg

N/A

Pulmonary vascular resistance

>3 WU

≥3 WU

PH = pulmonary hypertension; WU = Wood unit.

The pathophysiology of PH-LHD is thought to be a continuum, where the initial transmission of elevated left-sided filling pressures into the pulmonary circulation is followed by superimposed components, such as pulmonary vasoconstriction, decreased nitric oxide availability and desensitisation to natriuretic peptide-induced vasodilatation. This process leads to pulmonary vascular remodelling including thickening of the alveolar-capillary membrane, medial hypertrophy, intimal and adventitial fibrosis and small vessel luminal occlusion (Figure 1).3 More recently, Fayyaz et al. studied pulmonary arterial and venous remodelling in autopsy specimens from patients with PH-HFpEF and PH-HFrEF compared with normal controls and those with pulmonary veno-occlusive disease (PVOD). They found that more venous intimal thickening was present compared with arterial intimal thickening in those with PH-LHD, and this was similar to changes seen in people with PVOD. These changes correlated with PH severity, suggesting that the pulmonary venous remodelling promoted and dictated the development and severity of PH in the HF population.13 Additionally, recent work has further assessed the impact of left-sided valvular disease on PH, with nearly 50% of patients with severe aortic stenosis having PH, of whom 12% had CpcPH, which was associated with higher PAWP, lower pulmonary arterial compliance (PAC) and was a significant predictor of mortality.14

Diagnosis Echocardiography Echocardiography is one of the mainstays of investigation of LHD in general and efforts have been made to diagnose and monitor PH-LHD using routine echocardiography. This has been well summarised in a recent review by Maeder et al.9,15,16 Pulmonary artery systolic pressure (PASP), the most well-known parameter, can be estimated by measuring peak tricuspid regurgitation velocity, applying the modified Bernoulli equation (4v2) and adding estimated right atrial pressure (most commonly using inferior vena cava size and collapsibility).17–19 Studies have shown a good correlation with invasive haemodynamic measurements, although PASP estimates often have reduced accuracy due to: the technical ability required to acquire quality images; problems with tricuspid regurgitation velocity (low, absent or of poor quality or with severe tricuspid regurgitation); or when right atrial volume is unable to be assessed or is inaccurately estimated.20 Additionally, PASP alone cannot determine the underlying haemodynamic PH phenotype.21 Therefore, other more reliable and

informative measures for assessment have been evaluated for the PHLHD population. There has been a focus on assessing the RV–PA interaction and/or afterload elevation in people with PH-LHD. This includes the assessment of septal flattening (particularly in systole), RV dilatation, RV to LV ratio, RV apex angle and RV systolic impairment (as measured by RV fractional area change or tricuspid annular plane systolic excursion (TAPSE) and RV longitudinal strain (as measured by 2D and 3D speckle tracking) (Figure 2).22 Furthermore, the right ventricular outflow tract (RVOT) pulse wave Doppler profile contains several parameters to inform the underlying haemodynamic profile of a given patient or population with PH-LHD including acceleration time, velocity time integral (VTI) and presence/absence/timing of systolic notching.21,23 These right heart metrics should be evaluated in conjunction with standard left heart metrics, including LA size, estimated LA pressure (by mitral inflow and tissue Doppler assessment), LV size and function, and valvular dysfunction, which in turn can then aid in distinguishing IpcPH and CpcPH.16 The ratio of TAPSE/PASP has been described as an index of right ventriculo-arterial coupling independent of LV dysfunction, and has been validated with invasive haemodynamics by Tello et al.24 Gerges et al. demonstrated this as being valuable in being able to differentiate between IpcPH and CpcPH in the setting of both HFrEF and HFpEF.25 Guazzi et al. showed it could be used to prognosticate in HFpEF patients, with higher TAPSE/PASP correlating with higher levels of natriuretic peptides, worse systemic and pulmonary haemodynamics and abnormal exercise aerobic capacity.26 With recent attention to PAC across the PH spectrum, including in PHLHD, with increased pulsatile load (secondary to elevated PAWP) reducing PAC, we have described a non-invasive surrogate for PAC using the RVOT–VTI/PASP relationship, which we showed stratifies patients with IpcPH and CpcPH as compared with pulmonary arterial hypertension (PAH), and correlated with the 6-minute walk distance.14,27–29

Right Heart Catheterisation In patients with suspected PH-LHD, right heart catheterisation (RHC) is required to prove the diagnosis and to differentiate between precapillary PH (PAH) and PH-LHD and to further distinguish IpcPH and CpcPH. Although the procedure is relatively safe and is now routine practice in most centres, there is a hesitancy to apply this as routine in all PH-LHD patients, given its invasive nature and potential for misinterpretation of the data. Our recommendation is that RHC should be performed in the following circumstances: • diagnostic uncertainty based on noninvasive testing; • disproportionate symptoms compared with echocardiographic findings; • progressive symptoms despite optimal medical therapy; • when advanced therapies are planned especially transplantation or mechanical circulatory support. One major drawback with RHC in this patient population is that the pivotal measurement, PAWP, is the most prone to errors and extra time and care should be taken while documenting PAWP. To minimise this error, the reference level needs to be at the mid-thoracic position and the catheter tip position should be verified (with either fluoroscopy and

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Pulmonary Hypertension in Heart Failure Patients with aspiration and assessment of PAWP blood) and the PAWP should be measured at the end of the expiratory phase of normal respiration to minimise respirophasic variations.30,31 If there are still concerns about the accuracy of the PAWP measurement, then direct measurement of the left ventricular end-diastolic pressure (LVEDP) can be performed. However it must be remembered that LVEDP is a measure of LV preload and LV diastolic compliance, and this is not a true surrogate for PAWP, which is both the best reflection of the total effect of LHD on the pulmonary circulation and has been shown to be a better predictor of outcomes, especially in the HFpEF population.32–34 In addition to standard measurements, other procedural techniques may be required in patients with PH-LHD. These patients are frequently on diuretic therapy, which can lead to artificially lower PAWP measurements than are normal for the patient; in this case a 500 cc IV fluid challenge can be performed with reassessment of haemodynamic measurements. This can be especially helpful in patients with HFpEF, where there can be vast differences in haemodynamics based on volume status.35 Also, testing during exercise is important in this population as it is both required to diagnose or confirm HFpEF, especially if resting PAWP is <15 mmHg, and it is a useful in ‘unmasking’ exercise-induced PH where there may be a disproportionate rise in mPAP in relation to changes in cardiac output.36

Figure 1: Pathophysiology of Pulmonary Hypertension in Heart Failure Combined pre- and post-capillary pulmonary hypertension

Isolated post-capillary pulmonary hypertension

Chronic pulmonary venous congestion

Passive ‘backward’ transmission of pressure

Reduced NO availability Desensitisation to vasodilatation

Increased pulmonary venous pressures

Increased LA pressure

Management Optimising Goal-directed Therapy The main goal of management in this population should be optimisation of underlying medical therapies, using device therapy and addressing underlying valvular disease where indicated. In particular, the use of adequate diuretic therapy, an often under-emphasised avenue of therapy, is vital for symptom control. The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association functional Class III Heart Failure Patients (CHAMPION) trial showed that invasive monitoring of left-sided filling pressures using the pulmonary artery diastolic pressure (as a surrogate marker of PAWP) to guide diuretic therapy reduces HF hospitalisations in a homogenous HF population.37 This study has led to interest in the potential role of this form of monitor-guided diuretic therapy in PH-LHD and upcoming studies using the CardioMEMS device, such as the HemodynamicGUIDEd Management of Heart Failure trial (NCT03387813), may provide more evidence for its use. While there have been recent advances in the medical therapies of HFrEF using two new agents – angiotensin receptor neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors – these have not been specifically evaluated in PH-LHD. There is interest in the effect of these drugs on cardiopulmonary haemodynamics, with active trials enrolling for both drug classes – Pulmonary Artery Pressure Reduction with ENTresto (Sacubitril/Valsartan) (PARENT; NCT02788656) and Empagliflozin Impact on Hemodynamics in Patients With Heart Failure (EMBRACE-HF; NCT03030222). To date, there remains no specific therapy for HFpEF; however, there is promising data in the use of the interatrial shunt device, although this study and the pivotal trial have excluded patients with PVR >4 WU and therefore there is uncertainty as to its transferability to the broader PH-LHD population.38

Pulmonary Hypertension-specific Therapy As PAH and PH-LHD share a number of common pathophysiological pathways and neurohumoral perturbations, there have been a number of studies performed to assess the efficacy of PH-specific therapy in

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Increased LV pressure

Mitral regurgitation

Loss of LA compliance

Classical hypothesis of the post-capillary hemodynamic profile – backward transmission of elevated left ventricular filling pressures into the pulmonary circulation leading to pulmonary vascular remodelling and this pulmonary hypertension. LA = left atrial; LV = left ventricular.

the PH-LHD population.39 In general, given lack of positive trial data along with the potential increased risk of pulmonary oedema in the setting of improved trans-pulmonary flow, the use of PH-specific therapy is not recommended. We have summarised these studies in Tables 2 and 3.

Heart Failure with Preserved Ejection Fraction Given the paucity of other treatment options for heart failure with preserved ejection fraction, several studies have been undertaken in this population. The largest study has been the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial, which enrolled patients with HFpEF and assessed the effect of sildenafil, a PDE5 inhibitor, on the clinical endpoint of exercise tolerance and clinical status.40 This trial was negative and while showing the lack of benefit of sildenafil in the broader HFpEF population, it is important to note that this trial did not specifically study patients with PH-LHD, nor did it assess the effects on pulmonary haemodynamics. Another smaller study performed by Hoendermis et al. evaluated the haemodynamic effects of sildenafil versus placebo in PH-HFpEF, but this was also negative.41 The authors note that this study evaluated largely IpcPH (median PVR ~2.6 WU), which comprised 65% of the study population, and relatively mild PVR elevation in those with CpcPH (median PVR 4 [IQR 3.4–4.8]). Conversely, Guazzi et al. conducted a study evaluating the role of sildenafil in a randomised, placebocontrolled trial of 44 patients with PH-HFpEF (largely CpcPH; mean PVR 3.6 WU) and found sustained haemodynamic benefits and improvements in RV size and function in the sildenafil group.42 More

Pulmonary Hypertension Figure 2: Representative Echocardiographic Manifestations of IpcPH and CpcPH

IpcPH

CpcPH

Distinguishing features of CpcPH

Both patients have echocardiographic evidence of elevated tricuspid regurgitant jet velocity, with accompanying elevated calculated right ventricular systolic pressure.

CpcPH echo reveals a short right ventricular outflow tract acceleration time (between red line), as well as right ventricular outflow tract pulse wave spectral Doppler tracing notching (arrow).

CpcPH echo illustrates systolic interventricular septal flattening (double arrowheads).

CpcPH echo reveals a low tricuspid annular plane systolic excursion, which is indicative of decreased right ventricular systolic function.

CpcPH = combined post- and pre-capillary pulmonary hypertension; IpcPH = isolated post-capillary pulmonary hypertension.

Table 2: Summary of Clinical Trials of Pulmonary Hypertension-specific Therapy in Heart Failure with Preserved Ejection Fraction Study

Drug Studied Study Type

Inclusion Criteria

Outcome

Conclusion

RELAX40

Sildenafil

Multicentre randomised controlled trial

216

Clinical diagnosis of HF, LVEF >50%, stable medical therapy

Change in VO2 max after 24 weeks of treatment

No benefit

Guazzi et al.42

Sildenafil

Single-centre randomised controlled trial

Clinical diagnosis of HF, sinus rhythm and no hospitalisation in the 6 months prior, LVEF ≥50%, sPAP >40 mmHg on TTE

Change in mean PAP after 12 months of treatment

Improvement in all parameters

DILATE-144

Riociguat

Single-centre randomised controlled trial

Clinical diagnosis of HF, LVEF Change in mean PAP >50% and diastolic dysfunction 6 hours post drug on TTE administration

No benefit

Hoendermis et Sildenafil al.41

Single-centre randomised controlled trial

NYHA class II–IV, LVEF >45%, PAP >25 mmHg + PAWP >15 mmHg on RHC

Change in mean PAP after 12 weeks of treatment

No benefit

Simon et al.47

Inhaled inorganic Single-centre phase II nitrates study

36; 10 with Safety study, patients with PH HFpEF were enrolled

Acute change in haemodynamics on RHC

Reduction in PCWP and mPAP

BADDHY45

Bosentan

Single-centre randomised controlled trial

6MWT 150–450 m, LVEF >50%, PAP >25 mmHg + PCWP >15 mmHg on RHC

Change in 6-minute walk test after 12 and 24 weeks of treatment

Terminated early due to interim analysis that favoured the placebo

MELODY-146

Macitentan

Multicentre placebocontrolled randomised phase II study

LVEF >30%, NYHA class II/III, CpcPH by right heart catheterisation

Safety (fluid retention or worsening NYHA class)

Increased fluid retention in study arm

CpcPH = combined post- and pre-capillary pulmonary hypertension; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; LVEF = left ventricular ejection fraction; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PCWP = pulmonary capillary wedge pressure; PH = pulmonary hypertension; sPAP = systolic pulmonary artery pressure; RHC = right heart catheterisation; TTE = trans-thoracic echocardiography.

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Pulmonary Hypertension in Heart Failure Patients Table 3: Summary of Clinical Trials of Pulmonary Hypertension-specific Therapy in Heart Failure with Reduced Ejection Fraction Study

Drug

Type

Inclusion Criteria

Outcome

Conclusion

FIRST50

Epoprostenol IV

Multicentre randomised controlled trial

471

NYHA class IIIB/IV, no specific requirement for PH

Mortality

Terminated early due to mortality in treatment arm

HEAT51

Darusentan

Single-centre randomised 179 controlled trial

NYHA class III, no specific requirement for PH

Change in cardiac index and PAWP after 3 weeks of treatment

Improvement in cardiac output with no change in pulmonary artery pressures

EARTH52

Darusentan

Multicentre randomised controlled trial

642

NYHA class IIIB/IV, no specific requirement for PH

Change in LV size on cardiac MRI after 24 weeks of treatment

No benefit

REACH-149

Bosentan (500 mg twice a day)

Multicentre randomised controlled trial

370 aim, 174 recruited total

NYHA class III/IV, no specific requirement for PH

Change in HF symptoms after 26 weeks of treatment

Early termination, although trend to benefit in those that completed study

Guazzi et al.54

Sildenafil

Multicentre randomised controlled trial

NYHA class II/III, no specific requirement for PH

Change in VO2 max after 6 months of treatment

Improved exercise capacity

LEPHT56

Riociguat

Multicentre randomised controlled trial

201

LVEF ≤40%, mPAP ≥25 mmHg by right heart catheterisation

Change in mPAP

No benefit

PITCH-HF (NCT01910389)

Tadalafil

Multicentre randomised controlled trial

NYHA class II/III, documented PH within 6 months

Mortality and HF hospitalisations after up to 3 years of treatment

Terminated due to poor enrolment

SIL-HF (NCT01616381)

Sildenafil

Two-arm randomised controlled pilot study

NYHA class II/III, secondary PH >40 mmHg on TTE

Change in patientreported symptoms and 6-minute walk test after 6 months of treatment

Enrolment complete, results pending

HF = heart failure; LV = left ventricular; LVEF = left ventricular ejection fraction; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PAWP = pulmonary artery wedge pressure; PH = pulmonary hypertension; TTE = trans-thoracic echocardiography.

recently, Bermejo et al. found worse outcomes after long-term sildenafil use compared with placebo in patients’ status after corrective valvular surgery.43 Furthermore, riociguat, a nitric oxide pathway soluble guanylate cyclase stimulator, was studied in the Acute hemodynamic effects of riociguat in patients with PH associated with diastolic heart failure (DILATE-1) study and showed that, while there was safety using this medication, there was no significant benefit with regards to haemodynamic endpoints.44 The Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension (BADDHY) trial used bosentan, a dual endothelin A and B antagonist.45 It had to be prematurely halted as there was a trend to harm in the treatment arm. Macitentan in PH due to left ventricular dysfunction (MELODY-1) was a phase II trial studying macitentan, a dual endothelin A and B antagonist, in CpcPH due to either HFpEF or HFrEF (although overwhelmingly a HFpEF population), and showed increased fluid retention in the treatment arm within 4 weeks of initiating therapy and worsening functional class without an improvement in haemodynamic variables and a non-significant decrease in NT-proBNP in the macitentan arm.46 Finally, organic nitrates as a direct activator of the nitric oxide pathway has been investigated as a novel therapeutic area. Simon et al. conducted a phase II dosing clinical trial that demonstrated a reduction in PAWP and PA pressures from inhaled nitric oxide, and this effect was greater in HFpEF patients compared with those with PH alone.47 There are currently a number of ongoing trials in PH-HFpEF patients, including the Hemodynamic Evaluation of Levosimendan in Patients

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With PH-HFpEF (HELP) study (NCT03541603) evaluating levosimendan, a calcium sensitiser with inotropic, lusitropic and vasodilatory properties; a randomised, placebo controlled trial of organic nitrites, Oral Nitrite in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction (NCT03015402); and a phase II clinical trial of metformin – Metformin for PH HFpEF (NCT03629340) – among others.

Heart Failure with Reduced Ejection Fraction A number of trials have been performed in the broader HFrEF population, but at this stage data are lacking to support the use of PHspecific therapy. Initial clinic trials using bosentan, IV prostacyclins and darusentan (a selective endothelin AT antagonists) were all negative.48–52 A major criticism of these studies is that they failed to focus on the PHLHD population and often had higher doses of these therapies than used in the PAH population. More focused studies have been performed to assess the potential efficacy of sildenafil. In a single arm, open-label study, Lewis et al. showed a significant improvement in haemodynamics and cardiopulmonary exercise testing parameters (including VO2 max and increase in ventilation with respect to CO2 output) with 50 mg sildenafil, while Guazzi et al. performed a single-centre, randomised trial that showed improvements in haemodynamics, echocardiographic markers of left ventricular diastolic function and cardiac geometry, as well as functional status (by CPET) and quality of life.53–55 However, doubleblind, placebo-controlled trials with PDE5 inhibitors have been plagued by poor recruitment. The Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure (PITCH-HF; NCT01910389),

Pulmonary Hypertension evaluating tadalafil, was terminated after funding was withdrawn due to a number of factors, including poor enrolment. There have been two other recently published studies using PH-specific therapy. The Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction (LEPHT) evaluating riociguat failed to show a reduction in PAP or PVR after 16 weeks of treatment.56 The Study to Evaluate Whether Macitentan is an Effective and Safe Treatment for Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease (SERENADE; NCT03153111) trial is a phase IIb trial which is currently underway.

Left Ventricular Assist Device Left ventricular assist device (LVAD) therapy has become a mainstay in the treatment of end-stage HFrEF, with multiple devices now FDA approved for both bridge-to-transplant (BTT) and destination therapy (DT).57 Many studies have shown reversal of PH-LHD with LVAD support causing both mechanical unloading of the left ventricle, and the persistent reductions in filling pressures leading to reverse remodelling of the pulmonary vasculature changes in CpcPH. This has been shown in a number of single-centre observational studies in the pre-transplant population and in a more recent study which showed significant reduction in PH when compared with medical therapy in a similar population.58–62 However, there is a subgroup that has persistent CpcPH after LVAD implantation and there is no consensus on treatment for this group. There have been several small trials evaluating the role of sildenafil after LVAD placement. In a single-centre study, Tedford et al. showed sildenafil treatment led to a significant reduction in mPAP, improved cardiac output and reduction in PVR in LVAD patients with residual elevated pulmonary pressures more than 1-month post implant.63 Other agents, including bosentan, have been evaluated.64 The Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO; NCT02554903) study is ongoing.

Guazzi M, Borlaug B. Pulmonary hypertension due to left heart disease. Circulation 2012;126:975–90. https://doi.org/10.1161/ CIRCULATIONAHA.111.085761; PMID: 22908015. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J 2016;37:67–119. https://doi. org/10.1093/eurheartj/ehv317; PMID: 26320113. Rosenkranz S, Gibbs JSR, Wachter R, et al. Left ventricular heart failure and pulmonary hypertension. Eur Heart J 2016;37:942–54. https://doi.org/10.1093/eurheartj/ehv512; PMID: 26508169. Vachiéry JL, Tedford RJ, Rosenkranz S, et al. Pulmonary hypertension due to left heart disease. Eur Respir J 2018;53:pii:1801897 https://doi.org/10.1183/13993003.018972018; PMID: 30545974. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913. https://doi. org/10.1183/13993003.01913-2018; PMID: 30545968. Assad TR, Maron BA, Robbins IM, et al. Prognostic effect and longitudinal hemodynamic assessment of borderline pulmonary hypertension. JAMA Cardiol 2017;2:1361–8. https://doi.org/10.1001/jamacardio.2017.3882; PMID: 29071338. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183–8. https://doi.org/10.1016/ S0735-1097(00)01102-5; PMID: 11153735. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension

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Thus, while the data suggest that LVAD therapy is associated with improvements in cardiopulmonary haemodynamics acutely and over time, there are patients who have persistent PH and/or RV failure (early or late) after LVAD implantation. While several smaller trials suggest haemodynamic benefit from the use of PH-specific therapy, and we use such therapy in isolated cases, there is currently a lack of large randomised data to support its use more broadly across this population.

Transplantation Orthotropic heart transplantation (OHT) is still considered the definitive treatment for end-stage HFrEF. Unfortunately, patients with PH-LHD have worse outcomes post-transplantation, specifically those patients with a PVR >2.5 WU who do not demonstrate reversibility with vasodilator challenge, have significantly higher risk of mortality due to RV failure at 3 months (33%; 14% related to RV failure versus 6%).65 This was further shown in an analysis of the United Network for Organ Sharing (registry that showed pre-transplant PVR >2.5 WU was an independent predictor of mortality), although the degree of elevation of PVR modestly increased mortality in a non-linear manner.66 These studies demonstrate that the evaluation of PH-LHD in the context of OHT must be both dynamic and repeated, and that a stepwise approach to the transplant candidate with an elevated PVR is vital in patients where the PVR remains elevated. Without a viable mechanical support option, as may be the case in the congenital population, selected patients may be eligible for combined heart–lung transplantation. This option, however, is not without significant pitfalls, because this procedure is performed at only a select number of centres and has a high postoperative morbidity and mortality when compared with OHT.67

Conclusion PH-LHD is a major problem for patients with both HFrEF and HFpEF and limited targeted treatment options have proven beneficial for this population. Although trials to this date have been negative, the combination of more nuanced phenotyping of this patient population combined with novel modalities is providing hope of advances in treatment.

due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail 2013;1:290–9. https://doi.org/10.1016/j.jchf.2013.05.001; PMID: 24621932. Maeder MT, Schoch OD, Kleiner R, et al. Pulmonary hypertension associated with left-sided heart disease. Swiss Med Wkly 2017;147:w14395. https://doi.org/10.4414/ smw.2017.14395; PMID: 28102878. Borlaug BA, Obokata M. Is it time to recognize a new phenotype? Heart failure with preserved ejection fraction with pulmonary vascular disease. Eur Heart J 2017;38:2874–8. https://doi.org/10.1093/eurheartj/ehx184; PMID: 28431020. Miller WL, Mahoney DW, Enriquez-Sarano M. Quantitative Doppler-echocardiographic imaging and clinical outcomes with left ventricular systolic dysfunction. Circ Cardiovasc Imaging 2014;7:330–6. https://doi.org/10.1161/ CIRCIMAGING.113.001184; PMID: 24488981. Salamon JN, Kelesidis I, Msaouel P, et al. Outcomes in World Health Organization group II pulmonary hypertension: mortality and readmission trends with systolic and preserved ejection fraction-induced pulmonary hypertension. J Card Fail 2014;20:467–75. https://doi.org/10.1016/j.cardfail.2014.05.003; PMID: 24858070. Fayyaz AU, Edwards WD, Maleszewski JJ, et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation 2018;137:1796–810. https://doi. org/10.1161/CIRCULATIONAHA.117.031608; PMID: 29246894. Weber L, Rickli H, Haager PK, et al. Haemodynamic mechanisms and long-term prognostic impact of pulmonary hypertension in patients with severe aortic stenosis undergoing valve replacement. Eur J Heart Fail 2019;21:172–81. https://doi.org/10.1002/ejhf.1322; PMID: 30328215. Forfia PR, Vachiéry JL. Echocardiography in pulmonary arterial

hypertension. Am J Cardiol 2012;110:S16–24. https://doi. org/10.1016/j.amjcard.2012.06.012; PMID: 22921027. 16. Mazurek JA, Forfia PR. Enhancing the accuracy of echocardiography in the diagnosis of pulmonary arterial hypertension: looking at the heart to learn about the lungs. Curr Opin Pulm Med 2013;19:437–45. https://doi.org/10.1097/ MCP.0b013e3283645966; PMID: 23884296. 17. Sade LE, Gulmez O, Eroglu S, et al. Noninvasive estimation of right ventricular filling pressure by ratio of early tricuspid inflow to annular diastolic velocity in patients with and without recent cardiac surgery. J Am Soc Echocardiogr 2007;20:982–8. https://doi.org/10.1016/j.echo.2007.01.012; PMID: 17555928. 18. Sundereswaran L, Nagueh SF, Vardan S, et al. Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–7. https://doi.org/10.1016/S0002-9149(98)003464; PMID: 9708666. 19. Beigel R, Cercek B, Luo H, Siegel RJ. Noninvasive evaluation of right atrial pressure. J Am Soc Echocardiogr 2013;26:1033–42. https://doi.org/10.1016/j.echo.2013.06.004; PMID: 23860098. 20. Amsallem M, Sternbach JM, Adigopula S, et al. Addressing the controversy of estimating pulmonary arterial pressure by echocardiography. J Am Soc Echocardiogr 2016;29:93–102. https://doi.org/10.1016/j.echo.2015.11.001; PMID: 26691401. 21. Opotowsky AR, Clair M, Afilalo J, et al. A simple echocardiographic method to estimate pulmonary vascular resistance. Am J Cardiol 2013;112:873–82. https://doi. org/10.1016/j.amjcard.2013.05.016; PMID: 23735649. 22. Kiely DG, Levin D, Hassoun P, et al. EXPRESS: Statement on imaging and pulmonary hypertension from the Pulmonary Vascular Research Institute (PVRI). Pulm Circ 2019. https://doi. org/10.1177/2045894019841990; PMID: 30880632; epub ahead of press.

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Pulmonary Hypertension in Heart Failure Patients 23. Arkles JS, Opotowsky AR, Ojeda J, et al. Shape of the right ventricular Doppler envelope predicts hemodynamics and right heart function in pulmonary hypertension. Am J Respir Crit Care Med 2011;183:268–76. https://doi.org/10.1164/ rccm.201004-0601OC; PMID: 20709819. 24. Tello K, Wan J, Dalmer A, et al. Validation of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio for the assessment of right ventricular-arterial coupling in severe pulmonary hypertension. Circ Cardiovasc Imaging 2019;12:e009047. https://doi.org/10.1161/ CIRCIMAGING.119.009047; PMID: 31500448. 25. Gerges M, Gerges C, Pistritto AM, et al. Pulmonary hypertension in heart failure. epidemiology, right ventricular function, and survival. Am J Respir Crit Care Med 2015;192:1234– 46. https://doi.org/10.1164/rccm.201503-0529OC; PMID: 26181215. 26. Guazzi M, Dixon D, Labate V, et al. RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes. JACC Cardiovasc Imaging 2017;10:1211–21. https://doi.org/10.1016/j.jcmg.2016.12.024; PMID: 28412423. 27. Thenappan T, Prins KW, Pritzker MR, et al. The critical role of pulmonary arterial compliance in pulmonary hypertension. Ann Am Thorac Soc 2016;13:276–84. https://doi.org/10.1513/ AnnalsATS.201509-599FR; PMID: 26848601. 28. Assad TR, Brittain EL, Wells QS, et al. Hemodynamic evidence of vascular remodeling in combined post- and precapillary pulmonary hypertension. Pulm Circ 2016;6:313–21. https://doi. org/10.1086/688516; PMID: 27683608. 29. Bhattacharya PT, Troutman GS, Mao F, et al. Right ventricular outflow tract velocity time integral-to-pulmonary artery systolic pressure ratio: a non-invasive metric of pulmonary arterial compliance differs across the spectrum of pulmonary hypertension. Pulm Circ 2019. https://doi.org/10.1177/ 2045894019841978; PMID: 30880577; epub ahead of press. 30. Kovacs G, Avian A, Pienn M, et al. Reading pulmonary vascular pressure tracings. How to handle the problems of zero leveling and respiratory swings. Am J Respir Crit Care Med 2014;190:252–7. https://doi.org/10.1164/rccm.201402-0269PP; PMID: 24869464. 31. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62:D42–50. https://doi.org/10.1016/j.jacc.2013.10.032; PMID: 24355641. 32. Hemnes AR, Opotowsky AR, Assad TR, et al. Features associated with discordance between pulmonary arterial wedge pressure and left ventricular end diastolic pressure in clinical practice: implications for pulmonary hypertension classification. Chest 2018;154:1099–107. https://doi. org/10.1016/j.chest.2018.08.1033; PMID: 30148982. 33. Reddy YNV, El-Sabbagh A, Nishimura RA. Comparing pulmonary arterial wedge pressure and left ventricular end diastolic pressure for assessment of left-sided filling pressures. JAMA Cardiol 2018;3:453–4. https://doi.org/10.1001/ jamacardio.2018.0318; PMID: 29590308. 34. Mascherbauer J, Zotter-Tufaro C, Duca F, et al. Wedge pressure rather than left ventricular end-diastolic pressure predicts outcome in heart failure with preserved ejection fraction. JACC Heart Fail 2017;5:795–801. https://doi.org/10.1016/j. jchf.2017.08.005; PMID: 29032138. 35. Andersen MJ, Olson TP, Melenovsky V, et al. Differential hemodynamic effects of exercise and volume expansion in people with and without heart failure. Circ Heart Fail 2015;8:41– 8. https://doi.org/10.1161/CIRCHEARTFAILURE. 114.001731; PMID: 25342738. 36. Borlaug BA, Nishimura RA, Sorajja P, et al. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588–95. https://doi.org/10.1161/CIRCHEARTFAILURE.109.930701; PMID: 20543134. 37. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S0140-6736(11)60101-3; PMID: 21315441. 38. Shah SJ, Feldman T, Ricciardi MJ, et al. One-year safety and clinical outcomes of a transcatheter interatrial shunt device

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53. Lewis GD, Lachmann J, Camuso J, et al. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation 2007;115:59–66. https://doi. org/10.1161/CIRCULATIONAHA.106.626226; PMID: 17179022. 54. Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50:2136–44. https://doi.org/10.1016/j. jacc.2007.07.078; PMID: 18036451. 55. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail 2011;4:8–17. https:// doi.org/10.1161/CIRCHEARTFAILURE.110.944694; PMID: 21036891. 56. Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Circulation 2013;128:502–11. https:// doi.org/10.1161/CIRCULATIONAHA.113.001458; PMID: 23775260. 57. Miller LW, Rogers JG. Evolution of left ventricular assist device therapy for advanced heart failure: a review. JAMA Cardiol 2018;3:650–8. https://doi.org/10.1001/jamacardio.2018.0522; PMID: 29710092. 58. Zimpfer D, Zrunek P, Roethy W, et al. Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates. J Thorac Cardiovasc Surg 2007;133:689– 95. https://doi.org/10.1016/j.jtcvs.2006.08.104; PMID: 17320566. 59. Torre-Amione G, Southard RE, Loebe MM, et al. Reversal of secondary pulmonary hypertension by axial and pulsatile mechanical circulatory support. J Heart Lung Transplant 2010;29:195–200. https://doi.org/10.1016/j.healun.2009.05.030; PMID: 19782604. 60. Mikus E, Stepanenko A, Krabatsch T, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg 2011;40:971– 7. https://doi.org/10.1016/j.ejcts.2011.01.019; PMID: 21354812. 61. Beyersdorf F, Schlensak C, Berchtold-Herz M, Trummer G. Regression of ‘fixed’ pulmonary vascular resistance in heart transplant candidates after unloading with ventricular assist devices. J Thorac Cardiovasc Surg 2010;140:747–9. https://doi.org/10.1016/j.jtcvs.2010.05.042; PMID: 20850652. 62. Kumarasinghe G, Jain P, Jabbour A, et al. Comparison of continuous‐flow ventricular assist device therapy with intensive medical therapy in fixed pulmonary hypertension secondary to advanced left heart failure. ESC Heart Fail 2018;5:695–702. https://doi.org/10.1002/ehf2.12284; PMID: 29573567. 63. Tedford RJ, Hemnes AR, Russell SD, et al. PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support. Circ Heart Fail 2008;1:213–9. https://doi.org/10.1161/CIRCHEARTFAILURE.108.796789; PMID: 19808294. 64. LaRue SJ, Garcia-Cortes R, Nassif ME, et al. Treatment of secondary pulmonary hypertension with bosentan after left ventricular assist device implantation. Cardiovasc Ther 2015;33:50–5. https://doi.org/10.1111/1755-5922.12111; PMID: 25759010. 65. Costard-Jäckle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: Testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48–54. https://doi. org/10.1016/0735-1097(92)90050-W; PMID: 1729345. 66. Vakil K, Duval S, Sharma A, et al. Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: A UNOS registry analysis. Int J Cardiol 2014;176:595–9. https://doi.org/10.1016/j.ijcard.2014.08.072; PMID: 25305706. 67. Chambers DC, Cherikh WS, Goldfarb SB, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report – 2018; Focus theme: Multiorgan Transplantation. J Heart Lung Transplant 2018;37:1169–83. https://doi.org/10.1016/j.healun.2018.07.020; PMID: 30293613.

Digital Health

Telemonitoring in Heart Failure Management Ivo Planinc, Davor Milicic and Maja Cikes Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Zagreb, Croatia

Abstract Telemonitoring (TM) aims to predict and prevent worsening heart failure (HF) episodes and improve self-care, patient education, treatment adherence and survival. There is a growing number of TM options for patients with HF, but there are numerous challenges in reaching positive outcomes. Conflicting evidence from clinical trials may be the result of the enormous heterogeneity of TM devices tested, differences in selected patient populations and variabilities between healthcare systems. This article covers some basic concepts of TM, looking at the recent advances in the most frequently used types of TM and the evidence to support its use in the care of people with HF.

Keywords Telemonitoring, heart failure, remote patient monitoring, structured telephone support, pulmonary artery pressure monitoring, cardiac implantable electronic device, left ventricular assist device Disclosure: IP has received personal fees and non-financial support related to travel from Novartis, Pfizer, Boehringer-Ingelheim, Teva Pharmaceutical Industries, Berlin-Chemie Menarini, PharmaS, Sanofi, Bayer, Krka and Servier. DM has received personal fees from Abbott, Novartis, Roche diagnostics, Bayer, Pfizer, Boehringer Ingelheim, Amgen, Sanofi and Krka. MC has received grants, personal fees and non-financial support related to travel from Novartis, GE Healthcare, Abbott, Roche Diagnostics, Bayer, Pfizer, Boehringer-Ingelheim, Berlin-Chemie Menarini, Servier, Corvia, AstraZeneca, Sanofi Genzyme, Sandoz, Amgen, Teva Pharmaceutical Industries and Orion Pharma. Received: 23 August 2019 Accepted: 11 November 2019 Citation: Cardiac Failure Review 2020;6:e06. DOI: https://doi.org/10.15420/cfr.2019.12 Correspondence: Ivo Planinc, Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia. E: ivo.planinc@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure (HF) affects more than 2% of the adult population worldwide; it is responsible for about 1 million hospitalisations per year in the US and it carries a high mortality risk.1 Recent population data indicate overall better survival rates, albeit with greater healthcare costs.1 Altogether, HF syndrome represents one of the biggest challenges to modern medicine, and places an enormous economic burden on society. A large proportion of HF management costs comprise of ambulatory patient visits, emergency department visits and hospitalisations, with no difference between patients with HF with preserved and reduced ejection fraction (EF).1,2 Up to 40% of patients with HF have at least four hospitalisations during the course of the condition, and mortality risk increases with multiple previous hospitalisations.1,3 One of the contributory factors for repeat hospitalisations is low patient adherence to recommended drug treatments and lifestyle changes, shown to rapidly decline with the time elapsed from the previous hospitalisation.1–4 Advancements in HF drugs and devices, as well as in overall patient management and education, aim to improve outcomes, including a reduction in non-scheduled patient visits. Equally important, better understanding of underlying mechanisms of acute decompensated HF enables more timely management of patients at risk.5 Over the past decades and increasingly over the past several years, great effort has been invested in telemonitoring (TM) methods that would improve patient adherence, predict and/or prevent episodes of

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worsening HF and allow patients to be more closely monitored without presenting at healthcare centres. Over this time, various methods of remote patient care, monitoring and management have been introduced.

Definition and Types of Telemonitoring TM or remote patient monitoring is a type of telemedicine. It is the provision of care to patients from care providers at a different location, using information technology. In general, telemedicine methods can be categorised to asynchronous (store and forward, non-simultaneous) or synchronous (real-time, simultaneous) depending on the timing of the information transfer.6,7 Both types have been used for TM of patients with chronic HF individually and in combination. As described in the existing literature, telemedicine for patients with HF mainly consists of the following: • Structured telephone support (STS). • Non-invasive TM of pre-specified parameters, such as daily weight, blood pressure, ECG, pulse oximetry, subjective assessment of HF symptoms or depression levels and medication adherence. • Invasive TM by implanted devices with the sole function of remote patient monitoring (measuring surrogates of left ventricular filling pressures, such as right ventricular pressure, pulmonary artery pressure and left atrial pressure). • Invasive TM by cardiovascular implantable electronic devices (CIEDs), such as ICDs or cardiac resynchronisation devices (CRT-D).8–11

Telemonitoring in Heart Failure Recommendations for Telemonitoring in Recent Heart Failure Guidelines The European Society of Cardiology (ESC) provided limited recommendations for TM in its 2016 guidelines for the diagnosis and treatment of acute and chronic HF.12 Monitoring of pulmonary artery pressure (PAP) using a wireless implantable haemodynamic monitoring system (CardioMEMS HF System, Abbott) in symptomatic patients with reduced or preserved EF and a previous HF hospitalisation received a IIb class recommendation for the risk reduction of recurrent HF hospitalisations. The only other approach mentioned was multiparameter monitoring by ICD – an approach suggested by the Implant-based Multiparameter Telemonitoring of Patients with HF (IN-TIME) trial – that received the same recommendation for improvement of clinical outcomes in symptomatic patients with left ventricular EF (LVEF) ≤35%.12,13 All other TM methods were considered to lack sufficient evidence to support recommendation, based on different clinical trial results and lack of uniformity. An individual approach to the patient and TM method selection was highlighted. The American College of Cardiology Foundation/American Heart Association Guidelines for the management of HF from 2013 did not provide any specific recommendation for TM practice, but stated that there was a need for clear evidence to identify the best processes of care.14 To fill that gap, the Heart Failure Society of America Scientific Statements Committee issued an official report on TM in 2018, highlighting the paucity of evidence from clinical trials to support the use of external electronic devices for TM (including STS and noninvasive TM), while implanted devices for monitoring PAP and/or other parameters may be beneficial in selected populations under a structured programme of care. The general message on TM was a need to shift the focus from using TM as a treatment to using it as a tool to improve organisation and effectiveness of care.15 The Canadian Cardiovascular Society gives no exact recommendation for TM and it is classified as an intervention with limited evidence of outcome improvement on a systematic level.16 On the other hand, the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand HF Guidelines for the prevention, detection and management of HF recognise and have a strong GRADE recommendation for TM as a model of care to improve evidence-based practice in areas where access to a face-to-face multidisciplinary HF disease management programme after discharge is limited. TM of PAP by implantable devices received a weak GRADE strength of recommendation for patients with prior HF hospitalisation who are New York Heart Association (NYHA) class III, despite optimal care, with an aim to decrease hospitalisations for HF if a system is provided to ensure daily upload and weekly review of pressure data.17 These recommendations by influential professional associations are driven by the results of randomised controlled trials (RCTs), some of which are large, but provide inconsistent results for TM care of HF patients (primarily STS and non-invasive TM; Table 1). Nonetheless, consecutive Cochrane reviews show a significant reduction in major outcomes (all-cause mortality and HF hospitalisations) when using STS or non-invasive TM, but these were not included in the latest ESC guidelines.18–20 In addition to the trials and meta-analyses, there is a growing number of expert opinion and review publications addressing the issue of equivocal evidence for the use of TM in the management of HF patients.8–11,21

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Recent Evidence Structured Telephone Support and Non-invasive Telemonitoring The Efficacy of Telemedical Interventional Management in Patients with HF (TIM-HF2) RCT, conducted in multiple centres in Germany, included 1,571 patients with HF and a HF hospitalisation in the previous 12 months, NYHA functional class II or III and LVEF ≤45% or >45% if receiving a diuretic.22 Of note, exclusion criterion was major depression because the original TIM-HF trial had found that these patients did not respond well to TM.23 The primary outcome of TIMHF2 was the percentage of days lost due to unplanned cardiovascular hospitalisation or all-cause death. The intervention included STS, daily remote transmission of multiple physical parameters to the 24/7 telemedical centre, assessment of patient’s risk for adverse events, education, and collaboration of the telemedical centre and patient’s healthcare providers (general practitioners and cardiologists). Patients in the intervention group had significantly lower percentage of days lost due to unplanned cardiovascular hospitalisation or death of any cause and significantly lower all-cause mortality, but not significantly lower cardiovascular mortality. The study showed that a specific multimodality TM is feasible and effective in terms of reduction of hospital days in a specific cohort of HF patients in the German healthcare system.22,23 Conversely, a multicentre RCT from California, US, Better Effectiveness After Transition – Heart Failure (BEAT-HF), studied 1,437 patients with treated HF with new or increased diuretics and recent HF hospitalisation, using pre-discharge HF education, regular health coaching telephone calls in combination with TM of multiple physical parameters as an intervention, and did not show a difference in readmission rates for any cause within 180 days after last discharge.24 However, BEAT-HF had a very low adherence rate to TM procedures, similar to the older Tele-HF trial (TM in patients with HF), another large RCT from the US that showed no significant differences in readmission rates for any reason, or death from any cause within 180 days in patients telemonitored by daily use of an interactive voice-response TM system.25 At most, 61.4% of patients were adherent to more than 50% of telephone calls and TM in the first 30 days in BEAT-HF, while in Tele-HF only 86% of patients randomised to the intervention used it at least once, and the adherence to intervention reduced to 55% by the final week of the study.24,25 Besides monitoring of physical or self-reported parameters, patient education on recognition of HF symptoms and signs, education on possible lifestyle changes to reduce the number of worsening HF episodes and surveillance of medication or diet adherence may be part of TM programmes aimed at improving self-care and self-management.26 A Dutch RCT, the EVIdence Based TreAtment – Heart Failure (e-Vita HF) study, has made an important addition to evidence for the value of patient education. It has shown improved short-term self-care of stable HF patients (NYHA class I and II) over 3 months by the intervention that promoted the use of the website heartfailurematters.org and/or an e-health adjusted care pathway using the e-Vita platform with TM equipment.27

Invasive Telemedicine with Implantable Devices for Remote Patient Monitoring Recommendations by professional associations have included PAP monitoring by a specific device in a specific population, providing a

Treatment Arms

TM + standard care versus standard care

EACP + HFM website + standard care versus HFM + standard care versus standard care

TIM-HF23 (n=710)

TIM-HF222 (n=1,571)

BEAT-HF24 (n=1,437)

Tele-HF25 (n=1,653)

e-Vita HF27 (n=450)

STS and Non-invasive Telemedicine

Trial

Education via HFM and education via HFM plus TM with e-Vita platform (daily transmission of BP, BW, HR, medications, comorbidities)

Daily use of interactive voice-response system TM general health, symptoms and signs of HF, BW and symptoms of depression

Pre-discharge education, health coaching telephone calls and daily transmission of BP, HR, BW, symptoms

Cooperation between the TM centre, and the patient’s GP and cardiologist (follow-up 365–93 days)

HF diagnosis of at least 3 months duration, access to internet

HFH in past 30 days

Age >50 years, HF patients receiving active treatment for decompensated HF (initiation of or an increase in diuretic treatment), HFH or observation for HF

Patients were excluded if they had major depression

Definition of a patient’s risk category by the baseline and follow-up visit BM data in combination with the daily transmitted data Patient education

CHF, HFH within 12 months before randomisation, NYHA II or III, LVEF ≤45% (or if >45% had to be treated with oral diuretics)

CHF, NYHA II–III, optimal drug treatment, LVEF ≤35% (if LVEF>25% must have had at least 1 HFH or treatment with IV diuretics within 24 months before randomisation)

Key Inclusion Criteria

Daily transmission of BW, BP, HR, analysis of the heart rhythm, SpO2 and a self-rated health status to the TM centre

Portable devices for ECG, BP and BW connected to a PDA that sent automated encrypted transmission via mobile phones to the TM centre (mean follow-up 26 months)

Intervention Used (Follow-up)

Table 1: Overview of the Main Randomised Controlled Trials in Telemonitoring for Patients with Heart Failure

Patient’s self-care measured by European Heart Failure Self-care Behaviour scale at 3, 6 and 12 months

Any-cause readmission or any-cause death within 180 days of randomisation

Any-cause readmission within 180 days after discharge

The percentage of days lost due to unplanned CV hospitalisation or all-cause death

All-cause mortality

Primary Endpoint

After 3 months, significantly better self-care in intervention groups (overall p<0.001) The difference attenuated during the following 9 months (p=0.070 at 6 months and p=0.184 at 12 months)

No difference in 180-day all-cause readmission rates or all-cause death (HR 1.04, 95% CI [0.91–1.19])

No difference in 180-day all-cause readmission rates (unadjusted HR 1.03, 95% CI [0.89–1.19]; p=0.73; adjusted HR 1.03, 95% CI [0.88–1.20]; p=0.74)

Significant reduction in all-cause mortality (HR 0.70 95% CI [0.50–0.96]; p=0.0280)

Significant reduction in the percentage of days lost due to unplanned CV hospitalisation and all-cause death (ratio 0.80, 95% CI [0.65–1.00]; p=0.0460)

No difference in all-cause mortality (HR 0.97, 95% CI [0.67–1.41]; p=0.87)

Results (Primary Outcome)

Digital Health

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Treatment Arms

Intervention Used (Follow-up)

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TM of PAP randomised arm versus standard care, TM of PAP single arm versus standard care (different populations)

GUIDE-HF (NCT03387813) Currently recruiting 3,600 participants

TM information available to physicians versus standard care

Fluid status TM to physicians versus standard care

CRT-D device TM check-ups versus in-office follow-ups

DOT-HF43 (n=335)

OptiLink HF44 (n=1,002)

MORE-CARE46 (n=865) Scheduled TM interrogation of the CRT-D, automatic alert for fluid accumulation, atrial tachyarrhythmias and system integrity alarms (24 months)

TM alerts triggered by intrathoracic fluid index threshold crossing followed by a protocol-specified algorithm with TM of device data and telephone contact (22.8 months)

Intrathoracic impedance alarms trigger a patient–physician visit (14.9 months)

Automatic, daily, implant-based, multiparameter TM via CIED (12 months)

Daily TN of PAP to guide medical therapy

Daily TM of PAP was used to guide medical therapy (mean follow-up 18 months + 13 months in open-access extension of the study)

Composite of cardiovascular hospitalisations and all-cause mortality

Composite of all-cause mortality and CV and device-related hospitalisations

CHF patients with de novo CRT-D implantation within 8 weeks

Composite of HFH and all-cause mortality

Composite clinical score combining all-cause mortality, overnight hospital admission for HF, change in NYHA and change in patient global selfassessment

Composite outcome of HFH, IV diuretic visits and all-cause mortality in 12 months post-implantation

Rate of HFH

Primary Endpoint

CHF patients, NYHA II–III, LVEF ≤3, with ICD or CRT-D and one of the following: prior HFH, recent diuretic treatment, recent NT-probing increase

CHF, NYHA II–IV, optimal medical therapy, LVEF ≤35%, HFH within 12 months, OptiVol-enabled device

CHF, NYHA II–III, LVEF ≤35%, optimal drug treatment, no permanent AF, recent dual ICD or CRT-D implantation

CHF, optimal drug therapy, NYHA II/III/IV (randomised arm), NYHA III (single arm), HFH within 12 months and/or elevated NT-proBNP

NYHA III HF patients, regardless of LVEF or cause, with HFH in previous 12 months, optimal drug/device therapy

Key Inclusion Criteria

No significant difference in the all-cause mortality and cardiovascular and device-related hospitalisations (HR 1.02, 95% CI [0.80-1.30]; p=0.89)

No significant differences in number of cardiovascular hospitalisations or all-cause mortality (HR 0.87, 95% CI [0.72–1.04]; p=0.13)

No significant differences in number of HFH or all-cause mortality (HR 1.52, 95% CI [0.97–2.37]; p=0.063)

18.9% of patients in the TM versus 27.2% in the control group had worsened composite score (OR 0.63, 95% CI [0.43–0.90]; p=0.013)

Expected in 2023

In the open-access extension (HR 0.52, 95% CI [0.40–0.69]; p<0.0001)

Significant reduction in the rate of HFH in the randomised access period (HR 0.67, 95% CI [0.55–0.80]; p<0.0001)

Results (Primary Outcome)

BM = biomarker; BP = blood pressure; BW = body weight; CHF = chronic heart failure; CIED = cardiovascular implantable electronic device; CRT-D = cardiac resynchronisation device with defibrillator; CV = cardiovascular; EACP = e-health adjusted care pathway; GP = general practitioner; HFH = heart failure hospitalisation; HF = heart failure; HFM = Heart Failure Matters (http://www.heartfailurematters.org); HR = heart rhythm; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association; PAP = pulmonary artery pressure; PDA = portable digital assistant; STS = structured telephone support; TM = telemonitoring.

TM + standard care versus standard care

IN-TIME13 (n=664)

Invasive TM by CIEDs

TM of PAP + standard care versus standard care

CHAMPION28,29 (n=550)

Invasive TM with Implantable Devices for Remote Patient Monitoring

Trial

Table 1: (cont.)

Telemonitoring in Heart Failure

Digital Health supporting environment, but the level of recommendation is overall weak considering limited data from RCTs.12,14–17 The CardioMEMS implantable PAP sensor was proved to be effective in significantly reducing the rate of HF hospitalisations, decreasing PAP and improving quality of life of HF patients in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) RCT.28,29 The results supporting a reduction in HF hospitalisation for the intervention group were consistent across the initial phase of the RCT and during the continuous open-access period with overall 31 months of mean follow-up (HR 0.67, 95% CI [0.55–0.80]; p<0.0001 for the randomised controlled epoch and HR 0.52, 95% CI [0.40–0.69]; p<0.0001 for the open-access epoch).28,29 The obligatory post-approval study finished recruiting in 2018 and the preliminary results show that PAP-guided therapy of HF decreased PAPs, HF and all-cause hospitalisations in the real-world setting.30

RCT has been published with other implantable TM devices in recent years, of which left-atrial pressure monitoring devices should be mentioned, such as HeartPOD (Abbott) and V-LAP (Vectorious Medical Technologies).39 A niche for those devices exists since there is a substantial proportion of chronic HF patients where the estimation of PAP is not a real representation of left-sided filling pressures, such as patients with significant mitral valve disease, a component of pulmonary arterial hypertension or high pulmonary vascular resistance, pulmonary vasculature disease in chronic obstructive pulmonary disease or chronic thromboembolic disease.40 The primary concern lies in the implantation procedure that requires puncture of the interatrial septum with somewhat higher complication rates. The only prospective RCT of the HeartPOD system was terminated early due to a high rate of implant-related complications.39,41

Further studies done with this implantable PAP sensor were not RCTs, but they contributed data to the role of the PAP monitoring system in the management of HF patients. A retrospective cohort study on the use of haemodynamic TM in clinical practice included 1,114 patients with HF implanted with the device and showed a significant reduction in the number of HF hospitalisations after implantation; however, the study was observational and since it used Medicare claims data, little was known about patient characteristics and treatment prior to implantation.31,32

TM of HF patients with implanted devices seemed feasible and credible until it was tested in RCTs. Almost all trials with CIEDs in the role of early prediction of HF events – such as the Sensitivity and Positive Predictive Value of Implantable Intrathoracic Impedance Monitoring as a Predictor of Heart Failure Hospitalizations (SENSE-HF) trial, the Diagnostic Outcome Trial in Heart Failure (DOT-HF) trial and the Optimization of Heart Failure Management Using Medtronic OptiVol Fluid Status Monitoring and CareLink Network (OptiLink HF) trial – were neutral, and showed very low predictive value of measuring intrathoracic impedance – a surrogate of worsening fluid status or impending acute decompensation.42–44

Overall safety of the device in clinical practice was assessed as similar to the results of the CHAMPION trial (2.8% adverse events from 5,500 CardioMEMS HF System implants in the US versus 2.6% from 575 implant attempts in the CHAMPION trial), bearing in mind that the implantation is an invasive procedure with uncommon but possible serious injury to the pulmonary artery, that this resulted in deaths in the RCT and clinical practice.33 Cost-effectiveness of PAP monitoring has been studied for appropriate patient populations and deemed effective in studies in the US and the UK, although questions have arisen whether a TM system with additional cost-reduction benefits would become available.15,34,35 PAP monitoring has been shown to be useful in individual patients with advanced HF, while patients with left ventricular assist devices (LVAD) present another challenging patient population, in which continuous monitoring of PAP may improve proper timing and adequacy of LVAD optimisation.36 The Design and rationale of Haemodynamic guidance with CardioMEMS in patients with a left Ventricular Assist Device (HEMO-VAD) pilot study is planned to investigate the safety and feasibility of PAP monitoring for the optimisation of LVADs, while Investigation to Optimize Hemodynamic Management of Left Ventricular Assist Devices Using the CardioMEMS (Intellect 2; NCT03247829) is already under way.37 Further trials will produce data on the use of PAP monitoring in the broader HF population and these include the RCT HemodynamicGUIDEd Management of Heart Failure (GUIDE-HF; NCT03387813) and real-world setting trial CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF).38 Several other PAP monitoring devices with different features are being researched, but there are no RCT data available so far. No new large

Invasive Telemonitoring by Cardiovascular Implantable Electronic Devices

TM of a single surrogate parameter of congestion, such as fluid index via a CIED was substituted with multiparameter TM, integrating several standard pacing parameters with symptoms and signs of HF and STS. This approach was successfully tested in the IN-TIME RCT, which showed how automatic CIED multiparameter monitoring can improved outcomes for HF patients. This evidence allowed the IN-TIME approach for TM to be included in the last ESC guidelines for the diagnosis and treatment of acute and chronic HF.12,13 A similar approach has been proven to reduce hospitalisation rates in the Telemonitoring in heart failure patients treated by CARdiac resynchronization Therapy with defibrillator (TELECART study, an Italian multicentre RCT that included 191 patients with an indication for CRT-D).45 Following CRT-D implantation, the patients were randomised to usual care versus usual care and intervention consisting of TM for ventricular and atrial tachyarrhythmias and premature contractions, low percentage of biventricular pacing, decreased patient activity and abnormal intracardiac electrograms.45 Similarly, a larger international multicentre RCT Monitoring Resynchronization devices and cardiac patients (MORE-CARE) showed significant reduction in healthcare resources in 865 CRT-D patients. Intervention in MORE-CARE included multiparameter TM of lung fluid accumulation, atrial arrhythmias and system integrity.46 A promising CIED diagnostic tool is the HeartLogic (Boston Scientific), a multisensor algorithm for CRT-D devices that was tested in an international, multicentre study Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients (MultiSENSE).47 The HeartLogic index consists of sensing heart sounds, thoracic impedance, respiration rate and its ratio to tidal volume, heart rate and patient activity. In the MultiSENSE study, the sensitivity for detection of HF events was up

CARDIAC FAILURE REVIEW

Telemonitoring in Heart Failure to 70%, while the median time from the alert onset to the event occurrence was 34 days, indicating the potential for a very early warning of worsening HF. Although further observational studies with this diagnostic tool are ongoing, RCTs are lacking. Besides CIEDs, LVADs may also demand optimisations that require healthcare resources and generate numerous parameters that could potentially be telemonitored. The most frequently used LVADs (HeartMate II or HeartMate 3 [Abbott] and Heart Ware HVAD [Medtronic] currently do not have options for TM, posing a challenge for their future development. Currently available VADs capable of TM are the HeartAssist 5 LVAD and aVAD (ReliantHeart). The first experience with remote monitoring of LVAD patients has been recently published, emphasising its importance in early detection of pump thrombosis, oscillations of volume status or arrhythmias.48

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Benjamin EJ, Muntner P, Alonso A, et al. AHA statistical update: heart disease and stroke statistics – 2019 update. A report from the American Heart Association. Circulation 2019;139:e56–528. https://doi.org/10.1161/CIR.00000000000; PMID: 30700139. Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart Fail 2014;7:590–5. https://doi.org/10.1161/ CIRCHEARTFAILURE.113.001281; PMID: 24874200. Dunlay SM, Redfield MM, Weston SA, et al. Hospitalizations after heart failure diagnosis: a community perspective. J Am Coll Cardiol 2009;54:1695–702. https://doi.org/10.1016/j. jacc.2009.08.019; PMID: 19850209. Sueta CA, Rodgers JE, Chang PP, et al. Medication adherence based on part D claims for patients with heart failure after hospitalization (from the Atherosclerosis Risk in Communities study). Am J Cardiol 2015;116:413–9. https://doi.org/10.1016/j. amjcard.2015.04.058; PMID: 26026867. Adamson, PB. Pathophysiology of the transition from chronic compensated to acute decompensated heart failure: New insights from continuous monitoring devices. Curr Heart Fail Rep 2009;6:287. https://doi.org/10.1007/s11897-009-0039-z; PMID: 19948098. Kamenca A. Telemedicine: A Practical Guide for Professionals. Phoenix, Arizona: Mindview Press, 2017. Allely EB. Education and training in telemedicine: synchronous and asynchronous telemedicine. J Med Syst 1995;19:207–12. https://doi.org/10.1007/bf02257174; PMID: 7643019. Brahmbhatt DH, Cowie MR. Remote management of heart failure: an overview of telemonitoring technologies. Card Fail Rev 2019;5:86–92. https://doi.org/10.15420/cfr.2019.5.3; PMID: 31179018. Anker SD, Koehler F, Abraham WT. Telemedicine and remote management of patients with heart failure. Lancet 2011;378:731–9. https://doi.org/10.1016/S0140-6736(11)612294; PMID: 21856487. Dierckx R, Pellicori P, Cleland JGF, Clark AL. Telemonitoring in heart failure: Big Brother watching over you. Heart Fail Rev 2015;20:107–16. https://doi.org/10.1007/s10741-014-9449-4; PMID: 24972644. Karamichalakis N, Parissis J, Bakosis G, et al. Implantable devices to monitor patients with heart failure. Heart Fail Rev 2018;23:849–57. https://doi.org/10.1007/s10741-018-9742-8; PMID: 30284661. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology. Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014;384:583– 90. https://doi.org/10.1016/S0140-6736(14)61176-4; PMID: 25131977. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;128:e240–7. https://doi.org/10.1161/CIR.0b013e31829e8776; PMID: 23741058. Dickinson MG, Allen LA, Albert NA, et al. Remote monitoring of patients with heart failure: a white paper from the Heart Failure Society of America Scientiﬁc Statements Committee. J Card Fail 2018;24:682–94. https://doi.org/10.1016/j. cardfail.2018.08.011; PMID: 30308242.

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Conclusion Overall, TM for HF is still scarcely represented in the recommendations from professional associations, except for PAP monitoring, which is supported by RCT data. The paucity of evidence required to base informed recommendations may seem surprising, especially considering the current wide availability of different e-health technologies and the increase in recent popularity of health devices. This reality is a result of the enormous heterogeneity of TM devices tested of differences in selected patient populations, such as type of HF, age, LVEF, clinical stage, background treatment of geographical determinants (densely populated against remote areas far from HF centres) and variabilities between healthcare systems. Furthermore, the strengthening of regulatory processes over time provides additional variability in the testing and approval of TM devices. All these factors contribute to the body of evidence that provides arguments both for and against different types of TM for HF.

16. Ezekowiz JA, O’Meara E, McDonald MA, et al. 2017 comprehensive update of the Canadian Cardiovascular Society Guidelines for the management of heart failure. Can J Cardiol 2017;33:1342–3. https://doi.org/10.1016/j. cjca.2017.08.022; PMID: 29111106. 17. NHFA CSANZ Heart Failure Guidelines Working Group, Atherton JJ, Sindone A, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: guidelines for the prevention, detection, and management of heart failure in Australia 2018. Heart Lung Circ 2018;27:1123– 208. https://doi.org/10.1016/j.hlc.2018.06.1042; PMID: 30077227. 18. Clark RA, Inglis SC, McAlister FA, et al. Telemonitoring or structured telephone support programmes for patients with chronic heart failure: systematic review and meta-analysis. BMJ 2007;334:942. https://doi.org/10.1136/ bmj.39156.536968.55; PMID: 17426062. 19. Inglis SC, Clark RA, McAlister FA, et al. Structured telephone support or telemonitoring programmes for patients with chronic heart failure. Cochrane Database Syst Rev 2010;8:CD007228. https://doi.org/10.1002/14651858. CD007228.pub2; PMID: 20687083. 20. Inglis SC, Clark RA, Dierckx R, et al. Structured telephone support or non-invasive telemonitoring for patients with heart failure. Cochrane Database Syst Rev 2015;10:CD007228. https://doi.org/10.1002/14651858.CD007228.pub3; PMID: 26517969. 21. Dierckx R, Inglis SC, Clark RA, et al. Telemedicine in heart failure: new insights from the Cochrane meta-analyses. Eur J Heart Fail 2017:19:304–6. https://doi.org/10.1002/ejhf.759; PMID: 28251777. 22. Koehler F, Koehler K, Deckwart O, et al. Efficacy of telemedical interventional management in patients with heart failure (TIMHF2): a randomised, controlled, parallel-group unmasked trial. Lancet 2018;392:1047–57. https://doi.org/10.1016/S01406736(18)31880-4; PMID: 30153985. 23. Koehler F, Winkler S, Schieber M, et al. Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the Telemedical Interventional Monitoring in Heart Failure study. Circulation 2011;123:1873–80. https://doi.org/10.1161/ CIRCULATIONAHA.111.018473; PMID: 21444883. 24. Ong MK, Romano PS, Edgington S, et al. Effectiveness of remote patient monitoring after discharge of hospitalized patients with heart failure: the Better Effectiveness After Transition – Heart Hailure (BEAT-HF) randomized clinical trial. JAMA Intern Med 2016;176:310–8. https://doi.org/10.1001/ jamainternmed.2015.7712; PMID: 26857383. 25. Chaudry SI, Mattera JA, Curtis JP, et al. Telemonitoring in patients with heart failure. N Engl J Med 2010;363:2301–9. https://doi.org/10.1056/NEJMoa1010029; PMID: 21080835. 26. Gallagher BD, Moise N, Haerizadeh M, et al. Telemonitoring adherence to medications in heart failure patients (TEAM-HF): a pilot randomized clinical trial. J Card Fail 2017;23:345–9. https://doi.org/10.1016/j.cardfail.2016.11.001; PMID: 27818309. 27. Wagenaar KP, Broekhuizen BDL, Jaarsma T, et al. Effectiveness of the European Society of Cardiology/Heart Failure Association website heartfailurematters.org and e-health adjusted care pathway in patients with stable heart failure: results of the e-Vita HF randomized control trial. Eur J Heart Fail 2019;21:238–46. https://doi.org/10.1002/ejhf.1354; PMID: 30485612. 28. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi. org/10.1016/S0140-6736(11)60101-3; PMID: 21315441. 29. Abraham WT, Stevenson LW, Bourge RC, et al. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from

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Digital Health 44. Böhm M, Drexler H, Oswald H, et al. Fluid status telemedicine alerts for heart failure: a randomized controlled trial. Eur Heart J 2016;37:3154–63. https://doi.org/10.1093/eurheartj/ehw099; PMID: 26984864. 45. Sardu C, Santamaria M, Rizzo MR, et al. Telemonitoring in heart failure patients treated by cardiac resynchronization therapy with defibrillator (CRT-D): the TELECART study. Int J Clin Pract 2016;70:569–76. https://doi.org/10.1111/ijcp.12823;

PMID: 27291327. 46. Boriani G, Da Costa A, Quesada A, et al. Effects of remote monitoring on clinical outcomes and use of healthcare resources in heart failure patients with biventricular defibrillators: results of the MORE-CARE multicentre randomized controlled trial. Eur J Heart Fail 2017;19:416–25. https://doi.org/10.1002/ejhf.626; PMID: 27568392. 47. Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor

algorithm predicts heart failure events in patients with implanted devices. Results from the MultiSENSE Study. JACC Heart Fail 2017;5:216–25. https://doi.org/10.1016/j. jchf.2016.12.011; PMID: 28254128. 48. Hohmann S, Veltmann C, Duncker D, et al. Initial experience with telemonitoring in left ventricular assist device patients. J Thorac Dis 2019;11(Suppl 6):853–63. https://doi.org/10.21037/ jtd.2018.10.37; PMID: 31183165.

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Digital Health

Telemonitoring for the Management of Patients with Heart Failure Ferdinando Iellamo,1,2 Barbara Sposato1 and Maurizio Volterrani1 1. Department of Medical Sciences, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy; 2. Department of Clinical Science and Translational Medicine, University Tor Vergata, Rome, Italy

Abstract Advances in technology now make it possible to manage heart failure (HF) from a remote to a telemonitoring approach using either noninvasive solutions or implantable devices. Nowadays, it is possible to monitor at-home parameters that can be recorded, stored and remotely transmitted to physicians, allowing them to make decisions for therapeutic modification, hospitalization or access to the emergency room. Standalone systems are available that are equipped with self-intelligence and are able to acquire and elaborate data that can inform the remote physician of impending decompensation before it results in additional complications. The development of miniature implantable devices, which could measure haemodynamic variables and transmit them to a monitor outside the body, offers the possibility for the physician to obtain more frequent evaluations of HF patients and the opportunity to take these data into account in management decisions. At present, several telemonitoring devices are available, but the only Food and Drug Administration-approved system is the cardio-microelectromechanical system, which is an implantable pulmonary arterial pressure (PAP) monitoring device that allows a direct monitoring of the PAP via a sensor implanted in the pulmonary artery. This information is then uploaded to a web-based interface from which healthcare providers can track the results and manage patients. At present, the challenge point for telemedicine management of HF is to find the more relevant biological parameter to monitor the clinical status. Disclosure: The authors have no conflicts of interest to declare. Received: 16 December 2019 Accepted: 23 January 2020 Citation: Cardiac Failure Review 2020;6:e07. DOI: https://doi.org/10.15420/cfr.2019.20 Correspondence: Maurizio Volterrani, IRCCS San Raffaele Pisana, Via della Pisana 235, 00163 Rome, Italy. E: maurizio.volterrani@sanraffaele.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The contemporary treatment planning of heart failure (HF) is based on guideline-directed medical therapy recommendations. The management of HF patients at home has become more driven by symptoms and nurse evaluation, as well as by simple monitoring techniques, such as daily weight measurements, to adjust diuretic therapy.

Noninvasive Monitoring Nowadays, technological developments have made it possible to monitor at home more precise parameters that can be recorded, stored and remotely transmitted to the physician, facilitating more appropriate management decisions. In the past, a simple observation of patient clinical variables, collected using bulky devices that did not always work properly, was subsequently sent to the specialist physician. The next stage involved the collection and storage of data in a cloud system that the physician could consult remotely at any time, thereby enabling modification of the ongoing therapy. Each of these systems was linked to its own platform and there was no communication between them. Monitoring devices were secured and impossible to customise to meet specific user needs. In addition, these devices functioned only in selected environments, with a very limited range of action. Today’s standalone systems are intelligent and are able to acquire and elaborate on data in order to inform the patient (who has been previously instructed in the use of the system), and inform the

physician, who can decide on either therapeutic modification, hospitalisation or presentation to the emergency room. At the beginning of the telemedicine approach, acute MI was the main target, with the objective of reducing time to admission to the intensive care unit or haemodynamic room and, ultimately, mortality. This approach was focused on pre-hospital ECG transmission, with or without teleconsultation. Since then, telemedicine research has been directed towards other cardiovascular diseases, particularly HF. Telemedicine can allow for remote monitoring and management of HF patients, making it possible to assess medication adherence and to detect early signs of decompensation before it results in additional complications and hospital readmission.1 As outlined by Bosson in a recent editorial, transmission of data from the patient’s home and the ability of the physician to evaluate the patient remotely can expand the possibilities for home-based care.1 The 2016 European Society of Cardiology (ESC) HF guidelines indicated the need to include patients with HF in education programmes, as well as in multidisciplinary programmes, which include adequate training on compliance and self-care, given the involvement of patients in selfmonitoring and therapeutic control (such as with regard to diuretic control; class II, evidence level B).2

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Digital Health Consistent with this statement, a meta-analysis showed how simple phone support associated with a telemonitoring system significantly reduced hospitalisations and mortality for all causes.3

Implantable Monitoring Solutions The development of miniature implantable devices that could measure haemodynamic variables and transmit them to a monitor outside the body offered, for the first time, the possibility for the physician to obtain more frequent evaluation of HF patients, and the opportunity to take these data into account in management decisions. The 2016 ESC guidelines recommended the use of pulmonary arterial pressure (PAP) monitoring in symptomatic patients with previous HF hospitalisation in order to reduce the risk of recurrent HF hospitalisation (with a class IIb recommendation), utilising a microelectromechanical system (MEMS): the CardioMEMS HF System.2 Multiparameter monitoring based on implanted ICDs with this capacity (the Implant-based Multiparameter Telemonitoring of Patients with Heart Failure [IN-TIME] approach [NCT00538356]), was also advised in symptomatic patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤35%) in order to improve clinical outcomes.4 To date, the data collected have indeed indicated that this kind of approach is not suitable for all patients with HF, highlighting greater benefits in those at high risk. Using this telemedicine approach, the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial demonstrated a significant reduction in HF-related hospitalisations at 6 months and during the entire follow-up.5 The treatment group had a 39% reduction in HF-related hospitalisation compared with the control group. Also, medication was observed to change more often in patients followed using a telemedicine approach, resulting in a 49% decrease in HF hospitalisations compared with the control group.6 At present, several telemonitoring devices capable of assessing different haemodynamic variables are available. The IN-TIME trial studied HF patients with a recent dual-chamber ICD or CRT-D implantation randomly assigned to either automatic, daily, implant-based, multiparameter telemonitoring in addition to standard care, or to standard care without telemonitoring.4 The primary outcome (death; or HF hospitalisation; or change in either New York Heart Association class or patient global self-assessment) was significantly improved in the treatment group. A possible explanation for these results is that blood volume expansion and incipient pulmonary oedema may start many days before the appearance of classical decompensation symptoms or weight changes, and hence monitoring physiologic signals via implanted devices may provide earlier warning of impending decompensation episodes, facilitating diuretic or haemodynamically acting drug intervention.7 An alternative approach involves the implantable impedance monitors, which can detect fluid volumes in the thorax and lungs. However, several studies failed to show significant or meaningful

benefits over standard care on primary outcomes, such as death and/or HF-related hospitalisation during the follow-up period.8–10 Other approaches that have been tested include implantable left atrial or ventricular pressure monitoring,11,12 but these studies had to be prematurely stopped for various safety problems and still need to be adequately verified. Currently, many devices are under investigation for the monitoring of HF, but the only Food and Drug Administration-approved remote monitoring system for patients with HF is the CardioMEMS HF system (Abbott). This is an implantable PAP monitoring device that allows direct monitoring of PAP via a sensor implanted in the pulmonary artery. The sensor monitors changes in PAP and communicates via wireless to an external analyser. This information is then uploaded to a web-based interface from which healthcare providers can track the results and manage patients. Such a novel diagnostic/therapeutic tool should be incorporated into existing HF management strategies. Patients should be monitored using individualised PAP thresholds to trigger medication follow-up by specifically trained nurses in a multidisciplinary HF management team for all patients with advanced HF. A European prospective, observational study is ongoing to evaluate the safety and feasibility of the CardioMEMS HF system, which could shed new light on the possibility of using haemodynamically guided HF management to improve clinical outcomes (including quality of life) in people with HF.13

Perspectives Telemedicine should also be considered for out-of-hospital rehabilitation programmes in patients with HF. Some studies appear promising in this context. In a recent study, a home-based integrated project of tele-surveillance and remote monitoring of exercise training in patients with chronic HF and pulmonary comorbidity (chronic obstructive pulmonary disease), has been proven effective in increasing functional capacity and quality of life while reducing hospitalisations and mortality.14 Similarly, Frederix et al. showed that a telemedical care programme reduced hospital readmissions in a long-term study in patients with chronic HF.15 Despite the progress made, there are still many obstacles preventing the use of telematic systems in assistance and monitoring, the first of which is the patient opinion that it is not as reliable as face-to-face assessment. From the point of view of healthcare professionals, there is a need for adequate training and education courses on how to use these systems and how to share duties and tasks. Therefore, today it seems even more necessary to identify the more relevant of the biological parameters involved in the monitoring of clinical profile, indicating in which specific healthcare subset the intervention should be implemented. There are no certainties as to what the best system or strategy is, but remote monitoring associated with precise nursing management and scheduled visits are the elements of a successful programme.

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Expert Opinion 1.

Bosson N. Telemedicine to improve outcomes for patients with acute myocardial infarction. Heart 2019;105:1454–5. https://doi.org/10.1136/heartjnl-2019-315278; PMID: 31296594. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129– 200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. Inglis SC, Clark RA, Dierckx R, et al. Structured telephone support or non invasive telemonitoring for patients with heart failure. Cochrane Database Syst Rev 2015;(10):CD007228. https:// doi.org/10.1002/14651858.CD007228.pub3; PMID: 26517969. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014;384:583– 90. https://doi.org/10.1016/S0140-6736(14)61176-4; PMID: 25131977. Abraham WT, Stevenson LW, Bourge RC, et al. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016;387:453–61. https://doi.org/10.1016/S0140-6736(15)00723-0; PMID: 26560249. Adamson PB, Abraham WT, Stevenson LW, et al. Pulmonary artery pressure-guided heart failure management reduces

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30-day readmissions. Circ Heart Fail 2016;9:e002600. https:// doi.org/10.1161/CIRCHEARTFAILURE.115.002600; PMID: 27220593. 7. Adamson PB. Pathophysiology of the transition from chronic compensated and acute decompensated heart failure: new insights from continuous monitoring devices. Curr Heart Fail Rep 2009;6:287–92. https://doi.org/10.1007/s11897-009-0039-z; PMID: 19948098. 8. Abraham WT, Compton S, Haas G, et al. Intrathoracic impedance vs daily weight monitoring for predicting worsening heart failure 100 events: results of the Fluid Accumulation Status Trial (FAST). Congest Heart Fail 2011;17:51– 5. https://doi.org/10.1111/j.1751-7133.2011.00220.x; PMID: 21449992. 9. Conraads VM, Tavazzi L, Santini M, et al. Sensitivity and positive predictive value of implantable intrathoracic impedance monitoring as a predictor of heart failure hospitalizations: the SENSE-HF trial. Eur Heart J 2011;32:2266– 73. https://doi.org/10.1093/eurheartj/ehr050; PMID: 21362703. 10. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012;125:2985–92. https://doi.org/10.1161/ CIRCULATIONAHA.111.088971; PMID: 22626743. 11. Maurer MS, Adamson PB, Costanzo MR, et al. Rationale and

12.

13.

14.

15.

design of the Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy Study (LAPTOP-HF). J Card Fail 2015;21:479–88. https://doi.org/10.1016/j.cardfail.2015.04.012; PMID: 25921522 Adamson PB, Gold MR, Bennett T, et al. Continuous hemodynamic monitoring in patients with mild to moderate heart failure: results of the reducing decompensation events utilizing intracardiac pressures in patients with chronic heart failure (REDUCEhf) trial. Congest Heart Fail 2011;17:248–54. https://doi.org/10.1111/j.1751-7133.2011.00247.x; PMID: 21906250. Angermann CE, Assmus B, Anker SD, et al. Safety and feasibility of pulmonary artery pressure-guided heart failure therapy: rationale and design of the prospective CardioMEMS Monitoring Study for Heart Failure (MEMS-HF). Clin Res Cardiol 2018;107:991–1002. https://doi.org/10.1007/s00392018-1281-8; PMID: 29777373. Bernocchi P, Vitacca M, La Rovere MT, et al. Home-based telerehabilitation in older patients with chronic obstructive pulmonary disease and heart failure: a randomised controlled trial. Age Ageing 2018;47:82–8. https://doi.org/10.1093/ageing/ afx146; PMID: 28985325. Frederix I, Vanderlinden L, Verboven AS, et al. Long-term impact of a six-month telemedical care programme on mortality, heart failure readmissions and healthcare costs in patients with chronic heart failure. J Telemed Telecare 2019;25:286–93. https://doi.org/10.1177/1357633X18774632; PMID: 29742959.

Letter to the Editor

High-flow Nasal Cannula Oxygenation Revisited in COVID-19 Aniket S Rali, Krishidhar R Nunna, Christopher Howard, James P Herlihy and Kalpalatha K Guntupalli Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, US

Disclosure: The authors have no conflicts of interest to declare. Received: 10 April 2020 Accepted: 11 April 2020 Citation: Cardiac Failure Review 2020;6:e08. DOI: https://doi.org/10.15420/cfr.2020.06 Correspondence: Aniket S Rali, 7200 Cambridge St, A 10.189, BCM 903, Houston, TX 77030, US. E: aniketrali@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Dear Editor, As of 31 March 2020, the Centers for Disease Control has reported a total of 163,593 confirmed coronavirus disease 2019 (COVID-19) cases and 2,860 COVID-19-related deaths in the US. According to several public health predictive models, these numbers are expected to continue to rise in the upcoming weeks, leading to a nationwide shortage of hospital beds and especially intensive care unit (ICU) beds. Owing to its predominantly respiratory manifestations, including acute respiratory distress syndrome (ARDS), one of the treatment modalities that is expected to run short is mechanical ventilators. A case series of 138 COVID-19 patients from Wuhan, China showed that a total of 36 (26%) patients required ICU level care, of whom 22 (61%) developed ARDS and 17 (47.2%) required invasive mechanical ventilation.1 Other retrospective analyses have reported similarly that 20–31% of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) patients develop ARDS and require ICU care.2–4 Therefore, it is critical that we explore the utility and safety of other forms of respiratory support devices, including high-flow nasal cannula oxygenation (HFNCO) in the treatment of acute respiratory failure. In the above mentioned case series from China, 4 (11%) of the patients admitted to the ICU were successfully treated with HFNCO (Figure 1).1 Similarly, in other case series of 191 COVID-19 patients, 41 (21%) were treated with HFNCO (33 in ICU and 8 in non-ICU).4 We present a case of a SARS-CoV-2-positive patient with acute respiratory failure who was successfully treated with HFNCO. We also discuss the mechanisms of action, clinical effects, and available literature on the efficacy and safety of HFNCO, including the risk of aerosolising SARS-CoV-2 particles.

examination was significant for respiratory distress, with use of accessory muscles and crackles in bilateral lung bases upon auscultation. Chest X-ray showed bilateral multifocal hazy interstitial opacities (Figure 2). Respiratory viral panel, including influenza, was negative, but a SARS-CoV-2 polymerase chain reaction test that was sent while the patient was in the ED returned positive on day 4. The patient was initially admitted to the progressive care unit under droplet and contact precautions pending SARS-CoV-2 test results, and ceftriaxone and azithromycin were initiated for presumed communityacquired pneumonia. On day 3, his hypoxic respiratory failure worsened, requiring high-flow nasal cannula at 40 l/min and 90% fractional inspired oxygen, (FiO2) and he was transferred to the medical ICU. The infectious diseases team was consulted and the patient commenced a 5-day course of lopinavir/ritonavir and hydroxychloroquine once the SARS-CoV-2 test was confirmed to be positive. Over the next 5 days, the patient was gradually weaned to room air. When he was haemodynamically stable, he was discharged with instructions to continue self-isolation at home for 14 additional days.

Discussion Our report discusses a COVID-19 patient who presented with acute respiratory failure with moderate ARDS, in whom endotracheal intubation was prevented; the patient was successfully treated on HFNCO. The physiological benefits of HFNCO are improved oxygenation, decreased anatomical dead space, decreased metabolic demand of breathing, decreased production of carbon dioxide, superior comfort and improved work of breathing, positive nasopharyngeal and tracheal airway pressure and better secretion clearance.

