CFR 5,3 by Radcliffe Cardiology

©Radcliffe Cardiology

Volume 5 • Issue 3 • Winter 2019

www.CFRjournal.com

Sodium–Glucose Cotransporter-2 Inhibitors and Heart Failure Prevention in Type 2 Diabetes Muhammad Shahzeb Khan and Javed Butler

Hyperkalemia and Renin–Angiotensin–Aldosterone System Inhibitors Dose Therapy in Heart Failure With Reduced Ejection Fraction Giuseppe MC Rosano, Ilaria Spoletini, Cristiana Vitale and Stefan Agewall

Inotropes in Acute Heart Failure: From Guidelines to Practical Use: Therapeutic Options and Clinical Practice Vasiliki Bistola, Angelos Arfaras-Melainis, Eftihia Polyzogopoulou, Ignatios Ikonomidis and John Parissis

State-of-the-art Structural Interventions in Heart Failure Jeffrey Park and Hussam S Suradi

Left ventricular assist device attached to the left ventricle of the heart and the aorta

Intra-operative fluoroscopy showing successful placement of MitraClip

Pathophysiology, diagnosis and treatment of right ventricular failure

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Volume 5 • Issue 3 • Winter 2019

www.CFRjournal.com

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

Ohio State University College of Medicine, US

Ali Ahmed

Washington DC VA Medical Center, US

John J Atherton

Royal Brisbane and Women’s Hospital, Australia

Michael Böhm

University of the Saarland in Homburg/Saar in Germany

Francesco Maisano

Charité University Medicine, Germany

University Hospital, Zurich

Finn Gustafsson

Theresa A McDonagh

University of Copenhagen, Denmark

King’s College Hospital, UK

David L Hare

Kenneth McDonald

University of Melbourne, Australia

St Vincent’s Hospital, Ireland

Ileana L Piña

Dipak Kotecha University of Birmingham, UK

Montefiore Einstein Center for Heart and Vascular Care, US

University of Medicine Carol Davila, Romania

Lars H. Lund Karolinska Institutet and Karolinska University Hospital, Sweden

Kian Keong Poh

Alain Cohen-Solal

Carmine De Pasquale

Alexander Lyon

Maurizio Volterrani

Royal Brompton Hospital, UK

IRCCS San Raffaele Pisana, Italy

Ovidiu Chioncel

Paris Diderot University, France Flinders University, Australia

Cover image © stock.adobe.com.

Frank Edelmann

Department of Cardiology, National University Heart Center, Singapore

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Published by Radcliffe Cardiology. 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. © 2019 All rights reserved ISSN: 2057–7540 • eISSN: 2057–7559

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Established: March 2015 | Frequency: Tri-annually | Current issue: Winter 2019

Aims and Scope

Submissions and Instructions to Authors

• Cardiac Failure Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in heart failure. • Cardiac Failure Review comprises 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 continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the Editor-in-Chief with the support of the Editorial Board and Managing Editor. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.CFRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Rosie Scott rosie.scott@radcliffe-group.com • Articles may be submitted directly at www.editorialmanager.com/cfr

Structure and Format • Cardiac Failure Review is a tri-annual journal comprising review articles, expert opinion articles and guest editorials. • 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. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Cardiac Failure Review is available in full online at www.CFRjournal.com

Reprints All articles included in Cardiac Failure Review are available as reprints. Please contact the Sales Director, Rob Barclay rob.barclay@radcliffe-group.com

Distribution and Readership Cardiac Failure Review is distributed tri-annual through controlled circulation to senior healthcare professionals in the field in Europe.

Editorial Expertise

Abstracting and Indexing

Cardiac Failure Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by the Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

CFR is abstracted, indexed and listed in PubMed and Crossref. All articles are published in full on PubMed Central one month after publication.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Open Access, Copyright and Permissions Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/ legalcode). Radcliffe Cardiology retains all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor. To support open access publication costs, Radcliffe Cardiology charge an Article Publication Charge (APC) to authors upon acceptance of an unsolicited paper as follows: £1,050 UK | €1,200 Eurozone | $1,369 all other countries. Waivers are available as specified in the ‘Information for authors’ section on www.CFRjournal.com.

Online All manuscripts published in Cardiac Failure Review are available free to view at www.CFRjournal.com. Also available at www.radcliffecardiology.com are articles from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Interventional Cardiology Review, European Cardiology Review and US Cardiology Review.

Cardiology

Lifelong Learning for Cardiovascular Professionals

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Contents

Foreword Andrew JS Coats and Giuseppe Rosano

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DOI: https://doi.org/10.15420/cfr.2019.5.3.FO1

Clinical Practice Hyperkalemia and Renin–Angiotensin–Aldosterone System Inhibitors Dose Therapy in Heart Failure With Reduced Ejection Fraction

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Giuseppe MC Rosano, Ilaria Spoletini, Cristiana Vitale and Stefan Agewall DOI: https://doi.org/10.15420/cfr.2019.8.2

Inotropes in Acute Heart Failure: From Guidelines to Practical Use: Therapeutic Options and Clinical Practice

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Vasiliki Bistola, Angelos Arfaras-Melainis, Eftihia Polyzogopoulou, Ignatios Ikonomidis and John Parissis DOI: https://doi.org/10.15420/cfr.2019.11.2

Advanced Heart Failure Right Ventricular Failure: Pathophysiology, Diagnosis and Treatment

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Mattia Arrigo, Lars Christian Huber, Stephan Winnik, Fran Mikulicic, Federica Guidetti, Michelle Frank, Andreas J Flammer and Frank Ruschitzka DOI: https://doi.org/10.15420/cfr.2019.15.2

State-of-the-art Structural Interventions in Heart Failure

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Jeffrey Park and Hussam S Suradi DOI: https://doi.org/10.15420/cfr.2019.12.2

Haemodynamic Balance in Acute and Advanced Heart Failure: An Expert Perspective on the Role of Levosimendan

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Piergiuseppe Agostoni, Dimitrios T Farmakis, Jose M García-Pinilla, Veli-Pekka Harjola, Kristjan Karason, Dirk von Lewinski, John Parissis, Piero Pollesello, Gerhard Pölzl, Alejandro Recio-Mayoral, Alexander Reinecke, Patrik Yerly and Endre Zima DOI: https://doi.org/10.15420/cfr.2019.01.R1

Left Ventricular Assist Device Support Complicates the Exercise Physiology of Oxygen Transport and Uptake in Heart Failure

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Erik H Van Iterson DOI: https://doi.org/10.15420/cfr.2019.10.2

Co-morbidities Sodium–Glucose Cotransporter-2 Inhibitors and Heart Failure Prevention in Type 2 Diabetes

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Muhammad Shahzeb Khan and Javed Butler DOI: https://doi.org/10.15420/cfr.2019.06.R1

Why is Iron Deficiency Recognised as an Important Comorbidity in Heart Failure?

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Nicole Ebner and Stephan von Haehling DOI: https://doi.org/10.15420/cfr.2019.9.2

Correspondence Red Cell Volume Distribution Width as Another Biomarker

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Artemio García-Escobar and Juan Manuel Grande Ingelmo DOI: https://doi.org/10.15420/cfr.2019.13.1

Red Cell Distribution Width as a Biomarker for Heart Failure: Still Not Ready for Prime-Time

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Sunil K Nadar and Mohammed Mujtaba Shaikh DOI: https://doi.org/10.15420/cfr.2019.16.1

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Foreword

Andrew JS Coats is the inaugural Joint Academic Vice-President of Monash University, Australia and the University of Warwick, UK and Director of the Monash Warwick Alliance

Giuseppe Rosano is Professor of Pharmacology, Director of the Centre of Clinical and Experimental Medicine at the IRCCS San Raffaele, Italy and Professor of Cardiology and Consultant Cardiologist (Hon) at St George's University of London, UK

t is with great pleasure that we introduce to you to this issue of Cardiac Failure Review. In this issue, we focus on clinical practice research and observations in advanced heart failure, a topic of increasing interest to triallists, innovators and practising physicians alike. We know the prognosis and outlook remains poor for advanced heart failure, especially if the patient is unlikely receive a cardiac transplant, due to a lack of donor organs, but there is much more we may be able to do if some of the new approaches to advanced heart failure therapy establish themselves as being effective in future trials. In this issue, Rosano and colleagues review the interrelated phenomena of low dosing of renin–angiotensin–aldosterone system inhibitor (RAASi) drugs and the perceived risk and dangers of RAASi-induced hyperkalemia. Although RAASi agents are well known to improve outcomes in heart failure with reduced ejection fraction (HFrEF), this has been proven in randomised controlled trials (RCTs) where protocol and processes force the physicians to make multiple attempts to up-titrate the drugs to a target dose. Such prompting rarely happens in real-world practice, so that the eventual doses taken in real life are well below the doses we know are effective from the RCTs. The maximally tolerated dose is a rarity in most registries that have reported, despite being achievable in 50% or more of patients in RCTs. The well-known RAASi side-effect of hyperkalemia often leads to down-titration or even discontinuation of RAASis.1 As Rosano and colleagues explain, this and other complaints that could be linked to RAASi use, such as symptomatic hypotension, syncope, hypoperfusion and reduced kidney function, are often quoted as a reason to reduce or stop RAASi drugs. This RAASi under-dosing is not innocent. It can itself lead to adverse outcomes and increased death rates. Thus, novel ways to manage common RAASi side-effects may allow the use of higher and more effective RAASi dosages in HFrEF. Foremost of these are two newly registered agents to manage hyperkalemia, zirconium cyclosilicate and Patiromer. They conclude that these agents, which have been shown convincingly to be able to control serum potassium in patients with hyperkalemia on RAASis, may in fact help allow RAASi therapies to be used at the effective doses shown from trials. They warn, however, that large-scale clinical trials will be needed to prove safety and resulting outcomes from this approach. Next, the team of John Parissis reviews the use of inotropes in acute heart failure covering what is said in guidelines through to what we know about their use in routine clinical practice. They review the use of inotropic agents (the main ones being beta-receptor agonists, phosphodiesterase 3 inhibitors and calcium sensitisers), which remain indicated to a limited extent to treat the complications of acute decompensated heart failure (ADHF), where hypoperfusion is a clinical problem when due to a decrease in cardiac pumping capacity because of left ventricular systolic dysfunction. As there is no evidence that these agents improve long-term outcomes – in fact, many are associated with a risk of dangerous ventricular arrhythmias – their use is restricted to short periods to allow haemodynamic stabilisation if it cannot be sensibly achieved by other procedures (such as surgery or mechanical circulatory support). Another clinical situation where their use is justifiable is to support patients as a bridge to a more definitive treatment, such as cardiac transplantation or a left ventricular assist device (LVAD). Newer inotropic agents remain under development and there remains an urgent need for a safe, effective and long-term beneficial positive inotropic agent. The most advanced of these is omecamtiv mecarbil, the first cardiac myosin activator, with an intriguing mechanism of action, priming the myosin head, which may be safer than conventional inotropes by being free of significant calcium or cAMP effects.2 A second approach under clinical trial evaluation is that of sarcoplasmic reticulum Ca2+-ATPase (SERCA) 2a modulation, a sarcolemmal membrane-bound enzyme that handles free calcium influx back in the sarcoplasmic reticulum, including via SERCA2a direct gene therapy, although the CUPID II trial with 250 HF patients did not significantly decrease heart failure-related endpoints.3 Ruschitzka and colleagues consider the role of the right ventricle (RV) in heart failure syndromes. They review the distinct and complex anatomy and physiology of the RV and explain how it has been relatively neglected compared to the left ventricle for many years. They discuss the important interactions between preload, contractility, afterload, ventricular interdependence and heart rhythm in assessing RV function. They present a recommended treatment algorithm for acute RV failure that takes you through the steps of diagnosis

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Foreword and identification of the cause of the RV disorder (including the most appropriate imaging techniques to understand the specific pathophysiological mechanisms operative), and then proceeding to optimising the patient’s volume status, restoring perfusion pressures, correcting any contractility deficiency and lastly considering specialist procedures for RV failure, such as inhaled NO, inhaled prostacyclins or the use of mechanical circulatory support. Park and Suradi review the rapidly developing field of structural interventions for heart failure. They explain how, following decades of advances in the pharmacological treatment of heart failure, we are now seeing the emergence of structural heart interventions to improve our heart failure patients with devices and procedures with the potential to improve exercise capacity, quality of life and maybe even survival and outcomes. They consider transcatheter interventions for severe aortic stenosis, including balloon aortic valvuloplasty and transcatheter aortic valve replacement, the latter of which has been demonstrated of increasing clinical value in multiple clinical trials. The article then considers mitral stenosis and mitral and tricuspid regurgitation and the interventional options for their correction. Most recent attention has been given to the possible benefits of correcting functional mitral regurgitation (FMR) secondary to HFrEF. Guideline-directed medical therapy and cardiac resynchronisation therapy may reduce the severity of FMR in some patients, but residual FMR remains a risk factor for increased mortality, spiking interest in percutaneous options for its amelioration. In this regard, there has been considerable interest in the results of the MitraClip procedure. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial recruited patients with HFrEF and moderate-to-severe or severe secondary mitral regurgitation. In this study, MitraClip was associated with a reduced rate of hospitalisation for heart failure and improved all-cause mortality, although neutral results were seen in another study of the same device.4,5 Continuing the theme of the management of advanced and complicated heart failure, Agostoni and colleagues review the role of the calcium sensitiser, levosimendan, in achieving haemodynamic balance in the setting of acute and advanced heart failure. They remind us of the difficult and complicated task of restoring haemodynamic stability and organ perfusion in the setting of ADHF, juggling the use of IV vasodilators and inotropes. Of the inotropic agents, levosimendan, they argue, is best suited to the needs of the patients, for it is free of the increased mortality seen with of the beta-adrenergic receptor agonists and phosphodiesterase 3 inhibitors reviewed earlier by Parissis. The intermittent use of levosimendan in advanced heart failure has received some recent attention. Van Iterson reviews the complex interactions between LVAD support and exercise cardiopulmonary physiology and oxygen transport and uptake in advanced heart failure. We also have excellent reviews of sodium-glucose co-transporter-2 inhibitors and heart failure prevention in type 2 diabetes by Khan and Butler and of iron deficiency and its treatment in heart failure by Ebner and von Haehling. We do hope you enjoy the issue. 1. 2. 3. 4. 5.

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. Teerlink JR. A novel approach to improve cardiac performance: cardiac myosin activators. Heart Fail Rev 2009;14:289–98. https://doi.org/10.1007/s10741-009-9135-0; PMID: 19234787. Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 2016;387:1178–86. https://doi.org/10.1016/S0140-6736(16)00082-9; PMID: 26803443. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med. 2018;379:2297–306. https://doi.org/10.1056/NEJMoa1805374; PMID: 30145927.

DOI: https://doi.org/10.15420/cfr.2019.5.3.FO1

C A R D I A C FA I L U R E R E V I E W

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Clinical Practice

Hyperkalemia and Renin–Angiotensin–Aldosterone System Inhibitors Dose Therapy in Heart Failure With Reduced Ejection Fraction Giuseppe MC Rosano, 1 Ilaria Spoletini, 1 Cristiana Vitale 1 and Stefan Agewall 2 1. Department of Medical Sciences, L’Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy; 2. Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway

Abstract Renin–angiotensin–aldosterone system inhibitors (RAASi) are known to improve outcomes in patients who have heart failure with reduced ejection fraction (HFrEF). To reduce mortality in these patients, RAASi should be uptitrated to the maximally tolerated dose. However, RAASi may also cause hyperkalemia. As a result of this side-effect, doses of RAASi are reduced, discontinued and seldom reinstated. Thus, the therapeutic target needed in these patients is often not reached because of hyperkalemia. Also, submaximal dosing of RAASi may be a result of symptomatic hypotension, syncope, hypoperfusion, reduced kidney function and other factors. The reduction of RAASi dose leads to adverse outcomes, such as an increased risk of mortality. Management of these side-effects is pivotal to maximise the use of RAASi in HFrEF, particularly in high-risk patients.

Keywords Heart failure with reduced ejection fraction, hyperkalemia, RAASi Disclosure: The authors have no conflicts of interest to declare. Received: 19 February 2019 Accepted: 14 May 2019 Citation: Cardiac Failure Review 2019;5(3):130–2. DOI: https://doi.org/10.15420/cfr.2019.8.2 Correspondence: Giuseppe Rosano, Centre for Clinical & Basic Research IRCCS San Raffaele Pisana, via della Pisana, 235, 00163 Rome, Italy. E: giuseppe.rosano@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 non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) affects 1–2% of the population in developed countries and absorbs a significant amount of human and economic resources.1,2 HF is a complex syndrome characterised by a spectrum of symptoms and phenotypes: HF with preserved ejection fraction, HF with midrange ejection fraction and HF with reduced ejection fraction (HFrEF).3 Differentiating patients according to left ventricular ejection fraction (LVEF) is relevant as these syndromes have distinct patterns of underlying aetiologies, demographics, comorbidities and response to therapies.4,5

contraindicated or not tolerated, to reduce mortality and morbidity. Clinical trials provide strong evidence of prognostic benefits for combination therapy with ACEi and beta-blockers in the treatment of HFrEF. In particular, an ACEi is recommended in addition to a betablocker for symptomatic patients with HFrEF to reduce the risk of HF hospitalisation and death. ACEi are also recommended in patients with asymptomatic left ventricular systolic dysfunction to reduce the risk of HF development, HF hospitalisation and death.

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in HFrEF (Figure 1). Its activation has harmful long-term effects, such as water and salt retention, and promotes adverse ventricular remodelling.6 RAAS inhibitors (RAASi) are a group of drugs that act by antagonising the RAAS and include angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs). Therapies that target the RAAS have been shown to reduce both morbidity and mortality in HFrEF patients.7

If ACEi are not tolerated, an ARB is recommended as secondline treatment in symptomatic HFrEF patients. 3 With the same aim – to reduce the risk of HF hospitalisation and death – an MRA is recommended for patients with HFrEF who remain symptomatic despite treatment with an ACEi and a beta-blocker.8 An ARB may be considered in patients who remain symptomatic despite treatment with a beta-blocker and who are unable to tolerate an MRA.3

Renin–Angiotensin–Aldosterone System Inhibition in Heart Failure With Reduced Ejection Fraction According to the latest European Society of Cardiology (ESC) HF guidelines, RAASi are recommended in all symptomatic (New York Heart Association class II–IV) patients with HFrEF.3 ACEi are recommended as first-line treatment in all HFrEF symptomatic patients, unless

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Finally, angiotensin receptor-neprilysin inhibitors (ARNis) – a new class of agent acting on the RAAS and neutral endopeptidase system – have been developed. Among these, LCZ696 combines the moieties of an ARB (valsartan) and a neprilysin inhibitor (sacubitril) and has been found to reduce mortality and several other endpoints in HFrEF.3 Of note, a secondary analysis of the baseline characteristics and treatment of patients in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) showed that hyperkalemia was reduced in patients

Hyperkalemia and RAASi Dose Therapy in HFrEF treated with sacubitril/valsartan compared with enalapril.9 However, the long-term safety of sacubitril/valsartan still needs to be investigated.