A 51-year-old man presented to the emergency department (ED) with a 1-week history of worsening dyspnoea, fevers and non-productive cough in light of negative influenza testing at his primary care physician’s office. The patient had no travel history, but reported contact with international clients through his work.

First, the most important clinical benefit of HFNCO is that of efficient supplemental oxygen delivery. HFNCO therapy generates a flowdependent FiO2.5 HFNCO therapy is able to maintain a high FiO2 by delivering flows higher than the spontaneous inspiratory demand, thus minimising room-air entrainment. In order to maximise the benefit of HFNCO, the flow rate must be titrated to match the patient’s inspiratory demand and severity of respiratory distress.

His vital signs at the time of presentation were oral temperature of 99.7°C, heart rate of 105 BPM, respiratory rate of 35, blood pressure of 113/99 mmHg and oxygen saturation of 80% of room air. His physical

Second, HFNCO is also able to decrease anatomic dead space by washing CO2 out of the upper airways. Reduction in anatomic dead space then leads to improved work of breathing and lower

Case Presentation

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High-flow Nasal Cannula Oxygenation in COVID-19 Figure 1: High-flow Nasal Cannula Oxygenation Device

Figure 2: Chest X-ray Showing Diffuse Bilateral Ground Glass Opacities

Flow meter Air/oxygen blender Nasal cannula

Heated inspiratory circuit

Active humidifier

An air/oxygen blender, allowing 90% fractional inspired oxygen, ranging from 0.21 to 1.0, generates flows of up to 60 l/min. The gas is heated and humidified by an active heated humidifier and delivered via a single limb.

respiratory rates. Mauri et al. demonstrated this effect in their study of hypoxemic patients with arterial partial pressure of oxygen to FiO2 ratios <300, where high-flow nasal cannula set at 40 l/min significantly reduced work of breathing and respiratory metabolic demand compared with oxygen delivered by face mask at 12 l/min.6 Therefore, patients with hypercarbia, in addition to hypoxaemia, gain benefit from HFNCO, not only through reduction in anatomic dead space but also through reduced CO2 production via lowered metabolic demand. Third, HFNCO further reduces the work of breathing by optimally conditioning the delivered gas by warming and humidifying it to physiological conditions. This spares the body the energy cost of warming and humidifying inspired gas. Warm humid gas is also associated with better conductance and pulmonary compliance compared to dry and cooler gas. It also improves mucociliary function, thereby facilitating secretion clearance, decreasing risk of atelectasis and improving the ventilation/perfusion ratio and oxygenation. Finally, HFNCO generates low-level positive pressure, which increases lung volumes and improves gas exchange. While alveolar recruitment results from the positive airway pressure, the magnitude of this effect is variable, and its clinical significance remains somewhat controversial. However, studies have estimated the positive pressure delivered through HFNCO to equal roughly 1 mm H2O for every 10 l of flow.7,8 In order to maximise the above-mentioned benefits of HFNCO, it is

Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. https://doi.org/10.1001/ jama.2020.1585; PMID: 32031570; epub ahead of press. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–13. https://doi.org/10.1016/S01406736(20)30211-7; PMID: 32007143. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020;368:m606. https://doi.org/10.1136/bmj.m606; PMID: 32075786. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for

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imperative to maintain the flow at the highest tolerated by the patient, usually at least 30–40 l/minute. One potential concern that has been raised about the use of HFNCO in COVID-19 patients is that it could aerosolise the respiratory tract pathogen. Using evidence from several recently published studies, the WHO concluded that HFNCO does not create widespread dispersion of exhaled air, and therefore, should be associated with low risk of transmission of respiratory viruses.9 They do recommend wearing a standard medical face mask if a medical provider is within 2 m of the patient. However, a newer study showed that the distance of droplet dispersion from coughing increases by an average of 0.42 m with highflow nasal cannula, and travelled further than the WHO-recommended 2-m safe exclusion zone.10 Based on this evidence, at our institution we ensure that COVID-19 patients on HFNCO are at the least in singleoccupancy rooms with either negative pressure or high-efficiency particulate air filtration systems, and that all our healthcare workers caring for those patients wear full airborne personal protective equipment (i.e. N95 masks or equivalent, gown, gloves, goggles, hair covers and face shields).

Conclusion HFNCO is an effective treatment modality for COVID-19-associated acute respiratory failure. Particularly in patients with mild to moderate ARDS and in negative pressure rooms, it could be a viable initial alternative to mechanical ventilation.

mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054–62. https://doi.org/10.1016/S0140-6736(20)30566-3; PMID: 32171076. Sztrymf B, Messika J, Bertrand F, et al. Beneficial effects of humidified high flow nasal oxygen in critical care patients: a prospective pilot study. Intensive Care Med 2011;37:1780–6. https://doi.org/10.1007/s00134-011-2354-6; PMID: 21946925. Mauri T, Turrini C, Eronia N, et al. Physiologic effects of highflow nasal cannula in acute hypoxemic respiratory failure. Am J Respir Crit Care Med 2017;195:1207–15. https://doi.org/10.1164/ rccm.201605-0916OC; PMID: 27997805. Parke RL, Eccleston ML, McGuinness SP. The effects of flow on airway pressure during nasal high-flow oxygen therapy. Respir Care 2011;56:1151–5. https://doi.org/10.4187/respcare.01106; PMID: 21496369.

Parke RL, McGuinness SP. Pressures delivered by nasal high flow oxygen during all phases of the respiratory cycle. Respir Care 2013;58:1621–4. https://doi.org/10.4187/respcare.02358; PMID: 23513246. 9. WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance. Geneva: WHO, 2020. https://www.who.int/ publications-detail/clinical-management-of-severe-acuterespiratory-infection-when-novel-coronavirus-(ncov)-infectionis-suspected (accessed 13 April 2020). 10. Loh NW, Tan Y, Taculod J, et al. The impact of high-flow nasal cannula (HFNC) on coughing distance: implications on its use during the novel coronavirus disease outbreak. Can J Anaesth 2020. https://doi.org/10.1007/s12630-020-01634-3; PMID: 32189218; epub ahead of press.

COVID-19

Cardiovascular Clinical Trials in a Pandemic: Immediate Implications of Coronavirus Disease 2019 Ernest Spitzer,1,2 Ben Ren,1,2 Jasper J Brugts,1,2 Joost Daemen,1,2 Eugene McFadden,2,3 Jan GP Tijssen2,4 and Nicolas M Van Mieghem1,2 1. Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands; 2. Cardialysis, Clinical Trial Management and Core Laboratories, Rotterdam, the Netherlands; 3. Department of Cardiology, Cork University Hospital, Cork, Ireland; 4. Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

Abstract The coronavirus disease 2019 (COVID-19) pandemic started in Wuhan, Hubei Province, China, in December 2019, and by 24 April 2020, it had affected >2.73 million people in 185 countries and caused >192,000 deaths. Despite diverse societal measures to reduce transmission of the severe acute respiratory syndrome coronavirus 2, such as implementing social distancing, quarantine, curfews and total lockdowns, its control remains challenging. Healthcare practitioners are at the frontline of defence against the virus, with increasing institutional and governmental supports. Nevertheless, new or ongoing clinical trials, not related to the disease itself, remain important for the development of new therapies, and require interactions among patients, clinicians and research personnel, which is challenging, given isolation measures. In this article, the authors summarise the acute effects and consequences of the COVID-19 pandemic on current cardiovascular trials.

Keywords COVID-19, SARS-CoV-2, clinical trials, cardiovascular, monitoring, regulatory agencies Disclosure: The authors have no conflicts of interest to declare. Received: 17 April 2020 Accepted: 21 April 2020 Citation: Cardiac Failure Review 2020;6:e09. DOI: https://doi.org/10.15420/cfr.2020.07 Correspondence: Ernest Spitzer, Thoraxcenter, Erasmus University Medical Center, ‘s-Gravendijkwal 230, 3015 CE, Rotterdam, the Netherlands. E: ernest.spitzer@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The coronavirus disease 2019 (COVID-19) pandemic started in Wuhan, Hubei Province, China, in December 2019, and by 24 April 2020, it had affected >2.73 million people in 185 countries and caused >192,000 deaths.1 The pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was believed to have reached humans through a zoonotic infection.2 SARS-CoV-2 is the third coronavirus outbreak in two decades, following the SARS-CoV outbreak in November 2002 in Foshan, Guangdong, China, which was subsequently contained, and the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in 2012. All three have bats as the primary reservoir, but unlike SARSCoV and MERS-CoV, where the civet cat and the camel have been detected as the intermediary hosts, respectively, this remains unknown for SARS-CoV-2.3 COVID-19 is characterised by flu-like symptoms, such as fever, cough and shortness of breath. Approximately 15–20% of COVID-19 cases evolve into severe diseases, such as pneumonia, that require hospital admission, and approximately 5% of patients develop critical conditions, such as acute respiratory distress syndrome, requiring ventilatory support, as well as multiorgan failure and death.4 Epidemiologically, these three coronaviruses share a similar incubation time (mean of ~5 days). MERS-CoV leads to death in one-third of cases and SARS-CoV in one-tenth; for SARS-CoV-2, reports indicate rates between 2% and 11% in confirmed cases.1,3 Notably, testing has been restricted to hospitalised patients in many territories. The basic

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reproduction number or new cases caused by one infected person characterises the virus spread (R0 = R nought).5 If R0 <1, the transmission is likely to stop. If R0 >1, there is a high risk of epidemic spread if there is not timely and effective containment. Although MERS-CoV has not been contained, it is currently controlled, due to R0 ~1. In contrast, SARS-CoV had an R0 ~4, and reached 29 countries and a total of 8,096 cases, with the last cases reported in May 2004.6 The reported R0 for SARS-CoV-2 is ~3; however, its current spread may indicate this to be higher.7,8 Importantly, the fact that infected individuals could become contagious before developing symptoms may augment R0. Despite diverse societal measures to avoid the spread of SARS-CoV-2, such as social distancing, self-isolation, quarantines, curfews and total lockdowns, which limit spread significantly, its control seems yet remote. With the number of COVID-19 patients increasing exponentially, and a significant minority requiring hospitalisation and intensive care support,4 hospitals have massively reallocated resources to the pandemic, reduced elective care activities and limited the availability of investigators and research personnel to continue activities for ongoing clinical trials. Moreover, coordinating centres and sponsors in affected countries have shifted to home-based organisations, requiring adaption of operations to the current crisis. In addition, participants in clinical trials may not be able to attend hospitals for follow-up visits or to collect study medications. A careful and periodic risk assessment by

Cardiovascular Clinical Trials and COVID-19 sponsors and investigators is required to preserve the safety of trial participants (and employees) and the integrity of trials. In this article, we summarise the immediate implications of the COVID-19 pandemic on ongoing cardiovascular trials.

Figure 1: Impact of a Pandemic on the Conduct of Cardiovascular Clinical Trials

Trial participants

Regulatory Framework This review incorporates recent recommendations from the US Food and Drug Administration (FDA), the European Medicines Agency, the UK’s Medicines and Healthcare products Regulatory Agency and Australia’s Therapeutic Goods Administration, as well as personal views.9–14

Basic Principles Planning, executing and reporting clinical trials designed for the approval of (or to extend indications for) drugs, biological products, devices and combinations thereof, are highly regulated activities. Clinical trialists must observe national regulations, as well as international standards, such as those proposed by the International Conference of Harmonization, the International Organization for Standardization and the International Medical Device Regulators Forum. Two general principles governing the execution of clinical trials are ensuring patient safety and clinical trial integrity. According to the WHO, patient safety is “the absence of preventable harm to a patient during the process of health care and reduction of risk of unnecessary harm associated with health care to an acceptable minimum.”15 As defined by the FDA, data integrity refers to “the completeness, consistency, and accuracy of data. Complete, consistent and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy and accurate (ALCOA).”16 Data are to be recorded exactly as intended, and when retrieved at a later time, should be the same as originally recorded. While patient safety is paramount, both should be prioritised for the successful execution of clinical trials. If data integrity is compromised, study results may no longer be interpretable, reliable or usable.

Impact of a Pandemic on the Conduct of Clinical Trials A pandemic has the potential to directly impact all individuals and organisations involved in clinical research (Figure 1). Highly contagious and rapidly spreading viruses, such as SARS-CoV-2, require comprehensive measures to avoid human-to-human spread. With the ongoing pandemic, the world has progressively witnessed a reduction of airline activity to almost zero with widespread travel bans, and limitation of private and public transportation, temporary closure of retail businesses, banning of public gatherings and the requirement to work from home. All these measures are designed to limit exposure to potential carriers of the virus. Individual measures, such as meticulous hand hygiene, self-isolation and social distancing, are encouraged. Public measures, such as quarantines, curfews or lockdowns, have been implemented. However, sectors, such as healthcare, food supply chains, law enforcement, governmental agencies and regulatory bodies, remain indispensable, with an increased workload challenging the capacity of local and national systems, as well as risking (if not sufficiently protected) the well-being of individuals. Overall, the majority of people stay at home, work remotely and limit use of healthcare systems as much as possible.

Impact on the Clinical Trial Life Cycle The clinical trial life cycle can be divided into trial design and registration, trial start-up, enrolment, follow-up, reporting and regulatory submission.

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Healthcare professionals (including local investigators)

Hospitals and other investigational sites

Regulatory agencies

Ethics committees

Sponsors and manufacturers

Coordinating centres and monitors Safety reporting units

Research staff

Steering and executive committees

Core laboratories

Independent committees

For non-pandemic-related trials that have not yet started, feasibility should be critically assessed, and postponement strongly considered (Figure 2). For trials that are enrolling, activation of new sites should be postponed. Moreover, given that enrolment requires adequate assessment of eligibility, including protocol-required tests and written informed consent procedures, enrolment should be suspended or, if possible, slowed down. Follow-up visits should be performed via telehealth when possible. Extension of follow-up periods may be required to facilitate complete data collection. The reporting of adverse events should continue as usual.9–11,13,14 The reporting of trial results is encouraged through virtual international conferences. Overall, priority is given to pandemic-related clinical trials. Changes in trial conduct should be documented and, if substantial, incorporated as protocol amendments (although not in an expedited manner unless impacting on patient safety); lesser changes may be captured as protocol deviations related to the pandemic. Regulatory agencies offer a diverse range of flexibility in such procedures, and applicable guidance documents should be consulted to establish the most appropriate approach for a particular trial.9–11,13,14 Trial enrolment should be put on hold or stopped if there is significantly reduced feasibility (e.g. drug trials with infusions), when participants require intensive care post-treatment (e.g. surgical trials) or when the investigator is unavailable. When inclusion is delayed by the pandemic, it should be dealt with in a similar manner to other circumstances that lead to a low recruitment rate. If appropriate, and especially if foreseen by the protocol, a data and safety monitoring board may assess futility due to severe impact on data collection or outcomes. However, if stopping or putting on hold a trial puts participants at increased risk, efforts should be taken to continue with trial-related activities.

Impact on Trial Participants Enrolment in cardiovascular trials generally takes place at outpatient visits or during hospitalisation. Trials in patient populations with acute presentations (e.g. ST-elevation MI [STEMI]) may identify potentially suitable trial candidates; however, the capacity to comply with study procedures needs to be assessed, as well as considerations related to patient safety during follow-up. It is also pertinent to consider that COVID-19 may mimic some classical presentations, such as STEMI; ECG changes are shown to reflect myocarditis, after angiography demonstrates non-obstructive disease. It is problematic when the trial design mandates a protocol-related treatment before angiography. Furthermore, the analysis of outcomes may be rendered more

COVID-19 Figure 2: Recommendations for Cardiovascular Clinical Trials During a Pandemic

Ongoing trials

TRIAL LIFE CYCLE

Perform riskâ&#x20AC;&#x201C;benefit assessment. Decide to continue with or without changes, to put on hold or stop trials. Evaluate feasibility of protocol adherence or need for modification. Evaluate capacity to continue trials based on human resources, logistics and drug distribution. Limit enrolment.

Safety reporting and data and safety monitoring boards

SAFETY OVERSIGHT

Periodic meetings in clinical trials

New trials

Prioritise pandemic-related research, as evidence-based treatments are lacking. Incorporate measures that limit physical contact between researchers and participants. Consider novel approaches that allow remote data capture and remote monitoring.

MEETINGS AND COMMITTEES

PROTOCOL ADHERENCE AND REPORTING

COVID-19 and trial participants TRIAL PARTICIPANTS

Participants should inform the research team if they are experiencing symptoms suggestive of COVID-19, if they have been in contact with COVID-19 patients. Advice should be given for adequate triage and management of potential SARS-CoV-2 infection.

Investigational sites have reduced capacity, and measures should be taken to avoid excessive workload. Investigators should ensure adequate oversight and communication with participants. Adequate documentation of protocol deviations is required.

Remote site management and monitoring could be considered, if feasible (i.e. privacy issues and site workload are considered). Consider virtual visits, telemedicine, electronic consent or teletrials. Change site location outside the hospital. Deliver medication to homes.

Ongoing activities during a pandemic COORDINATING CENTRES

Healthcare professionals and research staff

RESEARCH STAFF

Consideration should be given to changes that limit the exposure of participants, investigators and staff to SARS-CoV2; changes in enrolment and testing. Reporting should differentiate between pre-pandemic, peri-pandemic and post-pandemic, as well as COVID-19 positivity/negativity.

Novel trial approaches that reduce physical contact

NOVEL APPROACHES

Recruitment in non-pandemic-related trials

Patients should be discouraged from attending areas with a high density of COVID-19 patients, due to the risk of contracting and spreading the virus. However, with adequate protection measures, enrolment might be considered for life saving interventions, if feasible.

All meetings should be remote, by means of teleconference/ video conferencing. Steering committee calls, investigator meetings, endpoint adjudication committees and DSMBs should meet remotely with appropriate technology in place.

Protocol amendments, deviations and reporting

Communication with trial participants

The safety of trial participants and their families is paramount. Participants should be informed of change in follow-up (i.e. calls instead of visits, postponement of tests). Participants should be given the option to continue, suspend or withdraw participation.

Reporting of sever adverse events is expected to continue according to standard procedures and regulation. DSMBs may be appointed to determine feasibility of continuing trials based on overall conduct, patient safety and date integrity.

Clinical research organisations need to swiftly transition into home-based organisations and increase level of oversight to deliver urgent and ongoing responsibilities. Remote systems need to be upgraded to allow adequate online execution and oversight.

Ongoing core laboratory activities during a pandemic

CORE LABORATORIES

Core laboratories continue operations utilising virtual environments to analyse and review materials. Remote analysts and supervisors utilise secure platforms with access to required validated analysis software and study datasets. Continued ICT support is pivotal.

COVID-19 = coronavirus infectious disease 2019; DSMB = data and safety monitoring board; ICT = information and communications technology; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

difficult, and parallel analyses of the intention-to-treat and per protocol populations will be pertinent. Participants in the follow-up phase (when they are generally at home) constitute a higher-risk population in the COVID-19 pandemic. In addition, with isolation measures, participants have limited access to investigational sites. Therefore, a switch to telehealth (with data protection measures in place) should be considered, as well as postponement/cancellation of face-to-face visits. Ascertainment of primary endpoints should be prioritised, and if these need a particular test, consideration should be given to local laboratories or imaging centres closer to the participantâ&#x20AC;&#x2122;s home. Postponing or changing follow-up or study intervals/windows, or not performing secondary assessments, may be considered. Importantly, a common approach to follow-up during the pandemic should be agreed upon among sponsors and investigators, and investigators should inform trial participants of any changes by means of newsletters or individual communications, including aspects affecting follow-up visits. Communication is critical. When adjusting visits or study procedures, the patient perspective must be captured. More specifically, participants may need to re-consent after being informed of the changes with the explicit possibility of stopping participation. Notwithstanding, participants should not visit investigational sites for the purpose of re-consenting. An alternative approach is a video call supplemented with a confirmatory email.11 Drug trials add the complexity of drug supply and the need to maintain blinding. Consideration should be given to shipping drugs directly to homes from the investigational sites, ensuring that transportation and storage conditions are appropriate. Drug accountability and compliance should be monitored.9,11,13,14

Impact on Healthcare Professionals and Research Staff General medical practices, emergency departments and intensive care or pulmonary units are most exposed to direct contact with known COVID-19 patients. An excessive workload is also evident in imaging, laboratory and pharmacy departments, as well as other departments supporting the care of hospitalised COVID-19 patients, generally elderly people with accompanying comorbidities. Healthcare professionals from every discipline have been called upon to fight the pandemic, including retired professionals and those who have just completed formal education. Additionally, at some sites, research personnel with relevant accreditation are assigned to patient care at COVID-19 clinics. Running clinical trials at hospitals requires the oversight of a principal investigator; the involvement of collaborators, including research fellows; and the execution of trial activities by research staff. All might become unavailable due to duties associated with the pandemic, such as the need to remain at home for parental responsibilities or due to COVID-19 infection. Communication is pivotal. Principal investigators should ensure adequate trial oversight and communication with trial participants. The unavailability of the principal investigator should be reported to the coordinating centre and sponsor, and delegation or a designated replacement communicated to ethics committees and applicable local authorities.9,11,13,14 Reduced capacity at investigational sites will impact on availability to perform study visits (or phone calls) to assess and confirm eligibility, enter data in electronic case report forms (eCRFs), to report (serious) adverse events and to follow the protocol in general. All protocol deviations should be noted, with those that are pandemic related clearly

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Cardiovascular Clinical Trials and COVID-19 identified. Most importantly, principal investigators must ensure that enrolled subjects fully comply with eligibility criteria and that all measures are taken to report adverse events in a timely fashion, given that these two are of paramount importance for patient safety. Coordinating centres may require an increased level of monitoring of eCRFs and a degree of flexibility in terms of timing for data cleaning.9,11,13,14

Impact on Coordinating Centres and Monitors Large, multicentre collaborative trials require the participation of a coordinating centre, either a contract or an academic research organisation. Coordinating centres execute the study, or activities within, on behalf of the sponsor or manufacturer. A study team is composed of a project manager, clinical research associates and study monitors, data managers, biostatistician, quality assurance manager and safety reporting units, with or without a medical monitor. A pandemic prompts the need to work from home and cancel face-toface visits. Where systems are upgraded to allow remote work and staff remain available for reception of materials, coordinating centres can continue to operate during a pandemic. Site initiation and monitoring visits are cancelled, postponed or performed remotely using webbased technology (although source data verification can be postponed). Remote monitoring is possible, but might not be feasible at all participating sites in a trial and increases the workload at the site. Moreover, technical requirements, confidentiality issues, updated consents and the increased burden to site personnel could make it impractical.13 In line with this, quality assurance measures, such as site audits, are postponed unless serious non-compliance is identified.

Impact on Trial Committees The participation of several committees in clinical trials ensures proper scientific and operational oversight, data integrity and quality, as well as patient safety. Typically, the steering committee is composed of established investigators or key opinion leaders, and representatives from parties involved (e.g. coordinating centres, sponsor, grant givers). During the pandemic, office-based professionals work from home, and participation may be limited. Nevertheless, given the oversight duties of the steering committee and data and safety monitoring boards, the frequency of meetings might need to be increased to address immediate pandemic-related needs. At the beginning of the pandemic, cardiovascular clinicians saw a reduction in patient load, as the population was advised to stay at home. Unfortunately, this has resulted in late presentations of severe conditions (e.g. non-STEMI or decompensated heart failure). However, as hospital resources are depleted, not only in materials but also in personnel, cardiovascular clinicians are required to perform pandemic-related tasks and to self-isolate, potentially limiting their availability for participation in committees. The same applies to members of clinical event committees and data and safety monitoring boards. Potential exceptions are data managers and biostatisticians. In theory, this could reduce the availability of clinicians to participate in committee calls; however, in practice, this might not be the case. Committed investigators tend to stretch time when required, as shown by Chinese investigators who managed to report initial cohorts despite being at the centre of the pandemic.2,4 All meetings are planned as teleconferences.

Impact on Core Laboratories Cardiovascular trials, particularly interventional trials, rely heavily on imaging. For the purpose of an unbiased and consistent analysis, central laboratories are utilised. Imaging modalities, such as

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echocardiography, ECG, cardiac MRI, angiography assessments, intracoronary imaging and cardiac CT, are frequently used. Thus, for a core laboratory to ensure timely delivery during a pandemic, conditions should allow analysts and supervisors to work remotely. Data should reach core laboratories electronically, with secure and certified datatransfer providers. Time windows for imaging follow-up might need to be adjusted and uploading activities may also be interrupted. Analysing cardiovascular images might not be as efficient at home when compared with a well-equipped work environment. However, remote access through a secure connection to software and datasets, as well as databases, will allow continuity of activities. Information and communication technology departments play a pivotal role in setting up and maintaining reliable infrastructure. A lack of remote access could force activities to stop during a pandemic.

Safety Oversight Safety reporting should continue in line with national regulations and following standard procedures.9–11,13,14 Investigators should ensure timely capture of serious adverse events, a process that might involve extended use of telehealth. Moreover, serious adverse events should be identified, where possible, as pandemic or non-pandemic related. The inability to deliver investigational drugs could pose additional risks to participants and warrants an increased level of safety monitoring.9,10 Ongoing trials lacking data and safety monitoring boards might need to revisit that decision on a per-case basis. Data and safety monitoring boards may independently assess an ongoing trial that has been severely affected by the pandemic (e.g. incomplete data, incomplete follow-up) to help investigators and sponsors elucidate, without compromising the integrity of the trial, whether continuing the trial will yield interpretable data.12

Impact on Protocol Adherence and Trial Reporting A pandemic has a significant impact on the ability to adhere to protocol requirements (e.g. missed follow-up visits or tests). Importantly, protocol deviations should be documented with an indication that they are pandemic-related following standard procedures.9,12–14 Data collection could be challenging, but should not stop. When reporting the results of a trial, cohorts might need to be divided as pre-pandemic, peri-pandemic and post-pandemic.12 Statistical analysis plans might need adaptions when considering the influence of the pandemic in the interpretability of results, especially when endpoints share characteristics with COVID-19related events.9 Guidance on the interpretability of results when analysing data with missing values, unbalanced completeness or out-of-window assessments (e.g. echocardiograms, control angiograms, laboratory values) might also be required, depending on the duration of the pandemic. For multicentre trials, a per-site assessment might be required for outbreak areas versus non-outbreak areas. The interpretability of the overall evidence generated should be discussed with regulatory authorities.9,12–14 The use of vaccines, once available, might also require adequate documentation in study databases to avoid unbalanced usage.

Impact on Ethics Committees and Regulatory Agencies Ethics committees (ECs; or institutional review boards [IRBs]) and regulatory agencies experience a significant increase in activity during a pandemic. ECs/IRBs face the burden of protocol amendments for ongoing trials, and prioritise activities related to the pandemic, including the review of COVID-19 trial submissions.9,12–14 Regulatory agencies play a critical role in protecting citizens from threats, including emerging infectious diseases, thus the importance of providing timely guidance, such as the regulatory documents that form the basis of this article.9–14

COVID-19 Based on accumulating experience, the advice of ECs/IRBs and regulatory agencies to sponsors and investigators could be critical to determine the continuation, modification or pause of trial activities. Such recommendations are complex, given the uncertainties related to the pandemic duration.

Conclusion A pandemic has a significant impact on every component of cardiovascular clinical research. When facing a rapidly spreading

Johns Hopkins University & Medicine. COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). 2020. https://coronavirus.jhu. edu/map.html (accessed 24 April 2020). Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727–33. https://doi.org/10.1056/NEJMoa2001017; PMID: 31978945. Bassetti M, Vena A, Giacobbe DR. The novel Chinese coronavirus (2019-nCoV) infections: challenges for fighting the storm. Eur J Clin Invest 2020;50:e13209. https://doi.org/10.1111/ eci.13209; PMID: 32003000. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020. https:// doi.org/10.1056/NEJMoa2002032; PMID: 32109013; epub ahead of press. Liu Y, Gayle AA, Wilder-Smith A, Rocklov J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. J Travel Med 2020;27:taaa021. https://doi.org/10.1093/jtm/ taaa021; PMID: 32052846. Liang WN, Zhao T, Liu ZJ, et al. Severe acute respiratory syndrome – retrospect and lessons of 2004 outbreak in China. Biomed Environ Sci 2006;19:445–51. PMID: 17319269.

disease with no effective treatment or vaccine, efforts should be focused on facilitating the day-to-day work of healthcare professionals with required personal protective equipment. Pandemic-related investigations should be prioritised. Nevertheless, sponsors and investigators should take all necessary actions to ensure patient (and employee) safety and to maintain trial integrity in ongoing, nonpandemic-related clinical trials, and capture pandemic-induced trial adjustments in focused amendments so that meaningful conclusions can be achieved when reporting results.

Lee PI, Hsueh PR. Emerging threats from zoonotic coronaviruses – from SARS and MERS to 2019-nCoV. J Microbiol Immunol Infect 2020. https://doi.org/10.1016/j.jmii.2020.02.001; PMID: 32035811; epub ahead of press. 8. Sanche S, Lin YT, Xu C, et al. High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2. Emerg Infect Dis 2020. https://doi.org/10.3201/eid2607.200282; PMID: 32255761; epub ahead of press. 9. US Food and Drug Administration. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency. Washington, DC: FDA, 2020. https://www. fda.gov/media/136238/download (accessed 24 April 2020). 10. US Food and Drug Administration. Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During a Pandemic. Washington, DC: FDA, 2020. https://www.fda.gov/media/72498/download (accessed 24 April 2020). 11. European Medicines Agency. Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic. Brussels: European Medicines Agency, 2020. https://ec. europa.eu/health/sites/health/files/files/eudralex/vol-10/ guidanceclinicaltrials_covid19_en.pdf (accessed 24 April 2020). 12. European Medicines Agency. Points to consider on

13.

14.

15. 16.

implications of coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials. Brussels: European Medicines Agency, 2020. https://www.ema.europa. eu/en/implications-coronavirus-disease-covid-19methodological-aspects-ongoing-clinical-trials (accessed 24 April 2020). Medicines and Healthcare products Regulatory Agency. Managing clinical trials during coronavirus (COVID-19). London: MHRA, 2020. https://www.gov.uk/guidance/managingclinical-trials-during-coronavirus-covid-19 (accessed 24 April 2020). Australian Government Department of Health. COVID-19: guidance on clinical trials for institutions, HRECs, researchers and sponsors. Canberra: DoH, 2020. https://www1.health.gov. au/internet/main/publishing.nsf/Content/Clinical-Trials (accessed 24 April 2020). WHO. Patient safety. 2020. https://www.who.int/patientsafety/ about/en/ (accessed 24 April 2020). US Food and Drug Administration. Data integrity and compliance with CGMP. Washington, DC: FDA, 2016. https:// www.fda.gov/files/drugs/published/Data-Integrity-andCompliance-With-Current-Good-Manufacturing-PracticeGuidance-for-Industry.pdf (accessed 24 April 2020).

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Heart Failure with Preserved Ejection Fraction

Abstract Patients with a broad range of systemic rheumatic diseases are at increased risk of heart failure (HF), an event that is not related to traditional cardiovascular risk factors or underlying ischaemic heart disease. The magnitude of risk is linked to the severity of arthritic activity, and HF is typically accompanied by a preserved ejection fraction. Subclinical evidence for myocardial fibrosis, microcirculatory dysfunction and elevated cardiac filling pressures is present in a large proportion of patients with rheumatic diseases, particularly those with meaningful systemic inflammation. Drugs that act to attenuate pro-inflammatory pathways (methotrexate and antagonists of tumour necrosis factor and interleukin-1) may ameliorate myocardial inflammation and cardiac structural abnormalities and reduce the risk of HF events.

Keywords Ankylosing spondylitis, heart failure with preserved ejection fraction, psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus. Disclosure: The author has no conflicts of interest to declare. Received: 23 December 2019 Accepted: 7 March 2020 Citation: Cardiac Failure Review 2020;6:e10. DOI: https://doi.org/10.15420/cfr.2019.23 Correspondence: Milton Packer, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall St, Dallas, TX 75226, US. E: milton.packer@baylorhealth.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Patients with a broad range of systemic inflammatory rheumatic diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis) are exceptionally prone to cardiovascular disorders, but previous work concerning the development of heart disease in these individuals has largely focused on the risk of MI.

dysfunction and cardiac fibrosis on cardiac imaging.10–17 This finding is not surprising; of the two main phenotypes of HF, that is, HFrEF or HF with preserved EF (HFpEF), the former is related to cardiomyocyte loss and stretch, whereas the latter is primarily related to the presence of systemic inflammatory disorders, most commonly, obesity and diabetes.18–20

However, the most important cardiovascular complication in these individuals is the development of heart failure (HF), an event that may not be readily apparent to many clinicians and is not related to traditional cardiovascular risk factors or to clinically evident ischaemic heart disease.1,2 HF develops with increasing rapidity following a diagnosis of systemic rheumatic diseases, and the magnitude of risk is related to the severity of arthritic activity.2 Typically, the four principal systemic rheumatic disorders, that is, rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis, increase the risk of new-onset HF as much as two- to threefold, when compared with the general population.2–9

Mechanisms by Which Systemic Inflammatory Disorders Cause the Phenotype of HFpEF

Importantly, both the clinical presentation and the outcome of HF differ between patients with and without these systemic rheumatic diseases. Although patients with systemic rheumatic diseases are prone to MI (a form of injury that is typically linked to HF with reduced ejection fraction [HFrEF]), the phenotype of HF in most patients with systemic rheumatic diseases is characterised by the absence of coronary artery disease (CAD) and a preserved EF, with its characteristic features of diastolic filling abnormalities, microvascular

Systemic inflammatory disorders can target the microcirculation of the myocardium, leading to microvascular endothelial dysfunction and fibrosis. The inflammatory injury can directly affect the coronary microvasculature; additionally, its effect can be mediated indirectly, because systemic inflammation promotes the expansion and biological transformation of epicardial adipose tissue (EAT), which acts as an amplifier to focus the systemic inflammatory process onto the underlying myocardium, with which it shares an unobstructed microcirculation.21,22 In healthy people, epicardial fat has the biological properties of brown adipose tissue, which combusts pro-inflammatory fatty acids and secretes adipokines (e.g. adiponectin) that suppress inflammation and nourish the heart. However, in the presence of systemic inflammation, mesenchymal cells in the epicardium proliferate and develop features of white adipose tissue, which is prone to lipolysis and causes the release of fatty acids that trigger infiltration of the tissues by macrophages, as well as the secretion of pro-inflammatory cytokines (e.g. leptin, tumour necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-1beta and resistin).22–25

Access at: www.CFRjournal.com

Heart Failure with Preserved Ejection Fraction Figure 1: Postulated Mechanisms by Which the Systemic Inflammation of Many Rheumatic Disorders can Lead to Heart Failure Systemic inflammatory rheumatic disorders

Local and systemic release of pro-inflammatory mediators

Expansion and biological transformation of epicardial adipose tissue

Cardiac inflammation, microvascular dysfunction and myocardial fibrosis

Impaired ventricular distensibility and diastolic filling abnormalities

Heart failure with preserved ejection fraction

It is therefore noteworthy that EAT mass is increased in patients with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis.26–30 The intimacy of its interface with the myocardium allows the biological derangements in epicardial fat to be readily transmitted to the neighbouring muscle.23 Acting locally, proinflammatory adipocytokines synthesised in and released from epicardial fat depots can cause a spread of the inflammatory process to underlying tissues, which includes the coronary arteries, as well as the atrial and ventricular myocardium, leading to the epicardial adipose inflammatory triad: coronary atherosclerosis, AF and HFpEF.31 The extension of inflammation to the perivascular tissues surrounding the coronary arteries likely explains the increased risk of MI in rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis.32–34 The spread of inflammation to myocardial tissues leads to microcirculatory dysfunction and rarefaction, as well as to increased deposition of collagen.35,36 MRI in patients with heightened quantities of epicardial fat reveals increases in extracellular volume, indicative of underlying myocardial fibrosis.36 If the process abuts the atria, the resulting electroanatomical remodelling and fragmentation leads to AF, thus explaining the increased incidence and prevalence of the arrhythmia in rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis.37–40 Finally, if the abnormalities in EAT adjoin the left ventricle, the microvascular dysfunction and cardiac fibrosis act together to impair the distensibility of the chamber, thereby limiting its ability to accommodate blood volume, but without a decrease in systolic function as measured by EF.41,42 The result is the HF phenotype known as HFpEF (Figure 1).

Mediating Effects of Leptin, Aldosterone and Natriuretic Peptides in the Pro-inflammatory Expansion of EAT Why does systemic inflammation cause an expansion and proinflammatory transformation of EAT? The interactions among several endogenous hormonal mediators that are known to play a role in systemic inflammation (i.e. aldosterone, natriuretic peptides and leptin) contribute importantly to the development of epicardial adiposity and inflammation.4,5 Aldosterone promotes adipogenesis

and causes an expansion and pro-inflammatory transformation of EAT,43,44 whereas epicardial adiposity is inversely related to the level of endogenous natriuretic peptides,45 presumably because natriuretic peptide signalling antagonises adipocyte hypertrophy.46 Additionally, aldosterone promotes pro-inflammatory pathways;47 mineralocorticoid receptor antagonism attenuates inflammasome activity and blocks the production of pro-inflammatory cytokines in adipocytes and macrophages.48 Conversely, endogenous natriuretic peptides also play an important role in the pathogenesis of systemic inflammatory disorders, but in a manner that opposes the actions of aldosterone. Natriuretic peptides inhibit biological pathways involved in inflammation and attenuate the production of pro-inflammatory cytokines in macrophages and adipocytes.49,50 Finally, EAT secretes leptin, which is also known to play a central role in immune responses and inflammation.51 Leptin mediates the proliferation of monocytes and their production of pro-inflammatory cytokines;51,52 circulating levels of the adipokine are elevated in systemic inflammatory states and are directly related to epicardial fat volume.53,54 Patients with obesity have increased circulating levels of aldosterone and leptin and decreased levels of natriuretic peptides.55–57 These relationships can be explained by the secretion of both aldosterone and leptin by an expanded mass of adipocytes,58 as well as by an ability of adipocytes to enhance the degradation of natriuretic peptides, either through an action to secrete neprilysin or to enhance peptide clearance.59,60 The increase in aldosterone and leptin (accompanied by the decrease in natriuretic peptides) acts to promote the systemic proinflammatory state. The interplay of these mediators may explain why obesity increases the incidence, enhances the clinical and radiographic severity and attenuates the degree of symptomatic improvement following the use of anti-inflammatory treatment in patients with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis.61–68 In patients with expanded and dysfunctional EAT, the release of leptin and aldosterone can promote inflammation, microcirculatory dysfunction and fibrosis in the underlying myocardium,69 effects that are opposed by the anti-inflammatory and antifibrotic actions of endogenous natriuretic peptides.70 The result of these interactions is an impairment of the distensibility of the left ventricle, such that blood volume is accommodated only at the expense of a disproportionate increase in cardiac filling pressures, thus leading to exertional dyspnoea and HF. These observations explain why patients with HFpEF have elevated circulating levels of leptin and aldosterone but inappropriately suppressed levels of natriuretic peptides.25,42,71 Interference with the actions of aldosterone (and possibly leptin), as well as potentiation of natriuretic peptides, has yielded structural and clinical benefits in patients with HFpEF in randomised controlled trials.72–77

Activation of Pathogenetic Mechanisms for HFpEF in Systemic Rheumatic Diseases Both rheumatoid arthritis and ankylosing spondylitis are characterised by increased levels of aldosterone in circulating blood and inflamed tissues,78,79 and spironolactone’s anti-inflammatory actions have been proposed as a treatment for these arthritides, as well as for lupus nephritis.80,81 At the same time, levels of leptin in blood (and often synovial fluid) are increased in rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis; are associated with the degree of joint and skeletal involvement; and are linked with patient-reported outcomes and measures of disease

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HFpEF in Systemic Rheumatic Diseases activity.82–93 Interestingly, high levels of leptin may identify patients with rheumatic diseases who respond poorly to anti-inflammatory treatment.94 Interestingly, increased leptin signalling may play a direct pathogenetic role in both rheumatoid arthritis and systemic lupus erythematosus by increasing the production of pro-inflammatory cytokines and autoantibodies and inhibiting immune regulation;95–99 interference with leptin signalling ameliorates the course of experimental lupus.100 Finally, the activity of neprilysin is increased at sites of joint involvement in rheumatoid arthritis,101 where it may play a role in degrading locally active natriuretic peptides and limiting their counterbalancing antiinflammatory and anti-adipogenic actions. The release of neprilysin from the expanded mass of epicardial adipocytes may further diminish the ability of natriuretic peptides to minimise local cardiac fibrosis.102 This accelerated degradation of biologically active natriuretic peptides should not be confused with increased circulating levels of N-terminal pro-B-type natriuretic peptide (an inactive prohormone) in systemic rheumatic diseases; the prohormone is indicative of cardiac stress and is not degraded by neprilysin. As a result of these proadipogenic and pro-inflammatory interactions, EAT is increased in patients with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis, and the magnitude of increase is generally proportional to the duration and severity of the underlying systemic inflammatory process.26–30 The transmission of epicardial inflammation to the underlying myocardial tissues explains why many patients with systemic rheumatic disease have coronary microcirculatory dysfunction, cardiac fibrosis, ventricular diastolic filling abnormalities, left atrial enlargement and HF in the absence of any evidence for or a history of MI or myocardial injury.1,11–17,26,103–110 Subclinical evidence for myocardial fibrosis on cardiac MRI and echocardiographic features of elevated cardiac filling pressures (as reflected by abnormal diastolic filling dynamics or abnormal left atrial geometry, and derangements in coronary microcirculatory dysfunction) are present in 30–50% of patients with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis, particularly those with meaningful systemic inflammatory activity, and these cardiac structural and functional abnormalities parallel the severity and duration of joint involvement.26,105–107,110–112 These are the hallmarks of the ventricular myopathy that underlies the development of HFpEF, and they are often undiagnosed in clinical practice.

Effect of Anti-cytokine Agents and Neurohormonal Antagonists on the Development of HF In Systemic Rheumatic Disorders If the proposed framework is valid, then interventions that directly interrupt inflammatory pathways might be useful in preventing and treating HFpEF in patients with systemic rheumatic disorders. Methotrexate exerts anti-inflammatory effects in adipose tissue and reduces cardiac fibrosis following experimental cardiac injury.113 Its use in rheumatic disorders reduces pro-inflammatory cytokines and has been associated with a lower risk of HF hospitalisations.114

Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a populationbased study over 46 years. Arthritis Rheum 2005;52:412–20. https://doi.org/10.1002/art.20855; PMID: 15692992. 2. Mantel Ä, Holmqvist M, Andersson DC, et al. Association between rheumatoid arthritis and risk of ischemic and

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The IL-1 family has been implicated in adipose tissue inflammation, and experimental inhibition has been accompanied by decreases in proinflammatory cytokines and cardiac fibrosis. In a small cross-over trial, the IL-1 antagonist anakinra reduced systemic inflammation and improved exercise capacity in patients with HFpEF.115 More impressively, in a randomised controlled trial of >10,000 patients with evidence for systemic inflammation, long-term treatment with the IL-1beta antagonist canakinumab decreased inflammatory biomarkers and the risk of hospitalisation for HF.116 The use of antagonists of TNF-alpha in the management of patients with rheumatic diseases (who are prone to HFpEF) has been associated with amelioration of myocardial inflammation, coronary microvascular dysfunction and cardiac functional abnormalities, and little change in or a reduced risk of HF events.117–121 These findings stand in contrast to concerns that the use of antagonists of TNF-alpha may exacerbate the clinical course of HFrEF (as is commonly seen following MI).122,123 If activation of the leptin-aldosterone-neprilysin axis plays a role in mediating the pro-inflammatory expansion of EAT,25 then drugs that modulate this axis could influence the course of HFpEF in patients who have rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis. Trials of mineralocorticoid receptor antagonists and neprilysin inhibitors in patients with HFpEF have not specifically targeted patients with systemic rheumatic disorders. However, it is noteworthy that these systemic rheumatic disorders are particularly common in women;124–127 and on subgroup analysis the benefits of mineralocorticoid receptor antagonists and neprilysin inhibitors have been reported to be greater in women than in men.74,128

Conclusion Many systemic inflammatory rheumatic diseases, that is, rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis and ankylosing spondylitis, are accompanied by an increased risk of HF, which begins at the onset of diagnosis and increases in proportion to the clinical severity and duration of the systemic inflammatory process. HF is not the result of accelerated CAD and ischaemic myocardial injury, but instead is related to myocardial inflammation, coronary microvascular dysfunction and fibrosis leading to HFpEF. A conceptual framework is proposed to explain the evolution of HF in these patients. Pro-inflammatory mediators characteristic of systemic inflammatory states (e.g. leptin, aldosterone and neprilysin) can cause expansion and biological transformation of EAT, leading to coronary microvascular injury and fibrosis of the underlying myocardium. EAT volume is increased in these systemic rheumatic disorders, and 30–50% of afflicted patients have subclinical evidence of cardiac inflammation, microcirculatory dysfunction and fibrosis, as well as the structural and functional features of HFpEF. Current anti-inflammatory agents that are used for the treatment of these systemic rheumatic diseases have the potential to minimise the development of cardiac involvement and thereby reduce the risk of HF. In addition, it is possible that drugs that modulate the leptin-aldosterone-neprilysin axis could modify the cardiovascular consequences of systemic inflammation and change the clinical course of HFpEF in these patients.

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Relationship between serum adipokine levels and radiographic progression in patients with ankylosing spondylitis: a preliminary 2-year longitudinal study. Medicine (Baltimore) 2017;96:e7854. https://doi.org/10.1097/ MD.0000000000007854; PMID: 28816988. 93. Gonzalez-Lopez L, Fajardo-Robledo NS, Miriam Saldaña-Cruz A, et al. Association of adipokines, interleukin-6, and tumor necrosis factor-α concentrations with clinical characteristics and presence of spinal syndesmophytes in patients with ankylosing spondylitis: a cross-sectional study. J Int Med Res 2017;45:1024–35. https://doi.org/10.1177/0300060517708693; PMID: 28534699. 94. Hambardzumyan K, Bolce RJ, Wallman JK, et al. Serum biomarkers for prediction of response to methotrexate monotherapy in early rheumatoid arthritis: results from the SWEFOT trial. J Rheumatol 2019;46:555–63. https://doi. org/10.3899/jrheum.180537; PMID: 30709958. 95. Toussirot É, Michel F, Binda D, et al. The role of leptin in the pathophysiology of rheumatoid arthritis. Life Sci 2015;140:29– 36. https://doi.org/10.1016/j.lfs.2015.05.001; PMID: 26025594. 96. Muraoka S, Kusunoki N, Takahashi H, et al. Leptin stimulates interleukin-6 production via Janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts. Clin Exp Rheumatol. 2013;31:589–95. PMID: 23622344. 97. Tong KM, Shieh DC, Chen CP, et al. Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. Cell Signal 2008;20:1478–88. https://doi. org/10.1016/j.cellsig.2008.04.003; PMID: 18501560. 98. Lourenço EV, Liu A, Matarese G, La Cava A. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci USA 2016;113:10637–42. https://doi.org/10.1073/ pnas.1607101113; PMID: 27588900. 99. Barranco C. Systemic lupus erythematosus: leptin linked to SLE. Nat Rev Rheumatol 2016;12:623. https://doi.org/10.1038/ nrrheum.2016.161; PMID: 27652502. 100. Fujita Y, Fujii T, Mimori T, et al. Deficient leptin signaling ameliorates systemic lupus erythematosus lesions in MRL/ Mp-Fas lpr mice. J Immunol 2014;192:979–84. https://doi. org/10.4049/jimmunol.1301685; PMID: 24391210. 101. Matucci-Cerinic M, Lombardi A, Leoncini G, et al. Neutral endopeptidase (3.4.24.11) in plasma and synovial fluid of patients with rheumatoid arthritis. A marker of disease activity or a regulator of pain and inflammation? Rheumatol Int 1993;13:1–4. https://doi.org/10.1007/BF00290326; PMID: 8390712. 102. Standeven KF, Hess K, Carter AM, et al. Neprilysin, obesity and the metabolic syndrome. Int J Obes (Lond) 2011;35:1031–40. https://doi.org/10.1038/ijo.2010.227; PMID: 21042321. 103. Davis JM 3rd, Lin G, Oh JK, et al. Five-year changes in cardiac structure and function in patients with rheumatoid arthritis compared with the general population. Int J Cardiol 2017;240:379–85. https://doi.org/10.1016/j.ijcard.2017.03.108; PMID: 28427850. 104. Liang KP, Myasoedova E, Crowson CS, et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis 2010;69:1665–70. https://doi.org/10.1136/ ard.2009.124362; PMID: 20498217. 105. Holmström M, Koivuniemi R, Korpi K, et al. Cardiac magnetic resonance imaging reveals frequent myocardial involvement and dysfunction in active rheumatoid arthritis. Clin Exp Rheumatol 2016;34:416–23. PMID: 27050802. 106. Aslam F, Bandeali SJ, Khan NA, Alam M. Diastolic dysfunction in rheumatoid arthritis: a meta-analysis and systematic review. Arthritis Care Res (Hoboken) 2013;65:534–43. https://doi. org/10.1002/acr.21861; PMID: 23002032. 107. Myasoedova E, Crowson CS, Nicola PJ, et al. The influence of rheumatoid arthritis disease characteristics on heart failure. J Rheumatol 2011;38:1601–6. https://doi.org/10.3899/ jrheum.100979; PMID: 21572155. 108. Mavrogeni S, Koutsogeorgopoulou L, Dimitroulas T, et al. Complementary role of cardiovascular imaging and laboratory indices in early detection of cardiovascular disease in systemic lupus erythematosus. Lupus 2017;26:227–36. https:// doi.org/10.1177/0961203316671810; PMID: 27687024. 109. Faccini A, Kaski JC, Camici PG. Coronary microvascular

dysfunction in chronic inflammatory rheumatoid diseases. Eur Heart J 2016;37:1799–806. https://doi.org/10.1093/eurheartj/ ehw018; PMID: 26912605. 110. Schillaci O, Laganà B, Danieli R, et al. Technetium-99m sestamibi single-photon emission tomography detects subclinical myocardial perfusion abnormalities in patients with systemic lupus erythematosus. Eur J Nucl Med 1999;26:713–7. https://doi.org/10.1007/s002590050442; PMID: 10398819. 111. Erre GL, Buscetta G, Paliogiannis P, et al. Coronary flow reserve in systemic rheumatic diseases: a systematic review and meta-analysis. Rheumatol Int 2018;38:1179–90. https://doi.org/10.1007/s00296-018-4039-8; PMID: 29732488. 112. Caliskan M, Erdogan D, Gullu H, et al. Impaired coronary microvascular and left ventricular diastolic functions in patients with ankylosing spondylitis. Atherosclerosis 2008;196:306–12. https://doi.org/10.1016/j. atherosclerosis.2006.11.003; PMID: 17169363. 113. Zhang Z, Zhao P, Li A, et al. Effects of methotrexate on plasma cytokines and cardiac remodeling and function in postmyocarditis rats. Mediators Inflamm 2009;2009:389720. https://doi.org/10.1155/2009/389720; PMID: 19884981. 114. Gong K, Zhang Z, Sun X, et al. The nonspecific antiinflammatory therapy with methotrexate for patients with chronic heart failure. Am Heart J 2006;151:62–8. https://doi. org/10.1016/j.ahj.2005.02.040; PMID: 16368293. 115. Van Tassell BW, Arena R, Biondi-Zoccai G, et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am J Cardiol 2014;113:321–7. https://doi.org/10.1016/j.amjcard.2013.08.047; PMID: 24262762. 116. Everett BM, Cornel JH, Lainscak M, et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 2019;139:1289–99. https://doi. org/10.1161/CIRCULATIONAHA.118.038010; PMID: 30586730. 117. Ntusi NAB, Francis JM, Sever E, et al. Anti-TNF modulation reduces myocardial inflammation and improves cardiovascular function in systemic rheumatic diseases. Int J Cardiol 2018;270:253–9. https://doi.org/10.1016/j.ijcard.2018.06.099; PMID: 30017519. 118. van Eijk IC, Peters MJ, Serné EH, et al. Microvascular function is impaired in ankylosing spondylitis and improves after tumour necrosis factor alpha blockade. Ann Rheum Dis 2009;68:362–6. https://doi.org/10.1136/ard.2007.086777; PMID: 18390569. 119. Batko B, Maga P, Urbanski K, et al. Microvascular dysfunction in ankylosing spondylitis is associated with disease activity and is improved by anti-TNF treatment. Sci Rep 2018;8:13205. https://doi.org/10.1038/s41598-018-31550-y; PMID: 30181568. 120. Heslinga SC, Van Sijl AM, De Boer K, et al. Tumor necrosis factor blocking therapy and congestive heart failure in patients with inflammatory rheumatic disorders: a systematic review. Curr Med Chem 2015;22:1892–902. https:// doi.org/10.2174/0929867322666150209160701; PMID: 25666788. 121. Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med 2004;116:305–11. https://doi.org/10.1016/j. amjmed.2003.09.039; PMID: 14984815. 122. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594–602. https://doi.org/10.1161/01. CIR.0000124490.27666.B2; PMID: 15023878. 123. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–40. https://doi.org/10.1161/01. CIR.0000077913.60364.D2; PMID: 12796126. 124. Di WT, Vergara F, Bertiller E, et al. Incidence and prevalence of rheumatoid arthritis in a health management organization in Argentina: a 15-year study. J Rheumatol 2016;43:1306–11. https://doi.org/10.3899/jrheum.151262; PMID: 27084906. 125. Fatoye F, Gebrye T, Svenson LW. Real-world incidence and prevalence of systemic lupus erythematosus in Alberta, Canada. Rheumatol Int 2018;38:1721–6. https://doi.org/10.1007/ s00296-018-4091-4; PMID: 29987494. 126. Muilu P, Rantalaiho V, Kautiainen H, et al. Increasing incidence and shifting profile of idiopathic inflammatory rheumatic diseases in adults during this millennium. Clin Rheumatol 2019;38:555–62. https://doi.org/10.1007/s10067-018-4310-0; PMID: 30259249. 127. Love TJ, Gudbjornsson B, Gudjonsson JE, Valdimarsson H. Psoriatic arthritis in Reykjavik, Iceland: prevalence, demographics, and disease course. J Rheumatol 2007;34:2082– 8. PMID: 17696270. 128. Merrill M, Sweitzer NK, Lindenfeld J, Kao DP. Sex differences in outcomes and responses to spironolactone in heart failure with preserved ejection fraction: a secondary analysis of TOPCAT trial. JACC Heart Fail 2019;7:228–38. https://doi. org/10.1016/j.jchf.2019.01.003; PMID: 30819379.

Digital Health

Artificial Intelligence, Data Sensors and Interconnectivity: Future Opportunities for Heart Failure Patrik Bachtiger,1 Carla M Plymen,2 Punam A Pabari,2 James P Howard,1,2 Zachary I Whinnett,2 Felicia Opoku,3 Stephen Janering,3 Aldo A Faisal,4 Darrel P Francis1,2 and Nicholas S Peters1,2 1. Imperial Centre for Cardiac Engineering, National Heart and Lung Institute, Imperial College London, UK; 2. Department of Cardiology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK; 3. IT Department, Imperial College Healthcare NHS, London, UK; 4. Departments of Bioengineering and Computing, Data Science Institute, Imperial College London, UK

Abstract A higher proportion of patients with heart failure have benefitted from a wide and expanding variety of sensor-enabled implantable devices than any other patient group. These patients can now also take advantage of the ever-increasing availability and affordability of consumer electronics. Wearable, on- and near-body sensor technologies, much like implantable devices, generate massive amounts of data. The connectivity of all these devices has created opportunities for pooling data from multiple sensors – so-called interconnectivity – and for artificial intelligence to provide new diagnostic, triage, risk-stratification and disease management insights for the delivery of better, more personalised and cost-effective healthcare. Artificial intelligence is also bringing important and previously inaccessible insights from our conventional cardiac investigations. The aim of this article is to review the convergence of artificial intelligence, sensor technologies and interconnectivity and the way in which this combination is set to change the care of patients with heart failure.

Keywords Artificial intelligence, data sensors, heart failure, remote monitoring, machine learning, deep learning, connected care Disclosure: The authors have no conflicts of interest to declare. Received: 4 October 2019 Accepted: 23 January 2020 Citation: Cardiac Failure Review 2020;6:e11. DOI: https://doi.org/10.15420/cfr.2019.14 Correspondence: Patrik Bachtiger, National Heart and Lung Institute, Hammersmith Hospital, Du Cane Rd, London W12 0HS, UK. E: p.bachtiger@imperial.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Although cardiovascular disease is the leading cause of death globally, an increasing proportion of patients are surviving with heart failure (HF), which is substantially increasing in incidence and prevalence.1,2 In the management of HF the indications for implanted devices have widened, resulting in more patients living with an expanding variety of sensor-enabled implanted devices than any other patient group. Patients with HF can now also take advantage of the ever-increasing availability and affordability of consumer electronic devices – both wearable and environmental. All these devices generate massive amounts of data, and the connectivity of these devices has created opportunities for pooling data from multiple sensors – so-called interconnectivity – and for artificial intelligence (AI) to provide new diagnostic, triage, risk stratification and disease management insights for the delivery of better, more personalised and costeffective healthcare. AI is also bringing important and previously inaccessible insights from our conventional cardiac investigations, which are becoming increasingly accessible outside of the hospital setting. This article reviews this convergence of AI, sensor technologies and interconnectivity and how this combination is set to change the care of

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patients with HF. This decade is tasked with the significant challenge of frontline implementation of technology-enabled care, which will first need rigorous clinical trials to validate what we have learned so far.3

Overview of Artificial Intelligence The established and emerging technologies outlined in this review all share the opportunity to collect low-cost data, passively obtained and at massive scale across populations. The subsequent datasets qualify as ‘big data’, characterised as high volume, high velocity and/ or high variety information assets that require new forms of processing to enable enhanced discovery, insight, decision-making and process optimisation. 3 The combination of possessing massive amounts of data alongside advances in computing power has marked the resurgence of AI, composed of a set of powerful tools that can analyse big data to confer previously inaccessible insights. AI is a broad term that encompasses machine-based data processing to achieve objectives that typically require human-level cognitive function, such as recognising images (Table 1). Complex datasets can now be mined with potential to identify patterns and novel representations of data beyond direct human interpretation. Through AI, paradigms across all sectors of society are being disrupted. In medicine, the most high-profile research has been

Artificial Intelligence, Data Sensors and Interconnectivity Table 1: Glossary of Terms Artificial intelligence

Machine-based data processing to achieve objectives that typically require human intelligence

Machine learning

Subdiscipline of artificial intelligence, referring to the algorithms and statistical models used to learn how to achieve objectives just from data, without using much knowledge of the underlying domain that is learned

Supervised machine learning

Uses data as input and can learn to predict a desired output. The aim is for models to ‘generalise’, that is, they can learn from (training) data so that the system can make correct predictions on unseen data. This is evaluated by using a separate test dataset. If the predicted output is categorical in nature (e.g. recognising a named disorder from ECG traces), then the problem is called classification. If the predicted output is numerical in nature (e.g. predicting potassium levels from ECG traces), then we refer to the problem as regression. Models require subsequent validation and testing using independent input data. Crucially, systems should be tested on data from different patients than the ones in the training data

Unsupervised machine learning

Identification of patterns within complex data, without the specific objective of prediction. Does not require the input data to have corresponding labels nor separate training and testing data

Deep learning

Artificial neural networks, algorithms inspired by the human brain, learn from large amounts of data (training datasets) to generate automated predictions from new inputs

Feature

Quantifiable property of the data

Training dataset

The large dataset of values for the machine learning model to learn from (model building)

Test dataset

Data that have not been seen by the model during the training process, which are used to make sure that during training the model has learned useful principles that work on cases beyond the training set, rather than simply learn to recognise particular individuals within the training set

across ophthalmology, dermatology, radiology, intensive care and mental health.4–9 Many of these studies focus on algorithm-enhanced risk prediction, diagnosis and treatment selection, but there is also significant enthusiasm for AI liberating clinical staff from tedious administrative tasks in order to spend more time with patients.10 However, despite much hype, most applications for AI in HF and medicine, in general, remain theoretical and have yet to be validated at scale in routine practice.11 Automation is not a new concept in cardiology (attempts at automated ECG interpretation date back to the 1970s).12 However, this last decade has seen significant AI breakthroughs through the use of machine learning (ML) and, more specifically, deep learning (Table 1). ML aims to learn from data in order to correctly answer a question, which is different to conventional computer programming, that is, handcrafting the answer into the system. The subfield of deep learning is modelled on a conceptual representation of networks between neurons in our brains that are exquisite at soaking up information containing data that help us generate predictions. Deep learning is responsible for nearly all currently tangible daily-life advances of AI, from image interpretation to spoken word recognition. It is a very powerful technique that is very data hungry, requiring a lot of data to work well. The power of deep learning lies in its ability to circumvent the problem of finding meaningful features in the data. Deep learning systems are capable of learning from complex data without much preprocessing (labelling) beyond the essential clean, uniform formatting that ‘denoises’ and normalises a dataset.

Abundance of Implanted Sensors in Heart Failure Cardiology has long been at the frontline of pioneering and adopting new technology. After the first cardiac pacemaker was implanted into a patient in Sweden in 1958, rapid iteration on the original prototype has made this life-saving technology available to a much larger population.13 Now cardiologists implant more sensor-enabled devices into patients than any other specialists, encompassing 1.4 million pacemakers per year.14 Patients with HF are among those who have benefited most from device-based treatments. ICDs, pacemakers and CRT have revolutionised both mortality and symptom control and comprise

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standard guideline therapy around the world. Looking forwards, HF patients will continue to have significant representation in the implanted device population, and thus likely stand to become test cases for new sensor technologies (Figure 1).

New Opportunities with Established Implanted Sensors The addition of further sensors to devices that are already being implanted poses a significant opportunity. Every cardiac pacemaker or defibrillator provides such a platform. However, clinically unutilised data could also be captured from existing pacemaker sensors. As established, physical activity is highly predictive of cardiovascular outcomes. Internal accelerometers, incorporated for the primary purpose of rate-responsive pacing, passively generate low-cost data that can serve as a surrogate of physical activity, highlighting an as-yet untapped clinical and ML opportunity that could inform interventions.15 CRT devices have already demonstrated capacity for additional sensing features, including intrathoracic impedance, which has been clinically available for over a decade. Rising impedance can be used to stratify patients into varying mortality risk and serves as a superior measure by preceding weight gain by 2 weeks, predicting an increased risk of HF hospitalisation sooner.16 The clinical utility of these current and new sensor technologies is manifest when combined with the increasing interconnectivity of implanted devices. These are mostly already capable of transmitting data to healthcare providers, with nearly 70% of patients with CRT devices using a remote monitoring feature.17 However, this is currently limited to, at best, once-daily transmission from a home-based transceiver, which in turn transmits the data through landlines or data networks to the manufacturer’s server and then on to clinical teams for action. Therefore, a rich datastream exists, but is underused, with manufacturers capable of collecting a wealth of clinically meaningful data that could be built into preventative care. Little of this datastream has been built into clinical pathways and feedback loops that benefit patients, in part because of challenges with false positives (FPs). Specifically, the high FP rate of telemedicine

Digital Health Figure 1: Overview of External and Internal Sensors Relevant to Heart Failure Patients External sensors

Internal sensors

High-power, high-functionality smartphones

Pacemakers/CRT devices Repertoire of inbuilt and capacity for additional sensors

Wearable sensors, e.g. rich variety of vital signs (including waveform BP), ECG, impedance

Pulmonary artery pressure sensor, e.g. CardioMems, Cordella

Heart failure patient

Wallet-sized ECG monitors, e.g. KardiaMobile 6 lead

Left atrial pressure sensor, e.g. V-LAP

Health-impacting Internet of Things, e.g. smart scales, motion sensors, smart home

Ingestible sensor, e.g. Proteus Digital, pill-taking adherence Data

Insight

INTERCONNECTIVITY

Artificial intelligence/machine learning Facilitated by cloud-based architecture

The interconnected nature of these devices facilitates the collection of data, which can be stored and processed in the cloud back end, facilitating machine learning or other analytic techniques to generate predictions, visualisations or decision support. These insights can then be fed back to the patient and clinical teams. BP = blood pressure.

initiatives has significantly hindered their scaling, which could be addressed by an algorithm-based method to refine identification of those most at risk.18 One approach that has navigated the challenge of FPs is testament to the value of using different data sources to inform a patient’s true clinical state. Research by Ahmed et al. in the Triage-HF Plus study showed that among patients flagged as being at high risk for HF decompensation based on CRT-D physiological data (Heart Failure Risk Score, received via CareLink, Medtronic), FPs can be mitigated through the addition of a simple telephone triage questionnaire.19 The achieved sensitivity of 98.6% demonstrates the potential of patient-centric pathways that leverage sensors, interconnectivity and data variety, where further augmentation with AI becomes a natural next step. Several previous attempts to bring rising impedance alerts into clinical pathways have failed.20,21 These studies highlight several challenges to implementation, including physician and patient adherence to remote and telemonitoring systems, reinforcing the need for human-centric design for any technology-enabled clinical pathway.

New Implanted Sensors for Heart Failure Several newer implantable sensor technologies deviate from the traditional box-and-wires design, including two for measuring pulmonary artery pressure (PAP) that are directly deployed into the pulmonary artery – one established (CardioMEMs, Abbot) and one emerging (Cordella, Endotronix). Using home transmission of PAP with an implanted pressure sensor, long-term hospital admission rates for New York Heart Association Class III HF showed significant improvements. Rates of admissions to hospital for HF were reduced in the treatment group by 33% (HR 0.67; 95% CI [0.55−0.80]; p<0.0001) compared with the control group.22 Raised left atrial pressure (LAP) is the most specific and earliest sign of impending HF exacerbation, long before clinical symptoms occur. At

the vanguard of new implantable sensor technology is a new digital, wireless, battery-less device (V-LAP, Vectorious Medical) capable of transmitting a high-resolution waveform that represents LAP.23 This device is due to undergo its first clinical trial in patients this year. Remote PAP, LAP and other monitoring carries significant setup and running costs, but this may also be a problem amenable to a ML solution by training an algorithm on the data from previous PAPmonitored patients to ‘learn’ who benefits most, thus enabling targeting the intervention to those most likely to benefit. 24,25 Use of all such devices poses significant technical challenges, particularly optimising CRT-D function, but clinical benefits could be maximised without the need for new hardware by using AI to build models capable of enhancing decision-making around implantation and optimisation.26,27

External Sensors For All Since Norman J Holter’s achievement in 1949, substantial progress has been made away from the weighty backpack that acquired the first remotely recorded ECG trace. The increasing prevalence of implanted sensor technology is now far outweighed by the ubiquity of consumerdirected wearable sensor technologies, a rapidly growing market set to achieve a net worth of US$34 billion by 2020.28 There has been rapid deployment of powerful smartphones, wearable sensor devices (e.g. smartwatches), and the healthcare Internet of Things (IoT), together providing unprecedented levels sensor feedback.29 Self-monitoring and the transmission of signals of cardiovascular status to healthcare providers is one of the defining strengths of this technology (Figure 1). Initially this was limited to measuring simple parameters, such as step count and heart rate, with subsequent progress extending to most other vital signs. Wearable healthmonitoring technologies are now usually accompanied by or integrated into a mobile phone app – technology that itself is now heavily

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Artificial Intelligence, Data Sensors and Interconnectivity integrated with a wealth of sensors.30 This increased access to and visibility of health and vital signs data is accompanied by a wider shift towards promoting self-management by giving patients online access to their health records.31

now exist that enable accurate single-lead ECG traces. The development of portable AI now makes it possible to automate detection of AF using these traces, offering opportunities for early intervention to prevent progression to HF.41

Current and New External Sensors for Heart Failure

AF is the most common arrhythmia in HF. If AF with a fast ventricular rate can be detected and treated early, this may reduce episodes of decompensated HF. In addition, those with new AF can be identified early and anticoagulation promptly instigated to prevent stroke, which causes significant morbidity and mortality.42 The diagnosis of AF has been made easier by the availability of commercial, AI-powered AFdetecting wearables (AppleWatch 4 and 5) and external sensors (Kardia, AliveCor). The latter has since advanced to six-lead ECG (KardiaMobile 6L), with 12-lead detection in development. These technologies enable patients to have more agency over their own health through prompt, automated feedback on the presence of arrhythmias. This has broad implications for enhanced diagnostic accuracy and rhythm determination â&#x20AC;&#x201C; an important area for further study and evaluation.

There are several potential early warning signs that may predict acute decompensation in HF, but many of these are not clinically detectable. The most basic, that of early morning weight, requires a patient to manually document this (often on paper). This data point has the potential to be exploited for monitoring and timely prevention of decompensation. This is already being done in some instances; Bluetooth-connected scales can upload data to a patientâ&#x20AC;&#x2122;s electronic health record (EHR) for accurate self-monitoring and healthcare provider oversight, acting as an early warning sign of deterioration that has been integrated into successful care management strategies to reduce HF admissions.32,33 Physical activity measured with implantable devices has already been shown to predict risk of hospitalisation.34 Pedometers have been surpassed by more informative accelerometers, present in most smartphones. They offer a non-invasive opportunity to monitor a patientâ&#x20AC;&#x2122;s activity level, particularly useful in the HF population where comorbidity, including the risk of falls, is the rule. 35,36 Newer external sensors for haemodynamic measurements have been developed. For example, remote dialectic sensing (ReDS, Sensible Medical Innovations) is able to use electromagnetic signals to give a numerical measurement of the degree of pulmonary congestion, allowing extrapolation of lung fluid concentration that correlates well with CT assessments of lung fluid concentrations.37 ReDS is yet to be validated for benefit against more simple (and cheaper) technologies for predicting deterioration. However, surface electrodes adapted to measure transthoracic impedance, a marker of intrathoracic fluid levels, have been shown to precede worsening HF prior to the usual go-to measure of weight gain, with a sensitivity of 76% versus 23% (p<0.0001).16 The authors of this study make several references to thoracic impedance as an important diagnostic tool. However, it is important to note that the success of this technology has been thwarted by its poor sensitivity. Peripheral, wearable equipment has seen some of the most drastic price drops in the history of the electronic goods and services sector.38 This increasing affordability also extends to hardware, such as ultrasound equipment, offering the opportunity for wider use not just of echocardiography, but also of lung ultrasonography, which may improve diagnosis of acute HF episodes.39 All of these noninvasive technologies have the potential to complement established monitoring methods and widen the capture of patients becoming sick in hospital and at home, with the promise of reducing rates and duration of hospital admission. New technologies have emerged at the intersection of implanted and external sensors, such as a pill embedded with a miniature sensor (Proteus Digital) that, when it enters the acidic environment of the stomach, emits a signal to a wearable sensor patch.40 This highlights an opportunity to monitor adherence to the medication regimens at the centre of HF management.

The Commodification of ECGs In a short space of time, consumer technology has developed to not only be able to measure most vital signs, but several technologies also

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The opportunity for near continuous ECG monitoring offers particular promise for improving early diagnosis of paroxysmal AF. This aligns with the ambition to limit development or progression of the HF syndrome by leveraging user-friendly, increasingly low-cost technologies to anticipate potential triggers (for 50% of patients with AF and HF, the arrhythmia came first).43,44 The study of the risk of short bursts of AF has mostly been limited to patients with implanted devices; populationwide representation of AF bursts, enabled by cheap wearable sensors, may help to reach clinical consensus for what constitutes a significant burden of AF activity.45

Opportunities for Heart Failure Using Artificial Intelligence Outside of implantable devices, a successful approach to external sensor technology will be one that simplifies self-monitoring by means of user-friendly hardware that integrates collecting a variety of actionable health data, allowing AI opportunities to follow naturally. Industry is already pushing ahead with this, with some large companies (General Electric) and smaller start-ups (Current Health) vying for their AI-driven multisensor monitoring devices (patches and armbands) to be adopted to facilitate the liberation of both patients and providers from the burden of actively recording and monitoring vital signs.46,47

Understanding the Heart Failure Population Achieving the goal of personalised medicine will require a granular understanding of subgroups within a population. Improving on traditional linear models, ML methods can process a diverse dataset, including sensor outputs, to unearth complex, higher-level interactions among a multitude of features to improve discrimination and predictive range with respect to HF outcomes. This can address the significant challenge of heterogeneity in the populations that make up the HF syndrome. Changes in weight, ECG, impedance, PAP and LAP can be viewed with a patient-specific reference range, instead of one-size-fitsall averages. Already, notable AI successes in HF include a ML model that draws on phenoytypic data, including echocardiogram images, to identify patients with HF with preserved ejection fraction (HFpEF).48,49 AI is not necessary to make the already relatively straightforward diagnosis of HFpEF, but could serve to better segment subpopulations into previously unidentified clusters. This could inform participant selection

Digital Health for clinical trials and, therefore, increase the chance of observing a genuine disease-modifying effect of a treatment for HFpEF, a diagnosis currently lacking in any prognostically beneficial medications. Such an approach would involve unsupervised ML, using unlabelled data, designed to find hidden patterns. This approach could also add new value to clinical trials in HF that have fallen short of expectations; for example, by identifying a subclass of patients who might benefit from specific drug treatments, including spironolactone, enalapril and sildenafil.50–52 Importantly, any AI-driven hypothesis would of course still need to be tested to a high standard using randomised controlled trials.

ECG has traditionally not been considered a good diagnostic test for asymptomatic LV dysfunction (affecting 2–5% of the population), but researchers have now trained a deep learning model using pairings of ECG and echocardiogram images, achieving good performance in the detection of LV dysfunction (sensitivity and specificity 86.3% and 85.7%, respectively) when subsequently predicting this using ECG alone.47,58 A recent study highlights an even more impressive achievement: 100% accuracy in categorising ECGs as healthy or HF, by analysis of a single ECG heartbeat using convolutional neural network models, a form of ML that can visualise to researchers what morphological features are important.59

Artificial Intelligence for Heart Failure Imaging Studies that, for example, have used cardiac MRI in the past suddenly have renewed value by being able to offer a potentially high-quality, labelled dataset with which to interrogate new AI powered research questions. Echocardiography, the diagnostic stalwart of HF, shows much promise for being enhanced by AI. Data quality will be key, and specifically with image recognition there still remains a need for humans to annotate and label the images that become the training set. ML algorithms can subsequently assist in the discrimination of physiological versus pathological patterns of hypertrophic remodeling.41 AI’s impact on echocardiography could see a convergence towards a real-time, ML-based system for automated capture and interpretation of echocardiographic images, drastically expanding accessibility, accuracy, consistency (on second scanning, the same operator will change their categorical assessment of left ventricular [LV] function 30% of the time) and affordability.53 AI may also enhance the diagnostic utility of more advanced echocardiographic techniques. Global longitudinal strain (GLS) can serve towards early detection of myocardial changes and prediction of cardiotoxicity in patients receiving cancer therapy, but is a technique that manifests the common challenges of reproducibility (operator dependence), which could be improved by AI’s potential to automate GLS calculation.54,55 Combined with a degree of AI-enabled automated interpretation and ever-cheaper ultrasound technology, the diagnostic power of echocardiography could be made accessible to a much wider pool of patients. More broadly, the advances across all modalities of cardiac imaging have been myriad, continuing to produce rich databases of diverse images and thus highlighting a wealth of opportunities for cardiac imaging to be enhanced by AI.55

New Insights Using Old Investigations AI is unearthing ways of deriving unanticipated physiological and other insights from established investigations and sensor inputs. For example, it is now possible to predict 1-year mortality from normal-appearing ECGs.56 The ECG is already known to reflect elevated potassium levels in the form of tall T waves; deep learning has taken this to the next level by being able to quantify potassium levels after the model was trained on over 1.5 million ECGs.57 This has highlighted the opportunities for ‘bloodless blood tests’. HF patients taking significant diuretic doses, as well as their clinicians, may welcome the prospect of being able to monitor the electrolytes of otherwise stable patients non-invasively and remotely through the use of ECG-sensing wearable technology. A further revolutionary application of deep learning can accurately recognise – on what to the human eye looks like a sinus rhythm ECG – patterns that indicate a propensity towards AF, therefore by proxy highlighting a cohort also at risk of developing HF.46 Furthermore, the

As ECG and other technologies become increasingly commodified, these noninvasive tools will become more prevalent in community settings. The UK’s National Health Service has highlighted community ECG facilities as a priority addition to standard care.60 Lastly, ECG data (QRS morphology, QRS duration, presence of AF) was included among a set of common clinical variables to build a ML model capable of predicting outcomes for CRT. ML demonstrated better outcome prediction than guidelines (area under the curve 0.70 versus 0.65; p=0.012).27 This could improve shared decision-making and better patient selection for a procedure with inconsistent impacts on clinical outcomes.61

Catalysing AI with Novel Data Sources It has been reported that 38% of patients will die within the first year of diagnosis of HF.62 Understanding this population on a more granular level will enable tailored disease-modifying therapies that maximise individual patient outcomes. The goal of redefining HF into clinically meaningful homogenous subclasses using AI will be aided by the burgeoning stream of data derived from sensor technologies. These inputs may be combined with other novel data opportunities, including ‘omics’ (spanning but not limited to genomics, metabolomics, proteomics and environmental exposures), along with patient-reported outcome measures and social determinants of health, thus refining how HF is characterised beyond just an echocardiographic- and symptom-based classification and facilitating a more personalised diagnosis than ever before.63 Several countries are advancing towards the mass digitisation of health records. Much like the unanticipated insight of being able to derive age and sex from ECGs using AI, access to a richer digital patient profile through EHRs could deliver AI-based insights into propensity towards developing HF that we currently could not anticipate.64 With this abundance of data, AI can serve as a means to contend with the risk of information overload, which has marked some of the present criticism of EHRs, by processing and highlighting the most salient points and assisting in workflows.10

Catalysing AI with Interconnectivity To achieve a vision of personalised medicine, the integration of sensor technology and AI will require the addition of a third feature: interconnectivity. This is not just of medical devices, but also everyday objects. This health-impacting IoT is becoming increasingly commonplace in patients’ homes, adding a wealth of new sensors, data and, therefore, opportunities for insight. The next decade will see the mass rollout of 5G internet, setting a new precedent for powerful interconnectivity between different digital technologies. This will draw heavily on cloud computing, which provides data storage and

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Artificial Intelligence, Data Sensors and Interconnectivity computing power at scale, on-demand without direct active management by the user.65 5G is predicted to enable a move towards real-time health services becoming the norm rather than the exception.66,67 Connectivity of objects used in daily life can create new sensors that can inform how patients with HF are faring; a smart, IoTenabled environment can infer when patients are not preparing meals, monitor if they are suitably mobile and if they are in safe environmental conditions.65

New healthcare technologies are often treated with suspicion by clinicians, wary of the risk of an even greater workload with further decisions and actions to be taken. This is just one of several challenges acknowledged in a recent WHO report on transitioning from innovation to implementation of digital technologies.74 Responsive reimbursement models are needed to increase adoption of new healthcare technologies, success of which also depends on a viewpoint that encapsulates tech-agnostic, patient and user-centric design.75

Challenges with the Adoption of AI and New Technologies

Future Outlook

Algorithms continue to prove themselves to be diagnostically more ‘accurate’. However, for many of these ML methods, their ‘black box’ nature makes it difficult to infer any diagnostic reasoning. This lack in interpretability of AI models marks a challenge to adoption, which is understandable when considering the risk of hidden biases in training datasets being learned by models whose output can exhibit discrimination without us realising.68 HF transcends all socioeconomic and cultural divides, thus requiring AI models to be drawn from a dataset reflecting this diversity. Ensuring training datasets are generating among a representative population is therefore essential to minimise biases. Further dealing with this Achilles’ heel of AI requires development of fair, accountable and transparent ML techniques, augmented by improved algorithmic literacy across society.69–71 As an example of a potentially more acceptable ML model, a generative adversarial network (GAN) is capable of generating synthetic data that resemble the real data. GANs are trained to capture the most defining features of the real dataset and, without compromising patients’ identity, can produce new ‘generated’ datasets capable of training a ML model for arrhythmia detection.72 Governments are slowly catching up to the new legislative questions that AI poses. Patient safety, data protection and evidence-based action should be core tenets of law-making in this area, requiring a rigorous approach that at the same time avoids reactive regulation that could stifle innovation. The likely natural progression to the capability of a real-time monitoring ‘feed’ will – especially for implanted devices with a pacing or defibrillation function – prioritise the agenda for discussing significant safety, privacy and ethical implications of being able to adjust a device’s function remotely (a capability that already exists). This will need balancing against the benefits of early intervention for adverse events, which AI will be able to predict with high accuracy. However, developing such models may be limited by the often proprietary nature of data; data sharing between researchers and device companies, in a way that incorporates informed consent from patients, needs to be prioritised to realise the full potential of AI in HF and beyond.73

WHO. The top 10 causes of death. 2018. https://www.who.int/ news-room/fact-sheets/detail/the-top-10-causes-of-death (accessed 17 March 2020). Conrad N, Judge A, Tran J, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 2018;391:572–80. https://doi. org/10.1016/S0140-6736(17)32520-5; PMID: 29174292. De Mauro A, Greco M, Grimaldi M. A formal definition of big data based on its essential features. Library Review 2016;65:122–35. https://doi.org/10.1108/LR-06-2015-0061. Ting DSW, Liu Y, Burlina P, et al. AI for medical imaging goes deep. Nat Med 2018;24:539–40. https://doi.org/10.1038/s41591018-0029-3; PMID: 29736024.