Figure 1: Role of Renin–Angiotensin–Aldosterone System and its Inhibitors in Heart Failure with Reduced Ejection Fraction

Uptitration of Renin–Angiotensin–Aldosterone System Inhibitors and Hyperkalemia A systematic review and meta-analysis compared higher versus lower doses of ACEi and ARBs in HFrEF.10 The results suggest that higher doses of ACEi and ARBs reduce the risk of HF worsening compared with lower doses. Higher doses also increase the likelihood of adverse effects compared with lower doses. Uptitration should occur in a gradual manner, starting from low doses – preferably in a controlled setting – to avoid side-effects, as recommended by the ESC guidelines.3 As for ACEi, results from the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial showed that HFrEF patients taking high-dose lisinopril had a significant reduction in risk of death or hospitalisation for any cause and fewer hospitalisations for HF than the low-dose group.11 Thus, uptitration of a RAASi to the maximum tolerated dose to achieve adequate inhibition of the RAAS is pivotal in improving outcomes in HFrEF.7 Similarly, the Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study showed that the ARB losartan at high dose significantly reduced the rate of death or admission for HF and reduced LVEF, compared with low-dose losartan.12 All these findings indicate the value of uptitrating RAASi doses to confer clinical benefit. Unfortunately, uptitration of RAASi is associated with an increased risk of hyperkalemia. For this reason, RAASi are frequently omitted or discontinued in clinical practice. In particular, data from the ESC HF registry reveal that RAASi were frequently underdosed because of persistent and consistent hyperkalemia and/or worsening renal function.13 Hyperkalemia is more often observed when RAASi are administered in combination than when administered individually.14 Of note, a substantial proportion of patients receiving RAASi therapy have their therapy downtitrated or, more often, discontinued even after a single episode of elevated potassium level.7 In a retrospective study, RAASi discontinuation was observed in up to 25% of patients and underdosing of RAASi in about two-thirds of patients.15 Thus, despite their well-known efficacy, most patients receive submaximal doses of RAASi in clinical practice.16,17 RAASi-induced hyperkalemia hinders the use of these drugs, countering their survival benefits.7,13,14 Analyses from Swedish and Danish registries found that hyperkalemia was associated with increased mortality.18,19 Interestingly, increased risks of mortality are similar for patients who received reduced RAASi doses and those who discontinued.20 As such, hyperkalemia is a crucial limitation to fully titrating RAASi, with harmful consequences such as increased risk of worsening HF and mortality.

Management of Hyperkalemia and Implementation of Renin–Angiotensin– Aldosterone System Inhibitors Dosage To avoid these severe outcomes, treatment for lowering potassium levels may be initiated.7 Treatment should be personalised according to the severity of hyperkalemia and other factors such as comorbidities, age and levels of RAASi. According to the ESC expert consensus document, when hyperkalemia develops, it is recommended that patients’ potassium level is lowered to enable them to continue their RAASi therapy.7 The ESC guidelines recommend that if a withdrawal of

C A R D I A C FA I L U R E R E V I E W

RAAS activation

• Water and salt retention • Adverse ventricular remodelling, etc

Inhibition of the RAAS is needed

Failing heart

MRAs not uptitrated, reduced or withdrawn even after a single episode of elevated potassium

• Worsening of HF symptoms and progression • Mortality

Side-effects: hyperkalemia, etc

Management of hyperkalemia

RAASi therapy

Improved outcomes in HFrEF

RAASi downtitration or withdrawal lead to worsening of HF and increased risk of mortality. Management of hyperkalemia improves outcomes in HFrEF. HF = heart failure; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; RAAS = renin–angiotensin–aldosterone system; RAASi = renin–angiotensin–aldosterone system inhibitors.

these drugs is necessary, this should be a short-term cessation only and RAASi should be cautiously re-established as soon as possible while monitoring potassium levels.3 Also, potassium elevations below 5 mmol/l should not lead to RAASi cessation because only an increase above 5.5 mmol/l is harmful.3,21 In this case, only temporary dose reduction should be considered.7 Dose reduction or discontinuation of RAASi is not always needed. Hyperkalemia should be considered as an expected adverse event of RAASi.20 Potassium levels quickly rise after induction of RAASi, but the risk of hyperkalemia is low if potassium level is properly monitored. For this reason, when starting an ACEi or an ARB, close monitoring of potassium, blood pressure and creatinine is recommended.3 Of note, the combination of ACEi or ARBs and MRAs with thiazide diuretics may neutralise the risks of hyperkalemia.7 However, prevention of hyperkalemia remains a controversial issue. Potassium monitoring should be tailored to the individual patient. Patients at high risk of hyperkalemia should undergo potassium measurements initially, at 2 weeks, 1 month and every 3 months thereafter. Patients at low risk of hyperkalemia should undergo testing at 1, 3 and 6 months after the initial event and twice yearly thereafter. In any case, potassium should be measured whenever there is a clinical indication and/or change in medications. Unfortunately, it has been shown that measurements of potassium are not regularly executed in practice.20,22 Quality-improvement programmes are strongly needed to improve rates of laboratory monitoring for patients initiated on RAASi therapy, particularly in high-risk patients.7 RAASi discontinuation and restarting should be planned following an algorithm, as in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).23 In the near future, new potassium binders may help optimise RAASi therapy by allowing uptitration of RAASi dosage.

Conclusion New therapeutic options exist to enhance potassium excretion, such as patiromer and sodium zirconium cyclosilicate (ZS-9), which have been

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Clinical Practice shown in randomised trials to significantly reduce serum potassium in patients with hyperkalemia on RAASi. Clinical studies of patiromer and ZS-9 demonstrated their dose-dependent potassium-lowering effects. These new potassium binders may be helpful in optimising RAASi therapies in patients with hyperkalemia or at increased risk of developing it.7 However, the safety and long-term benefits for outcomes and drug–drug interactions, should be further evaluated in proper clinical trials. Future studies should consider the inclusion of patients with RAASiinduced hyperkalemia – who are usually excluded from clinical trials – to overcome the knowledge gap in this important subgroup.24 Further

oumsse M, Franco V, Abraham WT. Epidemiology of sudden H cardiac death in patients with heart failure. Heart Fail Clin 2011;7:147–55. https://doi.org/10.1016/j.hfc.2010.12.008; PMID: 21439494. 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. 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. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Eur J Heart Fail 2012;14:803–69. https://doi. org/10.1093/eurjhf/hfs105; PMID: 22828712. Butler J, Fonarow GC, Zile MR, et al. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail 2014;2:97–112. https://doi. org/10.1016/j.jchf.2013.10.006; PMID: 24720916. Nochioka K, Sakata Y, Shimokawa H. Combination therapy of renin angiotensin system inhibitors and b-blockers in patients with heart failure. Adv Exp Med Biol 2018;1067:17–30. https:// doi.org/10.1007/5584_2018_179; PMID: 29542073. Rosano GMC, Tamargo J, Kjeldsen KP, et al. Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the working group on cardiovascular pharmacotherapy of the European Society of Cardiology. Eur Heart J Cardiovasc Pharmacother 2018;4:180–8. https://doi.org/10.1093/ehjcvp/pvy015; PMID: 29726985. Pitt B, Pedro Ferreira J, Zannad F. Mineralocorticoid receptor antagonists in patients with heart failure: current experience and future perspectives. Eur Heart J Cardiovasc Pharmacother 2017;3:48–57. https://doi.org/10.1093/ehjcvp/pvw016;

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10.

11.

12.

13.

14.

15.

16.

17.

studies of uptitration to optimal dosing of RAASi in HF are also needed. Future research should focus on prevention of hyperkalemia and strategies to optimise RAASi. Beyond hyperkalemia, it should be noted that submaximal dosing of RAASi may be caused by other factors, such as symptomatic hypotension, syncope, hypoperfusion and reduced kidney function. In particular, hypotension and worsening renal function are common barriers to the treatment of HFrEF. Thus, correcting hyperkalemia often does not resolve the problem and management of these sideeffects is needed.

PMID: 27530337. Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/ valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF Trial. JAMA Cardiol 2017;2:79–85. https://doi. org/10.1001/jamacardio.2016.4733; PMID: 27842179. Turgeon RD, Kolber MR, Loewen P, et al. Higher versus lower doses of ACE inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction: Systematic review and meta-analysis. PLoS One 2019;14:e0212907. https://doi.org/10.1371/journal. pone.0212907; PMID: 30817783. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312–8. PMID: 10587334. Konstam MA, Neaton JD, Dickstein K, et al. Effects of highdose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009;374:1840–8. https://doi. org/10.1016/S0140-6736(09)61913-9; PMID: 19922995. Maggioni AP, Anker SD, Dahlström U, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 Patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173–84. https://doi. org/10.1093/eurjhf/hft134; PMID: 23978433. Takaichi K, Takemoto F, Ubara Y, Mori Y. Analysis of factors causing hyperkalemia. Intern Med 2007;46:823–9. PMID: 17575373. Epstein M, Reaven NL, Funk SE, et al. Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors. Am J Manag Care 2015;21:S212–20. PMID: 26619183. Montero D, Haider T. Relationship of loop diuretic use with exercise intolerance in heart failure with preserved ejection fraction. Eur Heart J Cardiovasc Pharmacother 2018;4:138–41. https://doi.org/10.1093/ehjcvp/pvy001; PMID: 29319788. Kapelios CJ, Malliaras K, Kaldara E, et al. Loop diuretics for

18.

19.

20.

21.

22.

23.

24.

chronic heart failure: a foe in disguise of a friend? Eur Heart J Cardiovasc Pharmacother 2018;4:54–63. https://doi.org/10.1093/ ehjcvp/pvx020; PMID: 28633477. Savarese G, Xu H, Trevisan M, et al. Incidence, predictors, and outcome associations of dyskalemia in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2019;7:65–76. https://doi.org/10.1016/j. jchf.2018.10.003; PMID: 30553905. Aldahl M, Jensen AC, Davidsen L, et al. Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J Cardiovasc Pharmacother 2017;38:2890–6. https://doi.org/10.1093/eurheartj/ehx460; PMID: 29019614. Zannad F. Pharmacotherapy in heart failure with reduced ejection fraction during the last 20 years, and the way ahead for precision medicine. Eur Heart J Cardiovasc Pharmacother 2015;1:10–2. https://doi.org/10.1093/ehjcvp/pvu006; PMID: 27533958. Vardeny O, Claggett B, Anand I, et al. Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail 2014;7:573–9. https://doi. org/10.1161/CIRCHEARTFAILURE.114.001104; PMID: 24812304. Raebel MA, McClure DL, Simon SR, et al. Laboratory monitoring of potassium and creatinine in ambulatory patients receiving angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Pharmacoepidemiol Drug Saf 2007;16:55–64. https://doi.org/10.1002/pds.1217; PMID: 16470693. Rossignol P, Dobre D, McMurray JJ, et al. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EmphasisHF). Circ Heart Fail 2014;7:51–8. https://doi.org/10.1161/ CIRCHEARTFAILURE.113.000792; PMID: 24297687. Sarwar CM, Papadimitriou L, Pitt B, et al. Hyperkalemia in heart failure. J Am Coll Cardiol 2016;68:1575–89. https://doi. org/10.1016/j.jacc.2016.06.060; PMID: 27687200.

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Clinical Practice

Inotropes in Acute Heart Failure: From Guidelines to Practical Use: Therapeutic Options and Clinical Practice Vasiliki Bistola, 1 Angelos Arfaras-Melainis, 1 Eftihia Polyzogopoulou, 2 Ignatios Ikonomidis 1 and John Parissis 1 1. Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 2. Emergency Medicine Department, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece

Abstract Inotropes are pharmacological agents that are indicated for the treatment of patients presenting with acute heart failure (AHF) with concomitant hypoperfusion due to decreased cardiac output. They are usually administered for a short period during the initial management of AHF until haemodynamic stabilisation and restoration of peripheral perfusion occur. They can be used for longer periods to support patients as a bridge to a more definite treatment, such as transplant of left ventricular assist devices, or as part of a palliative care regimen. The currently available inotropic agents in clinical practice fall into three main categories: beta-agonists, phosphodiesterase III inhibitors and calcium sensitisers. However, due to the well-documented potential for adverse events and their association with increased long-term mortality, physicians should be aware of the indications and dosing strategies suitable for different types of patients. Novel inotropes that use alternative intracellular pathways are under investigation, in an effort to minimise the drawbacks that conventional inotropes exhibit.

Keywords Traditional inotropes, novel inotropes, inotropes, acute heart failure, cardiogenic shock, cardiac myosin activators, calcium sensitisers, sarcoplasmic reticulum Ca2+-ATPase modulators, weaning Disclosure: JP has received honoraria for lectures and advisory meetings from Orion Pharma and Roche Diagnostics. All other authors have no conflicts of interest to declare. Received: 20 April 2019 Accepted: 11 September 2019 Citation: Cardiac Failure Review 2019;5(3):133–9. DOI: https://doi.org/10.15420/cfr.2019.11.2 Correspondence: Angelos Arfaras-Melainis, 1 Rimini Street, Athens, 12461 Greece. E: angelosarfaras@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 non-commercial purposes, provided the original work is cited correctly.

Acute heart failure (AHF) is defined as the sudden presentation or sudden aggravation of signs and symptoms of heart failure, often requiring hospitalisation.1 It is a life-threatening condition, with in-hospital mortality ranging from 22% to 37% in severe cases of cardiogenic shock.2–4 Inotropes have been used in the management of patients with AHF for decades, especially for patients with systolic dysfunction – heart failure with reduced ejection fraction – due to their enhancing effect on cardiac contractility.3 They also have chronotropic and peripheral vascular effects that accompany their positive inotropic effect. They are most commonly used in hospital settings for patients with peripheral organ hypoperfusion and severely diminished cardiac output.5 However, the use of inotropes does have some adverse effects, including arrhythmogenesis and myocardial ischaemia, contributing to an unfavourable impact on long-term survival. As a result, their use is not recommended as routine practice for all patients with HF.1 However, they remain useful as short-term regimens for patients who present with AHF and evidence of hypoperfusion and impaired cardiac contractility. Careful selection of the most appropriate inotrope for each individual patient is of utmost importance (Table 1).

Traditional Inotropes Currently available inotropic agents for the management of patients with AHF can fall into three categories, based on their mechanism of action: dopamine, dobutamine, norepinephrine and epinephrine that

act as beta-agonists; milrinone, a phosphodiesterase (PDE) type 3 inhibitor; and levosimendan, a calcium sensitiser (Table 2).6,7

Beta-agonists Dopamine Dopamine is an endogenous catecholamine that exerts its dosedependent effects on the cardiovascular system via its interaction with four different receptors: dopaminergic type 1 and type 2 and adrenergic alpha-1 and beta-1. When used at lower doses of up to 2.5 µg/kg/min, its primary net effect is vasodilation of the splanchnic, coronary and renal vasculature. While theoretically this effect seems favourable for the renal function of AHF patients, as it increases renal perfusion, there is no evidence that this translates to significant clinical benefit. In a cohort of patients in intensive care with impending renal failure, the administration of low-dose IV dopamine did not prove to have any benefit in terms of reduction of peak creatinine levels or prevention of worsening renal function compared with placebo.8 Also, in the Dopamine in Acute Decompensated Heart Failure II (DAD-HF) trial published in 2014, the addition of low-dose dopamine to low-dose furosemide was not associated with improvements in symptoms, readmissions, mortality or renal function in patients with acutely decompensated chronic HF.9 Additionally, in the Renal Optimization

Access at: www.CFRjournal.com

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Clinical Practice Table 1: Commonly Encountered Concomitant Conditions in Acute Heart Failure Patients 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

Strategies Evaluation – Acute Heart Failure (ROSE-AHF) trial, adding low-dose dopamine or low-dose nesiritide to the standard diuretic regimen for patients with AHF and renal dysfunction did not lead to either decongestion or recovery of renal function.10 When administered in intermediate doses of 3–5 µg/kg/min, dopamine exhibits significant chronotropic and inotropic effects primarily by stimulating sarcolemmal beta-1 receptors in cardiomyocytes, but it also increases the pulmonary capillary wedge pressure (PCWP). When used at higher doses of more than 5 µg/kg/min, its net effect is a potent vasoconstriction, facilitated mostly via its effect on alpha-1 adrenergic receptors of the vasculature. This leads to a significantly elevated afterload that can prove detrimental for patients with AHF and systolic dysfunction. The most notable adverse effects of dopamine include hypertension and tachyarrhythmias that are more frequently encountered at doses of >10 µg/kg/min.5

infusion rate of dobutamine ranges from 1–2 µg/kg/min up to 40 µg/kg/ min. When prescribing dobutamine, it should be noted that the effect of dobutamine may be blunted in patients who are under chronic beta-blockade therapy, at least in usual doses. Another important limitation of dobutamine is that tolerance may develop even after short administration periods.12 In terms of adverse effects, dobutamine and has been proven to be arrhythmogenic in most dosage schemes, it has also been linked to the rare occurrence of eosinophilic myocarditis.13–15

Norepinephrine Norepinephrine is an endogenous molecule, acting most potently on vascular alpha-1 adrenergic receptors, inducing vasoconstriction and increasing systolic and diastolic blood pressures. It also acts on cardiac beta-1 receptors, thereby exerting chronotropic and inotropic effects. Based on these properties, norepinephrine is primarily used in patients with AHF who present with cardiogenic shock, always in addition to another more potent inotropic agent. Norepinephrine is also used in combination with inodilators to prevent the development of hypotension.1 Norepinephrine is widely used for the management of other aetiologies, including septic shock. The Comparison of Dopamine and Norepinephrine in the Treatment of Shock (SOAP II) trial compared norepinephrine to dopamine as first-line agents for 1,679 patients with shock. Even though no statistically significant difference was found between the two arms in terms of mortality, dopamine was associated with an increased risk for adverse events including arrhythmias compared with norepinephrine. Notably, a subgroup analysis from the same trial including only patients with cardiogenic shock showed that norepinephrine was superior to dopamine in terms of reduction in mortality.16 In clinical practice, norepinephrine is usually infused at a rate of 0.01–0.03 µg/kg/min but can reach up to 1 µg/kg/min, until target blood pressure is achieved. Adverse events of norepinephrine include tachycardia that can significantly increase myocardial oxygen demand, which may be detrimental, especially in cases of active myocardial ischaemia. Also, it has been documented that norepinephrine has a direct toxic effect on cardiac cells, primarily due to cell apoptosis induced by beta adrenergic stimulation.17 Hypertension and tachyarrhythmias have also been reported with the use of norepinephrine.