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The trifecta of interconnectivity, diverse sensor technology and AI tools sets a course towards the ultimate goal of cost-effective, clinically beneficial closed-feedback loops. AI models can offer decision support and could be enabled to run autonomously in some instances. It will be a sum of different sensor technologies and their varied data outputs that will be able to realise the full potential of any interconnected AI tool. For example, modification of therapies in HF, such as adjusting diuretic dosing, may be amenable to decision support from a ML model, trained and continually iterating at superhuman levels of accuracy by incorporating datastreams from sensors. Eric Topol, cardiologist, geneticist and digital medicine researcher, outlines how these insights will ultimately converge towards a fully automated, individualised AIdriven virtual health coach.10 Though such solutions are years away, they could not align more with the necessary paradigm shift in HF and medicine in general – away from a model of break-and-fix and towards predict and prevent. In the more immediate future, machine vision interfaces could revolutionise how proponents of HF are identified. Deep learning has demonstrated that mass screening for AF is possible by algorithmic interpretation of video from a smartphone camera.76 The capability of accurately measuring blood pressure using a smartwatch, that is, without a cuff, has been realised and is destined to become a standard feature of health-related wearables.77 Beyond the scope of this review, the convergence of genomics, digital medicine (encompassing sensors), AI and robotics will enable staff working within an ethical and legal framework to deliver a more holistic approach to personalised healthcare and disease prevention.78

Conclusion The next decade of advances in HF care will need to confront several challenges: leveraging an exponentially growing repertoire of interconnected internal and external sensors for patient benefit and processing massive, multimodal datasets with new AI tools. The opportunity lies in fostering a greater degree of empowerment for patients and improving the accuracy and efficiency of HF management. Success will depend on a human-centric approach that makes use of new technologies appropriately, without assuming they are always the right solution.

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Letter to the Editor

Cardiopulmonary Ultrasonography for Severe Coronavirus Disease 2019 Patients in Prone Position Aniket S Rali,1 Sergio Trevino,1 Edward Yang,2 James P Herlihy1 and Jose Diaz-Gomez2 1. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Baylor College of Medicine, Houston, TX, US; 2. Department of Anesthesiology, Baylor College of Medicine, Houston, TX, US

Disclosure: The authors have no conflicts of interest to declare. Received: 2 May 2020 Accepted: 3 May 2020 Citation: Cardiac Failure Review 2020;6:e12. DOI: https://doi.org/10.15420/cfr.2020.12 Correspondence: Aniket S Rali, 7200 Cambridge St, A 10.189, BCM 903, Houston, TX 77030, US. E: aniketrali@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Dear Editor,

Medical History

Case Presentation

Her medical history was significant for morbid obesity (BMI of 54), type 2 diabetes, hypertension, non-alcoholic steatohepatitis, bipolar disorder and anxiety.

A 50-year old female presented to the emergency department with a 6-day history of fever, progressively worsening cough and shortness of breath. The patient did not report any contact with anyone who had been recently unwell or had been travelling. Upon arrival to the emergency room, the patient was noted to be severely hypoxaemic by pulse oximetry (66%) and in impeding respiratory failure, so she was emergently intubated for mechanical ventilatory support. Immediately post-intubation, arterial blood gas was as follows: pH 7.34, pCO 2 31 mmHg, pO 2 60 mmHg, O 2 saturation 90%, calculated HCO 3 16 mmol/l on FiO 2 of 100% and PaO 2/FIO2 ratio of 60. Her ventilatory mode was set at controlled minute ventilation, with a respiratory rate of 24, tidal volume of 300 cc (6 cc/ ideal body weight), positive end-expiratory pressure (PEEP) of 20 cmH 2O and FiO 2 of 100%. The patient’s chest X-ray at the time of admission showed diffuse bilateral pulmonary opacities consistent with multifocal pneumonia or pulmonary oedema (Figure 1). Polymerase chain reaction (PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was sent and came back positive after 48 hours. The patient was diagnosed with severe acute respiratory distress syndrome (ARDS), so was treated with inhaled pulmonary vasodilators, neuromuscular blockade and prone-position ventilation. In addition, she was evaluated for extracorporeal membrane oxygenation (ECMO) support. Her respiratory ECMO survival prediction score was 5, which classified her as risk class II, with an expected in-hospital survival of 76%. Cardiac biomarkers of brain natriuretic peptide (BNP) and troponin were 150 pg/ml and w0.26 ng/ ml, respectively, on admission. Therefore, the critical care team deemed that the patient would benefit from ECMO. However, her underlying cardiovascular comorbidities raised concerns, such as the evaluation of volume status, cardiac function, lung and pleura evaluation, reassessment of lung recruitment with high PEEP and decision-making with regard to ECMO support. Furthermore, the results of the SARS–CoV2 test were still pending, thus the exact aetiology of her ARDS remained unclear.

Our current diagnostic options for COVID-19 suspected/confirmed patients include supine transthoracic echocardiography, supine transthoracic echocardiography, prone transthoracic echocardiography and prone transoesophageal echocardiography. Forty-eight hours after initial presentation, the patient’s PCR testing for SARS-CoV-2 returned positive, confirming the diagnosis of COVID-19.

Diagnosis and Treatment The key to the correct diagnosis, monitoring and management in this case of a patient presenting in severe acute hypoxic respiratory failure with multiple cardiac risk factors and elevated biomarkers is an appropriate utilisation of the point-of-care assessment of cardiopulmonary ultrasound. Transthoracic echocardiography (apical four-chamber view) in the prone position was performed and revealed normal right ventricular function by visual estimation (Figure 2). The left ventricular function appeared mildly decreased (estimated left ventricular ejection fraction 45–50%), which was also reflected in a left ventricular outflow tract velocity time integral of 14.5 cm and mitral annulus tissue velocity 10.2 cm/second (Figures 3 and 4). The lung ultrasonography findings included bilateral normal lung sliding, thickening of pleural lines, absence of pleural effusions and presence of 1–2 B-lines (Figures 5 and 6). The patient’s respiratory failure was not in proportion to the mild degree of left ventricular failure, and thus ARDS remained the most likely diagnosis. The decision was made to continue monitoring the patient’s clinical course with current medical therapy, and in the setting of further decompensation, transition to VV ECMO. Lung ultrasonography has been utilised in evaluation of COVID-19 patients, and the characteristic findings have included thickening of the pleural line with pleural line irregularity; B lines in a variety of patterns, including multifocal and confluent; consolidations in a variety of patterns, including multifocal small, non-translobar and translobar with occasional mobile air bronchograms; appearance of A lines during recovery phase; and pleural effusions being uncommon.1 Our patient’s

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Letter to the Editor Figure 1: Chest X-ray Showing Diffuse Bilateral Pulmonary Opacities

Figure 4: Mitral Annulus Tissue Velocity in Prone Position

Figure 5: Right Lung Ultrasound Showing Pleural Thickening and B-lines Figure 2: Transthoracic Echocardiography (Apical Four-chamber View) in the Prone Position

Figure 6: Left Lung Ultrasound Showing Pleural Thickening and B-lines Figure 3: Left Ventricular Outflow Tract Measurement in Prone Position

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Cardiopulmonary Ultrasonography for Severe COVID-19 point of care (POC) lung ultrasonography demonstrated several of these features, making COVID-19 a probable aetiology of her ARDS. While lung ultrasonography may not be able to detect lesions deep in the lung parenchyma, the peripheral lung involvement noted in COVID-19 lends itself to ultrasonography evaluation.

head. This technique allows for all apical views and for related measurements to be obtained. In the case of our patient, prone-position echocardiography was critical in establishing a non-cardiac cause of her ARF, and also helping decide the type of ECMO (VV versus VA).

Conclusion Cardiogenic pulmonary oedema (CPE) is a known cause of acute respiratory failure (ARF). Although most frequently encountered in patients with reduced ejection fraction, CPE is increasingly attributed to heart failure with preserved ejection fraction, especially among patients with known cardiovascular risk factors.2 In patients with suspected ARDS, as in the case of our patient, it is important to rule out cardiac failure or acute fluid overload as the aetiology of ARF.3 POC echocardiography is ideally suited for evaluating intravascular fluid status, as well as cardiac function.4 However, prone-position ventilation (PPV) is often considered a hindrance in obtaining transthoracic cardiac ultrasound. While technically difficult, transthoracic echocardiogram in the prone position has been previously described.5 It is performed with the patient in the left prone position, with the left arm raised above the

Peng QY, Wang XT, Zhang LN. Findings of lung ultrasonography of novel corona virus pneumonia during the 2019–2020 epidemic. Intensive Care Med 2020;46:849–50. https://doi.org/10.1007/s00134-020-05996-6; PMID: 3216634. Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:7–22. https://doi.org/10.1056/

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Prone-position echocardiography is an extremely useful diagnostic modality in caring for ARDS patients undergoing PPV. In the hands of a trained operator, it can provide a reliable evaluation of biventricular function, valvular abnormalities and intravascular volume status. Especially in COVID-19 patients, where limiting the exposure of healthcare workers and the contamination of diagnostic equipment is important, prone-position echocardiography serves as a relatively quick, bedside and non-invasive diagnostic modality that can help guide time-sensitive clinical care. Characteristic pulmonary findings on POC ultrasound can help in the diagnosis of COVID-19 while awaiting confirmatory testing. Prone-position echocardiography is an extremely useful diagnostic modality in caring for ARDS patients undergoing prone-positioning ventilation.

NEJM200101043440103; PMID 11136955. Vignon P, Repessé X, Vieillard-Baron A, Maury E. Critical care ultrasonography in acute respiratory failure. Crit Care 2016;20:228. https://doi.org/10.1186/s13054-016-1400-8; PMID: 27524204. Legras A, Caille A, Begot E, et al. Acute respiratory distress syndrome (ARDS)-associated acute cor pulmonale and patent

foramen ovale: a multicenter noninvasive hemodynamic study. Crit Care 2015;19:174. https://doi.org/10.1186/s13054-0150898-5; PMID: 25887151. Ugalde D, Medel JN, Romero C, Cornejo R. Transthoracic cardiac ultrasound in prone position: a technique variation description. Intensive Care Med 2018;44:986–7. https://doi. org/10.1007/s00134-018-5049-4; PMID: 29349690.

Digital Health

Would You Prescribe Mobile Health Apps for Heart Failure Self-care? An Integrated Review of Commercially Available Mobile Technology for Heart Failure Patients Andrea Mortara,1 Lucia Vaira,2 Vittorio Palmieri,3 Massimo Iacoviello,4 Ilaria Battistoni,5 Attilio Iacovoni,6 Francesca Macera,7 Daniele Pasqualucci,8 Mario Bochicchio2 and Renata De Maria9 1. Department of Cardiology, Monza Polyclinic, Monza, Italy; 2. Department of Engineering for Innovation, University of Salento, Lecce, Italy; 3. Department of Cardiac Surgery and Transplantation, AORN dei Colli Monaldi-Cotugno–CTO, Naples, Italy; 4. Cardiology Unit, Cardiothoracic Department, University Hospital Policlinico, Bari, Italy; 5. SOD Cardiology–Haemodynamics–UTIC, Department of Cardiovascular Sciences, University Hospital Azienda, United Hospitals of Ancona, Ancona, Italy; 6. Cardiovascular Department, ASST Pope John XXIII Hospital, Bergamo, Italy; 7. Cardiology, Heart Failure and Transplantation, ASST Great Metropolitan Hospital Niguarda, Milan, Italy; 8. SC Cardiology, AOG Brotzu–San Michele, Cagliari, Italy; 9. National Research Council, Institute of Clinical Physiology, ASST Great Metropolitan Hospital Niguarda, Milan, Italy

Abstract Treatment of chronic diseases, such as heart failure, requires complex protocols based on early diagnosis; self-monitoring of symptoms, vital signs and physical activity; regular medication intake; and education of patients and caregivers about relevant aspects of the disease. Smartphones and mobile health applications could be very helpful in improving the efficacy of such protocols, but several barriers make it difficult to fully exploit their technological potential and produce clear clinical evidence of their effectiveness. App suppliers do not help users distinguish between useless/dangerous apps and valid solutions. The latter are few and often characterised by rapid obsolescence, lack of interactivity and lack of authoritative information. Systematic reviews can help physicians and researchers find and assess the ‘best candidate solutions’ in a repeatable manner and pave the way for well-grounded and fruitful discussion on their clinical effectiveness. To this purpose, the authors assess 10 apps for heart failure self-care using the Intercontinental Marketing Statistics score and other criteria, discuss the clinical effectiveness of existing solutions and identify barriers to their use in practice and drivers for change.

Keywords Digital health, mHealth, mobile app, heart failure, chronic care management, self-care, monitoring, smartphone Disclosure: AM, VP, MI, IB, AI, FM, DP and RDM were all board members of the Italian Association of Hospital Cardiologists HF Working Group and contributed to the ideation and development of the CuorMio app. All other authors have no conflicts of interest to declare. Received: 22 August 2019 Accepted: 5 November 2019 Citation: Cardiac Failure Review 2020;6:e13. DOI: https://doi.org/10.15420/cfr.2019.11 Correspondence: Andrea Mortara, Policlinico di Monza, Via Amati 111, 20900 Monza, Italy; E: andreamortara@libero.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Innovative patient-centred interventions are required to improve the self-management of complex, costly and relapsing conditions, such as heart failure (HF). Mobile health (mHealth) technology is a promising tool that could potentially help us reach these goals, but evidence of its clinical benefits and the security of personal health information is still scarce. In view of the increasing number of research activities involving mHealth apps and the EU’s reference framework for the digitalisation of health, this article aims to summarise helpful information for physicians and researchers when assessing the potential benefits of mHealth apps for HF patients.1–3 The management needs of patients discharged from hospital after new-onset acute HF and the individuals involved are shown in Table 1. The medical goals of treatment include the prevention of rehospitalisation and major adverse cardiac events. Meaningful goals for the patient revolve around clinical stability, autonomy and recovery of function to allow the continuation of daily activities, including work and caregiving. Within this framework, technology may offer selfmanagement systems that facilitate home monitoring, potentially

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increasing patient adherence and favouring the efficient integration of everyone involved in disease management.

The Rationale for Developing mHealth Apps for HF Patients Clinical outcomes in HF are influenced by patients’ knowledge, selfmanagement skills and readiness to seek early care for symptoms.4 Polypharmacy, defined as the use of at least five medications, is almost the rule in HF and makes adherence to treatment plans complex. Moreover, extracardiac multimorbidity is common among HF patients and significantly contributes to polypharmacy, disability and worse outcomes.5 HF places a burden on daily routines. Patients, particularly those in the more severe stages of HF, need to frequently monitor physiological parameters and may find the pressure to adhere to prescribed medication, diet, physical activity and follow-up plans stressful. The WHO defines mHealth as the “medical and public health practice supported by mobile devices, such as mobile phones, patient

Commercial Apps for Heart Failure Care monitoring devices, personal digital assistants, and other wireless devices.”6 As of January 2019, there were 5.1 billion smartphone users worldwide, equating to 67% of the population in Europe and 78% in the US, and demonstrating a 4.2% growth rate in mobile connectivity compared to 2018.7 Personal mobile devices may soon be available to most HF patients or their caregivers.

Table 1: Management Needs for Patients Discharged from Hospital After Acute Heart Failure Individuals Involved

Management Needs

Patient, caregiver

• Symptom recognition • Activity tracking • Weight loss and healthy diet

The use of mHealth apps can improve education on different aspects of HF and promote the importance of self-care. Such apps can enable the patient to self-monitor symptoms and vital signs in order to actively participate in the control and management of the disease. Patients can record physical activity and daily moods, and profit from notification systems that help them keep track of medication consumption and follow the prescribed treatment plan. Cameras in mobile phones may also be used to record medical documents; for example, ECGs. Hence, mHealth apps have great potential to facilitate HF management.

The Digital HF Patient: Meeting the Challenges Various reviews have previously assessed mHealth apps for HF. Some analyse apps that are not available on the market but are prototypes or have been used for feasibility purposes.9–14 Others are not based on systematic and well-recognised classification methods and many include tools that are more generally related to tracking symptoms or medication consumption. Masterson Creber et al. conducted a systematic assessment of 34 mHealth apps that were commercially available as of January 2016 using the Mobile Application Rating Scale (MARS), an accurate and complex analytical tool; only one of these apps, Heart Failure Health Storylines, had been specifically developed for HF.14,15 HF is a disease of the elderly: >80% of prevalent cases in the US and Europe are aged >65 years, with a median age at onset of 76 years.16 Physical barriers, encompassing sensory, motor and cognitive changes related to normal ageing, and poor acceptance of the use of smartphones by the older population have been reported in the literature.17,18 The proportion of older people who own and use a smartphone decreases sharply with increasing age, from 59% in those aged 65–69 years to 31% of those aged 75–79 years, and just 17% of people aged >80 years.19 Health problems and disability are the most common reasons for not using digital technologies. Many older people lack confidence in their ability to learn about and properly use electronic devices: over three-quarters of US subjects aged >65 years reported that they needed someone to set up and show them how to use a new electronic device.19 This attitude may undermine patients’ motivation to engage with mHealth apps, limit their perceived value and lead patients to poorly rate their ease of use. Physical barriers and poor self-confidence may be impossible to overcome when users are faced with poorly designed technology. mHealth apps dedicated to HF self-care should take into account the difficulties a patient is likely to experience and give specific consideration to user-centric design features.17 Issues that have been highlighted as particularly important in the literature include easy navigation, restricting the number of items in the menu, streamlining the data entry processes, making recovery from errors clear and simplifying visualisations of data patterns.

Analysis of Commercially Available mHealth Apps for HF Self-care Our review focused on apps to improve HF self-care that were available to download via Google Play and Apple’s App Store. The keywords

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• Reminder of follow-up appointments Patient, healthcare professionals • Monitoring of vital signs • Check parameters • Arrange periodic visits and examinations Patient, caregiver, healthcare professionals

• Education about heart failure • Medication schedule • Adherence check

Table 2: IMS Institute for Healthcare Informatics App Functionality Scoring System Functionality Scoring Criteria

Description

1. Inform

Provides information in a variety of formats (text, photo, video)

2. Instruct

Provides instructions to the user

3. Record

Capture user-entered data

a. Collect data

Able to enter and store health data on individual phone

b. Share data

Able to transmit health data

c. Evaluate data

Able to evaluate the health data entered by patient and provider, provider and administrator, or patient and caregiver

d. Intervene

Able to send alerts based on the data collected or propose behavioural intervention or changes

4. Display

Graphically display user-entered data/output user-entered data

5. Guide

Provide guidance based on user-entered information, and may further offer a diagnosis, or recommend a consultation with a physician/a course of treatment

6. Remind or alert

Provide reminders to the user

7. Communicate

Provide communication between healthcare professionals and patients and/or provide links to social networks

Total score (0–11): one point is assigned to each functionality that is present.

‘heart failure’, ‘cardiac failure’ and ‘congestive heart failure’ were used to search for apps. This search was carried out in all European languages, but not in Arabic, Russian, Japanese or Chinese due to a language barrier. The original search yielded more than 100 apps for heart diseases. We excluded apps designed for physicians; those relating to general cardiovascular conditions, such as hypertension or AF; and those managing medications in general or physical activity only. After the exclusion criteria were applied, 10 apps were downloaded. The strengths and weaknesses of the selected apps as innovative tools for HF management were independently evaluated using the 11-item IMS Institute for Healthcare Informatics app functionality scoring system (Table 2).8 The higher the score, the more complete and potentially helpful the app is. Unlike other assessment scores, including the MARS, the IMS scoring system is based on an independent and

Digital Health objective assessment of app functionality and does not reflect subjective patient/user or physician evaluation or evidence that users benefit from app use from an outcomes perspective.15

Results Details of the 10 apps analysed are given in Table 3. Four apps have been developed by scientific societies: HF Path (American Heart Association), Heart Failure Health Storylines (Heart Failure Society of America), CuorMio (Italian Association of Hospital Cardiologists) and Living with Heart Failure (Swiss Federation of Cardiology); the others by private companies. All apps have been developed for Android and iOS. Seven of the apps were developed in the US and three in Europe. Four of them may be considered multilingual; however, the majority are only available in English. All apps are free and most require registration before they can be used. The itemised and total IMS scores for the apps are given in Table 4. The majority of the apps performed well, with nine out of 10 IMS items achieving a score >8. These items are discussed in more detail below.

Information All apps include large educational sections on the disease and about the purpose of the app. They have areas devoted to explaining the importance of the different HF self-care domains (symptoms and signs of HF, physical activity, medication regimens, dietary intake, daily moods, education and use of sensors).

Instruction User instructions are included in all of the apps, but provide different levels of detail. Instructions may therefore be difficult for the beginner to comprehend and training is required.

Record and Display The apps have mainly been designed for HF self-management and to prompt users to seek early care for symptoms. They all track vital parameters (mainly blood pressure, heart rate and weight) and display them graphically. All record medication plans and send users reminders to take medication. Data are usually displayed using a colour-coding scheme and use a weekly calendar format. Data relating to vital signs are displayed in a line graph, so daily fluctuations are easy to see. The mHealth apps rarely deal with daily mood and dietary intake. Facilities to record exercise and activity, which are included in many smartphones, are not often integrated in the apps. ‘Share data’ and ‘evaluate data’ are the most critical sections; clinical data entered into the smartphone may be evaluated by the patient, caregiver and healthcare professional (HCP). The regular transmission of clinical data – which may be crucial – together with possible behavioural interventions based on the data collected is currently rarely incorporated into apps (Table 4). It must be underlined that regular transmission of clinical data implies close monitoring by HCPs and requires a dedicated organisation to respond quickly to requests from app users.

Reminder or Alert Reminder functions that enhance adherence to medication are included in all of the apps. Patients’ smartphones issue an alert, reminding app users that they are due to take their medication; this alert can be text only or text and an alarm. CuorMio requires the user to switch off the alarm, confirming that their medication has been taken.

Communication This is important, since the functionality and effectiveness of the app may be improved through HF patients’ participation in social media and virtual/online support groups. Two apps, Heart Failure Health Storylines and HF Path, have a section detailing how users can connect with other HF patients through the group chat function or through the American Heart Association/American Stroke Association support network. These features may be relevant in addressing users’ fear of losing faceto-face contact, which is often quoted as a barrier to technology use, particularly by older people. Several other aspects of the apps were also evaluated. The extracardiac comorbidities that often accompany HF, such as diabetes, chronic obstructive pulmonary disease, renal failure and anaemia, are not always considered. Two apps (@POINTofCARE and MyHF) include comorbid diseases as a list, but do not have features that monitor them over time. Heart Failure Health Storylines and CuorMio allow users to check comorbidities through blood test profiling. However, in general, the attention paid to other important diseases seems modest for all of the apps. During the development of its HealthManager app and platform, Beuer paid particular attention to the protection of health data collected and saved during user registration and has obtained a security certificate. In many other mHealth apps, this important legal item has not been clarified. Finally, smartphones have cameras that may play an important role in a novel concept of HF management. The CuorMio app, among other functions, can store files relating to the patient’s treatment. These files can be added by all HCPs treating the patient, thus building a portable electronic health record that moves with the patient.

Future Development Suggestions The mHealth apps we analysed have been designed for HF patients and appear to be simple and easy to navigate. However, a hierarchical approach with different menus is used by all and may require a fair amount of technological skill to navigate (see examples in Figure 1). Since older people may need assistance to use many smartphone features, instruction and support is critical. Family members are an invaluable source of help for many older patients, but not all caregivers – who are often spouses and of an older age themselves – may be able to overcome the digital challenges. However, when older patients and caregivers are provided with guidance/trained to use mHealth apps, as shown by several usability analyses, feedback is positive and participants may follow mHealth app instructions, even over long periods of time.20,21

Guide The apps perform well as a guide. All monitor vital signs and symptoms and advise the user when these parameters are out of range or his/ her quality of life is getting worse. In some cases, the message may be sent directly to the physician or caregiver (@POINTofCARE and MyHF), but more often the patient is advised to contact his/her doctor.

Interdisciplinary approaches to mHealth app design and development are paramount. Technology experts, HCPs and end-users (both patients and their caregivers) need to be involved. Patients should be consulted in the design and preferably act as co-developers of the tools. A wide range of groups needs to be included in assessment studies and it is

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Commercial Apps for Heart Failure Care Table 3: General Characteristics of the mHealth Apps Designed to be Used by Patients with Heart Failure Heart Failure Health Storylines

HF Path

Heart Failure Manager @Point of Care

Med-HF

Manage HF4Life

MyHF

L’insuffisance cardiaque

MyTherapy Beurer Health Manager

CuorMio

iOS

iOS, Android

Android

iOS, Android

Operating system

iOS, Android iOS, Android (US and Canada only)

iOS

Developer

Heart Failure American Society Heart of America/ Association Self Care Catalysts

Point of Care Alberta Health Services

University of Michigan

Les Laboratoires Servier

Schweizerische Herzstiftung

Smartpatient Beuer

ANMCO (Associazone Nazionale Medici Cardiologi Ospedalieri)

Star rating

iOS: 3.4 Android: 4

iOS: 3 Android: 4.5

–

iOS: – Android: 4.1

Android: 4

iOS: 4.8 Android: 4.7

iOS: 2.4

–

Cost

Free

Version

iOS: 7.17 Android: 5.5.3

iOS: 5.0.3 Android: 5.2

iOS: 10.1.2

iOS: 2.1

iOS: 1.0.1 Android: 1.0.1

iOS: 2.0.3 Android: 2.0.4

Android: 1.0

iOS: 3.36 Android: 3.5.1

iOS: 2.4

iOS: 5.0.3 Android: 5.2

Last version year

iOS: 2018 Android: 2018

iOS: 2019 Android: 2019

iOS: 2018

iOS: 2017

iOS: 2017 Android: 2017

iOS: 2016 Android: 2016

Android: 2018

iOS: 2019 Android: 2019

iOS: 2019

iOS: 2019 Android: 2019

Languages

English

English and Hebrew

English

11 languages French, (Brazilian German, Portuguese, Italian Czech, English, French, German, Korean, Italian, Portuguese, Russian, Slovakian and Spanish)

21 languages, including English, German, Spanish, Arabic, Greek, Hindi, Italian and Japanese

23 Italian languages, including English, French, Italian Chinese, Spanish and Swedish

Installs

iOS: N/A Android: 1,000+

iOS: N/A

iOS: N/A Android: 100+

iOS: N/A Android: 1,000+

iOS: N/A Android: 10+

iOS: N/A Android: 1,000,000+

iOS: N/A

iOS: N/A Android: 10+

Category

Health and fitness

Medical

Health and fitness

Medical

Yes

important to engage with patients who may be less independent and more likely experience barriers to use.

iOS

Apps as Medical Devices: A Continuing Debate

monitoring and the treatment of any disease – it should be considered a medical device. An app that provides patient education, monitors fitness/health/wellbeing or stores and transmits medical data without changing its purpose is not defined as a medical device.

The new European Medical Devices Regulation was published in 2017 and will enter into force on 25 May 2020.22 The market access framework for EU Member States will change significantly and will probably differ from US regulation. All medical devices require CE marking, that is, the manufacturer’s claim that a product meets the essential requirements of all relevant European Medical Device Directives, that it is fit for purpose and is safe. Stand-alone software, such as an mHealth app, is currently classified based on purpose.23,24 If the app has a medical purpose – a definition that encompasses prevention, diagnosis,

The mHealth apps analysed in this article may be considered portable systems for improving knowledge about HF self-management, recognising and seeking early care for symptoms and increasing adherence to treatment plans. The monitoring of physiological parameters, such as blood pressure, heart rate, weight and oxygen saturation, may be considered an important part of HF self-care: data input on the app is simply a patient note when the parameters are not obtained through other devices. Hence, the mHealth app is a sort of

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Digital Health Table 4: IMS Scores of the mHealth Apps Analysed Heart Failure Health Storylines

HF Path

Heart Failure Manager @Point of Care

Med-HF

Manage HF4Life

MyHF

L’insuffisance cardiaque

MyTherapy Beurer Health Manager

CuorMio

Inform

Instruct

Record

Collect data

Share data

Evaluate data 0

Intervene

Display

Guide

Alert

Communicate 1

IMS Score

data repository that can only be used by the patient. HCPs will consult the mHealth app only during regular patient visits or when specific alerts occur that suggest patients consult them. The border is blurred by the transmission of data. mHealth apps that regularly transmit data to hospitals or HCPs, as now happens with implantable devices, can result in the HCP taking an action – be it changing a patient’s therapy, calling them to arrange an appointment or referring them for an urgent consultation. Such mHealth apps would be considered medical devices. The debate is still ongoing. EU Member States will probably deliberate as to whether or not individual mHealth apps are devices based on the new Medical Devices Regulation. However, it is important to note that the presence of a CE mark does not imply that the app meets best practice or has been tested for accuracy or clinical benefits.

What Level of Evidence is Needed to Assess the Value of mHealth Apps? The IMS Institute for Healthcare Informatics highlighted the generation of evidence of value – in terms of behaviour change and improved health outcomes from using apps – as one of the most important areas for future research in mHealth. Lack of efficacy testing is one of the biggest barriers to adopting mHealth apps. Most reports on the evaluation of mHealth apps are small pilots and descriptive studies. The randomised controlled trial (RCT) paradigm, the cornerstone of evidence-based medicine, has been applied not only to drugs and devices but also to educational programmes and disease management strategies. However, the cost and complexities of running RCTs may render the clinical trial model inappropriate or impractical for the validation of mHealth apps for self-care: the technology evolves very rapidly and this tumultuous pace may be at variance with the times needed to plan, approve and execute an RCT.

The review by Cajita et al. is exemplary in this sense: among nine studies that assessed the efficacy of mHealth-based intervention on HF outcomes performed in the past decade, eight used telemonitoring systems of health status, but the wide range of technologies (including invasive devices), provider response, duration and health outcomes assessed made meta-analysis impossible.10 The studies reported contradictory findings relating to mortality, morbidity, functional status, self-rated quality of life and self-care. Patient adherence rates to mHealth intervention were consistently low: only one study achieved 100% adherence; 20% of the intervention group in another study failed to even start due to difficulties operating their smartphone’s browser; two other studies reported attrition rates of 60% and 30%, respectively, due to technical difficulties. This review highlights the critical issue with mHealth: high dropout rates due to poor function or problems with acceptability. An app is basically a digital way to access information and functions. It is a conduit to appropriately designed content based on the foundations of HF self-care. The role of scientific societies is pivotal in setting agreed content standards. The European Society of Cardiology, American Heart Association and American College of Cardiology, and Heart Failure Society of America have produced documents on the core aspects of self-care and recommendations for self-care education programmes are incorporated into international HF guidelines.25–27 Close adherence to those principles should be a mandatory requirement for any mHealth app focused on HF patients. Alternative strategies for efficient and accurate validation should take into account the evolving nature of apps and the requirement for continuous refinement to ensure tools are sufficiently attuned to patients’ need for sustained use. Previous studies have shown that daily use declines consistently after the first month.28 Close cooperation between scientific societies and information technology experts is needed to foster the appropriate development

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Commercial Apps for Heart Failure Care Figure 1: Examples of App Menus Heart Failure Health Storylines

HF Path

Heart Failure Manager @Point of Care

and continuous upgrade of mHealth apps and to set standards for validation. Studies should be planned to assess the consistent functioning, usability and acceptability of the app and to verify its sustained uptake at meaningful time intervals to measure its impact on outcomes, such as adherence or quality of life. Sex-balanced cohorts should be enrolled, including individuals of different ages and levels of digital and health literacy. Unstructured user experience ratings are important at the pilot testing stage to refine the app. Validated scales such the IMS or the Mobile App Rating Scale should be used to test fully developed versions.8,15 Initiatives, such as the NHS Apps Library in the UK, exemplify useful assessment frameworks for apps based on a set of criteria, including legislative and regulatory issues, standard or best practice and national health policies.29

Conclusion There is great potential for mHealth apps to foster patient engagement in HF self-care and improve interaction with HCPs in a

Cavallini S, Soldi R, Friedl J, Volpe M. Using the Quadruple Helix Approach to Accelerate the Transfer of Research and Innovation Results to Regional Growth. EU Publications, 2016. 2. Innovative Medicines Initiative. Reference documents. Brussels: IMI, 2019. https://www.imi.europa.eu/about-imi/ reference-documents (accessed 10 April 2020). 3. European Commission. Green Paper on mobile health (mHealth). Brussels: European Commission, 2014. https://ec.europa.eu/ digital-single-market/en/news/green-paper-mobile-healthmhealth (accessed 10 April 2020). 4. Harkness K, Spaling MA, Currie K, et al. A systematic review of patient heart failure self-care strategies. J Cardiovasc Nurs 2015;30:121–35. https://doi.org/10.1097/ JCN.0000000000000118; PMID: 24651683. 5. Tisminetzky M, Gurwitz JH, Fan D, et al. Multimorbidity burden and adverse outcomes in a community-based cohort of adults with heart failure. J Am Geriatr Soc 2018;66:2305–13. https://doi. org/10.1111/jgs.15590; PMID: 30246862. 6. WHO. mHealth: New Horizons for Health Through Mobile Technologies. Geneva: WHO, 2011. 7. We Are Social. Digital 2019 Report. London: We Are Social, 2019. https://wearesocial.com/global-digital-report-2019 (accessed 10 April 2020). 8. Aitken M, Gauntlett C. Patient Apps for Improved Healthcare: from Novelty to Mainstream. Parsippany, NJ: IMS Institute for Healthcare Informatics, 2013. 9. Whitehead L, Seaton P. The effectiveness of self-management mobile phone and tablet apps in long-term condition management: a systematic review. J Med Internet Res 2016;18:e97. https://doi.org/10.2196/jmir.4883; PMID: 27185295. 10. Cajita MI, Gleason KT, Han HR. A systematic review of mHealth-based heart failure interventions. J Cardiovasc Nurs 2016;31:E10–22. https://doi.org/10.1097/ 1.

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MyHF

CuorMio

cost-effective way. To ensure that the tools add value and really meet patient needs, patients need to participate in their design, development and refinement. Scientific societies will play a pivotal role in the development of guidance on the use of mHealth apps in clinical practice, suggesting when (e.g. after discharge, as an outpatient), to which type of patient (e.g. based on literacy level, caregiver support) and under which terms of use it is advisable to prescribe an mHealth app for HF self-care. Scientific societies also have a role in reassuring HCPs and patient organisations about the quality and effectiveness of the approach. The next target for digital HF self-care should be the integration of multimorbidity monitoring and management. This development should reflect multidisciplinary cooperation as fostered by professional scientific societies.

JCN.0000000000000305; PMID: 26544175. 11. Scott IA, Scuffham P, Gupta D, et al. Going digital: a narrative overview of the effects, quality and utility of mobile apps in chronic disease self-management. Aust Health Rev 2020;44:62–82. https://doi.org/10.1071/AH18064; PMID: 30419185. 12. Coorey GM, Neubeck L, Mulley J, Redfern J. Effectiveness, acceptability and usefulness of mobile applications for cardiovascular disease self-management: systematic review with meta-synthesis of quantitative and qualitative data. Eur J Prev Cardiol 2018;25:505–21. https://doi. org/10.1177/2047487317750913; PMID: 29313363. 13. Tripoliti EE, Karanasiou GS, Kalatzis FG, et al. The evolution of mHealth solutions for heart failure management. Adv Exp Med Biol 2018;1067:353–71. https://doi.org/10.1007/5584_2017_99; PMID: 28980271. 14. Masterson Creber RM, Maurer MS, Reading M, et al. Review and analysis of existing mobile phone apps to support heart failure symptom monitoring and self-care management using the Mobile Application Rating Scale (MARS). JMIR Mhealth Uhealth 2016;4:e74. https://doi.org/10.2196/mhealth.5882; PMID: 27302310. 15. Stoyanov SR, Hides L, Kavanagh DJ, et al. Mobile app rating scale: a new tool for assessing the quality of health mobile apps. JMIR Mhealth Uhealth 2015;3:e27. https://doi.org/10.2196/ mhealth.3422; PMID: 25760773. 16. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 2011;8:30–41. https://doi. org/10.1038/nrcardio.2010.165; PMID: 21060326. 17. Joe J, Demiris G. Older adults and mobile phones for health: a review. J Biomed Inform 2013;46:947–54. https://doi. org/10.1016/j.jbi.2013.06.008; PMID: 23810858. 18. Wildenbos GA, Peute L, Jaspers M. Aging barriers influencing mobile health usability for older adults: a literature based

19.

20.

21.

22.

23.

24.

framework (MOLD-US). Int J Med Inform 2018;114:66–75. https://doi.org/10.1016/j.ijmedinf.2018.03.012; PMID: 29673606. Hernandez A. Infographic: Are seniors as crazy for the internet as the younger generation? TechAeris 22 March 2019. https:// techaeris.com/2019/03/22/infographic-are-seniors-as-crazyfor-the-internet-as-the-younger-generation (accessed 10 April 2020). Matthew-Maich N, Harris L, Ploeg J, et al. Designing, implementing, and evaluating mobile health technologies for managing chronic conditions in older adults: a scoping review. JMIR Mhealth Uhealth 2016;4:e29. https://doi.org/10.2196/ mhealth.5127; PMID: 27282195. Portz JD, Vehovec A, Dolansky MA, et al. The development and acceptability of a mobile application for tracking symptoms of heart failure among older adults. Telemed J E Health 2018;24:161–5. https://doi.org/10.1089/tmj.2017.0036; PMID: 28696832. Evans J, Papadopoulos A, Silvers CT, et al. Remote health monitoring for older adults and those with heart failure: adherence and system usability. Telemed J E Health 2016;22:480–8. https://doi.org/10.1089/tmj.2015.0140; PMID: 26540369. EU. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. Brussels: EU; 2017. https://eur-lex.europa.eu/eli/reg/2017/745/oj (accessed 10 April 2020). Medicines and Healthcare products Regulatory Agency. Medical device stand-alone software including apps (including IVDMDs). London: MHRA, 2018. http://www.gov.uk/ government/publications/medical-devices-software-

Digital Health applications-apps (accessed 10 April 2020). 25. Lainscak M, Blue L, Clark AL, et al. Self-care management of heart failure: practical recommendations from the Patient Care Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2011;13:115–26. https://doi.org/10.1093/eurjhf/hfq219; PMID: 21148593. 26. Riegel B, Moser DK, Anker SD, et al. State of the science:

promoting self-care in persons with heart failure: a scientific statement from the American Heart Association. Circulation 2009;120:1141–63. https://doi.org/10.1161/ CIRCULATIONAHA.109.192628; PMID: 19720935. 27. Hauptman PJ, Rich MW, Heidenreich PA, et al. The heart failure clinic: a consensus statement of the Heart Failure Society of America. J Card Fail 2008;14:801–15. https://doi. org/10.1016/j.cardfail.2008.10.005; PMID: 19041043.

28. Loeckx M, Rabinovich RA, Demeyer H, et al. Smartphonebased physical activity telecoaching in chronic obstructive pulmonary disease: mixed-methods study on patient experiences and lessons for implementation. JMIR Mhealth Uhealth 2018;6:e200. https://doi.org/10.2196/mhealth.9774; PMID: 30578215. 29. NHS. NHS Apps Library. https://apps.beta.nhs.uk (accessed 10 April 2020).

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Digital Health

Apps and Online Platforms for Patients with Heart Failure Nida Ahmed,1 Sabahat Ahmed2 and Julia Grapsa1 1. Cardiology Department, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 2. GKT School of Medical Education, King’s College London, London, UK

Abstract The use of the internet for health advice and information has burgeoned over recent years. This corresponds with an increasing number of people living with heart failure and, in the context of a greater focus on patient engagement, producing accurate online health information is becoming vitally important. To help meet this need, major cardiology societies have designed dedicated, patient-specific areas on their websites. This article aims to provide an overview of the patient information resources from three main professional societies: the European Society of Cardiology, American Heart Association and American College of Cardiology. A summary of the content of these dedicated websites and two smartphone apps is provided, along with a brief look into the future role of these technologies and resources in supporting both patients and their clinicians in the management of heart failure.

Keywords Heart failure, European Society of Cardiology, American Heart Association, American College of Cardiology, patient resource, app, internet Disclosure: The authors have no conflicts of interest to declare. Received: 8 October 2019 Accepted: 29 January 2020 Citation: Cardiac Failure Review 2020;6:e14. DOI: https://doi.org/10.15420/cfr.2019.15 Correspondence: Nida Ahmed, Cardiology Department, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: nidaahmed@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The internet has an all-encompassing influence in our professional and private lives, and a crucial part of this is information on matters relating to our health. The online search ‘how to know chest pains are serious’ increased by 8,781% between 2015 and 2018.1 More than just acute presentations are being searched online. An analysis of 10 million cardiovascular disease (CVD)-related searches of the MayoClinic consumer health information portal showed that approximately 1.18 million of these searches related to living with and the control and management or cure of CVD.2 Patient access to online health records is a topical issue, and a systematic review has found that this can positively impact on patient safety and patient convenience and satisfaction.3 In the UK, it is estimated that as many as 920,000 people have heart failure, and the incidence is rising.4 There are many support groups for these patients, such as the British Heart Foundation and Pumping Marvellous, and the major professional societies have designed dedicated patient-specific areas on their websites.5,6 The aim of this article is to provide an overview of online patient information resources from three main societies: the European Society of Cardiology (ESC), American Heart Association (AHA) and American College of Cardiology (ACC).

Websites Table 1 provides a summary of the items available on each of the three main society platforms.

European Society of Cardiology The Heart Failure Association of the ESC has an aptly named ‘Heart Failure Matters’ domain.7 With input from the multidisciplinary team

and promoted as an educational website available in multiple languages, it is quoted to attract 2.5 million visits a year.

A Journey Through the Website The homepage sets the tone with images of (implied) patients of varying ages and ethnicities. Whether or not you use its virtual guide, clear distinct sections on the homepage take readers through the condition itself, videos from patients and a social media link. It is a comprehensive resource – various symptoms each have their own page with a stylised animated image with or without a short explanatory video. Topics that patients may find difficult to broach with their healthcare provider or would prefer to explore in the privacy of the online world are also tackled. For example, there are dedicated pages on the topic of sex and heart failure. It is worth noting that perhaps this section could have been further enhanced by taking the opportunity to showcase some real patient comments. In terms of mental health considerations, anxiety and depression are listed under ‘other symptoms of heart failure’, with a dedicated section on emotional health and heart failure openly discussing the matter. The website continues with pages on common tests (with associated images on its echocardiogram page but not on its ECG one), a mythbusters section and information for caregivers. It also covers the growing entity of cardio-oncology and heart failure as well as talking through advanced heart failure therapies. Ultimately, this resource is very engaging for the user. For now it is not available as a smartphone or tablet app, although this would be a welcome transition for the layout used.

Access at: www.CFRjournal.com

Digital Health Table 1: Summary of Items Available on Each Online Platform Item

ESC

AHA

ACC

Virtual guide to the website

√

Content available in other language(s)

√

Symptom guide

√

Support for advanced disease

√

Information on clinical trials

√

Link to support groups

√

Support for care givers

√

Downloadable content

√

Links to social media

√

Link to app

√

Introduces the MDT

√

ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology; MDT = multidisciplinary team.

American Heart Association Under the ‘Health Topics’ section, the Heart Failure pages by the AHA make use of bold still images and white space.8 Right from the start, it defines various conditions and sets the user on their way to its other pages including support groups or red flag symptoms.

A Journey Through the Website The website has a large, eye-catching search box on its homepage, almost calling users to search the site for what they want rather than walking them through the pages available. It is split into nine sections set out in a logical and structured manner. While the font styling is thin and unimposing with subheadings breaking up the page, it can at times be word heavy. Symptoms are discussed in the form of a table and the common investigations used in the diagnosis begin with a basic outline of procedure for the patient. This text is offset by elaborate and bespoke images and downloadable patient-engaging resources, making this a vibrant and interactive resource. The ‘Shared Decision Making’ section is set out in a question-and-answer-inspired layout that candidly discusses emotive matters including a ‘Disagreeing with the Doctor’ section. The final section, ‘Personal Stories’, features patients with heart failure, including the story of their diagnosis and the role of volunteer ambassadors, presenting a new avenue of empowerment for those with the diagnosis. Unlike its European counterpart, the smartphone app is proudly on display, including glowing comments from reported users. Their platforms for users to share their thoughts and connect with others are prominent, and the ease by which one can share information through well-placed links to social media is welcome.

American College of Cardiology The ACC offers CardioSmart.9 It is available in both English and Spanish, with a trim and neat appearance that is designed to lead the patient through the informative pages. It has quick links to related conditions sections and downloadable infographics prominently displayed.

unique and helpful service to both patients and healthcare professionals and enticing titles provide an extensive source of engaging content. This website views patient empowerment in a slightly different light then the other sites, entitling one section ‘Your Responsibilities’. Instead of being a behemoth of knowledge, it supports patients by providing key questions they should ask their doctor. It appears less extensive than other sources when discussing the symptoms of heart failure; after listing them they are not taken much further forward in terms of details. The main investigations do have their own pages and are supplemented well with text and/or videos. For some of the more complex and significant decisions in heart failure management, for example ICD insertion, it has a useful online Decision Point tool, which allows patients to work through some key information and a series of questions to try and help them understand their choice. A printable version that can be used when discussing with the doctor is also available. The site also tackles – in an honest and motivating manner – the pitfalls of sensational headlines about heart failure seen in the media. There is information on the latest advances as reviewed by a cardiologist and details of clinical trials including their stage of progress. In recognising the large teams of healthcare staff involved in managing chronic and at times complex conditions, it supports patients by having a dedicated section on the roles of the various healthcare professionals involved in the management of heart failure. The site has inviting and easily accessible links to the many social media platforms. They even make available their logo and encourage readers to link their site with its own. A series of apps are advertised, although these are targeted at clinicians or for patient-clinician consultations.

Apps Heart Failure Path (American Heart Association) “A self-management tool that empowers heart failure patients to better manage and live with their condition.” This app is designed for patients and runs very much along the lines that would be expected. It supports patients by taking them through 12 different courses that aim to empower, with lifestyle choices, symptom tracking and treatment adherence. It also allows patients to connect with others, providing a new dimension to the well-known concept of patient groups.

CardioSmart Heart Explorer App (American College of Cardiology) “Enhance the clinician–patient relationship at the point of care.” Available on a smartphone or tablet, the app offers high-resolution cardiac graphics and patient education animations. It is not designed to be a patient-only resource. Instead it aims to bring to life and help visualisation of issues discussed during a consultation, whether that be heart failure, MI or arrhythmias, such as AF.

The Future of Heart Failure Management A Journey Through the Website At first glance, it has an eye-catching upper portion directing you to the various pages to explore. This is followed by an introduction to the condition that subtly guides you to the first in a series of pages starting with diagnosis right through to a section on clinical trials. At the bottom of the homepage is a ‘Heart Failure News and Events’ section. This is a

Online technologies are not simply a repository of knowledge. Artificial intelligence (AI) and deep learning are the next frontiers in cardiology and are already making headway in the realm of heart failure. Algorithms have been found to be helpful in predicting those who may develop heart failure based on electronic health records and research continues on how AI can be used to predict hospital readmission in these

CARDIAC FAILURE REVIEW

Apps and Online Platforms in Heart Failure patients.10,11 Wearable smart technologies – well known for their role in monitoring heart rate and physical exercise – are also developing rapidly, with novel innovations, such as wearable vests, to assess lung volume to prevent hospital readmission.12 The platforms described here each bring an individual approach and unique energy to the space for patients living with heart failure. From the comprehensive knowledge repository delivered by the ESC to the interactive downloadables of the AHA and the ACC illustrating all things heart failure, each resource has its own place on the stage. At a time

Peat J. Internet searches for serious health conditions on the rise. Independent 20 November 2018. https://www. independent.co.uk/life-style/analaysis-google-data-raisesconcerns-hypochondria-sciatica-acne-ibs-a8642711.html (accessed 22 April 2020). Jadhav A, Sheth A, Pathak J. Analysis of online information searching for cardiovascular diseases on a consumer health information portal. AMIA Annu Symp Proc 2014;2014:739–48. PMID: 25954380. Mold F, de Lusignan S, Sheikh A, et al. Patients’ online access to their electronic health records and linked online services: a systematic review in primary care. Br J Gen Pract 2015;65:141– 51. https://doi.org/10.3399/bjgp15X683941; PMID: 25733435. British Heart Foundation. Heart statistics. 2020. https://www. bhf.org.uk/what-we-do/our-research/heart-statistics (accessed

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7. 8.

when online technologies are taking over as the primary mode of information retrieval, each resource can be used as a fountain of knowledge to help empower patients with information they can digest at their own pace. As clinicians, they can support us when tackling some of the most challenging topics with our patients, such as end-oflife issues in heart failure. On the whole, we believe these resources need to be actively promoted. They have the power to morph the clinician–patient conversation into perhaps the purest form of the patient-centred care model.

22 April 2020). British Heart Foundation. Heart failure. 2020. https://www.bhf. org.uk/informationsupport/conditions/heart-failure (accessed 22 April 2020). Pumping Marvellous. What we do. 2020. https:// pumpingmarvellous.org/what-we-do-pm (accessed 22 April 2020). Heart Failure Matters. Heart failure matters. https://www. heartfailurematters.org/en_GB/ (accessed 22 April 2020). Heart.org. Heart failure. American Heart Association, 2020. https://www.heart.org/en/health-topics/heart-failure (accessed 22 April 2020). CardioSmart. Heart failure. American College of Cardiology, 2020. https://www.cardiosmart.org/Heart-Conditions/HeartFailure (accessed 22 April 2020).

10. Choi E, Schuetz A, Stewart WF, Sun J. Using recurrent neural network models for early detection of heart failure onset. J Am Med Inform Assoc 2017;24:361–70. https://doi.org/10.1093/ jamia/ocw112; PMID: 27521897. 11. Frizzell JD, Liang L, Schulte PJ, et al. Prediction of 30-day allcause readmissions in patients hospitalized for heart failure: comparison of machine learning and other statistical approaches. JAMA Cardiol 2017;2:204–9. https://doi.org/10.1001/jamacardio.2016.3956; PMID: 27784047. 12. Amir O, Ben-Gal T, Weinstein JM, et al. Evaluation of remote dielectric sensing (ReDS) technology-guided therapy for decreasing heart failure re-hospitalizations. Int J Cardiol 2017;240:279–84. https://doi.org/10.1016/j.ijcard.2017.02.120; PMID: 28341372.

COVID-19

Mechanisms of Myocardial Injury in Coronavirus Disease 2019 Aniket S Rali,1 Sagar Ranka,2 Zubair Shah2 and Andrew J Sauer2 1. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Baylor College of Medicine, Houston, TX, US; 2. Division of Advanced Heart Failure and Heart Transplantation, Department of Cardiovascular Medicine, University of Kansas Health System, Kansas City, KS, US

Abstract Coronavirus disease 2019 (COVID-19) predominantly presents with symptoms of fever, fatigue, cough and respiratory failure. However, it appears to have a unique interplay with cardiovascular disease (CVD); patients with pre-existing CVD are at highest risk for mortality from COVID-19, along with the elderly. COVID-19 contributes to cardiovascular complications including arrhythmias, myocardial dysfunction and myocardial inflammation. Although the exact mechanism of myocardial inflammation in patients with COVID-19 is not known, several plausible mechanisms have been proposed based on early observational reports. In this article, the authors summarise the available literature on mechanisms of myocardial injury in COVID-19.

Keywords Myocardial injury, myocarditis, cardiac failure, COVID-19, ACE-2 receptors Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: ASR and SR contributed equally. Received: 24 April 2020 Accepted: 14 May 2020 Citation: Cardiac Failure Review 2020;6:e15. DOI: https://doi.org/10.15420/cfr.2020.10 Correspondence: Aniket S Rali, 7200 Cambridge St, A 10.189, BCM 903, Houston, TX 77030, US. E: aniketrali@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Coronavirus disease 2019 (COVID-19) has evolved into a global pandemic, having affected more than 2.3 million people and claiming more than 160,000 lives. Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus predominantly causes fever (77–98% of cases), fatigue (52–75%) and cough (60–81%).1,2 While it primarily affects the respiratory system, it also appears to have a unique interplay with the cardiovascular system. Patients with pre-existing cardiovascular comorbidities appear to be at the highest risk for mortality from COVID-19, along with the elderly. The disease also contributes to cardiovascular complications, including acute coronary syndromes, arrhythmias, myocarditis, acute heart failure and, in the most severe cases, cardiogenic shock and death. 3 Although only a few population studies have detailed the spectrum of cardiovascular complications, the high prevalence of myocardial injury in patients with COVID-19 is suggested by frequently elevated cardiac biomarkers. Elevated troponin levels are noted in 7–28% of COVID-19 patients on presentation, some associated with depressed left ventricular function and haemodynamic shock.4–7 Although an elevation in cardiac troponin is a sensitive marker for myocardial injury, it does not distinguish between the various aetiologies of injury. Multiple potential mechanisms of acute myocardial injury from the viral infection have been proposed.8 The purpose of this article is primarily to summarise the available literature (Tables 1 and 2) on various proposed mechanisms of myocardial injury related to COVID-19 (Figure 1).

Access at: www.CFRjournal.com

Acute Coronary Syndromes Although the reported incidence of acute coronary syndrome (ACS) has gone down during the COVID-19 pandemic, it is possible this is because patients are being hesitant in visiting hospitals for their medical care.9 However, a variety of syndromes mimicking ACS have been reported in people with COVID-19 infection. In a case series of 18 patients with COVID-19, 56% were found to have ST-elevation at time of presentation, with the rest developing it at some point during hospitalisation.10 Focal ST elevations were present in 78% of patients. A total of nine patients (50%) underwent coronary angiography but only six patients (33%) were eventually found to have obstructive coronary artery disease (CAD). Inferior and lateral ST segment elevations were most common, and ECG findings were more likely to be focal in patients with obstructive CAD. Of note, all 18 patients had elevated D-dimer levels. In a recently published retrospective study of 191 COVID-19 patients from two separate hospitals in China, the incidence of elevation in high-sensitivity cardiac troponin I (cTnI; >28 pg/ml) was 17%, and it was significantly higher among non-survivors (46% versus 1%, p<0.001).11 Furthermore, elevation of this biomarker was noted to be a predictor of in-hospital death (univariable OR 80.07, 95% CI [10.34–620.36], p<0.0001). The most abrupt increase in cardiac troponin I in nonsurvivors was noted beyond day 16 after the onset of disease. In the same study, the incidence of acute cardiac injury was 17% among all patients but significantly higher in non-survivors (59% versus 1%, p<0.0001). Another study reported the incidence of acute cardiac injury

Mechanisms of Myocardial Injury in COVID-19 Table 1: Pooled Baseline Demographics and Comorbidities in Published Studies Author

Study period

Cases Died, Number (%)

Region, Country

Demographics and Baseline Cardiovascular Comorbidities

Mean Female Hypertension Type 2 Smoker Cardiovascular Chronic Age Diabetes Diseases Kidney (Range) Disease Zhou et al. 200011

29 December 191 2019– 31 January 2020

54 (28.2%)

Jinyintan/ Wuhan, China

Bhatraju et al. 20005

24 February– 24 9 March 2020

12 (50%)

Yang et al. 200054

24 December 52 2019– 29 January 2020

Phua, 20006 20 January 2020– 10 February 2020 Huang et al. 200029,55

416

31 December 41 2019– 2 January 2020 201

Wu et al. 200055

56 (18–87)

72 (38%)

58 (30%)

36 (19%)

11 (6%)

CAD: 15 (8%); HF 44 (23%)

2 (1%)

Washington, 64 (±18) US

9 (38%)

–

14 (58%)

5 (22%)

–

5 (21%)

32 (61.5%)

Wuhan, China

59.7 (±13.3)

17 (33%)

–

9 (17%)

2 (4%)

5 (10%)

–

57 (13.7%)

Wuhan, China

64 (21–95)

211 (50.7%)

127 (30.5%)

60 (14.4%)

–

44 (10.6%)

14 (3.4%

6 (15%)

Wuhan, China

49 (41–58)

11 (27%)

6 (15%)

8 (20%)

3 (7%)

6 (15%)

–

44 (21.9%)

Wuhan, China

52 (43–60)

75 (36.3%)

39 (19.4%)

22 (10.9%)

–

9 (4.0%)

2 (1.0%)

55.5 (13.1)

32 ( 32%) –

–

40 (40%) had both – cardiovascular and cerebrovascular illness CAD 27 (2.5%)

Chen et al. 200056

1–20 January 99 2020

11 (11%)

Wuhan, China

Guan et al. 200057

11 December 1,099 2019– 29 January 2020

15 (1.4%)

Entire China 47 (35–58)

459/1,096 165(15%) (41.9%)

81 (7.4%)

158 (14.5%)

Guo et al. 20007

23 January– 23 February 2020

187

43 (23.0%)

Wuhan, China

58.5 (14.6)

96 (51.3%)

61(32.6%)

28 (15.0%)

18 (9.6%) CAD 21 (11.2%); HF 8 (4.3%)

Petrilli et al. 1 March–2 200058 * April 2020 (only hospitalised cohort)

1,999

292 (14.6%)

New York, US

62 (50–74)

1,052 (52.6%)

742 (37.1%)

503 (25.2%) 520 (26%) CAD 197 (9.9%); HF 124 (6.2%)

195 (9.8%)

Richardson 1 March–1 et al. 200059 April 2020

5,700

553/2,634 (21%)

New York, US

63 (0–107)

2,263 (39.7%)

2036 (56.6%)

1,808 (33.8%)

558/3567 CAD 595 (11.1%) (15.6%)

268 (5%); ESRD 186 (3.5%

11 (52.4%)

Washington, 70 US (43–92)

9 (48%)

–

7 (33.3%)

COPD 7 (33.3%)

10 (47.6%) ESRD 2 (9.5%)

Arentz et al. 20 February– 21 5 March 2020 200060

HF 9 (42.9%)

8 (0.7%)

6 (3.2%)

CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; ESRD = end-stage renal disease; HF = heart failure. * = available on preprint server.

to be 7% (10 out of 138 patients), but significantly higher among patients requiring intensive care unit (ICU) admission (22.2% versus 2%, p<0.001).1 A meta-analysis of cardiac biomarkers in patients with COVID-19 showed that the values of cardiac troponin I were significantly higher in those with severe disease than in those without (SMD 25.6 ng/l; 95% CI [6.8–44.5 ng/l]).4 Hypercoagulability has also been reported among COVID-19 patients, which makes them more prone to arterial thrombi and ACS.12 In a recent review of COVID-19 patients, Violi et al. suggested that patients with severe disease (Pneumonia Severity Index >90, CURB-65 ≥2, acute

CARDIAC FAILURE REVIEW

respiratory distress syndrome, sepsis or requiring ICU admission) and those with elevated D-dimer levels have a hypercoagulable milieu and are likely to benefit from antithrombotic therapy with low molecular weight heparin or aspirin.13 It has been postulated that COVID-19 may cause direct vascular injury, as reported in a case report of right coronary artery subintimal haematoma associated with spontaneous coronary dissection.14 In a recently published case series of COVID-19 patients, Varga et al. found evidence of direct viral infection of the endothelial cells and resultant endotheliitis.15 Such endothelial inflammation would certainly

Natriuretic Peptide (NT pro-BNP)

2/13 (15%)

Wu et al. 200055

Huang et al. 200029

13 (13%) (CK)

9/198 (4.5%) (CK-MB)

Median TnI = 3.4 pg/mL

All patients: 5/41 (12%); – ICU patients 4/13 (31%); non-ICU patients 1/28 (4%)

–

Cardiac injury patients: median = 1,689 pg/ml

Phua, 20006

All patients: median = 219 pg/ml

82 (19.7%); cardiac injury patients Median TnI = 0.19 µg/l

Yang et al. 200054

Median TnI =161.0 pg/mL

–

All patients: 24/145 (17%); – non-survivor 23/50 (46%); survivor 1/95 (1%) (TnI)

Elevated Cardiac Biomarker

Bhatraju et al. 20005 All patients: 12 (23%); non-survivor 9 (28%); survivor 3 (15%)

Zhou et al. 200011

Author

UL PNA 25 (25%); BL PNA 74 (75%); GGO 14 (14%)

UL infiltrate 10 (5.0%); BL infiltrate 191 (95%)

Bilateral involvement 40 (98%)

UL infiltrate 105 (25.2%); BL 311 (74.8%); GGO 68 (16.3%)

–

BL infiltrates 23/23 (100%); GGO 4/5 (80%)

Consolidation 112 (59%); GGO 136 (71%); BL infiltration 143 (75%)

Respiratory Involvement (Chest X-ray/CT)

Table 2: Biomarkers, Clinical Parameters and Interventions in Published Studies

–

0/9 (0%)

–

4 (4%)

5 (2.5%)

4 (10%)

32 (7.7%)

22 (42%)

18/24 (75%)

32 (17%)

19 (19%)

62 (30.8%)

9 (22%)

204 (73.1%)

30 (58%)

57 (30%)

3 (3%)

1 (0.5%)

2 (5%)

–

6 (11.5%)

3 (2%)

9 (9%)

–

3 (7%)

2 (0.5%)

9 (17%)

–

10 (5%)

Symptoms: chest pain (2%); shortness of breath (31%); fever (83%); nausea/ vomiting (1%)

10 patients overlap with Huang et al.29 and Wu et al.55 ARDS in 41.8% of patients. Methylprednisolone reduced death (HR 0.38; 95% CI [0.20–0.72])

Earliest Chinese study reporting outcomes

HR 4.26 (95% CI [1.92–9.49]) for mortality from cardiac injury; only 22 (26.8%) underwent ECG. ARDS, AKI, coagulopathy, dyselectrolytemia more common in cardiac injury patients

Critically ill patients included only; ARDS (67%), AKI (29%), liver dysfunction (29%)

First published COVID-19 study in US; hypoxaemic respiratory failure was commonest reason for ICU admission

Compared survivor to non-survivors and found older age, higher SOFA score, and D-dimer were associated with mortality

Echocardiography Invasive Glucocorticoids ECMO Renal Comments/ Findings Mechanical Utilisation Replacement Sentinel Findings Ventilation Therapy

COVID-19

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All patients: median 385.5 pg/ml –

185/1,327 (13.9%)

801/3,533 (22.6%)

Petrilli et al. 200058 (only hospitalised cohort)*

Richardson et al. 200059

Cardiac injury patients: median 817.4 pg/ml

BL reticular opacities 18 (86%); GGO: 14 (67%)

–

All patients: median 268.4 pg/ml –

New reduced left ventricular systolic function 7 (33.3%)

–

15 (71%)

320/2,634 (12.2%)

445 (22.2%)

45 (24.1%)

25 (2.3%)

–

106 (56.7%)

204 (18.6%)

–

5 (0.5%)

81/2,634 (3.2%)

–

9 (0.8%)

Included only critical patients. Liver dysfunction 3 (14.3%)

Obesity 1737/4170 (41.7%); morbid obesity (BMI >35) 791/4170 (19.0%); liver dysfunction 56 (2.1%). Did not report medications Mortality in patients not taking ACEi/ARB 26.7% and taking ACEi 32.7% or ARB 30.6%. ACEi/ARB use: 48.1%/50.1% continued during hospitalisation

No treatment characteristics reported

ACEi/ARB use: 10.1%; VT/VF incidence: 5.9%); mortality in elevated TnT group was 31/52 (59.6%) versus 14/135 (10.4%) in normal TnT group

From National Health Commission in China. Lymphocytopenia in 83.2% of patients

Echocardiography Invasive Glucocorticoids ECMO Renal Comments/ Findings Mechanical Utilisation Replacement Sentinel Findings Ventilation Therapy

ACEi = angiotensin converting enzyme inhibitor; AKI = acute kidney injury; ARB = angiotensin receptor blocker; ARDS = acute respiratory distress syndrome; BL = bilateral; CK = creatinine kinase; CK-MB = creatinine kinase-MB; COVID-19 = coronavirus disease 2019; ECMO = extracorporeal membrane oxygenation; ESRD = end-stage renal disease; HF=heart failure; ICU = intensive care unit; NT pro-BNP = N-terminal brain natriuretic peptide; GGO = ground-glass opacities; PNA = pneumonia; SOFA= sequential organ failure assessment; TnI = troponin I; TnT = troponin T; UL = unilateral. * = available on preprint server. Standard abbreviations for measurement values are used. Data extracted on 23 April 2020.

Arentz et al. 200060

–

All patients: 52 (27.8%) (TnT)

GGO 55/274 (20.1%); UL PNA 77/274 (28.1%); BL PNA 100/274 (36.5%)

Guan et al. 200057

–

Respiratory Involvement (Chest X-ray/CT)

Chen et al. 200056

Natriuretic Peptide (NT pro-BNP)

Elevated Cardiac Biomarker

Author

Table 2: Cont.

Mechanisms of Myocardial Injury in COVID-19

COVID-19 Figure 1: Mechanisms of Myocardial Injury in COVID-19

Role of Cytokine Storm

Acute coronary syndrome

An excessive immune response to SARS-CoV-2 infection has been demonstrated in certain subgroups of infected patients and is referred to as a cytokine storm.29,30 This phenomenon has been demonstrated in previous studies where SARS-CoV-1 caused severe lung injury.31 ACE-2 mediated viral infiltration

Cytokine storm

Myocardial injury

Myocarditis

The exact aetiology of myocarditis in COVID-19 remains unknown. Possible mechanisms include direct viral infiltration and resultant inflammation, or a cytokine storm with myocardial inflammation.

Drug therapy

ACE-2 = angiotensin converting enzyme 2

predispose COVID-19 patients to ACS, especially given their hypercoagulable state. Although no studies have reported the precise incidence of ACS and acute MI with COVID-19, these conditions have been known to occur after severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and influenza infections.16–18

Myocarditis Myocarditis is another potential aetiology of acute myocardial injury in COVID-19 patients, although there remains a paucity of literature on cases confirmed with imaging or histopathology. SARS-CoV-2 can directly infect the cardiac tissue via angiotensinconverting enzyme 2 (ACE-2) receptors, which may cause myocardial inflammation and damage. Such a mechanism of myocardial injury through SARS-CoV has been well-established in animal models and cardiac autopsies.19,20 Some autopsy reports of COVID-19 patients have likewise reported myocardial interstitial infiltration by mononuclear cells and lymphocytic infiltration.21,22 Endomyocardial biopsy showing low-grade myocardial inflammation and viral infiltration directly into the myocardial tissue has also been reported.23 Isolated cardiac involvement with no respiratory symptoms or infiltrate has also been reported with cardiac MRI demonstrating marked biventricular myocardial interstitial oedema with late gadolinium enhancement.24,25 COVID-19-associated fulminant myocarditis has also been reported.26 As most patients do not undergo advanced cardiac imaging or cardiac biopsies (because of concerns of field contamination and increased viral dissemination), the true incidence of myocarditis remains unknown. In addition to myocardial inflammation, pericardial involvement in the form of pericardial effusion with tamponade has also been reported in COVID-19.27 A mimicker of COVID-19-associated myocarditis is stressinduced cardiomyopathy, which is another known cause of acute heart failure in these patients.28

A cytokine storm is triggered by an imbalanced response of type 1 and type 2 T helper cells, resulting in an excessive production of cytokines, particularly interleukin 6 (IL-6).32,33 Yang et al. showed that in 53 clinically moderately to severely affected COVID-19 patients, 14 cytokines were elevated, with three of them – interferon gamma induced protein 10 (IP-10), monocyte chemotactic protein 3 (MCP-3) and interleukin-1 receptor antagonist (IL-1ra) – being independently associated with hypoxaemia, disease progression and death.34 The cytokine profile in COVID-19 is similar to that in secondary haemophagocytic hymphohistiocytosis (SHH), a hyper-inflammatory syndrome seen in other viral infections.35,36 The inflammatory response may impact myocardial contractility and function by direct myocardial damage or via hypoxia-mediated myocardial damage.37 Certain anticytokine treatments, such as tocilizumab, have been proposed to treat this cytokine storm.38

Role of ACE Receptor in Pathogenesis ACE-2 is a membrane-bound aminopeptidate receptor expressed on the epithelial cells of the lungs, intestines, kidneys and blood vessels.39 It has important immune and cardiovascular roles. Angiotensinconverting enzyme (ACE) cleaves angiotensin I to generate angiotensin II (Ang II), which binds to and activates AT1R, thus promoting vasoconstriction. ACE-2 cleaves angiotensin II and generates angiotensin 1–7, a powerful vasodilator acting through Mas receptors. SARS-CoV-2 has a spike protein receptor-binding domain, similar to SARS-CoV-1, which interacts with the ACE-2 receptor and acts as the primary functional receptor for pathogenicity and human-to-human transmission.40 Furthermore, SARS-CoV-2 binding to ACE-2 leads to its downregulation and increases angiotensin II. This subsequently leads to lower amount of angiotensin 1–7. This causes AT1R-mediated pulmonary vascular permeability.41 The ACE-2 receptor is upregulated in patients with cardiovascular disease, especially with the use of renin-angiotensin-aldosterone system inhibitors.32 SARS-CoV-2 mainly affects the alveolar epithelial cells, resulting in respiratory symptoms, which are more severe in patients with cardiovascular disease. Some animal studies have reported the protective role of ACE-2 in the development of severe acute lung injury.42 This has led to speculation about the potential effects of antihypertensive medications with ACEinhibitors or angiotensin receptor blockers on COVID-19 positive patients. Guo et al. demonstrated that angiotensin-converting enzyme inhibitors/angiotensin receptor blockers had no effect of on mortality in 187 hospitalised patients with SARS-CoV-2.7 Furthermore, a retrospective analysis of 1,128 adult COVID-19 patients with a previous history of hypertension, inpatient use of ACE inhibitors or

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Mechanisms of Myocardial Injury in COVID-19 angiotensin receptor blockers (ARBs) was associated with lower risk of all-cause mortality compared to non-users.21 There is a lack of clear experimental or clinical data showing ACE receptor-mediated antihypertensive therapy has adverse effects in patients with COVID-19.43 Therefore, modification of pre-existing therapy is not recommended as per guidelines from both American and European cardiovascular societies.44,45 On the other hand, sacubitril/valsartan reduces the concentration of pro-inflammatory cytokines and neutrophil count, while increasing lymphocyte count more than valsartan alone or placebo. This finding might be related to the increase in plasma levels of atrial/brain/C-type natriuretic peptide, Ang I/II, substance P, bradykinin and endothelin secondary to neprilisin inhibition by sacubitril.46 Therefore, administration of an ACE, an ARB or sacubitril/valsartan may even be beneficial through inhibition of AT1R.47

Impact of Drug Therapy Currently, there is no known no curative therapy for SARS-CoV-2. Many drugs are being used as prophylaxis or for treatment of COVID-19 patients in an expedited manner.48 Hydroxychloroquine, proposed as an effective strategy for COVID-19 patients, has known cardiovascular toxicity, causing arrhythmias and biventricular failure.5,49 Hydroxychloroquine-related cardiac adverse events are rare but can be severe and, occasionally, life-threatening. A recent review of cardiac complications attributed to this medication found that most patients who developed cardiac symptoms had been on treatment for a long period of time (median 7 years), and had been exposed to large cumulative doses (median 1,235 g.50 Conduction abnormalities (prolonged QT and PR intervals) were the most common adverse events, affecting 85% of these patients. Although it appears that conduction abnormalities are a long-term consequence of high-dose

Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. https://doi. org/10.1001/jama.2020.1585; PMID: 32031570; epub ahead of press. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020. https://doi. org/10.1007/s00134-020-05991-x; PMID: 32125452; epub ahead of press. Rali AS, Sauer, Andrew J. COVID-19 pandemic and cardiovascular disease. US Cardiology Review 2020;14:e01. https://doi.org/10.15420/usc.2020.14 Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis 2020. https://doi. org/10.1016/j.pcad.2020.03.001; PMID: 32169400; epub ahead of press. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in critically ill patients in the Seattle region – case series. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2004500; PMID: 32227758; epub ahead of press. Phua J, Weng L, Ling, L, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med 2020; https://doi. org/10.1016/S2213-2600(20)30161-2; PMID: 32272080; epub ahead of press. Guo T, Fan Y, Chen M, et al., Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020. https://doi.org/10.1001/ jamacardio.2020.1017; PMID: 32219356; epub ahead of press. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiology 2020. https://doi.org/10.1001/ jamacardio.2020.1286; PMID: 32219363; epub ahead of press. Metzler B, Siostrzonek P, Binder RK, et al. Decline of acute coronary syndrome admissions in Austria since the outbreak of COVID-19: the pandemic response causes cardiac collateral damage. Eur Heart J. 2020;41:1852–3. https://doi.org/10.1093/ eurheartj/ehaa314; PMID: 32297932.

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and prolonged use of hydroxychloroquine, we recommend monitoring all patients with COVID-19 treated with this drug for cardiac arrhythmias. Azithromycin, which has been proposed for the treatment of COVID-19 pneumonia, is also known to increase the risk of adverse cardiovascular events. This risk is highest among patients with baseline cardiovascular comorbidities, conduction abnormalities and on concomitant QTprolonging medications.51 Indeed, concomitant use of hydroxychloroquine and azithromycin is associated with higher risk of QTc prolongation in COVID-19 patients than either medication alone.52 The potential of experimental treatment to cause myocardial damage remains a concern and patients receiving such therapies require close monitoring.

Long-term Cardiovascular Implications In addition to acute myocardial damage, COVID-19-related long-term cardiovascular morbidity is also a concern. SARS-CoV-2 is structurally and genetically very similar to its predecessor SARS-CoV-1. A small study of 25 patients who recovered from SARS-CoV-1 infection had abnormal lipid profiles and glucose metabolism, and a higher burden of cardiovascular abnormalities at 12 years’ follow-up.53 As serological antibody testing becomes readily available to identify patients who have recovered from COVID-19, it will be important to observe their long-term cardiovascular health after infection.

Conclusion Multiple mechanisms appear to contribute to myocardial injury in COVID-19. Individually or in conjunction with one another, they include respiratory failure induced hypoxia, inflammatory cytokine storms, direct viral infiltration and subsequent myocyte death, and myocardial dysfunction from acute illness.

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Digital Health

Telemedicine, Artificial Intelligence and Humanisation of Clinical Pathways in Heart Failure Management: Back to the Future and Beyond Domenico D’Amario,1 Francesco Canonico,1 Daniele Rodolico,1 Josip A Borovac,2,3 Rocco Vergallo,1 Rocco Antonio Montone,1 Mattia Galli,1 Stefano Migliaro,1 Attilio Restivo,1 Massimo Massetti1 and Filippo Crea1 1. Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 2. Department of Pathophysiology, University of Split School of Medicine, Split, Croatia; 3. Working Group on Heart Failure of Croatian Cardiac Society, Zagreb, Croatia

Abstract New technologies have been recently introduced to improve the monitoring of patients with chronic syndromes such as heart failure. Devices can now be employed to gather large amounts of data and data processing through artificial intelligence techniques may improve heart failure management and reduce costs. The analysis of large datasets using an artificial intelligence technique is leading to a paradigm shift in the era of precision medicine. However, the assessment of clinical safety and the evaluation of the potential benefits is still a matter of debate. In this article, the authors aim to focus on the development of these new tools and to draw the attention to their transition in daily clinical practice.

Keywords Artificial intelligence, personalised medicine, big data, data analysis, heart failure, patient monitoring, telemedicine, devices Disclosure: The authors have no conflicts of interest to declare. Received: 19 November 2019 Accepted: 12 March 2020 Citation: Cardiac Failure Review 2020;6:e16. DOI: https://doi.org/10.15420/cfr.2019.17 Correspondence: Domenico D’Amario, Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS (FPG), Largo Agostino Gemelli, no 8, 00168, Rome, Italy. E: domenico.damario@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a complex clinical syndrome associated with a heavy burden of symptoms and a wide range of therapeutic options.1–5 Despite improvements in HF management over past decades, we still need approaches that might mitigate the effects of this disease, preventing its insidious onset and worsening of symptoms, such as acute decompensations. A trend has recently emerged to extend the diagnostic and therapeutic approaches to include more complex ways of data collection and processing, thereby holding the potential to achieve a greater understanding of HF pathophysiology and to enhance patient care. Telemedicine – or telehealth – applied to chronic diseases such as HF is rapidly evolving and aims to improve and individualise patient care, as well as reducing financial costs.6 Telehealth is a broad term that encompasses the different applications of telematics to medicine, allowing diagnosis and/or remote treatment through a set of communication tools.7 Additionally, a branch of computer science that could enhance future HF management is artificial intelligence (AI), an area of study engaging computers in human processes, such as learning, reasoning or knowledge storage.8 AI techniques are of great interest in the healthcare and medical field because they can use sophisticated algorithms to analyse large volumes of physiological data obtained from thousands of patients, thus gathering information to assist clinical practice and decision making.9 In cardiology, AI is currently being investigated in several domains ranging from clinical decision support systems to imaging interpretation.

Some machine learning (ML) techniques allow computers to be trained with information acquired from large datasets that have been previously correctly classified and labelled by medical professionals. Such frameworks teach computers to acquire and develop autonomous rules aiding in classification and interpretation of new inputs, as long as these are similar enough to those used in training datasets. This results in the development of automated decision support systems that facilitate diagnosis and/or prognosis estimation. However, an appropriate classification of telemedical systems based on ML techniques is lacking and profiles of patients who could benefit most from ML telemedicine solutions are unknown and need to be adequately investigated.10 A promising application of these technologies is to exploit the relative computing speed now available in computers, which is made possible by parallel processing. This feature can quickly aggregate data from patient electronic health records (EHRs) acquired from multiple sources in order to create a streamlined summary of patient medical problems requiring attention by physician. Therefore, AI systems may perform a thorough search of individual or multiple patient EHRs. This technology could also be used to cross-reference data related to a patient’s family history to find similar patients and to evaluate the diagnoses and treatment responses.11 Furthermore, the software will be able to integrate relevant genomic, proteomic and metabolomic data and consequently formulate diagnostic work-up and therapeutic regimens, as well as providing recommendations for patient screening.

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Digital Health Such intelligent software solutions could also be used to direct safe patient work-ups and to guide selection of diagnostic tests that maximise effectiveness and safety, addressing questions pertaining to a precise medical problem while minimising health costs. 11 When these approaches are further optimised in the future, they could signify a quantum leap in clinical practice since diagnostic overtesting is a serious problem in modern medicine, often driven by defensive medicine, suboptimal knowledge and the need to increase profit and meet patients’ expectations. This consideration is mainly based on the erronous belief that more testing could be beneficial for the patient. 12 For example, a study by Sheffield et al. estimated that preoperative cardiac stress testing was unnecessary in more than 56,000 patients referred to elective non-cardiac surgery in a Medicare inpatient claims database.13 In addition, an increased trend for resting echocardiography testing has been reported in a large Canadian cohort of HF patients, but appropriateness was not assessed.14 Integrated solutions based on ML and AI have the potential to counter and attenuate such trends, thereby providing significant burden relief on often already overstretched healthcare systems worldwide.

Clinical Applications There is an increasing interest in the potential for telehealth to support the home-based management of patients with long-term conditions as a means of providing a more patient-centred, cost-efficient and joint service. AI can be used in the field of cardiology in several ways, including determining the most congruous type of imaging study for a specific set of symptoms. If applied properly, AI could reduce inappropriate imaging studies and help physicians adhere to practice guidelines and everchanging appropriate use criteria. For example, the Imaging in Formation of Optimal Cardiovascular Utilization Strategies (FOCUS) quality improvement initiative of the American College of Cardiology was recently introduced to reduce inadequate use of diagnostic imaging through the use of AI tracking appropriate use criteria.11 Another clinical application of the AI that has recently become available is the website-based verification of symptoms platforms available on numerous major medical websites, such as: • https://www.nhsinform.scot/symptoms-and-self-help/a-to-z • https://www.mayoclinic.org/symptom-checker/select-symptom/ itt-20009075 • https://www.mdlive.com • https://symptoms.webmd.com/default.htm Patients can access the app online and using the diagnostic tools, they receive a basic assessment of their symptoms. However, these self-diagnostic apparatus intended to help the doctor in decisionmaking and are not meant to rely only on the patient self-assessment, disjointed from any medical supervision. By means of teleconsultation, the patient may provide the doctor with relevant details of their medical problems by following the steps required by the diagnostic algorithm (Figure 1). Prescription Medical Electronics Mobile (PEM Mobile) platforms are mobile apps used for prescription of drugs, available in some public and private hospitals, in order to reduce the number of manual prescriptions associated with digital signature. This mobile app allows the doctor to process prescription drugs via a mobile phone or tablet:

the algorithm is able to fully integrate clinical information of pharmacy users, and trace the input from prescribers and pharmacists.15 Given that the physician is provided with an overview of patients’ medications, this tool enhances the drug-related safety, avoiding overdosing or interactions. This is a relevant issue for HF patients – particularly the elderly – because of the prevalence of several comorbidities requiring multiple treatments. Conveying all prescription data into a single platform helps also to build public registries, which are increasingly useful to understand HF mechanisms.16 However, PEM Mobile requires more extensive investigations in order to fully provide a quantitative assessment of its clinical benefit. A recent study by Vedanthan et al. investigated possible ways to better control blood pressure (BP) among patients with MI through the use of a smartphone app as a complement to traditional cardiac rehabilitation protocols when compared to patients receiving traditional cardiac rehabilitation alone.17 The automated positive feedback on in-range arterial BP measurements augments patient adherence to antihypertensive medication, thus fostering an improvement in arterial BP control. A randomised study in Kenya evaluated whether equipping community healthcare workers with behavioural communication strategies and smartphone technology could facilitate linkage of people with elevated BP to hypertension care programs, therefore lowering BP. The study enrolled 1,460 patients in three arms (usual care, paper-based care [behavioural communication using paper-based tools] and smartphone technology), and systolic arterial BP was evaluated. The strategy combining tailored behavioural communication and mobile health (mHealth) for community health workers led to improved linkage to care, since patients in the arm equipped with a smartphone received tailored messages, alerts and recommendations based on ML of individual assessments.17 The Medication Adherence Improvement Support App For EngagementBlood Pressure (MedISAFE-BP) study is a prospective, randomised controlled trial, with 413 patients, designed to evaluate the impact of the mHealth app on arterial BP and medication adherence. The results may inform the potential effectiveness of this simple system in enhancing cardiovascular disease risk factor assessment and the contribution on the clinical outcomes.18 More recently, ML-guided CT angiography (CTA) has been shown to be superior in assessing the diagnostic accuracy of the classification of the coronary stenoses based on the fractional flow reserve assessment when compared to computational-fluid-dynamics-guided CTA assessment.19 Similarly, ML-based algorithms were able to discriminate pathological versus physiological patterns of hypertrophic cardiac remodelling by ‘learning’ from expert-annotated speckle-tracking echocardiographic datasets, thereby showing potential in the identification of hypertrophic cardiomyopathy.20 These examples showed how ML-based diagnostic approaches offer many possibilities that may ultimately translate to better patient outcomes and lower financial expenditures.

Devices and Hardware The use of AI in medicine today is a matter of great interest, especially with respect to diagnostic or predictive analysis of medical data. Several studies investigating telehealth interventions in HF have been published in recent years (Table 1). To date, the most convincing evidence for a telemonitoring device relates to the implantable CardioMEMS device.

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Artificial Intelligence for Telemedicine in Heart Failure Table 1: Completed Studies Incorporating a Telemedicine Programme as an Intervention Trial

Author and Year

ClinicalTrials.gov

Results

CHAMPION

Abraham et al. 201121

NCT00531661

Reduced rates of hospitalisation with pulmonary pressure monitoring

COMPASS-HF

Bourge et al. 200823

NCT00643279

No significant decrease of HF morbidity with continuous intracardiac pressure monitoring

IN-TIME

Hindricks et al. 201424

NCT00538356

Telemonitoring significantly improves clinical outcomes for HF patients

TIM-HF2

Koehler et al. 2018

NCT01878630

Reduction of the percentage of days lost due to unplanned cardiovascular hospital admissions

COMMIT-HF

Kurek et al. 201728

NCT02536443

Reduction of long-term mortality by remote monitoring of HF patients with ICDs/CRT-Ds

EFFECT

De Simone et al. 201526

NCT01723865

Reduction of mortality with ICDs

HF = heart failure.

Figure 1: Artificial Intelligence and the Roadmap Towards Precision Medicine

Software: data processing • Recording and computing • Image detection • Patient’s self assessment • Personalised report

Physician: clinical decision • Final supervision and integration • Clinical dialogue • Precision medicine Devices: data collection • Multiparameter telemonitoring An ideal process is shown starting with the collection of data through wearable or implanted devices that allow telemonitoring of detailed cardiac and vascular function parameters. Data are recorded and computed by tools using sophisticated algorithms in order to provide the physician with personalised reports that further guide the final clinical decision. Source: Dilsizian and Siegel 2014.11 Reproduced with permission from Servier Medical Art (https://smart.servier.com/).

The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial tested the hypothesis that pulmonary artery pressure guiding HF management with a wireless implantable haemodynamic monitoring system would be a better way to reduce hospital admissions for HF compared to usual guideline-directed medical management alone.21 This device is implanted into the pulmonary artery (PA) and transmits PA pressures to a central service centre. The physician in charge receives the results, including the trends over time of these measurements. The study was not powered for mortality but showed a significant reduction in HF hospitalisation because of improved HF management. This effect was maintained over a long-term period.6 The continuous technical progress of implanted left ventricular assist devices (LVADs) has led to improved clinical outcomes in advanced HF patients. Telemonitoring can be conducted without any active participation by the patient. Since monitoring of LVAD patients is complex and sensitive, it would be necessary to have continuous access to LVAD controller parameters (alarms, rotation speed, energy consumption, flow, pulsatility index), BP, blood coagulation values and concomitant drug treatment. One of the most feared complications of LVAD treatment, especially in the long-term, is transmission infection.

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This makes prevention particularly important. An algorithm based on image pixelation transmitted by the smartphone of the driveline exit site to the hospital is currently under development to promptly detect inflammation around the site of transmission.22 The Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) trial was a prospective, multicentre, randomised, single-blind, parallel-controlled trial of 274 New York Heart Association (NYHA) functional class III or IV HF patients who received an implantable continuous haemodynamic monitor (ICHM). The ICHM is capable of continuously monitoring and storing heart rate, body temperature, patient activity, right ventricular systolic and diastolic pressure, maximal positive and negative rate of change in right ventricular pressure, right ventricular pre-ejection and systolic time intervals, and estimated pulmonary arterial diastolic pressure. The remote examination of the pressure information has occurred at least once a week, in order to undertake appropriate action before the anticipated HF-related event.23 The Implant-Based Multiparameter Telemonitoring of Patients with Heart Failure (IN-TIME) trial reported a positive impact on clinical outcomes by using multiparameter monitoring based on information from an ICD device among patients with chronic HF and NYHA class II–III symptoms.

Digital Health By using automatic and daily monitoring of several parameters, such as the incidence of ventricular tachyarrhythmias, biventricular pacing, heart rate variability, patient activity and intracardiac electrogram, a composite clinical score indicating worsening of HF was improved as compared with patients assigned to standard care.24 Moreover, this multiparameter telemonitoring approach seemed to yield the most absolute benefit in higher-risk populations with worse prognoses.25 The Clinical Efficacy of Remote Monitoring in the Management of Heart Failure (EFFECT) study was designed to test the hypothesis that remote monitoring (RM) can reduce death from any cause and cardiovascular hospitalisations in HF patients who receive ICD/CRT-D in current clinical practice. It was a prospective, non-randomised, multicentre trial of RM in a population of consecutive patients who underwent ICD/CRT-D implantation in 25 Italian centres, following current guidelines for the management of chronic HF.26 The study demonstrated that RM was associated with reduced death and cardiovascular hospitalisation among patients with an implanted ICD/CRT. Furthermore, a subsequent economic analysis of EFFECT study showed that RM was associated with reduced direct healthcare costs compared with standard monitoring.27 The Contemporary Modalities In Treatment of Heart Failure (COMMITHF) registry evaluated the impact of RM on a long-term prognosis in HF patients. Findings from this investigation, which involved different cardiac device brands for the telemonitoring, strongly suggest that the use of RM improves long-term prognosis.28 Of note, a significantly lower 1-year mortality was observed in the RM group compared to the usual care group (2.1% versus 11.5%; p<0.0001, respectively), and this result was maintained through a 3-year follow-up (4.9% versus 22.3%; p<0.0001, respectively). The Telemedical Interventional Management in Heart Failure II (TIMHF2) trial was a prospective, randomised, controlled, parallel-group, multicentre trial that recruited 1,571 HF patients. The remote patient management intervention consisted of a daily transmission of body weight, systolic and diastolic BP, heart rate, analysis of the heart rhythm, peripheral capillary oxygen saturation and a self-rated health status to the telemedical centre.29 This trial showed that a structured remote patient management intervention, when used in a well-defined HF population, could reduce the percentage of days lost because of unplanned cardiovascular hospital admissions and all-cause mortality compared to usual monitoring. Together with CHAMPION, these studies represent valid examples of wide and helpful data collection. However, processing of the information gathered throughout telemedicine in these particular cases could involve more sophisticated algorithms and deep learning to enable even deeper therapeutic pathways. This may stimulate researchers to extend the previous results with new applications. As a proof-of-concept, AI applications to ECG reading have been recently reported.30,31 Specifically, a convolutional neural network has allowed detection of patterns of left ventricular dysfunction for asymptomatic patients.30 However, a limitation is that deep-learning analyses are not able to provide physiological insights, such as meaningful ECG biomarkers. In addition to the HF studies described here, a new algorithm to monitor HF patients was tested in the Multisensor Chronic Assessment in Ambulatory Heart Failure study (MultiSENSE) study. The HeartLogic index

combines data from multiple sensors (first and third accelerometerbased heart sounds, intrathoracic impedance, respiratory rate, the ratio between respiratory rate and tidal volume, nocturnal heart rate and patient activity) integrated with the ICD and has proved to be a sensitive, timely and efficient predictor of HF decompensation.32 This device calculates daily a composite index by integrating inputs received from the sensors. The activation of the associated alert can enable early detection of clinical deterioration and suggest an action to be taken in patients who are not yet critical, potentially preventing adverse events by stratifying their risk of occurence.27 Similarly, the use of the HeartLogic sensor alone or in combination with N-terminal of the prohormone brain natriuretic peptide levels in the MultiSENSE study was able to identify time intervals during the natural history of patients with HF in which those individuals were at a significantly higher risk of worsening HF, thus facilitating preventive interventions.33

Costs and Sustainability Telemedicine is believed to have the potential to reduce costs related to healthcare. A recent study evaluated the impact of at-home telemonitoring on healthcare expenditures, number of admissions and length of hospilatisation in patients living with chronic HF, showing a statistically robust positive impact on healthcare costs, and decreasing the number of hospilatisations and their duration. These results were coupled with a reduction in mortality.34 A study enrolling patients with comorbidities, such as HF, chronic lung disease and/or diabetes recently showed how home telehealth, when integrated with the health facilityâ&#x20AC;&#x2122;s EHR system, significantly reduced the bed-days-of-care and urgent clinic/emergency room visits, with improvement in glycaemic control, cognitive status and patient satisfaction.35 Similar observations were consistently confirmed in studies examining integrated telehealth care services among geriatric home care patients and elderly people.36,37

Data Management Health data are defined by the general EU data protection regulation as they contain information on the subjectâ&#x20AC;&#x2122;s past, present and future physical and/or mental health status. For this reason, they represent sensitive and private data. Health data also apply to physiological information collected by cardiac implanted electronic devices, such as implantable defibrillators, pacemakers, CRT devices and implantable loop recorders. Therefore, in the interest of all parties involved in RM, it is important to analyse the legal implications regarding the data produced by RM devices.

Future Applications V-LAP (Vectorious Medical Technologies) is a miniature, wireless and battery-free microcomputer for cardiac monitoring in HF, able to directly monitor the left atrial pressure. Ex-vivo and animal findings have been published. and the first human study of the device is underway (NCT03775161).38 The device is designed to be inserted in the interatrial septum and aims to permit data collection on a daily basis. The sensor is not powered by batteries and can work for the life of the patient. It is charged remotely and transmits the patientâ&#x20AC;&#x2122;s cardiac activity information wirelessly to doctors and to the hospital, where it is analysed by cardiologists.

Dehumanisation The risk of potential dehumanisation of medicine because of the increased distance between the physician and the patient has to be

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Artificial Intelligence for Telemedicine in Heart Failure evaluated with caution. Telehealth should be used as a tool to improve patient care and serve as an adjunct to – rather than a replacement for – face-to-face contact. Telehealth, in particular, may exert a difference for patients who have physical disabilities or those with financial difficulties in travelling long distances. Telemedicine platforms might offer healthcare providers the opportunity to contact patients across long distances, reaching those in the most isolated locations. The topic of the evolving relationship between the physician and patient has been also recently addressed.41 Telemedicine, and AI in general, that allow a complete assessment of cardiac and vascular function are becoming a fundamental tool to optimise treatment of chronic diseases, following the Hippocratic principle that “healing is a matter of time, but it is sometimes also a matter of opportunity”.

Conclusion Telemonitoring includes several tools allowing the electronic transfer of patient data or self-reports to a doctor. So far, telemonitoring has been frequently used in patients with HF, supporting evidence that telemonitoring holds the potential to improve care, quality of life and prognosis. The combination of AI, big data and massive parallel computing offer the ability to create

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Conrad N, Judge A, Tran J, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 2018;391:572–80. https://doi.org/10.1016/ S0140-6736(17)32520-5; PMID: 29174292. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017;3:7–11. https://doi.org/10.15420/ cfr.2016:25:2; PMID: 28785469. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ejhf.592; PMID: 27207191. Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:1169–86. https:// doi.org/10.1002/ejhf.1531; PMID: 31129923. Crespo-Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:1505–35. https://doi.org/10.1002/ejhf.1236; PMID: 29806100. Eurlings CGMJ, Boyne JJ, de Boer RA, et al. Telemedicine in heart failure – more than nice to have? Neth Heart J 2019;27:5–15. https://doi.org/10.1007/s12471-018-1202-5; PMID: 30536146. Dorsey ER, Topol EJ. State of telehealth. N Engl J Med 2016;375:154–61. https://doi.org/10.1056/NEJMra1601705; PMID: 27410924. Krittanawong C, Zhang H, Wang Z, et al. Artificial intelligence in precision cardiovascular medicine. J Am Coll Cardiol 2017;69:2657-2664. https://doi.org/10.1016/j.jacc.2017.03.571; PMID: 28545640. Jiang F, Jiang Y, Zhi H, et al. Artificial intelligence in healthcare: past, present and future. Stroke Vasc Neurol 2017;2:230–43. https://doi.org/10.1136/svn-2017-000101; PMID: 29507784. Leslie SJ, Denvir MA. Clinical decision support software for chronic heart failure. Crit Pathw Cardiol 2007;6:121–6. https://doi. org/10.1097/HPC.0b013e31812da7cc; PMID: 17804972. Dilsizian SE, Siegel EL. Artificial intelligence in medicine and cardiac imaging: harnessing big data and advanced computing to provide personalized medical diagnosis and treatment. Curr Cardiol Rep 2014;16:441. https://doi.org/10.1007/s11886-0130441-8; PMID: 24338557. Greenberg J, Green JB. Over-testing: why more is not better. Am J Med 2014;127:362–3. https://doi.org/10.1016/j. amjmed.2013.10.024; PMID: 24269325. Sheffield KM, McAdams PS, Benarroch-Gampel J, et al. Overuse of preoperative cardiac stress testing in medicare patients undergoing elective noncardiac surgery. Ann Surg 2013;257:73– 80. https://doi.org/10.1097/SLA.0b013e31826bc2f4; PMID: 22964739. Braga JR, Leong-Poi H, Rac VE, et al. Trends in the use of cardiac imaging for patients with heart failure in Canada. JAMA Netw Open 2019;2:e198766. https://doi.org/10.1001/ jamanetworkopen.2019.8766; PMID: 31397858.

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a revolutionary way of practicing evidence-based, cost-effective and personalised medicine. However, barriers to the adoption of AI technologies must be surpassed from regulatory, legal, cultural and political perspectives. AI represents a different way to yield evidence for clinical practice, and deep learning challenges the usual ways by which the medical community has achieved scientific consensus to date. Because of the epidemic proportion of HF as a clinical syndrome, the ability to process big data from public health registries represents an ongoing opportunity for uncovering the evolving scope of the disease; however, the processing of ‘big medical data’ still must be addressed to build an open resource.42 The digitalisation process in cardiology is already with us. Now, clinicians, managers, policy-makers and scientists should start to consider the unique opportunity offered to them to work closely with the patients in order to plan, design, develop, implement and empower a new strategic relationship. Sharing the understanding of common goals that need to be achieved during the journey will allow physicians to provide a better, faster and more personalised treatment, while patients have the role of the ideal partner in forecasting their healthcare plan and wellness-enhancing processes.

15. Patrao L, Deveza R, Martins H. PEM – a new patient centred electronic prescription platform. Procedia Technol 2013;9:1313–9. https://doi.org/10.1016/j.protcy.2013.12.147. 16. Aimo A, Seghieri C, Nuti S, et al. Building medical knowledge from real world registries: the case of heart failure. Int J Cardiol Heart Vasc 2018;19:98–9. https://doi.org/10.1016/j. ijcha.2018.03.008; PMID: 29955669. 17. Vedanthan R, Kamano JH, DeLong AK, et al. Community health workers improve linkage to hypertension care in Western Kenya. J Am Coll Cardiol 2019;74:1897–906. https://doi. org/10.1016/j.jacc.2019.08.003; PMID: 31487546. 18. Morawski K, Ghazinouri R, Krumme A, et al. Rationale and design of the Medication adherence Improvement Support App For Engagement – Blood Pressure (MedISAFE-BP) trial. Am Heart J 2017;186:40–7. https://doi.org/10.1016/j.ahj.2016.11.007; PMID: 28454831. 19. Coenen A, Kim YH, Kruk M, et al. Diagnostic accuracy of a machine-learning approach to coronary computed tomographic angiography-based fractional flow reserve: result from the MACHINE Consortium. Circ Cardiovasc Imaging 2018;11:e007217. https://doi.org/10.1161/CIRCIMAGING.117.007217; PMID: 29914866. 20. Narula S, Shameer K, Salem Omar AM, et al. Machine-learning algorithms to automate morphological and functional assessments in 2D echocardiography. J Am Coll Cardiol 2016;68: 2287–95. https://doi.org/10.1016/j.jacc.2016.08.062; PMID: 27884247. 21. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S0140-6736(11)60101-3; PMID: 21315441. 22. Reiss N, Schmidt T, Boeckelmann M, et al. Telemonitoring of leftventricular assist device patients-current status and future challenges. J Thorac Dis 2018;10:S1794–s1801. https://doi. org/10.21037/jtd.2018.01.158; PMID: 30034855. 23. Bourge RC, Abraham WT, Adamson PB, et al. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASSHF study. J Am Coll Cardiol 2008;51:1073–9. https://doi. org/10.1016/j.jacc.2007.10.061; PMID: 18342224. 24. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014;384:583–90. https://doi.org/10.1016/S0140-6736(14)61176-4; PMID: 25131977. 25. Geller JC, Lewalter T, Bruun NE, et al. Implant-based multiparameter telemonitoring of patients with heart failure and a defibrillator with vs. without cardiac resynchronization therapy option: a subanalysis of the IN-TIME trial. Clin Res Cardiol 2019;108:1117–27. https://doi.org/10.1007/s00392-019-01447-5; PMID: 30874886. 26. De Simone A, Leoni L, Luzi M, et al. Remote monitoring improves outcome after ICD implantation: the clinical efficacy in the management of heart failure (EFFECT) study. Europace 2015;17:1267–75. https://doi.org/10.1093/europace/euu318;

PMID: 25842271. 27. Capucci A, Santini L, Favale S, et al. Preliminary experience with the multisensor HeartLogic algorithm for heart failure monitoring: a retrospective case series report. ESC Heart Fail 2019;6:308–18. https://doi.org/10.1002/ehf2.12394; PMID: 30632306. 28. Kurek A, Tajstra M, Gadula-Gacek E, et al. Impact of remote monitoring on long-term prognosis in heart failure patients in a real-world cohort: Results from all-comers COMMIT-HF Trial. J Cardiovasc Electrophysiol 2017;28:425–31. https://doi.org/ 10.1111/jce.13174; PMID: 28176442. 29. Koehler F, Koehler K, Deckwart O, et al. Efficacy of telemedical interventional management in patients with heart failure (TIMHF2): a randomised, controlled, parallel-group, unmasked trial. Lancet 2018;392:1047–57. https://doi.org/10.1016/S01406736(18)31880-4; PMID: 30153985. 30. Attia ZI, Kapa S, Lopez-Jimenez F, et al. Screening for cardiac contractile dysfunction using an artificial intelligence-enabled electrocardiogram. Nat Med 2019;25:70–4. https://doi. org/10.1038/s41591-018-0240-2; PMID: 30617318. 31. Hannun AY, Rajpurkar P, Haghpanahi M, et al. Publisher correction: Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network. Nat Med 2019;25:530. https://doi.org/10.1038/ s41591-019-0359-9; PMID:30679787. 32. Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE study. JACC Heart Fail 2017;5: 216–25. https://doi.org/10.1016/j. jchf.2016.12.011; PMID: 28254128. 33. Gardner RS, Singh JP, Stancak B, et al. HeartLogic multisensor algorithm identifies patients during periods of significantly increased risk of heart failure events: Results from the MultiSENSE study. Circ Heart Fail 2018;11:e004669. https://doi. org/10.1161/CIRCHEARTFAILURE.117.004669; PMID: 30002113. 34. Celler B, Varnfield M, Nepal S, et al. Impact of at-home telemonitoring on health services expenditure and hospital admissions in patients with chronic conditions: before and after control intervention analysis. JMIR Med Inform 2017;5:e29. https://doi.org/10.2196/medinform.7308; PMID: 28887294. 35. Noel HC, Vogel DC, Erdos JJ, et al. Home telehealth reduces healthcare costs. Telemed J E Health 2004;10:170–83. https://doi. org/10.1089/tmj.2004.10.170; PMID: 15319047. 36. Gellis ZD, Kenaley BL, Ten Have T. Integrated telehealth care for chronic illness and depression in geriatric home care patients: the Integrated Telehealth Education and Activation of Mood (I-TEAM) study. J Am Geriatr Soc 2014;62:889–95. https://doi. org/10.1111/jgs.12776; PMID: 24655228. 37. Finkelstein SM, Speedie SM, Zhou X, et al. Perception, satisfaction and utilization of the VALUE home telehealth service. J Telemed Telecare 2011;17:288–92. https://doi. org/10.1258/jtt.2011.100712; PMID: 21844178. 38. Perl L, Soifer E, Bartunek J, et al. A novel wireless left atrial pressure monitoring system for patients with heart failure, first ex-vivo and animal experience. J Cardiovasc Transl Res 2019;12:290–8. https://doi.org/10.1007/s12265-018-9856-3.

Digital Health PMID: 30604310. 39. Feldman T, Mauri L, Kahwash R, et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): a phase 2, randomized, sham-controlled trial. Circulation 2018;137:364–75. https://doi.

org/10.1161/CIRCULATIONAHA.117.032094; PMID: 29142012. 40. Kaye DM, Petrie MC, McKenzie S, et al. Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction. ESC Heart Fail 2019;6:62–9. https://doi.org/10.1002/ehf2.12350; PMID: 30311437.

41. Noseworthy J. The future of care – preserving the patient– physician relationship. N Engl J Med 2019;381:2265–9. https://doi. org/10.1056/NEJMsr1912662; PMID: 31800995. 42. Topol EJ. The big medical data miss: challenges in establishing an open medical resource. Nat Rev Genet 2015;16:253–4. https:// doi.org/10.1038/nrg3943; PMID: 26065035.

CARDIAC FAILURE REVIEW

Letter to the Editor

Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019-associated Acute Respiratory Distress Syndrome: An Initial US Experience at a High-volume Centre Yang Yang,1 Aniket S Rali,1 Christian Inchaustegui,1 Javid Alakbarli,1 Subhasis Chatterjee,2,3 James P Herlihy,1 Joggy George,4 Alexis Shafii,2,3 Ajith Nair1 and Leo Simpson1 1. Department of Internal Medicine, Baylor College of Medicine, Houston, TX, US; 2. Michael E DeBakey Department of Surgery, Baylor College Medicine, Houston, TX, US; 3. Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX, US; 4. Department of Cardiology, Texas Heart Institute, Houston, TX, US

Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: YY and ASR contributed equally. Received: 5 June 2020 Accepted: 8 June 2020 Citation: Cardiac Failure Review 2020;6:e17. DOI: https://doi.org/10.15420/cfr.2020.16 Correspondence: Leo Simpson, 7200 Cambridge St, A 10.189, BCM 903, Houston, TX 77030, US. E: Ls1@bcm.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Dear Editor, The use of extracorporeal membrane oxygenation (ECMO) as salvage therapy in the most severe cases of acute respiratory distress syndrome (ARDS) has been associated with reduced mortality, particularly at highvolume centres. We report a case series of seven patients with coronavirus disease 2019 (COVID-19)-associated ARDS treated with ECMO. In select COVID-19 patients suffering from severe ARDS refractory to conventional therapy, ECMO might be an outcome altering therapy. Respiratory ECMO Survival Prediction (RESP) score appears to be a reliable prognostication tool in selecting COVID-19 patients most likely to benefit from ECMO. Early and frequent evaluation of critically ill COVID-19 patients for ECMO therapy could facilitate timely initiation, and ultimately, favourable outcomes. ECMO is a finite resource, and thus must be used judiciously, especially in the midst of a pandemic where all resources are stretched thin. ECMO is a well-established salvage therapy in treatment of severe refractory ARDS. Venous–venous ECMO (VV-ECMO) is a modified cardiopulmonary bypass system in which venous blood is removed from the body and circulated through an artificial membrane lung and has successfully been deployed in the treatment of patients with severe ARDS. The initiation of VV-ECMO allows for ultra-lung protective/‘lung rest’ ventilation in ARDS patients with poor lung compliance. During the H1N1 influenza pandemic, a meta-analysis of 266 patients with severe ARDS supported with VV-ECMO showed a survival rate of 72.5%, albeit with prolonged hospitalisations.1 While previous reports on VV-ECMO in ARDS are encouraging, initial reports of its use in Chinese COVID-19 patients have been less promising. Of the six patients placed on ECMO in Wuhan, China, only one survived to hospital discharge.2 In Shanghai, only four of eight patients survived to ECMO decannulation.3 Early US data are similarly grim. A compiled study of 32 patients from nine different centres in the US showed a mortality rate of 31%, with 53% patients still on ECMO after 3 weeks.4 However, there remains a paucity of literature on its

utilisation and efficacy in the treatment of COVID-19-associated ARDS, especially among US patients.

Methods Baylor-St Luke’s Medical Center is a large, academic quaternary hospital with 661 beds in the Texas Medical Center, Houston, TX, US. It serves as a centre for advanced heart failure and heart transplantation, with a robust volume of mechanical circulatory support, including ECMO (approximately 100–150 per year). We present a case series of seven consecutive polymerase chain reaction-confirmed diagnoses of COVID-19 patients admitted to our centre between 29 March and 8 May 2020. Prior to the initiation of ECMO, patients were screened for major comorbidities, with an absolute age cut-off age of >65 years and predicted survival based on a RESP score of <40%.

Results The mean age of our cohort was 45 years and comprised three men and four women. The most common baseline comorbidities included obesity (four patients, mean BMI: 35.7) and hypertension (three patients). There was no history of smoking, chronic obstructive pulmonary disease, asthma, chronic kidney disease or coronary artery disease. Only one of seven (14%) patients had a prior history of diabetes mellitus, heart failure or angiotensin-converting enzyme/angiotensin receptor blocker use. A comprehensive list of baseline characteristics is provided in Table 1. Patients presented to the hospital on average 7 days after onset of symptoms, spent 1.9 days in hospital prior to intubation and 3.7 days from the time of intubation to the initiation of ECMO. All had refractory hypoxia, despite lung-protective ventilation; neuromuscular blockade; inhaled epoprostenol; and underwent prone position ventilation. Average positive end-expiratory pressure was 16.9 mmHg, with tidal volume of 5.75 ml/kg of ideal body weight and PaO2/FiO2 ratio of 84.5 prior to ECMO initiation. There was evidence of left and right ventricle dysfunction based on gross visual assessment in one patient, with a mean left ventricular ejection fraction of 55 ± 9%. The average RESP score was 3.7 at the time of ECMO cannulation. Hydroxychloroquine (six patients), azithromycin (seven patients) and hydrocortisone (100%)

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Letter to the Editor Table 1: Baseline Characteristics of Extracorporeal Membrane Oxygenation Cohort Age

45.2 ± 14.5 years

Male

42.8% (3/7)

Hypertension

42.8% (3/7)

Diabetes

14.3% (1/7)

Chronic kidney disease

Coronary artery disease

Heart failure

14.3% (1/7)

Prior smoker

Chronic obstructive pulmonary disease

Obesity (BMI ≥30)

57.1% (4/7)

Mean BMI

35.7 ± 9.2

Prior use of ACE/ARB

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

Table 2: Time to Hospitalisation, Pulmonary Status and Therapeutics Prior to the Initiation of ECMO Time from symptom onset to hospitalisation

5.0 ± 2.3 days

Time from symptom onset to intubation

6.9 ± 2.5 days

Time from intubation to ECMO initiation

3.7 ± 2.7 days

PEEP at time of ECMO

16.8 ± 3.0 mmHg

PaO2/FiO2 ratio at time of ECMO

88.6 ± 33.0

LVEF at time of ECMO

55 ± 9.1%

Incidence of RV dysfunction at time of ECMO

14.2% (1/7)

Therapeutics prior to ECMO Inhaled epoprostenol

100%

Mechanical proning

100%

Paralytics

100%

Steroids (hydrocortisone or methylprednisolone)

100%

Azithromycin

100%

Hydroxychloroquine

85.7% (6/7)

Tocilizumab (compassionate use)

14.2% (1/7)

ACCT trial enrolment

14.2% (1/7)

COVACTA trial enrolment

14.2% (1/7)

Convalescent plasma

57.1% (4/7)

IV immunoglobulin

14.2% (1/7)

ECMO = extracorporeal membrane oxygenation; LVEF= left ventricular ejection fraction; RV = right ventricle.

Table 3: Patient Outcomes VA-ECMO (n=1) Decannulated

1 (ECMO duration: 41 days)

VV-ECMO (n=6) Decannulated

5 (ECMO duration: 16 ± 8.6 days)

Deceased

1 (hospital day 28, ECMO duration: 8 days)

Discharged

1 (hospital day 40, ECMO duration: 7 days)

ECMO = extracorporeal membrane oxygenation; VA = veno-arterial; VV = venous–venous.

use was almost universal in our study cohort. Four patients were treated with at least one dose of convalescent plasma, while tocilizumab (for compassionate use 1/7, 14%) and IV immunoglobulin (1/7, 14%)

were rarely used (Table 2). One patient was enrolled in the Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA), and another patient was enrolled in the Adaptive COVID-19 Treatment Trial (ACTT) for remdesivir. At time of this report, one patient died from haemorrhagic shock on hospital day 23 after 8 days of VV-ECMO. The remaining six patients were decannulated from ECMO, and one patient was discharged home on hospital day 40 (Table 3). For all surviving patients, Acute Physiology and Chronic Health Evaluation (APACHE) II scores decreased from 28.8 at the time of ECMO initiation to 11.8 (p<0.001) over their clinical course. Similarly, Sequential Organ Failure Assessment (SOFA) scores dropped from 10.1 to 4.4 (p<0.001) (Table 4).

Discussion ECMO is a well-established salvage therapy in the treatment of severe refractory ARDS. However, its role in the treatment of COVID-19associated ARDS currently remains unknown. Our report describes the clinical course of COVID-19 patients treated with ECMO at a major highvolume academic medical centre in the US. The key findings of our study are as follows. First, the majority of our patients were successfully weaned off ECMO and continue to show clinical improvement. Second, COVID-19 patients require a prolonged runtime on ECMO prior to being weaned off. Third, the RESP score appears to be a reliable measure in predicting outcomes among COVID-19 patients treated with ECMO. Although clinical guidelines for the management of COVID-19 have been published by the WHO and Surviving Sepsis Campaign, the role of ECMO as salvage therapy for severe ARDS remains unclear, in part due to the lack of published evidence.5,6 Current observational studies from China and the US have not been encouraging.2,3 Our retrospective analysis provides evidence to the contrary. There are several plausible explanations for our findings. We are very proactive in ensuring early (48–72 hours) evaluation of our severe ARDS COVID-19 patients for ECMO cannulation if they show no improvement or clinical worsening on conventional therapy. As a matter of institutional practice, ECMO eligibility is discussed on daily bedside rounds for each of our COVID-19 intensive care unit (ICU) patients. As previously mentioned, ECMO renders clinical benefit by allowing ‘lung rest’ ventilation, and thus minimising the risk of ventilator-induced lung injury in non-complaint lungs. Therefore, it is imperative that ECMO be initiated early on in the disease process before irreversible lung damage ensues. The average number of days on mechanical ventilation prior to ECMO in the Shanghai cohort was just over 10 days, whereas that of our cohort was significantly lower at 3.7 days.3 The optimal selection of patients most likely to benefit from ECMO also appears to have contributed to the differences in outcomes between our cohort and the Shanghai cohort. In our study, we used the RESP score to calculate the probability of hospital survival and used 40% as our arbitrary cut-off for who was offered treatment with ECMO. On the contrary, ECMO was offered more broadly in the Shanghai cohort to any patient that met any of the following criteria, despite optimal mechanical ventilation: PaO2/FiO2 <50 mmHg for >1 hour; PaO2/FiO2 <80 mmHg for >2 hours; and the existence of uncompensated respiratory acidosis with PH <7.2 for >1 hour. It is crucial to appreciate that ECMO is a resource-intensive, highly-specialised and expensive form of life support, with the potential of significant complications, and thus should only be reserved for truly refractory cases that are most likely to benefit from it. While the RESP score has not been directly validated in the

CARDIAC FAILURE REVIEW

Extracorporeal Membrane Oxygenation in COVID-19 COVID-19 cohort, our study suggests that it still remains a relevant and reliable predictor of outcomes.7 Another key finding of our study was the prolonged ECMO runtime among our COVID-19 patients. Anecdotal reports and our experience in the COVID-19 ICU suggest that COVID-19 patients require supportive care for a much longer time than conventional ARDS patients. Houston has not seen the same surge of COVID-19 patients as other global epicentres, such as Wuhan, Lombardy and New York, and this has allowed us to allocate our ECMO circuits to our COVID-19 patients for extended durations. This too has contributed to our favourable outcomes. However, it is important to note that ECMO is a finite resource, and thus must be used judiciously, especially in the midst of a pandemic where all resources are stretched thin.

Zangrillo A, Biondi-Zoccai G, Landoni G, et al. Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: a systematic review and meta-analysis including 8 studies and 266 patients receiving ECMO. Crit Care 2013;17:R30. https://doi.org/10.1186/cc12512; PMID: 23406535. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061–9. https:// doi.org/10.1001/jama.2020.1585; PMID: 32031570. Li X, Guo Z, B Li, et al. Extracorporeal membrane oxygenation for coronavirus disease 2019 in Shanghai, China. ASAIO J

CARDIAC FAILURE REVIEW

Table 4: Change in Prognostic Scoring Systems for Survivors APACHE II score before ECMO (n=6)

APACHE II score as of 25 April 2020

28.8 ± 3.4

12.3 ± 5.0 (p<0.001)

SOFA score before ECMO (n=6)

SOFA score as of 25 April 2020

10.1 ± 2.9

4.8 ± 2.8 (p<0.001)

APACHE = Acute Physiology and Chronic Health Evaluation; ECMO = extracorporeal membrane oxygenation; SOFA = Sequential Organ Failure Assessment.

Conclusion ECMO can be a valuable tool in the management of COVID-19-associated ARDS if implemented early and in carefully selected patients.

2020;66:475–81. https://doi.org/10.1097/ MAT.0000000000001172; PMID: 32243266. Jacobs JP, Stammers AH, St Louis J, et al. Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in COVID-19: experience with 32 patients. ASAIO J 2020. https://doi.org/10.1097/ MAT.0000000000001185; PMID: 32317557; epub ahead of press. WHO. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance. Geneva: WHO; 2020. https://apps.who.int/iris/ bitstream/handle/10665/330854/WHO-nCoV-Clinical-2020.2-

eng.pdf (accessed 19 June 2020). Alhazzani W, Hylander Møller M, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med 2020;48:e440–69. https://doi.org/10.1097/ CCM.0000000000004363; PMID: 32224769. Schmidt M, Bailey, M, Sheldrake J, et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med 2014;189:1374–82. https://doi.org/10.1164/ rccm.201311-2023OC; PMID: 24693864.

COVID-19

Coronavirus Disease 2019: Where are we and Where are we Going? Intersections Between Coronavirus Disease 2019 and the Heart Emilia D’Elia and Michele Senni Cardiovascular Department, ASST Papa Giovanni XXIII, Bergamo, Italy

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has become a pandemic affecting every country in the world. In the province of Bergamo, Italy, more than 2,200 cases of COVID-19 have been reported, which include more than 300 deaths. Most hospitalisations have been at the Papa Giovanni XXIII Hospital. This has imposed a significant burden on our hospital in terms of healthcare personnel, dedicated spaces (including intensive care areas) and time spent by clinicians, who are committed to assisting COVID-19 patients. In this short expert opinion, the authors will focus on new insights related to COVID-19 and the cardiovascular system, and try to investigate the grey areas and uncertainties in this field.

Keywords Coronavirus disease 2019, cardiovascular system, hospital organisation, personal protection equipment, grey areas Disclosure: The authors have no conflicts of interest to declare. Received: 30 April 2020 Accepted: 19 May 2020 Citation: Cardiac Failure Review 2020;6:e18. DOI: https://doi.org/10.15420/cfr.2020.11 Correspondence: Michele Senni, Cardiovascular Department, Hospital Papa Giovanni XXIII, Piazza OMS 1, Bergamo, Italy. E: msenni@asst-pg23.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has reached a pandemic level worldwide. 1 Bergamo was the first western town affected by the COVID-19 pandemic and has the sad record of being the city with the highest number of COVID-19 cases and deaths, not only in the Lombardy region but also throughout Italy and the world. The first documented case at Papa Giovanni Hospital in Bergamo was recorded on 23 February 2020. The epidemic was unexpected, violent and prolonged; it was not comparable with any other natural event (such as a tsunami), but was more like trench warfare after a sustained attack. Although most patients are asymptomatic or have mild symptoms, in up to 15% of infected patients the clinical course of this pathology may be complicated by the onset of a severe form of interstitial pneumonia, which may progress towards acute respiratory distress syndrome (ARDS), multi-organ failure and death.2–3 An important, instructive finding gradually emerging from mini autopsies is that damage to the lungs with loss of surfactant is uneven (with serious structural alterations in patches), which is different from typical ARDS where the lung becomes wet and heavy, and is globally damaged. For this reason, lying prone allows more alveoli to be recruited and improves respiratory exchange. Although lung infection is the predominant pathophysiological scenario, awareness is increasing of the negative impact of the intersection between SARS-CoV-2 infection and the heart on prognosis. This intersection is related to underlying cardiovascular (CV) comorbidities

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(such as hypertension, diabetes and coronary artery disease) and direct involvement of the heart.4–6 Several case series and CV reports are coming out in the literature with the aim of shedding light on the cardiac implications of COVID-19 to make the international cardiology community better prepared worldwide, even in cases of not easily identified manifestations of the viral infection.7–10

How Hospitals can Prepare for COVID-19 In the coronavirus era, the organisation of wards and intensive care units in hospitals is of fundamental importance, considering that from one day to the next there could be changes depending on the level of the epidemic. First of all, during the ascending or the peak phase of the pandemic, patients with acute MI need a clean, fast track from the emergency room to the cath lab to avoid the risk of acquiring a SARS-CoV-2 infection. Every cardiology patient with or without symptoms suspected to have a SARS-CoV-2 infection should be given a swab test for the virus so they can be placed in an appropriate area of the cardiology department. The cardiology department should be organised into: a SARS-CoV-2free area; a SARS-CoV-2 area; and a grey area, which hosts patients suspected of having COVID-19 but whose first swab test was negative (given the high incidence of false negatives in nasopharyngeal swabs tests). In this early phase, a significant reduction in the absolute number of acute coronary syndromes and hospitalisation for heart failure (HF) was observed in the entire province of Bergamo.

Intersections Between COVID-19 and the Heart During the plateau phase, the cardiology department needs to be reorganised to meet the needs of hospitalised patients and those waiting for admission, maintaining a fluidity of beds (patient flow) to optimise the work of all medical staff. Another important recommendation we have learnt to adopt is to give priority to protecting hospital healthcare staff. A correct, constant use of personal protection equipment (PPE), preferably worn in case of contact with any patient, even if not clearly positive, should always be considered. We doctors should not underestimate the risk that we can unwittingly be a vehicle of infection if we do not adopt the appropriate safety measures using PPE. It is appropriate to test all medical staff with serological investigations to be aware of possible contagion, and to take the necessary precautions for both personal and professional life. Another suggestion is to enhance and implement telemedicine or telephone calls by nursing staff to manage patients with heart failure or chronic CV disease so they can monitor patients remotely, be aware of clinical events and give therapeutic advice to counteract any deterioration in underlying cardiological conditions. From a human perspective, on the front line in the hospital, we learnt at our expense that COVID-19 is highly and inexorably contagious. Almost 25% of our colleagues have been infected, which has significant repercussions for the workload of cardiologists who remained healthy or asymptomatic, but positive. Moreover, the wave of patients who entered our emergency room over a few days dramatically surprised us, filling spaces, organisations and all the comfort zones within the hospital in which we were used to living and sharing. As cardiologists, we therefore had to learn to adapt to a new, more worrying working conditions. One of the most challenging clinical scenarios we had to face was the recognition of signs and symptoms of HF in patients with COVID-19 pneumonia. In cases of fluid overload and pleural effusion, chest X-rays show pulmonary imbibition, which can be confused with interstitial infiltrates typical of COVID-19, especially if bilateral. Therefore, it often happened that one pathology masked the other, and we had to deal with cases of re-exacerbations of HF in cardiology patients affected by COVID-19, as if the infectious trigger precipitated the already weak haemodynamic compensation. As we also are an advanced HF centre, we observed a very high incidence of patients who had had heart transplants hospitalised for acute respiratory syndrome due to COVID-19 pneumonia, and deaths often occurred, especially in patients with longstanding heart transplants. As we also found, another sensitive issue concerns the management of patient with ST-elevation MI (STEMI) with pulmonary impairment. In our series of almost 50 patients admitted to the cath lab for acute coronary syndrome (both STEMI and non-STEMI), an age above 75 years, hypertension and diabetes were more frequently observed in COVID-19 compared to control patients. In-hospital mortality was more than 40% in patients with COVID-19 and 0% in the control group. Of note, patients who died presented with severe hypoxic respiratory failure, frequently combined with a reduced ejection fraction of the left ventricle (unpublished data).

CARDIAC FAILURE REVIEW

Cardiovascular Involvement: Several Doubts and Few Certainties COVID-19 causes not only pulmonary involvement with respiratory failure mainly due to bilateral interstitial pneumonia, but also systemic multi-organ involvement with a strong inflammatory response mediated by cytokines and interleukins.11,12 An important issue related to the CV impact of COVID-19 is the development of myocardial injury in infected patients, as reported in two Chinese studies by Shi et al. and Guo et al.13,14 Elevated troponin levels were detected in a cohort of hospitalised COVID-19 subjects; specifically, the higher the troponin levels, the higher the in-hospital mortality. Of note, the highest mortality rate was found in patients with a history of CV disease, as if a pathological cardiac substrate contributed to a poorer prognosis. Other recent observations corroborate this hypothesis, suggesting that patients with underlying CV comorbidities are most likely to experience complications from COVID-19, including death. At the cardiac level, few cases of myocarditis due to direct cardiac damage have recently been reported, and coronavirus has been found in histological slides of myocytes from infected patients, highlighting a marked cardiac tropism.7â&#x20AC;&#x201C;9 As mentioned above, an intense network of cytokines and chemokines are activated during COVID-19 infection, causing both vascular and myocardial inflammation, the latter probably due to a viral direct damage of the myocardium. Recently, Tavazzi et al. described a case of an acute cardiac injury directly linked to myocardial localisation of COVID-19, with an endomyocardial biopsy demonstrating viral particles, suggesting either a viraemic phase or macrophage migration from the lung.15 In this regard, a remarkable aspect to be investigated and clarified in the near future is the prevalence of myocarditis. Several reports show that patients at greater risk of developing acute myocarditis triggered by COVID-19 already have increased troponin values at first contact in the emergency room.7,16 Therefore, proper identification of those patients would be important to diagnose myocarditis, even in an atypical clinical scenario. Other cardiac effects of COVID-19 are related to ischaemic cardiac injury secondary to hypoxia, thrombosis of the microvascular vessels and MI due to thrombosis of the epicardial coronary artery. The role of not only troponins but also other cardiac biomarkers in confirmed cases of COVID-19 are uncertainties that needed to be addressed. In a retrospective analysis involving 799 patients with COVID-19 in Wuhan, concentrations of cardiac troponin I, N-terminal pro-brain natriuretic peptide and D-dimer were markedly higher in deceased patients than in recovered ones.17 Cardiac biomarker elevation seems to be a prominent feature in COVID-19 associated with worseÂ outcomes.13,18 Surprisingly, the mortality risk associated with elevated circulating biomarkers of acute cardiac injury was more significant than age, diabetes, chronic pulmonary disease or history of CV disease.12 In all this, the fact that comorbidities play a key role in the clinical evolution of COVID-19 patients and affect prognosis has been demonstrated and deserves attention.19 In particular, elderly people with CV comorbidities, included hypertension and a history of coronary artery disease, have a greater risk of a having a more severe clinical picture and a fatal outcome.20

COVID-19 A well-discussed grey area for cardiologists is concern regarding the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients with COVID-19. Recently, Reynolds at al. examined the relationship between previous treatment with angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), beta-blockers, calcium-channel blockers or thiazide diuretics and the likelihood of a positive or negative result of the swab test for COVID-19 among 12,594 patients. No association between any single medication class or an increased likelihood of a positive test was observed, nor were any medications associated with a substantial increase in the risk of severe illness in patients who tested positive.21 Similarly, Mancia et al. observed that, among a population of 6,272 positive patients in Lombardy, there was no evidence that ACE inhibitors or ARBs affected the risks of COVID-19.22 An important grey area for cardiologists is making a correct differential diagnosis between HF and pneumonia, since the symptoms often overlap. While it is true that in the acute phase of the pandemic many HF patients avoided the emergency room because they were afraid of being infected by COVID-19 in the hospital (with a consequent reduction of HF hospitalisations), it is also true that many complicated cases are now being observed. It is therefore inevitable that, in the near future, we will have to address this difficult issue, and try to

Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol 2020:27204. https://doi. org/10.1016/j.jacc.2020.03.031; PMID: 32201335. Alhazzani W, Hylander Møller M, Arabi YM, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (COVID-19). Crit Care Med 2020. https://doi.org/10.1097/CCM.0000000000004363; PMID: 32224769; epub ahead of press. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis 2020:101623. https://doi.org/10.1016/j.tmaid.2020.101623; PMID: 32179124; epub ahead of press. Ammirati E, Wang DW. SARS-CoV-2 inflames the heart. The importance of awareness of myocardial injury in COVID-19 patients. Int J Cardiol 2020. https://doi.org/10.1016/j. ijcard.2020.03.086; PMID: 32276774; epub ahead of press. Dixon DL, Van Tassell BW, Vecchié A, et al. Cardiovascular considerations in treating patients with coronavirus disease 2019 (COVID-19). J Cardiovasc Pharmacol 2020;75:359–67. https://doi.org/10.1097/FJC.0000000000000836; PMID: 32282502. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17: 259–60. https://doi.org/10.1038/s41569-020-0360-5; PMID: 32139904. Inciardi RM, Lupi L, Zaccone G et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) JAMA Cardiol 2020. https://doi.org/10.1001/jamacardio.2020.1096; PMID: 32219357; epub ahead of press. Zeng JH, Liu YX, Yuan J et al. First case of COVID-19

10.

11.

12.

13.

14.

15.

16.

acquire the knowledge and tools to categorise a patient properly as soon as possible. Interesting pathophysiological issues concern the right ventricle in regard to pressure overload due to pulmonary embolism, which is increasingly being documented in COVID-19 patients. This is probably due to an impaired coagulation drive with activation of fibrinolysis processes, and fluid overload because of a pulmonary shunt. In the end, from our perspective, COVID-19 has changed how our work is organised and the approach to clinical practice, leading us to study a new, unknown disease, with many grey areas and more doubts than certainties.23 We, therefore, propose some reflections that around three questions. • There is a clear intersection between the SARS-CoV-2 infection and the heart. How much will cardiac injury or pulmonary embolism due to COVID-19 affect the natural history of patients with chronic HF following the acute phase of the infection? • We all are facing a new disease and there are several doubts around it. Will the attitude of cardiologists, who have always been trained to work using the evidence-based medicine, have to be changed? • In a short time, international literature has provided a large number of articles related to COVID-19 and clinicians learn rapidly from each other. Is it more scientifically correct to think of waiting for robust data before drawing conclusions about the CV impact of COVID-19?

complicated with fulminant myocarditis: a case report and insights. Infection. 2020. https://doi.org/10.1007/s15010-02001424-5; PMID: 32277408; epub ahead of press. Kim IC, Kim JY, Kim HA, Han S. COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart J 2020;41:1859. https:// doi.org/10.1093/eurheartj/ehaa288; PMID: 32282027. Ullah W, Saeed R, Sarwar U, Patel R, Fischman DL. COVID-19 complicated by acute pulmonary embolism and right-sided heart failure. JACC Case Rep 2020. https://doi.org/10.1016/j. jaccas.2020.04.008; PMID: 32313884; epub ahead of press. Mehra M RF, Ruschitzka F. COVID-19 illness and heart failure: a missing link? JACC Heart Fail 2020;S2213-1779(20)30150-5. https://doi.org/10.1016/j.jchf.2020.03.004; PMID: 32360242. Zhang Y, Gao Y, Qiao L, Wang W, Chen D. Inflammatory response cells during acute respiratory distress syndrome in patients with coronaviurs disease 2019 (COVID-19). Ann Inter Med 2020. https://doi.org/10.7326/L20-0227; PMID: 32282871; epub ahead of press. Shi S, Qin M, Shen B et al. Association of cardiac injurt with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020. https://doi.org/10.1001/ jamacardio.2020.0950; PMID: 32211816; epub ahead of press. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID19). JAMA Cardiol. 2020;e201017. https://doi.org/10.1001/ jamacardio.2020.1017; PMID: 32219356. Tavazzi G, Pellegrini C, Maurelli M et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 2020. https://doi.org/10.1002/ejhf.1828; PMID: 32275347; epub ahead of press. Qiu H, Tong Z, Ma P, et al; China Critical Care Clinical Trials Group. Intensive care during the coronavirus epidemic.

Intensive Care Med 2020;46:576–8. https://doi.org/10.1007/ s00134-020-05966-y; PMID: 32077996. 17. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091. https://doi. org/10.1136/bmj.m1091; PMID: 32217556. 18. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846–8. https:// doi.org/10.1007/s00134-020-05991-x; PMID: 32125452. 19. Gabutti G, d’Anchera E, Sandri F, Savio M, Stefanati A. Coronavirus: update related to the current outbreak of COVID19. Infect Dis Ther 2020. https://doi.org/10.1007/s40121-02000295-5; PMID: 32292686; epub ahead of press. 20. Wu Z, McGoogan JM. Characteristics of and important lesson from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; https:// doi.org/10.1001/jama.2020.2648; PMID: 32091533; epub ahead of press. 21. Reynolds HF, Adhikari S, Pulgarin C. et al. Renin-angiotensinaldosterone system inhibitors and risk of COVID-19. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2008975; PMID: 32356628; epub ahead of press. 22. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Reninangiotensin-aldosterone system blockers and the risk of COVID-19. N Engl J Med 2020 May 1. https://doi.org/10.1056/ NEJMoa2006923; PMID: 32356627; epub ahead of press. 23. Senni M. COVID-19 experience in Bergamo, Italy. Eur Heart J 2020;41:1783–4. https://doi.org/10.1093/eurheartj/ehaa279; PMID: 32255476.

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Pharmacological Therapy

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use Zoltán Papp,1 Piergiuseppe Agostoni,2 Julian Alvarez,3 Dominique Bettex,4 Stefan Bouchez,5 Dulce Brito,6 Vladimir Černý,7 Josep Comin-Colet,8 Marisa G Crespo-Leiro,9 Juan F Delgado,10 Istvan Édes,1 Alexander A Eremenko,11 Dimitrios Farmakis,12 Francesco Fedele,13 Cândida Fonseca,14 Sonja Fruhwald,15 Massimo Girardis,16 Fabio Guarracino,17 Veli-Pekka Harjola,18 Matthias Heringlake,19 Antoine Herpain,20 Leo MA Heunks,21 Tryggve Husebye,22 Višnja Ivancan,23 Kristjan Karason,24 Sundeep Kaul,25 Matti Kivikko,26 Janek Kubica,27 Josep Masip,28 Simon Matskeplishvili,29 Alexandre Mebazaa,30 Markku S Nieminen,31 Fabrizio Oliva,32 Julius-Gyula Papp,33 John Parissis,34 Alexander Parkhomenko,35 Pentti Põder,36 Gerhard Pölzl,37 Alexander Reinecke,38 Sven-Erik Ricksten,39 Hynek Riha,40 Alain Rudiger,41 Toni Sarapohja,42 Robert HG Schwinger,43 Wolfgang Toller,44 Luigi Tritapepe,45 Carsten Tschöpe,46 Gerhard Wikström,47 Dirk von Lewinski,48 Bojan Vrtovec49 and Piero Pollesello50 1. Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 2. Department of Clinical Sciences and Community Health, Centro Cardiologico Monzino, IRCCS, Milan, Italy; 3. Department of Surgery, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; 4. Institute of Anaesthesiology, University Hospital of Zurich, Zurich, Switzerland; 5. Department of Anaesthesiology, University Hospital, Ghent, Belgium; 6. Cardiology Department, Centro Hospitalar Universitario Lisboa Norte, CCUI, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; 7. Department of Anaesthesiology, Perioperative Medicine and Intensive Care, Masaryk Hospital, J.E. Purkinje University, Usti nad Labem, Czech Republic; 8. Heart Diseases Institute, Hospital Universitari de Bellvitge, Barcelona, Spain; 9. Complexo Hospitalario Universitario A Coruña (CHUAC), CIBERCV, Instituto de Investigacion Biomedica A Coruña (INIBIC), Universidad de a Coruña (UDC), La Coruña, Spain; 10. Heart Failure and Transplant Program, Cardiology Department, University Hospital 12 Octubre, Madrid, Spain; 11. Department of Cardiac Intensive Care, Petrovskii National Research Centre of Surgery, Sechenov University, Moscow, Russia;12. Department of Cardiology, Medical School, University of Cyprus, Nicosia, Cyprus; 13. Department of Cardiovascular, Respiratory, Nephrology, Anaesthesiology and Geriatric Sciences, La Sapienza University of Rome, Rome, Italy; 14. Heart Failure Clinic, São Francisco Xavier Hospital, CHLO, Lisbon, Portugal; 15. Department of Anaesthesiology and Intensive Care Medicine, Division of Anaesthesiology for Cardiovascular Surgery and Intensive Care Medicine, Medical University of Graz, Graz, Austria; 16. Struttura Complessa di Anestesia 1, Policlinico di Modena, Modena, Italy; 17. Dipartimento di Anestesia e Terapie Intensive, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 18. Emergency Medicine, Meilahti Central University Hospital, University of Helsinki, Helsinki, Finland; 19. Department of Anaesthesiology and Intensive Care Medicine, University of Lübeck, Lübeck, Germany; 20. Department of Intensive Care, Hôpital Erasme, Brussels, Belgium; 21. Department of Intensive Care Medicine, Amsterdam UMC, Amsterdam, the Netherlands; 22. Department of Cardiology, Oslo University Hospital Ullevaal, Oslo, Norway; 23. Department of Anaesthesiology, Reanimatology and Intensive Care, University Hospital Centre, Zagreb, Croatia; 24. Departments of Cardiology and Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden; 25. Intensive Care Unit, National Health Service, Leeds, UK; 26. Global Medical Affairs, R&D, Orion Pharma, Espoo, Finland; 27. Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Torun, Poland; 28. Intensive Care Department, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain; 29. Lomonosov Moscow State University Medical Centre, Moscow, Russia; 30. Department of Anaesthesiology and Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, Paris, France; 31. Sydäntutkimussäätiö, Helsinki, Finland; 32. Department of Cardiology, Niguarda Ca’Granda Hospital, Milan, Italy; 33. MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary; 34. Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 35. Emergency Cardiology Department, National Scientific Centre MD Strazhesko Institute of Cardiology, Kiev, Ukraine; 36. Department of Cardiology, North Estonia Medical Centre, Tallinn, Estonia; 37. Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria; 38. Klinik für Innere Medizin III, Kardiologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany; 39. Department of Anaesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden; 40. Cardiothoracic Anaesthesiology and Intensive Care, Department of Anaesthesiology and Intensive Care Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 41. Department of Medicine, Spittal Limmattal, Schlieren, Switzerland; 42. Statistical Services, R&D, Orion Pharma, Espoo, Finland; 43. Medizinische Klinik II, Klinikum Weiden, Teaching Hospital of University of Regensburg, Weiden, Germany; 44. Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria; 45. Anaesthesia and Intensive Care Division, San Camillo-Forlanini Hospital, Rome, Italy; 46. Department of Cardiology, Campus Virchow Klinikum, Charité – University Medicine Berlin, Berlin, Germany; 47. Institute of Medical Sciences, Uppsala University, Uppsala, Sweden; 48. Department of Cardiology, Myokardiale Energetik und Metabolismus Research Unit, Medical University of Graz, Graz, Austria; 49. Advanced Heart Failure and Transplantation Centre, Department of Cardiology, University Clinical Centre, Ljubljana, Slovenia; 50. Critical Care Proprietary Products, Orion Pharma, Espoo, Finland

Access at: www.CFRjournal.com

Pharmacological Therapy

Abstract Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Keywords Acute heart failure, advanced heart failure, haemodynamics, inodilator, inotrope, neurohormone, regulatory clinical trial Disclosure: PP, TS and MK are full- or part-time employees of Orion Pharma. In the past 5 years, all other authors have received honoraria from Orion Pharma for educational lectures and/or unrestricted grants for investigator-initiated studies. Acknowledgements: The authors acknowledge Hughes Associates, Oxford, UK, for assistance in the editing of the manuscript. They thank Shrestha Roy for the initial graphic renditions of figures. Received: 6 February 2020 Accepted: 16 March 2020 Citation: Cardiac Failure Review 2020;6:e19. DOI: https://doi.org/10.15420/cfr.2020.03 Correspondence: Piero Pollesello, Orion Pharma, PO Box 65, FIN-02101 Espoo, Finland. E: piero.pollesello@orionpharma.com Open Access: This work is open access under the CC-BY 4.0 License which allows users to copy, redistribute and make derivative works, provided the original work is cited correctly.

Origins of a Unique Cardiovascular Agent Before the 1980s, therapy to enhance cardiac contractility in heart failure (HF) substantially meant oral digitalis glycosides, supplemented by beta-adrenergic agonists such as dopamine or dobutamine (introduced in the middle of the 1970s) in acute situations.1 It was therefore a matter of some note when the US Food and Drug Administration approved a new agent as a short-term IV therapy for patients with refractory HF. Amrinone was the product of a widespread research initiative that recognised the limitations of existing inotropic therapy and which, equipped with a new understanding of the cellular mechanisms of cardiac contractility, set out to develop what respected commentators of the time referred to as “non-glycoside, nonsympathomimetic positive inotropic agents”.2–4 Amrinone was the first agent to reach clinical use from the small but important family of phosphodiesterase (PDE) inhibitors, which would later include milrinone and enoximone.5,6 However, despite being nonsympathomimetic positive inotropic agents, all PDE inhibitors, in common with the catecholamines, were shown to be calcium mobilisers, probably due to their limited selectivity towards specific key PDE isoforms, and shared with catecholamines some unwanted effects intrinsic to any drug that raises intracellular calcium. In fact, all calcium mobilisers, by definition, exert an inotropic effect by providing increased ionic calcium levels for the contractile protein machinery, a process that may ultimately prove detrimental to individual cardiomyocytes and therefore also to patients.7 At about the same time, a new concept was proposed by the independent groups of J Caspar Rüegg in Heidelberg and R. John Solaro in Chicago, namely the potential of new agents to enhance the sensitivity to calcium of key targets in the contractile apparatus instead of increasing the intracellular calcium transient to augment

contractility.8,9 In 1984, Rüegg et al. described the pharmacology of a new agent, later known as pimobendan, which combined PDE inhibitor activity with a direct calcium-sensitising effect.10 It was in this climate of innovation that the new chemical entity R-((4(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono) propanedinitrile, known by the identifier OR-1259 at the time, appeared in the published records. An abstract was published in 1992 describing “a positive inotropic and vasodilatory compound with antiarrhythmic properties”.11 This preliminary report noted that OR-1259 exerted a positive inotropic effect despite a reduction in the voltage-sensitive Ca2+ current. As is not uncommon in abstract reports, the authors advised that “further studies… are in progress”. In 1995, Heimo Haikala reported the findings of in-depth research into the mechanism of action of this agent in his pioneering paper.12 At the same time, a paper describing the binding of a new Ca2+ sensitiser, levosimendan, to recombinant human cardiac troponin C was also published.13 Those first descriptions may be regarded as foundation publications in the chronology of this drug, and a starting point for the PubMed-cited literature on levosimendan, which had expanded to almost 1,500 reports by the end of 2019. Levosimendan was described as “a calcium sensitiser rationally designed and screened to act through its calcium-dependent binding to cardiac troponin C”, and the experimental basis for this description was set out in detail.12 From the beginning, clear mechanistic differences were spotted between levosimendan and several other drugs then in development, including pimobendan, MCI-154 and EMD 53998. Levosimendan was a first-in-class agent at the time of its emergence, promoting inotropy mainly through calcium sensitisation of

CARDIAC FAILURE REVIEW

Levosimendan Efficacy and Safety cardiac troponin C (cTnC). More than 20 years later it remains, remarkably, an only-in-class drug, with a mechanism of action that clearly differentiates it from adrenergic agents.

Figure 1: Early Molecular Model of the Levosimendan–cTnC Complex

Levosimendan, as reported by Pollesello et al. in 1994, binds to calciumsaturated human cTnC “in a hydrophobic patch of the N-domain near the site where the B helix is located when the protein is in its apoform”.13 Figure 1 shows an original diagram from the 1994 paper proposing a molecular model of the drug–ligand complex. That interaction leads to a stabilisation of the calcium-bound conformation of the regulatory (or N) domain of cTnC, which in turn causes a change in the conformation of the ‘switch’ region of cardiac troponin I (cTnI) and detachment of cTnI from actin filaments.14 Removal of the inhibitory effects of cTnI facilitates the formation of actin–myosin cross-bridges and the dis-inhibition of acto-myosin adenosine triphosphate (ATP) synthase, resulting in enhanced cardiac contractility.12,13,15–18 These findings, confirming that the binding of levosimendan to TnC is linked to calcium sensitisation, proved to be the first stage of what has since matured into a long-lasting research trail.19–22

28 23

The calcium-sensitising action of levosimendan is manifested as a leftward shift in the curve describing the relation between contractile force and calcium concentration, achieved via a direct effect on cTnC. That augmentation of contractility is not associated with increases in calcium transients, intracellular calcium or myocardial oxygen consumption and is not compromised by pre-treatment with betablockers. It should also be noted that the interaction between levosimendan and cTnC was shown to be more intense at high, systolic ionic calcium levels than at low, diastolic calcium levels, thus avoiding impairment of myocardial relaxation upon levosimendan administration. In addition to its principal action as a calcium-sensitising agent, levosimendan was found in the course of its development programme to mediate the opening of ATP-dependent potassium channels (KATP channels) in vascular smooth muscle cells in various vascular beds.23 By this mechanism of action, levosimendan induces an increase in blood perfusion in key organs and a systemic vasodilatation when levosimendan is used at doses within the recognised therapeutic range, which means that the drug must be considered and used as an inodilator and not simply as an inotrope. An essential aspect of the pharmacology and clinical profile of levosimendan is that its perfusion enhancement and systemic vasodilation effects are mediated through different mechanisms and may therefore be disentangled from each other. Levosimendan – acting on KATP channels – has a different regional/peripheral versus systemic effect when compared with drugs such as the PDE inhibitors.24 Separate emphasis must be placed on the discovery that levosimendan also opens the KATP channels on the mitochondrial inner membrane.25,26 This effect has been associated with cardioprotection, infarct size reduction and mitigation of ischaemia/reperfusion injuries in a range of in vitro, ex vivo and in vivo studies in non-human species,27–31 and in clinical studies.32 The aforementioned effects deriving from calcium sensitisation and vasodilation are shared by the long-acting levosimendan metabolite OR-1896, which is formed in the intestine via a reduction–acetylation pathway.33–35 Free plasma concentrations of the parent drug and the

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85 11 88

The dihydropyridazinone ring of levosimendan is enclosed within a hydrophobic cleft formed by the amino acid residues Phe20, Ala22, Ala23, Phe24, Val28 and Phe77 and the phenyl ring of levosimendan is aligned to Met81, Cys84 and Met85. cTnC = cardiac isoform of troponin C. Source: Pollesello et al. 1994.13 Reproduced with permission from the American Society for Biochemistry and Molecular Biology.

metabolite are similar, but clinically meaningful plasma concentrations of pharmacologically active OR-1896 are detectable for days after an infusion of levosimendan and contribute to persistence of the therapeutic effect after administration of the parent drug is stopped.36 Beyond these primary mechanisms, levosimendan has been identified as having a range of ancillary actions (often described as pleiotropic effects) that do not involve an enhancement of cardiac function, but which may be implicated in some of the clinical effects of and responses to levosimendan.37 These include anti-inflammatory, anti-oxidative and anti-apoptotic actions that may be exerted in non-cardiac organs, including the kidneys, liver, gut and splanchnic vasculature, lungs and/ or respiratory muscles (Figure 2). Levosimendan inhibits only one isoform of intracellular PDE enzymes (PDE-III) and in a highly selective manner. Of note, the PDE-III over PDEIV isoform selectivity of levosimendan is the highest known to date, with a ratio of 10,000, compared with 14 for milrinone.38,39 It was proposed that inhibition of only the PDE-III isoform, not that of PDE-IV, would be insufficient to increase intracellular levels of cyclic adenosine

Pharmacological Therapy Figure 2: Mode of Actions and Pharmacological Effects of Levosimendan By binding Ca2+-saturated cTnC in cardiomyocytes (EC50 5–8 nM)

By opening the KATP channels and possibly other K+ channels (BK, KV, SK)

Levosimendan

By binding Ca2+-saturated cTnC in slow-twitch fibres in other muscles (including diaphragm and skeletal) (same EC50 as in cardiomyocytes)

By selectively inhibiting PDE-III (EC50 5–8 nM) over PDE-IV (30 μM)

Action on vasculature smooth muscles

Exerts positive inotropy in heart muscle without disturbing relaxation or increasing oxygen consumption

Strengthens muscle contraction with effect on slow-twitch fibres

Increases peripheral perfusion (including brain and splanchnic)

Increases coronary flow

Provides cardio- and organ protection

Reduces preload and afterload

Exerts an anti-ischaemic effect (pre-, post-conditioning)

Increases kidney glomerular filtration rate

Inotropy

Action on mitochondria

Reduces PCWP

Vasodilation

Exerts an anti-apoptotic effect Organ protection

The mechanisms of action in the blue boxes contribute to the cardiovascular effects of the drug. Dotted lines mark the pathways that are still not fully elucidated. cTnC = cardiac isoform of troponin C; EC50 = half maximal effective concentration; KATP = adenosine triphosphate-dependent potassium channels; PDE III, IV = phosphodiesterase isoforms in cardiac tissue; PCWP = pulmonary capillary wedge pressure. Adapted from: Al-Chalabi et al. 2019.216 Used with permission from Wolters Kluwer Health.

monophosphate (cAMP) to the same levels as by simultaneous inhibition of the two isozymes.38 This lack of PDE dependence further differentiates levosimendan from non-selective PDE inhibitors, such as milrinone, and provides an explanation of their different pharmacological behaviours, as in the case of the oxygen consumption to force production ratios.38,40–42 However, this interpretation is not unanimous. Maack et al. have proposed that PDE-III inhibition by levosimendan may indeed play a relevant role in the pharmacological effects of levosimendan.43 In that interpretation, PDE-III inhibition by levosimendan synergises with Ca2+ sensitisation for the resulting inotropic action. Interestingly, from this synergy, the authors predict that the more beta-adrenergic receptors are pre-activated by endogenous or exogenous catecholamines, the more pronounced will be the inotropic effect of levosimendan, and the more this effect would be mediated by PDE-III inhibition rather than by Ca2+ sensitisation. Conversely, at low preactivation of beta-adrenergic receptors (such as during pharmacological beta-blockade), the Ca2+-sensitisation effect of levosimendan would become more important for inotropy. The takehome message of a consensus paper from the Translational Working Group of the Heart Failure Association of the European Society of Cardiology (ESC) is that long-term use of drugs that exclusively target adrenergic signalling (e.g. catecholamines and PDE inhibitors) is associated with adverse outcomes, while levosimendan, with its hybrid calcium sensitisation and PDE-III inhibition properties, should be given the benefit of the doubt and further attention.43 The effect of levosimendan has also been studied in the presence of beta-blockers and/or inopressors. Xanthos et al. reported that the combination of epinephrine, atenolol and levosimendan, when given during cardiac arrest and resuscitation in a pig model, resulted in improved 48-hour survival and post-resuscitation cardiac function.44

Concurrently, Lochner et al. reported that the effects of levosimendan were not blunted by the presence of beta-blockers, as in the case of adrenergic inotropes.45 Levosimendan entered formal clinical evaluation and development in acute heart failure (AHF) in the mid-1990s.46–48 Initially, it was established that IV levosimendan produced dose-dependent increases in cardiac output (CO) and decreases in pulmonary capillary wedge pressure (PCWP; Figure 3). Those effects were not accompanied by significant increases in myocardial energy consumption, thus confirming the paradigm envisioned on the basis of the preclinical data. 28,49–51

From Bench to Bedside Levosimendan entered clinical trials profiled as a novel inotrope with potential for the short-term treatment of acutely decompensated chronic HF. The regulatory studies programme devised to evaluate it in this indication enrolled almost 4,000 patients (Table 1), and produced the following key insights.

Clinical Effects Haemodynamic Effects The haemodynamic effects of levosimendan seen in preclinical studies were confirmed. In patients with AHF, levosimendan achieves significant dose-dependent increases in CO and stroke volume and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance.52 In line with preclinical data, clinical studies have confirmed that levosimendan does not have a negative effect on diastolic function. In contrast, levosimendan has lusitropic effects.53,54 Inodilation is not only seen in the left side of the heart; right ventricular contractility is also improved and pulmonary vascular resistance is decreased.55–57

CARDIAC FAILURE REVIEW

Levosimendan Efficacy and Safety Pharmacokinetics in Clinical Trials As anticipated in non-clinical studies, in humans the haemodynamic effects of a 24-hour infusion of levosimendan are protracted for several days in patients with AHF due to the presence of an active metabolite (Figure 4A).58–60

Figure 3: Change in Cardiac Output and Pulmonary Capillary Wedge Pressure p<0.001 for linear dose trend

Placebo Levosimendan

1.8

Effects on Neurohormones

1.4 ∆ CO (I/min)

Rapid and sustained reductions in levels of natriuretic peptides were characteristic of levosimendan in its regulatory clinical trials.61–63 The effect on natriuretic peptides closely follows the haemodynamic effects; both are evident for at least 1 week after the levosimendan infusion period (Figure 4B).58 In the trial Survival of Patients with Acute Heart Failure in Need of IV Inotropic Support (SURVIVE), in patients with acute decompensated HF, changes in brain natriuretic peptide (BNP) levels up to 5 days after the start of infusion of levosimendan could be seen, which was not the case after 48 hours of treatment with dobutamine.61

Dobutamine

1.0 0.6 0.2

PBO 0.05

−0.2

0.1

0.2

0.4

0.6

DOB

−0.6 Maintenance infusion rate (µg/kg/min)

−1.0 2

Impact on Signs and Symptoms in AHF

0 ∆ PCWP (mmHg)

Levosimendan induces a rapid and sustained improvement in symptoms, as evidenced by Packer et al. and Slawsky et al.62,64 In the second of those studies, relief of dyspnoea was reported in 29% of levosimendan-treated patients compared with 15% of the placebotreated patients 6 hours after starting the infusion (p=0.037).64 Improvement in symptoms was evident for up to 5 days.62 Data on the use of rescue medications in the Randomised Evaluation of IV Levosimendan Efficacy (REVIVE) programme further confirm the effectiveness of levosimendan for symptom relief (Table 2).62 Dyspnoea and fatigue symptoms also responded better to levosimendan than to dobutamine in the Levosimendan Infusion versus Dobutamine (LIDO) trial, although not to the level required for statistical significance.63

0.05

0.1

0.2

0.4

0.6

DOB

PBO

−2 −4 −6 −8 −10

Maintenance infusion rate (µg/kg/min)

Change from baseline at the conclusion of a 24-hour infusion of levosimendan (given as a 10-minute bolus of 6–24 µg/kg, then an infusion of 0.05–0.6 µg/kg/min), placebo or dobutamine (6 µg/kg/min) in patients with stable heart failure. CO = cardiac output; DOB = dobutamine; PBO = placebo; PCWP = pulmonary capillary wedge pressure. Data from: Nieminen et al. 2000.52

Clinical Outcomes Hospitalisations Patients treated with levosimendan in the LIDO study spent significantly more days alive and out of hospital than dobutamine-treated patients in a retrospective 180-day follow-up analysis (median 157 versus 133 days; p=0.027).63 In the Randomised Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure After an Acute Myocardial Infarction (RUSSLAN), the combined risk of death and worsening HF was significantly lower in patients treated with levosimendan than in the control group during the infusion period (2% versus 6%; p=0.033) and at 24 hours (4% versus 9%; p=0.044).65 In the REVIVE II study, a greater percentage of patients treated with levosimendan than placebo were released within 5 days (46% versus 37%) and the mean duration of the initial hospitalisation was almost 2 days shorter (7.0 versus 8.9 days).62 No significant intergroup difference was recorded in the SURVIVE trial (p=0.3).61

Mortality Thirty-one-day mortality in the LIDO trial indicated a survival advantage from levosimendan (mortality rate 8%, versus 17% with dobutamine, HR 0.43, p=0.049).63 This was corroborated in a retrospective extension of follow-up to 180 days (mortality rate 26%, versus 38% with dobutamine, HR 0.57, p=0.029). In RUSSLAN, a survival benefit from levosimendan persisted at 180-day follow-up (23% versus 31%; p=0.053).65 In the REVIVE and SURVIVE trials there were no significant differences in 3- and 6-month overall survival between the study groups.61,62 However, there was evidence of a survival gain from levosimendan treatment in SURVIVE patients who had a history of chronic

CARDIAC FAILURE REVIEW

decompensated HF or who were using beta-blockers.66 In patients with existing chronic HF (88% of the study population), mortality was lower in the levosimendan group than in the dobutamine group at day 5 (3.4% versus 5.8%, HR 0.58, 95% CI [0.33–1.01], p=0.05) and at day 14 (7.0% versus 10.3%, HR 0.67, 95% CI [0.45–0.99], p=0.045). In patients who used beta-blockers (50% of the study population), mortality was significantly lower for levosimendan than for dobutamine at day 5 (1.5% versus 5.1%, HR 0.29, 95% CI [0.11–0.78], p=0.01).

Safety A safety summary prepared by Orion Pharma in its capacity as sponsor of the regulatory studies found no difference in the proportion of patients with reduction in arterial blood pressure in response to treatment (23.1% versus 23.1%), although REVIVE II, considered as a single study, diverged from this overall trend by showing more hypotension in the levosimendan arm.62 In 2012, Landoni et al. collected data from 5,480 patients in 45 randomised clinical trials and also carried out a meta-analysis of the adverse events.67 No signals were seen for MI (data from 25 studies, RR 0.789, 95% CI [0.522–1.185], p=0.3), ventricular arrhythmias (data from nine studies, RR 0.885, 95% CI [0.611–1.281], p=0.5) or supraventricular arrhythmias (data from 19 studies, RR 1.005, 95% CI [0.782–1.291], p=0.9), but a numerical trend was seen for hypotension (data from 22 studies, RR 1.389, 95% CI [0.996–1.936], p=0.53). There are some contradictory or indirect and inconclusive reports related to the impact of levosimendan on platelet function, but a recent meta-analysis of nine randomised controlled trials (RCTs) found that levosimendan did not increase postoperative bleeding risk.68,69 Moreover, in the supplementary appendix of the large

Pharmacological Therapy Table 1: Regulatory Clinical Trials of Levosimendan Study

n (total/LS)

Dose (µg/kg/ min)/duration of LS infusion

Comparator

Diagnosis/ NYHA Class

Primary Endpoint

Dose ranging52

151/95

0.05–0.6 24 h

Placebo/dobutamine

CHF/III

Invasive haemodynamics

Dose escalation and withdrawal64

146/98

0.1–0.4 24 or 48 h

Placebo

CHF/III–IV

Invasive haemodynamics

LIDO63

203/103

0.1–0.2 24 h

Dobutamine

CHF/III–IV

Invasive haemodynamics

RUSSLAN65

504/402

0.1–0.4 6 h

Placebo

Post-AMI/IV

Safety

REVIVE I62

100/51

0.1–0.2 24 h

Placebo

CHF/IV

Clinical composite

REVIVE II62

600/299

0.1–0.2 24 h

Placebo

CHF/IV

Clinical composite

SURVIVE61

1,327/664

0.1–0.2 24 h

Dobutamine

CHF/IV

Mortality

AMI = acute MI; CHF = congestive heart failure; LS = levosimendan; NYHA = New York Heart Association.

Figure 4: Pharmacokinetics of Levosimendan

Differences in AUC of CO and PCWP

CO (l/min) PCWP (mmHg)

Max

End 0

24 h infusion End

−1 −2 −3

2 3

Hours

NT-proANP, change from baseline (%)

9 Days

Levosimendan

24 h infusion

Placebo * p<0.05

−20 *

−40

* * *

−60 0 2

24 Hours

Conversely, a later, independent meta-analysis of data from more than 5,000 patients indicated increased risks of extrasystoles (RR 1.88, 95% CI [1.26–2.81]), hypotension (RR 1.33, 95% CI [1.15–1.53]) and headache or migraine (RR 1.94, 95% CI [1.54–2.43]) when compared with reference therapies.71 Retrospective analyses of the REVIVE II dataset identified low blood pressure at baseline as a possible risk factor for the use of levosimendan, and the current, approved Summary of Product Characteristics reflects that finding.72

Dosing

Max

−4

regulatory trial Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) no signs of increase in peri- or post-procedural haemorrhage were seen after treatment with levosimendan.70

Days

A: Differences in the area under the receiver operating characteristics curve (AUC) for changes in Doppler echocardiography-derived pulmonary capillary wedge pressure (PCWP) and cardiac output (CO) in patients with acute heart failure treated with levosimendan or placebo (n=11 in both groups) for 24 hours. Due to the formation of the active metabolite, the haemodynamic effects are maintained several days after stopping levosimendan infusion. B: Median change in N-terminal prohormone atrial natriuretic peptide (NT-proANP) over 14 days in patients with heart failure receiving levosimendan or placebo (n=11 in both groups) for 24 hours. Source: Lilleberg et al. 2007.58 Reproduced with permission from John Wiley and Sons.