Epinephrine Dobutamine Dobutamine, a synthetic catecholamine, enhances cardiac contractility via its stimulatory effect on myocardial beta-1 receptors. It also affects the peripheral vasculature due to its combined action on vascular alpha-1 receptors and beta-2 receptors. In clinical practice, low doses of dobutamine (<5 µg/kg/min) for patients with AHF lead to increased cardiac output through enhanced inotropy, while simultaneously reducing afterload by exerting a vasodilatory effect on the peripheral arterial vasculature, thereby resulting in improved symptoms. However, several studies have linked its use with an increase in mortality rates. One meta-analysis showed that dobutamine was associated with higher risk of in-hospital mortality and future HF readmissions compared with the vasodilator nesiritide.11 Due to its potential for long-term complications, dobutamine is also used primarily in the in-hospital setting for short-term improvement of symptoms. It is noteworthy that in doses exceeding 5 µg/kg/min, the effect on peripheral vessels shifts towards vasoconstriction as the alpha-1 agonist effect becomes significantly more potent. The

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Epinephrine, also an endogenous catecholamine, exhibits dosedependent effects. When administered at lower doses of up to 0.01 µg/kg/min, it primarily acts on beta-2 peripheral adrenergic receptors thereby causing vasodilation. However, when administered at an increased rate of >0.2 µg/kg/min, its effect on beta-1 and alpha1 receptors predominates, resulting in overall positive inotropy and vasoconstriction. This vasoconstriction includes not only the peripheral vasculature but also pulmonary arterial and venous circulation. Despite its inotropic, chronotropic and vasoconstrictive properties, epinephrine has been limited in everyday clinical practice to cases of cardiac arrest. This is due to the results from a pilot study by Levy et al. in 2011, in which epinephrine was compared with a regimen comprising of norepinephrine and dobutamine in patients with cardiogenic shock.18 The treatment strategies demonstrated comparable results in terms of haemodynamics; however, there were significantly increased rates of lactic acidosis, tachycardia, arrhythmia and gastric mucosal hypoperfusion observed in the epinephrine group, rendering it less safe to use in such patients.18

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Inotropes in Acute Heart Failure Table 2: Main Characteristics of Commonly Used Inotropes Inotrope

Mechanism

Dosing

Inotropy Vasoconstriction Vasodilation BP

Diuresis

Recommendation/ Possible Level of Evidence

Side-effects

Beta-agonists Dobutamine

Beta-1>beta2>alpha

2–20 µg/kg/min ++ (−) bolus dose

+ High doses

Neutral

IIb/C

Tachyarrhythmias Hypotension Headache Eosinophilic myocarditis (rare) Peripheral blood eosinophilia

Dopamine

Dopa>beta, alpha in high doses

Renal effect ++ <3 µg/kg/min Inotropic effect 3–5 µg/kg/min Vasoconstriction >5 µg/kg/min (−) bolus dose

++ High doses

++ Low doses

+ High doses

++ IIb/C Low doses

Tachyarrhythmias Hypertension Myocardial ischaemia

Norepinephrine Beta-1> alpha>beta-2

0.2–10.0 µg/kg/ + min (−) bolus dose

Neutral

IIb/C

Tachyarrhythmias Hypertension Headache

Epinephrine

0.05–0.50 µg/ kg/min (+) bolus dose: 1 mg IV every 3–5 min during resuscitation

++ High doses

Neutral/+ Neutral

IIb/C

Tachyarrhythmias Headache Anxiety Cold extremities Pulmonary oedema Cerebral haemorrhage

Beta-1> beta-2>alpha

Phosphodiesterase III inhibitors Milrinone

PDE3 inhibition

0.375–0.750 µg/ + kg/min (+) bolus dose: 25–75 µg/kg over 10–20 min (optional)

Neutral

−

Neutral

IIb/C

Tachyarrhythmias Hypotension Headache

Calcium sensitiser PDE3 inhibition, opening of vascular Katp channels Inhibition in high doses

0.05–0.20 µg/ + kg/min (+) bolus dose 12 µg/kg over 10 min (optional, not routinely recommended)

Neutral

−

IIb/C

Hypotension Atrial and ventricular tachyarrhythmias Headache

Ca2+ sensitisers Levosimendan

BP = blood pressure; PDE3 = phosphodiesterase type 3.

To further solidify these findings, the Cardiogenic Shock (CardShock) study looked at the trends and outcomes regarding common vasopressors and inotropes. It was found that epinephrine use in patients with cardiogenic shock was associated independently with increased 90-day mortality and with declining renal and cardiac function.19 Additionally, Leopold et al., in an individual-data-level metaanalysis, associated the use of epinephrine in the management of cardiogenic shock patients with a three times increased mortality rate compared with alternative drug regimens (OR 3.3; 95% CI [2.8– 3.9]).20 Epinephrine is most commonly administered at an infusion rate ranging from 0.01–0.03 µg/kg/min to 0.50 µg/kg/min in refractory cases. Notable adverse effects of epinephrine include myocardial ischaemia, arrhythmias, hypertension, pulmonary congestion and intracranial bleeding.

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Phosphodiesterase Type 3 Inhibitors Milrinone Milrinone, a PDE3 inhibitor, is a commonly used inotropic agent in patients with severe HF or cardiogenic shock.7 It inhibits PDE3, which physiologically degrades intracellular cyclic adenosine monophosphate (cAMP). Through this inhibition, cAMP accumulates in the cell, causing protein kinase A activation. This facilitates more calcium ions to enter the myocardial cell, thus potentiating the actin-myosin crossbridging leading to increased cardiac contractility. This mechanism is independent of the beta-adrenergic pathway. As a result, the use of PDE3 inhibitors, and milrinone in particular, is suitable for patients with chronic HF under beta-blockade who present with AHF or cardiogenic shock compared with other inotropes.21 Another feature of the mechanism of action of milrinone is that the same intracellular processes is activated in smooth muscle cells of the

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Clinical Practice peripheral and pulmonary vasculature, leading to a net vasodilatory effect in addition to its positive inotropic effect.22 This combination of actions classifies milrinone as an inodilator. The short- and long-term effects of milrinone have been investigated. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) evaluated the addition of IV milrinone on top of standard medical treatment in patients with AHF. No statistically significant benefit was found from the use of milrinone in terms of mortality or hospitalisations, whereas milrinone was linked to increased risk of prolonged hypotensive episodes and arrhythmias.23 In a subgroup analysis, milrinone was associated with increased mortality rates in patients with HF of ischaemic aetiology.24 Additionally, data from the Acute Decompensated Heart Failure National Registry (ADHERE) registry point towards the direction of increased mortality for dobutamine and milrinone compared with IV nitroglycerin or nesiritide.25 The Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial concluded that the use of milrinone in symptomatic HF patients, despite optimal medical therapy, was associated with increased mortality and readmission rates compared with placebo.26 In clinical practice, milrinone is used in patients with AHF who maintain adequate systolic blood pressure (>85 mmHg). For patients with systolic blood pressure in the lower range (85–100 mmHg), milrinone is recommended to be used in combination with a vasoconstrictor, such as norepinephrine, to counteract its vasodilating effect. In addition, milrinone is preferred in patients who chronically receive betablockers, due to its beta-adrenergic pathway which is an independent mechanism of action.21 Due to its relatively long half-life and renal clearance, milrinone should be used with caution in patients with impaired renal function. Hypotension and tachyarrhythmias are also documented adverse effects of milrinone.23

Calcium Sensitisers Levosimendan Levosimendan exerts its effects by acting on troponin C, rendering the cardiomyocyte more sensitive to the already existing levels of intracellular calcium, thereby increasing its contractility. As its effects are not a result of influx of calcium in the myocyte, its arrhythmogenic potential is significantly limited. In addition to its positive inotropic effect, levosimendan leads to peripheral vasodilation via the opening of ATP-sensitive potassium channels on smooth muscle cells of the vasculature.27,28 Levosimendan has also been reported to have some PDE3 inhibitor properties and is also an inodilator.

Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE-II) trial, despite a documented improvement in HF symptoms, levosimendan failed to prove beneficial in terms of mortality reduction and led to more cases of arrhythmias and hypotension.31,32 As a result, the use of levosimendan remains a topic of debate and it is only approved for use in Europe. Current European Society of Cardiology guidelines reserve its use in AHF patients with hypoperfusion that may be related to beta-blockade therapy.1 Levosimendan is usually administered at a rate of 0.05–0.20 µg/kg/min. Adverse effects include hypotension, AF, hypokalemia, headache and arrhythmias.

Novel Inotropic Agents Omecamtiv Mecarbil Omecamtiv mecarbil (OM) is the first and most investigated agent in a new class of inotropes called cardiac myosin activators.33 It exerts its effect by binding on an allosteric site on myosin itself. This leads to a stabilisation of the lever arm of myosin, rendering it primed. This effect when multiplied for numerous intracellular myosin molecules prior to the initiation of contraction, produces an increased number of primed myosin molecules and consequently an increased number of myosin heads available to cross-bridge with actin generating increased contractile force.34 It is important to note that the mechanism of action of OM is independent from calcium and cAMP, both of which contribute to arrhythmogenesis and myocardial ischaemia, as documented for traditional inotropes acting through these mediators. Additionally, since OM acts independently of the adrenergic pathway, it can be used as an alternative to milrinone and levosimendan in HF patients who are taking beta-blockers.35,36 The haemodynamic effects of OM have been tested in previous studies. Specifically, when compared to placebo, OM increased stroke volume and ejection fraction in AHF patients.37,38 These beneficial results initially failed to translate into clinically relevant results, as in a phase II trial patients treated with the agent did not report an improvement in dyspnoea.39 It should also be noted that an increase in troponin levels in patients treated with excessive doses of OM has been found. This has been hypothesised to be a result of diminished coronary filling during diastole due to prolonged ventricular systolic phase.39,40 However, at the regular therapeutically relevant exposures, no relationship was identified between troponin increases and systolic ejection time. The mechanism for the increases in troponin at therapeutically relevant exposures is currently unknown.

Initial levosimendan studies showed promising results, despite their limited size. The Efficacy and Safety of Intravenous Levosimendan Compared with Dobutamine in Severe Low-Output Heart Failure (LIDO) study found that levosimendan was superior to dobutamine in terms of haemodynamic profile and mortality.29 Additionally, in the Safety and Efficacy of a Novel Calcium Sensitizer, Levosimendan, in Patients With Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN) trial, levosimendan was associated with significantly decreased rates of death and deteriorating HF.30

SERCA2a Modulation

However, two subsequent larger trials did not show positive results with levosimendan use. The 180-day mortality rate in the Levosimendan versus Dobutamine for Patients with Acute Decompensated Heart Failure (SURVIVE) trial was comparable in both arms and in the

SERCA2a Gene Therapy

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Sarcoplasmic reticulum Ca2+-ATPase (SERCA), and its 2a isoform, is a sarcolemmal membrane-bound enzyme that handles free calcium influx back in the sarcoplasmic reticulum in the post-systolic period. SERCA2a, via this mechanism, affects the mechanics of both diastole and systole and its expression is long known to be reduced in HF patients, leading to systolic impairment.41,42 Consequently, it could be hypothesised that targeting the function and/or expression of this enzyme could be beneficial for HF patients.

SERCA2a modulation in HF patients can be achieved through gene therapy. An initial approach involved intracoronary administration of an adeno-associated virus type 1 encoding sarcoplasmic reticulum

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Inotropes in Acute Heart Failure calcium ATPase (AAV1/SERCA2a). This gene therapy strategy initially proved to have an acceptable safety profile in and was tested in terms of efficacy in phase II trials.43 The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial included 39 patients with AHF in total. It was documented that gene delivery was superior to placebo in terms of symptomatic improvement, exercise tolerance, biomarkers and haemodynamic profile in the 6-month follow-up period.44 However, the larger CUPID II trial that followed, with 250 HF patients, could not replicate the results from the initial CUPID trial, as the administration of AAV1/ SERCA2a did not significantly reduce HF-related endpoints, such as HF hospitalisations and worsening HF compared with placebo.45

Recommendations on the Optimal Administration of Inotropes in Acute Heart Failure Approximately 10% of all hospitalised HF patients also have hypotension, decreased cardiac output and signs of peripheral hypoperfusion.25 In this considerable subgroup of patients, inotropes are recommended as part of their management (Figure 1).1 In refractory cases, circulatory support devices can be used in selected patients to maintain perfusion and haemodynamic stability for short periods of time.1 However, due to the sparsity of these devices compared with the large number of AHF patients, their use is reserved as bridge-to-transplant or other treatment decisions, while inotrope infusions as initial short-term support remain very common in everyday clinical practice. The general principle that applies for the use of inotropes is to use them for the shortest amount of time possible and in the lower effective dose until the therapeutic goal of haemodynamic stabilisation (maintaining adequate BP and CO) and restoration of vital organ perfusion and function is achieved. The types of AHF patients that usually receive inotropic support fall into two broad categories: those that present with cardiogenic shock and those with low BP and signs of hypoperfusion that do not present with overt cardiogenic shock. Patients presenting with cardiogenic shock have severely diminished cardiac output that leads to severe hypotension (below the 85 mmHg cut-off) and decreased peripheral and vital organ perfusion. This hypoperfusion becomes evident via clinical hallmarks of cardiogenic shock including cold extremities, elevation in lactate levels and reduced urine output and mentation changes. The first step in treating a patient in cardiogenic shock should be aimed towards haemodynamically stabilising the patient and restoring tissue and vital organ perfusion. The regimen of choice includes the immediate administration of an inotropic agent, notably dobutamine, in combination with a vasopressor to offset the possible vasodilatory effect of the inotrope.1 In terms of the vasopressor agent of choice, data support the use of norepinephrine instead of epinephrine, since the latter has been repeatedly associated with worse mortality and renal outcomes, increased markers of hypoperfusion (lactate) and myocardial ischaemia (troponin).19 It should be noted that the combination of an inotrope and a vasopressor is also preferable to the use of a single vasopressor agent at an increased dose, since that would lead to a more potent vasoconstrictive effect, increasing cardiac afterload and the risk of ischaemia.46 In refractory cardiogenic shock cases, circulatory support with mechanical devices is recommended when feasible. Inotropes are not only indicated for patients in overt cardiogenic shock (BP <85 mmHg), but also for HF patients with either marginal or even

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Figure 1: Practical Recommendations on the Use of Inotropes in Patients with Acute Heart Failure and Hypoperfusion AHF with hypoperfusion

SBP <90 mmHg

SBP >90 mmHg

Inotropes ± vasopressors

Vasodilators

Clinical stabilisation

Yes

Transition to CHF treatment

Inotropes

Yes

Transition to CHF treatment

Clinical stabilisation

Mechanical circulatory support

Yes

Transition to CHF treatment

AHF = acute heart failure; CHF = chronic heart failure; SBP = systolic blood pressure.

normal BP who do exhibit evidence of hypoperfusion. This evidence includes both clinical (cold extremities, altered mentation, diminished pulse pressure) and laboratory findings (increased blood urea nitrogen and creatine elevations in hepatic function tests and serum lactate and hyponatraemia). In these patients, the usual regimen of choice includes an inotrope or an inodilator with the goal to reverse the hypoperfusion. The decision to use which specific agent is individualised to each patient and dictated by the specific haemodynamic parameters of each case. Table 2 presents a summary of commonly encountered clinical scenarios and their corresponding inotropic agents. Inodilators (milrinone, levosimendan) possess some unique properties compared with other inotropic agents, which make them a more suitable therapeutic option for certain groups of patients. Due to their inherent vasodilatory effect, they are well suited for patients that have peripheral vasoconstriction. However, their use is not indicated if the systolic blood pressure is <90 mmHg. Additionally, if severe hypotension occurs after the administration of an inodilator, the concomitant use of a vasoconstrictive agent is recommended to counteract its vasodilatory effect. Also, since the inotropic effect of milrinone and levosimendan is independent of the beta-adrenergic pathway, they are the preferable option for the treatment of patients under chronic beta-blockade. It should be noted that in the Efficacy and Safety of Short‐term IV Treatment with Levosimendan vs Dobutamine in Decompensated HF Patients Treated with Beta‐ blockers (BEAT-CHF) trial, the use of levosimendan and dobutamine were comparable in terms of haemodynamic improvement (PCWP decrease and increased cardiac output) after 1 day of therapy.47 A third and more specific group of patients who might benefit

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Clinical Practice from the use of an inodilator over another inotrope are those with pulmonary arterial hypertension. Both milrinone and levosimendan may be indicated in these patients because of their documented vasodilatory effect on the pulmonary vasculature. Milrinone has been shown to reduce pulmonary vascular resistance in patients waiting for a heart transplantation.24 AHF patients commonly have concomitant renal and/or hepatic failure. In the case of primary renal failure, the choice of the appropriate inotropic agent is based primarily on its half-life. Dobutamine is the agent with the shortest half-life (2 minutes), whereas levosimendan has an 80-hour half-life. Therefore, dobutamine is the agent of choice for these patients. However, it should be noted that some data support the use of levosimendan in the subgroup of patients presenting with acute cardiorenal syndrome, as it increases renal perfusion more efficiently that other agents. 48 For patients with impaired hepatic function, dobutamine is also the first choice as levosimendan is predominantly excreted via the liver. However, similarly to the cardiorenal syndrome indications, levosimendan has better supporting evidence in normalising liver function tests compared with dobutamine in people with acute cardio-hepatic dysfunction.49 For patients undergoing coronary artery bypass graft (CABG), the most widely used inotrope is dobutamine, as it provides better coronary perfusion without serious metabolic adverse effects.50 Additionally, milrinone has the disadvantage of being more arrhythmogenic than dobutamine while it may also counteract the vasoconstrive effect of the inhaled anaesthetics on the pulmonary vasculature.51,52 Finally, levosimendan has been shown to improve post-surgical outcomes, including length of stay and time to extubation.53,54 However, in the Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass (LEVO-CTS) trial, the prophylactic use of levosimendan in isolated patients with reduced ejection fraction undergoing CABG failed to demonstrate benefit over placebo.55 When treating AHF that occurs after cardiotomy, the most widely accepted regimen comprises of dobutamine (or a different beta-agonist) in combination with milrinone or levosimendan. This combined approach is superior to

onikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines P 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. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2010;12:1076–84. https://doi.org/10.1093/eurjhf/hfq154; PMID: 20805094. Harjola VP, Lassus J, Sionis A, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock. Eur J Heart Fail 2015;17:501–9. https://doi.org/10.1002/ejhf.260; PMID: 25820680. Venkatason P, Zubairi YZ, Wan Ahmad WA, et al. In-hospital mortality of cardiogenic shock complicating ST-elevation myocardial infarction in Malaysia: a retrospective analysis of the Malaysian National Cardiovascular Database (NCVD) registry. BMJ Open 2019;9:e025734. https://doi.org/10.1136/ bmjopen-2018-025734; PMID: 31061031. Bistola V, Chioncel O. Inotropes in acute heart failure. Continuing Cardiology Education 2017;3:107–16. https://doi. org/10.1002/cce2.59. Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future directions. Eur Heart J 2011;32:1838–45. https://doi. org/10.1093/eurheartj/ehr026; PMID: 21388993. Overgaard CB, Dzavik V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation 2008;118:1047–56. https://doi.org/10.1161/ CIRCULATIONAHA.107.728840; PMID: 18765387. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356:2139– 43. https://doi.org/10.1016/S0140-6736(00)03495-4; PMID:

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11.

12.

13.

14.

monotherapy in terms of cardiac output, length of intubation and length of hospital stay.56 In sepsis-related AHF cases, recent data and recommendations suggest that dobutamine and norepinephrine should be the inotropic agents of choice.57,58 However, recent data concerning levosimendan use in these patients have been encouraging. Specifically, levosimendan has been shown to decrease serum lactate levels, exert a reno-protective role, and restore cardiac index without increasing myocardial oxygen demand leading to better short-term outcomes.59,60

Recommendations on the Optimal Weaning of Inotropes in Acute Heart Failure As soon as congestion is alleviated and renal function improves, shown by an increase in urinary output and a decrease in blood urea nitrogen and creatinine levels, inotropic support should be tapered with the goal of complete weaning. During this time, standard oral HF treatment should be reinstated, and target doses should be reached after inotropic support is completely withdrawn. Unfortunately, there is a subset of patients who are unable to maintain adequate BP and perfusion without inotropic support despite multiple attempts to discontinue them. These patients, often referred to as inotrope-dependent, are usually supported with inotropes for prolonged periods of time either as a bridge (to transplant or a left ventricular assist device) or as part of a broader palliative strategy aimed at symptomatic relief.

Conclusion Inotropic agents have long been associated with adverse events including arrhythmogenesis and unfavourable long-term mortality outcomes. However, they remain a key weapon in the arsenal of physicians that manage AHF patients, due to the lack of other efficacious medical or interventional strategies. Their use should be limited to the minimum possible dose for the shortest amount of time adequate to restore BP and peripheral perfusion. Ongoing and future research in the field of inotropes aims to assess the safety and efficacy of new molecules that act through novel or alternative pathways to reduce the adverse events profile of inotropes and reduce their negative effect on long-term survival.

11191541. Triposkiadis FK, Butler J, Karayannis G, et al. Efficacy and safety of high dose versus low dose furosemide with or without dopamine infusion: the Dopamine in Acute Decompensated Heart Failure II (DAD-HF II) trial. Int J Cardiol 2014;172:115–21. https://doi.org/10.1016/j.ijcard.2013.12.276; PMID: 24485633. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013;310:2533–43. https://doi.org/10.1001/ jama.2013.282190; PMID: 24247300. Wang XC, Zhu DM, Shan YX. Dobutamine therapy is associated with worse clinical outcomes compared with nesiritide therapy for acute decompensated heart failure: a systematic review and meta-analysis. Am J Cardiovasc Drugs 2015;15:429–37. https://doi.org/10.1007/s40256-015-0134-3; PMID: 26123415. Metra M, Nodari S, D’Aloia A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol 2002;40:1248–58. https://doi.org/10.1016/S07351097(02)02134-4; PMID: 12383572. Fenton M, Burch M, Sebire N. A dobutamine paradox: eosinophilic myocarditis in the explanted heart of a 9-yearold girl undergoing cardiac transplantation. Cardiology Young 2005;15:520–2. https://doi.org/10.1017/S1047951105001411; PMID: 16164793. El-Sayed OM, Abdelfattah RR, Barcelona R, Leier CV. Dobutamine-induced eosinophilia. Am J Cardiol 2004;93:1078–9. https://doi.org/10.1016/j.amjcard.2003.12.069; PMID:

15081466. 15. B arrett M, Fabre A, Tuohy G, et al. Eosinophilic myocarditis in patients on dobutamine therapy: an underappreciated and not uncommon phenomenon. Heart 2015;101(Suppl 5):A19–A. https://doi.org/10.1136/heartjnl-2015-308621.34. 16. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. New Engl J Med 2010;362:779–89. https://doi.org/10.1056/ NEJMoa0907118; PMID: 20200382. 17. Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation 1998;98:1329-–34. https://doi.org/10.1161/01. CIR.98.13.1329; PMID: 9751683. 18. Levy B, Perez P, Perny J, et al. Comparison of norepinephrinedobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med 2011;39:450–5. https://doi.org/10.1097/ CCM.0b013e3181ffe0eb; PMID: 21037469. 19. Tarvasmaki T, Lassus J, Varpula M, et al. Current real-life use of vasopressors and inotropes in cardiogenic shock – adrenaline use is associated with excess organ injury and mortality. Crit Care 2016;20:208. https://doi.org/10.1186/ s13054-016-1387-1; PMID: 27374027. 20. Leopold V, Gayat E, Pirracchio R, et al. Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients. Intensive Care Med 2018;44:847–56. https://doi.org/10.1007/s00134-018-5222-9; PMID: 29858926. 21. Lowes BD, Tsvetkova T, Eichhorn EJ, et al. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol 2001;81:141–9; https://doi.org/10.1016/

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Inotropes in Acute Heart Failure S0167-5273(01)00520-4; PMID: 11744130. 22. C olucci WS, Wright RF, Jaski BE, et al. Milrinone and dobutamine in severe heart failure: differing hemodynamic effects and individual patient responsiveness. Circulation 1986;73:Iii175–83. PMID: 3510774. 23. Cuffe MS, Califf RM, Adams KF Jr., et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002;287:1541–7. https://doi.org/10.1001/ jama.287.12.1541; PMID: 11911756. 24. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003;41:997–1003. https://doi.org/10.1016/S07351097(02)02968-6; PMID: 12651048. 25. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57–64. https://doi. org/10.1016/j.jacc.2005.03.051; PMID: 15992636. 26. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. New Engl J Med 1991;325:1468– 75. https://doi.org/10.1056/NEJM199111213252103; PMID: 1944425. 27. Parissis JT, Andreadou I, Bistola V, et al. Novel biologic mechanisms of levosimendan and its effect on the failing heart. Expert opinion on investigational drugs. 2008;17:1143– 50. https://doi.org/10.1517/13543784.17.8.1143; PMID: 18616411. 28. Papp Z, Edes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012;159:82–7. https://doi.org/10.1016/j.ijcard.2011.07.022; PMID: 21784540. 29. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002;360:196–202. https://doi.org/10.1016/S0140-6736(02)09455-2; PMID: 12133653. 30. Moiseyev VS, Poder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 2002;23:1422–32. https://doi. org/10.1053/euhj.2001.3158; PMID: 12208222. 31. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA 2007;297:1883–91. https://doi.org/10.1001/jama.297.17.1883; PMID: 17473298. 32. Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006;8:105–10. https://doi.org/10.1016/j. ejheart.2005.12.003; PMID: 16387630. 33. Teerlink JR. A novel approach to improve cardiac performance: cardiac myosin activators. Heart Fail Rev 2009;14:289–98. https://doi.org/10.1007/s10741-009-9135-0; PMID: 19234787. 34. Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J, et al. Mechanistic and structural basis for activation of cardiac

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Advanced Heart Failure

Right Ventricular Failure: Pathophysiology, Diagnosis and Treatment Mattia Arrigo, 1 Lars Christian Huber, 2 Stephan Winnik, 1 Fran Mikulicic, 1 Federica Guidetti, 1 Michelle Frank, 1 Andreas J Flammer 1 and Frank Ruschitzka 1 1. Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; 2. Department of Internal Medicine, Clinic for Internal Medicine, City Hospital Triemli, Zurich, Switzerland

Abstract The prognostic significance of the right ventricle (RV) has recently been recognised in several conditions, primarily those involving the left ventricle, the lungs and their vascular bed, or the right-sided chambers. Recent advances in imaging techniques have created new opportunities to study RV anatomy, physiology and pathophysiology, and contemporary research efforts have opened the doors to new treatment possibilities. Nevertheless, the treatment of RV failure remains challenging. Optimal management should consider the anatomical and physiological particularities of the RV and include appropriate imaging techniques to understand the underlying pathophysiological mechanisms. Treatment should include rapid optimisation of volume status, restoration of perfusion pressure and improvement of myocardial contractility and rhythm, and, in case of refractory RV failure, mechanical circulatory support.

Keywords Right heart failure, right ventricular failure, pathophysiology, management, treatment, mechanical circulatory support Disclosure: MA received lecture fees from Orion Pharma. SW received lecture fees from the European Society of Cardiology, and travel support from Bayer and Daichi Sankyo. All other authors have no conflicts of interest to declare. Received: 13 May 2019 Accepted: 5 July 2019 Citation: Cardiac Failure Review 2019;5(3):140–6. DOI: https://doi.org/10.15420/cfr.2019.15.2 Correspondence: Mattia Arrigo, Acute Cardiology and Heart Failure Unit, Department of Cardiology – University Heart Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E: mattia.arrigo@usz.ch 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.

In 1616, Sir William Harvey was the first person to describe the importance of right ventricular function.1 However, the right ventricle (RV) has received little attention in the past, with cardiology dealing mostly with the diseases of the left ventricle (LV) and their potential treatment. Since the early 1950s, however, the prognostic significance of RV function has been recognised in several conditions, primarily those involving the LV (e.g. chronic LV failure), the lungs and their vascular bed (e.g. pulmonary embolism, chronic pulmonary disease and pulmonary arterial hypertension) or the right-sided chambers (e.g. RV infarction, RV cardiomyopathies and congenital heart diseases).

thickness. Furthermore, venous return fluctuates, so the RV is much more compliant and is slightly larger (approximately 10–15%) than the LV, which allows it to accommodate large variations in venous return without altering end-diastolic pressure. Each systolic contraction leads to a primarily longitudinal shortening, whereas LV contraction is more circumferential.6 Notably, both ventricles share the septum, and up to 40% of the RV systolic function is dependent on septal contraction.7 During exercise, a 30–50% decrease in predicted VO2 max can be seen in healthy Fontan patients, which indirectly highlights the critical role of the RV for maintaining cardiac output.8

Recent advances in imaging techniques have created new opportunities to study RV anatomy, physiology and pathophysiology, and contemporary research efforts have opened the doors to new treatment possibilities.2,3 Nevertheless, the treatment of RV failure remains challenging. This article aims to provide an overview of the pathophysiology, diagnosis and treatment of RV failure.

The RV consists of the inlet with the tricuspid valve, chordae tendineae, at least three papillary muscles, the trabeculated apex and the infundibulum (a muscular structure supporting the pulmonary valve leaflets). For imaging analysis, the RV is divided into four segments: the infundibulum, and the anterior, lateral and inferior wall.9

Anatomical and Physiological Particularities of the Right Ventricle The RV is a unique chamber with distinct anatomy and physiology.4 It is coupled to systemic venous return and the pulmonary circulation. Since the pressure in the pulmonary circulation is generally much lower than it is in the systemic circulation, less muscle power is needed (a quarter of the LV stroke work).5 Therefore, the RV needs fewer muscle fibres and is much thinner than the LV, having about one-third of the

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The right coronary artery, at least in most individuals, perfuses the RV free wall and the posterior third of the interventricular septum. The left anterior descending artery perfuses the apex and the anterior part of the septum. Unlike the LV, RV perfusion occurs both in systole and diastole and the collateral vessels of the RV are denser than those of the LV. However, because of its thinner wall and higher dependence on coronary perfusion pressure, RV perfusion is more vulnerable to an increase in RV size (intramural pressure) and systemic hypotension.10

Right Ventricular Failure

A further important characteristic is ventricular interdependence. Excessive RV volume loading is constrained by the pericardium and therefore results in compression and D-shaping of the LV. Volume overload in the RV therefore indirectly leads to a decrease in LV stroke volume.

Figure 1: Effect of Increasing Afterload on Stroke Volume of the Right and Left Ventricles 100% Left ventricle

90% Stroke volume

One of the main characteristics of the RV is its greater sensitivity to changes in afterload. Brisk increases in afterload are poorly tolerated and lead to RV dilatation to preserve stroke volume. One seminal work highlighted the response of the right and left ventricle to experimental increases in afterload. While an increase on the left side leads to only a slight decrease in stroke volume, the same increase in the RV results in a marked fall in stroke volume (Figure 1).

80%

The anatomical and functional particularities of the RV have been reviewed in detail elsewhere.4 Right ventricle

Causes and Pathophysiology of Right Ventricular Failure The normal RV function is an interplay between preload, contractility, afterload, ventricular interdependence and heart rhythm. Most cases of RV failure follow existing or new-onset cardiac or pulmonary diseases or a combination of both, which may increase RV afterload, reduce RV contractility, alter RV preload or ventricular interdependence or cause-related arrhythmias (Table 1 and Figure 2). To understand RV failure, it is crucial to assess these five components.

Right Ventricular Failure in Cardiac Disease Increased afterload is the main pathophysiologic mechanism for RV failure of both pulmonary and cardiac origin. Indeed, the prevalence of left ventricular systolic or diastolic dysfunction and (post-capillary) pulmonary hypertension in patients with RV failure is particularly high, which corroborates the concept that the majority of RV failure is secondary to left-sided cardiac or pulmonary (vascular) diseases.11 Increased afterload is also a main cause of ventricular failure in patients with systemic RV (e.g. patients after atrial switch repair for complete transposition of the great arteries, with congenitally corrected transposition of the great arteries or after Fontan palliation) or with obstruction of the RV outflow tract. In patients with other forms of adult congenital heart disease (e.g. atrial septal defect with relevant left-to-right shunt or severe pulmonary regurgitation in repaired Fallot’s tetralogy), chronic volume overload may induce RV dilation and failure.

70%

+10

+20

+30

Change in afterload (mmHg) Right ventriclar stroke volume decreases rapidly when afterload is increased, in contrast to left ventricular stroke volume which is maintained against an augmented afterload. BL = baseline.

Notably, iatrogenic RV failure through excessive volume loading or mechanical ventilation is frequently seen in critically ill patients, while ischaemic RV injury is sometimes seen after cardiac surgery. Finally, RV failure may be exacerbated in patients undergoing left ventricular assist device (LVAD) implantation, causing high morbidity and mortality and requiring temporary RV support. This topic has been reviewed extensively elsewhere.12

Right Ventricular Failure in Pulmonary Disease RV failure as a consequence of lung disease is commonly described as cor pulmonale. These changes might occur dramatically – for example in fulminant pulmonary embolism – or might be due to longstanding respiratory disorders that result in chronic alterations of RV structure and function.

Virtually all myocardial diseases involving the left heart may affect the RV. These include myocardial ischaemia/infarction, myocarditis/septic cardiomyopathy, takotsubo cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, cardiac amyloidosis and Chagas disease. Cardiomyopathies with primary involvement of the RV include arrhythmogenic RV cardiomyopathy (characterised by fibrofatty replacement of the RV myocardium), Uhl’s anomaly (which involves aplasia or hypoplasia of most of the RV myocardium), and Ebstein’s anomaly (defined as apical displacement of the septal and posterior tricuspid leaflets, which induces severe tricuspid regurgitation).

In the context of acute respiratory insufficiency in a previously healthy individual, impending RV failure is almost exclusively seen with massive pulmonary embolism. Of note, the elevation of pulmonary pressure following acute pulmonary embolism is observed only when more than half of the pulmonary vasculature is obstructed by thrombotic material.13 This is because distension and recruitment of additional pulmonary capillaries might decrease vascular resistance and compensate for circulatory changes.14 When thrombotic occlusion extends to more than 50% of the lung vessels and, in turn, pressure elevation occurs, the unconditioned RV can overcome a mean pulmonary arterial pressure of up to 40 mmHg.15 A higher afterload results in acute RV failure and obstructive shock. Conversely, if there is acute pulmonary embolism and the RV is exposed to higher pressure values and can tolerate it, a pre-existing elevation of pulmonary pressure (i.e. the presence of pulmonary hypertension) with an antecedent adaption of the RV must be assumed.

Pericardial diseases may alter RV preload and ventricular interdependence, while arrhythmia may aggravate RV dysfunction.

Many chronic lung diseases affect the pulmonary circulation and the right heart, but chronic obstructive pulmonary disease

Cardiac diseases involving the right heart may primarily reduce RV contractility or, through reduced cardiac output, reduce RV preload, contributing to RV failure.