Levosimendan is given as a continuous infusion of 0.05 or 0.1 or 0.2 µg/kg/min for 24 hours, which may be preceded by a loading dose (bolus) of 6–12 µg/kg in 10 minutes. The loading dose was used in the activecontrolled regulatory studies LIDO and SURVIVE, in which dobutamine served as comparator. Given that the elimination half-life of dobutamine is a few minutes while that of levosimendan is approximately 1 hour, the haemodynamic effects of dobutamine are seen almost immediately after the infusion is started, whereas a bolus of levosimendan is needed to see immediate effects. For consistency, all other studies in the regulatory clinical programme were designed to include a bolus dose, followed by a maintenance infusion. It was later found that, in the case of hypovolaemia or initial low blood pressure, a levosimendan bolus could be associated with hypotension or arrhythmias. Therefore, the use of an initial bolus of levosimendan is now generally not recommended, and it has often been avoided in clinical practice and used only if an instant effect is sought and the systolic blood pressure (SBP) is adequate.73,74

Into Regular Clinical Use The experience gained in regulatory studies provided the basis for the first approval of IV levosimendan, which was introduced in Sweden in 2000 for the management of AHF with the name SIMDAX. Since then, more than 60 jurisdictions have approved the drug, including most of the countries of the EU and Latin America. Levosimendan is currently in active clinical evaluation in the US.

CARDIAC FAILURE REVIEW

Levosimendan Efficacy and Safety Table 2: Use of Rescue Medications in the REVIVE Programme REVIVE I62

Rescue therapy (%)

REVIVE II62

Levosimendan (n=51)

Placebo (n=49)

Levosimendan (n=299)

Placebo (n=301)

Worsening dyspnoea or tachypnoea (%)

Increased pulmonary oedema (%)

Diaphoresis (%)

Cool extremities and cyanosis (%)

Worsening renal function (%)

Decreased mental status (%)

Persistent/unresponsive symptoms (%)

In the 20 years since its first introduction, IV levosimendan has been one of the notably few successful drugs entering the market in an underserved area of cardiovascular medicine; attempts at drug innovation in AHF have been characterised by repeated disappointments (either partial or total) or contradictory findings that have hindered progress.75 Levosimendan itself has not been immune to some of the frustrations of research in this area; in particular, the non-univocal findings on 6-month mortality in its regulatory studies complicated the process of establishing its therapeutic niche. Innovation in this area may have been poorly served by a regulatory emphasis on longer-term survival effects. This was perhaps misaligned with clinical realities and led to an emphasis on large trials which, by aggregating data from patients with different underlying pathophysiologies plus variations in both pharmacological and non-pharmacological treatments, may have generated signal-to-noise ratios that precluded the identification of a meaningful effect on the central endpoint of all-cause mortality/ survival. The unsuitability of all-cause long-term mortality as an index of therapeutic effect was acknowledged by experts in the field of HF about a decade ago, but that realisation came too late to influence the conduct of the regulatory trials of levosimendan.76,77 These obstacles notwithstanding, pooled analysis of the outcomes of the levosimendan regulatory trials provided strong indications, albeit not always statistically conclusive proof, of an overall survival benefit (Figure 5). Extensive experience with levosimendan has been accrued in smaller, often single-centre, non-regulatory studies. Many of those studies indicate a survival benefit from levosimendan, a finding affirmed in meta-analysis.67 Levosimendan has been evaluated in more than 200 clinical trials during its lifetime, in an extensive range of therapeutic settings. Experience in all those areas has been evaluated in meta-analyses, 31 of which have been conducted in the past 3 years (Figure 6). In every instance, levosimendan was associated with a favourable impact on the outcomes under consideration but, depending on the data selected, statistical significance in some cases remained elusive. Key therapeutic areas analysed in this way have included AHF, advanced HF (AdHF), cardiac surgery and sepsis, all of which have provided indications of benefit from levosimendan therapy. The broadly affirmative findings of these exercises may be compared with similar appraisals of dobutamine and PDE inhibitors, which have been associated with overall worse mid-to-long-term prognosis.78–80 These

CARDIAC FAILURE REVIEW

Figure 5: Effect of Levosimendan on Survival in the Regulatory Clinical Trials Favours Levosimendan Comparator Levosimendan Comparator Study Events Total Events Total Dobutamine controlled 1 95 1 20 Dose-finding64 8 103 17 100 LIDO63 SURVIVE61 79 664 91 663 Placebo controlled Dose-finding64 Dose-escalation and withdrawal52 RUSSLAN65 REVIVE I62 REVIVE II62 Pooled analysis*

95% CI

0.21 0.46

(0.01; 3.23) (0.21; 1.01)

0.87

(0.65; 1.15)

1 3

95 98

0 3

36 48

1.15 0.49

(0.05; 27.51) (0.10; 2.34)

59 1 20

402 51 299

21 4 12

102 49 301

0.71 0.24 1.68

(0.46; 1.12) (0.03; 2.07) (0.84; 3.37)

0.82

(0.67; 1.01)

172 1,807

149 1,319

0.1

0.5 1

Relative Risk Ratio (95% CI)

Meta-analysis of the clinical trials considered by regulatory authorities for the introduction of levosimendan. *Pooled statistic calculated using the Cochran–Mantel–Haenszel test, controlling for study. Source: Pollesello et al. 2016.80 Reproduced with permission from Elsevier.

contrasting findings highlight the distinction between inotropes that act, via either adrenergic or PDE-targeted pathways, to increase intracellular cAMP levels in cardiomyocytes and levosimendan, realising the ambitions of its inventors by promoting cardiac contractility without compromising the longer-term viability of cardiac muscle cells. This distinction is also illuminated by findings from the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF) registry, data from which were strongly indicative of survival benefit from levosimendan vis-à-vis adrenergic/ calcium-mobilising inotropes, such as dobutamine.81

Levosimendan in Current Use The non-univocal findings of long-term survival benefit from short-term treatment with IV levosimendan have not prevented the drug from establishing itself in the therapeutic repertoire; it has been used in almost 2 million patients since 2000, when its first market authorisation was granted by the Swedish regulatory authorities on the basis of the data available at that time. Its favourable, rapid and sustained impact on haemodynamics, neurohormone levels and symptoms in acute decompensated HF are undisputed and of clear therapeutic value. Formal acknowledgement of that value emerged in 2005, when it was mandated in the ESC guidelines.82 In the subsequent European guidelines (2008, 2012), the endorsements

Pharmacological Therapy

Significantly positive

Borderline or in part positive

Positive trend

Number of published meta-analyses per year

Figure 6: Results of 64 Meta-analyses of Levosimendan Clinical Trials 15

0 2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Refer to supplementary material for details of the individual meta-analyses.

Table 3: Common Concomitant Conditions in Acute Heart Failure and the Corresponding Inotrope of Choice Commonly Encountered Concomitant Conditions in Acute Heart Failure

Inotrope of Choice

Hypotension

Norepinephrine Dobutamine Dopamine

Beta-blockade

Levosimendan Milrinone

Pulmonary hypertension

Levosimendan Milrinone

Acute cardiorenal syndrome

Dopamine Levosimendan Dobutamine

Heart failure of ischaemic aetiology

Levosimendan Dobutamine

Cardiopulmonary bypass surgery

Dobutamine Levosimendan Milrinone

Sepsis-related heart failure

Norepinephrine Dobutamine Levosimendan

Source: Bistola et al. 2019.105 Reproduced with permission from Radcliffe Cardiology.

of levosimendan were more cautious, reflecting a general dissatisfaction of the HF medical community with the concept of inotropy.83,84 Levosimendan is currently recommended in the acute treatment of HF to reverse the effect of beta-blockade, if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion.85 Due to the large therapeutic field they encompass, the European guidelines on acute and chronic HF are not as detailed as they could be and, in recommending therapeutic agents, ignore some of the different aetiologies and manifestations of AHF. Supplementary information and recommendations can be found in more than 20 expert consensus papers co-authored by more than 180 clinicians from 30 countries who have discussed when and how to use levosimendan in different therapeutic settings, including AHF and cardiogenic shock,74,81,86–88 AdHF,89–92 perioperative use,93–95 and use in the intensive care unit (ICU),96 and who have described its cardiorenal effects,88,97 its effects on quality of life,98,99 exercise performance,100 lung function,101 and pharmaco-economic considerations.102

In the context of a 20-year retrospective it is worth noting at this point that its complex mode of action might have had the potential to disadvantage levosimendan both in fact and in perception. In fact, that plurality of effects has emerged as both an important aspect of the drug’s clinical versatility and usefulness and as a stimulant to informed speculation among experts and to medical research.73,92,94,96,103

Levosimendan in Acute Settings The most recent ESC guidelines, issued in 2016, identify short-term treatment with IV levosimendan (along with adrenergic inotropes or PDE inhibitors) as an option in the acute-phase management of “patients with hypotension (SBP <90 mmHg) and/or symptoms of hypoperfusion despite adequate filling status, to increase CO, increase blood pressure, improve peripheral perfusion and maintain end-organ function”.85 The ESC statement further endorses the short-term use of levosimendan to circumvent the effects of beta-blockade “if betablockade is thought to be contributing to hypotension with subsequent hypoperfusion”. The high proportion of patients now receiving betablockers as part of the treatment repertoire for chronic HF means that levosimendan has become an important resource in the management of acute decompensations in those patients. The vasodilator dimension of levosimendan’s pharmacology is pertinent to the drug’s use in low-output states such as AHF, in which a key pathology is organ hypoperfusion. A drug that both augments CO and improves vasodilatation may be expected to have a more favourable impact in some cases than an agent that acts on CO alone.104 In this context, it is important to register that, in many acute settings, hypoperfusion and hypotension may not necessarily be only an effect of inadequate myocardial contractility but may also be related to shock-specific changes in vascular tone and vasodilatation. Thus, besides the need to exclude or correct inadequate volume status, concomitant treatment with a vasopressor agent before embarking on a course of inotropic therapy must also be considered. The importance of correcting inadequate volume before embarking on a course of vasodilatory or inotropic therapy must also be considered and monitored during therapy. These observations may be usefully contextualised into a ‘right patient, right drug’ schema that can be used to guide vasoactive and/or inotropic therapy (Table 3).105 The first phase of this schema examines whether or not an inotrope is needed at all and includes exclusion of otherwise treatable causes or the

CARDIAC FAILURE REVIEW

Levosimendan Efficacy and Safety availability of viable alternatives. The next step is to identify the most suitable inotrope; levosimendan figures prominently in several categories, including cardiogenic shock, cardiac surgery and right ventricular failure.

pathophysiology or dosing, or as a result of procedure-specific differences in surgical and perfusion management (i.e. too low a dose applied before cardiopulmonary bypass or use of crystalloid cardioplegia solutions), needs to be addressed in future studies.

Cardiogenic Shock

The emphasis on postoperative mortality in these recent studies was substantially driven by regulatory requirements in the design of LEVOCTS. Whether that outcome is the most relevant or revealing for evaluation of an intervention is an open question. Levosimendan exhibited efficacy in other measures, including a lower incidence of LCOS, less need for rescue catecholamines for inotropic support and augmentation of the cardiac index.118 Methodological difficulties also affected the interpretation of the LICORN and CHEETAH trials.

The purpose of inotropic support in cardiogenic shock secondary to left ventricular dysfunction is to aid the failing left ventricle by unloading it, increasing left ventricular output and improving coronary blood flow, and hence myocardial perfusion, at the same time decreasing pulmonary oedema. The inodilator profile of levosimendan provides a possibly more complete response to those needs than pure inotropic agents and its ability to promote inotropy with little or no adverse effect on metabolic rate, energy demand or oxygen consumption may be a bonus. The use of levosimendan may be beneficial in part via a substitution effect in which it reduces the need for catecholaminergic agents, which have less favourable effects on oxygen and energy consumption at the cellular level and a propensity to increase mortality.106 Formal experience with levosimendan in cardiogenic shock is limited, but it appears to be generally well-tolerated, to improve multiple indices of cardiac function and to reduce systemic vascular resistance.106–111 Levosimendan has also been reported to restore ventriculoarterial coupling and improve left ventricular function in various settings; this may be a further benefit in cardiogenic shock, but this conjecture is currently untested.112,113

Takotsubo Syndrome An example of cardiogenic shock in which treatment with levosimendan presents unique benefits is takotsubo syndrome, or stress cardiomyopathy.114 Takotsubo-induced HF and/or cardiogenic shock is commonly treated with aggressive diuresis, haemodynamic support and inotropic drugs. The fact that catecholamines may be implicated in its pathogenesis suggests that catecholamine inotropes may be contraindicated, because these drugs increase cAMP within the cell, increase myocardial oxygen consumption and may worsen myocardial stunning. Levosimendan, in contrast, as a non-catecholamine inotrope that does not increase myocyte cAMP or oxygen consumption, is a rational therapeutic option in takotsubo-related cardiogenic shock.115–117

Cardiac Surgery Levosimendan has been studied in more than 40 clinical trials in cardiac surgery, with indications emerging that it can reduce the risk of lowoutput cardiac syndrome (LCOS) or be effective in treating postoperative LCOS. The scale of this benefit (derived from a meta-analysis of 14 studies) is moderate but tangible, and is more marked in patients with baseline low left ventricular ejection fraction.118 A recalculation incorporating data from three recent large RCTs (Levosimendan in Coronary Artery Revascularisation [LICORN], Levosimendan to Reduce Mortality in High Risk Cardiac Surgery Patients [CHEETAH] and LEVO-CTS) causes dilution of the effect size of that estimate.119–122 Expert advice derived from these new data is that “levosimendan cannot be at the moment recommended for routine use in all cardiac surgery settings”.122 However, there appears to be potential for significant mortality benefit in some subgroups of patients, such as those with low ejection fraction or those undergoing isolated coronary artery bypass grafting (CABG) procedures.123,124 Whether these findings may be interpreted as a lack of efficacy of levosimendan in patients undergoing valve surgery due to differences in the underlying

CARDIAC FAILURE REVIEW

These caveats notwithstanding, mortality was numerically lower in levosimendan-treated patients in LEVO-CTS.118 In addition, the safety profile of levosimendan revealed in all these recent trials identifies it as arguably the safest agent among the broad grouping of inotropes and inodilators. There was no significant excess of arrhythmias or hypotension and no increase in mortality in levosimendan-treated patients.118 Encouragement for further evaluation of levosimendan in this area comes from other recent investigations. Wang et al. analysed data from 21 randomised trials (n=1,727) and calculated that IV levosimendan in patients undergoing CABG was associated with significant reductions in mortality rate (p=0.001) and postoperative AF (p=0.04), with benefit mostly restricted to patients pre-treated in advance of an isolated CABG procedure; on-pump status also affected outcomes.123 Levosimendan was associated with a higher incidence of hypotension (OR 2.26). These data are consistent with the findings from LEVO-CTS and offer indications of future lines of clinical appraisal.118,124 See also Weber et al.125

Right Ventricular Failure Determinative randomised trials of levosimendan in right ventricular failure (with or without pulmonary hypertension) have yet to be conducted, but a recent meta-analysis of 10 studies of levosimendan in acute right-sided HF identified statistically robust benefits over placebo, with increases in tricuspid annular plane systolic excursion and ejection fraction, plus reductions in systolic pulmonary artery pressure (p=0.0001) and pulmonary vascular resistance (p=0.003).126 Adverse events were reported not to differ significantly between groups.

Effects on Renal Function in HF and Critical Illness HF is a systemic syndrome involving the kidneys, lungs and liver, with a great impact on prognosis, and effects of cardiovascular drugs on non-cardiac organs are of the utmost importance.127 Evidence for a renal-protective action of levosimendan has been reported from preclinical experiments.128–130 It has been proposed that levosimendan may cause selective vasodilation on the afferent arterioles of the renal glomeruli, thus improving renal filtration.97 This suggestion is compatible with findings from the LIDO trial, in which levosimendan treatment was associated with an increase in estimated glomerular filtration rate (eGFR) but treatment with dobutamine was not, even though both drugs increased cardiac index and urine output.63 It is also consistent with recent reports by Fedele et al. and by Lannemyr et al.131,132 The substantial enhancement of eGFR observed in the second of those studies was not accompanied by impairment of renal oxygenation, given that renal oxygen delivery increased in proportion

Pharmacological Therapy Table 4: Current Clinical Applications of IV Levosimendan Indications

Described clinical benefits

Settings

Symptoms

Haemodynamics

Neurohormones

End-organ function

Re-hospitalisation

Survival

Acute HF

↓

↑

↓

↑

↓

↔↑

Cardiogenic shock

n.d.

↑

n.d.

↔

n.d.

↔

Takotsubo syndrome

↓

↑

↓

↑

n.d.

RV failure

↓

↑

n.d.

↑

n.d.

↔

HF after ACS

↓

↑

n.d.

↔

Cardiac surgery

n.d.

↑

↓

↑

n.d.

↔↑

LCOS after CABG

n.d.

↑

n.d.

↑

n.d.

↑

Septic shock

n.d.

↑

↔

n.d.

↔

Advanced HF

↓

↑

↓

↑

↓

↑

ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; HF = heart failure; LCOS = low-output cardiac syndrome; n.d. = not described; RV = right ventricular.

to the increase in eGFR. Non-impairment of the renal oxygen supply– demand relationship despite eGFR enhancement during levosimendan exposure has also been reported by Bragadottir et al.133 A recent report shows that the eGFR enhancement effect of levosimendan is not shared with milrinone.134 Data on the effects of levosimendan on renal function in various clinical situations, including cardiac surgery and critical illness, have been collated and the results support a renal-protective effect, making levosimendan the inotrope of choice in the case of worsening cardiorenal syndrome.135–138 However, in all these situations, specifically designed prospective trials of adequate statistical power will be needed to confirm the effects and their clinical consequences.

Levosimendan in AdHF Adoption of repeated intermittent cycles of IV levosimendan for the treatment of AdHF has been a significant milestone in both the lifecycle of the drug and the management of a complex aspect of HF. Patients with AdHF are on a trajectory ultimately either to a definitive intervention through heart transplantation or the implantation of a left ventricular assist device (LVAD), or to a palliative care pathway. Goals of therapy in AdHF include haemodynamic stabilisation and preservation of functional capacity, mitigation of symptoms and preservation of healthrelated quality of life. Prevention of HF-related hospitalisation is another key goal, both as a desirable outcome per se and as a way of averting the markedly worsened mortality that accompanies hospitalisation.139,140 All of the pharmacological properties of levosimendan outlined earlier – notably its metabolite-mediated persistence of effect – make it wellsuited for repeated or intermittent use in the management of AdHF. Three randomised, placebo-controlled, double-blind clinical trials, Randomised Trial Investigating the Efficacy and Safety of Pulsed Infusions of Levosimendan in Outpatients with Advanced Heart Failure (Levo-Rep; NCT01065194), Levosimendan Intermittent Administration in Outpatients: Effects on Natriuretic Peptides in Advanced Chronic Heart Failure (LION-HEART; NCT01536132) and Long-term Intermittent Administration of Levosimendan in Patients with Advanced Heart Failure (LAICA; NCT00988806), have examined the application of repeated cycles of levosimendan therapy in this setting.141–143 All these studies demonstrated that repeat-cycle levosimendan reduces N-terminal pro-BNP (NT-proBNP) levels and there were repeated and clear demonstrations of trends towards reductions in HF readmissions

and mortality that are consistent with, and corroborate, the findings of meta-analyses.144,145 A recognised overall conclusion from these studies is that repetitive application of levosimendan is feasible and safe in an outpatient setting.141–143 Notably, onset destabilisation is not invariably an immediate-onset event, however, and it may be possible to identify opportunities when timely recognition of – and intervention on – signs and symptoms of decompensation may avoid unplanned/urgent hospitalisations due to haemodynamic crises. The need for a larger randomised study (or studies) in this area is being addressed by the Repetitive Levosimendan Infusion for Patients with Advanced Chronic Heart Failure trial (LEODOR; NCT03437226), a multicentre, randomised, double-blind, placebo-controlled, three-arm trial, which will examine the impact and safety of intermittent levosimendan therapy, started during the vulnerable phase after a recent hospitalisation for HF.146 Treatment effectiveness will be assessed using a hierarchical composite clinical endpoint consisting of time to death or urgent heart transplantation or implantation of a ventricular assist device; time to non-fatal HF hospitalisation requiring IV vasoactive therapy; and time-averaged proportional change in NT-proBNP. Basing the trial on such an outcome measure should enhance the power to examine whether, compared with placebo, repeated use of levosimendan is associated with greater clinical stability over the course of subsequent weeks. In addition to its use in maintaining haemodynamic stability in patients with AdHF, preoperative use of IV levosimendan in patients undergoing implantation of an LVAD, or identification of LVAD candidates, has been reported to be “generally well-tolerated and not interrupted because of side effects” and associated with significant improvements in endorgan function, although with similar early mortality rates.147 This is an application where a substantial expansion in the use of levosimendan may be anticipated. The current clinical applications of IV levosimendan are summarised in Table 4.

The Next 20 Years of Levosimendan In addition to the LEODOR study, there are currently more than 20 investigator-initiated clinical trials in progress in which levosimendan is being evaluated for possible therapeutic benefits. These include a study designed to examine the effect of a single 24-hour infusion of levosimendan to prevent rehospitalisation in patients with severe

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Levosimendan Efficacy and Safety systolic HF (NCT03764722); Effect of Levosimendan or Placebo on Exercise in Advanced Chronic Heart Failure (LOCO-CHF; NCT03576677), a placebo-controlled appraisal of the effects of IV levosimendan on exercise capacity in patients with advanced chronic HF; and research into the effects of levosimendan in acute kidney injury after cardiac surgery (LEVOAKI; NCT02531724). The Early Management Strategies of Acute Heart Failure for Patients with NSTEMI study (EMSAHF; NCT03189901) is exploring whether early use of levosimendan in patients with acute MI combined with elevated BNP/NT-proBNP may reduce the risk of emergent AHF and improve outcome. Developments in the technology and science of telemedicine and telemonitoring may make this a practical proposition in the foreseeable future. The ambition (already under active exploration and with progress further accelerated by the introduction of artificial intelligence into the diagnostic loop) is to develop patient monitoring to such a degree of immediacy and accuracy that overt decompensations may be wholly avoided by prompt, appropriate clinical responses to the first signs of deterioration.148,149 Intermittent IV levosimendan may be an appropriate intervention in this ‘acute but non-hospitalised’ scenario, depending on the clinical circumstances of an individual patient. Investigations in this direction can be expected, although these are likely to be driven primarily by developments in telemedicine technologies, rather than by any focus on specific medical interventions.150 A range of ICU situations has been identified in which levosimendan may offer clinical benefits, either as an adjunct to existing interventions or as an alternative to conventional therapies. These situations include haemodynamic support in cardiac critical care,151 haemodynamic support in septic cardiomyopathy,152,153 weaning from the ventilator,154 weaning from venoarterial extracorporeal membrane oxygenation after cardiac surgery,155–159 and renal failure and kidney protection in cardiorenal syndrome.97,130,132,160–166 In several of these areas, notably low CO syndrome, cardiogenic shock, takotsubo cardiomyopathy and sepsis, a substantial element of any benefit accruing from use of levosimendan may be attributable to the substitution of a non-adrenergic stimulant for conventional catecholaminergic agents, such as dobutamine, thereby averting some of the potential toxic complications of adrenergic overstimulation.167 ‘Decatecholaminisation’ of the medical armamentarium is a developing line of practice in the management of critically ill patients.168–176 As an established non-adrenergic vasoactive agent that offers positive cardiovascular effects (e.g. ventriculoarterial recoupling, decongestion), as well as potentially advantageous ancillary effects on kidney function and cellular-protective actions, levosimendan is both a therapeutic resource and experimental tool for investigating this new approach.161,177–184 Developments in these areas, although already pioneered by promising exploratory studies will, inevitably, require well-designed and properly powered RCTs.151–153,185,186 Central to future investigations will be the identification of robust and relevant endpoints. An overemphasis on crude mortality may not be the most informative metric by which to judge outcomes. Trials directed towards establishing the best overall therapeutic strategy may be more progressive than studies framed to position any one agent as the best for a particular purpose or situation. Various commentaries have examined the challenges of conducting clinical trials in critically ill

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patients.187–190 Of notable significance in this respect is the work of Mebazaa et al., who have sought to apply lessons learned from trials in AHF to the more flexible and less prescriptive design of Phase III studies in sepsis.191 Principal among those lessons is the need to move towards composite primary endpoints, with isolated all-cause mortality addressed as a safety signal, not a primary marker of effectiveness. From that perspective, the model of HF as a complex condition of multifactorial causes and pathophysiology, and one therefore unlikely to be moderated by a single intervention on a simple outcome measure, such as total mortality, is an example of a needlessly restrictive approach to clinical trials design that has had a dampening effect on the development of needed therapies. In addition, there has been recent discussion about how syndrome-attributable risks of critical illness-associated diagnoses have often likely been overestimated using common statistical methods, contributing to very low success rates in this field.192 The authors of this article are unanimously supportive of that view, which we feel has frustrated advances in HF care. It is to be hoped that our colleagues in cardiac critical care are able to benefit in the design of their own clinical trials by examining some of the methodological missteps and misplaced emphases that have hampered some aspects of cardiology research in recent decades. Levosimendan has been approved by Chinese authorities on the basis of several local corroborative regulatory clinical trials, and SIMDAX will enter that important market this year.161,193–195 The use of levosimendan in paediatric patients is currently contraindicated due to a lack of regulatory studies. A few investigatorinitiated studies have been performed. The largest published study included retrospectively gathered data on 484 levosimendan infusions delivered to 293 patients at a single paediatric ICU; the majority of the patients (65%) were aged 12 months or younger.196 Levosimendan postponed or reduced the need for mechanical cardiac support in children with cardiomyopathy or who were undergoing cardiac surgery. In other reports, levosimendan was compared to the PDE inhibitor milrinone and found either to be similarly efficacious or superior.197–199 In a randomised double-blind study in children younger than 4 years of age undergoing cardiac surgery, patients receiving levosimendan had significantly higher cardiac index and lower pulmonary artery pressure than children receiving dobutamine.200 There is a strong rationale to perform properly powered clinical regulatory trials on the paediatric use of levosimendan in the near future.

Research and Development Outside Cardiology Respiratory Function Respiratory muscle dysfunction may develop in the course of several diseases, including chronic obstructive pulmonary disease (COPD), HF and critical illness.201,202 In addition to atrophy, reduced calcium sensitivity of contraction plays an important role in respiratory muscle weakness in these conditions.203,204 Levosimendan has been studied in non-cardiac muscle, especially in respiratory muscles. In vitro studies have demonstrated that levosimendan improves calcium sensitivity of force generation in diaphragm fibres from healthy subjects and patients with COPD.203 In a physiological study, levosimendan at a clinically used dose improved diaphragm contractile efficiency by 21% and reversed diaphragm fatigue induced by inspiratory muscle loading.205 In a placebo-controlled randomised study, the effects of levosimendan were evaluated in critically ill patients being weaned from mechanical

Pharmacological Therapy ventilation.206 There was no difference in the primary endpoint of contractile efficiency between groups, while tidal volume and minute ventilation were both significantly higher in the levosimendan group, and arterial CO2 tension significantly lower.206 Improved respiratory mechanics may facilitate liberation from mechanical ventilation, although this requires further clinical studies.

The Phase III Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients with ALS trial (REFALS; NCT03505021) is ongoing in North America, Europe and Australia. An open-extension phase of REFALS should offer important insights into the long-term safety and efficacy of oral levosimendan in ALS.

Translational and Early Development Phases Pulmonary Hypertension A Phase II regulatory clinical trial is currently underway in the US on the repeated use of IV levosimendan for pulmonary hypertension in patients with HF and preserved ejection fraction (NCT03541603). The results are expected in 2020.

Motor Neurone Disease There is interest in the potential of oral levosimendan in the management of amyotrophic lateral sclerosis (ALS). ALS is characterised by a progressive muscular paralysis arising from motor neurone degeneration.207 The disease eventually involves most skeletal muscles, plus the diaphragm and other respiratory muscles, leading to death from respiratory failure.208,209 It is the most common neurodegenerative disorder of midlife, with incidence and prevalence increasing with age.210 ALS is currently incurable and the medical options are limited. No treatment is currently approved to enhance motor function in ALS and recent clinical experiences have produced mixed results.211–214 The physiological and pharmacological rationale for levosimendan in ALS rest on the fact that both the diaphragm and skeletal muscle express genes for the slow-twitch (or cardiac) isoform of TnC (the diaphragm consists of approximately 50% slow-twitch fibres).215 As a calcium sensitiser with cTnC as molecular target, levosimendan can thus strengthen contractility also in the diaphragm and skeletal muscle. The multifaceted pharmacology of levosimendan may also provide supplementary clinical impact in patients with ALS through the alreadymentioned range of pharmacological effects not directly related to the drug’s calcium-sensitising action.37,216 Positive effects of short-term oral levosimendan in patients with ALS were seen in the Effects of ODM-109 on Respiratory Function in Patients With ALS (LEVALS; NCT02487407) study, a Phase II trial that used a randomised, double-blind, placebo-controlled, cross-over design to evaluate the efficacy and safety of oral levosimendan in patients with definite or probable ALS. The 66 patients enrolled had experienced symptoms of ALS for between 12 and 48 months and had an early decline in respiratory function. Therapy consisted of 2 weeks of oral levosimendan at doses of 1 or 2 mg/day or placebo, administered in random order during three study periods separated by a washout period.217

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Other trials are looking at the effects of IV levosimendan on cellular metabolic alterations in patients with septic shock (NCT02963454) and the possibility that IV levosimendan may improve the prognosis in acute respiratory distress syndrome (NCT04020003). Other recent research on the effect of levosimendan on oxidative stress in a mouse model of diabetes showing an effect of the drug in preventing memory impairment has opened up a new possible development path.218,219 A separate report, again on mice, highlighted the protective effects elicited by levosimendan against liver ischaemia/ reperfusion injury.220 Of particular interest, new pharmaceutical agents are currently being developed with levosimendan and cTnC as a pharmacophore model in unexpected fields such as oncology.221

Conclusion In the field of short-term haemodynamic treatments for acute cardiac care, levosimendan represents a rare case of an inotrope approved by regulatory authorities in the past 20 years. The approval was based on data from three Phase III clinical studies in which the endpoints were reached (LIDO, RUSSLAN and REVIVE).62,63,65 The safety data collected during those 20 years of clinical use are unprecedented and superior to those for any of the other inotropes or inodilators.222 In a recent consensus paper, the authors evaluated whether “the nearly total absence of evidence of benefit with some of the traditional IV drugs used in AHF and AdHF (such as the catecholamines or the PDE inhibitors) would warrant their elimination from routine use in favour of treatments where such evidence has been accrued (e.g. for levosimendan)”.75 With regard to posology, both a frequent use in the therapy of AdHF and an earlier use of levosimendan in the therapy of AHF have been shown to be of benefit.91,223 Beyond that, 20 years after its initial approval for clinical use, levosimendan remains an important resource in cardiovascular medicine and a valuable tool for clinical research, investigation and innovation in that and other areas of medicine.20 The clinical programme for the development of oral levosimendan as a treatment for ALS shows how retargeting a safe drug, even in a different formulation, is a rational strategy in pharmaceutical development.224

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Zhang YH, Qing EM, Zhang J, et al. Hemodynamic and efficacies of domestic levosimendan versus dobutamine in patients with acute decompensated heart failure. Zhonghua Yi Xue Za Zhi 2012;92:555–8 [in Chinese]. PMID: 22490161. 195. Wang L, Cui L, Wei JP, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in decompensated heart failure. Zhonghua Xin Xue Guan Bing Za Zhi 2010;38:527–30 [in Chinese]. PMID: 21033135. 196. Suominen PK. Single-center experience with levosimendan in children undergoing cardiac surgery and in children with decompensated heart failure. BMC Anesthesiol 2011;11:18. https://doi.org/10.1186/1471-2253-11-18; PMID: 21974814. 197. Lechner E, Moosbauer W, Pinter M, et al. Use of levosimendan, a new inodilator, for postoperative myocardial stunning in a premature neonate. Pediatr Crit Care Med 2007;8:61–3. https:// doi.org/10.1097/01.PCC.0000253026.67341.5D; PMID: 17149153. 198. Momeni M, Rubay J, Matta A, et al. 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Acute Heart Failure

Morphine in the Setting of Acute Heart Failure: Do the Risks Outweigh the Benefits? Oren Caspi and Doron Aronson Departments of Cardiology, Rambam Medical Centre and B Rappaport Faculty of Medicine, Technion Medical School, Haifa, Israel

Abstract The use of opioids in acute pulmonary oedema is considered standard therapy by many physicians. The immediate relieving effect of morphine on the key symptomatic discomfort associated with acute heart failure, dyspnoea, facilitated the categorisation of morphine as a beneficial treatment in this setting. During the last decade, several retrospective studies raised concerns regarding the safety and efficacy of morphine in the setting of acute heart failure. In this article, the physiological effects of morphine on the cardiovascular and respiratory systems are summarised, as well as the potential clinical benefits and risks associated with morphine therapy. Finally, the reported clinical outcomes and adverse event profiles from recent observational studies are discussed, as well as future perspectives and potential alternatives to morphine in the setting of acute heart failure.

Keywords Acute heart failure, congestion, opiates, morphine, mechanical ventilation Disclosure: The authors have no conflicts of interest to declare. Received: 23 December 2019 Accepted: 8 March 2020 Citation: Cardiac Failure Review 2020;6:e20. DOI: https://doi.org/10.15420/cfr.2019.22 Correspondence: Doron Aronson, Department of Cardiology, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E: daronson@technion.ac.il Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure is a growing pandemic worldwide, and it is associated with a high burden of morbidity and mortality. Acute heart failure (AHF) is one of the most prevalent causes of adult patients’ hospitalisation. While the treatment of most cardiovascular diseases has significantly improved since the beginning of this century, the outcomes of AHF have not progressed significantly, and AHF still carries a substantial risk for in-hospital mortality, readmission and post-discharge mortality.1,2 The use of opioids to relieve breathlessness in patients with respiratory disease dates back to the late 19th century.3 The immediate relieving effect of morphine on the key symptomatic discomfort associated with AHF, dyspnoea, facilitated the categorisation of morphine as a beneficial treatment in this setting. The rationale for the use of morphine as a decongestive therapy was further supported by animal studies showing a certain shift of volume between central and peripheral circulation, and has been attributed as medical phlebotomy.4,5 Evidence supporting morphine treatment for reducing AHF-associated mortality or morbidity are lacking. Nevertheless, current guidelines and textbooks continue the historical tradition mentioned above, and still accept morphine as a viable option for treating AHF and accordingly it is commonly prescribed.6–8 In particular, the relief of dyspnoea and anxiety is generally considered beneficial and serves as a justification for morphine administration. During the last decade, however, several retrospective studies raised concerns regarding the safety and efficacy of morphine in the setting of AHF.9–12 In the current review, the physiological effects of morphine on the cardiovascular and respiratory systems are summarised, as well as the potential clinical benefits and risks. This is followed by a

discussion on the reported clinical outcomes associated with morphine treatment in AHF.

Effects of Morphine on the Cardiovascular System The effect of morphine on reducing vascular tone has been the key rationale for using the drug in the setting of AHF (Table 1). Animal studies have shown that morphine reduces both venous and arterial tone.4,5 Morphine exerts the vasodilatory effect mainly by an indirect increase in histamine release and not directly via the mu-opioid receptors.13,14 Henney et al. demonstrated that morphine administration at high doses (0.5–1 mg/kg) in dogs results in an immediate decrease in peripheral vascular resistance (46%) and in venous tone (49%). This was accompanied by an increase in venous capacitance of 11 ml/kg.4 The resulting increase in venous capacitance was presumed to be beneficial for patients with AHF by facilitating a shift of blood volume from the central to peripheral circulation. Other studies, however, identified only a minor effect on venous tone with a slight reduction in blood pressure.15,16 Zelis et al. studied 69 subjects who were treated with 15 mg of morphine.16 Venous pressure and tone decreased significantly by 34% and 38%, respectively. Mean systemic arterial pressure remained unchanged, while the authors reported a decrease of 47% in arteriolar constrictor response. A similar evaluation of patients with mild pulmonary oedema revealed a comparable reduction in venous tone that translated into a modest shift of 116 ml of blood to the peripheral circulation.17 Such a volume shift is too small to explain the presumed beneficial effect on congestion. Timmis et al. examined the effect of morphine in 10 patients with severe LV dysfunction following MI. In this study, morphine was associated with a significant and persistent

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Acute Heart Failure Table 1: Effect of Morphine on the Cardiovascular and Respiratory Systems Cardiovascular System

Respiratory System

Vasodilatory effect,18,19 decrease in peripheral vascular resistance,13,14 hypotension

Diminished chemoreceptor response28,30,31 • Reduced hypoxic ventilatory response • Reduced hypercapnic ventilatory response

Decrease in venous tone4,16

Depression of the brainstem respiratory rhythm–pattern generation27 • Slow and irregular respiration • Reduced minute volume and tidal volume

Attenuation of sympathetic efferent discharge, reduction in heart rate18,19

reduction in heart rate and mean arterial pressure, and a small fall in cardiac index with minimal effect on systemic vascular resistance.18 The fall in cardiac output despite a reduction in systemic vascular resistance may be explained by attenuation of sympathetic efferent discharge from the central nervous system.16 Interestingly, Timmis et al. also observed a significant reduction in urine output, which was attributed to the stimulation of antidiuretic hormone release.18 In summary, there is little evidence, based on human studies, that morphine administration, in clinically relevant dosages, can exert a significant increase in venous capacitance that translates to the desired alleviation pulmonary congestion. Additional haemodynamic effects of morphine include decreases in heart rate and blood pressure.19

Effects of Morphine on the Respiratory System There are substantial analogies between dyspnoea and pain, as both these subjective experiences involve several common cerebral structures.20 Opioids have powerful effects on respiration and its associated sensations, and their effectiveness in relieving dyspnoea is well-established.21 Opioids can also improve dyspnoea by reducing the associated anxiety.22 Morphine has a direct respiratory depressant effect by activating muopioid receptors in a dose-dependent manner.23 In knockout mice lacking mu-opioid receptors, administration of morphine and other opioids failed to induce respiratory depression.24,25 The mu-opioid receptors are expressed in areas of the central nervous system involved in respiratory rhythmogenesis and frequency control, particularly the pre-Bötzinger complex, but also in the cortex and the peripheral chemoreceptors.26–28 The central pattern generator of the respiratory neuron network extends from the facial nucleus to the spinal cord (the ventral respiratory group neuron network).29 The central pattern generator converts tonic excitatory chemo-drive into a respiratory pattern with distinct inspiratory and expiratory phases, and includes the parabrachial and Kölliker-Fuse nuclei in the pons, and the pre-Bötzinger and Bötzinger complexes.29 The pre-Bötzinger complex is the main region of respiratory rhythm–pattern generation, and is believed to be the main site of opioid-induced respiratory depression. In addition, opioids have profound effects on the cortical centres that control breathing, thereby augmenting their actions in the brainstem.27 The most opioid-sensitive aspect of respiration is rhythm generation, and changes in the respiratory pattern are observed at lower opioid doses than a change in tidal volume. Opioids cause respiration to slow and progress to become irregular (or cyclic) breathing, and eventually into apnoea.28 The induction of respiratory depression by opioids causes gradual hypercapnia that maintains respiration.

Cough suppression

The peripheral chemoreceptors are responsible for 20–30% of the ventilatory drive at rest and for >80% during hypoxia, and express muopioid receptors.28 Consequently, opioids profoundly depress the hypoxic ventilatory response and the hypercapnic ventilatory response.28,30,31 Opioid-mediated respiratory depression has been studied mainly in the setting of acute and postoperative pain, with severe respiratory depression and related deaths occurring with an incidence of at least 0.5%.32,33 Data from studies conducted with patients experiencing chronic breathlessness demonstrated that opioid therapy (mostly oral) resulted in a small (~2 mmHg) increase in the levels of carbon dioxide without a significant effect on oxygen tension or saturation.34 While the risk for significant respiratory depression may be low in these settings, the associated hypoxia and the increased respiratory effort with pulmonary oedema is a vital compensatory mechanism for the compromised alveolar–capillary diffusion. Morphine results in a robust and instantaneous anxiolytic effect by activation of the delta and mu-opioid receptors in multiple brain regions, and by reciprocal interaction with the GABAergic system.35,36 Morphine administration may also lead to several additional significant adverse events, including over-sedation, delirium, cough depression, nausea and vomiting, and urinary retention.37–40

Potential Clinical Benefits of Morphine in the Treatment of Acute Heart Failure The haemodynamic benefits frequently cited as the rationale for using morphine to treat AHF include the reduction of venous tone with pooling of blood in the systemic (in particular, venous) circulation, peripheral arteriolar dilatation and antisympathetic effects (Table 2).4,5,15,41 Morphineinduced reduction in venous tone is considered advantageous in the setting of pulmonary oedema, as it may result in a volume shift from central to peripheral circulation. The venodilatation results in reduced venous return to the right heart and reduced right ventricular output, allowing the failing left ventricle to operate at a lower filling pressure, but may also lead to decreased cardiac output and hypotension, particularly with concomitant pulmonary hypertension. This negative effect on cardiac output may be mitigated by the mild reduction in systemic vascular resistance, resulting in decreased afterload and preserved stroke index.18 However, as discussed earlier, there is little compelling evidence that morphine causes either clinically significant venous pooling in the systemic circulation or a meaningful reduction of left or right ventricular filling pressures.16–18,42,43

Potential Clinical Risks of Morphine in the Treatment of Acute Heart Failure Opioids decrease both hypoxic and hypercapnic respiratory drive, and this effect is directly proportional to the opioid dose and its analgesic potency.44 Induction of sedation and respiratory depression are among

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Morphine in Acute Heart Failure Table 2: Summary of Studies Conducted on Morphine in the Setting of Acute Heart Failure Study

Study Year

Patients (n)

Morphinetreated Patients (n)

PSM Pairs

Primary Outcomes, HR [95% CI]*,†

Peacock et al.9

2008

147,362

20,782

In-hospital mortality 4.84 [4.52–5.18]

Gray et al.57

2010

1,052

541

7-day mortality 1.2 [0.79–1.81] In-hospital mortality 1.2 [0.6–2.5]

Iakobishvili et al.

2011

2,336

218

Miro et al.58

2017

6,516

416

275

30-day mortality: 1.66 [0.97–2.82]

Caspi et al.12

2019

13,788

761

672

Invasive ventilation: 2.13 [1.30–3.50] In-hospital mortality: 1.43 [1.05–1.96]

Secondary Outcomes HR [95% CI]*,†

Non-invasive ventilation: 2.78 [1.95–3.96] Inotropes use: 3.50 [2.10–5.82] Acute kidney injury: 1.81 [1.39–2.36]

*Outcomes are separated into primary and secondary if predefined, otherwise the outcomes field was merged. †Adjusted values. NA = not available; PSM = propensity score matching.

the most serious complications of morphine therapy. Opioids are second in the classes of medications contributing to adverse event reporting for hospitalised patients, with sedation and respiratory depression being among the most commonly reported adverse effects.45 Unfortunately, safety data on morphine use in the setting of AHF have not been systematically collected. Available data suggest that bolus administration of opioids is more likely to cause more severe respiratory depression than gradual administration.46,47 Various patient groups may be at higher risk for respiratory compromise, including the morbidly obese, patients who suffer from sleep apnoea, patients with respiratory muscle exhaustion and fatigue, patients with neurological or neuromuscular impairment, and the elderly. In addition, drugs, such as propofol and midazolam, have additive or synergistic effects on respiration when combined with opioids.28 Patients with metabolic alkalosis, which often accompanies diuretic therapy and depresses the respiratory centres, may also be susceptible to morphine. These deleterious respiratory effects are accompanied by the increased risk for nausea and vomiting, consequently leading to further sympathetic activation, hindering the use of non-invasive ventilation, and augmenting the risk for aspiration and further respiratory compromise.48,49 The frequency of these dose-dependent complications were not reported in the setting of pulmonary oedema, but based on surgical series, the expected proportions of vomiting with 5 mg and 10 mg of morphine is 8% and 14%, respectively.50 The addition of 10 mg metoclopramide is recommended to counteract nausea if morphine is administered.49 Furthermore, morphine may affect the absorption of oral medications and therefore confer indirect harm. A randomised trial in the setting of acute MI recently demonstrated that morphine can delay clopidogrel absorption and decrease the plasma level of its active metabolite.51 A similar study revealed that the same effect is also relevant for ticagrelor administration. 52–54 Inhibition of oral drugs absorption may be directly relevant to the treatment of AHF in the setting of MI, but presumably may be also relevant to treatment with oral drugs for AHF (e.g. thiazides and neurohormonal inhibitors). Finally, the haemodynamic effects of morphine can, directly and indirectly, affect urine output and renal function, resulting in decreased urine output in the setting of AHF.18,28,55,56

Morphine Therapy and Clinical Outcomes in Acute Heart Failure Morphine, together with nitrates and diuretics, is one of the most prescribed drugs for AHF, historically. Retrospective studies from the

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last decade raised doubts regarding the efficacy and safety of morphine therapy in AHF. In a large retrospective study including patients from the Acute Decompensated HEart Failure National REgistry (ADHERE), morphine therapy was associated with a marked increase in in-hospital mortality (OR 4.8), a higher rate of mechanical ventilation, intensive care admissions and longer duration of hospital stay.9 However, morphine dosage and timing of administration were not reported. A significant limitation of any non-randomised analysis of the effect of morphine in AHF is that morphine-treated patients represent a cohort with more severe illness and would have been predicted to have greater mortality. Therefore, more recent studies applied propensity score (PS) matching to partially address these limitations. In contrast, a study based on an Israeli registry of AHF (with two-thirds of morphine-treated patients having an acute coronary syndrome) showed that, in a multivariate analysis, morphine was associated with increased in-hospital mortality, but after PS matching (218 pairs), this effect was rendered insignificant.10 In addition, an analysis from the Three Interventions in Cardiogenic Pulmonary Oedema (3CPO) trial did not identify a relationship between opiate administration and mortality. However, opiate administration was independently associated with less improvement in arterial pH and did not improve breathlessness.57 Recently, a study based on the Spanish Epidemiology of Acute Heart Failure in Emergency Department (EAHFE) registry, which included 275 PS matched pairs, reported that morphine therapy during emergency department stay was associated with increased 30-day mortality (HR 1.66).58 We recently studied the association between morphine use within the first 24 hours after admission and in-hospital clinical outcomes in 673 PS matched pairs of patients admitted with the primary diagnosis of AHF.58 Morphine therapy was associated with a significant increase in the need for subsequent invasive ventilation (OR 2.13; 95% CI [1.32– 3.57], p=0.007) and in-hospital mortality (OR 1.43; 95% CI [1.05–1.98], p=0.024). Morphine therapy was also associated with a significant increase in the use of inotropes, non-invasive ventilation and acute kidney injury. Furthermore, we observed a significant direct relationship between morphine dose and the endpoints of invasive ventilation and mortality (Figure 1). Importantly, we should approach the results of PS-based studies with caution. A full discussion on the merits and limitations of PS matching is beyond the scope of this review. Although PS matching provides excellent covariate balance, it frequently greatly reduced the sample

Acute Heart Failure Conclusion

Figure 1: ORs and 95% CIs for Invasive Ventilation and In-hospital Mortality According to Morphine Dose

Morphine administration in the setting of AHF is not currently encouraged by European guidelines (except for palliative and end-of-life care).7 Older US guidelines advocated morphine use in acute pulmonary oedema, but it is not mentioned in recent US guidelines.63,64 However, it is still frequently used, despite accumulating signals for harm.65 The continued use of morphine may be attributed to the desire to rapidly manage dyspnoea and anxiety per se, rather than waiting for these symptoms to improve with the resolution of the pulmonary oedema.

Invasive ventilation

No Mo

In-hospital mortality

Mo ≤5 mg

Data from a study using propensity score-matched patients with acute heart failure (672 patient pairs). Invasive ventilation is shown in blue, and in-hospital mortality of shown in purple. The reference group includes patients who did not receive morphine. Mo = morphine. Source: Caspi et al. 2019.12 Reproduced with permission from Elsevier.

Some physicians believe that morphine-associated harmful effects may be restricted only to specific high-risk groups, such as those with hypoperfusion, low left ventricular ejection fraction or CO2 retention. However, the heterogeneity of treatment effect has not been shown in the above-mentioned studies.12,58 The association between morphine therapy and adverse events in AHF is complex, and likely requires the coexistence of several risk factors/patient susceptibilities to progress to a clinical event. Given the inability to acquire all the relevant patient data at the appropriate temporal resolution, causality remains to be established. However, there is little evidence that morphine is beneficial in the setting of AHF, and accumulating observational data demonstrating harm.

size, resulting in a loss of both precision and generalisability.59 The fact that PS methods cannot control for unmeasured confounding is particularly relevant to studies on morphine use in patients with AHF.60 Such ‘unobserved confounders’ may be highly unbalanced in the treated and untreated groups, and may arise when clinicians use their expert knowledge (or gut feeling) to make the decision to administer morphine. Such clinical judgement is often based on unmeasured clinical characteristics that introduce significant bias.61 Finally, under some circumstances, PS matching may actually increase bias.60,62

Clinicians encountering a distressed dyspnoeic AHF patient have no doubt that there is a compelling need for anxiolytic therapy, especially if this may be beneficial in alternative ways for the patient. Randomised controlled trials are required to assess the efficacy and safety of morphine in patients with AHF. In addition, the use of substituting agents, such as midazolam, may be explored. The ongoing MIdazolam Versus MOrphine in Acute Pulmonary Oedema (MIMO) randomised trial may provide this essential information.66 Alternative approaches focusing on agents with instantaneous anxiolytic effect and minimal respiratory depression (e.g. dexmedetomidine) may also be useful.67

Mo >5 mg

3. 4.

8. 9.

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56.

57.

58.

59.

60.

61.

62. 63.

64.

65.

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https://doi.org/10.1111/j.1467-2995.2008.00413.x; PMID: 18565200. Agewall S. Morphine in acute heart failure. J Thorac Dis 2017;9:1851–4. https://doi.org/10.21037/jtd.2017.06.129; PMID: 28839982; Gray A, Goodacre S, Seah M, Tilley S. Diuretic, opiate and nitrate use in severe acidotic acute cardiogenic pulmonary oedema: analysis from the 3CPO trial. QJM 2010;103:573–81. https://doi.org/10.1093/qjmed/hcq077; PMID: 20511258. Miro O, Gil V, Martin-Sanchez FJ, et al. Morphine use in the ED and outcomes of patients with acute heart failure: a propensity score-matching analysis based on the EAHFE registry. Chest 2017;152:821–32. https://doi.org/10.1016/j. chest.2017.03.037; PMID: 28411112. Elze MC, Gregson J, Baber U,et al. Comparison of propensity score methods and covariate adjustment: evaluation in 4 cardiovascular studies. J Am Coll Cardiol 2017;69:345–57. https://doi.org/10.1016/j.jacc.2016.10.060; PMID: 28104076. Pearl J. Remarks on the method of propensity score. Stat Med 2009;28:1415–6; author reply 1420–3. https://doi.org/10.1002/ sim.3521; PMID: 19340847. Fu EL, Groenwold RHH, Zoccali C, et al. Merits and caveats of propensity scores to adjust for confounding. Nephrol Dial Transplant 2019;34:1629–1635. https://doi.org/10.1093/ndt/ gfy283; PMID: 30215791. Pearl J. Causal inference in statistics: an overview. Statist Surv 2009;3:96–146. https://doi.org/10.1214/09-SS057. Guidelines for the evaluation and management of heart failure. Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure). Circulation 1995;92:2764–84. https://doi.org/10.1161/01. CIR.92.9.2764; PMID: 7586389. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;128:1810–52. https://doi. org/10.1161/CIR.0b013e31829e8807; PMID: 23741057. Miro O, Hazlitt M, Escalada X, et al. Effects of the intensity of prehospital treatment on short-term outcomes in patients with acute heart failure: the SEMICA-2 study. Clin Res Cardiol 2018;107:347–61. https://doi.org/10.1007/s00392-017-1190-2; PMID: 29285622. Dominguez-Rodriguez A, Burillo-Putze G, Garcia-Saiz MDM, et al. Study design and rationale of “a multicenter, open-labeled, randomized controlled trial comparing MIdazolam versus MOrphine in acute pulmonary edema”: MIMO trial. Cardiovasc Drugs Ther 2017;31:209–13. https://doi.org/10.1007/s10557017-6722-5; PMID: 28265880. Jun JH, Kim KN, Kim JY, Song SM. The effects of intranasal dexmedetomidine premedication in children: a systematic review and meta-analysis. Can J Anaesth 2017;64:947–61. https://doi.org/10.1007/s12630-017-0917-x; PMID: 28639236.

Cardiac Amyloidosis

Cardiac Transthyretin-derived Amyloidosis: An Emerging Target in Heart Failure with Preserved Ejection Fraction? Sebastiaan HC Klaassen,1,3 Dirk J van Veldhuisen,1,3 Hans LA Nienhuis,2,3 Maarten P van den Berg,1,3 Bouke PC Hazenberg3 and Peter van der Meer1,3 1. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 2. Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 3. Amyloidosis Centre of Expertise, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

Abstract Heart failure with preserved ejection fraction (HFpEF) comprises half of the heart failure population. A specific, but underdiagnosed, cause for HFpEF is transthyretin-derived (ATTR) amyloidosis. This article reviews the clinical characteristics of cardiac ATTR amyloidosis. The clinical suspicion of cardiac ATTR amyloidosis is strong if pronounced left ventricular hypertrophy is present in the absence of hypertension. Scintigraphy with a diphosphonate tracer is a diagnostic tool for the early detection of cardiac ATTR amyloidosis with high sensitivity and specificity. First treatment options for ATTR amyloidosis recently emerged, and showed a reduction in morbidity and mortality, especially if treatment was started in the early stages of disease. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with left ventricular hypertrophy might be useful.

Keywords Heart failure with preserved ejection fraction, cardiac transthyretin-derived amyloidosis, scintigraphy, tafamidis, cardiomyopathy, treatment Disclosure: HLAN received consultancy fees from Pfizer and Alnylam. PvdM received consultancy fees and/or research grants from Servier, Ionis, Astra Zeneca, Pfizer, Vifor Pharma and Novartis. All other authors have no conflicts of interest to declare. Received: 13 November 2019 Accepted: 29 January 2020 Citation: Cardiac Failure Review 2020;6:e21. DOI: https://doi.org/10.15420/cfr.2019.16 Correspondence: Peter van der Meer, Department of Cardiology, University Medical Center Groningen, PO Box 30001, 9700RB Groningen, the Netherlands. E: p.van.der.meer@umcg.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure with a preserved ejection fraction (HFpEF) comprises half of the heart failure population, and is associated with high morbidity and mortality. HFpEF is induced by multiple coexisting comorbidities, mostly of non-cardiac origin, leading to increased stiffness of the myocardial wall, diastolic dysfunction, elevated filling pressures and eventually to heart failure.1 The interplay between comorbidities greatly differs among patients; however, increasing age is a major driving force. Many studies, researching the pathogenesis of HFpEF, focus on intracellular pathways that lead to increased cardiomyocyte stiffness.1,2 In contrast, some diseases specifically alter the extracellular matrix of the cardiac tissue, which also results in stiffening of the myocardial wall.3 Transthyretin-derived (ATTR) amyloidosis is such a disease leading to deposition of misfolded proteins in the extracellular matrix of the myocardium, and is therefore a specific extracellular cause of HFpEF.4 The aim of this review was to discuss the potential usefulness of screening for ATTR amyloidosis in the general HFpEF population, as the first treatment options for ATTR amyloidosis are now emerging.5

What is Transthyretin-derived Amyloidosis? Two types of ATTR can be distinguished, namely the wild-type (ATTRwt) and the hereditary (ATTRv) form. The protein, transthyretin (TTR), is primarily produced in the liver, and is a transporter protein, carrying

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thyroxine and retinol-binding protein. A balance exists between the soluble TTR proteins in the tetrameric state and the folded monomer. In the case of the hereditary form, a mutation in the TTR gene causes the variant TTR monomers to become less stable and misfolded, leading to self-aggregation as insoluble amyloid fibrils that accumulate in the extracellular matrices of end-organs, in particular the heart, increasing myocardial stiffness and subsequently compromising normal cardiac function.6 In contrast, the pathogenesis of ATTRwt amyloid is still poorly understood; however, senescence of cardiomyocytes in combination with the cumulative exposure to oxidative stress is thought to facilitate destabilisation of the TTR tetramer, and misfolding and self-aggregation of the TTR monomer, resulting in amyloid fibrils. The prevalence of the ATTRv amyloidosis in white people is rather low, estimated to be one per 200,000. However, ATTRv amyloidosis caused by the pathogenic V122I (TTR p.Val142Ile) variant, which almost exclusively presents with cardiac involvement, is quite common in African-Americans, with an allele frequency of 3.5%.7 The prevalence of ATTRwt amyloidosis is much higher compared with ATTRv.8 A post-mortem study demonstrated that moderate or severe ATTRwt amyloid deposition is present in 5% of HFpEF patients aged >80 years.4 In addition, GonzĂĄlez-Lopez et al. screened 120 consecutive

ÂŠ RADCLIFFE CARDIOLOGY 2020

Cardiac Transthyretin-derived Amyloidosis patients with HFpEF and LV hypertrophy, and found that ATTRwt amyloidosis was present in 13% of patients with HFpEF.9 Finally, in 16% of patients with severe aorta valve stenosis, ATTRwt amyloid could be detected, which was associated with a higher mortality.10 Altogether, ATTRwt amyloidosis seems to be a common cause of HFpEF, albeit underappreciated.

Cardiac Features of Transthyretin-derived Amyloidosis The combination of late age of disease onset (>60 years), heart failure symptoms and left ventricular hypertrophy in the absence of hypertension increases the clinical suspicion of ATTRwt amyloidosis (Figure 1). A scintigram, as described below, is indicated to diagnose cardiac ATTR amyloidosis. Reduced exercise tolerance occurs in the early stage of the disease, whereas signs of congestive heart failure and peripheral oedema will develop later during disease progression. In approximately half of patients, AF or bundle branch blocks are present as a consequence of amyloid infiltration in atrial myocardium and the conduction system of the heart. Low QRS voltage ECGs may be present, but are less often observed.6 Non-cardiac manifestations of ATTRwt amyloidosis are frequently observed, often prior to the first cardiac manifestation.11 In half of ATTRwt patients, the presenting symptom of systemic ATTRwt amyloidosis is carpal tunnel syndrome (CTS), and it develops on average 8 years prior to the onset of the cardiomyopathy.12 Other non-cardiac manifestations include spinal canal stenosis, tendon ruptures and hip or knee arthroplasty.13,14 Therefore, (bilateral) CTS might be an early sign of ATTRwt amyloidosis, and a positive medical history for CTS should increase the clinician’s suspicion of ATTRwt amyloidosis in heart failure patients.11 Gillmore et al. proposed a staging system to further estimate the prognosis of patients with ATTR amyloid cardiomyopathy. The division is based on the plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), with a cut-off value of 3,000 ng/l, and the estimated glomerular filtration rate (eGFR), with a cut-off value of 45 ml/min/1.73 m2.15 Stage I is defined by NT-proBNP levels below the cut-off value and the eGFR above the cut-off value. In stage II, either NT-proBNP is elevated or the eGFR value is decreased. Finally, stage III is defined as elevated NT-proBNP levels in combination with a decreased eGFR.15 Patients with stage I disease had a median survival of 70 months, whereas median survival in stage III was only 24 months.

How to Diagnose Transthyretin-derived Amyloidosis Often ATTR amyloidosis is first considered in the case of the following echocardiographic findings: increased ventricular wall thickness, restrictive diastolic filling and speckle tracking that shows a bull’s eye pattern with apical sparing.6 However, as cardiac hypertrophy also often has causes other than ATTR amyloidosis, such as hypertension, aortic valve pathology and hypertrophic cardiomyopathy, the specificity of echocardiography is relatively low and thus is only useful in raising suspicion that cardiac amyloidosis is present. An endomyocardial biopsy is the gold standard for diagnosing cardiac ATTR amyloidosis. As endomyocardial biopsy is a rather invasive procedure, an abdominal subcutaneous fat aspirate is often used instead. However, a relatively low sensitivity in detecting ATTRwt in HFpEF has been reported.16

CARDIAC FAILURE REVIEW

Figure 1: ATTR Wild-type Clinical Hallmarks ATTR wild-type clinical hallmarks

Unexplained heart failure + >1 Following Age >60 years

Cardiac: - (Bi) ventricular hypertrophy in the absence of hypertension - Speckle tracking; bull’s eye pattern with apical sparing - Conduction disturbances; BBB - Low QRS voltage ECG

Non-cardiac: - (Bi) lateral CTS in medical history - Spinal stenosis in medical history - Arthroplasty in medical history - Biceps tendon rupture in medical history

Increased clinical suspicion for ATTR amyloidosis wild-type if unexplained heart failure, older age and at least one extra manifestation is present. Further evaluation, including bone scintigraphy, should be performed. These hallmarks do not exclude other types of amyloidosis, and the hereditary form of ATTR and amyloid light-chain amyloidosis, especially, should be considered as well. ATTR = transthyretin-derived; BBB = bundle branch block; CTS = carpal tunnel syndrome.

‘Bone’ scintigraphy has emerged as a very promising non-invasive alternative to diagnose ATTR amyloid cardiomyopathy (Figure 2).17 Scintigraphy detects ATTR deposition in the heart in the early stages of disease, and has a sensitivity of >99% and specificity of 86% in detecting ATTR.17 Therefore, scintigraphy is a suitable tool for the early detection of ATTRwt in the general HFpEF population.18 After a positive scintigram, genetic testing is performed to differentiate between the hereditary and wild-type form.7,17 For the hereditary form, genetic screening for the presence of a mutation in members of the family is paramount. Low- to moderategrade tracer uptake in the heart can be observed in amyloid light-chain amyloidosis. Therefore, to rule out other forms of cardiac amyloidosis, especially with regard to in amyloid light-chain amyloidosis, further work-up is required.17

Therapeutic Implications Until very recently, there were no proven treatment options for ATTR amyloidosis; however, several new treatment approaches have emerged that may likely change the field.5,19–22 Treatment principles are based on halting the production of the TTR protein, the stabilisation of the TTR tetramer and on the breakdown of already deposited amyloid fibrils. Recently, the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) reported a positive effect of the TTR stabiliser, tafamidis, on the progression of ATTR amyloidosis, and consequently has become available as the first established treatment for cardiac ATTR amyloidosis.5 A reduction in all-cause mortality was observed in the group that received tafamidis over a period of 30 months. Patients with less advanced heart failure (New York Heart Association class I and II) seemed to benefit more from treatment than patients with more advanced heart failure, suggesting that stabilising TTR is useful up to a point of no return. However, one should be cautious in drawing conclusions based on subgroups of an already relatively small trial. Another TTR tetramer stabiliser is AG10, which is capable of almost complete stabilisation of TTR.22 Although in this small study (n=49) no clinical response or effect on mortality was reported, treatment with AG10 led to normalisation of TTR plasma levels in both ATTRwt and

Cardiac Amyloidosis Figure 2: 99mTc-HDP Scintigraphy and Single-photon Emission/CT of Cardiac Transthyretin-derived Amyloidosis

Another option for gene silencing is the antisense oligonucleotide drug, inotersen. Inotersen delayed the progression of neurological disease, but as yet limited data on the effect of inotersen on cardiac parameters are available.28,29 Because of these promising results, currently both gene-silencing drugs are used in the treatment of ATTRv amyloidosis. The last principle of treatment is the degradation of already deposited amyloid in the extracellular matrix. In one small study, 20 patients were treated with a combination of doxycycline and tauroursodeoxycholic acid for 1 year, which seemed to stabilise disease progression of primarily neurological symptoms in ATTRv patients.20 This approach is currently being investigated in patients with cardiac ATTR amyloidosis in a phase III trial that started in 2018 (NCT03481972).

A and B: Anterior and posterior total body view of 99mtechnetium-hydroxymethylene diphosphonate scintigraphy showing increased myocardial tracer uptake (Perugini grade 3; strong myocardial uptake in combination with decreased bone uptake) and uptake in wrists, right knee and shoulders. C and D: Single-photon emission CT images of the 99mtechnetiumhydroxymethylene diphosphonate (99m Tc-HDP) scintigraphy revealing high uptake of tracer in the left ventricle.

ATTRv patients. This is promising, as decreased TTR plasma levels in untreated patients are associated with reduced survival.23 Decreased TTR plasma levels in untreated patients are deemed to reflect TTR tetramer destabilisation, leading to TTR disappearance from the circulation and ongoing accumulation of amyloid in tissue. In addition, AG10 might be more selective than tafamidis in stabilising the TTR tetramer.24 Another approach to stop amyloid accumulation is by gene silencing, which decreases the serum levels of TTR by 80–90%.25 Patisiran is a small interfering RNA drug that appeared to be safe and effective as a gene-silencing treatment option in ATTRv amyloidosis, during a treatment period of 18 months.21 Not only was disease progression of polyneuropathy halted in the treatment arm, there was also an improvement of multiple cardiac parameters, such as a reduction of the ventricular wall thickness. Collectively, this suggests that endogenous clearance of amyloid fibrils can occur to some extent if the supply of precursor protein – that is, the misfolded TTR monomer – can be significantly reduced. A similar phenomenon has been described in other systemic types of amyloidosis.26,27

Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–71. https://doi.org/10.1016/j.jacc.2013.02.092; PMID: 23684677. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/ eurheartj/ehw128; PMID: 27206819. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014;11:507–15. https://doi.org/10.1038/nrcardio.2014.83; PMID: 24958077. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113–22. https://doi.org/10.1016/j.jchf.2013.11.004; PMID: 24720917. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007–16. https://doi. org/10.1056/NEJMoa1805689; PMID: 30145929. Ruberg FJB. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012;126:1286–300. https://doi.org/10.1161/

Taken together, stabilisation of the TTR tetramer, to prevent dissociation into amyloidogenic monomers, is currently the leading principle of treatment in cardiac ATTR amyloidosis.14 Importantly, as described above, the treatment effect of TTR stabilisation is greatest during the early stages of disease, and is less sufficient in later disease stages. It is tempting to speculate that a combination of TTR tetramer stabilisers with small interfering RNA or future clinically applicable degraders can potentially be used to not only halt disease progression, but also lead to improvement of symptoms, particularly in patients with more advanced stages of disease.

Conclusion In this review, we described ATTR amyloidosis to be a relatively frequent, but underdiagnosed, cause of HFpEF. The suspicion of ATTRwt amyloidosis is strong if left ventricular hypertrophy is present in the absence of hypertension and patient history reports bilateral carpal tunnel syndrome or conduction disturbances. Currently, scintigraphy with diphosphonate or pyrophosphate tracer is a diagnostic tool that has both high specificity and sensitivity in detecting ATTR amyloid cardiomyopathy. To date, one phase III study with an ATTR stabiliser showed a beneficial effect on morbidity and mortality. Therefore, it seems that ATTR amyloidosis is becoming a treatable form of HFpEF. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with important red flags, such as left ventricular hypertrophy, conduction disturbances or a history of CTS, might be useful.

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0.3109/13506129.2012.678508; PMID: 22551192. 21. Solomon SD, Grogan M. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation 2019;139:431–43. https://doi.org/10.1161/ CIRCULATIONAHA.118.035831; PMID: 30586695. 22. Judge DP, Heitner SB, Falk RH, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol 2019;74:285–95. https://doi. org/10.1016/j.jacc.2019.03.012; PMID: 30885685. 23. Hanson J, Arvanitis M, Koch C, et al. Utility of serum transthyretin as a prognostic indicator and predictor of outcome in cardiac amyloid disease associated with wild-type transthyretin. Circ Hear Fail 2018;11:e004000. https://doi. org/10.1161/CIRCHEARTFAILURE.117.004000; PMID: 29449366. 24. Penchala SC, Connelly S, Wang Y, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A 2013;110:9992–7. https://doi.org/10.1073/ pnas.1300761110; PMID: 23716704. 25. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an

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COVID-19

Coronavirus Disease 2019 and Heart Failure: A Multiparametric Approach Estefania Oliveros,1 Yevgeniy Brailovsky,2 Paul Scully,3,4 Evgenia Nikolou,5 Ronak Rajani6 and Julia Grapsa5 1. Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, US; 2. Center for Advanced Cardiac Care, Columbia University Irving Medical Center, New York, NY, US; 3. Cardiothoracic Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 4. Institute of Cardiovascular Sciences, University College London, London, UK; 5. Cardiology Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 6. School of Bioengineering and Imaging Sciences, King’s College London, London, UK

Abstract Coronavirus disease 2019 (COVID-19) is a debilitating viral infection and, to date, 628,903 people have died from it, numbers that cannot yet be compared to the 50 million who died in the 1918 flu pandemic. As COVID-19 became better understood, cardiovascular manifestations associated with it were identified. This led to a complete healthcare restructuring with virtual clinics and changes to the triaging of critically ill patients. There are a lot of questions over how COVID-19 affects patients with heart failure (HF) as this condition is a leading cause of cardiovascular death. This review describes the cardiovascular implications of COVID-19 and new practices surrounding the use of telehealth to follow up and triage patients with HF. Current practices supported by medical societies, the role of angiotensin-converting enzyme inhibitors and, finally, a brief note regarding the management of advanced HF patients will also be discussed.

Keywords COVID-19, heart failure, viral infection, cardiovascular manifestations, telehealth Disclosure: The authors have no conflicts of interest to declare. Received: 28 April 2020 Accepted: 25 June 2020 Citation: Cardiac Failure Review 2020;6:e22. DOI: https://doi.org/10.15420/cfr.2020.09 Correspondence: Julia Grapsa, Cardiology Department, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Rd, London SE1 7EH, UK. E: julia.grapsa@gstt.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

This review focuses on the implications of coronavirus disease 2019 (COVID-19) in the heart failure (HF) population. First of all, we will describe the cardiovascular implications of COVID-19 and the new practices surrounding the use of telehealth to follow up and triage patients with HF. We will then discuss the current practices supported by medical societies, the role of pharmacotherapy and, finally, a brief note regarding the management of patients with advanced HF (Figure 1).

COVID-19 and Cardiovascular Manifestations COVID-19 is a debilitating viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, to date, management is supportive, while off-label treatments are still under scrutiny and not yet supported by randomised controlled trials.1 The symptoms of COVID-19 vary and may include cough, fever, shortness of breath, muscle aches, profound fatigue, dysgeusia, anosmia and diarrhoea. COVID-19 can induce respiratory failure and subsequently acute respiratory distress syndrome (ARDS), which is the leading cause of mortality. The well-known cytokine storm is characterised by a hyperinflammatory syndrome resulting from a fulminant and often fatal hypercytokinaemia with multiorgan failure. Important features of the inflammatory response include unremitting haemophagocytic lymphohistiocytosis, pulmonary involvement (including ARDS) in approximately 50% of patients, increased interleukin (IL)-2, IL-7, granulocyte–colony-stimulating factor, interferon-gamma inducible

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protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-alpha and tumour necrosis factor-alpha.2,3 Initial observations around COVID-19 were that it could cause organ failure. Approximately 85% of those infected are asymptomatic carriers, but a proportion will develop a severe condition and present to hospitals and some of them will require mechanical ventilation.4,5 Initial data suggest that predisposing risk factors for COVID-19 mortality include cardiovascular comorbidities, such as hypertension and diabetes; however, the prevalence of HF in these patients is not well known. There is also little to no data on myocardial performance in hospitalised or non-hospitalised patients who acquired COVID-19. Reports indicate that some patients hospitalised with COVID have developed viral myocarditis and experienced thrombotic events and cardiac tamponade, but predisposing risk factors are unknown.6,7,8 Our knowledge of COVID-19 has progressed significantly in the last 3 months, initially from clinical cases and subsequently from large studies. Cardiology societies were the first to suggest protocols on how to visualise potential cardiac dysfunction and, importantly, on how to protect staff (Supplementary Tables 1 and 2).9,10 The use of point-of-care ultrasound (POCUS) instead of a complete echocardiogram has also been suggested.11

Heart Failure Manifestation in COVID-19 There are reports describing the importance of endomyocardial biopsy and cardiac MRI in this population.6,12

COVID-19 and Heart Failure: A Multiparametric Approach Figure 1: Heart Failure Patients and Coronavirus Disease 2019 Management of patients with advanced heart failure • Difficulty with serial surveillance biopsies • Alternative use of other non-invasive surveillance methods • Discharging new transplants back to the community needs reassurance that caregivers are COVID-19 negative • Transplant numbers have decreased

• Use video or phone calls for televisits • Involve caretakers • Daily weights, track heart rate and blood pressure • Discuss medication adherence • Suggest monitoring for signs of COVID-19 • Reinforce hand hygiene and social isolation • Use remote monitoring devices Telemedicine

Transplant listing

HEART FAILURE AND COVID-19 • ACE2 has been identified as a functional receptor for coronaviruses • Lack of any evidence supporting harmful effect of ACEis and ARBs in the context of the COVID-19 pandemic • Continue ACEis and ARBs

ACEi

Societies

• Perform only emergent procedures • Appropriate use of PPE by catheterisation laboratory • Stay at home: elderly, transplant, pregnant, immunosuppressed and heart disease patients

ACE2 = angiotensin-converting enzyme 2; ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin 2 receptor blockers; COVID-19 = coronavius disease 2019; PPE = personal protective equipment.

Endomyocardial biopsy has identified diffuse T-lymphocytic inflammatory infiltrates (CD3+ >7/mm2) with huge interstitial oedema and limited foci of necrosis. No replacement fibrosis was detected, suggesting an acute inflammatory process.11 There was also localisation of viral particles in the myocardium.6 Cardiac MRI has shown hypokinesis and diffuse myocardial oedema without evidence of late gadolinium enhancement.12 Myocardial involvement and evidence of thrombosis have been recorded at autopsies but, because carrying these out poses risks to staff, hospital policies have restricted studies. There is a fine balance between scientific and clinical requirements and the occupational risk from exposure to SARS-CoV-2. Given the above, COVID-19 seems to insult the cardiovascular system in multiple ways. HF triggered by respiratory failure is common, especially in patients with comorbidities. Viral myocarditis, thrombotic events, takotsubo myocarditis, complete heart block and tamponade have been reported as initial presentations of COVID-19.7,12–15 Thrombotic events can include pulmonary embolism.7 In one of the first manuscripts on COVID-19 and cardiovascular effects, specifically myocardial injury, Rali et al. elegantly elaborated on the different manifestations of COVID-19, explaining the cytokine storm and the myocardial picture, as well as the thrombogenicity of the virus.16 As time allows bigger registries to be set up, we realised that impaired ventricular function as well as significant tricuspid regurgitation in

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patients with COVID-19 was associated with poor prognosis.17 Lala et al. described the significant prevalence of myocardial injury in patients with COVID-19, despite low troponin levels.18 Furthermore, they noted that, after adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g. troponin I 0.03–0.09 ng/ml; n=455; 16.6%) were significantly associated with death (adjusted HR 1.75; 95% CI [1.37–2.24]; p<0.001) while greater amounts (e.g. troponin I>0.09 ng/dl; n=530, 19.4%) were significantly associated with higher risk (adjusted HR 3.03; 95% CI [2.42–3.80]; p<0.001).18 Heart failure physicians have found themselves on the frontlines of this pandemic, as our patients are affected by this virus in novel ways and people with no cardiac history are developing a range of cardiac involvement. Specialists have been called upon to care for the influx of patients and radically modify well-established algorithms.

Value of Telemedicine in Heart Failure Patients Follow-up and Triage Healthcare providers revisited disaster response policies for infectious disease outbreaks to incorporate telemedicine systems to address some of the unique challenges posed by COVID-19 (Figure 1).19 Within weeks, a few hospitals moved entirely into telehealth and, as a predicted second wave will affect the future of face-to-face visits, physicians indicate that telemedicine can and should be a future strategy for the majority of patients. Telemedicine meets the needs of the majority of patients with HF,

COVID-19 particularly those in rural or remote areas, those with limited mobility or financial or time constraints, and those with limited access to transportation.20,21 These patients could remotely access services, seek expert advice and call nurses and specialists when needed – without the stress and opportunity cost of travel – and actively engage in and manage their care.22 Telemedicine in patients with HF may be challenging as those with New York Heart Association class II and III HF may need close follow-up. The priorities when managing these patients are following a healthy diet, measuring their weight daily and ensuring they are adhering to their medical management while at home. Most patients manage to weigh themselves daily and keep records of their blood pressure and heart rate. Furthermore, they are advised to have a low threshold for contacting the on-call physician, in case they experience shortness of breath or symptoms related to HF. HF specialist nurses coordinate with the physicians on risk stratification of patients and decide who will be followed up virtually. If a patient needs to be hospitalised, they are transferred to a COVID-19-negative ward with the highest level of precautions. Patients with HF are expected to: • Learn how to use their smartphone or computer to participate in telehealth video visits. • Keep track of missed visits and investigations, and work with caregivers to reschedule appointments once social distancing measures are relaxed. • Practise good hand hygiene and social distancing, and stay at home as much as possible. • Follow recommendations regarding the routine use of face masks. • Avoid unreliable information on social media but consult advice from healthcare organisations, such as the NHS or the Centers for Disease Control, and their government’s daily reports for recommendations to follow. • Access prescriptions. During video visits, simple manoeuvres can help to guide the patient in physical examination. These include digital pressure on the calf to assess for signs of lower extremity oedema, and neck examination while sitting to evaluate jugular venous pressure. HF services rely on remote haemodynamic monitoring with CardioMEMS (Abbott), watches to track heart rate and remote interrogation of ICDs to analyse the burden of ventricular tachycardia or impedance for volume status to ascertain if therapy needs to be adjusted. The goal is to avoid hospitalisation. People who are elderly or not technologically savvy may have problems using telemedicine, so there is a need for a robust structure that can synchronise calls and provide technological support and scheduling. This also poses a challenge for patients, as they may have difficulty navigating the system and limited access to healthcare providers. The routine channels have changed and we are constantly adapting to try to ensure patient safety. Despite the above difficulties and limitations, the use of telemedicine keeps growing and it is recognised that our lives as caregivers will change completely as we apply telehealth wherever we can and as much as possible.