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Advanced Heart Failure Table 1: Mechanisms and Causes of Right Ventricular Failure Mechanism

Cause

Increased afterload

LV backward failure (pulmonary hypertension associated with left-sided heart disease) Pulmonary embolism, chronic thromboembolic pulmonary hypertension Pulmonary artery hypertension (Exacerbated) chronic pulmonary disease Acute lung injury/acute respiratory distress syndrome Sleep-related breathing disorders, obesityhypoventilation syndrome Mechanical ventilation (Repaired) congenital heart disease with systemic RV or RV outflow obstruction

Reduced contractility

RV ischaemia/RV infarction RV injury, systemic inflammatory response (SIRS) Myocarditis Cardiomyopathies (e.g. dilated cardiomyopathy or hypertrophic cardiomyopathy) Arrhythmogenic RV cardiomyopathy, Uhl’s anomaly

Abnormal preload

Hypo- or hypervolaemia LV forward failure Pericardial tamponade Mechanical ventilation Chronic left-to-right shunt

Altered interdependence

Pericardial tamponade Pericardial disease Septal shift

Altered rhythm

Bradyarrhythmia Tacharrhythmia

The presence of pulmonary hypertension has long been considered as the conditio sine qua non for the development of a cor pulmonale.18 Recent data have challenged this assumption and suggested that, in patients with lung disease, structural alterations in cardiac myocytes predate the development of clinically manifested pulmonary hypertension.19 As such, cor pulmonale and failing RV syndrome in lung disease may be part of a disease spectrum rather than being distinct entities.20 With its impact on RV function, pulmonary hypertension – more than airflow limitation – is the strongest predictor of an adverse outcome and mortality in patients with lung disease.

Diagnosis of Right Ventricular Failure Clinical Signs The clinical signs of RV failure are mainly determined by backward failure causing systemic congestion. In severe forms, the right heart dilates and, through interventricular dependence, can compromise LV filling, reducing LV performance and causing forward failure (i.e. hypotension and hypoperfusion). Backward failure presents as elevated central venous pressure with distension of the jugular veins and may lead to organ dysfunction and peripheral oedema.21 The association between systemic congestion and renal, hepatic and gastrointestinal function in heart failure has been extensively studied.22 Elevated central venous pressure is the main determinant of impaired kidney function in acute heart failure.23,24 Hepatic dysfunction is also highly prevalent in acute heart failure; systemic congestion frequently presents with a cholestatic pattern, while hypoperfusion typically induces a sharp increase in circulating transaminases.25 Finally, systemic congestion may alter abdominal function, including reduced intestinal absorption and impaired intestinal barrier.26

LV = left ventricle; RV = right ventricle.

ECG Figure 2: Mechanisms of Right Ventricular Dysfunction

Altered rhythm

Increased afterload

Abnormal preload LA

Lungs RV

Altered interdependence

Imaging LV

Reduced contractility LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.

(COPD) is the most prevalent cause of respiratory insufficiency and cor pulmonale. COPD increases RV afterload by several mechanisms, including rarefaction of the vascular bed, hypercapnia and acidosis, pulmonary hyperinflation, airway resistance, endothelial dysfunction and hypoxia.16 Of these factors, hypoxia is arguably the most prominent driver of pulmonary hypertension and subsequent RV failure. Hypoxic pulmonary vasoconstriction (the Euler-Liljestrand effect) results in pulmonary pressure elevation and, when persistent, vascular remodelling and fixed pulmonary hypertension.17

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The ECG in chronic RV failure often shows right axis deviation as a consequence of RV hypertrophy. Other ECG criteria are RS-ratio in lead V5 or V6 ≤1, SV5 or V 6≥7 mm, P-pulmonale or a combination of these. While the sensitivity of those criteria is quite low (18–43%), the specificity ranges from 83% to 95%.27 RV strain is sometimes seen in massive pulmonary embolism as an initial S deflection in I, an initial Q-deflection in III and T-Inversions in III (high specificity, low sensitivity), as well as in V1–V4.28 Moreover, RV failure is often accompanied by atrial flutter or AF.

The primary working tool for imaging the (failing) RV is echocardiography. It should be emphasised that a comprehensive assessment of the anatomy and function of the right heart should include left heart function, pulmonary haemodynamics, the tricuspid valve and the right atrium. In most patients, transthoracic assessment by echocardiography is sufficient to describe RV morphology and function adequately. However, because of the RV’s complex shape, echocardiography can only partially visualise it. Careful attention should be paid in obtaining an RV focused view from the apical four-chamber view with rotation of the transducer to obtain the maximal plane.8 Other views, such as the short axis and RVOT view, add anatomical and functional information. The measurements of RV function that are most frequently used and easiest to perform are fractional area change, tricuspid annular plane systolic excursion (TAPSE), pulsed tissue Doppler S’ or RV index of myocardial performance (RIMP). However, RIMP is rarely used and cumbersome to calculate.29,30

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Right Ventricular Failure Guidelines recommend a comprehensive approach and using a combination of these measurements to assess RV function as none of them alone can adequately describe RV function in different scenarios.29 Moreover, these measurements are all somewhat load dependent and therefore subject to physiologic variation. Newer imaging techniques, such as 3D-echocardiography and strain imaging, have proven to be useful and accurate imaging modalities but have limitations because they depend on good image quality and lack validation in larger cohorts.31,32 Cardiac MRI has become the standard reference method for right heart acquisition as it is capable of visualising anatomy, quantifying function and calculating flow. In addition, it is useful in cases where image quality by echocardiography is limited. Moreover, it can provide advanced imaging with tissue characterisation, which is useful in different cardiomyopathies, such as arrhythmogenic RV cardiomyopathy, storage disease and cardiac tumours. Limitations are mainly due to the thinness of the RV wall, which can make it challenging to differentiate it from surrounding tissues.9 In addition, pacemakers or pacemaker leads may interfere with image acquisition during MRI and lead to artefacts that impair visualisation of the RV walls. Cardiac CT and nuclear imaging play a minor role although cardiac CT can help to visualise anatomy when MRI is not feasible. There are concerns regarding radiation exposure from both nuclear imaging and dynamic imaging by CT angiography.

Medical Treatment of Acute Right Ventricular Failure The Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology recently published a comprehensive statement on the management of acute RV failure.33 The triage and initial evaluation of patients presenting with acute RV failure aim to assess clinical severity and identify the cause(s) of RV failure, with a focus on those requiring specific treatment. Management of acute RV failure requires not only an understanding of the anatomical and physiological particularities of the RV but also rapid identification and treatment of the underlying causes and related pathophysiological disorders (see above). In this context, echocardiography and other imaging modalities are frequently essential to identify the cause of RV failure and guide treatment. In patients presenting with severe RV failure, rapid initiation of treatment to restore haemodynamic stability is essential to prevent significant, potentially irreversible end-organ damage. Acute treatment consists of four elements: volume optimisation; restoration of perfusion pressure; improvement of myocardial contractility; and advanced options (Figure 3).

Figure 3: Algorithm for the Treatment of Acute Right Ventricular Failure Confirm diagnosis Assess severity

Clinical parameters Lab values (BNP, troponin, lactate) lmaging (TTE)

Identify and treat the cause

ECG, imaging (TTE, CT scan) PCI for AMI, reperfusion for PE

Optimise volume status

Volume bolus if preload-dependent Diuretics in case of congestion

Restore perfusion pressure

Add noradrenaline MAP >65 mmHg, personalise target

Improve myocardial contractility

Add positive inotropic drug (levosimendan, dobutamine, PDE3i)

Consider advanced options

Inhaled NO, inhaled prostacyclins Mechanical circulatory support

AMI = acute MI; BNP = B-type natriuretic peptide; MAP mean arterial pressure; NO = nitric oxide; PCI = percutaneous coronary intervention; PDE3i = phosphodiesterase-3 inhibitor; PE = pulmonary embolism; TTE = transthoracic echocardiography. Adapted from Harjola et al. 2016.33

cardiac output and exacerbate organ dysfunction.24,33,34 In patients with RV failure and signs of venous congestion, diuretics are often the first option to optimise volume status. Notably, in patients with massive renal congestion due to severe RV dysfunction and/or severe tricuspid regurgitation, sufficient renal perfusion pressure (i.e. mean arterial pressure minus central venous pressure) and an adequate diuretics plasma concentration are crucial to achieving the desired effect. Furthermore, since most of the effect of IV loop diuretics occurs within the first hours – with sodium excretion returning to baseline within 6–8 hours – 3–4 daily doses or continuous infusion are required to maintain the decongestive effect.35 In the context of RV failure, early evaluation of the diuretic response (by measuring urine output or post-diuretic spot urinary sodium content) to identify patients with an inadequate diuretic response is even more important than it is in other forms of acute heart failure. If decongestion is insufficient, rapid intensification of loop diuretic dose, starting a sequential nephron blockade (combining diuretics with a different mode of action) or the use of renal replacement therapy/ ultrafiltration should be considered. In the absence of elevated filling pressure, cautious volume loading guided by central venous pressure monitoring may be appropriate.33

Restoration of Perfusion Pressure Volume Optimisation A common misconception is that RV failure should consistently be treated with volume supplementation. Conversely, while the RV might physiologically be able to accommodate large variations in preload and some patients with RV failure are preload dependent, a large proportion of RV failure is caused, associated with or aggravated by RV volume overload. In such cases, volume loading has the potential to overdistend the RV and thereby increase wall tension, decrease contractility, aggravate tricuspid regurgitation, increase ventricular interdependence, impair LV filling and, ultimately, reduce systemic

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Vasopressors are primarily indicated to restore arterial blood pressure and improve organ perfusion. Noradrenaline can restore systemic haemodynamics without increasing RV afterload (i.e. there is no effect on pulmonary vascular resistance).36 Restoration of coronary perfusion pressure by vasopressors is a mainstay of therapy since the failing RV dealing with volume and/or pressure overload is particularly susceptible to ischaemic injury. Furthermore, vasopressors restore cerebral, renal and hepato-splanchnic perfusion pressures. Clinical data suggest that targeting a mean arterial pressure (MAP) of 65 mmHg may be reasonable. However, MAP alone should not be

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Advanced Heart Failure used as a surrogate measure of organ perfusion pressure, especially in patients with RV failure and severe tricuspid regurgitation with massively elevated central venous pressure. Organ-specific perfusion pressure targets include 50–70 mmHg for the brain, 65 mmHg for renal perfusion and >50 mmHg for hepato-splanchnic flow.37 Therefore, the MAP targets should be personalised based on the measures of organ function and tissue perfusion.

success are optimal patient selection (according to age, comorbidities, RV dysfunction aetiology and reversibility potential) and optimal timing of implantation to avoid significant, potentially irreversible end-organ injury. For that reason, these patients require close haemodynamic and laboratory monitoring, with particular attention to liver and kidney function, and early transfer to a centre with experience in RVAD implantation in case of persistent haemodynamic instability.

Improvement of Myocardial Contractility

Choosing the most appropriate device also maximises the success of mechanical circulatory support. First, the strategy (e.g. bridge to recovery, bridge to bridge – i.e. LVAD/biventricular VAD/total artificial heart – or bridge to transplant) should be defined. Second, the need for an oxygenator should be anticipated because it may influence device selection. Third, the function of both the LV and RV should be carefully assessed to predict the need for isolated RV support or biventricular support (either durable or temporary). In addition to device characteristics, it is crucial to consider local expertise and availability.

Dobutamine, levosimendan and phosphodiesterase III inhibitors improve contractility and increase cardiac output and are indicated in patients with severe RV failure causing cardiogenic shock despite treatment with vasopressors.33 Levosimendan and phosphodiesterase III inhibitors may favourably affect the ventricular-arterial coupling by combining RV inotropy and pulmonary vasodilation and might be preferentially indicated in patients with pulmonary hypertension caused by left heart disease.24,38 The use of epinephrine is not recommended.39–41

Advanced Options In patients with pre-capillary pulmonary hypertension, therapy should be driven by treatment of the underlying disease. Long-term oxygen therapy in hypoxic patients might stabilise pulmonary hypertension despite continued progression of lung disease, whereas supplementary oxygen in patients without hypoxia or moderate desaturation is not beneficial.42,43 The role of pulmonary vasodilators is highly controversial. Intravenous prostacyclin analogues effectively reduce RV afterload, but may aggravate systemic hypotension. Alternatively, inhaled nitric oxide or inhaled prostacyclin may be considered.33 These agents should be used only in an appropriate setting (specialised units) and in selected patients because of the risk of an increase in ventilation/perfusion mismatch and subsequent clinical deterioration. Notably, long-term therapy with phosphodiesterase-5 inhibitors, endothelin receptor antagonists, guanylate cyclase stimulators, prostacyclin analogues and prostacyclin receptor agonists are not recommended for the treatment of pulmonary hypertension due to left heart disease, which is the most prevalent cause of RV dysfunction. In patients with refractory RV failure despite treatment with vasopressors and inotropes, advanced therapeutic options including fibrinolysis for pulmonary embolism or mechanical circulatory support should be considered (see below). In the absence of long-term therapeutic options, palliation and supportive care should be offered to patients and relatives.44

Mechanical Circulatory Support for Advanced Right Ventricular Failure Mechanical circulatory support with RV assist devices (RVADs) should be considered when RV failure persists despite treatment with vasopressors and inotropes (Figure 3). Because reversibility of severe RV failure is more likely to be possible and more rapid than LV failure of similar magnitudes, temporary RVADs (t-RVADs) can be a valuable therapeutic option for many patients.45 The often-reported poor survival rates of RVAD recipients should not discourage the appropriate use of t-RVADs, because patient mortality depends mainly on the primary cause of RV failure, the severity of end-organ dysfunction and the timing of RVAD implantation, and much less on adverse events and complications related to RVAD implantation, mechanical support or removal (selection bias).12 The most important determinants of

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For short-term support, several t-RVADs, both percutaneous and surgical devices, are available. Percutaneous t-RVADs allow early initiation of support without the need for surgery. They are approved for a shorter period of time, and can sustain a lower flow than surgical devices. They are categorised according to their mechanism of action as either ‘direct RV bypass’, such as the Impella RP (Abiomed) and TandemHeart RVADs (TandemLife) or ‘indirect RV bypass’ systems, such as venous-arterial ECMO (VA ECMO).46 Impella RP is a microaxial flow 22 Fr catheter, approved for 14 days’ use, that delivers blood (at a rate of up to 4 l/min) from the RA into the pulmonary artery (PA).47 The TandemHeart RVAD uses an extracorporeal centrifugal flow pump and two venous cannulas or a single cannula with two lumens (Protek Duo cannula) to deliver blood from the RA to the PA with the additional possibility of oxygenating the blood.48 Directly bypassing the RV function reduces RA pressure, raises mean PA pressure and increases left ventricular preload, while the left ventricular afterload remains unchanged. The VA ECMO is the less expensive device. It bypasses the RV indirectly, displacing venous blood from the RA across an oxygenator into the peripheral arterial circulation. It induces a decrease in RA and PA pressure and LV preload but increases LV afterload if not cannulated centrally via surgical access.49 Surgical t-RVADs require an open sternotomy or thoracotomy for direct RA and PA cannulation and their connection to an extracorporeal centrifugal flow pump. They allow more extended and greater support in terms of flow at the cost of an invasive implantation and removal. However, more recently developed surgically implantable short-term extracorporeal CF-RVADs can be removed without reoperation; that is, the CentriMag system (Chalice Medical), which allows 30 days of support with up to 10 l/min blood flow).50 For more durable, long-term support, isolated pulsatile RVADs, surgically deployed rotary-flow RVADs and biventricular support with pulsatile VADs or total artificial heart replacement are potential options; however, the majority of patients using these are required to remain in the hospital under close surveillance. This is one reason why the use of durable isolated right ventricular assist devices (e.g. LVADs in the RV position) to support isolated RV or biventricular failure has been evaluated.51–54 A significant limitation of this approach is that LVADs are

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Right Ventricular Failure designed to operate in the systemic circulation with higher resistance and, where pulmonary resistance is low, they are more prone to complications, such as repetitive suction events. Because of the many technical limitations of durable RV support and because RV function may not recover, cardiac transplantation remains the only successful long-term treatment.

Arrhythmic Aspects of Right Ventricular Failure Cardiac rhythm plays an important yet often underestimated role in RV function. One one hand, the failing RV, specifically if experiencing an increased afterload, such as in pulmonary hypertension, is highly dependent on a regular heart rate to function adequately, as its contractile reserve is very limited.55 The need for a constant sympathetic drive to maintain cardiac output may be one reason why beta-blocker therapy is not effective in right heart failure.56 On the other hand, RV pressure overload, an integral part in the pathophysiology of RV failure, is often associated with supraventricular arrhythmias, such as atrial fibrillation, atrial flutter or (multi-)focal atrial tachycardia, all of which negatively affect RV filling and thereby contribute to the vicious cycle of aggravating RV failure, eventually culminating in cardiogenic shock. Therefore, in addition to careful volume management to optimise RV preload and RV wall stress, prompt rhythm control of supraventricular tachyarrhythmias is central. Importantly, diastolic filling of the failing RV depends on atrial contraction (‘atrial kick’) and atrioventricular synchrony.57,58 Therefore, rate control alone is generally insufficient to restore haemodynamic stability.59 In the acute setting, prompt electrical cardioversion (ECV) is the treatment of choice to restore sinus rhythm, although ECV efficacy in restoring and maintaining sinus rhythm may be reduced in critically ill patients.58,60,61 Retrospective analyses in patients with pulmonary hypertension indicate that maintaining sinus rhythm is associated with a reduction in clinical deterioration.62 Since beta-blockers and calcium channel antagonists may hamper RV contractility because of their negative inotropic effect, amiodarone should be used if antiarrhythmic medical therapy to maintain sinus rhythm is warranted. Class Ic antiarrhythmics, as well as sotalol and dronedarone, should not be used in structural heart disease. If medical therapy fails, AV synchronous pacing, with either the patient’s indwelling device or transvenous pacing wires may be considered.2 The interplay of the right and left ventricles, sharing their interventricular septum and competing for the limited space within the pericardium, leads to ventricular interdependence.33 Consequently, the loss of synchronous ventricular contraction is associated with a significant deterioration of RV contractile force. Notably, cardiac resynchronisation therapy (CRT) is standard care in patients with heart failure with reduced LV ejection fraction (HFrEF) and a wide QRS complex

1. Harvey W. Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus. 1628. 2. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular disease, part i: anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation 2008;117:1436–48. https://doi.org/10.1161/ CIRCULATIONAHA.107.653584; PMID: 18347220. 3. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. 50. Circulation 2008;117:1717–31. https://doi. org/10.1161/CIRCULATIONAHA.107.653584; PMID: 18378625.