Role of Heart Failure Societies The Heart Failure Society of America (HFSA) and the Heart Failure Association of the European Society of Cardiology have ensured that HF patients are appropriately informed during the novel COVID-19 pandemic.10,11 The British Heart Foundation has identified extremely vulnerable groups who need to stay at home:23 • Those who have had a transplant at any time, including a heart transplant. • Immunosuppressed patients, such as those with cancer receiving chemotherapy or extensive radiotherapy.11 • Those who are pregnant and have significant heart disease – defined as any of the following: coronary heart disease, hypertrophic cardiomyopathy, hypertensive heart disease, pulmonary arterial hypertension, moderate or severe valvular heart disease, HF that affects left ventricular function, or significant congenital heart (cyanotic) disease. • People who are elderly. At the moment, there is no evidence that virus can be transmitted to patients upon insertion of implanted devices, such as pacemakers and ICDs; and no evidence that it causes infective endocarditis in those with valvular heart disease.11

Angiotensin-converting Enzyme inhibitors, COVID-19 and Heart Failure Patients Angiotensin-converting enzyme 2 (ACE2) is a cornerstone of the cardiovascular and immune systems.24 ACE2 has been identified as a functional receptor for coronaviruses, including SARS-CoV, as well as SARS-CoV-2. SARS-CoV-2 infection is triggered when the spike protein of the virus binds to ACE2, which is highly expressed in the heart and lungs.24 SARS-CoV-2 mainly invades alveolar epithelial cells, resulting in respiratory symptoms. These symptoms are more severe in patients with cardiovascular disease, which might be associated with increased secretion of ACE2 in these patients compared with healthy individuals. ACE2 is a homologue of angiotensin-converting enzyme (ACE). ACE2 negatively regulates the renin-angiotensin system by converting angiotensin II to vasodilatory angiotensin 1–7, diminishing and opposing the vasoconstrictor effect of angiotensin II. ACE2, ACE, angiotensin II and other renin-angiotensin-aldosterone system (RAAS) interactions are complex and, at times, paradoxical. In experimental studies, both ACE inhibitors and angiotensin II receptor blockers (ARBs) have been shown to limit severe lung injury in certain viral pneumonias, and it has been speculated that these agents could be beneficial in COVID-19.24 The Council on Hypertension of the European Society of Cardiology has highlighted the lack of evidence supporting the harmful effects of ACE inhibitors and ARBs in the context of the pandemic COVID-19 outbreak.25 The Council on Hypertension strongly recommends that physicians and patients should continue treatment with their usual antihypertensive therapy because there is no clinical or scientific evidence to suggest that treatment with ACE inhibitors or ARBs should be discontinued because of COVID-19 infection. Similarly, a joint HFSA, America College of Cardiology (ACC) and American Heart Association statement said there were no experimental or clinical data demonstrating beneficial or adverse outcomes with

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COVID-19 and Heart Failure: A Multiparametric Approach background use of ACE inhibitors, ARBs or other RAAS antagonists among COVID-19 patients with a history of cardiovascular disease treated with such agents.26–28 In addition, Vaduganathan et al. suggest withdrawing RAAS inhibitors may be harmful in certain high-risk patients with known or suspected COVID-19, and RAAS inhibitors may have a beneficial effect in patients with HF.29 Further evidence was provided in a retrospective cohort study of 4,480 patients with COVID-19, which showed that use of ACE inhibitors/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease in patients diagnosed with COVID-19.28

Advanced Heart Failure: Durable Left Ventricular Assist Devices and Transplant Patients Patients with a left ventricular assist device (LVAD) or who have had a heart transplant are a particularly challenging group to manage in the current pandemic.29–33 Patients with LVADs require frequent monitoring of anticoagulation levels, which requires blood draws in the laboratory or home monitoring if the person can do this. Additionally, the LVAD needs to be interrogated for any alarms and sometimes its speed may need to be adjusted, which cannot be done remotely. Furthermore, early in the postoperative period, LVAD patients may require in-person visits for assessment of surgical sites and echocardiograms to adjust pump speeds.30 Early clinical case reports have highlighted how LVAD patients respond to the cytokine storm of COVID-19.34,35 Transplant patients pose other issues. Early in the postoperative period, patients undergo frequent routine endomyocardial biopsies and right heart catheterisations for surveillance for any signs of graft rejection. As many as 10 biopsies may be carried out in the first 6 months after a transplant, assuming a smooth postoperative course. At the beginning of the pandemic, the ACC’s Interventional Council and the Society for Cardiovascular Angiography and Interventions suspended elective procedures in catheterisation laboratories to preserve resources and prevent patients being exposed to the hospital environment where COVID-19 may be more prevalent.36 That said, the

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA 2020;323:1824–36. https://doi. org/10.1001/jama.2020.6019; PMID: 32282022. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–4. https://doi.org/10.1016/S01406736(20)30628-0; PMID: 32192578. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506. https://doi.org/10.1016/S0140-6736(20)30183-5; PMID: 31986264. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020;323:1406–7. https://doi. org/10.1001/jama.2020.2565; PMID: 32083643. Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ 2020;369:m1375. https://doi.org/10.1136/ bmj.m1375; PMID: 32241884. Tavazzi G, Pellegrini C, Maurelli M, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 2020;22:911–5. https://doi.org/10.1002/ejhf.1828; PMID: 32275347. Ullah W, Saeed R, Sarwar U, et al. COVID-19 complicated by acute pulmonary embolism and right-sided heart failure. JACC Case Rep 2020;2:1379–82. https://doi.org/10.1016/j.

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10.

11.

12.

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definition of elective requires clinical judgement as, in some cases, deferring a procedure may have deleterious effects, such as in the case of allograft rejection. Some institutions have adopted a very early transition to non-invasive surveillance of rejection using AlloMap (CareDx) and Allosure (CareDx) to minimise patient exposure to a hospital setting, which require just a blood draw. It is also unclear how immunosuppression therapy plays a role in transplant patients’ vulnerability to COVID-19. If they do become infected, ideal immunosuppression management is not clear. Some have advocated reducing immunosuppression to allow the body to tackle the virus. Later in the course of the disease, it is believed that hyperactive immune responses are responsible for deleterious effects leading to ARDS, cardiac injury, cytokine release syndrome and multiorgan failure.37,38 Ongoing trials are evaluating the effects of immunosuppression to improve outcomes for these patients. In the US, at the first peak of the pandemic on 22 March 2020, the number of inactivations reached 85% in the transplant list.32 By 21 June 2020, most of the patients had been reactivated and only 4–9% remain inactive due to COVID-19.

The Aftermath We need to bear in mind that current clinical cases refer to hospitalised patients and a significant percentage of patients may exhibit mild symptoms and stay at home as per governmental recommendations. These patients may experience cardiovascular manifestations related to COVID-19 that may present later once the COVID-19 pandemic subsides. The other wave of admissions or complications that we will probably see are patients who stayed home with missed MIs, and those with a worsening HF functional class or underdiagnosed atrial or ventricular arrhythmias. There are numerous efforts around the world to gather and report findings regarding COVID-19 and cardiovascular involvement, such as the CAPACITY-COVID registry.36 We may need to rely on follow-up to see what the cardiovascular consequences, thrombotic concerns and possible lung impairment are for those who survive COVID-19. Most importantly, healthcare systems are now prepared for the second wave of the pandemic, the extent of which of course we cannot predict.37 However we are now prepared to protect our patients with HF as much as possible.

jaccas.2020.04.008; PMID: 32313884. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol 2020;5:2352–71. https://doi. org/10.1016/j.jacc.2020.03.031; PMID: 32201335. Skulstad H, Cosyns B, Popescu BA, et al. COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel. Eur Heart J Cardiovasc Imaging 2020;21:592–8. https://doi.org/10.1093/ehjci/jeaa072; PMID: 32242891. British Society of Echocardiography. Clinical guidance regarding provision of echocardiography during the COVID-19 pandemic. 2020. https://bsecho.org/covid19 (accessed 24 July 2020). Cheung JC, Lam KN. POCUS in COVID-19: pearls and pitfalls. Lancet Respir Med 2020;8:e34. https://doi.org/10.1016/ S2213-2600(20)30166-1; PMID: 32275856. Garot J, Amour J, Pezel T, et al. SARS-CoV-2 fulminant myocarditis. JACC Case Rep 2020;2:1342–6. https://doi. org/10.1016/j.jaccas.2020.05.060. Minhas AS, Scheel P, Garibaldi B, et al. Takotsubo syndrome in the setting of COVID-19 infection JACC Case Rep 2020;2:1321–5. https://doi.org/10.1016/j.jaccas.2020.04.023; PMID: 32363351. Kochav SM, Coromilas E, Nalbandian A, et al. Cardiac

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arrhythmias in COVID-19 infection. Circ Arrhythm Electrophysiol 2020;13:e008719. https://doi.org/10.1161/CIRCEP.120.008719; PMID: 32434385. Dabbagh MF, Aurora L, D’Souza P, et al. Cardiac tamponade secondary to COVID-19. JACC Case Rep 2020;2:1326–30. https://doi.org/10.1016/j.jaccas.2020.04.009; PMID: 32328588. Rali AS, Ranka S, Shah Z, Sauer AJ. Mechanisms of myocardial injury in coronavirus disease 2019. Card Fail Rev 2020;6:e15. https://doi.org/10.15420/cfr.2020.10; PMID: 32537248. Rath D, Petersen-Uribe Á, Avdiu A, et al. Impaired cardiac function is associated with mortality in patients with acute COVID-19 infection. Clin Res Cardiol 2020. https://doi. org/10.1007/s00392-020-01683-0; PMID: 32537662; epub ahead of press. Lala A, Johnson KW, Januzzi JL, et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol 2020. https://doi.org/10.1016/j. jacc.2020.06.007; PMID: 32517963; epub ahead of press. Hollander JE, Carr BG. Virtually perfect? Telemedicine for Covid-19. N Engl J Med 2020;382:1679–81. https://doi. org/10.1056/NEJMp2003539; PMID: 32160451. Poppas A, Rumsfeld JS, Wessler JD. Telehealth is having a moment: will it last? J Am Coll Cardiol 2020;75:2989–91. https:// doi.org/10.1016/j.jacc.2020.05.002; PMID: 32475633. D’Amario D, Canonico F, Rodolico D, et al. Telemedicine,

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artificial intelligence and humanisation of clinical pathways in heart failure management: back to the future and beyond. Card Fail Rev 2020;6:e16. https://doi.org/10.15420/cfr.2019.17; PMID: 32612852. Ayebare RR, Flick R, Okware S, et al. Adoption of COVID-19 triage strategies for low-income settings. Lancet Respir Med 2020;8:e22. https://doi.org/10.1016/S2213-2600(20)30114-4; PMID: 32171063. British Heart Foundation. Coronavirus: what it means for you if you have heart or circulatory disease. Heart Matters 21 July 2020. https://www.bhf.org.uk/informationsupport/heartmatters-magazine/news/coronavirus-and-your-health (accessed 27 July 2020). Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259–60. https://doi.org/10.1038/s41569-020-0360-5; PMID: 32139904. European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. 2020. https://www.escardio.org/Councils/ Council-on-Hypertension-(CHT)/News/position-statement-ofthe-esc-council-on-hypertension-on-ace-inhibitors-and-ang (accessed 7 July 2020). Heart Failure Society of America, American College of Cardiology and American Heart Association. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. 2020. https://www.acc.org/latest-in-cardiology/

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articles/2020/03/17/08/59/hfsa-acc-aha-statement-addressesconcerns-re-using-raas-antagonists-in-covid-19 (accessed 7 July 2020). Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA 2020. https://doi.org/10.1001/ jama.2020.4812; PMID: 32208485; epub ahead of press. Fosbøl EL, Butt JH, Østergaard L, et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA 2020;324:168–77. https://doi.org/10.1001/ jama.2020.11301; PMID: 32558877. Vaduganathan M, Vardeny O, Michel T, et al. Renin-angiotensinaldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020;382:1653–9. https://doi.org/10.1056/ NEJMsr2005760; PMID: 32227760. Li F, Cai J, Dong N. First cases of COVID-19 in heart transplantation from China. J Heart Lung Transplant 2020;39:496–7. https://doi.org/10.1016/j.healun.2020.03.006; PMID: 32362394. Imamura T. Therapeutic strategy for patients with coronavirus disease 2019 during left ventricular assist device supports. J Card Fail 2020;26:479. https://doi.org/10.1016/j. cardfail.2020.04.014; PMID: 32371279. Latif F, Farr MA, Clerkin KJ, et al. Characteristics and outcomes of recipients of heart transplant with coronavirus disease

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2019. JAMA Cardiol 2020. https://doi.org/10.1001/ jamacardio.2020.2159; PMID: 32402056; epub ahead of press. American Heart Association. Organ transplants make a turnaround from COVID-19 decline. 18 June 2020. https:// www.heart.org/en/news/2020/06/18/organ-transplants-makea-turnaround-from-covid-19-decline (accessed 7 July 2020). Mahmood K, Rashed ER, Oliveros E, et al. Predisposition or protection?: COVID-19 in a patient on LVAD support with HIV/ AIDS. JACC Case Rep 2020;2:1337–41. https://doi.org/10.1016/j. jaccas.2020.05.015. Chau VQ, Oliveros E, Mahmood K, et al. The imperfect cytokine storm: severe COVID-19 with ARDS in patient on durable LVAD support. JACC Case Rep 2020;2:1315–20. https://doi. org/10.1016/j.jaccas.2020.04.001; PMID: 32292915. Welt FGP, Shah PB, Aronow HD, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from the ACC’s Interventional Council and SCAI. J Am Coll Cardiol 2020;75:2372–5. https://doi.org/10.1016/j. jacc.2020.03.021; PMID: 32199938. Linschoten M, Asselbergs FW. CAPACITY-COVID: a European registry to determine the role of cardiovascular disease in the COVID-19 pandemic. Eur Heart J 2020;41:1795–6. https://doi. org/10.1093/eurheartj/ehaa280; PMID: 32267494. Argulian E. Anticipating the ‘second wave’ of health care strain in the COVID-19 pandemic. JACC Case Rep 2020;2:845–6. https://doi.org/10.1016/j.jaccas.2020.04.005; PMID: 32296782.

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Neprilysin

Neprilysin as a Biomarker: Challenges and Opportunities Noemi Pavo, Suriya Prausmüller, Philipp E Bartko, Georg Goliasch and Martin Hülsmann Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria

Abstract Neprilysin (NEP) inhibition is a successful novel therapeutic approach in heart failure with reduced ejection fraction. Assessing individual NEP status might be important for gathering insights into mechanisms of disease and optimising individualised patient care. NEP is a zincdependent multisubstrate-metabolising oligoendopeptidase localised in the plasma membrane with the catalytic site facing the extracellular space. Although NEP activity in vivo is predominantly tissue-based, NEP can be released into the circulation via ectodomain shedding and exosomes. Attempts to determine circulating NEP concentrations and activity have not yet resulted in convincingly coherent results relating NEP biomarkers to heart failure disease severity or outcomes. NEP is naturally expressed on neutrophils, opening up the possibility of measuring a membrane-associated form with integrity. Small studies have linked NEP expression on neutrophils with inflammatory state and initial data might indicate its role in heart failure with reduced ejection fraction. Future studies need to assess the regulation of systemic NEP activity, which is assumed to be tissue-based, and the relationship of NEP activation with disease state. The relationship between tissue NEP activity and easily accessible circulating NEP biomarkers and the impact of the latter remains to be established.

Keywords Neprilysin, biomarker, heart failure, angiotensin receptor neprilysin inhibitor, sacubitril/valsartan Disclosure: The authors have no conflicts of interest to declare. Received: 16 December 2019 Accepted: 10 March 2020 Citation: Cardiac Failure Review 2020;6:e23. DOI: https://doi.org/10.15420/cfr.2019.21 Correspondence: Noemi Pavo, Department of Cardiology, Medical University of Vienna, Austria, Währinger Gürtel 18–20, 1090 Vienna, Austria; E: noemi.pavo@meduniwien.ac.at Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Neprilysin (NEP) was more or less unrecognised by the cardiovascular community until 2014 when the Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study reported impressive clinical benefits resulting from the combination of an angiotensin receptor blocker (ARB) with a neprilysin inhibitor (angiotensin receptor neprilysin inhibitor [ARNi]) over angiotensin-converting enzyme (ACE) inhibition in heart failure with reduced ejection fraction (HFrEF).1 The study was stopped prematurely due to the positive results. The first ARNi holds a class IB recommendation for stable systolic heart failure (HF) with a left ventricular ejection fraction (LVEF) of ≤35% in individuals who remain symptomatic on recommended doses of ACE inhibitors/ARBs and have elevated natriuretic peptide levels according to current treatment guidelines.2 More recent data suggest that an extended spectrum of HFrEF patients, including those with moderately-to-mildly reduced LVEF, might also benefit from the therapy. Although the Efficacy and Safety of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure Patients with Preserved Ejection Fraction (PARAGON-HF) study, which tested ARNi in HF patients with LVEF 45% or higher, missed its primary endpoint, subgroup analysis implied it had a beneficial effect in patients with lower LVEF and, interestingly, women.3 The Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode

(PIONEER-HF) and Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event (TRANSITION) studies imply that initiation in decompensated HF patients is safe and effective.4,5 The new guidelines of the European Society of Cardiology are egarely awaited, especially concerning a potential upvaluation of ARNi within the therapeutic algorithm for treating HF. The success of this new therapeutic strategy has encouraged research into the role of NEP in HF, the regulation NEP and the mechanism of action of NEP inhibition. Understanding NEP regulation would probably enable the assessment of an individual patient’s NEP status, which is potentially useful for risk stratification and therapy guidance, and may reveal previously unrecognised pathomechanisms of HF, paving the way for novel therapies.

Biology of Neprilysin The human genome covers about 686 putative peptidases that regulate the breakdown of bioactive peptides involved in key biological processes.6 The zinc-dependent metallopeptidases form a large group of enzymes that includes NEP, ACE, carboxypeptidases and collagenases, among others.7 Human endopeptidase NEP shows a highly conserved sequence homology with other species, including rodents and pigs.8 It consists of 749 amino acid residues and, as a type II integral membrane protein, is located in the plasma membrane with the active site facing the extracellular space. This multisubstrate-metabolizing enzyme generally

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Neprilysin hydrolyses peptides of up to about 50 amino acids long, preferring the amino-terminal side of hydrophobic residues; it sometimes acts more efficiently as a dipeptidyl carboxypeptidase than a true endopeptidase.7 Given the diverse range of substrates, NEP has been discovered in many different enzymatic contexts in the past, resulting in it having multiple names, including membrane metalloendopeptidase EC 3.4.24.11, neutral endopeptidase 24.11, endoprotease 24.11, common acute lymphoblastic leukaemia antigen (CALLA), neutrophil antigen cluster differentiation antigen 10 (CD10) and enkephalinase. NEP is believed to be involved in the degradation of natriuretic peptides, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), adrenomedullin, endothelin-1 and angiotensin II, as well as primarily non-vasoactive peptides, such as glucagon, glucagon-like peptide, enkephalins and somatostatin.9 The specificity of NEP is determined by the length and subsites of the substrate and the dissociation rate of the two metabolites formed on release from the active site.7 Although the affinity of NEP towards its putative substrates may be predicted to some degree, and turnover rates have been investigated for some peptides, its singular functional relevance is difficult to forecast in vivo. Moreover, NEP is a fairly ubiquitous enzyme. It is found in the highest concentrations within the kidneys, followed by the gastrointestinal tract, liver, male genital organs, lungs and adipose tissue, and has also been detected in the brain and heart.10 NEP is expressed on a variety of cells, including epithelial cells, endothelial cells, fibroblasts, smooth muscle cells and cardiac myocytes.11

Neprilysin Inhibition by Sacubitril/Valsartan PARADIGM-HF was the first study definitively proving that NEP inhibition is beneficial in HFrEF, after decades of research investigating the effects of different NEP inhibitors in animal models, as well as human HF and hypertension. NEP inhibition consistently resulted in an increase in circulating natriuretic peptides (ANP and BNP), and was related to natriuretic peptide effects via elevated cyclic guanosine monophosphate concentrations, vasodilation and natriuresis.12–15 The enhanced activity of bradykinin, another substrate of NEP, might contribute to the beneficial effects, but this effect is still to be investigated in combination with an ARB/ARNi.16 NEP inhibition was regarded to primarily affect the natriuretic peptide system, whereas simultaneously activated the renin– angiotensin system (RAS). The inhibition of NEP was subsequently discussed as a beneficial cardiovascular target alongside the use of ACE inhibitors, which again alleviate the non-desirable activation of RAS. Encouraging preclinical data have led to the NEP inhibitor omapatrilat being tested in HF. In the Inhibition of Metalloprotease by omapatrilat in a Randomized Exercise Symptoms Study with heart failure (IMPRESS), omapatrilat reduced the composite endpoint compared to lisinopril in symptomatic HF patients already on an ACE inhibitor.17 However, when compared to enalapril in the Phase III Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), omapatrilat failed to show a reduction in the primary endpoint in symptomatic HF patients already on an ACE inhibitor.18 The increased risk of severe angioedema, probably due to excess bradykinin, led to the cessation of vasopetidase, that is, a NEP inhibitor plus an ACE inhibitor, development. This problem could be overcome by combining a NEP inhibitor with ARB instead of an ACE inhibitor in ARNi. In healthy controls, the administration of sacubitril/valsartan results in dose-dependent increases in ANP, cyclic guanosine monophosphate, renin concentration and activity, as well as angiotensin II.19 An increase in

renin and angiotensin II is also observed in HFrEF patients shortly after therapy initiation.20 Notably, angiotensin II actions are assumedly sufficiently blocked by the ARB component. Moreover, NEP inhibition in HFrEF leads to increased circulating levels of NEP substrates, such as ANP, glucagon-like peptide 1 and substance-P.21 Beyond these changes in plasma levels of bioactive peptides, which might be based on direct or indirect effects of NEP inhibition, more clinically apparent features of ARNi therapy have been described. ARNi results in a long-term improvement in echocardiographic parameters, might improve functional mitral regurgitation, exerts nephroprotective effects and improves glycaemic control.22–25 The precise mechanisms underlying these clinical features and, most interestingly, how NEP inhibition reduces cardiovascular mortality and HF hospitalisation remain elusive. Understanding NEP regulation in HF conditions and the effects during treatment with NEP inhibitors would grant profound insight into the pathophysiology of HFrEF, which is necessary for the progression of HF therapy.

Neprilysin as a Biomarker Given the convincing clinical benefit of NEP inhibition in HFrEF, it should be assumed that individual NEP regulation is associated with disease severity, therapy response, the occurrence of side-effects and outcome. The precise determination of NEP regulation could therefore be of great importance, especially as the number of patients treated with the drug is growing rapidly. Biomarker-guided strategies might enable the monitoring and optimisation of therapies in individuals. NEP inhibition is excitingly successful in HF, but also seems to exert beneficial effects on other conditions, such as chronic kidney disease (CKD) and diabetes.1,23 Understanding how NEP is regulated and the mechanisms involved in NEP inhibition might cast light on the pathomechanisms of HF and systemic disease, possibly pointing to novel therapeutic targets. To date, the clinical utility of measuring circulating NEP, that is, NEP concentrations or activity or neutrophil NEP expression, is hypothetical. Establishing reliable analytical methods for determining NEP concentrations and actions are a prerequisite. Yet, the determination of NEP – or at least its concentration – seems to be challenging.

Circulating Neprilysin Circulating plasma biomarkers represent the most convenient and feasible approach to addressing this issue. NEP, like many other membrane-bound metalloproteases, can be released from the cell surface by ectodomain shedding into the extracellular milieu, resulting in a non-membraneassociated ‘soluble’ form containing the catalytically active site. The processes responsible for the externalisation of the enzyme are largely unknown. A disintegrin and metalloprotease 17 (ADAM-17) plays a role in NEP release.26 Endothelial cells and human adipose-derived mesenchymal stem cells may also secrete NEP-bound exosomes.26,27 NEP is not only ubiquitously expressed in various tissues but can also be found on peripheral blood cells (called CD10 here), primarily on neutrophils. Figure 1 illustrates the relationship between tissue NEP and its mebrane and nonmembrane associated circulating forms. The following section summarises data on the possible use of different forms of circulating NEP as a biomarker, with a focus on cardiovascular diseases.

Non-membrane-associated Serum/ Plasma Neprilysin Concentrations Non-membrane-associated NEP has been detected in serum/plasma in addition to urine, cerebrospinal and synovial fluid.28,29 Circulating NEP concentrations have been evaluated in several types of HF and some other cohorts. Table 1 summarises the studies investigating circulating

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Neprilysin as a Biomarker Figure 1: Schematic Overview of Neprilysin (Content of Various Tissues, Location of the Enzyme and its Active Site, Mechanisms for Externalisation and Possible Forms of Circulating Neprilysin)

TISSUE NEP

CIRCULATING NEP

Tissue NEP expression

ANP, BNP, CNP, ET-1, ADM, AngII

Shedding NEP fragments

Inactive fragments

NEP (CD10)

NEP

Active site Ectodomain

Exosome Membrane-associated NEP

NEP is a type II integral membrane protein with the active site facing the extracellular space (ectoenzyme). It generally hydrolyses peptides up to about 50 amino acids long, preferring the amino-terminal side of hydrophobic residues. NEP has a broad range of substrates and is believed to be essentially involved in the degradation of natriuretic peptides, including ANP, BNP, CNP, bradykinin, ADM, ET-1, AngII and primarily non-vasoactive peptides, such as amyloid-beta, glucagon, glucagon-like peptide 1, insulin-like growth factor, enkephalins, somatostatin or substance P (the latter not shown). NEP can be released into the circulation by ectodomain shedding, resulting in a non-membrane-associated â&#x20AC;&#x2DC;solubleâ&#x20AC;&#x2122; form eventually containing the catalytically active site. The processes responsible for externalisation of the enzyme are largely unknown. Endothelial cells and human adipose-derived mesenchymal stem cells may also secrete NEP-bound exosomes. In addition to circulating NEP derived from the plasma membrane of tissues, NEP can be found on the surface of peripheral blood cells, primarily on neutrophils (CD10). ADM = adrenomedullin; AngII = angiotensin II; ANP = atrial natriuretic peptide; BNP = B-type peptide; CNP = C-type natriuretic peptide; ET-1 = endothelin-1; NEP = neprilysin. Reproduced with permission from Servier Medical Art. The figure was created using Servier Medical Art licensed under a Creative Commons Attribution 3.0 (https://smart.servier.com).

NEP in distinct diseases. Although there is a reasonable rationale as to why serum/plasma NEP might be related to disease states and prognosis in various cohorts, NEP levels were rarely observed to be associated with disease severity and outcomes. To date, seven studies have been conducted in HF cohorts: four included stable HFrEF, one acute decompensated HF and two HF with preserved ejection fraction (HFpEF). The first and largest study, which included 1,069 HFrEF patients reported a significant direct association between serum NEP concentrations and cardiovascular mortality with NEP as a risk factor, but no correlation between serum NEP and HF disease severity, as assessed by left ventricular ejection fraction, New York Heart Association class or N-terminal pro hormone BNP (NT-proBNP) levels.30 The same group reported data in an equally large, mostly HFrEF population, where elevated circulating NEP concentrations were associated with increased all-cause and HF hospitalisations.31 Again, circulating NEP concentrations were not related to HF severity or treatment.31 Circulating NEP concentrations were lower in decompensated HF than stable HF in another study.32 The initiation of ARNi therapy in HFrEF did not alter plasma NEP concentrations.21,33 For HFpEF, plasma NEP concentrations could not be associated with functional status or outcome.34,35 With regard to non-HF cohorts, plasma NEP concentrations did not correlate with NT-proBNP, haemodynamic parameters or outcome in pulmonary hypertension.36 In ST-elevation MI patients, plasma NEP levels

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did not change significantly in the early phase or 1 month after reperfusion and there was no association with infarct size, inflammation or outcome at 1 year.37 For patients with CKD, plasma NEP concentrations were not associated with hospitalisation for HF or atherosclerotic cardiovascular events.38 In contrast to these neutral results, elevated plasma NEP concentrations were associated with higher all-cause mortality in out-ofhospital cardiac arrest patients, albeit NEP levels were not related to lactate.39 In a relatively large community-based population study including 1,536 individuals, circulating NEP concentrations were not associated with natriuretic peptides or outcomes; however, a link between low NEP levels and an adverse cardiovascular risk profile was suggested.40 NEP is thought to play a major role in cancer development and progression.41 Nevertheless, there were no differences in plasma NEP concentrations for distinct tumour entities or stages, whereas it seemed to be a risk factor for mortality in myelodysplastic disease.42 It seems that plasma NEP concentrations are poor predictors of outcomes in HF and other diseases and might not be ideal biomarkers. The major limitation in interpreting these data is the lack of consistency between the different immunoassays used, as also there are no data available on pre-analytics, constitution of NEP fragments and corresponding antibodies.16

Non-membrane-associated Circulating Neprilysin Activity Circulating NEP retains some of its catalytic activity, as NEP activity is detectable in plasma. It has been suggested that plasma NEP activity

Study

Goliasch et al. 201634

HFpEF

Lyle et al. 201935

Vodovar et al. 201532

AHF

HFpEF

1,201 (571–1,997) EDTA plasma (+Zn)

Nougue et al. 201821

HFrEF

HFpEF: 242 Control: 891

144

EDTA plasma

497 (149–1,075)

Serum

1,148 (539–2,002) EDTA plasma

AHF: 468 920 (irBNP) CHF: 46 Non-AHF: 169

925 (374–1,700)

105

RevueltaLopez et al. 202032

HFrEF

Serum

1,248 (538–2,825) Serum

1,021

Heart failure Nunez et al. with mostly HF 201731 reduced ejection fraction (<40% left ventricular ejection fraction in 88%)

Matrix

1,302 (531–2,935) Serum

NT-proBNP (ng/l)

1,069

Size of Cohort

Bayes-Genis et al. 201530

HFrEF

Heart failure cohorts

Clinical setting

582 (160–772)

640 (390–1,220)

642 (385–1,219)

R&D System

1,550 (500–25,000)

Uscn Life Science 2,862 (2,068–3,827)

Uscn Life Science CHF: 352 (325–380) AHF: 314 (257–377) Non-AHF: 256 (58–339)

Uscn Life Science 241 (205–303)

Aviscera Bioscience

Assay for NEP NEP Concentration Concentration (pg/ml)

–

Fluorimetry

–

CHF: 0.29 (0.22–0.35) nmol/ml/min AHF: 0.22 (0.13–0.34) nmol/ml/min Non-AHF: 0.37 (0.3–0.5) nmol/ml/min

340 (254–445) pmol/ ml/min

–

Assay for NEP Activity NEP Activity

No association: left atrium size Negative association: dyslipidaemia, statin use

No association: sex, age, BMI, NYHA, glomerular filtration rate, fibrosis, 6-minute walk test Negative association: NT-proBNP

No correlation: plasma NEP concentration and activity Negative correlation: plasma NEP activity and immunoreactive BNP

–

Negative association: age, hypertension, ischaemic aetiology No association: sex, BMI, NYHA, NT-proBNP, estimated glomerular filtration rate, heart failure treatment

No correlation: estimated glomerular filtration rate, left ventricular ejection fraction, NT-proBNP, NYHA, blood pressure

Associations

Table 1: Summary of Studies Investigating Circulating Neprilysin Concentrations and Activity as Biomarkers in Heart Failure Patients and Other Cohorts

Plasma NEP concentrations in HFpEF are lower compared to controls

Plasma NEP concentrations are not associated with cardiovascular mortality or HF hospitalisation

Inhibitory effect of BNP and proBNP on plasma NEP activity?

Sacubitril/valsartan reduced plasma NEP activity, but not plasma NEP concentration

No significant changes in plasma NEP concentrations following angiotensin receptor NEP inhibitor initiation

Elevated plasma NEP concentrations were associated with increased all-cause, cardiovascular or AHF admissions for ambulatory patients with HFrEF

Plasma NEP concentration is a risk factor for cardiovascular mortality and the composite endpoint, i.e. cardiovascular mortality or heart failure hospitalisation

Main Findings

Neprilysin

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Study

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Pavo et al. 201942

Simonini et al. 200545

Treatmentnaive cancer

JIA

207

128 (64–279)

–

542

555

JIA: 58 Control: 52

578 (151–1,482) and 746 (120–1,371)

Heparin plasma

EDTA plasma

Plasma not specified

Serum

Baseline: 88 (14–375)

1,105 (565–2,047)

–

R&D System

–

276 (0–5,981)

Uscn Life Science 309 (231–444)

Fluorimetry

–

Fluorimetry

–

Fluorimetry

Control: 76.5 ± 24.0 pmol/ml/min JIA: 42.0 ± 16.6 pmol/ml/min

–

0.204 (0.156–0.285) nmol/ml/min

–

0.155 (0.048–0.310) nmol/l 0.358 (0.233–0.719) nmol/l divided by median

–

Assay for NEP Activity NEP Activity

3,900 (1,000–43,000) –

ELH-Neprilysin-1, 760 (510–930) RayBiotech 2,320 (1,840–4,010) divided by median

R&D System

–

R&D System

Assay for NEP NEP Concentration Concentration (pg/ml)

N/A

No correlation: BMI, sex

No correlation (plasma NEP concentration): age, estimated glomerular filtration rate, BMI, proBNP, BNP, plasma NEP activity

No correlation: age, creatinine, BMI, NT-proBNP, BNP

No correlation: age, gender, BMI, creatinine

No correlation: glomerular filtration rate, NT-proBNP, lactate

Positive correlation: BMI, homeostatic model assessment index, insulin resistance

No correlation: age, glomerular filtration rate, BMI, NT-proBNP, BNP

Associations

Plasma NEP concentrations were lower and synovial NEP concentrations higher in patients with JIA

Plasma NEP concentrations are not associated with all-cause mortality. Risk factor for myelodysplastic malignancies

Not predictive for cardiovascular outcome

Plasma NEP concentrations were not associated with all-cause mortality

Plasma NEP concentrations were not related to infarct size, inflammation or adverse outcomes at 1 year. No change of plasma NEP concentrations early or at 1 month post-reperfusion

Plasma NEP concentrations were a risk factor for all-cause mortality (Q4 versus Q1–Q3)

Plasma NEP activity is associated with cardiometabolic risk

Plasma NEP concentrations are not associated with all-cause mortality or HF hospitalisation

Main Findings

AHF = acute heart failure; BNP = B-type natriuretic peptide; CHF = chronic heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; JIA = juvenile idiopathic arthritis; NT-proBNP = N-terminal pro hormone BNP; NYHA = New York Heart Association; OHCA = out-of-hospital cardiac arrest; STEMI = ST-elevation MI.

Emrich et al. 201838

Chronic kidney disease, stage 2–4

Yoshihisa et al. 79 201936

Pulmonary hypertension

–

203

Bernelin et al. 201937

STEMI

1,774 (348–5,572) Serum

144

Zelniker et al. 201839

OHCA

Plasma not specified

–

318

Standeven et al. 201044

General population

EDTA plasma

Matrix

70 (29–142)

NT-proBNP (ng/l)

1,536

Reddy et al. 201940

Size of Cohort

General population

Other Cohorts

Clinical setting

Table 1: Cont.

Neprilysin as a Biomarker

Neprilysin might correlate with circulating concentrations of NEP fragments.43 However, the study investigating chronic and decompensated acute HF patients found no correlation between plasma NEP concentrations and activity.32 Plasma NEP concentrations were not related to activity in CKD patients either.38 In contrast, NEP inhibition in HFrEF patients receiving ARNi therapy resulted in decreased plasma NEP activity.21 In CKD, higher plasma NEP activity, but not concentration, was associated with a lower incidence of hospitalisation for HF or cardiovascular events.38 Plasma NEP activity has also been implicated in other non-HF contexts. Plasma NEP activity increased with indices of metabolic syndrome, such as insulin resistance, homeostatic model assessment index and BMI, in 318 otherwise-healthy adults in a previously published study.44 In patients with juvenile idiopathic arthritis, plasma NEP activity was lower than in control subjects.45 Membrane-associated and circulating NEP exhibit similar affinity for inhibitors, optimal pH and Km (Michaelis constant) range, although the maximum reaction rate of circulating NEP is lower than its membraneassociated equivalent; therefore, in vivo NEP activity is believed to be predominantly tissue-based.46,47 In vivo measurement of tissue NEP activity has not been established and is not feasible. Circulating NEP activity might better reflect tissue NEP regulation, suggesting its superior ability as a biomarker when compared to circulating NEP concentrations. However, the contribution of different tissues to systemic NEP actions remains unclear. As NEP has a wide anatomical distribution and diverse biological functions, it can be assumed that its regulation is complex and that altered levels might be found in many disease types. Cardiac disease-specific changes might be difficult to outline.

fluorescence intensities were inversely correlated with HF disease severity, that is, NT-proBNP levels and New York Heart Association class, whereas higher expression levels seemed to be associated with better overall survival.54 In summary, against the background of beneficial effects of NEP inhibition, the association between increased NEP expression and better disease state seems counterintuitive. Interesingly, data from the PARADIGM study imply that more stable patients, who might be characterised by higher NEP expression, profit more from NEP inhibition than those with more advanced disease.55 Within this context, the role of neutrophil NEP expression and its possible relationship with proinflammatory state remains to be understood. Whether neutrophil NEP expression could be a surrogate for systemic tissue NEP activity or may be associated with HFrEF outcomes through its reflection of inflammatory predisposition needs to be investigated in future studies.

Urinary Neprilysin and Neprilysin in Cerebrospinal Fluid For the sake of completeness on non-tissue-based NEP measurements, determination of NEP in urine and cerebrospinal fluid will be discussed shortly. NEP expression is highest in the kidneys, yet the main location of the enzyme is within the brush border of the proximal tubule on the luminal site. Urinary NEP concentrations are increased in critically ill patients with acute kidney injury and in patients with diabetes, especially those with microalbuminuria, suggesting that urinary NEP might be an indicator of acute and chronic kidney injury.56,57 However, urinary concentrations are not correlated with plasma concentrations, resulting in questions about the contribution of kidney NEP regulation to plasma NEP levels.56

Functional Membrane Neprilysin Expression on Neutrophils As discussed, there are currently no data on the relationship between tissue NEP activity and plasma NEP concentrations or activity. Based on the poor association of plasma NEP measures with clinically relevant parameters and the unknown mechanisms involved in enzyme release, it may be assumed that tissue NEP is not related to plasma NEP measures. Consequently, the assessment of functional, membraneassociated NEP might be more reasonable. As discussed, NEP is ubiquitously expressed in various tissues and on peripheral blood cells (here called CD10), primarily on neutrophils. NEP on neutrophils may play a role in chemotaxis and neutrophil responsiveness to inflammatory stimuli.48,49 It has been shown to modulate neutrophil function by regulating concentrations of ANP and BNP.50 NEP expression on neutrophils has rarely been investigated, and in different settings immunoreactive NEP expression on neutrophils was upregulated on the addition of stimulating agents and neutrophil NEP fluorescence was elevated in the early phase of acute MI, returning to normal values 7 days after the event.50,51 Patients with severe infections showed a marked decrease in neutrophil NEP expression; septic patients were characterised by decreased neutrophil CD10 expression capacity.51,52 NEP null mice appeared developmentally normal but were sensitive to endotoxic shock.53 A study of 99 patients with HFrEF confirmed the abundant expression of NEP on granulocytes.53 NEP

McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. https://doi.org/10.1056/NEJMoa1409077; PMID: 25176015. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of

NEP in cerebrospinal fluid has been investigated in Alzheimer’s disease. This disease is characterised by amyloid-beta deposits resulting from a disturbed balance between amyloid-beta biosynthesis and clearance.58 NEP is a member of the amyloid degrading enzyme family and seems to be the major enzyme responsible for amyloid-beta breakdown in the brain.59 A meta-analysis showed that NEP expression and activity are reduced in the cortex of individuals with Alzheimer’s disease.60 Accordingly, these patients have lower NEP activity levels in the cerebrospinal fluid compared to controls.61 NEP upregulation could therefore be a valuable therapeutic target in combatting Alzheimer’s disease. However, unselective upregulation of NEP might have deleterious effects on the cardiovascular system. The long-term effects of NEP inhibition by sacubitril/valsartan, with the potential promotion of amyloid accumulation in the brain, need to be fully assessed.

Future Directions The utility of non-membrane-associated circulating NEP concentrations and activity as biomarkers of NEP regulation are limited, as the physiological actions of NEP are localised to the tissues. Further studies are needed to investigate tissue NEP regulation in HF and establish a relationship with HF disease states and outcomes. Membraneassociated neutrophil NEP expression may be a surrogate for tissue NEP regulation or proinflammatory state.

Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensinneprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–20. https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794.

Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensinneprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539–48. https://doi.org/10.1056/ NEJMoa1812851; PMID: 30415601. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/ valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail 2019;21:998–

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and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2018;6:547–54. https://doi.org/10.1016/S2213-8587(18)301001; PMID: 29661699. Januzzi JL, Jr., Prescott MF, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1085–95. https://doi.org/10.1001/ jama.2019.12821; PMID: 31475295. Kuruppu S, Rajapakse NW, Minond D, et al. Production of soluble neprilysin by endothelial cells. Biochem Biophys Res Commun 2014;446:423–7. https://doi.org/10.1016/j. bbrc.2014.01.158; PMID: 24495806. Katsuda T, Tsuchiya R, Kosaka N, et al. Human adipose tissuederived mesenchymal stem cells secrete functional neprilysinbound exosomes. Sci Rep 2013;3:1197. https://doi.org/10.1038/ srep01197; PMID: 23378928. Matucci-Cerinic M, Lombardi A, Leoncini G, et al. Neutral endopeptidase (3.4.24.11) in plasma and synovial fluid of patients with rheumatoid arthritis. A marker of disease activity or a regulator of pain and inflammation? Rheumatol Int 1993;13:1–4. https://doi.org/10.1007/bf00290326; PMID: 8390712. Spillantini MG, Geppetti P, Fanciullacci M, et al. In vivo ‘enkephalinase’ inhibition by acetorphan in human plasma and CSF. Eur J Pharmacol 1986;125:147–50. https://doi. org/10.1016/0014-2999(86)90094-4; PMID: 3015640. Bayes-Genis A, Barallat J, Galan A, et al. Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients. J Am Coll Cardiol 2015;65:657–65. https://doi.org/10.1016/j.jacc.2014.11.048; PMID: 25677426. Nunez J, Nunez E, Barallat J, et al. Serum neprilysin and recurrent admissions in patients with heart failure. J Am Heart Assoc 2017;6:e005712. https://doi.org/10.1161/ JAHA.117.005712; PMID: 28862951. Vodovar N, Seronde MF, Laribi S, et al. Elevated plasma B-type natriuretic peptide concentrations directly inhibit circulating neprilysin activity in heart failure. JACC Heart Fail 2015;3:629–36. https://doi.org/10.1016/j.jchf.2015.03.011; PMID: 26251090. Revuelta-Lopez E, Nunez J, Gastelurrutia P, et al. Neprilysin inhibition, endorphin dynamics, and early symptomatic improvement in heart failure: a pilot study. ESC Heart Fail 2020;7:559–66. https://doi.org/10.1002/ehf2.12607; PMID: 32045114. Goliasch G, Pavo N, Zotter-Tufaro C, et al. Soluble neprilysin does not correlate with outcome in heart failure with preserved ejection fraction. Eur J Heart Fail 2016;18:89–93. https://doi.org/10.1002/ejhf.435; PMID: 26725876. Lyle MA, Iyer SR, Redfield MM, et al. Circulating neprilysin in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2020;8:70–80. https://doi.org/10.1016/j. jchf.2019.07.005; PMID: 31392960. Yoshihisa A, Yokokawa T, Misaka T, et al. Soluble neprilysin does not correlate with prognosis in pulmonary hypertension. ESC Heart Fail 2019;6:291–6. https://doi.org/10.1002/ ehf2.12404; PMID: 30681298. Bernelin H, Mewton N, Si-Mohamed S, et al. Neprilysin levels at the acute phase of ST-elevation myocardial infarction. Clin Cardiol 2019;42:32–8. https://doi.org/10.1002/clc.23090; PMID: 30284298. Emrich IE, Vodovar N, Feuer L, et al. Do plasma neprilysin activity and plasma neprilysin concentration predict cardiac events in chronic kidney disease patients? Nephrol Dial Transplant 2019;34:100–8. https://doi.org/10.1093/ndt/gfy066; PMID: 29635392. Zelniker TA, Spaich S, Stiepak J, et al. Serum neprilysin and the risk of death in patients with out-of-hospital cardiac arrest of non-traumatic origin. Eur Heart J Acute Cardiovasc Care 2018:2048872618815062. https://doi.org/10.1177/ 2048872618815062; PMID: 30449136. Reddy YNV, Iyer SR, Scott CG, et al. Soluble neprilysin in the general population: clinical determinants and its relationship to cardiovascular disease. J Am Heart Assoc 2019;8:e012943. https://doi.org/10.1161/JAHA.119.012943. PMID: 31345101. Maguer-Satta V, Besancon R, Bachelard-Cascales E. Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer. Stem Cells 2011;29:389–96. https://doi.org/10.1002/ stem.592; PMID: 21425402.

42. Pavo N, Arfsten H, Cho A, et al. The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naive cancer patients. Sci Rep 2019;9:2554. https:// doi.org/10.1038/s41598-019-38867-2; PMID: 30796257. 43. Bayes-Genis A, Prickett TC, Richards AM, et al. Soluble neprilysin retains catalytic activity in heart failure. J Heart Lung Transplant 2016;35:684–5. https://doi.org/10.1016/j. healun.2015.12.015; PMID: 26830756. 44. Standeven KF, Hess K, Carter AM, et al. Neprilysin, obesity and the metabolic syndrome. Int J Obes (Lond) 2011;35:1031–40. https://doi.org/10.1038/ijo.2010.227; PMID: 21042321. 45. Simonini G, Azzari C, Gelli AM, et al. Neprilysin levels in plasma and synovial fluid of juvenile idiopathic arthritis patients. Rheumatol Int 2005;25:336–40. https://doi.org/10.1007/s00296004-0447-z; PMID: 14997340. 46. Yandle T, Richards M, Smith M, et al. Assay of endopeptidase-24.11 activity in plasma applied to in vivo studies of endopeptidase inhibitors. Clin Chem 1992;38:1785– 91. https://doi.org/10.1093/clinchem/38.9.1785; PMID: 1526015. 47. Spillantini MG, Sicuteri F, Salmon S, et al. Characterization of endopeptidase 3.4.24.11 (“enkephalinase”) activity in human plasma and cerebrospinal fluid. Biochem Pharmacol 1990;39:1353–6. https://doi.org/10.1016/00062952(90)90012-a; PMID: 2322317. 48. McCormack RT, Nelson RD, LeBien TW. Structure/function studies of the common acute lymphoblastic leukemia antigen (CALLA/CD10) expressed on human neutrophils. J Immunol 1986;137:1075–82. PMID: 2941484. 49. Shipp MA, Stefano GB, Switzer SN, et al. CD10 (CALLA)/neutral endopeptidase 24.11 modulates inflammatory peptideinduced changes in neutrophil morphology, migration, and adhesion proteins and is itself regulated by neutrophil activation. Blood 1991;78:1834–41; PMID: 1717072. 50. Matsumura T, Kugiyama K, Sugiyama S, et al. Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophils-induced endothelial cytotoxity. J Clin Invest 1996;97:2192–203. https:// doi.org/10.1172/JCI118660; PMID: 8636398. 51. Martens A, Eppink GJ, Woittiez AJ, et al. Neutrophil function capacity to express CD10 is decreased in patients with septic shock. Crit Care Med 1999;27:549–53. https://doi. org/10.1097/00003246-199903000-00034; PMID: 10199535. 52. Morisaki T, Goya T, Ishimitsu T, et al. The increase of low density subpopulations and CD10 (CALLA) negative neutrophils in severely infected patients. Surg Today 1992;22:322–7. https://doi.org/10.1007/bf00308740; PMID: 1392343. 53. Lu B, Gerard NP, Kolakowski LF Jr, et al. Neutral endopeptidase modulation of septic shock. J Exp Med 1995;181(6):2271-5. https://doi.org/10.1084/jem.181.6.2271; PMID: 7760013. 54. Pavo N, Gugerell A, Goliasch G, et al. Increased granulocyte membrane neprilysin (CD10) expression is associated with better prognosis in heart failure. Eur J Heart Fail 2019;21:537–9. https://doi.org/10.1002/ejhf.1441; PMID: 30828920. 55. Solomon SD, Claggett B, Packer M, et al. Efficacy of sacubitril/ valsartan relative to a prior decompensation: the PARADIGMHF trial. JACC Heart Fail 2016;4:816–22. https://doi. org/10.1016/j.jchf.2016.05.002; PMID: 27395349. 56. Pajenda S, Mechtler K, Wagner L. Urinary neprilysin in the critically ill patient. BMC Nephrol 2017;18:172. https://doi. org/10.1186/s12882-017-0587-5; PMID: 28545475. 57. Gutta S, Grobe N, Kumbaji M, et al. Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes. Am J Physiol Renal Physiol 2018;315:F263– 74. https://doi.org/10.1152/ajprenal.00565.2017; PMID: 29561187. 58. Nalivaeva NN, Turner AJ. Targeting amyloid clearance in Alzheimer’s disease as a therapeutic strategy. Br J Pharmacol 2019;176:3447–63. https://doi.org/10.1111/bph.14593; PMID: 30710367. 59. Iwata N, Tsubuki S, Takaki Y, et al. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000;6:143–50. https://doi.org/10.1038/72237; PMID: 10655101. 60. Zhang H, Liu D, Wang Y, et al. Meta-analysis of expression and function of neprilysin in Alzheimer’s disease. Neurosci Lett 2017;657:69–76. https://doi.org/10.1016/j.neulet.2017.07.060; PMID: 28778804. 61. Maruyama M, Higuchi M, Takaki Y, et al. Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer’s disease. Ann Neurol 2005;57:832–42. https://doi.org/10.1002/ana.20494; PMID: 15929037.

Ejection Fraction

Transcriptomic Research in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives Sebastian Rosch,1 Karl-Philipp Rommel,1 Markus Scholz,2,3 Holger Thiele1 and Philipp Lurz1 1. Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany; 2. Institute of Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany; 3. Leipzig Research Center for Civilization Diseases (LIFE), Leipzig University, Leipzig, Germany

Abstract Heart failure with preserved ejection fraction (HFpEF) is increasing in incidence and has a higher prevalence compared with heart failure with reduced ejection fraction. So far, no effective treatment of HFpEF is available, due to its complex underlying pathophysiology and clinical heterogeneity. This article aims to provide an overview and a future perspective of transcriptomic biomarker research in HFpEF. Detailed characterisation of the HFpEF phenotype and its underlying molecular pathomechanisms may open new perspectives regarding early diagnosis, improved prognostication, new therapeutic targets and tailored therapies accounting for patient heterogeneity, which may improve quality of life. A combination of cross-sectional and longitudinal study designs with sufficiently large sample sizes are required to support this concept.

Keywords Heart failure with preserved ejection fraction, gene expression, transcriptome, peripheral blood mononuclear cells, RNA, LIFE-Heart Disclosure: The authors have no conflicts of interest to declare. Received: 11 December 2019 Accepted: 22 June 2020 Citation: Cardiac Failure Review 2020;6:e24. DOI: https://doi.org/10.15420/cfr.2019.19 Correspondence: Philipp Lurz, Department of Internal Medicine/Cardiology, Leipzig Heart Center, Strümpellstraße 39, 04289 Leipzig, Germany. E: Philipp.Lurz@gmx.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure with preserved ejection fraction (HFpEF) is a common disease with rapidly increasing incidence and prevalence due to demographic changes.1 Well-known risk factors, such as metabolic syndrome (arterial hypertension, diabetes, obesity and dyslipidaemia), chronic kidney disease and AF, predispose to the development of HFpEF, especially in older people. Establishing the clinical diagnosis of HFpEF can be complex, as the diagnostic gold standard is the invasive evidence of elevated left ventricular (LV) filling pressures in the presence of HF symptoms and an echocardiographic preserved LV ejection fraction.2 Often, clinical symptoms of heart failure (HF) are non-specific and do not sufficiently discriminate HF and differential pathologies, and invasive work-up is unfeasible in every case. Non-invasive diagnostic algorithms, such as the Heart Failure Association’s PEFF score and the H2FPEF score, have been proposed to comprehensively associate symptoms with structural cardiac changes and elevated natriuretic peptides.2–4 However, they are characterised by limited diagnostic certainty in the detection of invasively elevated LV filling pressures and the identification of specific sub-phenotypes.5 HFpEF is associated with morbidity and a poor prognosis.6,7 However, no effective treatment addressing the whole HFpEF patient group has yet been established.2 The initially promising pharmacological approach of combined angiotensin-neprilysin inhibition failed to unequivocally demonstrate benefits.8 Current guidelines confine their recommendations to symptomatic relief and treatment of comorbidities.2 Shah et al.

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consequently proposed a phenotype-specific roadmap involving a multiorgan concept to provide tailored treatment strategies.9

Pathophysiological Paradigms in the Development of HFpEF Difficulties achieving standardised management for HFpEF can be explained by the high heterogeneity of the patient group. Thorough characterisation of HFpEF patients can identify masked phenotypes, such as amyloidosis or hypertrophic cardiomyopathy, which can be partially treated.4 For HFpEF patients without an identifiable specific cardiomyopathy, a pathophysiological paradigm has been proposed by Paulus et al.10 Herein, myocardial remodelling and dysfunction result from a sequence of systemic inflammation triggered by comorbidities, especially obesity, which leads to the production of reactive oxygen species, mainly in the microcirculation, causing microvascular dysfunction.11 Subsequently, nitric oxide (NO) expression in the endothelium is reduced. In cardiomyocyte NO-triggered cyclic guanosine monophosphate (cGMP) synthesis is altered negatively, which downregulates the activity of protein kinase G (PKG). In a rat model, PKG was shown to act like a break in hypertrophic response of the myocardium, which indicates vice versa that a downregulation of PKG results in hypertrophy and HFpEF.12 In mice, inhibition of cGMP breakdown by phosphodiesterase 5 (PDE5) prevented and reversed myocardial hypertrophy and fibrosis.13 However, in the placebo-controlled Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People

Transcriptomic Biomarker Research With Diastolic Heart Failure (RELAX) trial, PDE5 inhibition showed no improvements.14 An alternative pharmacological approach to enhance cGMP signalling was suggested by Lee et al.15 They found PDE9A to be upregulated, with the highest affinity and selectivity for cGMP signalling independent of the NO pathway. A PDE9A knock-out in a murine model of hypertrophic heart disease showed promising results.15 In a sheep model, Scott et al. found a beneficial effect of PDE9-inhibition compared with an untreated control, indicating a crucial role in HF and a potential therapeutic target in HFpEF.16 However, the generalisability of these findings to humans still needs to be demonstrated. Most recently, Schiattarella et al. proposed in a murine two-hit model (metabolic and mechanical stress induced by obesity, metabolic syndrome and hypertension), whereby the abundance of myocardial NO was caused by increased activity of the inducible NO synthase (iNOS) and resulting nitrosative stress.17 This was linked to excessive protein nitrosylation within myocardial cells, including proteins central to the evolutionary conserved and cytoprotective unfolded protein response. The group elegantly demonstrated that HFpEF is characterised by a deficient unfolded protein response, which was restored after pharmacological or genetic suppression of iNOS with consecutive amelioration of an experimental HFpEF phenotype. On a myocardial level, the common final pathway in all pathophysiological scenarios is the development of fibrosis. It has been demonstrated that clinically non-invasive phenotyping regarding the amount of myocardial fibrosis is feasible and can identify different haemodynamic abnormalities.18 However, given the proposed mechanistic link of comorbidities, inducing inflammation and the development of fibrosis, a better characterisation of the underlying inflammatory stimuli affecting the myocardium is desirable to improve diagnosis, treatment and prognosis of HFpEF, and potentially to further specify certain HFpEF subgroups in order to develop tailored therapies. Since inflammatory processes are well detected in the transcriptome, transcriptomics is supposed to be a valuable yet understudied technique to improve diagnostics and to identify new therapy targets. As Porrello et al. have pointed out, new strategies are required to explore how changes in the human transcriptome might interact with environmental stressors leading to the development of the heterogenic clinical phenotypes resulting in HFpEF.19 Moreover, new insights into the pathophysiology may enable the identification of potential new targets.

Molecularâ&#x20AC;&#x201C;Pathological Evaluation of Gene-expression Profile in HFpEF Since the human genome project was successfully accomplished, identification and characterisation of gene-expression profiles and their regulating factors in diseases offer a huge advantage in understanding the pathophysiology and developing new targeted treatment strategies.20,21 The applicability of this approach has been demonstrated in oncology, where gene-expression profiling of tumour tissue has been used to individualise treatments and consecutively enhance survival and medical quality in the past few decades. As a prominent example, the treatment of breast cancer has been revolutionised by analysing the individual tumour gene expression.22 In a 5-year follow-up, Druker et al. described promising results in patients suffering from chronic myeloid leukaemia treated with a specific antibody therapy (imatinib) adapted to the underlying gene mutation (BRC-ABL tyrosine-kinase).23

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At the molecular level, gene expression produces messenger RNA (mRNA) during the process of transcription, which forms the basis for protein synthesis during translation. Gene expression itself can be regulated by the transcribed, but not protein-translated, non-coding RNA, for which several sub-types are known. Among them, microRNA (miRNA, 20â&#x20AC;&#x201C;25 nucleotides) and long non-coding RNA (lncRNA, >200 nucleotides) are the most comprehensively investigated, due to their high regulatory potential. The miRNAs are one of the major regulatory gene families inducing degradation or repression of mRNA through specific base pairing. Their small size allows them to target many genes, interacting with other miRNAs to create complex regulatory networks, which affect cellular processes, such as cell differentiation. Therefore, they have become attractive targets for biomarker studies and may potentially be used as treatment targets in the future.24,25 The lncRNAs act as transcriptional factors and are more tissue specific than mRNA. Generally, lncRNAs have been less well-studied in human pathophysiology, because of methodological limitations in the past. However, newer sequencing methods, such as next-generation sequencing (NGS), have overcome some of those limitations and pose an attractive tool for further investigation in human diseases.26,27 While non-coding RNA analysis may have great potential for biomarker establishment, the investigation of its regulative function is complex. Analysing protein-coding mRNA reflects the definitely transcribed proteins in the analysed tissue as a result of transcription and regulatory processing. A number of techniques exist for transcriptomic analysis. Three commonly applied approaches are real-time quantitative polymerase chain reaction (RT-PCR), microarray analysis and NGS. In RT-PCR amplification of RNA is monitored in real time and exact amounts of amplified RNA can be quantified. It has a low dynamic range and is precise. However, this method is limited by a low scalability and has virtually no power to discover potentially novel transcripts.28 The microarray technique overcomes the scalability limitation, allowing for transcriptome-wide analysis. Microarrays use probes to simultaneously analyse the expression of thousands of genes, with each probe targeting a unique sequence within a given mRNA transcript of interest. The result is a snapshot of actively expressed genes at a given point in time.29 However, relying on predefined probes hinders the detection of previously unidentified genes or transcripts. NGS is the most recent technique and combines a high dynamic range, high precision and high throughput with the ability to detect novel transcripts, but it is the most expensive option.30

Gene-expression Analyses in Clinical Trials The potential of transcriptomic tissue analysis in cardiology was demonstrated by Heidecker et al. who published 100% specificity and sensitivity in detecting myocarditis in myocardial biopsies from a mixed dilated (n=32) and inflammatory (n=16) cardiomyopathy cohort by a transcriptome-based biomarker containing 62 out of 9,878 differentially expressed genes on microarray and RT-PCR assessment.31 In HFrEF, identification of several monogenic subtypes has been suggested.32 Furthermore a reactivation of fetal genes in the adult failing heart has been described based on a complex process involving transcriptional, post-transcriptional and epigenetic regulation of the cardiac genome.33 However, little is known about potential genetic determinants of HFpEF. Given the diagnostic potential of transcriptome analysis, gene expression could also facilitate the differentiation of HFpEF patients.4 Indeed, transcriptomic analysis of mRNA using an NGS approach of

Ejection Fraction myocardial biopsies of HFpEF patients (n=5) and non-HF patients (n=11) taken during coronary artery bypass grafting showed up to 750 differentially expressed genes in the myocardium related to impaired myocardial contraction, tissue remodelling, extracellular matrix organisation and oxidative phosphorylation.34 Those mechanisms are known to result in systolic dysfunction, especially of the LV, which has also been suggested as a characteristic of HFpEF patients.35 However, uneven distribution of relative myocardial ischaemia in both groups cannot be ruled out as a confounder. Apart from these studies, human myocardial transcriptomics in HFpEF have rarely been described, due to the fact that harvesting myocardial tissue is an invasive procedure and currently not routinely performed in patients with preserved ejection fraction. This means that the potential benefits of analysing myocardial tissue in HFpEF might largely stay limited to clinical studies. Thus, we need to find a potent diagnostic tool, potentially using blood biomarkers, that could reasonably be applied more universally in routine clinic tests. Circulating RNA markers, mainly miRNAs that can be assessed conveniently in the peripheral blood, could be the answer. Ellis et al. evaluated circulating miRNA expression in plasma using a RT-PCR approach in patients admitted to hospital for acute shortness of breath showing a distinct gene-expression profile depending on underlying HF (HFpEF and HFrEF, n=32) or chronic obstructive pulmonary disease (COPD, n=15) compared with the control group (n=14). After external validation (n=150), they found that of 742 evaluated miRNAs, four could distinguish between the clinical scenarios, with a diagnostic value mainly in combination with the wellestablished cardiac biomarker N-terminal pro B-type natriuretic peptide (NT-proBNP) supporting the diagnostic potential of miRNAs in the blood plasma.36 While the study could not validate the use of miRNAs to distinguish between HFrEF and HFpEF, discrimination between HFrEF (n=15; n=39) and HFpEF (n=15; n=19) was shown to be possible by analysing circulating miRNA in plasma in two other studies using an RT-PCR and microarray approach, respectively.37,38 More challenging, but of high relevance in daily practice, is the differentiation of a well-compensated, non-acute HFpEF patient from a non-HF patient. Wong et al. addressed this issue in about 900 compensated HF patients and 800 non-HF patients by analysing eight miRNAs in plasma using an RT-PCR approach. Multiple miRNA panels in combination with NT-proBNP were shown to have a diagnostic power in identifying non-acute HF and discriminating between HF phenotypes. Results were independently validated in an external cohort.39

Peripheral Blood Mononuclear Cells as a Potential Peripheral Diagnostic Biomarker Peripheral blood mononuclear cells (PBMCs) are interesting in this context, as they are peripherally available, nucleus-carrying cells and have the potential for full transcriptome analysis.40 Additionally, they are integral to systemic inflammation, which is proposed to be the common underlying condition, as described above. Gerling et al. investigated the role of PBMCs in hyperaldosteronism and hypertensive heart disease in rats using a microarray approach. Transcriptional signatures in PBMCs showed comparable results to the cardiomyocytes. Whether PBMCs may serve as early and non-invasive sentinels for myocardial gene expression in humans needs to be

further evaluated, but in any case the PBMC transcriptome might inform on gene regulation in the inflammatory state, which is assumed to be the cornerstone of HFpEF pathophysiology.41 Evidence for a pathology-specific PBMC transcriptome comes from Gupta et al., who found a specific signature of PBMCs in patients with dilated cardiomyopathy (DCM, n=44) resulting in HFrEF compared with healthy controls (n=48) using a microarray approach. External validation was performed in patients with breast cancer as an extracardiac disease, which showed a distinct gene expression comparable to healthy controls.42,43 In patients with HFpEF, a study has shown a positive correlation between exercise capability on cardiopulmonary exercise testing and expression of microRNA-208b in PBMCs (n=56) using an RT-PCR approach. These results indicate the possibility to measure the symptom-correlated severity of HFpEF in PBMCs.44 A chronologically structured overview of currently published studies addressing RNA analysis in HFpEF conditions is given in Table 1 comparing the considered RNA species, sample types, study sizes, HF types and the main findings.

Translation of Transcriptomic Discoveries to Bedside Given the heterogeneity of the HFpEF syndrome, application of one therapeutic agent addressing all HFpEF patients appears unlikely. In contrast, better characterisation of patients in subgroups with predominate phenotypes might help to personalise pharmacological treatment.9 Transcriptomic research and genetic phenotyping has the potential to unravel individual HFpEF pathomechanisms and to identify key treatments for new therapies in the future. Moreover, clustering patients according to transcriptomic findings might offer a more immediate clinical benefit. While the pathophysiological paradigm focuses on a myocardial inflammation triggered myocardial (and peripheral tissue) remodelling in HFpEF, which results in a downstream fibrotic effect, clinically patients present as a fibrotic or inflammatory phenotype.18 The potential of transcriptomic studies to be used as complex biomarkers could help the clinician to tailor treatments with already available pharmacological agents. For example, anti-fibrotic treatments with spironolactone failed to prove overall benefit in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) study, but might be a useful drug in the presence of enhanced myocardial fibrosis and stiffness, as indicated by a beneficial effect in patients with less atrial compliance (and more BNP).45â&#x20AC;&#x201C;47 Recently, the use of specific anti-inflammatory therapies, such as interleukin-1beta and low-dose colchicine, have been shown to offer benefit in cardiovascular disease with chronic inflammation, and might further complement the clinical toolbox of heart failure treatments if used in susceptible patients.48,49

Differential Gene Expression in Cross-sectional and Longitudinal Analyses Out of the Framingham Heart study (n=8,372), which was established in 1947, Andersson et al. recently published cohorts of prevalent HFrEF (n=62) and HFpEF (n=35) to elucidate potential genetic contributors to cardiac remodelling and HF.50 Genome-wide single-nucleotide polymorphisms, gene expression and DNA methylation were

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Transcriptomic Biomarker Research Table 1. Chronological Overview of Studies Addressing RNA Expression in HFpEF Author

Species

RNA Type

Sample

Sample Size (n) HF Type

Methods

Findings

Gerling et al. 201341

Rat

miRNA

PBMC cardiomyocyte

HFpEF

RT-PCR

Comparable transcriptional signatures in cardiomyocyte and PBMCs

Ellis et al. 201336

Human

miRNA

Plasma

HFrEF RT-PCR HFpEF (COPD)

4 miRNAs can distinguish between HF and COPD in acute breathlessness

Watson et al. 201538

Human

miRNA

Plasma

HFrEF HFpEF

RT-PCR

8 miRNAs distinguish between HFrEF and HFpEF, improved sensitivity and specificity in combination with NT-proBNP

Wong et al. 201537

Human

miRNA

Plasma

HFrEF HFpEF

Microarray

4 miRNAs distinguish between HFrEF and HFpEF, improved sensitivity and specificity in combination with NT-proBNP

Chen et al. 201754

Human

miRNA

Plasma

HFrEF HFpEF

Microarray RT-PCR

Specific miRNA profile in HF, 2 miRNAs can discriminate HFrEF and HFpEF, 1 miRNA associated with NYHA class

Marketou et al. 201844

Human

miRNA

PBMCs

HFpEF

RT-PCR

Positive correlation between miRNA expression and clinical severity of HFpEF

Das et al. 201834

Human

miRNA

Myocardial biopsies

HFpEF

NGS

750 differentially expressed genes relating to myocardial configuration

Wong et al. 201939

Human

miRNA

Plasma

546

HFpEF

RT-PCR

miRNA + NT-proBNP as a diagnostic tool in non-acute, compensated HFpEF

Schiattarella et al. 201917

Mouse, rat, human

Total RNA

Myocardium (mice/rat) Myocardial biopsies (human)

HFpEF HFrEF

RT-PCR

Increased activity of iNOS and resulting nitrosative stress linked to an unfolded protein response causing HFpEF

COPD = chronic obstructive pulmonary disease; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; iNOS = inducible nitric oxide synthase; mIRNA = microRNA; NGS = next-generation sequencing; NT-proBNP = N-terminal pro B-type natriuretic peptide; NYHA = New York Heart Association; PBMC = peripheral blood mononuclear cells; RT-PCR = real-time quantitative polymerase chain reaction.

characterised using a transomics analytical approach. During a mean follow-up of 8.5 years, 2.7% (n=223) and 2.8% (n=234) developed HFrEF and HFpEF, respectively. Gene-expression analysis found distinct profiles in prevalent and incident HFrEF, as well as HFpEF indicating molecular contributors of HF development. However, the findings need to be validated externally.

In addition, a prospective follow-up study of patients initially not affected by HF was established to detect the incidence of HFpEF in a longitudinal assessment (Predictors for the Development of Heart Failure and preserved Ejection fraction; PREDICT-HFpEF). Genome, proteome and PBMC transcriptome are characterised at baseline and after an average follow-up period of 7 years.

Heart Failure Cohort of LIFE-Heart Study

Based on this and other large-scale cohorts, the gap between crosssectional and longitudinal studies in HFpEF could be closed. Our multiomics approach has the potential to improve identification and characterisation of underlying molecular mechanisms causing systemic inflammation conditions in these patients and their impact on HFpEF development. Finally, biomarkers and classifiers developed in a crosssectional approach in order to distinguish HFpEF from other entities could be longitudinally validated by our approach.

At the Heart Center, Leipzig, and Leipzig University, the Leipzig Heart study (LIFE-Heart) recruited 6,995 patients with suspected coronary artery disease (CAD), stable CAD or acute MI from 2006 to 2014. Patients were characterised by clinical data, echocardiography, coronary angiography and laboratory and molecular genetic tests.51 Samples were also stored in biobanks, allowing further retrospective analyses. From this cohort, we identified 719 patients fulfilling HFpEF diagnostic criteria and 1,106 patients without HF and available geneexpression data. At baseline, gene-expression profile of PBMCs in HFpEF and non-HF samples was performed using a microarray approach. In this huge cohort, we observed a HFpEF-specific geneexpression profile compared with non-HF patients.52,53 External validation in an appropriate and independent cohort confirmed these findings.

Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation 2002;106:3068–72. https://doi.org/10.1161/01. CIR.0000039105.49749.6F; PMID: 12473553. Ponikowski P, Adriaan AV, Ankeret SD, al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J

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Conclusion Transcriptome analysis appears to be a promising tool for the identification and characterisation of HFpEF patients. Multi-omics analysis in HFpEF could enhance our understanding of underlying pathophysiologies and may help to identify patients at risk. It also offers the hope of new potential therapeutic targets.

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40. Liew CC, Jun Ma, Tang HC, et al. The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Clin Med 2006;147:126–32. https://doi.org/10.1016/j.lab.2005.10.005; PMID: 16503242. 41. Gerling IC, Ahokas RA, Kamalov G, et al. Gene expression profiles of peripheral blood mononuclear cells reveal transcriptional signatures as novel biomarkers for cardiac remodeling in rats with aldosteronism and hypertensive heart disease. JACC Heart Fail 2013;1:469–76. https://doi. org/10.1016/j.jchf.2013.09.003; PMID: 24622010. 42. Gupta MK, Halley C, Duan ZH, et al. miRNA-548c: a specific signature in circulating PBMCs from dilated cardiomyopathy patients. J Mol Cell Cardiol 2013;62:131–41. https://doi. org/10.1016/j.yjmcc.2013.05.011; PMID: 23735785. 43. Wang H, Chen F, Tong J, et al. Circulating microRNAs as novel biomarkers for dilated cardiomyopathy. Cardiol J 2017;24:65–73. https://doi.org/10.5603/CJ.a2016.0097; PMID: 27748501. 44. Marketou ME, Kontaraki JE, Maragkoudakis S, et al. MicroRNAs in peripheral mononuclear cells as potential biomarkers in hypertensive patients with heart failure with preserved ejection fraction. Am J Hypertens 2018;31:651–7. https://doi. org/10.1093/ajh/hpy035; PMID: 29506053. 45. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92. https://doi.org/10.1056/NEJMoa1313731; PMID: 24716680. 46. Pfeffer MA, Claggett B, Assmannet SF, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation 2015;131:34–42. https://doi.org/10.1161/CIRCULATIONAHA.114.013255; PMID: 25406305. 47. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387–95. https://doi. org/10.1016/S0140-6736(12)61227-6; PMID: 22932717. 48. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. https://doi.org/10.1056/ NEJMoa1707914; PMID: 28845751. 49. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of lowdose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–2505. https://doi.org/10.1056/NEJMoa1912388; PMID: 31733140. 50. Andersson C, Lin H, Liu C, et al. An integrated multi-omics approach to identify genetic underpinnings of heart failure and its echocardiographic precursors: The Framingham Heart Study. Circ Genom Precis Med 2019; 12:e002489. https://doi. org/10.1161/CIRCGEN.118.002489; PMID: 31703168. 51. Beutner F, Teupser D, Gielen S, et al. Rationale and design of the Leipzig (LIFE) Heart Study: phenotyping and cardiovascular characteristics of patients with coronary artery disease. PLoS One 2011;6:e29070. https://doi.org/10.1371/journal. pone.0029070; PMID: 22216169. 52. Besler C Rommel KP, Kirsten H, et al. Phosphodiesterase 9A expression in patients with heart failure with preserved ejection fraction: results from endomyocardial biopsies and the Leipzig (LIFE) Heart Study Cohort. Clin Res Cardiol 2019;108(Suppl 1):V120. https://www.abstractserver.com/ dgk2019/jt/abstracts/V120.HTM (accessed 10 August 2020). 53. Rommel KP, Kirsten H, Besler, C, et al. Genome-wide gene expression analysis to unpuzzle the pathomechanistic traits of heart failure with preserved ejection fraction (HFpEF) – insights from the Leipzig Heart Study. Clin Res Cardiol 2019;108(Suppl 1):V715. https://www.abstractserver.com/ dgk2019/jt/abstracts/V715.HTM (accessed 10 August 2020). 54. Chen F, Yang J, Li Y, Wang H. Circulating microRNAs as novel biomarkers for heart failure. Hellenic J Cardiol 2018;59:209–14. https://doi.org/10.1016/j.hjc.2017.10.002; PMID: 29126951.

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Clinical Syndromes

Congestion and Diuretic Resistance in Acute or Worsening Heart Failure Ingibjörg Kristjánsdóttir, Tonje Thorvaldsen and Lars H Lund Karolinska Institutet, Department of Medicine, Stockholm, Sweden; and Karolinska University Hospital, Heart and Vascular Theme, Stockholm, Sweden

Abstract Hospitalisation for acute heart failure (AHF) is associated with high mortality and high rehospitalisation rates. In the absence of evidencebased therapy, treatment is aimed at stabilisation and symptom relief. The majority of AHF patients have signs and symptoms of fluid overload, and, therefore, decongestion is the number one treatment goal. Diuretics are the cornerstone of therapy in AHF, but the treatment effect is challenged by diuretic resistance and poor diuretic response throughout the spectrum of chronic to worsening to acute to post-worsening HF. Adequate dosing and monitoring and evaluation of diuretic effect are important for treatment success. Residual congestion at discharge is a strong predictor of worse outcomes. Therefore, achieving euvolaemia is crucial despite transient worsening renal function.

Keywords Diuretic resistance, acute heart failure, worsening heart failure, congestion, worsening renal failure, prognosis Disclosure: TT has received speaker’s fees from Orionpharma, Bayer, and Novartis. LHL has received research grants to author’s institution, speaker’s and/or consulting fees from AstraZeneca, Novartis, Bayer, Vifor Pharma, Relypsa, Abbott, Sanofi, Merck, and Pharmacosmos. IK has no conflicts of interest to declare. Received: 6 December 2020 Accepted: 7 May 2020 Citation: Cardiac Failure Review 2020;6:e25. DOI: https://doi.org/10.15420/cfr.2019.18 Correspondence: Tonje Thorvaldsen, Heart and Vascular Theme, Section for Heart Failure, Karolinska University Hospital, Heart Failure Research Group, Karolinska Institutet, 17176 Stockholm, Sweden. E: tonje.thorvaldsen@sll.se Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

From Acute Heart Failure Towards Worsening or De Novo Heart Failure The natural history of heart failure (HF) is characterised by disease progression and episodes of worsening HF and acute decompensation requiring outpatient treatment intensification, emergency department or in-hospital care. Acute HF (AHF), also known as acute decompensated HF, is defined as a progressive and sometimes rapid onset or worsening of symptoms and/or signs of HF.1 AHF may present as new onset HF (de novo HF) or worsening chronic HF (WHF), where WHF may be defined as worsening signs and symptoms requiring additional therapy. WHF represent 80–90% of HF hospitalisations. 2 Compared with WHF, de novo HF patients have a different clinical profile. Generally, the patients are younger, with less previous MI and less global comorbidity burden. 3 Accordingly, mortality rates are lower and the potential for improvement and possibly recovery is greater in de novo than in chronic HF (CHF). 4,5 However, hospitalisation for de novo HF is still considered a critical event in the trajectory of the disease, given that mortality rates are tripled compared with patients who are never hospitalised.6 AHF is increasingly recognised as an event rather than a distinct syndrome, and this event is heterogeneous with variable onset and presentation, may increasingly be managed in outpatient day clinics or emergency departments, and may be more appropriately termed WHF. In patients with WHF, the profile of haemodynamic congestion is similar regardless of reduced (HFrEF) or preserved ejection fraction (HFpEF), but patients with HFpEF as compared with HFrEF appear to

have more interstitial than intravascular fluid overload, possibly due to reduced venous capacitance and lower arterial compliance.7–9 Patients hospitalised for HF are at high risk for adverse outcomes in hospital, but also after discharge.10 In the European Heart Failure Long-term Registry (ESC-HF-LT) 1-year mortality in AHF and in chronic stable HF was 23.6% and 6.4%, respectively. Rates of death or hospitalisation for HF were 36% in AHF patients and 14.5% in CHF patients.11 Despite intensive research, no treatment has yet been shown to reduce mortality or risk of rehospitalisation in AHF.12 However, with optimal therapy it has been suggested that early rehospitalisation may be preventable in up to 70% of cases.13

Congestion Regardless of HF aetiology, HF patients can be divided into four different profiles depending on clinical status. Patients may be described as either wet or dry, depending on their congestion status, and as warm or cold, depending on their perfusion status, with the combination of wet and cold (congested and hypoperfused) having the worst prognosis.14 Clinical signs of hypoperfusion include cold, sweaty extremities, narrow pulse pressure, dizziness, oliguria and mental confusion. Typical clinical signs of congestion include increased jugularis venous pressure, orthopnoea, pulmonary rales, peripheral oedema, third heart sound and hepatomegaly. The terms congestion and fluid overload are often used interchangeably, however haemodynamic congestion reflects increased cardiac filling

Access at: www.CFRjournal.com

Clinical Syndromes Figure 1: Modifications to the Traditional View of the Course of Chronic Heart Failure

Myocardial Function

Acute event

discharged with weight gain), and strongly associated with higher mortality and higher rehospitalisation rates.23,29–32 The traditional view holds that after WHF, the patient recovers to a point that is lower than before WHF but still represents a distinct recovery (Figure 1; blue line). We suggest that the reality is closer to hospital discharge being an arbitrary event determined only in part by clinical appropriateness, with a highly variable post-hospital course (Figure 1; red dotted line). The heterogeneity and poor treatment of WHF may be one reason recent WHF trials such as the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial and the Trial of Ularitide Efficacy and Safety in Acute Heart Failure (TRUE-AHF) have failed to demonstrate a clinical benefit of vasoactive and decongestive therapy.33,34 Why does congestion continue to present such a considerable clinical problem?

Euvolaemia Time Black line reflects the traditional view of the course of chronic heart failure with episodes of acute decompensation. Red dotted line reflects the theory that the acute decompensated event is an arbitrary culmination of a preceding subclinical worsening that occurs gradually and unpredictably before the distinct clinical event, and a subclinical vulnerable state that remains after apparent clinical recovery and discharge from hospital. Adapted from Gheorghiade et al. 2005.23 Used with permission from Elsevier.

pressures, but does not necessarily equal volume overload in the extracellular compartments, particularly in the acute setting. Over time, if haemodynamic congestion continues to progress, clinical signs of congestion may evolve. In contrast, in acute pulmonary oedema, pulmonary congestion is predominantly due to an acute increase in afterload with a relative volume redistribution rather than an absolute fluid accumulation.15 Overall, congestion and fluid overload (the wet haemodynamic profile) is the most common profile in patients presenting with AHF. Less than 10% of patients present with signs of hypoperfusion and low blood pressure (the cold haemodynamic profile).16,17 Even if patients have some degree of pulmonary congestion, relatively few present with fulminant pulmonary oedema18,19 and the majority of patients instead have gradual onset of backward failure, fluid retention, congestion and often (but not always) weight gain.20–22 The traditional view of the course of CHF is shown by the blue line in Figure 1.23 Due to chronic maladaptive neurohormonal activation, HF progresses gradually and then some inciting event, such as an infection or poor adherence to medical treatment, causes sudden AHF needing hospitalisation. However, accumulating data from implantable devices are suggesting that the AHF event is really an arbitrary culmination of a chronic WHF that has occurred over weeks (Figure 1; red dotted line).20,24–26 Thus, AHF may be more appropriately considered WHF resulting from progressive insidious congestion. Implantable haemodynamic monitoring may be effective by recognising worsening congestion in the subclinical state, allowing prompt adjustment of therapy and averting hospitalisation.24 In the absence of mortality-reducing therapy, the main goal in WHF treatment is symptom and congestion relief. A cornerstone in the treatment of WHF and excessive volume overload is IV loop-diuretics, a therapy used in approximately 90% of AHF hospitalisations.27,28 Analogously to the insidious progressive congestion preceding WHF events, residual congestion at discharge is underrecognised and/or undertreated, exceedingly common (in one study half of patients were

First, determination of euvolaemia can be challenging, given that even patients with limited signs and symptoms of fluid overload may have substantial subclinical congestion.35 Furthermore, dyspnoea relief and the patient’s return to normal body weight after treatment have been shown to be poor predictors of successful decongestion.36,37 Hence, simple clinical tools to determine euvolaemia are lacking. Lung ultrasound is increasingly being recognised as a tool to assess pulmonary congestion and has been shown to be superior to X-ray in ruling out interstitial oedema or pleural effusions.38,39 A multiparameterbased pre-discharge evaluation of euvolaemia/residual congestion is suggested by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).10 This comprehensive evaluation including assessment of jugular venous pressure, hepatomegaly, oedema, 6-minute walk test, natriuretic peptides, chest X-ray, vena cava imaging and lung ultrasound, may be a useful tool in recognising residual congestion, but this method has not been evaluated prospectively.