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(>130 ms), and serves to resynchronise LV contraction. Many patients with HFrEF also have reduced RV function, either as a consequence of increased RV afterload (post-capillary pulmonary hypertension) or secondary to a cardiomyopathy affecting both ventricles.33 Because of anatomical and technical obstacles (difficult reliable assessment of RV function and the absence of an epicardial RV venous system for safe lead placement) and as RV function has gained attention only in recent years, very limited data on isolated right cardiac resynchronisation exist. However, though scarce, there are data on the interplay of LV resynchronisation and RV function. Indeed, reverse LV remodelling is associated with reduced RV afterload.63 Not surprisingly, several observational studies have demonstrated significant improvement in RV function after CRT.64 Similarly, CRT was associated with significant improvement of RV fractional area change in a post-hoc analysis of the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy trial (MADITCRT).65 However, no such effect was observed in a post-hoc analyses of the REsyncronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) and Cardiac Resynchronization-Heart Failure (CARE-HF) trials, which used TAPSE to assess RV function.66,67 Of note, TAPSE is mainly influenced by longitudinal movement of the RV free wall and may underestimate the contribution of the interventricular septum and outflow tract. Importantly, both observational studies and post-hoc analyses of randomised clinical trials may serve only to generate hypotheses and do not allow reliable conclusions. The value of left cardiac resynchronisation in isolated RV failure is unknown. Similarly, data on the prevalence of sudden cardiac death (SCD) in isolated RV failure are scarce, at best. It is therefore not surprising that current guidelines do not recommend ICD therapy for primary prevention of SCD in patients with isolated RV failure.68 An exemption is patients with arrhythmogenic RV cardiomyopathy, in whom, if certain risk factors for SCD are present, an ICD for primary prevention of SCD may be considered (IIb; level of evidence C). In cases of secondary prevention, on the other hand, after documented haemodynamically relevant ventricular tachycardia or following survived SCD, and after secondary causes have been excluded, ICD therapy is recommended, regardless of right or left ventricular function.

Conclusion The assessment of RV failure should consider the anatomical and physiological particularities of the RV and include appropriate imaging techniques to understand the underlying pathophysiological mechanisms. Treatment should include rapid optimisation of volume status, restoration of perfusion pressure, and improvement of myocardial contractility and rhythm and, in case of refractory RV failure, mechanical circulatory support.

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Echocardiogr 2010;23:685–71. https://doi.org/10.1016/j. echo.2010.05.010; PMID: 20620859. Valsangiacomo Buechel ER, Mertens LL. Imaging the right heart: the use of integrated multimodality imaging. Eur Heart J 2012;33:949–60. https://doi.org/10.1093/eurheartj/ehr490; PMID: 22408035. van der Zwaan HB, Geleijnse ML, McGhie JS, et al. Right ventricular quantification in clinical practice: two-dimensional vs. three-dimensional echocardiography compared with cardiac magnetic resonance imaging. Eur J Echocardiogr 2011;12:656–64. https://doi.org/10.1093/ejechocard/jer107; PMID: 21810828. Focardi M, Cameli M, Carbone SF, et al. Traditional and innovative echocardiographic parameters for the analysis of right ventricular performance in comparison with cardiac magnetic resonance. Eur Heart J Cardiovasc Imaging 2015;16:47–52. https://doi.org/10.1093/ehjci/jeu156; PMID: 25187607. Harjola VP, Mebazaa A, Čelutkienė J, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016;18:226–41. https://doi.org/10.1002/ejhf.478; PMID: 26995592. 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. Mullens W, Damman K, Harjola V-P, et al. The use of diuretics in heart failure with congestion – a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:137–55. https://doi. org/10.1002/ejhf.1369; PMID: 30600580. Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984;60:132–5. https://doi. org/10.1097/00000542-198402000-00009; PMID: 6198941. Kato R, Pinsky MR. Personalizing blood pressure management in septic shock. Ann Intensive Care 2015;5:41. https://doi. org/10.1186/s13613-015-0085-5; PMID: 26573630. Arrigo M, Mebazaa A. Understanding the differences among inotropes. Intensive Care Med 2015;41:912–5. https://doi. org/10.1007/s00134-015-3659-7; PMID: 25605474. Levy B, Perez P, Perny J, et al. Comparison of norepinephrinedobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med 2011;39:450–5. https://doi.org/10.1097/ CCM.0b013e3181ffe0eb; PMID: 21037469. Levy B, Clere-Jehl R, Legras A, et al. Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2018;72:173–82. https://doi. org/10.1016/j.jacc.2018.04.051; PMID: 29976291. Léopold V, Gayat E, Pirracchio R, et al. Epinephrine and shortterm survival in cardiogenic shock: an individual data metaanalysis of 2583 patients. Intensive Care Med 2018;44:847–56. https://doi.org/10.1007/s00134-018-5222-9; PMID: 29858926. Zieliński J, Tobiasz M, Hawryłkiewicz I, et al. Effects of longterm oxygen therapy on pulmonary hemodynamics in COPD patients: a 6-year prospective study. Chest 1998;113:65–70. https://doi.org/10.1378/chest.113.1.65; PMID: 9440570. Ekström M. Clinical usefulness of long-term oxygen therapy in adults. N Engl J Med 2016;375:1683–4. https://doi.org/10.1056/ NEJMe1611742; PMID: 27783914. Nieminen MS, Dickstein K, Fonseca C, et al. The patient perspective: quality of life in advanced heart failure with frequent hospitalisations. Int J Cardiol 2015;191:256–64. https:// doi.org/10.1016/j.ijcard.2015.04.235; PMID: 25981363. Verbelen T, Claus P, Burkhoff D, et al. Low-flow support of the chronic pressure-overloaded right ventricle induces reversed remodeling. J Heart Lung Transplant 2018;37:151–60. https://doi. org/10.1016/j.healun.2017.09.014; PMID: 29056459. Kapur NK, Esposito ML, Bader Y, et al. Mechanical circulatory support devices for acute right ventricular failure. Circulation 2017;136:314–26. https://doi.org/10.1161/ CIRCULATIONAHA.116.025290; PMID: 28716832. Pieri M, Pappalardo F. Impella RP in the treatment of right ventricular failure: what we know and where we go. J Cardiothorac Vasc Anesth 2018;32:2339–43. https://doi. org/10.1053/j.jvca.2018.06.007; PMID: 30093192. Kapur NK, Paruchuri V, Jagannathan A, et al. Mechanical circulatory support for right ventricular failure. JACC Heart Fail 2013;1:127–34. https://doi.org/10.1016/j.jchf.2013.01.007; PMID: 24621838. Truby L, Mundy L, Kalesan B, et al. Contemporary outcomes of venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock at a large tertiary care

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center. ASAIO J 2015;61:403–9. https://doi.org/10.1097/ MAT.0000000000000225; PMID: 26125665. Bhama JK, Kormos RL, Toyoda Y, et al. Clinical experience using the Levitronix CentriMag system for temporary right ventricular mechanical circulatory support. J Heart Lung Transplant 2009;28:971–976. https://doi.org/10.1016/j. healun.2009.04.015; PMID: 19716053. Krabatsch T, Hennig E, Stepanenko A, et al. Evaluation of the HeartWare HVAD centrifugal pump for right ventricular assistance in an in vitro model. ASAIO J 2011;57:183–7. https:// doi.org/10.1097/MAT.0b013e318211ba2b; PMID: 21336105. Frazier OH, Myers TJ, Gregoric I. Biventricular assistance with the Jarvik FlowMaker: a case report. J Thorac Cardiovasc Surg 2004;128(4):625–6. https://doi.org/10.1016/j.jtcvs.2004.02.023; PMID: 15457169. Strueber M, O’Driscoll G, Jansz P, et al. Multicenter evaluation of an intrapericardial left ventricular assist system. J Am Coll Cardiol 2011;57:1375–82. https://doi.org/10.1016/j. jacc.2010.10.040; PMID: 21414534. Connellan M, Iyer A, Robson D, et al. The HeartWare transvalvular miniature ventricular assist device used for right ventricular support. J Heart Lung Transplant 2013;32:S149. https:// doi.org/10.1016/j.healun.2013.01.339. Groepenhoff H, Westerhof N, Jacobs W, et al. Exercise stroke volume and heart rate response differ in right and left heart failure. Eur J Heart Fail 2010;12:716–20. https://doi.org/10.1093/ eurjhf/hfq062; PMID: 20413396. Andersen S, Andersen A, de Man FS, Nielsen-Kudsk JE. Sympathetic nervous system activation and β-adrenoceptor blockade in right heart failure. Eur J Heart Fail 2015;17:358–66. https://doi.org/10.1002/ejhf.253; PMID: 25704592. Goldstein JA, Tweddell JS, Barzilai B, et al. Right atrial ischemia exacerbates hemodynamic compromise associated with experimental right ventricular dysfunction. J Am Coll Cardiol 1991;18:1564–72. https://doi.org/10.1016/07351097(91)90691-2; PMID: 1939962. King C, May CW, Williams J, Shlobin OA. Management of right heart failure in the critically ill. Crit Care Clin 2014;30:475–98. https://doi.org/10.1016/j.ccc.2014.03.003; PMID: 24996606. Hoeper MM, Granton J. Intensive care unit management of patients with severe pulmonary hypertension and right heart failure. Am J Respir Crit Care Med 2011;184:1114–24. https://doi. org/10.1164/rccm.201104-0662CI; PMID: 21700906. Kholdani CA, Fares WH. Management of right heart failure in the intensive care unit. Clin Chest Med 2015;36:511–20. https:// doi.org/10.1016/j.ccm.2015.05.015; PMID: 26304287. Arrigo M, Jaeger N, Seifert B, et al. Disappointing success of electrical cardioversion for new-onset atrial fibrillation in cardiosurgical ICU patients. Crit Care Med 2015;43:2354–9. https://doi.org/10.1097/CCM.0000000000001257; PMID: 26468695. Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 2007;153:127–32. https:// doi.org/10.1016/j.ahj.2006.09.008; PMID: 17174650. Abraham WT, Hayes DL. Cardiac resynchronization therapy for heart failure. Circulation 2003;108:2596–603. https://doi.org/10.1161/01.CIR.0000096580.26969.9A; PMID: 14638522. Ricci F, Mele D, Bianco F, et al. Right heart-pulmonary circulation unit and cardiac resynchronization therapy. Am Heart J 2017;185:1–16. https://doi.org/10.1016/j. ahj.2016.11.005; PMID: 28267462. Campbell P, Takeuchi M, Bourgoun M, et al. Right ventricular function, pulmonary pressure estimation, and clinical outcomes in cardiac resynchronization therapy. Circ Heart Fail 2013;6:435–42. https://doi.org/10.1161/ CIRCHEARTFAILURE.112.000127; PMID: 23524528. Damy T, Ghio S, Rigby AS et al. Interplay between right ventricular function and cardiac resynchronization therapy: an analysis of the CARE-HF trial (Cardiac ResynchronizationHeart Failure). J Am Coll Cardiol 2013;61:2153–60. https://doi. org/10.1016/j.jacc.2013.02.049; PMID: 23541971. Kjaergaard J, Ghio S, St John Sutton M, Hassager C. Tricuspid annular plane systolic excursion and response to cardiac resynchronization therapy: results from the REVERSE trial. J Card Fail 2011;17:100–7. https://doi.org/10.1016/j. cardfail.2010.09.002; PMID: 21300298. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;26:2793–867. https://doi.org/10.1093/eurheartj/ehv316; PMID: 26320108.

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Advanced Heart Failure

State-of-the-art Structural Interventions in Heart Failure Jeffrey Park and Hussam S Suradi 1. Department of Internal Medicine, Division of Cardiovascular Medicine, Rush University Medical Center, Chicago, IL, US

Abstract Heart failure (HF) is a leading cause of hospitalisation and healthcare costs worldwide. Acute decompensated heart failure accounts for more than 1 million hospitalisations in the US. Despite advances in the quality of acute and chronic HF disease management, gaps in knowledge about effective interventions to support the transition of care for patients with HF remain. Despite multiple trials of promising therapies, standard care consists of decongestion with IV diuretics and haemodynamic support with vasodilators and inotropes and this has remained largely unchanged during the past 45 years. Newer advances in medical innovations and structural heart disease interventions have now given promise to improved survival, outcomes and quality of life for patients with advanced HF of multiple aetiologies. In this article, we focus on structural interventions in the treatment of patients with HF.

Keywords Structural interventions, heart failure interventions, percutaneous valve replacement Disclosure: The authors have no conflicts of interest to declare. Received: 25 April 2019 Accepted: 5 July 2019 Citation: Cardiac Failure Review 2019;5(3):147–54. DOI: https://doi.org/10.15420/cfr.2019.12.2 Correspondence: Hussam Suradi, 1725 W Harrison Street, Suite 1159, Chicago, IL 60612, US. E: Hussam_Suradi@rush.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 non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a major national and international pandemic with a prevalence of more than 5.8 million in the US and over 26 million worldwide. It is the leading cause of hospitalisation and healthcare costs in the US and it accounts for more than 1 million hospitalisations annually. In the US, up to 25% of patients hospitalised with HF are readmitted within 30 days.1 The financial burden of acute decompensated heart failure (ADHF) on the healthcare system was estimated at $30.7 billion in 2012, with a projected threefold increase by 2030, leading to a total of $160 billion total annual cost.2

Identiﬁcation of the mechanisms responsible for HF is essential in the management of patients with SHD because these can become targets for therapies.4,5

HF has multiple aetiologies and the goal of therapy is aimed not only at resolving the root cause but providing symptomatic relief in light of medication failure. The major causes of HF are distinguished between those involving heart muscle disease including those with ischaemic and non-ischaemic cardiomyopathies and those with structural abnormalities.

Acquired Defects

The adult with CHD (ACHD) or structural heart disease (SHD) represents a large proportion of the HF epidemic. With congenital heart disease (CHD) present in 0.8% to 1.0% of live births, and the advances in medical and surgical therapies for children with CHD, the growing proportion of these patients reaching adulthood now exceeds 85% with an estimated 1.2 million patients in this group in the US.3 SHD essentially encompasses a wide range of non-coronary cardiac disease processes, some of which include valvular disease, paravalvular leak and septal defects. Historically, the mainstay of therapy has been cardiac surgery for these types of disease, but with the advent of new minimally invasive technologies and techniques, structural intervention has changed the way this subset of patients receives treatment and has resulted in newer therapies that can be used in patients with HF.

Over the past decades, the rapid development of successful transcatheter procedures has led to interventional procedures becoming the primary treatment for many forms of SHD. In this article, we focus on structural interventions for the treatment of patients with HF due to both acquired and congenital defects.

Aortic Stenosis Aortic stenosis (AS) is one of the most common valvular pathologies with sclerosis being present in 21–26% of people aged 65 years or older. The most common aetiology is senile or calcific aortic stenosis with younger people either being diagnosed at birth or with early degenerative valves (i.e. bicuspid valves).6,7 Patients are usually asymptomatic until late in the course of the disease when they have a high risk of acute decompensation especially when associated with congestive HF.8 Survival analyses have demonstrated that the interval from the onset of symptoms to the time of death is about 2 years in patients with HF.9,10 Stewart et al. reported that among symptomatic patients with moderate-to-severe AS who had been treated medically, mortality rates after the onset of symptoms were about 25% at 1 year and 50% at 2 years.11 More than 50% of deaths were sudden. Transcatheter interventions are at the forefront of treatment options for severe AS. Balloon aortic valvuloplasty (BAV) has been a

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Advanced Heart Failure Figure 1: Valve-in-valve Transcatheter Aortic Valve Replacement

Cinefluoroscopic steps during valve-in-valve transcatheter aortic valve replacement (TAVR) using an Edwards Sapien III. A: Intra-operative fluoroscopy with pigtail catheter positioned across prior bioprosthetic valve. B: Contrast injection with visualisation of coronary heights in relation to TAVR valve for positioning. C:TAVR deployment. D: Post-TAVR injection showing valve position with no significant aortic regurgitation.

Figure 2: Percutaneous Balloon Mitral Valvuloplasty

Cinefluoroscopic steps during percutaneus balloon mitral valvuloplasty using Inoue balloon for severe mitral stenosis. A: Intra-operative transesophageal echocardiography with visualisation of severe mitral stenosis. B: Balloon catheter advanced across mitral valve in position. C,D: Sequential inflation of the Inoue balloon across the mitral valve.

long-standing option for younger patients with bicuspid valves with current practice guidelines recommending it for symptomatic young adults without severe calcification and less than moderate regurgitation with a peak-to-peak gradient of 50 mmHg, or asymptomatic young adults with ST-T changes and a peak-to-peak gradient of 60 mmHg.11,12 BAV is also a viable option for patients who have advanced HF who are haemodynamically unstable or as a palliative approach when the effect is time limited. Since the onset of transcatheter aortic valve replacement (TAVR), multiple trials have supported its use in patients with severe AS in various stages of their disease process. The Placement of AoRTic TraNscathetER Valve Trial (PARTNER) trials have studied TAVR in patients with severe AS and high-, moderate- and low-risk patients, respectively. The results of the trials have all favored TAVR as an option over surgical AVR and has now become one of the most promising advances in structural heart disease. Recent data have shown a decline in hospitalisation from HF from 15.9% pre-TAVR to 14.2% in the year after TAVR with the majority of hospitalisations being due to non-cardiac causes.13 In a retrospective study performed by Muratori et al., TAVR patients showed an average improvement in New York Heart Association (NYHA) class of â&#x2030;Ľ1 at 6 and 12 months post-implantation with marked reduction in the degree of LV diastolic dysfunction regardless of baseline LV ejection fraction. There was improvement in LV end-systolic volume and LV mass index at 6 and 12 months.14 With newer technologies, such as the CoreValve Evolut Pro (Medtronic) self-expanding valve and the enhanced paravalvular sealing effect

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of the third-generation SAPIEN 3 valve, TAVR has become a viable option for bicuspid aortic valve stenosis and can effectively treat AS before the onset of worsening clinical symptoms and deterioration. The benefits of TAVR extend further to a subset of patients who have had prior valve replacement. As bioprosthetic valves degenerate, recurrent severe AS or regurgitation can progress with limited means of intervention. Transcatheter valve in valve (ViV) TAVR procedures have been performed in patients who are considered high surgical risk with excellent results and this technology is being further studied in the low surgical risk population (Figure 1).