Diuretic Resistance Second, diuretic resistance, a phenomenon often seen in CHF, may hamper the success of decongestive therapy. Diuretic resistance is most commonly defined as the inability to achieve an adequate natriuretic and diuretic response despite high doses of diuretics;27,40 however, no universal definition exists. Diuretic response is a measure of decongestive effect in relation to diuretic dose, often defined as weight change per 40 mg furosemide.41 The pathophysiology of diuretic resistance is multifactorial, including the influence of neurohormonal activation, inflammation and fluctuating renal function.27 The pharmacokinetics and pharmacodynamics of the drug given is of importance for the diuretic response. Oral bioavailability may be reduced because of gut congestion. Furthermore, diuretics are 95% protein bound, hypoalbuminemia secondary to cachexia may thereby reduce the amount of the drug that reaches the kidney. Additionally, prolonged exposure to loop diuretics leads to nephron remodelling with hypertrophy of the distal tubular cells, which, in turn, may alter the diuretic response due to a compensatory increased sodium reabsorption.42 In the Spanish Heart Failure Registry (Registro de Insuficiencia Cardiaca; RICA), diuretic resistance was defined as “persistent congestion requiring hospitalisation despite adequate doses of loop diuretic (≥80 mg furosemide per day)“, and according to this definition diuretic resistance was prevalent in 21% of the admitted patients.40 The patients with diuretic resistance had lower blood pressure, more comorbidities, lower haemoglobin, lower estimated glomerular filtration rate (eGFR)

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HF Congestion and Diuretic Resistance and sodium, higher uric acid at admission and the patients with diuretic resistance had 37% higher risk of dying within a year.40

Worsening Renal Function Third, a fear of worsening renal function (WRF) induced by diuretic treatment may cause clinicians to use suboptimal dosing or reduce diuretic treatment too early, before congestion relief is achieved. Traditionally, intensive diuretic treatment has been considered relatively contraindicated in HF to avoid WRF. However, mounting evidence suggests that transient WRF is not so harmful if decongestion is achieved.43,44 Importantly, renal function may improve with diuretic treatment. As part of the systemic congestion in HF with increased intraabdominal pressure and increased venous pressures, congestion also occurs in the kidneys (renal congestion).45 Elevated central venous pressure as a marker of congestion has been associated with lower eGFR; and aggressive diuretic treatment and increased urine volume in the first 24 hours of hospitalisation in HF has been associated with lower incidence of WRF.46,47 Therefore, the perceived fear of WRF may not be justified; on the contrary, it may hamper optimal congestion therapy and put patients at higher risk for adverse events.

Treatment Options There is little guidance in choosing loop diuretics, but there is a tradition for the use of furosemide despite the fact that torsemide has increased bioavailability and a longer half-life compared with furosemide. The ongoing Torsemide comparison with Furosemide for Management of Heart Failure trial (TRANSFORM-HF trial, NCT03296813) is investigating whether torsemide is superior to furosemide in HF patients discharged from hospital. More important than diuretic agent is adequate dosing of the diuretic treatment and evaluation of the response. In the Diuretic Strategies in Patients with Acute Decompensated Heart Failure (DOSE AHF) trial comparing patients receiving IV 2.5-fold their daily oral dose with patients receiving their daily oral dose IV, the higher dose tended to be associated with favourable effects on dyspnoea relief, weight and fluid loss.31 Diuretic response is mostly assessed clinically by measuring daily change in body weight and net fluid balance. However, the correlation between weight and fluid loss is poor.37 New measures of diuretic effectiveness are called for to improve treatment strategies and tailor therapy. Measuring the concentration of sodium and chloride in urine in addition to urinary output has been suggested as a better way of evaluating congestion effect.48 The ESC recommends measuring sodium in a spot urine sample 1–2 hours following initiation of diuretics to evaluate effect on natriuresis.10 When the response to loop diuretics alone is found to be inadequate, other treatment options exist, but the level of evidence is weak. The add-on of a thiazide or thiazide-like agent, such as metolazone (sequential nephron blockade), has been associated with a higher weight and fluid loss without resulting in reduced kidney function,49 but other studies indicate increased risk of hypokalaemia and WRF.50 Mineralocorticoid receptor antagonists (MRA) may be used as diuretics and to reduce the hypokalaemic effect of loop diuretics and thiazides; however, the use in acute setting needs further investigation.51,52 In the Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure trial (ATHENA), high-dose spironolactone was not associated with a reduction in natriuretic peptides or congestion relief as compared with placebo.51 However, as in many AHF trials, the control group received aggressive treatment, which may explain why intensive MRA therapy was not effective. The Acetazolamide in

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Decompensated Heart Failure with Volume Overload trial (ADVOR trial, NCT03505788) is currently studying whether the combination of acetazolamide and loop diuretic compared with loop diuretics alone improve diuretic response.53 A treatment option for diuretic resistance and hyponatraemia is tolvaptan, a vasopressin antagonist that enhances free water diuresis. However, convincing evidence for effectiveness is lacking.54,55 Nesiritide, a recombinant B-type natriuretic peptide, has been tested in WHF without convincing evidence.56 Serelaxin, a recombinant form of human relaxin-2 (a hormone that contributes to cardiovascular and renal adaptions during pregnancy) did not improve outcomes in acute HF.33 The new antidiabetic agent, sodium–glucose co-transporter-2 (SGLT2) inhibitor, has been shown to reduce the risk for WHF or cardiovascular death in CHF;57 future investigation will tell whether this drug has a role in the acute setting of HF. Ultrafiltration may be used for patients who do not respond to diuretic treatment, but results regarding safety and efficacy have been unconvincing. Potential advantages of ultrafiltration were thought to be greater control over the rate and volume of fluid removal, greater net loss of sodium and less neurohormonal activation; and initial studies were promising.58 However, in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) study, weight loss was not significantly greater with ultrafiltration compared with diuretic-based therapy, and ultrafiltration was associated with a greater increase in creatinine at 96 hours.59 Furthermore, ultrafiltration has been shown to be associated with more pronounced neurohormonal activation than diuretic treatment.60 The Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial was stopped prematurely due to slow enrolment, but there was a non-significant trend towards longer time to first HF event in the ultrafiltration arm.61 More trials are needed to prove effectiveness for this treatment, but recently the Peripheral Ultrafiltration for the Relief from Congestion in Heart Failure (PURE-HF) trial (NCT03161158), an outcomes trial evaluating the efficacy of peripheral ultrafiltration, was also closed due to poor enrolment. A standardised approach on diuretic dosing is difficult to propose because treatment response depends on several factors, such as body weight, kidney function, previous treatment with loop diuretics and degree of volume overload. However, in the recently published position paper on diuretic use in HF by the HFA of the ESC, a detailed algorithm for diuretic use in AHF is suggested.10 The paper emphasises the importance of early initiation of IV loop diuretics due to lowered uptake from the gut of oral medications because of gut oedema. Diuretic naive acute HF patients should receive 20–40 mg furosemide IV or an equivalent dose of other loop diuretics if kidney function is normal, otherwise a higher dose.10 Patients already on a loop diuretic admitted for AHF should receive 1–2-fold their 24-hour oral home dose intravenously. Of importance is that oral bioavailability for furosemide is highly variable (10–90%), whereas torsemide and bumetanide have a bioavailability between 80% and 100%; this needs to be taken into consideration when switching from oral to IV diuretic treatment.10,62 Additionally, evaluation of treatment effect is crucial, and diuretic doses need to be adjusted according to the response. As outlined above, the evidence for add-on therapy when the response to loop diuretic treatment is insufficient, is weak. Detailed strategies and algorithms for treating diuretic resistance have been developed based on clinical experience and existing evidence.10,49,63 Briefly, sequential nephron blockade is mostly recommended as the second step after non-response to IV loop diuretics. Metolazone may be given

Clinical Syndromes in a starting dose of 2.5–5 mg once daily in combination with loop diuretics. Electrolytes should be monitored closely, and potassium substitution should be given as needed. Once a diuretic response has been generated, the frequency of metolazone treatment should be decreased or stopped completely. For patients with diuretic resistance managed in the outpatient setting, lower doses of metolazone are recommended (e.g. 2.5 mg once or twice a week). In patients with severe hyponatraemia, add-on therapy with tolvaptan may serve as an option instead of metolazone. Due to the inconclusive risk–benefit analyses, ultrafiltration should be limited to a last bail-out option if all pharmacological therapy fails.

Follow-up As outlined above, patients discharged after an episode of AHF are at high risk for rehospitalisation. These patients should be monitored closely in the outpatient HF clinic after discharge. When a patient has reached euvolaemia, loop diuretic therapy should be reduced to the lowest dose possible to minimise WRF, neurohormonal activation and electrolyte abnormalities.10,64 However, defining the lowest effective dose is challenging. For patients already treated with diuretics before a WHF episode, a higher dose is likely needed following discharge, and accordingly, patients with no diuretic treatment before a WHF episode should be prescribed a low-dose daily loop diuretic following discharge. There is limited evidence for or against loop diuretic use, but a metaanalysis does suggest that in CHF, loop diuretics reduce the risk of death or worsening HF.65 While natriuretic peptide-guided HF therapy has not been proven effective,66 implantable haemodynamic monitoring may reduce HF hospitalisation by providing information to guide early and appropriate diuretic increases.24 At the same time, in chronic stable HF, it has been described that patients on high doses versus low doses have higher risk for mortality, sudden death and pump failure death.67

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891–975. https://doi. org/10.1002/ejhf.592; PMID: 27207191. Butler J, Braunwald E, Gheorghiade M. Recognizing worsening chronic heart failure as an entity and an end point in clinical trials. JAMA 2014;312:789–90. https://doi.org/10.1001/ jama.2014.6643; PMID: 25157719. Younis A, Mulla W, Goldkorn R, et al. Differences in mortality of new-onset (de novo) acute heart failure versus acute decompensated chronic heart failure. Am J Cardiol 2019;124:554–9. https://doi.org/10.1016/j.amjcard.2019.05.031; PMID: 31221464. Greene SJ, Hernandez AF, Dunning A, et al. Hospitalization for recently diagnosed versus worsening chronic heart failure: from the ASCEND-HF Trial. J Am Coll Cardiol 2017;69:3029–39. https://doi.org/10.1016/j.jacc.2017.04.043; PMID: 28641792. Degoricija V, Trbusic M, Potocnjak I, et al. Acute heart failure developed as worsening of chronic heart failure is associated with increased mortality compared to de novo cases. Sci Rep 2018;8:9587. https://doi.org/10.1038/s41598-018-28027-3; PMID: 29942050. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482–7. https://doi.org/10.1161/CIRCULATIONAHA.107.696906; PMID: 17724259. Van Aelst LNL, Arrigo M, Placido R, et al. Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion. Eur J Heart Fail 2018;20:738–47. https://doi. org/10.1002/ejhf.1050; PMID: 29251818. Balmain S, Padmanabhan N, Ferrell WR, et al. Differences in arterial compliance, microvascular function and venous capacitance between patients with heart failure and either preserved or reduced left ventricular systolic function. Eur J Heart Fail 2007;9:865–71. https://doi.org/10.1016/j. ejheart.2007.06.003; PMID: 17644472. Miller WL, Mullan BP. Volume overload profiles in patients with preserved and reduced ejection fraction chronic heart failure: are there differences? A pilot study. JACC Heart Fail 2016;4:453–9. https://doi.org/10.1016/j.jchf.2016.01.005; PMID: 26970830.

This certainly reflects confounding by severity, but loop diuretics reduce intravascular fluid and cause compensatory maladaptive neurohormonal activation and may be a risk factor, in addition to a risk marker, for worse outcomes.10 Indeed the beneficial haemodynamic effects of angiotensin receptor neprilysin inhibitors (ARNi) may reduce the need for diuretics.64 Furthermore, SGLT2 inhibitors have potent natriuretic and diuretic effects; however, the effect is dependent on volume status with less effect in euvolaemic patients, hence the treatment is associated with less adverse neurohormonal activiation.68 As hospitalised patients with WHF stabilise, evidence-based HF medication should be optimised. It has been shown that patients are more likely to be adherent to new medication initiated in hospital as compared with the outpatient clinic.69 Finally, treatment of underlying comorbidities and potential precipitation factors for the current WHF episode should be treated if possible.

Conclusion WHF is common, underrecognised, treated too late and treated insufficiently, and associated with high risk of rehospitalisation and death. Congestion and diuretic resistance contribute to an insidious course of gradually but initially subclinical worsening HF, as well as insufficient decongestion during WHF and AHF episodes. Fear of and actual WRF limits the use of loop diuretics in WHF, but recent data suggest that residual congestion is worse than WRF, and that decongestion should be strived for, even at the risk of WRF. We believe that in contemporary clinical practice, in CHF, loop diuretics are not adjusted carefully enough, and in WHF and AHF, loop diuretic use is not aggressive enough. Improved implementation of ARNi and the introduction of SGLT2 inhibitors may alter and hopefully improve the landscape of congestion, diuretic resistance, and WHF and AHF.

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COVID-19

Gone, but not Forgotten Barbara Pisani1 and Rahul Sharma2 1. Department of Internal Medicine, Section of Cardiovascular Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, US; 2. Department of Medicine, Division of Cardiology, Structural Heart and Valve Center, Virginia Tech Carilion School of Medicine, Roanoke, VA, US

Abstract The global health and economic impact of the coronavirus disease 2019 (COVID-19) pandemic has rocked our communities and way of life. With millions infected around the globe, and hundreds of thousands of lives lost, there has been a paradigm shift in how clinicians evaluate and care for patients in multiple different types of healthcare settings. Many patients are reluctant to seek medical attention for cardiovascular illnesses, and late presentations of acute cardiac issues are raising the morbidity and mortality for treatable cardiac conditions. In this expert opinion, the authors canvas the many challenges in the diagnosis, treatment and delivery of care to patients with congestive heart failure and acute coronary syndromes during the COVID-19 pandemic.

Keywords COVID-19, hospitalisation, clinic visits, televisits, heart failure Disclosure: BP is involved in heart failure clinical trials sponsored by Amgen, Zoll and Novartis, which are not relevant to the content of this paper. RS has no conflicts of interest to declare. Received: 6 June 2020 Accepted: 8 June 2020 Citation: Cardiac Failure Review 2020;6:e26. DOI: https://doi.org/10.15420/cfr.2020.18 Correspondence: Barbara Pisani, Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, US. E: bpisani@wakehealth.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The direct impact of coronavirus disease 2019 (COVID-19) has resulted in a shift from inpatient to offsite care, as bed utilisation is appropriated to COVID-19 patients or potential COVID-19 patients. The mean number of hospitalisations for acute coronary syndrome was significantly reduced in northern Italy when compared to same time period in 2019 and prior to the national lockdown.1 Data from the Veterans Affairs Corporate Data Warehouse showed that, from 29 January–10 March 2020 to 11 March–21 April 2020, there was an overall 41.9% reduction in hospitalisations, with admissions decreasing by 51.9% for strokes, 40.3% for MI and 49.1% for heart failure. There was no decline during the same time period in 2019.2 At the University of Mississippi, a comparison of heart failure hospitalisations during the comparable timeframe in 2019 showed a 50% decline (average cases 30 per week) after the first case of COVID-19 was diagnosed (mean heart failure hospitalisations declined to 15 per week). After a state of emergency was declared in Mississippi, there was a further decrease. Hospitalisations continued to decline even further, once the shelter-in-place order was mandated.3 There was a median reduction in the cardiac surgery case volume of 50–75% in 60 centres included in the international Randomized comparison of the Outcome of single versus Multiple Arterial grafts (ROMA) trial.4 In addition, there has been a decline in patients presenting by emergency medical services or to the emergency department with ST-elevation MI. Patients and family members are less apt to call the 911 emergency number, perhaps due to fear of contracting coronavirus.5 As a result,

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numerous organisations have initiated public awareness campaigns highlighting the safety of their facilities and reminding patients to seek help when they have symptoms of a heart attack or stroke. It is interesting to postulate that a decline in heart failure hospitalisations may be related to improvements in access to care related to telehealth, patients’ newly developed appreciation for salt and fluid restriction, changes in access to food sources, discontinuation of smoking, initiation of exercise regimens or adherence to medication. The impact of COVID-19 has no less an effect on outpatient visits. There was a 60% reduction in ambulatory patient visits to physicians by early April 2020. Although there has been some rebound recently, outpatient visits remain approximately one-third lower than prior to the pandemic. As onsite clinic visits declined, telehealth visits increased.6 Unfortunately, many patients are unable to utilise video visits, due to lack of familiarity with technology, inadequate internet service or lack of access due to financial constraints. Many patients have expressed concern over co-payments related to video visits. The lack of these options may further enhance disparities in care. Many patients admit they are not exercising and cannot provide weights or blood pressures or recite their medication information. At times, they are out driving during video visits. They do not respond to calls in a timely manner, delaying visits with onsite and other offsite patients. One patient said via video visit that she was delighted she had lost 4.5 kg (10 lb), as she was running after her grandchildren. When she arrived at the clinic 2 weeks later, she had actually gained 4.5 kg. Another patient

Gone but not Forgotten gained 31.5 kg (70 lb) over 100 days and ignored her husband’s advice to contact us. She declined a visit at our facility in lieu of adjusting oral diuretics, due to fear of COVID-19. Admittedly, these are not new behaviours, but highlight the deficiencies in care. Thus, although many centres utilise televisits, it is difficult to say that they are ‘ready for prime time’, particularly for patients with a history of non-adherence or advanced heart failure, the elderly, and the indigent and fearful. Unfortunately, there has been a fair amount of misinformation disseminated to physicians and non-physicians regarding COVID-19. This has added to the panic and confusion regarding transmission and treatment. The United Nations has developed a new initiative to address this. Peer-reviewed literature is more carefully scrutinised.7,8 We acknowledge that patients are fearful of presenting to a hospitalbased clinic. They are concerned there is a greater risk for exposure to COVID-19 in our clinic space, despite screening measures, compared to their primary care physician’s office, the grocery store or leisure activity. They fear hospitalisation and loss of contact with family members and other significant others. These are just a few considerations impacting patients. If we scrutinise advanced heart failure patients, delays in hospitalisation and initiation of therapy have an even greater impact. A recent patient in need of a ventricular assist device (VAD) was unable to see his family members while hospitalised. He declined a VAD in lieu of returning home for family discussions, despite three recent hospitalisations. While some would opine that a VAD is an elective procedure, there is significant variability in mortality with regard to Interagency Registry for Mechanically Assisted Circulatory Support class. Unfortunately, patients who delay surgery may deteriorate further and no longer remain candidates for device or other therapies, or succumb to their disease. Importantly, in high COVID-19 areas, intensive care unit resources may be diverted to these patients. Alternatively, an expedited VAD implant or heart transplant may increase bed availability, particularly in centres with high numbers of status 1–3 patients on the United Network for Organ Sharing (UNOS) scale. There are additional challenges regarding heart transplant. Some centres have opted to decline all donors or inactivate recipients, as they are in the midst of the pandemic. Others have carefully selected patients who may proceed with transplant, based on risk/benefit ratio. UNOS has developed codes to temporarily inactivate candidates who providers believe cannot or should not receive organ offers due to COVID-19 concerns. When considering donor acceptance, particularly if the recipient is critically ill, allosensitised, blood group O or has a high height/ weight profile, waitlist mortality must also be taken into consideration.9 Challenges not previously faced include screening donors for COVID-19,

De Filippo O, D’Ascenzo F, Angelini F, et al. Reduced rate of hospital admissions for ACS during Covid-19 outbreak in northern Italy. N Engl J Med 2020;383:88–9. https://doi. org/10.1056/NEJMc2009166; PMID: 32343497. Baum A, Schwartz M. Admissions to Veterans Affairs hospitals for emergency conditions during the COVID-19 pandemic. JAMA 2020;324:96–9. https://doi.org/10.1001/jama.2020.9972; PMID: 32501493. Hall M, Vaduganathan M, Khan MS, et al. Reductions in heart failure hospitalizations during the COVID-19 pandemic. J Card Fail 2020;26:462–3. https://doi.org/10.1016/j.cardfail.2020. 05.005; PMID 32405232.

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the accuracy of testing, time delays in getting test results, request to screen procurement teams, the need to provide personal protective equipment to procurement teams, procurement by offsite teams to reduce exposure risk, the need to ensure flight staff are COVID-19 negative and concerns for procurement team exposure when entering or leaving high caseload areas. In the event a transplant recipient contracts COVID-19, we need to consider modifications in immunosuppressant therapy, management of the disease and exposure of other patients within our clinic space. Finally, in an era of patient-centred care, we need to be aware of these influences on patient choice. The fear of dying alone should not be dismissed. For those who lose employment, and thus insurance benefits, along with potential changes in state or national funding for Medicare/ Medicaid programmes, or a patient’s desire to remain outside the hospital, there may be no viable medical or surgical options available. It is even more disturbing when we consider that certain areas of the US are yet to have a COVID-19 ‘surge’. As anticipated, our hospitals are well prepared, and some have been extremely fortunate not to be exposed to the consequences of COVID-19. However, our patients are not attended to, and as described above, may not recognise the impact of heart failure on mortality. On a positive side, the current reduced readmission rates are a potential cost saving, due to loss of Centers for Medicare and Medicaid Services penalties, although offset by empty beds in low COVID-19 areas. Even if we disregard the financial ramifications, we cannot help but look to the future and anticipate poor cardiovascular outcomes, due to the downstream effect of COVID-19. Hopefully, the reduction in hospitalisations for heart failure (and other cardiovascular events) is a sign of patient wellbeing. If that is the case, hospitalisations and readmissions should remain low once there is a resolution of COVID-19. However, delays in seeking healthcare may ultimately lead to more acutely ill patients, with limited insurance benefits and limited options if presenting with cardiogenic shock or multiorgan dysfunction. Importantly, it may result in adverse patient behaviour with respect to direct provider interactions. Based on our current patient interactions, they have and will continue to require onsite care for advanced heart failure. The illusion that telehealth is a panacea for all patients is an illusion. At some point, patients will venture from their homes or the ‘safety’ of televisits to the doctor’s office, hospital or emergency department. At that point, we may be able to more fully assess the non-COVID-19 cardiac ramifications of social distancing, loss of insurance, lack of medication/dietary compliance and inactivity. There may be a different type of ‘surge’, as elusive as COVID-19, which is related to unremitting heart failure, acute MI, cardiac arrest and stroke.

Gaudino M, Chikwe J, Hameed I, et al. Response of cardiac surgery units to COVID-19: an internationally-based quantitative survey. Circulation 2020;142:300–2. https://doi. org/10.1161/CIRCULATIONAHA.120.047865; PMID: 32392425. Jacobs AK, Ali M, Best PJ, et al. Temporary emergency guidance to STEMI systems of care during the COVID-19 pandemic: AHA’s mission: Lifeline. Circulation 2020;142:199– 202. https://doi.org/10.1161/CIRCULATIONAHA.120.048180; PMID: 32363905. Mehrotra A, Chernew M, Linetsky D, et al. The impact of the COVID-19 pandemic on outpatient visits: a rebound emerges. The Commonwealth Fund 19 May 2020. https://www.

commonwealthfund.org/publications/2020/apr/impact-covid19-outpatient-visits (accessed 19 May 2020). Stephenson J. United Nations seeks to counter COVID-19 misinformation with digital first responders. JAMA Health Forum 2 June 2020. https://doi.org/10.1001/jamahealthforum. 2020.0700. Rubin EJ. Expression of concern: Mehra MR et al. Cardiovascular disease, drug therapy, and mortality in Covid19. N Engl J Med 2020;382:2464. https://doi.org/10.1056/ NEJMe2020822; PMID: 32484612. United Network for Organ Sharing. Data. 2020. https://unos. org/data/ (accessed 13 August 2020).

HFpEF

Effects of Exercise Training on Cardiac Function in Heart Failure with Preserved Ejection Fraction Hidekatsu Fukuta Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Abstract Nearly half of patients with heart failure in the community have heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance. Left ventricular diastolic dysfunction is associated with the pathophysiology of HFpEF and is an important contributor to exercise intolerance in HFpEF patients. The effects of exercise training on left ventricular diastolic function in HFpEF patients have been examined in several randomised clinical trials. Meta-analysis of the trials indicates that exercise training can provide clinically relevant improvements in exercise capacity without significant change in left ventricular structure or function in HFpEF patients. Further studies are necessary to elucidate the exact mechanisms of exercise intolerance in HFpEF patients and to develop recommendations regarding the most effective type, intensity, frequency, and duration of training in this group.

Keywords Exercise, inspiratory muscle training, functional electrical stimulation, diastolic function, exercise capacity Disclosure: The author has no conflicts of interest to declare. Received: 26 June 2020 Accepted: 20 August 2020 Citation: Cardiac Failure Review 2020;6:e27. DOI: https://doi.org/10.15420/cfr.2020.17 Correspondence: Hidekatsu Fukuta, Core Laboratory, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho Mizuho-ku, Nagoya, 467-8601, Japan. E: fukuta-h@med.nagoya-cu.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Nearly half of patients with heart failure (HF) in the community have HF with preserved ejection fraction (HFpEF) and mortality and morbidity in this group of patients is high.1–4 However, to date, there is no established pharmacotherapy to improve survival in HFpEF.5–9 Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance, which results in a reduced quality of life.10,11 There is much evidence that left ventricular (LV) diastolic dysfunction is associated with the pathophysiology of HFpEF and that LV diastolic dysfunction contributes importantly to exercise intolerance in HFpEF patients.12–18 Furthermore, emerging evidence suggests that non-cardiac factors such as skeletal myopathy and vascular dysfunction also contribute to exercise intolerance in this patient group.4,19–21 The effect of exercise training on LV diastolic function in HFpEF has been examined in many randomised clinical trials (RCTs). The aim of this brief review is to summarise the RCTs examining the effects of exercise training on LV structure and function, as well as exercise capacity in HFpEF patients.

Pathophysiology of Heart Failure with Preserved Ejection Fraction HF is defined as the pathological state in which the heart is unable to pump blood at a rate required by the metabolising tissues or can do so only with an elevated filling pressure. Inability of the heart to pump blood sufficiently to meet the needs of the body’s tissues may be due to the inability of the LV to fill (diastolic performance) and/or eject (systolic performance). When the HF is associated with a reduced ejection fraction (EF), the pathological

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state is called HF with reduced EF (HFrEF). In contrast, when the heart failure occurs in the absence of a reduced EF, the pathological state is called HFpEF.22 HFrEF and HFpEF have several similarities in LV structural and functional characteristics, including increased LV mass and increased LV end-diastolic pressure. The clearest difference between the two forms of HF is the difference in LV geometry and LV function; HFrEF is characterised by LV dilatation, eccentric LV hypertrophy and abnormal systolic and diastolic function, whereas HFpEF is characterised by concentric LV hypertrophy, a normal or near-normal EF and abnormal diastolic function.23 Exercise capacity is similarly impaired in HFrEF and HFpEF.24 Limited exercise tolerance because of fatigue and dyspnoea is a major symptom and a cause of disability in HFpEF. It results from abnormal central haemodynamics and peripheral non-cardiac factors. Abnormal central haemodynamics includes the inability to maintain (or augment) LV stroke volume adequately or maintaining (or augmenting) LV stroke volume at the expense of exaggerated increase in LV filling pressure during exercise.25 In addition, limited increase in HR during exercise (chronotropic incompetence) also contributes to limited increase in cardiac output. Peripheral non-cardiac factors contributing to exercise intolerance include impaired vascular function and alterations in the skeletal muscle. In HFpEF patients, arterial stiffness is increased and endothelial function is impaired, both of which contribute to the exercise intolerance.19 Furthermore, recent studies have shown that alterations in skeletal muscle, such as impaired microvascular function, reduced capillary density and mitochondrial dysfunction, are important contributors to exercise intolerance in HFpEF patients.4,20,21

Exercise Training in HFpEF Table 1: Characteristics of Exercise Trials (Cycling or Walking) in HFpEF Patients

Control

Outcomes (Cardiac Structure/ Function)

Kitzman et al. 201027

26/27

≥50% II–III

1 h/ Three times a week/ ~70% of HR reserve/ 16 weeks

CAD, pulmonary disease, renal dysfunction (creatinine >2.5 mg/dl)

Walking/ cycling

Attention control telephone call

E/A, DT, EF, LVEDV, LV mass

Peak VO2, 6MWD

Edelmann et al. 201143

46/21

≥50% II–III

20–40 min/ Two to three times a week/ ~60% of peak VO2/ 24 weeks

Pulmonary disease, CAD, anaemia

Cycling + resistance training

Usual care (maintenance of usual activity level)

E/e’, e’, EF, LVEDV LV mass

Peak VO2, 6MWD

Smart et al. 201244

16/14

>45% II–III

30 min/ Three times a week/ ~70% of peak VO2/ 16 weeks

CAD

Cycling

Usual care (maintenance of usual activity level)

E/A, DT, E/e’, e’, EF

Peak VO2

Alves et al. 201245

20/11

>55% NR

30 min/ ACS, uncontrolled Treadmill/ Three times a week/ metabolic disease cycling ~75% of maximal HR/ 24 weeks

Usual care

E/A, EF

Kitzman et al. 201329

32/31

≥50% II–III

1 h/ Three times a week/ ~70% of HR reserve/ 16 weeks

CAD, pulmonary Walking/ disease, anaemia cycling

Attention control telephone call

E/A, DT, EF, LVEDV

Peak VO2, 6MWD

Kitzman et al. 201646

51/49

≥50% II–III

1 h/ Three times a week/ ~70% of HR reserve/ 20 weeks

As above

Attention control telephone call or caloric restriction

E/A, E/e’, e’, EF, LVEDV, LV mass

Peak VO2, 6MWD

Fu et al. 201647

30/30

≥50% II–III

30 min/ Three times a week/ 80% of peak VO2/ 12 weeks

AF, recent Cycling (<4 weeks) ACS or coronary revascularisation, COPD, renal dysfunction (eGFR <30 ml/min)

Usual care

E/e’, EF

Study

N (Intervention/ EF/NYHA Control) Class

Session Time/ Frequency/ Intensity/ Duration

Major Exclusion Criteria

Training Modality

Walking

Outcomes (Exercise Capacity)

6MWD = 6-minute walk distance; ACS = acute coronary syndrome; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; DT = E-wave deceleration time; eGFR = estimated glomerular filtration rate; E/A; the ratio of peak early to late diastolic mitral inflow velocities; E/e’ = the ratio of early diastolic mitral inflow to annular velocities; e’ = early diastolic mitral annular velocity; EDV = end-diastolic volume; EF = ejection fraction; HFpEF = heart failure with preserved EF; HR = heart rate; LV = left ventricular; NR = not reported; NYHA = New York Heart Association; peak VO2 = peak exercise oxygen uptake.

Effect of Exercise Training in Heart Failure with Preserved Ejection Fraction Many RCTs have reported the effect of exercise training on LV structure and function, as well as exercise capacity in HFpEF. Most of these trials used cycling and/or walking as the primary training modality (Table 1). Other physical training modalities included inspiratory muscle training and functional electrical stimulation of the lower limbs (Tables 2 and 3). Of note, most of the participants in these RCTs were taking standard medications for HF, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers and diuretics.

Cycling or Walking The effect of cycling or walking on LV structure and function, as well as exercise capacity in HFpEF, has been examined in seven RCTs (Table 1). A meta-analysis of these RCTs has recently been reported.26 In the meta-analysis, the ratio of peak early to late diastolic mitral inflow velocities (E/A), E-wave deceleration time, ratio of early diastolic mitral inflow to annular velocities (E/e), and early diastolic mitral annular velocity (e’) were extracted for the measures of LV diastolic function; peak exercise oxygen uptake (VO2) by expired gas analysis and 6-minute

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walk distance (6MWD) for the measures of exercise capacity; LV enddiastolic volume and LV mass for the measures of LV structure; and left ventricular ejection fraction (LVEF) for the measure of LV systolic function. HR reserve, which was defined as the difference between peak HR during exercise test and HR before exercise, was also extracted. In the pooled analyses, cycling and/or walking did not significantly change LV diastolic function in HFpEF patients. There was no significant difference in changes of E/A (weighted mean difference [WMD] 0.030; 95% CI [−0.023–0.082]; I2=6.252%; p=0.266), E-wave deceleration time (WMD −2.040; 95% CI [−26.534–22.454] ms; I2=50%; p=0.870), or e’ (WMD 0.317; 95% CI [−0.952–1.587] cm/s; I2=87.523%; p=0.624) between exercise training and control groups. Similarly, the exercise training did not significantly change LV structure and systolic function. There was no significant difference in changes of LV end-diastolic volume (standardised mean difference [SMD] −0.034; 95% CI [−0.276– 0.208]; I2=0%; p=0.784), LV mass (SMD 0.072; 95% CI [−0.205–0.350]; I2=0%; p=0.609) or LVEF (WMD 0.850; 95% CI [−0.128–1.828]; I2=0%; p=0.088) between the exercise training and control groups.

HFpEF Table 2: Characteristics of Exercise Trials (Inspiratory Muscle Training) in HFpEF Patients

Session Time/ Frequency/ Duration Control

Outcomes (Cardiac Structure/ Function)

Outcomes (Exercise Capacity)

Intervention/ Control (n)

EF/NYHA Class

Major Exclusion Criteria

Palau et al. 201435

14/13

>50% ≥II

Recent (<3 months) ACS or cardiac surgery, pulmonary disease, smokers

20 min/ twice a day/ 12 weeks

Usual care

E/e’, e’, EF, LV mass

Peak VO2, 6MWD

TRAINING-HF Trial. 201936

15/13

>50% ≥II

Recent (<3 months) ACS or cardiac surgery, COPD

20 min/ twice a day/ 24 weeks

Usual care

E/e’, LA volume

Peak VO2

Study

6MWD = 6-minute walk distance; ACS = acute coronary syndrome; COPD = chronic obstructive pulmonary disease; E/e’ = the ratio of early diastolic mitral inflow to annular velocities; e’ = early diastolic mitral annular velocity; EF = ejection fraction; HFpEF = heart failure with preserved EF; LA = left atrial; LV = left ventricular; NYHA = New York Heart Association; peak VO2 = peak exercise oxygen uptake.

Table 3: Characteristics of Exercise Trials (Functional Electrical Stimulation) in HFpEF Patients

Intervention/ Control (n)

EF/NYHA Class

Major Exclusion Criteria

Session Time/ Frequency/ Duration

Control

Outcomes (Cardiac Structure/ Function)

Karavidas et al. 201339

15/15

>50% II or III

Recent (≤4 weeks) HF decompensation, ACS

30 min/ 5 days a week/ 6 weeks

Sham stimulation

E/A, E/e’, LA volume

Peak VO2, 6MWD

TRAINING-HF 201936

15/13

>50% ≥ II

Recent (<3 months) ACS or cardiac surgery, COPD

45 min/ 2 days a week/ 12 weeks

Usual care

E/e’, LA volume

Peak VO2

Study

Outcomes (Exercise Capacity)

6MWD = 6-minute walk distance; ACS = acute coronary syndrome; COPD = chronic obstructive pulmonary disease; E/A; the ratio of peak early to late diastolic mitral inflow velocities; E/e’ = the ratio of early diastolic mitral inflow to annular velocities; e’ = early diastolic mitral annular velocity; EDV = end-diastolic volume; EF = ejection fraction; HFpEF = heart failure with preserved EF; LA = left atrial; LV = left ventricular; NYHA = New York Heart Association; peak VO2 = peak exercise oxygen uptake.

Figure 1: Mechanisms of Improved Exercise Capacity With Exercise Training in HFpEF Patients ΔPeak VO2 = SV (↔) • HR (↑) • A-VO2diff (↑)

• Distribution of blood (↑) • Mitochondrial function (↑) • Microvascular function (↑) A-VO2 diff = arteriovenous-oxygen difference; HR = heart rate; HFpEF = heart failure with preserved ejection fraction; peak VO2 = peak exercise oxygen uptake; SV = stroke volume.

Despite the neutral effect on LV structure and function, cycling and/or walking improved exercise capacity in HFpEF patients. Exercise training significantly increased peak VO2 (WMD 1.660; 95% CI [0.973–2.348] ml/min/kg; I2=21%; p<0.001) and 6MWD (WMD 33.883; 95% CI [12.384– 55.381] m; I2=0%; p<0.01) compared with the control group. Furthermore, exercise training increased HR reserve compared with the control group (WMD 7.521; 95% CI [1.797–13.246] bpm; I2=0%; p<0.05). The meta-analysis clearly showed that exercise training improved exercise capacity without an improvement in LV structure or function in HFpEF patients.26 To consider the possible mechanisms for these observations, it may be useful to look over the pathophysiological background of exercise intolerance in HFpEF patients. During exercise, oxygen consumption in the metabolising tissues increases dramatically. Normally, this is accomplished by an increase in cardiac output (a product of HR and stroke volume) and an increased use of oxygen by the metabolising tissues. Earlier studies have reported that, in HFpEF

patients, stroke volume during exercise increases or is maintained at the expense of increased LV end-diastolic pressure due to diastolic abnormalities, resulting in exertional dyspnoea.15–18 However, emerging data suggest that chronotropic incompetence, as well as peripheral non-cardiac factors, such as reduced oxygen delivery to exercising skeletal muscle and impaired oxygen use by active muscles during exercise, may play a relatively greater role in limiting exercise performance in HFpEF patients.4,20,21 Considering these points, the following mechanisms may underlie the improved exercise capacity with exercise training in HFpEF patients. In pooled analyses, exercise training improved HR reserve but not LV diastolic or systolic function.26 Thus, improved chronotropic incompetence resulting from exercise training may contribute at least in part to improved exercise capacity in HFpEF patients. Furthermore, in an ancillary study of the included trial, exercise training increased use of oxygen by active muscles but not peak stroke volume during exercise.27,28 Finally, another included trial reported that exercise training did not improve endothelial function or arterial stiffness, both of which are important determinants of exercise intolerance in HFpEF patients.29 Taken together, in HFpEF patients, the improved exercise capacity with exercise training may result from improved chronotropic incompetence, as well as increased use of oxygen by active muscles (Figure 1). Although the mechanisms underlying increased use of oxygen by active muscles with exercise training remain elusive, several potential mechanisms have been proposed. First, improvement in skeletal muscle mitochondrial function with exercise training may be a significant contributor to increased use of oxygen in HFpEF patients. Multiple

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Exercise Training in HFpEF reports support that muscle mitochondrial function is impaired in HFpEF and is a strong factor for reduced use of oxygen.4,20,21 In an animal model of HFpEF, exercise training prevented the impairment of mitochondrial function.30 Second, exercise-induced upregulation of endothelial nitric oxide synthetase may increase bioavailability of nitric oxide, thereby improving vascular function and increasing distribution of blood to skeletal muscle.31 Finally, exercise training may induce anti-inflammatory cytokines, thereby reducing metabolic inflammation and oxidative stress and improving microvascular circulation in skeletal muscle.31 The neutral effect of exercise training on LV structure and function should be interpreted with caution. First, exercise intervention period was relatively short (12–24 weeks; Table 1). Further studies are necessary to examine whether longer exercise intervention may favourably affect LV structure and function in HFpEF patients. Second, Doppler measurements of LV diastolic function at rest may be insufficient to detect subtle changes in diastolic function with exercise training. Because more sophisticated measurements of diastolic function, such as left atrial strain, have been developed, the effect of exercise training on the newly developed measurements merits further investigation. Finally, many HFpEF patients experience dyspnoea only during exertion. In these patients, LV filling pressure becomes markedly elevated during exercise. However, no included trials examined the effect of exercise training on LV function or LV filling pressure during exercise. Future trials should examine the effect of exercise training on LV function measures during exercise using exercise echocardiography. Although minimal clinically important differences in exercise capacity in HFpEF patients have not been established, the reported improvements of 1.660 ml/min/kg in peak VO2 and 33.883 m in 6MWD with exercise training in the meta-analysis26 appear to be clinically important based on the results of earlier studies. Specifically, a mean change of 15.9–55.2 m in 6MWD has been reported to be associated with a mild to moderate improvement in HF status in HFrEF patients.32 Additionally, a metaanalysis of 22 RCTs with 3,826 HFrEF patients showed improvements of 1.85 ml/min/kg in peak VO2 and 47.9 m in 6MWD with exercise training.33 Finally, even small increments in peak VO2 following exercise training have been reported to be associated with improved survival in patients with a wide range of cardiovascular diseases and healthy subjects.34 Recent studies have shown that up to one-third of patients fail to demonstrate a meaningful increase in peak VO2 in response to exercise training, despite adequate compliance to training.34 Factors possibly influencing the response to exercise training are varied and are grouped as cardiac (systolic and diastolic function, chronotropic incompetence), non-cardiac (skeletal myopathy, vascular function, endothelial function, autonomic control), external (adherence, exercise dose and intensity) and comorbidities (obesity, anaemia, kidney diseases and pulmonary diseases). However, which factors predict the response to the training remains to be elucidated and warrants future investigation.

Inspiratory Muscle Training The effect of inspiratory muscle training on LV structure and function, as well as exercise capacity in HFpEF, has been examined in two RCTs (Table 2).35,36 Specifically, Palau et al. reported that 12-week inspiratory muscle training did not significantly change LV diastolic function; there was no significant difference in changes of e’ or E/e’ between the training and control groups. Similarly, the training did not significantly change LV systolic function or LV structure; there was no significant difference in changes of LVEF or LV mass between the training and control groups.

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Despite the neutral effect on LV structure or function, inspiratory muscle training significantly increased peak VO2 (3.9 ml/min/kg; p<0.001) and 6MWD (67.4 m; p<0.001) compared with control group. Furthermore, the training reduced resting HR (−6 BPM; p<0.05) and increased peak exercise HR (5 BPM; p<0.01) compared with the control group, indicating that the training improved HR reserve. Similar results have been reported recently by the same investigators.36 In the Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of HFpEF (TRAINING-HF) trial, 12-week inspiratory muscle training did not change cardiac function or structure; there was no significant difference in changes of E/e’ or left atrial volume index between exercise training and control groups. Despite the neutral effect on cardiac structure or function, inspiratory muscle training improved peak VO2 (2.98 ml/min/kg; p<0.001) compared with the control group. Patients with congestive HF reportedly have reduced maximal inspiratory pressure and endurance of inspiratory muscle, both of which contribute to the exercise intolerance.37 Inspiratory muscle training may delay the development of diaphragmatic fatigue and increase ventilatory efficiency, resulting in an improvement in exercise capacity in HF patients.38 The reported improvement in peak VO2 with inspiratory muscle training is greater compared to that with cycling or walking.35,36 However, there are no RCTs comparing the effect of inspiratory muscle training versus cycling or walking on exercise capacity in HFpEF patients. The comparative effectiveness of inspiratory muscle training and cycling or walking in HFpEF patients merits further investigation.

Functional Electrical Stimulation The effect of functional electrical stimulation of the lower limbs on cardiac structure and function as well as exercise capacity in HFpEF has been examined in two RCTs (Table 3).36,39 Specifically, Karavidas et al. reported that 6-week functional electrical stimulation did not significantly change cardiac function or structure; there was no significant difference in changes of E/A, E/e’ or left atrial volume between the stimulation and control groups.39 Despite the neutral effect on cardiac structure or function, functional electrical stimulation improved 6MWD (52.8 m; p<0.01) compared with control group. Similar results were reported in the TRAINING-HF trial.36 Specifically, 12week functional electrical stimulation did not significantly change cardiac function or structure; there was no significant difference in changes of E/e’ or left atrial volume index between the stimulation and control groups. Despite the neutral effect on cardiac structure or function, functional electrical stimulation improved peak VO2 (2.93 ml/min/kg; p<0.001) compared with the control group. The possible mechanisms underlying the improved exercise capacity with the functional electrical stimulation in HFpEF patients include the improvement of endothelial function.39 In HFpEF patients, endothelial function is impaired and is an important contributor to exercise intolerance.29

Perspectives As described above, recent RCTs and meta-analyses of RCTs have shown that physical training such as cycling or walking, inspiratory muscle training and functional electrical stimulation can improve

HFpEF Table 4: Characteristics of On-going Exercise Trials in HFpEF Patients

Study

Intervention/ Control (n)

Entry EF/ NYHA Class

Ex-DHF41

160/160

≥50% II–III

12 months

Endurance and resistance training

OptimEx-CLIN42

120/60

>50% II–III

12 months

Moderate intensity Usual care continuous training or high intensity interval training

Duration

Training Modality

Control

Primary Endpoint

Secondary Endpoint

Usual care

Combined outcome score* after 6 and 12 months

Components of the primary endpoint, submaximal exercise capacity, echocardiographic parameters of LV geometry and dimensions, diastolic and systolic function, ventilatory efficacy, HRQoL and NT-proBNP after 6 and 12 months

Peak VO2 after 3 months

Peak VO2 after 12 months Echocardiographic parameters of LV diastolic function, HRQoL, endothelial function and NT-proBNP after 3 and 12 months.

*Components of the outcome score are all-cause mortality, hospitalisations, NYHA functional class, global self-rated health, maximal exercise capacity and diastolic function. EF = ejection fraction; HFpEF = heart failure with preserved EF; HRQoL = health-related quality of life; LV = left ventricular; NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York Heart Association; peak VO2 = peak exercise oxygen uptake.

exercise capacity in HFpEF patients. Nevertheless, clinicians should take several points into consideration. First, although not specific to this topic, RCTs usually have strict enrolment criteria, and thus, the findings of the RCTs cannot be generalised to routine clinical practice. Specifically, in most of the trials listed in Tables 1–3, patients with cardiac and non-cardiac comorbidities such as AF, coronary artery disease, chronic obstructive pulmonary diseases, chronic kidney disease and anaemia were excluded. Importantly, registry studies have reported that HFpEF patients commonly have these co-morbidities.40 Thus, the reported beneficial effect of physical training may not be extended into real-world HFpEF patients. Further studies are warranted to examine the effect of physical training on functional capacity in HFpEF patients with these co-morbidities. Second, the most effective type, intensity, frequency and duration of training are not determined in HFpEF patients. There are several on-going exercise trials in HFpEF patients that are expected to be published (Table 4). Specifically, the Exercise Training In Diastolic Heart Failure (Ex-DHF) trial is designed to investigate whether long-term (12-month) supervised exercise training can improve a clinically meaningful composite outcome score in HFpEF patients.41 Components of the outcome score are all-cause mortality,

Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a populationbased cohort. J Am Coll Cardiol 1999;33:1948–55. https://doi. org/10.1016/s0735-1097(99)00118-7; PMID: 10362198. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–9. https://doi.org/10.1056/ NEJMoa052256; PMID: 16855265. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, et al. Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 2009;73:1893–900. https://doi. org/10.1253/circj.cj-09-0254; PMID: 19644216. Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction in perspective. Circ Res 2019;124:1598–617. https://doi.org/10.1161/CIRCRESAHA.119.313572; PMID: 31120821. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777–81. https://doi.org/10.1016/S01406736(03)14285-7; PMID: 13678871. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-2467. https://doi.org/10.1056/ NEJMoa0805450; PMID: 19001508. Cleland JG, Tendera M, Adamus J, et al. The perindopril in

10.

11.

12.

13.

hospitalisations, New York Heart Association functional class, global self-rated health, maximal exercise capacity and diastolic function after 6 and 12 months. The Optimizing Exercise Training In Prevention and Treatment of Diastolic Heart Failure (OptimEx-CLIN) trial aims to define the optimal dose of exercise training in patients with HFpEF.42 Patients with stable symptomatic HFpEF will be randomised (1:1:1) to moderate intensity continuous training, high intensity interval training or a control group. The primary endpoint of the OptimEx-CLIN trial is peak VO2 after 3 months. The results of these trials may provide further insights into exercise prescriptions in HFpEF patients.

Conclusion In summary, available evidence suggests that physical training in addition to standard HF medication can provide clinically relevant improvements in exercise capacity without significant changes in LV function or structure in HFpEF patients. Further studies are necessary both to elucidate more exact mechanisms of exercise intolerance and to develop recommendations regarding the most effective training approach, including type, intensity, frequency and duration, in patients with HFpEF.

elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338–45. https://doi.org/10.1093/eurheartj/ ehl250; PMID: 16963472. Yamamoto K, Origasa H, Hori M. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail 2013;15:110–8. https://doi.org/10.1093/eurjhf/hfs141; PMID: 22983988. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92. https://doi.org/10.1056/NEJMoa1313731; PMID: 24716680. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–50. https://doi.org/10.1001/jama.288.17.2144; PMID: 12413374. Reddy YNV, Rikhi A, Obokata M, et al. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail 2020;22:1009–18. https://doi.org/10.1002/ejhf.1788; PMID: 32150314. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure-abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350:1953–9. https://doi. org/10.1056/NEJMoa032566; PMID: 15128895. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 2007;115:1982–90. https://doi.org/10.1161/CIRCULATIONAHA.106.659763;

PMID: 17404159. 14. Zile MR, Gottdiener JS, Hetzel SJ, et al. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation 2011;124:2491–501. https://doi.org/10.1161/ CIRCULATIONAHA.110.011031; PMID: 22064591. 15. Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–72. https://doi. org/10.1016/0735-1097(91)90832-t; PMID: 2007704. 16. Zile MR, Kjellstrom B, Bennett T, et al. Effects of exercise on left ventricular systolic and diastolic properties in patients with heart failure and a preserved ejection fraction versus heart failure and a reduced ejection fraction. Circ Heart Fail 2013;6:508–16. https://doi.org/10.1161/ CIRCHEARTFAILURE.112.000216; PMID: 23515277. 17. Maeder MT, Thompson BR, Brunner-La Rocca HP, et al. Hemodynamic basis of exercise limitation in patients with heart failure and normal ejection fraction. J Am Coll Cardiol 2010;56:855–63. https://doi.org/10.1016/j.jacc.2010.04.040; PMID: 20813283. 18. Abudiab MM, Redfield MM, Melenovsky V, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail 2013;15:776–85. https://doi.org/10.1093/eurjhf/hft026; PMID: 23426022. 19. Kitzman DW, Haykowsky MJ. Vascular dysfunction in heart failure with preserved ejection fraction. J Card Fail 2016;22:12–

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Exercise Training in HFpEF 6. https://doi.org/10.1016/j.cardfail.2015.11.004; PMID: 26585367. 20. Haykowsky MJ, Tomczak CR, Scott JM, et al. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. J Appl Physiol (1985) 2015;119:739–44. https://doi.org/10.1152/ japplphysiol.00049.2015; PMID: 25911681. 21. Kitzman DW, Haykowsky MJ, Tomczak CR. Making the case for skeletal muscle myopathy and its contribution to exercise intolerance in heart failure with preserved ejection fraction. Circ Heart Fail 2017;10:e004281. https://doi.org/10.1161/ CIRCHEARTFAILURE.117.004281; PMID: 28705911. 22. Fukuta H, Little WC. Diagnosis of diastolic heart failure. Curr Cardiol Rep 2007;9:224–8. https://doi.org/10.1007/BF02938354; PMID: 17470335. 23. Fukuta H, Little WC. Contribution of systolic and diastolic abnormalities to heart failure with a normal and a reduced ejection fraction. Prog Cardiovasc Dis 2007;49:229–40. https://doi.org/10.1016/j.pcad.2006.08.009; PMID: 17185111. 24. Kitzman DW. Exercise intolerance. Prog Cardiovasc Dis 2005;47:367–79. https://doi.org/10.1016/j.pcad.2005.02.002; PMID: 16115516. 25. Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management. Ann Intern Med 1992;117:502–10. https://doi. org/10.7326/0003-4819-117-6-502; PMID: 1503353. 26. Fukuta H, Goto T, Wakami K, et al. Effects of exercise training on cardiac function, exercise capacity, and quality of life in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials. Heart Fail Rev 2019;24: 535–47. https://doi.org/10.1007/s10741-019-09774-5; PMID: 31032533. 27. Kitzman DW, Brubaker PH, Morgan TM, et al. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Fail 2010;3:659–67. https://doi.org/10.1161/ CIRCHEARTFAILURE.110.958785; PMID: 20852060. 28. Haykowsky MJ, Brubaker PH, Stewart KP, et al. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol 2012;60:120–8. https://doi.org/10.1016/j. jacc.2012.02.055; PMID: 22766338. 29. Kitzman DW, Brubaker PH, Herrington DM, et al. Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and

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stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction. Am Heart J 2013;166:760–7. https://doi.org/10.1016/j. ahj.2013.06.021; PMID: 24093858. Vaduganathan M, Michel A, Hall K, et al. Spectrum of epidemiological and clinical findings in patients with heart failure with preserved ejection fraction stratified by study design: a systematic review. Eur J Heart Fail 2016;18:54–65. https://doi.org/10.1002/ejhf.442; PMID: 26634799. Edelmann F, Bobenko A, Gelbrich G, et al. Exercise training in Diastolic Heart Failure (Ex-DHF): rationale and design of a multicentre, prospective, randomized, controlled, parallel group trial. Eur J Heart Fail 2017;19:1067–74. https://doi. org/10.1002/ejhf.862; PMID: 28516519. Suchy C, Massen L, Rognmo O, et al. Optimising exercise training in prevention and treatment of diastolic heart failure (OptimEx-CLIN): rationale and design of a prospective, randomised, controlled trial. Eur J Prev Cardiol 2014;21:18–25. https://doi.org/10.1177/2047487314552764; PMID: 25354950. Edelmann F, Gelbrich G, Dungen HD, et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure. pilot study. J Am Coll Cardiol 2011;58:1780–91. https://doi. org/10.1016/j.jacc.2011.06.054; PMID: 21996391. Smart NA, Haluska B, Jeffriess L, et al. Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity. Congest Heart Fail 2012;18:295–301. https:// doi.org/10.1111/j.1751-7133.2012.00295.x; PMID: 22536983. Alves AJ, Ribeiro F, Goldhammer E, et al. Exercise training improves diastolic function in heart failure patients. Med Sci Sports Exerc 2012;44:776–85. https://doi.org/10.1249/ MSS.0b013e31823cd16a; PMID: 22005747. Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2016;315:36–46. https://doi.org/10.1001/ jama.2015.17346; PMID: 26746456. Fu TC, Yang NI, Wang CH, et al. Aerobic interval training elicits different hemodynamic adaptations between heart failure patients with preserved and reduced ejection fraction. Am J Phys Med Rehabil 2016;95:15–27. https://doi.org/10.1097/ PHM.0000000000000312; PMID: 26053189.

Advanced Heart Failure

Heart Failure With Mid-range or Recovered Ejection Fraction: Differential Determinants of Transition Davide Margonato,1,2 Simone Mazzetti,1 Renata De Maria,3 Marco Gorini,4 Massimo Iacoviello,5 Aldo P Maggioni4 and Andrea Mortara1 1. Department of Clinical Cardiology, Policlinico di Monza, Monza, Italy; 2. Department of Cardiology, University of Pavia, Pavia, Italy; 3. National Research Council, Institute of Clinical Physiology, ASST Great Metropolitan Hospital Niguarda, Milan, Italy; 4. ANMCO Research Center, Firenze, Italy; 5. Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy

Abstract The recent definition of an intermediate clinical phenotype of heart failure (HF) based on an ejection fraction (EF) of between 40% and 49%, namely HF with mid-range EF (HFmrEF), has fuelled investigations into the clinical profile and prognosis of this patient group. HFmrEF shares common clinical features with other HF phenotypes, such as a high prevalence of ischaemic aetiology, as in HF with reduced EF (HFrEF), or hypertension and diabetes, as in HF with preserved EF (HFpEF), and benefits from the cornerstone drugs indicated for HFrEF. Among the HF phenotypes, HFmrEF is characterised by the highest rate of transition to either recovery or worsening of the severe systolic dysfunction profile that is the target of disease-modifying therapies, with opposite prognostic implications. This article focuses on the epidemiology, clinical characteristics and therapeutic approaches for HFmrEF, and discusses the major determinants of transition to HFpEF or HFrEF.

Keywords Heart failure phenotype, mid-range ejection fraction, predictors of transition, prognosis, ischaemic aetiology, AF Disclosure: The authors have no conflicts of interest to declare. Received: 10 May 2020 Accepted: 13 July 2020 Citation: Cardiac Failure Review 2020;6:e28. DOI: https://doi.org/10.15420/cfr.2020.13 Correspondence: Andrea Mortara, Chief, Department of Cardiology, Policlinico di Monza, Via Amati 111, 20900 Monza (MB), Italy. E: andrea.mortara@policlinicodimonza.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a complex syndrome caused by functional and structural abnormalities of the left ventricle (LV) resulting in a combination of typical signs and symptoms. Historically, HF has been classified according to LV ejection fraction (EF) as either HF with reduced EF (HFrEF; LVEF <40%) or HF with preserved EF (HFpEF; LVEF >50%).1,2 The 2016 European Society of Cardiology (ESC) guidelines on acute and chronic HF established an HF category of ‘HF with mid-range ejection fraction’ (HFmrEF), defined as EF between 40% and 49% in patients with HF, to promote research into the main characteristics of this separate group of patients.3 In recent years, increasing evidence has emerged that HFmrEF may represent a subgroup of HF patients with a peculiar clinical, biomarker and diagnostic profile. However, a considerable number of HFmrEF patients experience improvement in LVEF, even to normal values. Therefore, whether this is a unique subtype of HF patients or whether it represents a ‘transition phase’ from HFrEF to HFpEF or vice versa is still a matter of debate. This article focuses on the epidemiology, clinical characteristics and therapeutic approaches to HFmrEF with the aim of discussing the major determinants of transition to preserved or reduced EF.

Epidemiology Extensive data are lacking about the prevalence of HFmrEF because there have been no population-based clinical studies and most epidemiological studies have divided HF patients into two groups using

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an EF cut-off value of 50%. Therefore, to obtain putative epidemiological information, we rely on subanalyses of clinical registries and on investigations that report the prevalence of different EF values within the populations under investigation. A recent analysis of the Get With The Guidelines-HF (GWTG-HF) registry, which provides data on almost 100,000 patients hospitalised acute HF from 2005 to 2013, found that HFmrEF accounted for 13% of cases.4 In the Swedish HF registry, 21% of all hospitalised HF patients had HFmrEF.5 In the US, HFmrEF has been reported to account for 13–24% of patients with HF.6 Finally, the Chinese HF registry reported a prevalence of HFmrEF of 26.6% within the HF population, with no differences in trends between urban and rural areas.7 HF phenotypes do not unusually represent transitory stages due to fluctuations in LV volumes and systolic function. Research has increasingly confirmed that, among all HF phenotypes, EF variations are most common in HFmrEF. Transition from HFmrEF towards preserved LVEF has been reported in 25–44% of patients, and towards reduced LVEF in 16–33% of patients.5,8,9 Mesquita et al. subdivided the HFmrEF population into three different categories according to LVEF transition, namely recovered HF (73%; from HFrEF to HFmrEF), impaired HF (17%; from HFpEF to HFmrEF) and unchanged (10%; showing no changes in EF during follow-up).10

Mid-range Ejection Fraction in Heart Failure These data clearly point to a need for close clinical follow-up in order to determine whether the current HFmrEF phenotype in the patients we are examining represents a stable stage of mild disease or a transitional step towards different LVEF levels.

Diagnosis of HFmrEF: Role of Multimodality Imaging It is imperative to keep in mind that, as an endocardial measurement, LVEF quantification is disproportionately influenced by loading conditions and by chamber geometry, and has important limitations in identifying subclinical LV dysfunction. Echocardiography remains the most common modality for both LVEF measurements and analysis of sequential variability during time. However, due to the possibility of suboptimal views and the presence of a myocardial ischaemic area or other factors that make it difficult to correctly identify the endocardium, 2D biplane echocardiography is believed to be less accurate than other techniques, including 3D echocardiography and global longitudinal strain (GLS) for measurements of both ventricular volume and EF.11–13 GLS, a direct measurement of myocardial fibre deformation, can contribute to the identification of residual LV impairment despite normal or near-normal LVEF. In HF patients with recovered LVEF, an abnormal GLS predicts the likelihood of decreasing LVEF at follow-up and is associated with a significantly worse outcome than that seen in patients with normal GLS values.14,15 Moreover, HFpEF patients with reduced GLS (less than –14%) represent a high-risk group that could slide towards clinical instability and reductions in LVEF.16 Cardiac magnetic resonance imaging (CMR) is another tool that, through its high spatial resolution and multiple imaging modalities, can guide physicians in evaluating LV status. Recent studies have confirmed the roles of CMR in predicting LVEF deterioration through analysis of late gadolinium enhancement and in uncovering undetected cardiac pathology in HFpEF.17,18 Finally, elevated T1 and T2 relaxation times are typical of HFmrEF patients relative to healthy controls, and could be instrumental in predicting increasing fibrosis and inflammation despite normal LVEF.19 It has been suggested that a complete echocardiographic examination, including 2D and 3D echocardiography, GLS and analysis of diastolic dysfunction, should be performed to characterise HFmrEF in HF patients. In cases in which borderline data have been obtained, or results from different examinations are contradictory, ventricular function should be analysed using CMR.

Clinical Features of HFmrEF Most clinical information on HFmrEF has been derived from comparative investigations with HFrEF and HFpEF. In fact, given the low prevalence of HFmrEF compared with that of HFrEF or HFpEF, it may not be feasible, despite being scientifically desirable, to obtain a considerable number of trials focusing on HFmrEF as a separate population.

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program found that HFmrEF patients more closely resembled HFrEF patients in terms of age and sex.2 Conversely, Kapooer et al., in a study based on the GWTG-HF Registry, reported that HFmrEF patients were older (mean age 77 years) and a higher proportion were female (48%) compared with HFrEF patients.4 Of note, patients with HFmrEF seem to be mostly male and younger than those with HFpEF.23,24 The prevalence of non-cardiac comorbidities, in particular chronic obstructive lung disease, anaemia and renal insufficiency, in HFmrEF is intermediate compared with HFrEF and HFpEF.4,5,25,26 Data from the Swedish HF registry analysed the interaction between comorbidities and prognosis, finding that coexisting chronic kidney dysfunction and AF increased the risk of cardiovascular events to a significantly greater extent in HFmrEF than in HFrEF or HFpEF.27 Cardiac ischaemic disease appears to be common in patients with HFmrEF: in fact, an ischaemic comorbidity burden higher than in HFpEF but similar to that in HFrEF has been reported for HFmrEF almost worldwide.4,5,20,24,28,29 This relatively high amount of concordant data on the higher prevalence of ischaemic heart disease in HFmrEF than in HFpEF suggests that a significant percentage of HFmrEF patients may represent a group in the early phase after an ischaemic event, a clinical picture that is similar to that of HFpEF but enhanced by a significant ischaemic burden.

Medical Therapy The main controversies regarding therapeutic options in HFmrEF include which therapy is best and how to decide whether to maintain, modulate or interrupt medical treatment in HFmrEF patients. The CHARM study showed that candesartan may reduce cardiovascular (CV) and HF events in HFmrEF (7.4 versus 9.7 per 100 patient years; HR 0.76; 95% CI [0.61–0.96]; p=0.02).22 Similar findings have been reported in studies of beta-blockers. For example, Cleland et al. reported a reduction in CV death in HF patients in sinus rhythm and with LVEF between 40% and 49% treated with beta-blockers compared with placebo (HR 0.48; 95% CI [0.24–0.97]; p=0.04) and improved LV systolic function.30 The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study demonstrated a decrease in HF hospitalisations in patients treated with spironolactone, with the greatest benefit observed in those with LVEF ranging from 45% to 55%.31 In another recent study, spironolactone use at discharge after an acute HF episode was associated with better long-term outcomes.32 A retrospective analysis of the Digitalis Investigation Group (DIG) suggested a slightly higher decrease in CV death and HF hospitalisation in HFmrEF than HFpEF patients.33 However, the most fascinating question that remains unanswered is whether specific treatments in HFmrEF patients could be associated with the transition to preserved or reduced LVEF.

Predictors of LVEF Transition With regard to cardiovascular risk factors, the prevalence of hypertension in HFmrEF ranges from 60% to 82%, which is higher than in HFrEF, but lower than in HFpEF.4,5,20,21 Diabetes is also common in HFmrEF, with a prevalence ranging from 28% to 48%, which is comparable to the prevalence of diabetes in HFpEF but higher than the prevalence in HFrEF.4,5,20,22–24

CARDIAC FAILURE REVIEW

LVEF transition in HF patients is a critical turning point because it may represent a spontaneous or therapy-induced improvement in the natural history of the disease, and therefore in the prognosis, or a possible point of no return towards a decline in the condition.34 For this reason, it is mandatory that the clinical picture of every HFmrEF patient seen is carefully examined so that the evolution of the condition can be

Advanced Heart Failure Figure 1: Main Determinants of Transition from Heart Failure with Mid-range Ejection Fraction Main determinants of transition to HFmrEF Young age

Controlled hypertension

Takotsubo

Peripartum

CRT-D

Beta-blocker

HFrEF

Normal HR

Tachycardia MRA

Improved GLS

Hyperthyroidism

ACEI/ARB

ARNI

SGLT2

HFmrEF

HFpEF

Old age LBBB LVEDD >60 mm Long HF history BNP elevation Diabetes Ischaemic HF Genetic factors (mutations in lamin, beta-1-adrenoceptors and ACE receptors) Low adherence to therapies, target dose not achieved or Class I drugs Transition to HFrEF Clinical characteristics

Aetiology

Therapy

Main determinants of transition from HFmrEF to either HFpEF and recovery or HFrEF. Determinants are grouped into clinical characteristics, phenotypic aetiology and effect of therapy. ACE = angiotensin-converting enzyme; ACEI = ACE inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BNP = B-type natriuretic peptide; CRT-D = cardiac resynchronisation therapy defibrillator; GLS = global longitudinal strain; HF = heart failure; HFmrEF = Heart failure with mid-range ejection fraction; HFpEF = Heart failure with preserved ejection fraction; HFrEF = Heart failure with reduced ejection fraction; HR = heart rate; LBBB = left bundle branch block; LVEDD = left ventricular end-diastolic diameter; MRA, mineralocorticoid receptor antagonist; SGLT2 = sodium–glucose cotransporter 2.

predicted as much as possible. Indeed, because HF classification is derived from an artificial arbitrary construct based on EF thresholds, patients in the HFmrEF cohort are part of a continuum of known heterogeneous pathophysiologies. Predictors of transition from HFmrEF towards either HFpEF (and recovery) or HFrEF are shown in Figure 1.

Predictors of LVEF Improvement It is clear that the frequency and degree of LVEF improvement depend primarily on the cause of HF. For example, patients with Takotsubo cardiomyopathy often present a rapid improvement towards normal LVEF values, even in the absence of medical therapy, and have a good longterm prognosis.35,36 Patients with acute myocarditis, who survive the critical phase, frequently exhibit LVEF recovery and excellent outcomes.37,38 Peripartum cardiomyopathy, once excluded from the group of genetically determined dilated cardiomyopathies, is another type of HF that has a satisfactory rate of recovery towards normal LVEF values.39 Significant rates of LVEF improvement to values in the preserved range have been reported when considering causes of recent onset (<6 months) HF, such as tachycardia- and hyperthyroidism-induced cardiomyopathy.40 Similarly, the duration of HF is a primary factor predicting HF transition: in both HFmrEF and HFrEF, patients with long-standing HF show low rates of LVEF improvement.41 Systemic hypertension, AF, lower NYHA functional class (I–II) and younger age (<65 years) have been reported as clinical features

associated with LVEF recovery to preserved values.42–44 It seems reasonable to suggest that specific treatment of comorbidities should be addressed first, whenever possible. It is also clear that in patients with HFmrEF, uncontrolled hypertension is one of the main determinants of hospitalisation for HF: therefore, extended use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors from the early phase of the disease may reduce the risk of LVEF decline. Cardiac resynchronisation therapy (CRT) is a milestone treatment in HFrEF, with a significant proportion of patients showing improvements in LVEF to values comparable with the phenotype of HFmrEF following implantation of a CRT device, with only a minority, the so called ‘superresponders’, showing improvements in LVEF to values >50%.45,46 This highlights two important factors, namely the main role of LV dyssynchrony in fuelling LV deterioration and the importance of HF therapies in reversing different HF phenotypes according to individual patient’s responses and their adherence to available therapies. Some patients who exhibit left bundle branch block (LBBB) improve less on optimal medical therapy alone and often present mid-range EF.47 This association of LBBB and HFmrEF raises the question as to whether this cohort of patients may benefit significantly from expanding the indications for implantation of a CRT device to LVEF >35%, particularly in the absence of reasons other than LBBB itself as the cause of LV dysfunction.48 It has been suggested that patients with a history of HFrEF and a subsequent improvement in LVEF, which reclassifies them as HFmrEF, should be treated by maintaining all HFrEF therapies at the maximum tolerated dose.49 In particular, an important step towards clinical and

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Mid-range Ejection Fraction in Heart Failure prognostic improvement has come from the introduction of new therapeutic options, namely an angiotensin receptor–neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 (SGLT2) inhibitors. Many studies have shown improvement in the main echocardiographic parameters in patients with HFrEF after the introduction of ARNI.50,51 The benefits in terms of prognosis, rehospitalisation and quality of life offered by ARNI suggest that therapy initiated at the maximum tolerated dose, during the HFrEF stage, has to be continued at the same dosage, and should be downtitrated only if acute kidney failure or severe hypotension occur.52,53 In the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) trial, ARNI failed to reduce the primary composite endpoint of total hospitalisations for HF and CV death in patients with HF and LVEF ≥45%. 54 However, when data from Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure (PARADIGM-HF; eligibility criterion LVEF ≤40%; n=8,399) and PARAGON-HF (eligibility criterion LVEF ≥45%; n=4,796) were combined in a prespecified pooled analysis, the therapeutic effects of sacubitril/valsartan (ARNI) compared with a renin–angiotensin system inhibitor alone varied according to LVEF, but treatment benefits, particularly for heart failure hospitalisations, appeared to extend to patients with HFmrEF.55 The attention to HF care in patients with type 2 diabetes (T2D) has increased markedly after results were published from three randomised clinical trials evaluating the effects of SGLT2 inhibitors.56–58 Three different SGLT2 inhibitors have been demonstrated to prevent the development of HF and prolong life in patients with T2D. More recently, data have been presented for patients with HFrEF and with and without T2D. In that study, patients who received the SGLT2 inhibitor dapagliflozin had a lower risk of worsening HF or death from CV causes and better symptom scores than those who received placebo, regardless of the presence or absence of diabetes.59 Although at the present time we lack specific studies in the HFmrEF population, SGLT2 inhibitors represent a promising class of drugs for the treatment of HF in the future.60

Predictors of LVEF Deterioration Among 174 HF patients with EF ≥45% who were on beta-blockers and were followed for 4–10.8 years, older age (mean [±SD] 56 ± 12 years), lower heart rate (59 ± 9 BPM), the presence of complete LBBB and a larger LV end-diastolic diameter (60 ± 7 mm) were reported as independent predictors of LVEF deterioration.61 LVEF deterioration and the absence of a transition towards recovered HF have been associated with an ischaemic aetiology of HF and with comorbid diabetes.43,62 These results, together with the reported connection between both a non-ischaemic origin of HF and the absence of diabetes and LVEF improvement, strongly suggest the importance of early, aggressive treatment of diabetes and ischaemic heart disease in order to defuse their detrimental effects on the benefit of optimised HF therapy.63 Recent studies have proved that genetic factors can help physicians predict the evolution of LVEF and HF. In fact, dilated cardiomyopathies with lamin mutations, certain polymorphisms in beta-1-adrenoceptors and angiotensin-converting enzyme receptors are all associated with progressive LV dysfunction in chronic HF patients.64 Moreover, physicians need to be aware that HFmrEF resulting from deterioration

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of LVEF previously >50% is associated with a higher risk of all-cause mortality and hospitalisation, as reported recently.65 In summary, certain clinical characteristics may help predict LVEF transition. However, none of these factors has a predictive value high enough to suffice as a prognostic tool on its own. Furthermore, classification efforts are hampered by a lack of homogeneity in study populations for the characteristics mentioned above. Therefore, as research continues into the mechanisms underlying LVEF variation, we believe that a tailored approach to individual patients that encompasses HF aetiology, duration, comorbidities, response and adherence to therapies is the optimal way to manage these patients (Figure 2).

Data From the Italian Network on Congestive Heart Failure Registry Of the 7,559 congestive heart failure (CHF) patients enrolled between 2009 and 2016 in the Italian Network on Congestive Heart Failure (INCHF) registry,66 data were analysed for 1,414 who had a second echocardiographic examination during a phase of clinical stability at a median time of 6 months since recruitment. Patients were classified according to baseline EF as either HFpEF (n=220), HFmrEF (n=335) or HFrEF (n=859). Clinical characteristics, therapy, transition to a different HF phenotype and long-term mortality are reported in Table 1. HFmrEF patients were more similar to HFrEF than HFpEF patients and, during follow-up, showed greater variability than patients in the other two groups. At the second echocardiographic examination, only 60% of patients with HFmrEF at the time of enrolment stayed in the same group (compared with 71% of HFrEF and 82% of HFpEF patients). When patients were reclassified according to EF at the follow-up echocardiogram, mortality after a mean (±SD) follow-up of 36 ± 28 months was 3.7%, 8.1% and 6.4% for patients in the HFmrEF, HFrEF and HFpEF groups, respectively (p=0.01).67 When considering EF changes over time in patients with HFrEF and HFmrEF, variables associated with reclassification to HFmrEF or full EF recovery at follow-up differed between baseline phenotypes.67 Multivariable logistic regression revealed that a lower likelihood of recovery was associated with ischaemic aetiology in both the HFmrEF (OR 0.66; 95% CI [0.19–0.68]) and HFrEF (OR 0.46; 95% CI [0.33–0.64]) groups, as well as with NYHA Class III–IV in the HFrEF group (OR 0.57; 95% CI [0.38–0.68]). Conversely, in the HFmrEF group, a history of HF <6 months (OR 2.44; 95% CI [1.76–3.39]) and AF (OR 2.66; 95% CI [1.37– 5.17]) independently predicted phenotype transition or full recovery.67 These data suggest that clinical studies on HFmrEF should consider its peculiar temporal trend to possible transition into either HFrEF or HFpEF, with associated changes in mortality.

Prognosis There is considerable published data concerning prognosis in HFmrEF. However, the information available regarding outcomes and prognosis does not apply to acute HF episodes. Moreover, whether HFmrEF patients obtain the same benefit from the disease-modifying drugs in the HFrEF armamentarium remains unclear. Large registries report 1-year mortality of 7.6% for HFmrEF, which is intermediate between the 1-year mortalities reported for HFpEF (6.3%) and HFrEF (8.8%), and a 5-year mortality of 75% among HFmrEF patients aged ≥65 years.4,68 No difference in mortality between the three HF phenotypes was demonstrated in the Trial of Intensified (BNP-guided) versus standard

Advanced Heart Failure Figure 2: Multimodality Imaging Evaluation for Correct Diagnosis, Evidence-Based Therapy and Possible Causes of Transition During Follow-up

Routine echocardiography LVEF evaluation

LVEF 40–49%

LVEF <40% Diagnosis

Pathological diastolic pattern

Reduced GLS

LVEP ≥50% LVEF confirmed by 3D echocardiography

Diagnosis of HFmrEF confirmed? If the answer is ‘No’ Cardiac MRI LVEF evaluation

Therapy

HFmrEF

Hypertension LV remodelling

LBBB

ACEI/ARB/ARNI Beta blockers

CRT

Rate control

Rhythm control

Beta-blockers

E/ICV + beta-blockers Amiodarone

Tachycardia

Diabetes

OSAS

Beta-blockers/ ivabradine

SGLT2 + metformin

CPAP

Ambulatory evaluation at 3–6 months with standard echocardiography + GLS/3D/diastolic function

Unchanged

Follow-up transition

Worsened

Diagnosis of HFrEF

Old age LVEDD >60 mm Long HF history BNP elevation Ischaemic HF Genetic factor Low adherence to therapies Target dose not achieved

HFmrEF confirmed

Improved Young age Controlled hypertension Normal heart rate Improved GLS Takotsubo Peripartum CRT responders Target dose achieved

Diagnosis of HFpEF

ACE = angiotensin-converting enzyme; ACEI = ACE inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BNP = B-type natriuretic peptide; CPAP = continuous positive airway pressure; CRT = cardiac resynchronisation therapy; E/ICV=external/internal cardioversion; GLS = global longitudinal strain; HF = heart failure; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LBBB = left bundle branch block; LV = left ventricle; LVEDD = left ventricular end-diastolic diameter; LVEF = left ventricular ejection fraction; OSAS = obstructive sleep apnoea syndrome; SGLT2 = sodium–glucose cotransporter 2.

(symptom-guided) Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) cohort after a median follow-up of 794 days.28 In the meta-analysis of Altaie et al., only a few outcomes differed between HF phenotypes: patients with HFmrEF had a lower rate of all-cause death than those with HFrEF, whereas patients in the HFpEF group had a higher rate of cardiac mortality than those in the HFmrEF group.69 With regard to sudden cardiac death, Pascual-Figaz et al. revealed a higher risk for HFmrEF than HFpEF patients (HR 2.73; 95% CI [1.07–6.98]; p=0.036).70 Conversely, noncardiac mortality was higher among patients with HFrEF than HFmrEF.70 In the CHARM program, HFmrEF patients had a lower HRs for cardiac and all-cause mortality than HFrEF patients.22 Clearly, LVEF transitions have a crucial role in terms of prognosis: lower mortality, hospitalisation for HF and better functional capacity characterise HFmrEF patients moving towards HFpEF compared with

those with HFrEF and HFmrEF who did not transition.71–73 A sharp decline in the composite outcome of death, LV assist device implantation or heart transplantation has been reported even in patients transitioning from HFrEF to HFmrEF compared with HFrEF or HFmrEF without LVEF recovery during follow-up.71 Conversely, decreases in LVEF are correlated with a worse outcome: HFmrEF transitioning to HFrEF is associated with higher mortality, rates of heart transplantation and hospitalisation for acute HF than HFmrEF with no decrease in LVEF.4,74 Nonetheless, HF patients with recovered LVEF should not be considered as ‘healed’, and a complete clinical examination is mandatory. In particular, abnormal concentrations of B-type natriuretic peptide (BNP), uric acid and troponin I, which denote persistent neurohormonal

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Mid-range Ejection Fraction in Heart Failure Table 1: Clinical Characteristics, Therapy, Transition and Long-term Mortality According to Heart Failure Phenotype

Patients (n)

HFrEF

HFmrEF

HFpEF

859 (60)

335 (24)

220 (16)

p-value

Age

65 ± 12

63 ± 15

69 ± 16

0.001

Female sex

204 (24)

91 (27)

104 (47)

0.001

Diabetes

223 (26)

99 (30)

54 (25)

Chronic obstructive pulmonary disease

133 (16)

65 (20)

52 (24)

0.011

Chronic kidney disease

194 (23)

60 (18)

55 (26)

Ischaemic aetiology

370 (43)

122 (36)

41 (19)

0.001

HF history <6 months

226 (26)

73 (22)

38 (17)

0.012

116 (14)

54 (17)

65 (30)

0.001

NYHA Class III–IV

190 (22)

40 (12)

45 (20)

0.001

HF hospitalisation in previous year

346 (40)

98 (29)

67 (30)

0.001

RAS inhibitors

742 (86)

291 (87)

190 (86)

NS NS

RAS inhibitors at ≥50% of target dose

351 (48)

139 (49)

89 (46)

Beta-blockers

731 (85)

294 (88)

188 (85)

Beta-blockers at ≥50% of target dose

225 (29)

92 (30)

61 (30)

NS NS

MRA

454 (53)

183 (55)

122 (56)

Mortality (%)

4.5

7.3

To HFrEF

To HFmrEF

To HFpEF

Transitioned at follow-up (%)

0.001

Unless indicated otherwise, data are expressed as the mean±SD or as n (%). HF = heart failure; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonists; NYHA = New York Heart Association RAS = renin–angiotensin system.

activation, increased oxidative stress and cardiomyocyte injury, have been associated with a persistent risk of hospitalisation for HF and clinical instability, despite LVEF recovery.41,75

Differences in the prevalence of risk factors and underlying aetiology may generate different triggers of transition to either preserved or reduced EF, and thus different outcomes.

These findings suggest that, despite improvements or recovery in LVEF, a continuous comprehensive evaluation through biomarkers and using modern imaging tools is needed in order to carefully plan the timing of clinical followup and the eventual long-term continuation of medical therapies.