Mitral Stenosis Mitral stenosis (MS) is characterised by a reduction in the mitral valve (MV) orifice area causing obstruction of left ventricular (LV) inflow and decreased LV filling. Although its prevalence has declined, especially in developed countries, it is still an important cause of morbidity and mortality. Rheumatic fever still remains the predominant cause of MS worldwide accounting for about 10% of native valve disease, but the incidence of degenerative MS has been more pronounced in developed countries. MS caused by rheumatic fever occurs due to post-rheumatic commissural fusion usually in adolescents. The calcified changes of the mitral annulus cause degenerative MS most commonly seen in the elderly. The decrease in the mitral valve (MV) orifice area causes stagnation of blood proximal to the MV that results in elevated left atrial, pulmonary venous and pulmonary artery pressures ultimately leading to HF.

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State-of-the-art Structural Interventions in Heart Failure Figure 3: MitraClip Placement

A: Intra-operative transesophageal 3D ECG showing severe mitral insufficiency. B: Transesophageal echo-guided advancement of MitraClip system via transseptal access. C: MitraClip successfully placed across the anterior and posterior leaflets. D: Transesophageal echocardiography showing signficant decrease in mitral regurgitant jet. E: Transesophageal echocardiography 3D image showing MitraClip successfully placed between the A2/P2 leaflets with mild mitral regurgitation. F: Intraoperative fluoroscopy showing MitraClip successfully in place.

Mitral valve intervention has been the mainstay of therapy for symptomatic patients with the option of balloon valvuloplasty or surgical valve replacement.15 Percutaneous mitral balloon valvuloplasty (PMBV) is the preferred treatment for patients with favourable anatomy based on their Wilkins score which takes into account MV leaflet mobility, thickening, calcification and subvalvular thickening with a score ÂŁ8 favouring PMBV.16 Recent data have shown that patients with suitable anatomy for PMVB exhibited a 75% sustained durability over a 23-year span with median 8.3-year follow-up. Meneguz-Moreno reported that during follow-up, the majority of patients (93.1%) had improvement in NYHA classification in the first post-procedural year with 13% developing NYHA class III/ IV symptoms associated with poor outcomes; 19.1% of patients had a primary endpoint, including 0.6% who died, 8.8% who underwent mitral valve surgery and 10% who required another PMBV (Figure 2).16 In the case of degenerative MS, patients tend to be older with higher surgical risks and significant calcification making PMBV suboptimal leaving them with few treatment options.17 Transcatheter mitral valve replacement (TMVR) is an evolving therapy where the mitral valve is accessed via a transseptal or transapical approach and a new valve is deployed reducing the risks of a more aggressive surgical approach. It has allowed for an expanded treatment option for patients with degenerative MS with the ability of valve replacement in patients with significant mitral annular calcification (MAC). Complications vary and include compromised left circumflex artery, severe bleeding and atrioventricular rupture but TMVR has been a promising field for advancement especially for the symptomatic patients with recurrent HF admissions deemed non-surgical candidates.18

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Mitral and Tricuspid Valve Regurgitation Long-standing HF leads to distortion of the structural integrity of the heart causing LV dilatation and dislocation of the papillary muscles and chordae tendinae cause worsening mitral regurgitation (MR) from impaired coaptation of the mitral valve leaflets. Such secondary (functional) mitral regurgitation increases the severity of volume overload and has been strongly associated with a reduced quality of life, an increased rate of hospitalisation for HF and shortened survival.19 Guideline-directed medical therapy and cardiac resynchronisation therapy may provide symptomatic relief, improve LV function and, in some patients, lessen the severity of MR but whether the correction of secondary MR improves the prognosis among patients with HF is unknown.20 Although mitral valve surgery is curative for primary (degenerative) MR, neither surgical repair nor surgical replacement of the mitral valve has been shown to lower the rate of hospitalisation or death associated with secondary MR and both procedures confer a substantial risk of complications.21 One of the most innovative advances in SHD stems from the recently published Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial which involved patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy; transcatheter mitralvalve repair with MitraClip (Abbott) resulted in a lower rate of hospitalisation for HF and lower all-cause mortality within 24

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Advanced Heart Failure Figure 4: Valve-in-valve Transcatheter Mitral Valve Replacement

A: Intra-operative fluoroscopy with visualisation of prior mitral bioprosthetic valve. B: Stiff wire advanced across previously placed valve. C: Percutaneous valve (SAPIEN III) advanced across valve and positioned. D: Valve deployment across mitral prosthesis.

months of follow-up compared with medical therapy alone.22 The study found that the annual rate of all-hospitalisation for HF was significantly lower in the device group at 35.8% compared with 67.9% in the control group with a number needed to treat of 3.1. All-cause mortality benefit was also significantly lower in the device group at 29.1% versus 46.1% (HR: 0.62, p<0.001) with the number needed to treat to save one life within 24 months being five.22 The MitraClip has also been approved for degenerative (primary) MR in patients who are

conduit is used between the right ventricle and pulmonary artery, are the two largest adult patient groups who are receiving these valves. Even though tPVR is not currently a standard indication in adults with native RVOT dysfunction, many centres have performed tPVR in a select group of adults who have a native outflow tract (post transannular patch repair of tetralogy of Fallot) that is an appropriate size or one that can be altered to a suitable size by insertion of multiple stents.25

considered high risk for surgery (Figure 3).

It is crucial that only appropriate patients are selected for pulmonary valve replacement and the guidelines for surgical and transcatheter pulmonary valve replacement have continued to evolve over the past decade.26–30 Pulmonary valve replacement should ideally be performed before RV function declines. In addition to clinical indications, several anatomical criteria need to be fulfilled to qualify for tPVR with the ideal anatomy being a uniform diameter from RVOT to pulmonary artery with adequate main pulmonary artery length to avoid stenting into the pulmonary artery bifurcation (Figure 5). When the conduit is placed on the anterior surface of the heart, coronary branches may pass directly beneath it, and they may be compressed by the placement of the stented valve and distension of the conduit.7 If no evidence of coronary compression is noted, pre-stenting of the RVOT is performed to create an appropriate landing zone for the transcatheter valve. Pre-stenting the landing site has significantly improved the survival of the implant, minimising stent fracture which affected 23% of the initially reported cases of the Melody valve (Medtronic).25

With the advances in transcatheter therapies, new innovations for the treatment of tricuspid regurgitation has emerged MitraClip device has been used as an off-label treatment option as reported by Nickenig et al.23 In their report, patients with HF symptoms and severe TR were randomised to medical therapy versus MitraClip for chronic, severe TR and with a successful implantation rate of 97%, they found the grade of TR to be reduced by at least one grade in 91% with significant reduction in echo parameters associated with severe TR. Newer technologies and studies are ongoing for TTVR repair including a large Triclip study creating a ‘triple-orifice technique’ of clipping between the septal and anterior, as well as the septal and posterior leaflets, while avoiding grasping between the posterior and anterior leaflet.24 The Trialign and TriClinch annuloplasty systems are also showing promises to alternative valvular interventions.24 Similar to patients with failed bioprosthetic aortic valves, ViV transcatheter approaches have also been used with great success in patients with dysfunctional mitral and tricuspid bioprosthetic valves using the Edwards Sapien 3 valve (Figure 4).

Percutaneous Pulmonary Valve Implantation Transcatheter pulmonary valve replacement (tPVR) is one of the more recent developments in the treatment of SHD and HF and has evolved as an attractive alternative to surgery in patients with dysfunctional right ventricle-pulmonary artery conduits or bioprosthetic valves. The most common indication of pulmonary valve implantation is residual right ventricular outflow tract (RVOT) lesion after repair of CHD that can be stenotic, regurgitant or mixed. The advent of tPVR with Melody and Sapien valves has dramatically altered the management of these patients. Patients with tetralogy of Fallot who have had valved conduits or bioprosthetic valves placed and patients who have had the Ross procedure, where the pulmonary valve is autotransplanted to replace the diseased aortic valve and a valved

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Outcomes were recently reported from the COngenital Multicenter Trial of Pulmonic VAlve Regurgitation Studying the SAPIEN InterventIONal THV (COMPASSION) trial showing a significant improvement in NYHA functional class in 93.5% of patients with freedom from all-cause mortality at 3 years being 98.4%.31 Similar findings were reported from the Melody Trial with functional outcomes improving post tPVR.31 The patients enrolled were NYHA class I (17%), class II (67%) or class III (16%) with median RV systolic pressure of 74 mmHg. At 12 months, the median RV pressure decreased to 51 mmHg and there was a significant improvement in NYHA functional class with patients. At 6-month, 1-year and 2-year follow-up, patients continued to see improvement in their functional status with only 1–2% being class III or IV at the median followup of 4.5 years.32

Paravalvular Leak Prosthetic paravalvular leaks (PVLs) are a well-recognised complication of both surgical and transcatheter valve replacement. Various series have demonstrated that 5–15% of all surgical valve replacements are

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State-of-the-art Structural Interventions in Heart Failure Figure 5: Transcatheter Pulmonary Valve Replacement

Cinefluoroscopic steps during transcatheter pulmonic valve replacement and evaluation post-deployment. A: Initial injection showing severe pulmonic regurgitation. B: Balloon valvuloplasty of pulmonic valve in preparation for stent placement. Aortography confirms no compression of the epicardial coronary arteries. C: Bare-metal stent placement with aortography confirming no coronary compression. D,E: SAPIEN III valve positioning and deployment. F: Successful implantation of transcatheter pulmonary valve replacement with no residual regurgitation.

complicated by some form of PVL and 40–70% of patients who undergo transcatheter aortic valve replacement.33–35 Significant PVL can lead to major clinical and haemodynamic consequences and it can affect long-term survival. Symptoms may range from a decrease in functional class to severely decompensated CHF and/or haemolysis. Furthermore, persistent PVL has been shown to increase mortality.35 Reoperation for PVL is associated with a high recurrence rate and carries significant morbidity and mortality risks. With the advent of recent developments in percutaneous interventions for the treatment of SHD, efforts have been made to seal PVL percutaneously by delivering occluders to the site of leak, preventing or reducing the amount of regurgitation. The percutaneous approach is now an established therapy for symptomatic patients with PVL and is frequently considered as a primary therapy for eligible patients and can be performed via a retrograde transaortic, anterograde transseptal or transapical (TA) approach (Figure 6).36 In the US, there are no approved devices that are designed specifically for PVL closure and Amplatzer occluders are the most commonly used off-label devices (Figure 1). For large PVLs, multiple devices might need to be used either sequentially or simultaneously. Outside the US, there are devices designed specifically for closure of paravalvular mitral leaks, such as Occlutech PLD devices and Amplatzer Vascular Plug-III Figure 1).37,38

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Congenital Defects Pulmonary Valve Stenosis Pulmonary valve stenosis (PVS) is a common congenital lesion found in children that may escape detection in childhood and present in adulthood with significant stenosis. It is typically caused by commissural fusion resulting in diminished valve orifice and increased RV afterload. Symptoms may vary from mild exertional dyspnoea to signs and symptoms of right HF, depending upon the severity of obstruction and the degree of myocardial compensation. Balloon pulmonary valvuloplasty has evolved to be the procedure of choice for the treatment of pulmonary valve stenosis. Indications for intervention on isolated pulmonic stenosis include peak gradient >50 mmHg or mean gradient >30 mmHg in symptomatic patients. In asymptomatic patients, intervention may be considered with peak gradient greater than 60 mmHg or mean gradient greater than 40 mmHg.37 Balloon pulmonary valvuloplasty has uniformly excellent results in all age groups, with results comparable to surgical valvotomy, it has low recurrence risk and can be easily repeated if necessary. The double-balloon technique, which uses two smaller balloons from each femoral vein, has also been applied to pulmonary valve stenosis with excellent results.39

Atrial Septal Defects Atrial septal defect (ASD) is the most common form of CHD to escape detection in childhood comprising between 20 and 40% of all newly

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Advanced Heart Failure Figure 6: Paravalvular Leak Closure

A,B: Intraoperative transesophageal echocardiography showing severe paravalvular regurgitation in the septal position. C: 3D transesophageal echocardiography post-implantation of occluder device showing no significant paravalvular leak. D: Mitral paravalvular leak crossed using wire following percutaneous apical access. E: Closure of paravalvular leak using Amplatzer muscular ventricular septal defect. F: Post-deployment ventriculogram showing no significant mitral regurgitation.

Figure 7: Atrial Septal Defect Closure

Cinefluoroscopic steps during Amplatzer septal occluder (ASO) device deployment and evaluation post deployment. A: Right upper pulmonary vein angiogram in the four chamber view profiling the atrial septum with a central secundum atrial septal defect (ASD). B: Balloon sizing of the ASD to measure the â&#x20AC;&#x2DC;stop-flow diameterâ&#x20AC;&#x2122;. C: ASO deployment. D: Right atrial angiogram after the device has been deployed but not released showing good device position; E: ASO device has been released.

diagnosed CHD in adults. Under normal physiological conditions, flow through an ASD occurs from left to right at a variable degree depending on the defect size, ventricular compliance and the pulmonary vascular resistance. Excessive flow through the defect can eventually result in chronic right heart volume loading state, eventually leading to longterm complications in the second or third decade of life including premature death, atrial arrhythmias, reduced exercise tolerance, RV diastolic and systolic failure, LV diastolic failure and pulmonary arterial hypertension.40,41 Therefore, early closure of haemodynamically significant defects is recommended.

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Percutaneous closure of secundum ASD is currently the standard of care with a success rate exceeding 98% among patients who have suitable margins and defect size. Depending on the experience of the operator, the procedure may be done under conscious sedation using intracardiac echocardiography (ICE) or under general anaesthesia with the use of transesophageal echocardiography (TEE) to define the anatomy of the defect and to guide device deployment. The choice of device depends on its availability, the exact anatomy of the defect as well as operator preference. In the US, two devices are approved for this indication: the Amplatzer Septal Occluder device (St Jude Medical)

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State-of-the-art Structural Interventions in Heart Failure Figure 8: Membranous Ventricular Septal Defect Closure

Perimembranous iatrogenic ventricular septal defect closure using Amplatzer membranous ventricular septal defect (VSD) device. A: Left ventricular angiogram in long axial oblique view demonstrating a membranous VSD. B,C: Amplatzer membranous VSD positioned across defect. D: Repeat left ventricular angiogram after device release demonstrating good device position and minimal residual flow through the device.

Figure 9: Patent Ductus Arteriosus Closure

Cineangiographic images during patent ductus arteriosus (PDA) closure using Amplatzer duct occluder (ADO) device. A: Aortic angiogram demonstrating small PDA (arrow). B: Repeat angiogram prior to device release demonstrating good device position. C: Final angiogram after device release demonstrating good device position and no residual shunt. Source: Dr Ziyad Hijazi. Used with permission.

and the Gore Helex Septal Occluder (Gore Medical). Multiple other devices are available internationally, the most commonly used is the Occlutech Figulla Flex II device (Occlutech), a double-desk device similar in design to the Amplatzer septal occluder (Figure 7).

Ventricular Septal Defect Ventricular septal defects (VSD) comprise as many as 10% of SHD patients and are classified as inflow, muscular, or perimembranous depending on their location in the septum. VSDs can also be iatrogenic from previous procedures including post-septal myomectomy or aortic valve replacement. Significant VSD can result in LV volume overload, ventricular failure and pulmonary hypertension, typically at a younger age than patients with ASDs. Therefore, most patients with large shunts are usually diagnosed and treated in childhood. VSD closure in the adult is recommended for significant left-to-right shunt greater than 1.5:1, evidence of LV volume overload, symptoms of HF or when accompanied by progressive aortic regurgitation or after an episode of endocarditis.42 Device closure of VSDs has become more common and can be performed safely and effectively.43 Only muscular VSD closure is FDA approved. Since the introduction of the Amplatzer devices to close VSDs in 1998, the outcomes of

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percutaneous VSD closure have significantly improved and results have been promising as these were specifically designed for closure of VSDs.43 The wide variability in VSD location, size and morphology led to the development of different designs of the Amplatzer VSD devices (Figure 3). Other non-Amplatzers devices are also available for use. Additionally, perventricular â&#x20AC;&#x2DC;hybridâ&#x20AC;&#x2122; surgical approaches have been performed, in which a surgical incision exposes the right ventricular free wall followed by device closure in the usual fashion (Figure 8).

Patent Ductus Arteriosus The overwhelming majority of patent ductus arterioses (PDA) are diagnosed and treated during childhood with medications or with catheter-based techniques. Our standard practice for PDA closure in the paediatric population is for hemodynamically significant shunt with evidence of left heart enlargement or when there is a continuous murmur. Silent PDA without an audible murmur is considered benign and does not warrant closure. PDA is a relatively uncommon finding in adults, usually discovered incidentally while investigating symptoms, such as dyspnoea or palpitations, evaluation of a murmur or after an episode of endarteritis. Similar to the paediatric population, large PDAs with significant left-to-right shunt should be closed to reduce occurrence of the sequelae of ventricular failure or pulmonary arterial hypertension.

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Advanced Heart Failure Catheter-based closure of PDAs in adults can be more challenging and complex compared with closure in the paediatric population, as PDAs tend to be calcified and more tortuous.44 Nevertheless, transcatheter closure remains more desirable compared with surgery because of the potential for recurrent laryngeal nerve damage during surgery for calcified PDAs. With the availability of different devices developed specifically for PDA closure, greater than 99% of PDAs are amenable to transcatheter closure (Figure 9).

Coronary Artery Fistula Coronary artery fistulae are connections between the coronary arteries and the cardiac chambers or great vessels. The majority of fistulae originate from the right coronary artery, with the left anterior descending artery being the next most frequently involved. The major termination sites are the right cardiac chambers and pulmonary arteries. Less frequently, fistulae drain into the superior vena cava, coronary sinus or left cardiac chambers. Most fistulae are small and clinically silent. However, larger fistulae can lead to significant left-toright shunting with right-sided volume overload and effective coronary arterial steal leading to ischaemia.