A multiparametric approach to accurately profile HFmrEF is needed to predict disease evolution; moreover, we stress the importance of considering complete multimodal imaging evaluation (i.e., 3D, GLS and eventually CMR) to carefully evaluate LVEF beyond the physiological and inherent technical limitations of 2D echocardiography. Evidencebased therapies, particularly for patients with EF <45%, and aggressive treatment of comorbidities are crucial for favourable transitions. Trials of future treatments need to take into account the highly dynamic nature of this peculiar phenotype.

Conclusion Since its classification as a separate entity, it has become increasingly clear that HFmrEF mostly represents a transition phenotype, either to full recovery or to a downhill course of worsening systolic function.

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Cardiac resynchronization therapy in patients with heart failure and moderately reduced ejection fraction: could it trigger a superresponse? Indian Heart J 2019;71:229–34. https://doi. org/10.1016/j.ihj.2019.04.010; PMID: 31543195. 49. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomized trial. Lancet 2019;393:61–73. https://doi. org/10.1016/S0140–6736(18)32484-X. 50. Martens P, Beliën H, Dupont M, et al. The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovasc Ther 2018;36:e12435. https://doi.org/10.1111/1755–922.12435; PMID: 29771478. 51. Mazzetti S, Scifo C, Abete R, et al. Short-term echocardiographic evaluation by global longitudinal strain in patients with heart failure treated with sacubitril/valsartan. ESC Heart Fail 2020;7:964–72. https://doi.org/10.1002/ ehf2.12656; PMID: 32233080. 52. Pharithi RB, Ferre-Vallverdu M, Maisel AS, et al. Sacubitril– valsartan in a routine community population: attention to volume status critical to achieving target dose. ESC Heart Fail 2020;7:158–66. https://doi.org/10.1002/ehf2.12547; PMID: 31903729. 53. Bozkurt B, Ezekowitz J. Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials. Circulation 2020;141:362–6. https://doi.org/10.1161/ CIRCULATIONAHA.120.045008; PMID: 32011927. 54. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin– neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019; 381:1609–20 https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794.

55. Solomon SD, Vaduganathan M, Claggett BL, et al. Sacubitril/ valsartan across the spectrum of ejection fraction in heart failure. Circulation 2019;141:352–61 https://doi.org/10.1161/ CIRCULATIONAHA.119.044586; PMID: 31736342. 56. Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2016;374:1094 [Comment]. https://doi.org/10.1056/ NEJMc1600827; PMID: 26981940. 57. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/ NEJMoa1611925; PMID: 28605608. 58. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 59. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829. 60. Lan NSR, Fegan PG, Yeap BB, Dwivedi G. The effects of sodium–glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions. ESC Heart Fail 2019;6:927–35. https://doi.org/10.1002/ehf2.12505; PMID: 31400090. 61. de Groote P, Fertin M, Duva Pentiah A, et al. Long-term functional and clinical follow-up of patients with heart failure with recovered left ventricular ejection fraction after β-blocker therapy. Circ Heart Fail 2014;7:434–9. https://doi.org/10.1161/ CIRCHEARTFAILURE.113.000813; PMID: 24563449. 62. Park J-S, Kim J-W, Seo K-W, et al. Recurrence of left ventricular dysfunction in patients with restored idiopathic dilated cardiomyopathy. Clin Cardiol 2014;37:222–6. https://doi. org/10.1002/clc.22243; PMID: 24452755. 63. Rigolli M, Cicoira M, Bergamini C, et al. Progression of left ventricular dysfunction and remodelling under optimal medical therapy in CHF patients: role of individual genetic background. Cardiol Res Pract 2011;2011:798658. https://doi. org/10.4061/2011/798658; PMID: 21253480. 64. Jansweijer JA, Nieuwhof K, Russo F, et al. Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy. Eur J Heart Fail 2017;19:512–21. https:// doi.org/10.1002/ejhf.673; PMID: 27813223. 65. Brann A, Janvanishstaporn S, Greenberg B. Association of prior left ventricular ejection fraction with clinical outcomes in patients with heart failure with midrange ejection fraction. JAMA Cardiol 2020. https://doi.org/10.1001/ jamacardio.2020.2081; PMID: 32584922; epub ahead of press. 66. Opasich C, Rapezzi C, Lucci D, et al. Precipitating factors and decision-making processes of short-term worsening heart failure despite ‘optimal’ treatment (from the IN-CHF Registry). Am J Cardiol 2001;88:382–7. https://doi.org/10.1016/S00029149(01)01683-6; PMID: 11545758. 67. De Maria R, Macera F, Gorini M, et al. Heart failure with midrange (HFmrEF) or recovered (HFrecEF) ejection fraction: differential determinants of transition. Eur Heart J 2019;40(Suppl 1):P320 [Abstract]. https://doi.org/10.1093/eurheartj/ ehz747.0155. 68. Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. Am J Coll Cardiol 2017;70:2476–86. https://doi. org/10.1016/j.jacc.2017.08.074; PMID: 29141781. 69. Altaie S, Khalife K. The prognosis of mid-range ejection fraction heart failure: a systematic review and meta-analysis. ESC Heart Fail 2018;5:1008–16. https://doi.org/10.1002/ehf2.12353; PMID: 30211480. 70. Pascual-Figal DA, Ferrero-Gregori A, Gomez-Otero I, et al. Midrange left ventricular ejection fraction: Clinical profile and cause of death in ambulatory patients with chronic heart failure. Int J Cardiol 2017;240:265–70. https://doi.org/10.1016/j. ijcard.2017.03.032; PMID: 28318662. 71. Nadruz W Jr, West E, Santos M, et al. Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes. Circ Heart Fail 2016;9:e002826. https://doi.org/10.1161/ CIRCHEARTFAILURE.115.002826; PMID: 27009553. 72. The Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429–35. https://doi. org/10.1056/NEJM198706043162301; PMID: 2883575. 73. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-preserved trial. Lancet 2003;362:777–81. https://doi.org/10.1016/S01406736(03)14285-7; PMID: 13678871. 74. McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-added trial. Lancet 2003;362:767–71. https://doi.org/10.1016/S01406736(03)14283-3; PMID: 13678869. 75. Merken J, Brunner-La Rocca HP, Weerts J, et al. Heart failure with recovered ejection fraction. Am J Coll Cardiol 2018;72:1557–8. https://doi.org/10.1016/j.jacc.2018.06.070; PMID: 30236318.

CARDIAC FAILURE REVIEW

Left Ventricular Assist Device

Determinants of Functional Capacity and Quality of Life After Implantation of a Durable Left Ventricular Assist Device Kiran K Mirza and Finn Gustafsson Department of Cardiology, Rigshospitalet, Copenhagen, Denmark

Abstract Continuous-flow left ventricular assist devices (LVAD) are increasingly used as destination therapy in patients with end-stage heart failure and, with recent improvements in pump design, adverse event rates are decreasing. Implanted patients experience improved survival, quality of life (QoL) and functional capacity (FC). However, improvement in FC and QoL after implantation is not unequivocal, and this has implications for patient selection and preimplantation discussions with patients and relatives. This article identifies preimplantation predictors of lack of improvement in FC and QoL after continuous-flow LVAD implantation and discusses potential mechanisms, allowing for the identification of potential factors that can be modified. In particular, the pathophysiology behind insufficient improvement in peak oxygen uptake is discussed. Data are included from 40 studies, resulting in analysis of >700 exercise tests. Mean peak oxygen uptake was 13.4 ml/ kg/min (equivalent to 48% of predicted value; 259 days after implantation, range 31–1,017 days) and mean 6-minute walk test distance was 370 m (182 days after implantation, range 43–543 days). Finally, the interplay between improvement in FC and QoL is discussed.

Keywords Predictors, 6-minute walk test, peak oxygen uptake, exercise, Kansas City Cardiomyopathy Questionnaire, Minnesota Living with Heart Failure Questionnaire, 5-Level EQ-5D Disclosure: FG is a consultant for Abbott and has received speakers’ fees from Abbott and Carmat. KKM has no conflicts of interest to declare. Received: 5 June 2020 Accepted: 10 July 2020 Citation: Cardiac Failure Review 2020;6:e29. DOI: https://doi.org/10.15420/cfr.2020.15 Correspondence: Finn Gustafsson, Department of Cardiology, Section 2142, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E: Finn.Gustafsson@regionh.dk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

According to the third report from the International Society for Heart and Lung Transplantation (ISHLT) Mechanically Assisted Circulatory Support Registry, more than 15,500 left ventricular assist devices (LVADs) were implanted worldwide between 2013 and 2017.1 Originally, LVADs were exclusively implanted as part of a bridge to transplantation (BTT) strategy, but in recent years a large proportion of patients undergoing LVAD implantation received the device as final treatment for advanced heart failure (HF), so-called destination therapy. Survival rates after LVAD implantation have increased greatly over the past decade, as improvements in LVAD technology and management have resulted in a lower risk of adverse events.1–7 Hence, in recent studies, 2-year survival rates range from 80% to 90%.5,8 Patients treated with LVADs experience significant improvements in HF symptoms, quality of life (QoL) and functional capacity (FC), although the latter remains reduced in this patient group, especially when measured as peak oxygen uptake (pVO2).3,6–11 Given the increased use of LVAD as destination therapy and the long wait times for transplantation in those implanted with an LVAD as BTT, optimisation of FC and QoL is critically important.1 In order to identify potential strategies to improve FC and QoL after LVAD implantation, a detailed understanding of the mechanisms behind residual impairment of these parameters is essential.

This review summarises the available evidence describing improvement in FC and QoL after LVAD implantation with the specific aim of identifying reproducible predictors of improvement in QoL and FC with the intervention.

Methods Search Strategy On 1 November 2019, a PubMed search was conducted using the search terms ‘quality of life’, ‘EuroQoL-5 Dimensions-5 levels’, ‘Minnesota Living With Heart Failure’, ‘Kansas City Cardiomyopathy Questionnaire’, ‘exercise’, ‘six minute walk test’, ‘six-minute walk test’, ‘peak oxygen uptake’, ‘exercise capacity’, ‘peak oxygen consumption’, ‘exercise training’, ‘cardiac rehabilitation’, ‘ventricular assist device’ and ‘continuous-flow left ventricular assist device’ (Supplementary Material Table 1). The search resulted in 609 items (Figure 1). After excluding studies published prior to 2006 and those written in languages other than English, the titles of 417 publications were screened by both investigators independent of each other (i.e. blinded). This process resulted in the identification of 143 publications by FG and 241 publications by KM. Mismatch and disagreement in 98 cases led to fulltext review. The full text of one article could not be acquired, which resulted in its exclusion. Finally, 36 papers and four ‘add-on’ studies (e.g. extra studies found by reference review or other sources) were included in this narrative review.9,12–50

Left Ventricular Assist Device Figure 1: Flowchart of the Article Selection and Review Process Search on 1 November 2019: n=609

Limitations applied: n=417

Title screening: n=417 FG: n=143 KM: n=241 • Full text studied: n=240 1 study excluded because full text was not available • Add-ons (see text for details)

Total number of publications included: n=36 + add-ons (n=4) Titles of 417 publications were independently screened by both investigators (FG and KM). The limitations applied to search were publication in English and studies conducted after 2006.

Table 1: Preimplantation Predictors of Quality of Life and Functional Capacity Preimplantation predictor

References

Quality of life Communication (patient–healthcare worker; patient–patient)

Modica et al. 201517

Patient resources

Modica et al. 201517

Diabetes

Kiernan et al. 201618

Pulmonary artery pressure

Kiernan et al. 201618

Right ventricular function

Kiernan et al. 201618

Younger age

Cowger et al. 201849

Higher preoperative haemoglobin

Cowger et al. 201849

Higher baseline quality of life score

Cowger et al. 201849

Ability to complete the 6MWT preoperatively

Cowger et al. 201849

Functional capacity Diabetes

Kiernan et al. 201618 Hasin et al. 2012 24

Right atrial pressure

Hasin et al. 2012 24

Chronic obstructive pulmonary disease

Kiernan et al. 201618

Gustafsson et al. 202048

Age

Gustafsson et al. 202048 Schmidt et al. 201841 Cowger et al. 201849

NYHA Class IV

Gustafsson et al. 202048

INTERMACS profile 1–2

Gustafsson et al. 202048

Higher baseline functional capacity

Gustafsson et al. 202048 Cowger et al. 201849

See text for explanation and Supplementary Material Table 2 for a full list of studies that have investigated predictors (before and/or after implantation). 6MWT = 6 minute walk test; INTERMACS = Interagency Registry of Mechanically Assisted Circulatory Support; NYHA = New York Heart Association.

Calculations Mean values weighted for population size for pVO2 and the 6-minute walk test (6MWT) were calculated as follows:

Weighted mean pVO2 = Σ(pVO2 × npVO2)/ΣNpVO2 Weighted mean 6MWT = Σ(6MWD × n6MWT)/ΣN6MWT Where n refers to the number of patients in each study, while N is the total number of all studied patients. 6MWD is the distance covered in the 6MWT.

Results and Discussion Functional Capacity After LVAD Implantation The most widely accepted measures of functional capacity in HF are symptoms, measured by New York Heart Association (NYHA) class, 6MWD and pVO2. Each of these measures has its own advantages and disadvantages, such as variable reproducibility or technical demands, but all are useful and required to characterise different aspects of the exercise limitation of HF populations. Patients referred for LVAD implantation are almost invariably severely symptomatic (e.g. NYHA IIIb–IV with 6MWD <300–400 m and low pVO2). The latter is typically below 12 ml/kg/min, which is also the limit used as part of the indication for destination therapy LVAD in the US Medicare system. In all studies of patients undergoing LVAD implantation, NYHA class improves in most patients from Class III/IV before implantation (100%) to Class I or II.9,49 Studies are remarkably consistent in finding that approximately 80% of patients are in NYHA Class I–II after implantation, and the improvement in symptoms has been documented to be sustained over time.9,20,49 However, some patients (<5%) remain severely symptomatic (NYHA Class IV) even 12 months after LVAD implantation.9,49 The 6MWD is widely used in LVAD recipients.9,13,16,24,31,48,49 FC measured using the 6MWT prior to implantation is low (mean 6WMD 221 m [range 39–356 m]; mean 6MWD weighted for population size 215 m), and significant improvements are observed soon after implantation (mean 6WMD 373 m [range 126–531 m]; mean 6MWD weighted for population size 357 m; Figure 2A).9,18,24,43,49 The improvement from baseline to the 6-month follow-up is, on average, +144 m (range 41–319 m; mean improvement weighted for population size 113 m), which is equivalent to an approximate 40% improvement.9,18,24,43,48,49 Improvement in the 6MWD can be difficult to interpret across different studies because some studies include mostly ambulatory patients and some include patients who would not be able to complete any exercise testing prior to implantation due to critical clinical condition (e.g. Interagency Registry of Mechanically Assisted Circulatory Support [INTERMACS] profile 1–2). In the large LVAD trials, increments in 6MWD were in the range 98–250 m from baseline to a maximum 2 years after implantation 5,9,51–60 When investigating FC expressed as pVO2, the reported preimplantation values are low (mean 11 ml/kg/min [range 10.1–11.8 ml/kg/min]; mean pVO2 weighted for population size 11 ml/kg/min), although improvement is observed because studies reporting pre- and postimplantation pVO 2 values show an improvement of approximately 20% after implantation.27,38,43 Postimplantation mean pVO2 values (Figure 2B) vary from 8.8 to 21.4 ml/ kg/min (mean pVO2 weighted for population size 13.2 ml/kg/min), showing that pVO2 generally remains reduced after implantation at, on average, 48% of the expected value for age and sex.12–16,21–23,25–29,31–37,39– 42,44–47,61–63 A considerable proportion of the variance of postimplantation pVO2 between published studies can be attributed to differences in the mean age of included patients.11

Predictors of FC and QOL in LVADs Figure 2: Studies of Functional Capacity After Left Ventricular Assist Device Implantation Schmidt et al. 201945 68

Schmidt et al. 201841

Rosenbaum et al. 201843 post implantation only Rogers et al. 2010 DT arm

199

Rogers et al. 20109 BTT arm

Racca et al. 201844 test#2 arm

46 41

Marko et al. 201737 first CR

Lairez et al. 201839 RVEF>40% arm Lairez et al. 201839 RVEF<40% arm

18 499

Kiernan et al. 2016 responder arm

6MWT study

Kiernan et al. 201618 non-responder arm

Peak oxygen uptake study

51 18

Kiernan et al. 201416 exercise arm Kiernan et al. 201416 control arm

8 7

Imamura et al. 201531 AV open arm Imamura et al. 201531 AV closed arm

Hayes et al. 201213 stable phase, exercise data

Hayes et al. 201213 stable phase, control data

7 20

Hasin et al. 201224 poor performers arm Hasin et al. 201224 good performers arm

45 194

ELEVATE substudy, 6 month data Cowger et al. 201849 HMII arm

Cowger et al. 201849 HM3 arm

114 200

300

400

500

6MWT distance (m)

Vignati et al. 201736 test 2 Vignati et al. 201736 test 1 Schmidt et al. 201945 test 2 Schmidt et al. 201841 Rosenbaum et al. 201843 test 2 Noor et al. 201225 test 2 Noor et al. 201225 test 1 Mirza et al. 202012 no CI Mirza et al. 202012 CI Mirza et al. 202063 Mezzani et al. 201842 Martina et al. 201328 6 month data Martina et al. 201328 12 month data Marko et al. 201737 test 2 Marko et al. 201532 Lim et al. 201738 postimplantation data Lairez et al. 201839 RVEF >40% Lairez et al. 201839 RVEF <40% Koshy et al. 201947 Kerrigan et al. 201433 pace Kerrigan et al. 201433 non-pace Kerrigan et al. 201416 exercise arm Kerrigan et al. 201416 control arm Kerrigan et al. 201314 Karapolat et al. 201326 baseline Karapolat et al. 201326 follow-up Jung et al. 201719 Jung et al. 201620 Jung et al. 201450 intervention arm Jung et al. 201450 control arm Jakovljevic et al. 201415 Jakovljevic et al. 201122 AT value Jacquet et al. 201123 Imamura et al. 201531 AV open arm Imamura et al. 201531 AV closed arm Hayes et al. 201213 exercise arm Hayes et al. 201213 control arm Gross et al. 201946 Grosman-Rimon et al. 201327 Dimopoulos et al. 201121 Camboni et al. 201429 Apostolo et al. 201855 test 2 Apostolo et al. 201855 test 1

15 68

10 49

30 30

30 14

15 38 18

20 24

8 26

11 11

19 25

18 30 10 8 15 15

10 7

7 7 15 7

10 12 14 16 18 20 Peak oxygen uptake (ml/kg/min)

A: Studies reporting on 6-minute walk test (6MWT) distances. The mean walking distance after implantation with a sole LVAD was 370 m (182 days after implantation; range 43–543 days). The number of patients included in each study or study arm, as stated, is indicated by the size of the circles, with the exception of Lairez et al.39 in which n for both shown study arms is set to 18, which is in fact the total study n. The mean 6MWT distance weighted for population size was 354 m. B: Studies reporting on peak oxygen uptake (pVO2 ). The mean reported pVO2 was 13.4 ml/ kg/min or 48% of predicted pVO2 (values not shown). Mean pVO2 weighted for population size was 13.2 ml/kg/min. The number of patients included in each is indicated by the size of the circles. AT = anaerobic threshold; AV = aortic valve; BTT = bridge to transplantation; CI = chronotropic incompetence; CR = cardiac rehabilitation; DT = destination therapy; HM3 = HeartMate 3; HMII = HeartMate II; RVEF = right ventricular ejection fraction.

Although the improvement from pre- to postimplantation FC, measured as both 6MWT and pVO 2, may appear modest, these changes are much larger than the effect of other device therapies in HF, such as cardiac resynchronisation therapy or the use of vasodilators.64,65 Furthermore, it should be re-emphasised that the sickest patients were excluded from studies presenting changes in FC from before to after implantation because these patients were not able to complete preimplantation measurements (e.g. because of the need for ventilator treatment or temporary mechanical circulatory support). Hence, the improvement in 6MWD and pVO 2 from before to after implantation is often underestimated in the literature.

age performed significantly better than LVAD recipients >50 years of age.28 Several other studies have confirmed age as an independent preoperative determinant of postimplantation FC.41,46,48

Preimplantation Predictors of Postimplantation Functional Capacity

The importance of perioperative diabetes has been suggested in four studies, although the largest study did not find perioperative diabetes of importance for postimplantation FC.18,24,48,66 This may be due to differences in the definitions of FC used, as well as follow-up time, and more studies dissecting the interplay between diabetes and outcome after LVAD implantation are clearly needed. These studies provide important information that can be used in the clinical setting when aligning expectations with potential LVAD recipients and their families and carers.

Several studies have elucidated preimplantation determinants of postimplantation QoL and/or FC (Table 1 and Supplementary Material Table 2).17,18,24,27,38,43,48,49 Advanced age is generally a predictor of inferior outcomes in cardiovascular medicine; this also holds true for patients implanted with an LVAD. In a Multicenter Study of MAGLEV Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) substudy including 265 patients from the US, younger age was one of the strongest predictors of the ‘living well on a left ventricular assist system’ endpoint (6MWD >300 m and Kansas City Cardiomyopathy [KCCQ] score >50).49 Confirming these findings, Martina et al. showed that HeartMate II (HMII) recipients <50 years of

Other strong preoperative predictors of FC are a lower INTERMACS profile, NYHA class, chronic obstructive pulmonary disease (COPD), diabetes and lower estimated glomerular filtration rate (eGFR).15,24,24 Higher haemoglobin, eGFR and INTERMACS profile and better NYHA class at the time of implantation all reflect a general better health status, which is linked to better FC after implantation. In general, these findings are suggestive of benefits, at least in terms of FC improvement, of early implantation of LVADs in advanced HF.

In general, most of the studies mentioned above investigated HMI recipients in a historical period where knowledge regarding patient selection was sparse. Further, studies including data on preoperative cardiopulmonary exercise testing (which is the gold standard for studying FC), are limited.27,38,43 A few studies evaluated preoperative

Left Ventricular Assist Device predictors of postimplantation FC, with FC measured as walking ability (6MWT), and these have been discussed above.28,41,46,48,49

Relationship Between Postimplantation Functional Capacity and Adverse Events Overall, few studies report adverse events (AEs) in relation to exercise testing in this patient group, with one case of syncope and one event of ventricular tachycardia reported, both of which were well tolerated.16,32 The potential concern of AEs occurring in relation to exercise seems clinically unimportant because exercise and cardiac rehabilitation programs have been well-tolerated in both the short and long (weeks) term.19,25,42,45,49,54,56,60 An investigation of determinants of FC in 204 patients at 6 months after implantation in a substudy of the MOMENTUM 3 trial (HeartMate 3 [HM3]=114, HMII=90) found that individuals with no severe AEs (SAEs) had larger improvements in walking distance than those who experienced an SAE (e.g. the presence of a single SAE was associated with less improvement in walking distance regardless of device type).49 Similarly, Imamura et al. showed that an increased pVO2 was associated with lower readmission rates, underlining the clinical relevance (beyond patient mobility) of markers for exercise capacity also in the LVAD population.30 The correlation between FC and survival is well described in HF patients not receiving mechanical circulatory support, but has not been extensively studied in LVAD recipients; hence, the prognostic value of pVO2 has never been reported in this patient group. In contrast, the prognostic value of the 6MWT was elucidated by Hasin et al. in 2012.24 That study included 65 patients, of whom 20 were deemed poor performers (i.e. 6MWD <300 m) postoperatively. Despite similar perioperative HF severity, the poor performers showed poorer survival (i.e. 6MWD <300 m was found to be independently associated with worse survival). 24

Why Does Exercise Capacity Remain Reduced After LVAD Implantation? Right and Left Ventricular Contractility Noor et al. showed that in HMII recipients (n=30) 6 months after implantation, pump speed reduction led to significant decline in pVO2 in patients with a left ventricular ejection fraction (LVEF) <40%, but did not alter FC in those with left ventricular (LV) recovery (i.e. LVEF >40%). 25 In 2014, in a double-blind crossover study including HMII recipients, Jung et al. showed that increasing pump speed augments pVO2, leading to the conclusion that future generations of continuous-flow LVADs should include a speed change function to improve FC in this patient group. 50 In 2018, these findings were confirmed in a study investigating Jarvik 2000 recipients, although that study reported a possible increased risk of AEs (obstructive sleep apnoea).40 However, conflicting data exist, because a recent retrospective study including 49 patients (HeartWare [HW]=6, HMII=43) found that neither right ventricular (RV) nor LV function was associated with the improvement in pVO2.43 In accordance with these data, we recently documented that RV function, even during exercise, was not correlated with pVO2 in LVAD recipients.63 This is in contrast with the results obtained in HF patients not supported by an LVAD. For example, Murninkas et al. found that with every 10% worsening of RV function, pVO2 worsened by 0.97 ml/kg/min.67

The studies described above are small, with considerable heterogeneity, and clearly more studies are needed to establish the importance of intrinsic cardiac contractility in the FC of LVAD recipients.

Chronotropic Incompetence, Arrhythmia and Pacing Several studies have documented the negative effects of chronotropic incompetence on exercise capacity in LVAD recipients.12,21,27,38,46 Depending on the definition of chronotropic incompetence, it has been reported in approximately half of all examined LVAD recipients. Chronotropic incompetence may represent a somewhat clinically modifiable factor, because many LVAD recipients receive betablockers, digoxin or amiodarone and are equipped with pacing devices that could be programmed to improve chronotropic competence. In fact, in a recent study in 30 patients, turning on rate response pacing in LVAD recipients with pacing devices was shown to improve FC (6MWT and treadmill FC) most clearly in patients with chronotropic incompetence.68 Perioperative AF has also been associated with lower FC after LVAD implantation.48 In an analysis from the ELEVATE registry of 194 patients with an HM3, preimplantation AF was an independent predictor of poor performance (6MWD <300 m) 6 months after implantation.48,58 In patients with LVADs, LV preload is of dire importance, and patients with AF (with or without symptoms) lack the atrial kick that could impair RV function, which, in turn, affects the LV preload. Whether pharmacological therapy or AF ablation after LVAD implantation to restore sinus rhythm will improve exercise capacity has not been tested. Future studies are needed to further explore these findings to enable improvements in current technologies.

Pump Design, Placement and Settings There is no evidence to suggest that one continuous-flow LVAD (e.g. axial versus centrifugal design) is associated with better postimplantation FC than other continuous-flow LVADs. Suboptimal cannula position will lead to reduced circulatory support and would likely impair FC, but this has not been studied in detail.69 Increasing pump speed during exercise has been investigated in several studies and, in most, has been associated with improved FC.36,40,43,50,70 Likely, a future ‘smart pump’ with the ability to increase pump speed in response to increased LV filling during exercise would be beneficial for the FC of LVAD recipients.

Comorbidities Recently, Schmidt et al. showed that weight gain after implantation is linked to less improvement in FC (specifically, there was a negative correlation between weight gain and absolute pVO2 improvement) and that pVO2 plateaus after implantation with LVADs.45 Regarding weight, recent reports suggest that BMI does not affect patient survival.71–73 However, it could be speculated that weight gain (as seen in Schmidt et al.45) could affect specific AEs; in particular, large body size and associated comorbidities, such as diabetes, may leave the patient more prone to infection, thereby lowering FC, as discussed above.74 In studies investigating blood chemistry, haemoglobin, preoperative C-reactive protein and persistently low perioperative serum albumin concentrations were associated with lower FC after implantation.30,41,44 All these parameters are adjustable. Surprisingly, B-type natriuretic peptide (BNP) was not associated with FC measured as pVO2, although increasing BNP concentrations were associated with a lower QoL.20 Iron deficiency is common in LVAD recipients, but its effect on survival,

Predictors of FC and QOL in LVADs hospitalisations and FC has not been clearly established.75–77 A recent pilot study of 33 patients was unable to show the expected significant improvement in the 6MWT after intravenous iron replacement 6 months after implantation.78 These findings have yet to be challenged in a randomised prospective study.

Figure 3: Interplay Between Adverse Events, Functional Capacity and Quality of Life

Regardless of age, physical training programs (e.g. cardiac rehabilitation) after LVAD implantation have been investigated in several studies, some of which have demonstrated a beneficial effect on FC.21,26,32,37,41 However, others have shown no effect of physical training on FC.13 All studies have shown that physical training is safe and generally well tolerated.14,15,20–23,25,37,38,42–46,49,51–62,80–83

Quality of life

Quality of Life Overall, both large clinical studies and smaller studies included in this review have reported that QoL improves significantly after LVAD implantation.9,13–18,20,26,49,58 Different studies have assessed QoL using different QoL scores, including the 36-Item Short Form Health Survey (SF-36),13,17,26 KCCQ,9,14,16,18,49 Minnesota Living with Heart Failure (MLWHF) questionnaire9,15,17,18,20,45,49 and the 5-Level EQ-5D (EQ-5D-5L).49,58 There is no consensus as to which QoL score is superior in the LVAD population, and this complicates comparisons between studies. However, data are consistent in showing significant improvements in QoL both in the short and long term (i.e. after a minimum of 6 months follow-up), regardless of methods of quantification.9,13–18,20,26,45,49,58 There is only one exception: a study of 10 LVAD recipients in the early postimplantation stage.45 The mean improvement in KCCQ score was 27 points from approximately 6 weeks to 6 months after implantation.16,49 The greatest increase in KCCQ overall summary score of 178% was seen 24 months after implantation.49 No differences between centrifugal and axial flow pumps have been reported regarding improvements in QoL.49 In two studies that investigated QoL at either 8 weeks or 6 months after implantation, there was a mean change in SF-26 score of 9.8 points versus preimplantion.17,26 The same pattern was seen when investigating QoL using the MLWHF questionnaire and the EQ-5D-5L.9,15,17,18,20,45,49,58 As earlier studies showed that a five-point change in both MLWHF and KCCQ scores is a clinically meaningful change, the improvements described above are highly important.83–85 Some factors related to postimplantation QoL, including exercise rehabilitation in different forms, comorbidities and device characteristics, have been described (Table 1 and Supplementary Material Table 2).13,14,16–18,20 Of these, the most consistent were COPD, diabetes and FC,14,16,20 although conflicting data exist.13 The continued focus on alleviating AEs in LVAD recipients is highlighted by the documented correlation between QoL and AEs.49 Interestingly, one

Goldstein DJ, Meyns B, Xie R, et al. Third Annual Report From the ISHLT Mechanically Assisted Circulatory Support Registry: a comparison of centrifugal and axial continuous-flow left ventricular assist devices. J Hear Lung Transplant. 2019;38:352363. https://doi.org/10.1016/j.healun.2019.02.004; PMID: 30945637. de By TMMH, Mohacsi P, Gahl B, et al. The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) of the European Association for Cardio-Thoracic Surgery (EACTS): second report. Eur J Cardiothorac Surg 2018;53:309–16. https://doi.org/10.1093/ejcts/ezx320; PMID: 29029117.

Functional capacity

Adverse events

For details, refer to the text and Supplementary Material Table 2.

study highlighted the importance of the patient–physician relationship for QoL in LVAD, and it could be speculated that this may be particularly important in patients with AEs.17 Exercise capacity is closely linked to QoL. Better QoL is related to better muscular strength, treadmill time, anaerobic threshold and pVO2, all of which are factors describing aspects of FC.14,16,26 The fact that increasing FC is associated with better QoL in patients implanted with a continuous-flow LVAD, as in HF patients not supported by an LVAD, highlights the need for continued focus on optimising exercise tolerance.20 Indeed, an interplay between AEs, FC and QoL exists in LVAD recipients, and to improve overall QoL the other two components must be addressed (Figure 3).

Conclusion Based on a literature review, it is clear that both FC and QoL are severely impaired in advanced HF patients prior to LVAD implantation, but significant improvements are observed after implantation, even though FC remains severely reduced after implantation. Important preoperative predictors of low FC are age, diabetes, COPD, INTERMACS profile, NYHA class, AF and baseline walking distance (e.g. the ability to perform an FC test at baseline). Importantly, poor FC after LVAD implantation is closely related to QoL and is associated with the risk of AEs. These factors should be considered when considering LVAD implantation, especially as destination therapy, and reversible modifiable factors should be aggressively managed both before and after LVAD implantation.

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85.

2014;9:93. https://doi.org/10.1186/1749-8090-9-93; PMID: 24884921. Imamura T, Kinugawa K, Nitta D, et al. Novel scoring system using postoperative cardiopulmonary exercise testing predicts future explantation of left ventricular assist device. Circ J 2015;79:560–6. https://doi.org/10.1253/circj.CJ-14-1058; PMID: 25746540. Schmidt T, Bjarnason-Wehrens B, Mommertz S, et al. Changes in total cardiac output and oxygen extraction during exercise in patients supported with an HVAD left ventricular assist device. Artif Organs 2018;42:22–30. https://doi.org/10.1111/ aor.12936; PMID: 28621882. Majani G, Giardini A, Opasich C, et al. Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure trial. J Card Fail 2005;11:253–9. https://doi.org/10.1016/j.cardfail.2004.11.004; PMID: 15880333. Spertus J, Peterson E, Conard MW, et al. Monitoring clinical changes in patients with heart failure: A comparison of methods. Am Heart J 2005;150:707–15. https://doi. org/10.1016/j.ahj.2004.12.010; PMID: 16209970. Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: Reliability and validity during a randomized, double-blind, placebocontrolled trial of pimobendan. Am Heart J 1992;124:1017–25. https://doi.org/10.1016/0002-8703(92)90986-6.

Corrigendum

Corrigendum to: Pulmonary Hypertension in Heart Failure Patients Sriram D Rao,1 Srinath Adusumalli2 and Jeremy A Mazurek1,3 1. Advanced Heart Failure/Transplantation Programme, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, US; 2. Department of Medicine, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, US; 3. Pulmonary Hypertension Programme, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, US

Citation: Cardiac Failure Review 2020;6:e30. DOI: https://doi.org/10.15420/cfr.2020.1.1 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

In the article by Rao et al. entitled Pulmonary Hypertension in Heart Failure Patients (Cardiac Failure Review 2020;6:e05. https://doi. org/10.15420/cfr.2019.09), the following correction should be made. The authors incorrectly stated that higher TAPSE/PASP correlates with “higher levels of natriuretic peptides, worse systemic and pulmonary haemodynamics and abnormal exercise aerobic capacity”, when it should have stated that lower TAPSE/PASP correlates with those outcomes.

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The corrected sentence reads: “Guazzi et al. showed it could be used to prognosticate in HFpEF patients, with lower TAPSE/PASP correlating with higher levels of natriuretic peptides, worse systemic and pulmonary haemodynamics and abnormal exercise aerobic capacity.” The authors and Cardiac Failure Review apologise for this error.

Treatment

Sodium–Glucose Co-transporter 2 Inhibitors in Heart Failure: Recent Data and Implications for Practice Giuseppe Rosano,1 David Quek2 and Felipe Martínez3 1. IRCCS San Raffaele Rome, Italy; 2. Pantai Hospital, Kuala Lumpur, Malaysia; 3. National University of Cordoba, Cordoba, Argentina.

Abstract Heart failure is a shared chronic phase of many cardiac diseases and its prevalence is on the rise globally. Previous large-scale cardiovascular outcomes trials of sodium–glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) have suggested that these agents may help to prevent primary and secondary hospitalisation due to heart failure and cardiovascular death in these patients. Data from the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF) and Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) have demonstrated the positive clinical impact of SGLT2 inhibition in patients with heart failure with reduced ejection fraction both with and without T2D. These data have led to the approval of dapagliflozin for the treatment of patients with heart failure with reduced ejection fraction, irrespective of T2D status. This article reviews the latest data reported from the DAPA-HF and EMPEROR-Reduced trials and their clinical implications for the treatment of patients with heart failure.

Keywords Cardiovascular, clinical trials, heart failure, sodium–glucose co-transporter 2 inhibitors, type 2 diabetes Disclosure: DQ has received honoraria for lecture/speaker engagements from AstraZeneca, Boehringer Ingelheim and Merck. FM has received honoraria from AstraZeneca, Boehringer Ingelheim, Novartis and Vifor Pharma. GR has no conflicts of interest to declare. Acknowledgements: The authors thank Maria Haughton and Vanessa Lane for providing medical writing support. Received: 23 September 2020 Accepted: 31 October 2020 Citation: Cardiac Failure Review 2020;6:e31. DOI: https://doi.org/10.15420/cfr.2020.23 Correspondence: Giuseppe Rosano, IRCCS San Raffaele Roma, Via di Val Cannuta, 247 00166, Rome, Italy. E: giuseppe.rosano@gmail.com Support: The development of this manuscript was funded by an unrestricted educational grant from AstraZeneca. Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a shared chronic phase of many cardiac diseases, including ischaemic heart disease, chronic obstructive pulmonary disease and hypertension. It is characterised by structural or functional impairment of ventricular filling or ejection of blood from the heart.1–3 It is estimated that there are more than 37.7 million cases of HF globally and its prevalence is on the rise.2 HF can be categorised into two subtypes: HF with reduced ejection fraction (HFrEF), defined by guidelines as an ejection fraction ≤40%, and HF with preserved ejection fraction (HFpEF), defined as an ejection fraction ≥50%, with those falling between these ranges considered to have borderline HFpEF or mid‑range ejection fraction.3,4 Treatment options for HFrEF include combining angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with mineralocorticoid receptor antagonists (MRAs), beta-blockers or diuretics as needed.3 The evidence for the efficacy of these treatments in HFrEF was published in the early 1990s and 2000s; since this time, the only treatment to demonstrate a benefit for patients with HFrEF has been the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril–valsartan, which reported superiority to ACE inhibition in reducing the risks of death and hospitalisation for HF in 2014.5 Disappointingly, the vast majority of trials in patients with HFpEF have failed to demonstrate robust efficacy.

The much-anticipated Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) trial of sacubitril–valsartan in patients with HFpEF missed its primary endpoint, although there were some indicators of efficacy in specific patient subgroups, meaning that patients with HFpEF still have very few treatment options with demonstrated benefit in hospitalisation and mortality.6 The US Food and Drug Administration (FDA) has recently approved the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin for the treatment of patients with HFrEF.7 Originally developed to aid glycaemic control in type 2 diabetes (T2D), dapagliflozin has the potential to substantially improve outcomes for HFrEF patients. This approval follows the release of data from the groundbreaking Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPAHF) trial, which was the first large-scale trial to demonstrate the efficacy of an SGLT2 inhibitor in a patient population that included both those with and without T2D.8 More recently, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial investigating another SGLT2 inhibitor, empagliflozin, in patients with HFrEF also reported reductions in

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Treatment Figure 1: Impact of SGLT2 Inhibition on Cardiovascular Disease Endpoints in Patients with Type 2 Diabetes MACE

HHF

Established ASCVD

HR [95% CI]

Established ASCVD

HR [95% CI]

EMPA-REG OUTCOME

0.86 [0.74–0.99]

EMPA-REG OUTCOME

0.65 [0.50–0.85]

CANVAS

0.82 [0.72–0.95]

CANVAS

0.68 [0.51–0.90]

DECLARE-TIMI 58

0.90 [0.79–1.02]

DECLARE-TIMI 58

0.78 [0.63–0.97]

FE model for ASCVD

0.86 [0.80–0.93]

FE model for ASCVD

0.71 [0.62–0.82]

Multiple risk factors EMPA-REG OUTCOME

Multiple risk factors No MRF patients

EMPA-REG OUTCOME

No MRF patients

CANVAS

0.98 [0.74–1.30]

CANVAS

0.64 [0.32–1.15]

DECLARE-TIMI 58

1.01 [0.86–1.20]

DECLARE-TIMI 58

0.64 [0.46–0.88]

FE model for MRF

1.00 [0.87–1.16]

FE model for MRF

0.64 [0.48–0.85]

0.5 1 1.5 Favours treatment Favours placebo

ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; HHF = hospitalisation for heart failure; FE = fixed effects; MACE = major adverse cardiovascular events; MRF = multiple risk factors; SGLT2 = sodium–glucose co-transporter 2; T2D = type 2 diabetes. Source: Zelniker et al. 2019.12 Reproduced with permission from Elsevier.

hospitalisation for HF, but failed to demonstrate benefit in terms of mortality.9 This article aims to discuss the evidence supporting the use of dapagliflozin and empagliflozin in patients with HFrEF with and without T2D and the optimal place for SGLT2 inhibitors in HF therapy.

The Impact of SGLT2 Inhibition on Cardiovascular Outcomes in Type 2 Diabetes Patients T2D is a major cardiovascular (CV) risk factor; CV disease (CVD) affects around one-third of people with T2D and is a major cause of mortality.10 Amid this background of increased CV risk, and following concerns surrounding the CV safety profile of the thiazolidinedione rosiglitazone, the FDA and European Medicines Agency issued guidance requiring sponsors to investigate the CV safety profiles of new glucose-lowering drugs through CV outcomes trials (CVOTs).11 Unexpectedly, rather than simply providing assurance surrounding the CV safety of SGLT2 inhibitors, results from three large-scale trial programmes in T2D suggested that these therapies could prevent serious CV events.12 In 2015, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) was the first trial to demonstrate that treatment with an SGLT2 inhibitor significantly reduced the rate of CV events compared with placebo in patients with T2D and established CVD.13 The trial reported a significant reduction in the primary outcome, a composite of death from CV causes, non-fatal MI or non-fatal stroke in the empagliflozin group compared with placebo (10.5% versus 12.1%; HR 0.86; 95% CI [0.74–0.99]; p<0.001 for non-inferiority and p=0.04 for superiority).13 The outcome was primarily driven by CV death, with rates of 3.7% in the empagliflozin versus 5.9% in the placebo groups (p<0.001). Rates of all MI (4.8% versus 5.4%; p=0.23) and all stroke (3.5% versus 3.0%; p=0.26) did not differ significantly between treatment groups. Subsequently, the Canagliflozin Cardiovascular Assessment Study (CANVAS) programme, consisting of sister randomised controlled trials CANVAS and CANVAS-Renal (CANVAS-R), demonstrated similar outcomes in terms of CV events, also in patients with T2D, the majority of whom had established CVD.14

Both trials demonstrated substantial improvements in the rates of hospitalisation for HF for the investigational treatment versus placebo (35% reduction compared with placebo, HR 0.65; 95% CI [0.50–0.85]; p=0.002 in EMPA-REG OUTCOME, and 33% reduction compared with placebo, HR 0.67; 95% CI [0.52–0.91] in the CANVAS programme).13,14 Following the disclosure of these trial results, the protocol of the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI 58) trial was amended to include a composite of hospitalisation for HF and CV death as a coprimary endpoint. DECLARE-TIMI 58 reported a significant reduction in this co-primary endpoint (HR 0.83; 95% CI [0.73–0.95]; p=0.005), driven primarily by a lower rate in hospitalisation for HF (27% reduction compared with placebo, HR 0.73; 95% CI [0.61–0.88]).15 There was a nonsignificant numerical reduction in the second primary endpoint (CV death, MI or stroke).15 This was speculated to be due to the lower overall rate of CV events in the study population, the majority of whom (59.5%) had multiple CVD risk factors but not established CVD, when compared with the populations recruited for the other SGLT2 inhibitor CVOTs.15 In addition to the CVOTs, the renal outcomes trial Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), investigating the efficacy of canagliflozin in patients with diabetic nephropathy, also reported a substantial reduction in terms of a composite of hospitalisation for HF and CV death (HR 0.69; 95% CI [0.57–0.83]; p<0.001) and hospitalisation for HF (HR 0.61; 95% CI [0.47–0.80]; p<0.001) for patients treated with canagliflozin compared with those receiving placebo.16 Meta-analyses of CVOTs reported that SGLT2 inhibitors, as a class, reduced the risk of hospitalisation for HF by 31–32% in patients with T2D, and that this risk reduction was consistent in patients with and without recognised CVD (~30% reduction in risk of hospitalisation for HF in both subgroups).12,17 Furthermore, they demonstrated that the event reductions were similar in comparable patient populations (Figure 1).

CARDIAC FAILURE REVIEW

SGLT2 inhibitors in Heart Failure Figure 2: Number and Clinical Categorisation of Patients With Prior HF in Large-scale Randomised Controlled Trials of SGLT2 Inhibitors Study results pending SGLT2 inhibitor investigated Empagliflozin Dapagliflozin

Diabetes status T2D only

Mixed

HFrEF

HF subtype

Mixed CANVAS n=1,461

Non-T2D only

EMPERORReduced n=3,730

DAPA-HF n=4,744

DECLARE-TIMI 58 n=1,724

Canagliflozin Sotagliflozin

EMPA-REG OUTCOME n=706 CREDENCE n=652

SOLOIST-WHF* n=4,000

HFpEF

EMPERORPreserved n=5,988

DELIVER n=6,100

Each n is the number of patients with reported prior diagnosis of HF within each trial. *SOLOIST-WHF trial was terminated early due to financial concerns; data from the final analysis is pending. HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; SGLT2 = sodium–glucose co-transporter 2; T2D = type 2 diabetes. Source: Zinman et al. 2015,13 Neal et al. 2017,14 Wiviott et al. 2019,15 Perkovic et al. 2019,16 McMurray et al. 2019,8 NCT03057977, NCT03521934, NCT03057951 and NCT03619213.

Subgroup analyses of EMPA-REG OUTCOME and DECLARE-TIMI 58 demonstrated consistent benefit on the composite of hospitalisation for HF or CV death, irrespective of baseline HF status.15,18 Results from an equivalent analysis of the CANVAS programme suggested that the benefit of canagliflozin on the composite of hospitalisation for HF and CV death may have been more pronounced in those with a prior history of HF compared with those without (p interaction = 0.021). However, all other outcomes were similar between the subgroups (Figure 2).19 A meta-analysis of EMPA-REG OUTCOME, DECLARE-TIMI 58 and the CANVAS programme reported similar benefits for patients with and without a history of HF, with low heterogeneity between interventions.12

SGLT2 Inhibitors in Patients with HFrEF Limited additional post-hoc analyses provided more insights on the impact of SGLT2 inhibitors by HF subtype. An analysis of the CANVAS programme found that canagliflozin reduced the overall risk of HFrEF (ejection fraction <50%) events leading to hospitalisation or death (HR 0.69; 95% CI [0.48–1.00]).20 Ejection fraction classification for patients with a history of HF was not required at baseline within the CANVAS programme, and this analysis was not restricted to those with a history of HF, resulting in a limited application of these results for those with a history of HF specifically.20 A post-hoc analysis of DECLARE-TIMI 58, which collected more complete baseline data, found a 36% risk reduction for hospitalisation for HF, a 45% risk reduction for CV death and a 51% risk reduction in all-cause death in patients with a history of

CARDIAC FAILURE REVIEW

HFrEF (known ejection fraction <45%).21 These subgroup analyses, although suggestive of the potential benefits of SGLT2 inhibitors for patients with HFrEF, are difficult to interpret owing to low patient numbers: only 10–14% of patients reported prior HF at baseline across the SGLT2 inhibitor CVOTs.13–15 Additionally, as well as the limitation of incomplete classification of HF subtypes, these trials only included patients with T2D (Figure 2).20,21 Dedicated studies were needed to confirm the signals observed in SGLT2 inhibitor CVOTs and to investigate whether these benefits extend to patients with HF without T2D.

The DAPA-HF Trial DAPA-HF was the first outcomes trial of an SGLT2 inhibitor to investigate the treatment of HF in patients with HFrEF with and without T2D.8 DAPA-HF was a multicentre Phase III placebo-controlled clinical trial in 4,744 patients with New York Heart Association class II, III or IV HF and ejection fraction ≤40%. Patients were required to have a plasma level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥600 pg/ml (≥400 pg/ml if they had been hospitalised for HF within the previous 12 months and ≥900 pg/ml if they had AF or atrial flutter on baseline ECG). Exclusion criteria were recent treatment with, or intolerance to, an SGLT2 inhibitor, type 1 diabetes, systolic blood pressure <95 mmHg, an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2, or rapidly declining renal function. Patients received dapagliflozin 10 mg once daily or placebo, and were required to receive standard bestpractice HF device and drug therapy, including an ACE inhibitor, an ARB, or sacubitril–valsartan plus a beta-blocker, unless contraindicated.8

Treatment Table 1: Summary of Heart Failure Outcomes in SGLT2 Inhibitor Clinical Studies

Outcome

Meta-analysis of SGLT2 Inhibitors in T2D CVOTs (Empagliflozin, Canagliflozin and Dapagliflozin)17

DAPA-HF (Dapagliflozin)8

EMPEROR-Reduced (Empagliflozin)9

Overall Population (n=38,723)

History of HF (n=4,543)

HFrEF (n=4,744)

HFrEF (n=3,700)

HHF

HHF and CV death

HHF

0.68 (95% CI [0.60–0.76]; p<0.001)

0.69 (95% CI [0.57–0.83]; p<0.001)

0.70 (95% CI [0.59–0.83]; p<0.001)

0.70 (95% CI [0.58–0.85]; p<0.001)

HHF and CV death

0.76 (95% CI [0.63–0.84]; p<0.001)

0.73 (95% CI [0.63–0.84]; p<0.001)

0.74 (95% CI [0.65–0.85]; p<0.001)

0.75 (95% CI [0.65–0.86]; p<0.001)

Relative risk reduction (%)

CV = cardiovascular; CVOT = cardiovascular outcomes trial; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HHF = hospitalisation for heart failure; SGLT2 = sodium– glucose co-transporter 2; T2D = type 2 diabetes. Source: Arnott et al. 2020,17 McMurray et al. 20198 and Packer et al. 2020.9

At baseline, 45% of patients had T2D and 55% did not. Baseline therapies were similar between groups, with 93.4% and 93.5% receiving a diuretic, 71.5% and 70.6% receiving MRAs, 56.1% receiving an ACE inhibitor, 28.4% and 26.7% receiving an ARB, 10.5% and 10.9% receiving sacubitril–valsartan, and 96.0% and 96.2% receiving a beta-blocker, for dapagliflozin and placebo groups, respectively. The majority of patients were men (76.2% in the dapagliflozin group and 77% in the placebo group).8 Mean eGFR was 66.0 ml/min/1.73m2 in the dapagliflozin group and 65.5 ml/min/1.73m2 in the placebo group at baseline. The primary outcome was a composite of worsening HF (hospitalisation or an urgent visit resulting in IV therapy for HF) or CV death. Over a median of 18.2 months, the primary outcome occurred in 386 out of 2,373 patients (16.3%) in the dapagliflozin group and in 502 out of 2,371 patients (21.2%) in the placebo group (HR 0.74; 95% CI [0.65–0.85]; p<0.001). Death from CV causes occurred in 9.6% of the dapagliflozin group and in 11.5% of the placebo group (HR 0.82; 95% CI [0.69–0.98]). During the trial period, the number of patients needed to treat to prevent one primary event was 21 (95% CI [15–38]). Hospitalisation for HF occurred in 9.7% of the dapagliflozin group and in 13.4% of the placebo group (HR 0.70; 95% CI [0.59–0.83]; p<0.001; Table 1).8 Both first and recurrent hospitalisations for HF were significantly reduced in the dapagliflozin group compared with placebo.22 The incidence of the secondary composite outcome of hospitalisation for HF or death from CV causes was also lower in the dapagliflozin group than in the placebo group (567 events versus 742 events, HR 0.74; 95% CI [0.65– 0.85]; p<0.001; Table 1). In addition, there was a 17% reduction in allcause mortality (HR 0.83; 95% CI [0.71–0.97]) in the dapagliflozin arm of DAPA-HF compared to placebo.8 A 29% reduction in the worsening of renal function, which was not statistically significant (HR 0.71; 95% CI [0.44–1.16]), was also observed in the dapagliflozin arm.8 Overall numbers of renal progression events were low in DAPA-HF, with 40.6% of patients having impaired renal function (eGFR between ≥30 ml/min/1.73m2 and <60 ml/min/1.73m2), but the relative reduction observed in the dapagliflozin arm was similar to renal composite results for patients with T2D from DECLARE-TIMI 58.15 Moreover, recent results from DAPA-CKD, the first dedicated renal outcomes trial assessing the efficacy and safety of an SGLT2 inhibitor in patients with chronic kidney disease with and without T2D, supported the renoprotective effects of dapagliflozin in patients with impaired renal function (eGFR ≥25 ml/min/1.73 m2 and ≤75 ml/min/1.73 m2).

Dapagliflozin treatment was associated with a 39% reduction in renal function decline (HR 0.61; 95% CI [0.51–0.72]; p<0.001) and a 31% reduction in all-cause death (HR 0.69; 95% CI [0.53–0.88]; p=0.004) compared to placebo in this patient population.23 Subgroup analyses from DAPA-HF, both prespecified and post-hoc, demonstrated similar effects of dapagliflozin compared with placebo regardless of diuretic, MRA or ARNI use in patients who received ≥50% of target ACE inhibitor/ARB or beta-blocker dose as well as those who did not, suggesting that treatment with dapagliflozin is beneficial regardless of baseline HFrEF therapy.24 Similar treatment benefits of dapagliflozin over placebo were also observed, irrespective of the underlying cause of HF, baseline renal function (eGFR <60 ml/min/1.73m2 versus eGFR ≥60 ml/min/1.73 m2),8 systolic blood pressure,8,25 BMI,8,26 or NT-pro-BNP concentration.27 Dapagliflozin was also found to reduce the risk of death and worsening HF and to improve symptoms across a broad spectrum of age (range 22–94 years; mean age 66.3 years [SD 10.9]).28 In addition to major clinical events, DAPA-HF also used the Kansas City Cardiomyopathy Questionnaire (KCCQ) patient-reported outcome measure to assess HF symptom burden from the patients’ perspective. A clinically meaningful ≥5-point improvement from baseline to 8 months was reported in 58.3% of dapagliflozin-treated patients versus 50.9% of placebo-treated patients (OR 1.15; 95% CI [1.08–1.23]; p<0.001). The number needed to treat for one patient experiencing a ≥5-point KCCQ improvement was 14.8 Moderate (≥10 points) and large (≥15 points) improvements were also more likely in the dapagliflozin group compared with placebo (OR 1.15; 95% CI [1.08–1.22] and OR 1.14; 95% CI [1.08–1.22], respectively).29 There was also less deterioration in KCCQ score from baseline to 8 months in the dapagliflozin group than in the placebo group (25.3% and 32.9%, respectively; OR 0.84; 95% CI [0.78–0.90]; p<0.001).8 A recent post-hoc analysis also demonstrated that dapagliflozin reduced CV death and worsening HF across the range of baseline KCCQ scores (p heterogeneity = 0.52).29 Dapagliflozin was well tolerated and the rate of treatment discontinuation was low. The rates of serious adverse events related to volume depletion were slightly lower in the dapagliflozin group compared with placebo (1.2% and 1.7%, respectively; p=0.23), and the rate of serious renal adverse events was significantly lower in dapagliflozin-treated patients than those receiving placebo (1.6% and 2.7%, respectively; p=0.009).8 There had been concern that the use of dapagliflozin might lead to

CARDIAC FAILURE REVIEW

SGLT2 inhibitors in Heart Failure hypoglycaemia in patients without T2D. However, major hypoglycaemic episodes were extremely rare and equal (0.2%) in both the dapagliflozin and placebo groups.8 There were no issues with ketoacidosis and no other significant safety concerns were reported,8 even in elderly individuals.28 Unlike other SGLT2 inhibitors, dapagliflozin did not increase the risk of fractures or amputations.

Effect of Dapagliflozin in HFrEF Patients with and without Type 2 Diabetes At baseline, 42% of patients in DAPA-HF had T2D, and an additional 3% received a new diagnosis of T2D during the course of the trial, resulting in a total of 2,139 (45%) patients with T2D.8 The reduction in the rate of the primary outcome was very similar between patients with T2D at baseline (HR 0.75; 95% CI [0.63–0.90]) and those without T2D at baseline (HR 0.73; 95% CI [0.60–0.88]), although the overall risk of events was higher in the T2D group, as expected.8,30 Similar benefits were observed across secondary outcomes, including risk reductions of total hospitalisation for HF and CV death of 23% (HR 0.77; 95% CI [0.63–0.94]) for patients with baseline T2D, and 27% (HR 0.73; 95% CI [0.59–0.91]) for those without T2D at baseline for dapagliflozin compared with placebo.30

The DEFINE-HF Trial The Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF) was a small trial of 263 patients with HFrEF, eGFR ≥30 ml/min/1.73m2 and elevated natriuretic peptides.31 Patients were randomised to receive either 10 mg dapagliflozin or placebo in addition to optimal medical therapy for 12 weeks. The dual primary outcomes were mean NT-proBNP and the proportion of patients with ≥5-point increase in the KCCQ Overall Summary Score (KCCQ-OSS) or a ≥20% decrease in NT-proBNP. Although there was no significant difference in average-adjusted NTproBNP at 6 and 12 weeks, more patients in the dapagliflozin group than in the placebo group met the second dual primary outcome of clinically meaningful improvement in quality of life as measured by KCCQ-OSS or a reduction of ≥20% in NT-proBNP (61.5% versus 50.4%; p=0.039). This was attributable to both higher proportions of patients with a ≥5-point improvement in KCCQ-OSS (42.9% versus 32.5%; adjusted OR 1.73; 95% CI [0.98–3.05]; p=not significant) and with a ≥20% reduction in NTproBNP (44.0% versus 29.4%; adjusted OR 1.9; 95% CI [1.1–3.3]; p=not significant) by 12 weeks. The results were consistent in patients with and without T2D, and across other prespecified subgroups including gender, baseline left ventricular ejection fraction and AF.31

and placebo groups, respectively). Baseline therapies were similar between treatment groups; 70.5% and 68.0% received an ACE inhibitor or ARB, 18.3% and 20.7% received sacubitril–valsartan in the empagliflozin and placebo groups, respectively, while 94.7% in each group received a beta-blocker.9 The primary endpoint was a time-to-first-event analysis of the combined risk of CV death and hospitalisation for HF. After a median of 16 months, the primary outcome occurred in 361 of 1,863 patients (19.4%) in the empagliflozin group and in 462 of 1,867 patients (24.7%) in the placebo group (HR 0.75; 95% CI [0.65–0.86]; p<0.001; Table 1).9 This was primarily driven by reduced rates of hospitalisation for HF in the empagliflozin group (HR 0.70; 95% CI [0.58–0.85]; p<0.001; Table 1) and the trial failed to demonstrate a significant reduction in CV death (HR 0.92; 95% CI [0.75–1.12]) compared to placebo.9 There was also a significant reduction in the rate of renal disease progression, as measured by eGFR slope over time, in the empagliflozin group compared to patients receiving placebo (–0.55 versus –2.28 ml/min/1.73m2 per year; absolute difference 1.73 ml/min/1.73m2 per year; 95% CI [1.10–2.37]; p<0.001).9 Unlike dapagliflozin in DAPA-HF, empagliflozin failed to demonstrate efficacy in terms of quality of life as measured using KCCQ.9 Also, empagliflozin did not affect all-cause mortality (HR 0.92; 95% CI [0.77–1.10]).9,13 Subgroup analyses demonstrated similar effects of empagliflozin on the primary endpoint irrespective of baseline diabetes status (HR 0.72; 95% CI [0.60–0.87] with diabetes; HR 0.78; 95% CI [0.64–0.97] without diabetes).9 Comparable treatment benefits of empagliflozin over placebo were also observed regardless of MRA or ARNI use, underlying cause of HF, or baseline renal function.9 The adverse events profile for empagliflozin was similar to that reported in previous studies.9,13 The overall rates of adverse events and serious adverse events were lower in the empagliflozin group compared to the placebo group, with only genital infections reported substantially more frequently in the empagliflozin group (1.7%) compared to the placebo group (0.6%).9 As in DAPA-HF, hypoglycaemic episodes of any severity were infrequent and rates were similar between treatment groups (1.4% versus 1.5% in empagliflozin and placebo groups, respectively).9 No cases of ketoacidosis were recorded. Although rates of fractures and amputations were slightly more frequent in the empagliflozin group compared to placebo (2.4% versus 2.3% and 0.7% versus 0.5%, respectively), the differences were not statistically significant.9

The EMPEROR-Reduced Trial Results from the EMPEROR-Reduced Phase III, placebo-controlled study (NCT03057977), which involved 3,730 patients with class II, III or IV HF with ejection fraction ≤40% randomised to placebo or empagliflozin 10 mg daily, added to guideline-directed medical therapy (ACE inhibitors/ARBs/ARNIs, beta‐blockers and MRAs), were recently published.9 Plasma NT-proBNP level required for enrolment was dependent on ejection fraction at baseline; ≥600 pg/ml for patients with ejection fraction ≤30%, ≥1,000 pg/ml for patients with ejection fraction 31–35%, and ≥2,500 pg/ml for patients with ejection fraction 36–<40% (NT-proBNP threshold was doubled for patients with AF). Exclusion criteria included recent treatment with, or intolerance to, an SGLT2 inhibitor, systolic blood pressure ≥180 mmHg or <100 mmHg, eGFR <20 ml/min/1.73m2, and impaired renal function requiring dialysis. Approximately half of patients had diabetes at baseline (49.8%), and the majority of patients were men (76.5% and 75.6% in empagliflozin

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The EMPERIAL-Reduced Trial The Empagliflozin Compared With Placebo On Exercise Ability and Heart Failure Symptoms, in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPERIAL-Reduced; NCT03448419) study investigated the impact of empagliflozin on exercise capacity in 312 patients with HFrEF over 12 weeks.32 The trial did not meet its primary endpoint, the 6-minute walk test, with no significant differences reported between the empagliflozin and placebo arms. Initial reports outlined substantial improvements in KCCQ total symptom score in the empagliflozin group compared to placebo.33 However, the results are yet to be published in full.

Recent Trials of SGLT2 Inhibitors in HFrEF with Results Pending Data are still awaited from some recently completed trials of SGLT2 inhibitors treating patients with HFrEF. Dapagliflozin Effect on Exercise

Treatment Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Reduced Ejection Fraction (DETERMINE-reduced; NCT03877237), investigating the impact of dapagliflozin compared to placebo on exercise capacity and quality of life in 313 patients with HFrEF, completed in March 2020 with results pending. The co-primary endpoints of this study were KCCQ total symptom score, the KCCQ physical limitation score and 6-minute walk test following 16 weeks of treatment. In addition, the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF; NCT03521934) trial targeted 4,000 patients with T2D and HFrEF or HFpEF in the immediate post-hospitalisation setting. In May 2020, the study was discontinued early because of financial concerns. Sotagliflozin is a dual SGLT1/SGLT2 inhibitor and thus differs slightly from the SGLT2 inhibitors studied to date.34 Despite the early closure, it is still anticipated that results from the trial will be made available, and it will be interesting to see whether the safety and efficacy of this drug replicate those observed for dapagliflozin and empagliflozin.

SGLT2 Inhibitors in Patients with HFpEF A post-hoc subgroup analysis of the CANVAS programme suggested that canagliflozin may reduce the rates of HFpEF (ejection fraction ≥50%) hospitalisation or mortality events (HR 0.83; 95% CI [0.55–1.25]).20 However, the subgroup analysis did not achieve statistical significance because the study was not powered to detect such a difference in this small subpopulation (<1% of the overall study population).20 A post-hoc subgroup analysis of patients with known HFpEF at baseline in the DECLARE-TIMI 58 study also found a signal for reduced risk of hospitalisation for HF in this study population (HR 0.74; 95% CI [0.48– 1.14]), but not for CV death (HR 1.44; 95% CI [0.83–2.49]).21 Again, only 4.7% of the total trial population of DECLARE-TIMI 58 had a documented history of HFpEF; therefore, these results should be interpreted with caution.21 The Empagliflozin Compared With Placebo on Exercise Ability and Heart Failure Symptoms, In Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPERIAL-Preserved; NCT03448406) trial investigated the impact of empagliflozin on exercise capacity in 312 patients with HFpEF, however, found no significant difference between the empagliflozin and placebo groups in terms of 6-minute walk test or KCCQ total symptom scores after 12 weeks.33 Two major trials of SGLT2 inhibitors in patients with HFpEF are currently on-going (Figure 2). The Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPERORPreserved; NCT03057951) trial will follow a similar study design to the EMPEROR-Reduced trial and has randomised 5,988 patients with HFpEF to empagliflozin or placebo.35 The study is due to be completed in 2020. The Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER; NCT03619213) trial is aiming to recruit 6,100 patients with HFpEF, who will be randomised to dapagliflozin or placebo in addition to current standard therapy. The study is due to be completed in mid-2021. In addition, Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Preserved Ejection Fraction (DETERMINE-Preserved; NCT03877224), a randomised controlled trial investigating the impact of dapagliflozin compared with placebo on exercise capacity and quality of life in 504 patients with HFpEF, is anticipated to complete in 2020, and the recently discontinued SOLOIST-WHF trial of the dual SGLT1/ SGLT2 inhibitor sotagliflozin included both patients with HFpEF and those with HFrEF, and may still provide some insights if sufficient data were collected.

Many aspects of HFpEF diagnosis and treatment remain unresolved. The HFpEF umbrella describes a population of patients that are very heterogeneous, and though there is overlap between the causes and risk factors for HFrEF and HFpEF, the pathophysiologies of these two subtypes are very distinct.36 It is hoped that the SGLT2 inhibitors will succeed where other drugs have failed, and the on-going trial results are widely anticipated.

Mechanism of SGLT2 Inhibitors in CVD Although originally investigated as agents for glucose management, SGLT2 inhibitors are now recognised to impact a wider range of systems, primarily in the cardio–renal axis, many of which are independent of glycaemic control.37–39 The SGLT2 channel is primarily located in the proximal tubule of the kidney, where the majority of glucose reabsorption takes place.40 It has been postulated that the mechanisms underlying SGLT2 inhibitor-associated CV benefits could include improvements in ventricular load through the effect on natriuresis and osmotic diuresis (Figure 3).37–39 SGLT2 inhibitors have a profound effect on haemodynamics. Unlike diuretics, they do not deplete intravascular volume, but instead reduce interstitial volume.40 Optimised ventricular loading conditions, through reduction in preload and afterload, result in a lowering of blood pressure, improved endothelial function, and reduced vascular stiffness.40 It has also been suggested that SGLT2 inhibitors may improve cardiac metabolism and bioenergetics. The utilisation of both glucose and fatty acids is believed to be inefficient in the hearts of patients with HF and T2D. SGLT2 inhibition shifts metabolism towards the oxidation of ketone bodies, which has been shown to be associated with myocardial benefits.41 Preliminary in-vitro studies have also explored the role of SGLT2 inhibitors in ion exchange, cardiac remodelling and their influence on adipokine expression, cytokine production, and epicardial adipose tissue mass.40 Downstream myocardial Na+/H+ exchange inhibition has been shown to lead to lower levels of sodium and thus lower levels of calcium in cardiomyocytes, which improve contractility and mitochondrial function.40,42 The efficacy of dapagliflozin and empagliflozin in patients with HFrEF irrespective of T2D status has challenged our assumptions about the dominant mechanisms of action of SGLT2 inhibitors.43 Several relevant studies investigating the impact of SGLT2 inhibitors are currently underway or have recently been completed, including mechanistic studies of empagliflozin and dapagliflozin. The empagliflozin studies include: Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction (EMPIRE-HF; NCT03198585),44 A Study That Looks at the Function of the Heart in Patients With Heart Failure Who Take Empagliflozin (EMPA-VISION; NCT03332212), and Empagliflozin Impact on Hemodynamics in Patients With Heart Failure (EMBRACE-HF; NCT03030222). For dapagliflozin the studies include: Dapagliflozin in PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF; NCT03030235), A Clinical Study to Investigate the Effects of Dapagliflozin on Heart Work, Heart Nutrient Uptake, and Heart Muscle Efficiency in Type 2 Diabetes Patients (DAPACARD; NCT03387683),45 Study to Evaluate Average 24-hr Sodium Excretion During Dapagliflozin Treatment in Patients With Type 2 Diabetes Mellitus With Preserved or Impaired Renal Function or Non-diabetics With Impaired Renal Function (DAPASALT; NCT03152084) and Effects of 5 Weeks Treatment With Dapagliflozin in Type 2 Diabetes Patients on How the Hormone Insulin Acts on Sugar Uptake in Muscles (DAPAMAAST; NCT03338855). These studies are investigating the effect of SGLT2 inhibition on cardiac biomarkers, cardiac function, cardiac haemodynamics and

CARDIAC FAILURE REVIEW

SGLT2 inhibitors in Heart Failure Figure 3: Proposed Mechanism of Cardiovascular Benefits of SGLT2 Inhibitors SGLT2 inhibition and cardiorenal protection (benefits independent of HbA1c, BP, weight, eGFR) Afferent arteriole

Normal ↑ATP Direct effects on NHE

Potential mechanisms

Efferent arteriole

↓ Myocardial energetics

↓ Beta-hydroxybutyrate (ketone body)

Afferent arteriolar dilatation ↑Intraglomerular pressure ↑Na+/glucose co-transport

Adipokines

• Myocardial energetics and metabolomics

EAT ↓ Afterload

Fibrosis

• Improve ventricular loading conditions: - Diuresis - Natriuresis - Afterload reduction

SGLT2 inhibitors cause afferent arteriolar constriction

↓ LV wall stress

• Direct effects on myocardium • TGF and reduction in IGH

Diuresis, natriuresis glycosuria, ↓ proteinuria

↓ Preload

ATP = adenosine triphosphate; BP = blood pressure; EAT = epicardial adipose tissue; eGFR = estimated glomerular filtration rate; IGH = intraglomerular hypertension; LV = left ventricular; NHE = sodium-hydrogen exchanger; SGLT2 = sodium–glucose co-transporter 2; TGF = tubuloglomerular feedback. Source: Verma et al. 2017.37 Adapted with permission from the American Medical Association.

Figure 4: Proposed Modification to the Therapeutic Algorithm for a Patient with Symptomatic Heart Failure with Reduced Ejection Fraction Following Results From DAPA-HF and EMPEROR-Reduced Class of recommendation Class I Class IIa

Patient with symptomatic HFrEF*

Update following DAPA-HF and EMPEROR-Reduced

Still symptomatic and LVEF ≤35% Add MR antagonist†,‡ Still symptomatic and LVEF ≤35%

Able to tolerate ACEi (or ARB)§

ARNI to replace ACEi

Sinus rhythm QRS duration ≥130 ms

Sinus rhythm, heart rate ≥70 BPM

Evaluate need for CRT

Ivabradine

Add SGLT2 inhibitor||

Diuretics to relieve symptoms and signs of congestion

ACEi (or ARB) and beta-blocker†

If resistance symptoms, consider digoxin or H-ISDN or LVAD or heart transplantation Green indicates a class I recommendation; orange indicates a class IIa recommendation; blue indicates the suggested revision to the algorithm based on recent DAPA-HF trial results. * NYHA class II–IV, LVEF <40%; †Up-titrate to maximum tolerated evidence-based dose; ‡With a hospital admission for HF within the last 6 months or with elevated natriuretic peptides (BNP >250 pg/ml or NT-proBNP >500 pg/ml in men and 750 pg/ml in women); §With an elevated plasma natriuretic peptide level (BNP ≥150 pg/ml or plasma NT-proBNP ≥600 pg/ml, or if HF hospitalisation within 12 months plasma BNP ≥100 pg/ml or plasma NT-proBNP ≥400 pg/ml); ||Dapagliflozin is the only SGLT2 inhibitor that has demonstrated significant and clinically meaningful reductions in both the CV deaths and worsening HF components of the primary composite endpoint in patients with HFrEF, both with and without T2D. ACEi = angiotensinconverting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BNP = B-type natriuretic peptide; CRT = cardiac resynchronisation therapy; H-ISDN = hydralazine and isosorbide dinitrate; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MR = mineralocorticoid receptor; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; SGLT2 = sodium–glucose co-transporter 2. Source: Ponikowski et al. 2016.46 Reproduced with permission from Oxford University Press.

metabolism.44 The outcomes of this research will enable us to better understand how the mechanism of action of SGLT2 inhibitors directly influences HF outcomes in the clinical setting.

Updating Clinical Guidelines

HFrEF and HFpEF patients. SGLT2 inhibitors have been confirmed as a new disease-modifying class of drug for the prevention of HF.12 Accumulating evidence also suggests that SGLT2 inhibitors induce combined cardiac and renal beneficial effects in patients with HFrEF, and potentially HFpEF.8,9,12,23,37–41

The importance of prevention of symptomatic HF will be a key consideration in current guidelines. There has also been recognition of the unmet need for disease‐modifying therapies that have an immediate impact on patient well‐being without dose‐limiting side-effects in both

The 2016 European Society of Cardiology (ESC) guidelines stated that empagliflozin should be considered in patients with T2D in order to prevent or delay the onset of HF (class of recommendation IIa, level of

CARDIAC FAILURE REVIEW

Treatment evidence B).46 In 2019, prior to the availability of results from DAPA-HF, the ESC updated its guidelines on diabetes, prediabetes and CVD, and recommended that canagliflozin, dapagliflozin or empagliflozin should be considered in patients with T2D and CVD, or those at very high/high CV risk, to reduce CV events (class of recommendation Ia).47 Empagliflozin was also recommended in patients with T2D and CVD to reduce the risk of death (class of recommendation Ia) and all SGLT2 inhibitors were recommended in patients with T2D to lower the risk of hospitalisation for HF (class of recommendation Ia).47 An ESC/Heart Failure Association (HFA) position paper published in 2019 stated that, because the three SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) have consistently demonstrated a substantial reduction in the risk of hospitalisation for HF across the spectrum of CV risk and regardless of a history of HF, they should be recommended to prevent hospitalisation for HF in patients with T2D and high CV risk.48 More recently, an ESC/HFA position paper on the role of SGLT2 inhibitor in the treatment of HF has clearly stated that these drugs should be used in all patients with HFrEF as soon as possible on top or together with class Ia recommended medications (beta-blockers, ACE inhibitors/ ARBs and MRAs) and also on top of sacubitril/valsartan. The clear and significant impact of dapagliflozin on cardiovascular and total mortality in addition to the significant reduction in hospitalisation for HF suggest this drug is the SGLT2 inhibitor of choice in patients with HFrEF. Therefore, the initiation of dapagliflozin should be pursued in all patients with HFrEF regardless of their background therapy at any stage of the disease (Figure 4).49

Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol 2016;13:368–78. https://doi.org/10.1038/ nrcardio.2016.25; PMID: 26935038. 2. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 19902010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163–96. https://doi.org/10.1016/ S0140-6736(12)61729-2; PMID: 23245607. 3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:e240–327. https://doi.org/10.1161/ CIR.0b013e31829e8776; PMID: 23741058. 4. Andronic AA, Mihaila S, Cinteza M. Heart Failure with midrange ejection fraction – a new category of heart failure or still a gray zone. Maedica (Bucur) 2016;11:320–4. PMID: 28828050. 5. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. https://doi.org/10.1056/NEJMoa1409077; PMID: 25176015. 6. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin– neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–20. https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794. 7. US Food and Drug Administration. FDA approves new treatment for a type of heart failure. FDA. 5 May 2020. https:// www.fda.gov/news-events/press-announcements/fdaapproves-new-treatment-type-heart-failure (accessed 3 November 2020). 8. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829. 9. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377. 10. Einarson TR, Acs A, Ludwig C, et al. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol 2018;17:83. https://doi. org/10.1186/s12933-018-0728-6; PMID: 29884191. 11. Eckel RH, Farooki A, Henry RR, et al. Cardiovascular outcome trials in type 2 diabetes: what do they mean for clinical practice? Clin Diabetes 2019:37:316–37. https://doi.org/10.2337/ cd19-0001; PMID: 31660005. 12. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal

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Conclusion The results from the DAPA-HF and EMPEROR-Reduced trials represent a completely new approach to HF management, strengthening the rationale for the use of SGLT2 inhibitors in patients with HFrEF, which will impact future clinical practice. These results establish a new standard of care in HFrEF consisting of four branches: ACE inhibitors/ ARBs/ARNIs, beta-blockers, MRAs, and SGLT2 inhibitors, with these four agents being used together to reduce mortality and morbidity and to slow the progression of the disease. Dapagliflozin is the only SGLT2 inhibitor to demonstrate a significant and clinically meaningful reduction in both the CV death and worsening HF components of the primary composite endpoint in patients with HFrEF, both with and without T2D. Therefore, dapagliflozin should be the agent of choice in all patients with HFrEF, irrespective of their current HFrEF treatment, as well as in those with T2D at increased risk of developing HF. Subgroup analyses suggest the addition of dapagliflozin following recommended first-line ACE inhibitors/ARBs is beneficial whether ACE inhibitor/ARB dosing is optimal or not, therefore dapagliflozin can be added to therapy at any point following HFrEF diagnosis. The reported renoprotective impact of dapagliflozin extends its use to the many patients with HFrEF who have impaired renal function, patients with chronic kidney disease with HFrEF and those at risk of developing it. Further on-going studies will also determine whether these results can be observed in patients with HFpEF, for whom there are currently no therapies that clearly improve outcomes.

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Letter to the Editor

Acute Heart Failure in Coronavirus Disease 2019 and the Management of Comedications Chia Siang Kow1 and Syed Shahzad Hasan2,3 1. School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia; 2. Department of Pharmacy, University of Huddersfield, Huddersfield, UK; 3. School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan, Australia

Disclosure: The authors have no conflicts of interest to declare. Received: 23 September 2020 Accepted: 4 October 2020 Citation: Cardiac Failure Review 2020;6:e32. DOI: https://doi.org/10.15420/cfr.2020.24 Correspondence: Chia Siang Kow, International Medical University, 126, Jln Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia. E: chiasiang_93@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Dear Editor,

professional cardiology societies, extreme caution should be taken in COVID-19 patients who develop acute heart failure.1

We read, with great interest, the review article written by Oliveros et al. entitled ‘Coronavirus Disease 2019 and Heart Failure: A Multiparametric Approach’, which comprehensively summarises the clinical characteristics of cardiovascular complications associated with coronavirus disease 2019 (COVID-19) and the use of telehealth in patients with heart failure.1 This review should be highly valued considering that the rather high prevalence of cardiovascular comorbidities, including heart failure, among patients with COVID-19 is now recognised. Individuals with underlying cardiovascular conditions are at increased risk of myocardial injury associated with COVID-19, as reported previously, possibly due to reduced cardiorespiratory reserves.2 We would like to complement the discussion of Oliveros et al. on acute heart failure and the use of renin–angiotensin system (RAS) inhibitors.1 Acute heart failure represents a common cardiovascular complication of COVID-19, which may be precipitated by acute illness in patients with pre-existing known or undiagnosed heart disease or incident acute myocardial injury. Although Oliveros et al. are correct to suggest that routine antihypertensive therapy including RAS inhibitors should not be altered in the context of COVID-19 by citing recommendations from several

Oliveros E, Brailovsky Y, Scully P, et al. Coronavirus disease 2019 and heart failure: a multiparametric approach. Card Fail Rev 2020;6:e22. https://doi.org/10.15420/cfr.2020.09; PMID: 32944292. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802–10.

Patients with acute heart failure, regardless of COVID-19 status, often develop hypotension and/or worsening renal function, which are markers for increased activation of the RAS and therefore increased reliance on angiotensin II for blood pressure maintenance.3 Hence, the development of hypotension and/or worsening renal function should prompt dose reduction or even discontinuation of RAS inhibitors, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. In fact, hypotension following the administration of these agents may be prolonged, given the long effective half-lives of most of these agents.4,5 As acute heart failure can be common in COVID-19 patients with cardiovascular comorbidities, it is important to pay attention to the medications prescribed to these patients for their cardiovascular conditions. The use of other common concomitant medications, such as beta-blockers, also requires caution, especially in patients with severe decompensation (severe fluid overload and/or requiring inotropic support), in whom beta-blockers may need to be withheld. At present, with a definite cure for COVID-19 still elusive, individualised management of concomitant medications can be important in preventing a more complicated course of illness, and a one-size-fits-all approach should be discouraged.

https://doi.org/10.1001/jamacardio.2020.0950; PMID: 32211816. Nakada Y, Takahama H, Kanzaki H, et al. The predictability of renin–angiotensin–aldosterone system factors for clinical outcome in patients with acute decompensated heart failure. Heart Vessels 2016;31:925–31. https://doi.org/10.1007/s00380015-0688-7; PMID: 25964073.

Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation 1998;97:1411–20. https://doi. org/10.1161/01.CIR.97.14.1411; PMID: 9577953. Burnier M. Telmisartan: a different angiotensin II receptor blocker protecting a different population? J Int Med Res 2009;37:1662–79. https://doi. org/10.1177/147323000903700602; PMID: 20146864.

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