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ariell J, Brozena S. Heart failure. N Engl J Med 2003;348:2007– M 18; https://doi.org/10.1056/NEJMra021498; PMID: 12748317. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 2010;8:30–41. https://doi. org/10.1038/nrcardio.2010.165; PMID: 21060326. Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5-year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005;26:2325–33. https://doi.org/10.1093/eurheartj/ehi396; PMID: 15996978. Ziaeian B, Fonarow GC. The prevention of hospital readmissions in heart failure. Prog Cardiovasc Dis 2015;58:379–85. https://doi. org/10.1016/j.pcad.2015.09.004; PMID: 26432556. Kripalani S, Theobald CN, Anctil B, Vasilevskis EE. Reducing hospital readmission rates: current strategies and future directions. Annu Rev Med 2013;65:471–85. https://doi. org/10.1146/annurev-med-022613-090415; PMID: 24160939 Supino PG, Borer JS, Preibisz J, Bornstein A. The epidemiology of valvular heart disease: a growing public health problem. Heart Fail Clin 2006;2:379–93. https://doi.org/10.1016/j.hfc. 2006.09.010; PMID: 17448426. Pibarot P, Dumesnil JG. New concepts in valvular hemodynamics: implications for diagnosis and treatment of aortic stenosis. Can J Cardiol 2007;23:40B–7. https://doi. org/10.1016/S0828-282X(07)71009-7; PMID: 17932586. Rashedi N, Otto CM. Aortic stenosis: changing disease concepts. J Cardiovasc Ultrasound 2015; 23:59–69. https://doi. org/10.4250/jcu.2015.23.2.59; PMID: 26140146. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95. https://doi.org/10.1056/ NEJMoa1200384; PMID: 22443479. Eveborn GW, Schirmer H, Heggelund G, et al. The evolving epidemiology of valvular aortic stenosis. The Tromsø study. Heart 2013;99:396–400. https://doi.org/10.1136/ heartjnl-2012-302265; PMID: 22942293. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630–4. https://doi. org/10.1016/S0735-1097(96)00563-3; PMID: 9060903. Perlman GY, Blanke P, Dvir D, et al. Bicuspid aortic valve stenosis: favorable early outcomes with a next-generation transcatheter heart valve in a multicenter study. JACC Cardiovasc Int 2016;9:817–24. https://doi.org/10.1016/ j.jcin.2016.01.002; PMID: 27101906. Pibarot P, Burkhoff D. Post-TAVR heart failure. Structural Heart 2018;2:286–90. https://doi.org/10.1080/24748706.2018.1456705. Muratori M, Fusini L, Tamborini G, et al. Sustained favourable haemodynamics 1 year after TAVI: improvement in NYHA functional class related to improvement of left ventricular diastolic function. Eur Heart J Cardiovas Imaging 17;11:1269–78. https://doi.org/10.1093/ehjci/jev306; PMID: 26588980. Nishimura R, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease. J Am Coll Cardiol 2014;63:e57–e185; https://doi. org/10.1016/j.jacc.2014.02.536; PMID: 24603191. Meneguz-Moreno RA, Costa Jr, Gomes NL, et al. Very long term follow-up after percutaneous balloon mitral valvuloplasty. JACC Cardiovasc Interv 2018;11:1945-1952. https:// doi.org/10.1016/j.jcin.2018.05.039. PMID: 30077684. Soliman OI, Anwar AM, Metawei AK, et al. New scores for the assessment of mitral stenosis using real-time threedimensional echocardiography. Curr Cardiovasc Imaging Rep 2011;4:370–7. https://doi.org/10.1007/s12410-011-9099-z;

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Most coronary fistulae are amenable to percutaneous closure either via a retrograde or antegrade approach, using a variety of coils, plugs or duct occluders. The aim of catheter closure is to occlude the fistulous artery as distally as possible, avoiding any possibility of occluding branches to the normal myocardium. Risks of fistula closure with these devices include MI (due to inadvertent closure of viable branches or retrograde propagation of thrombus occluding viable branches) and migration of coils or discs to extra-coronary vascular structures or in the coronary artery branches.45 Long-term effects of intravascular fistula occlusion are yet to be demonstrated.

Conclusion As one of the leading causes of morbidity and mortality, HF has become a pandemic not only in the US but worldwide. Patients with SHD possess anatomical variations that may alter their response to medical therapy alone. Transcatheter-based structural interventions provide newer, less-invasive techniques accounting for anatomical variations that present a cornerstone of therapeutic options for these patients and the management of HF that can be expanded to the general population.

PMID:21949566. 18. B ertrand PB, Mihos CG, Yucel E. Mitral annular calcification and calcific mitral stenosis: therapeutic challenges and considerations. Curr Treat Options Cardio Med 2019;21:19. https:// doi.org/10.1007/s11936-019-0723-6; PMID: 30929092. 19. Dal-Bianco JP, Beaudoin J, Handschumacher MD, Levine RA. Basic mechanisms of mitral regurgitation. Can J Cardiol 2014;30:971–81. https://doi.org/10.1016/j.cjca.2014.06.022; PMID: 25151282. 20. Suradi HS, Kavinsky CJ, Hijazi ZM. Percutaneous mitral valve repair: the MitraClip device. Glob Cardiol Sci Pract 2016;2016:e201617. https://doi.org/10.21542/gcsp.2016.17; PMID: 29043265. 21. Lavall D, Hagendorff A, Schirmer SH, et al. Mitral valve interventions in heart failure. ESC Heart Fail 2018;5:552–61. https://doi.org/10.1002/ehf2.12287; PMID: 29676043. 22. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. 23. Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricuspid regurgitation with the edgeto-edge MitraClip technique. Circulation 2017;135:1802–14. https://doi.org/10.1161/CIRCULATIONAHA.116.024848; PMID: 28336788. 24. Asmarats L, Puri R, Latib A, et al. Transcatheter tricuspid valve intervention. J Am Coll Cardiol 2018;71:293–556; https://doi. org/10.1016/j.jacc.2018.04.031; PMID: 29929618. 25. Malekzadeh-Milani S, Ladouceur M, Cohen S, et al. Results of transcatheter pulmonary valvulation in native or patched right ventricular outflow tracts. Arch Cardiovasc Dis 2014;107:592–8. https://doi.org/10.1016/j.acvd.2014.07.045; PMID: 25218009. 26. O’Byrne ML, Glatz AC, Mercer-Rosa L, et al. Trends in pulmonary valve replacement in children and adults with tetralogy of Fallot. Am J Cardiol 2015;115:118–24. https://doi. org/10.1016/j.amjcard.2014.09.054; PMID: 25456860. 27. Quail MA, Frigiola A, Giardini A, et al. Impact of pulmonary valve replacement in tetralogy of Fallot with pulmonary regurgitation: a comparison of intervention and nonintervention. Ann Thorac Surg 2012;94:1619–26. https://doi. org/10.1016/j.athoracsur.2012.06.062; PMID: 22959579. 28. Baumgartner H, Bonhoeffer P, De Groot NM, et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31:2915–57. https://doi.org/10.1093/eurheartj/ehq249. PMID: 20801927. 29. Silversides CK, Kiess M, Beauchesne L, et al. Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: outflow tract obstruction, coarctation of the aorta, tetralogy of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J Cardiol 2010;26:e80–97. https://doi.org/10.1016/S0828282X(10)70355-X; PMID: 20352138. 30. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation 2008;118:e714–833. https://doi.org/10.1161/ CIRCULATIONAHA.108.190811; PMID: 18997168. 31. Kenny D, Rhodes JF, Fleming GA, et al. 3-year outcomes of the Edwards SAPIEN transcatheter heart valve for conduit failure in the pulmonary position from the COMPASSION multicenter clinical trial. JACC Cardiovasc Interv 2018;11:1920–9. https://doi.

org/10.1016/j.jcin.2018.06.001; PMID: 30286853. 32. C heatham JP, Hellenbrand WE, Zahn EM, et al. Clinical and hemodynamic outcomes up to 7 years after transcatheter pulmonary valve replacement in the US Melody valve investigational device exemption trial. Circulation 2015;131:1960–70. https://doi.org/10.1161/ CIRCULATIONAHA.114.013588; PMID: 25944758. 33. Davila-Roman VG, Waggoner AD, Kennard ED, et al. Prevalence and severity of paravalvular regurgitation in the Artificial Valve Endocarditis Reduction Trial (AVERT) echocardiography study. J Am Coll Cardiol 2004;44:1467–72. https://doi.org/10.1016/ j.jacc.2003.12.060; PMID: 15464329. 34. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95. https://doi.org/10.1056/ NEJMoa1200384; PMID: 22443479. 35. Hahn RT, Pibarot P, Stewart WJ, et al. Comparison of transcatheter and surgical aortic valve replacement in severe aortic stenosis: a longitudinal study of echocardiography parameters in cohort A of the PARTNER trial (placement of aortic transcatheter valves). J Am Coll Cardiol 2013;61:2514–21. https://doi.org/10.1016/S0735-1097(13)60817-7; PMID: 23623915. 36. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2014;148:e1–e132. https:// doi.org/10.1016/j.jacc.2017.03.011; PMID: 28315732. 37. Goktekin O, Vatankulu MA, Tasal A, et al. Transcatheter transapical closure of paravalvular mitral and aortic leaks using a new device: first in man experience. Catheter Cardiovasc Interv 2014;83:308–14. https://doi.org/10.1002/ccd.25006; PMID: 23703912. 38. Goktekin O, Vatankulu MA, Ozhan H, et al. Early experience of percutaneous paravalvular leak closure using a novel Occlutech occluder. EuroIntervention 2016;11:1195–200. https:// doi.org/10.4244/EIJV11I10A237; PMID: 26897292. 39. Mullins CE, Nihill MR, Vick GW, et al. Double balloon technique for dilation of valvular or vessel stenosis in congenital and acquired heart disease. J Am Coll Cardiol 1987;10:107–14. https:// doi.org/10.1016/S0735-1097(87)80168-7; PMID: 2955014. 40. Webb G, Gatzoulis MA. Atrial septal defects in the adult: recent progress and overview. Circulation 2006;114:1645–53. https://doi.org/10.1161/CIRCULATIONAHA.105.592055; PMID: 17030704. 41. Campbell M. Natural history of atrial septal defect. Br Heart J 1970;32:820–6. https://doi.org/10.1136/hrt.32.6.820; PMID: 5212356. 42. Carminati M, Butera G, Chessa M, et al. Transcatheter closure of congenital ventricular septal defects: results of the European Registry. Eur Heart J 2007;28:2361–8. https://doi. org/10.1093/eurheartj/ehm314; PMID: 17684082. 43. Nguyen HL, Phan QT, Doan DD, et al. Percutaneous closure of perimembranous ventricular septal defect using patent ductus arteriosus occluders. PLoS One 2018;13:e0206535. https://doi. org/10.1371/journal.pone.0206535; PMID: 30439981. 44. van de Sandt FM, Boekholdt SM, Bouma BJ, et al. Patent ductus arteriosus in adults – indications and possibilities for closure. Neth Heart J 2011;19:297–300. https://doi.org/10.1007/s12471-011-0138-9; PMID: 21584804. 45. Kharouf R, Cao QL, Hijazi ZM. Transcatheter closure of coronary artery fistula complicated by myocardial infarction. J Invasive Cardiol 2007;19:E146–9. PMID: 17470976.

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Advanced Heart Failure

Haemodynamic Balance in Acute and Advanced Heart Failure: An Expert Perspective on the Role of Levosimendan Piergiuseppe Agostoni, 1,2 Dimitrios T Farmakis, 3,4 Jose M García-Pinilla, 5 Veli-Pekka Harjola, 6 Kristjan Karason, 7 Dirk von Lewinski, 8 John Parissis, 4,9 Piero Pollesello, 10 Gerhard Pölzl, 11 Alejandro Recio-Mayoral, 12 Alexander Reinecke, 13 Patrik Yerly 14 and Endre Zima 15 1. Centro Cardiologico Monzino, IRCCS, Milan, Italy; 2. Department of Clinical Sciences and Community Health – Cardiovascular Section, University of Milan, Milan, Italy; 3. University of Cyprus Medical School, Nicosia, Cyprus; 4. Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 5. Heart Failure and Familial Cardiopathies Unit, Cardiology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain; 6. Emergency Medicine, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; 7. Departments of Cardiology and Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden; 8. Department of Cardiology, Myokardiale Energetik und Metabolismus Research Unit, Medical University, Graz, Austria; 9. Emergency Department, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 10. Orion Pharma, Espoo, Finland; 11. Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Austria; 12. Hospital Universitario Virgen Macarena, Seville, Spain; 13. Klinik für Innere Medizin III, Kardiologie, Universitätskllinikum Schleswig-Holstein, Kiel, Germany; 14. Service de Cardiologie, CHUV, Université de Lausanne, Lausanne, Switzerland; 15. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

Abstract Acute and advanced heart failure are associated with substantial adverse short- and longer-term prognosis. Both conditions necessitate complex treatment choices to restore haemodynamic stability and organ perfusion, relieve congestion, improve symptoms and allow the patient to leave the hospital and achieve an adequate quality of life. Among the available intravenous vasoactive therapies, inotropes constitute an option when an increase in cardiac contractility is needed to reverse a low output state. Within the inotrope category, levosimendan is well suited to the needs of both sets of patients since, in contrast to conventional adrenergic inotropes, it has not been linked in clinical trials or wider clinical usage with increased mortality risk and retains its efficacy in the presence of beta-adrenergic receptor blockade; it is further believed to possess beneficial renal effects. The overall haemodynamic profile and clinical tolerability of levosimendan, combined with its extended duration of action, have encouraged its intermittent use in patients with advanced heart failure. This paper summarises the key messages derived from a series of 12 tutorials held at the Heart Failure 2019 congress organised in Athens, Greece, by the Heart Failure Association of the European Society of Cardiology.

Keywords Acute heart failure, advanced heart failure, cardiorenal syndrome, inotropes, inodilators, levosimendan. Disclosure: PP is a full-time employee of Orion Pharma. In the past 5 years, all other authors have received honoraria from Orion Pharma for educational lectures. This project did not receive any financial support, apart from logistical expenses related to the organisation of the hands-on tutorials at the annual meeting of the Heart Failure Association of the European Society of Cardiology in Athens, Greece on 26–27 May 2019, which were covered by Orion Pharma. The lecturers and programme were approved by the congress organisers. Acknowledgement: The authors acknowledge Hughes Associates, Oxford, UK, for assistance in the preparation and editing of the manuscript. Received: 10 June 2019 Accepted: 9 August 2019 Citation: Cardiac Failure Review 2019;5(3):155–61. DOI: https://doi.org/10.15420/cfr.2019.01.R1 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-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.

The use of IV vasoactive drugs, diuretics, vasodilators and inotropes for correcting haemodynamic dysfunction in patients with decompensated heart failure has been described over many decades.1 However, data on their effects on prognosis do not offer a convincing picture of clinical benefit.2 This is particularly true regarding IV inotropes. Clinical data collected on the effects of cardiac glycosides, catecholamines and phosphodiesterase inhibitors indicate an overall increase in mortality risk.3,4 Increased cardiomyocyte oxygen consumption in ischaemically jeopardised myocardium, plus a heightened propensity to cardiac arrhythmias, have been proposed as possible explanations for these findings.5

The calcium sensitiser and potassium channel opener levosimendan has emerged in recent years as potentially a safer inotropic option than the traditional classes of cardio-mobilising drugs by virtue of its different mechanism of action.6,7 Levosimendan delivers inotropy via a broadly energy-neutral route, and vasodilation, including reduction of central venous pressure, relief of hepatic congestion and indications of improvement in renal function.8 Taken in combination with an extended duration of effect ascribable to a long-acting metabolite, this profile identifies levosimendan as a unique inotrope for the management of acute heart failure (AHF) and advanced heart failure (AdHF).9–12

Access at: www.CFRjournal.com

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Advanced Heart Failure This article presents some views on the use of vasoactive drugs in the management of AHF and AdHF that emerged during a series of tutorials held in conjunction with the annual congress of the Heart Failure Association of the European Society of Cardiology (ESC), in Athens, Greece in May 2019. Twelve speakers (from Austria, Cyprus, Finland, Germany, Greece, Hungary, Italy, Spain, Sweden and Switzerland) delivered the tutorials and collaborated in the development of this text.

Levosimendan in Acute Heart Failure The assessment and management of AHF have been set on a robust practical footing by the most recent ESC guidelines, to which readers are referred for a comprehensive statement on this subject.13 Summarising broadly, AHF may be described as a situation of rapid onset or worsening of the signs and symptoms of HF. AHF must, inter alia, be characterised as a life-threatening medical condition that requires urgent evaluation and management and frequently leads to hospitalisation. AHF may present de novo or as a deterioration in chronic HF. Many cases will arise from primary cardiac dysfunction, notably MI, but extrinsic precipitants, such as infection or anaemia, may play a role, along with an extensive range of triggering factors.13 Other high-risk cohorts include patients with severe aortic stenosis, mitral regurgitation, acute pulmonary embolism or serious cardiac arrhythmias. An immediate priority in the work-up of a case of suspected AHF is to identify patients with either cardiogenic shock (CS) and/or respiratory failure. These are among the approximately 10% of patients who are critically ill and require intensive care. Systemic blood pressure is an important guide to the classification and management of AHF. A systolic blood pressure level <90 mmHg is encountered in about 10% of patients, but the occurrence of hypotension of this degree, in conjunction with evidence of inadequate peripheral perfusion, identifies those who are candidates for inotropic therapy and, possibly, vasopressors. These patients usually correspond to the ‘wet and cold’ quadrant of the AHF clinical classification, which is associated with notably poor prognosis.14 From a pathophysiological perspective, a key aspect of HF is that it flattens the increase in cardiac output to a given afterload, giving rise to ‘forward’ failure. Use of inotropic drugs can be a valid response to this situation, but the repertoire of available agents is restricted. Indeed, it may be argued that levosimendan is one of the few inotropes for which a compelling justification of use can be provided, and in some circumstances it is perhaps the only one. Clinical trials and meta-analyses conducted over the past quarter of a century have repeatedly indicated that conventional adrenergic inotropes and phosphodiesterase (PDE)-3 inhibitors increase cellular energy consumption and are sometimes associated with increased mortality, arrhythmias, or other safety concerns. By contrast, levosimendan does not cause an increase in cellular oxygen demand or calcium content, thus having a more favourable safety profile, as seen in an overview of the long-term mortality outcome of the regulatory clinical trials (Figure 1). Levosimendan, which has been in clinical use for more than 20 years and has been evaluated in controlled clinical trials involving >3,000 HF patients, represents an established inotropic therapy in AHF.15

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Of course, these remarks should not be regarded as carte blanche for the use of levosimendan or any other specific inotrope. Indeed, it may be argued on the basis of various sources of clinical evidence that inotropes are, in general, overused in AHF, whereas vasodilators are possibly underused.16–19 Appreciation of causative pathophysiology is central to correcting this situation. AHF is a phenotype suitable for treatment with vasodilators, as the product of vasoconstriction with increase in venous return, increased left ventricular pressure and fluid redistribution leading to pulmonary congestion. Inotrope therapy is properly confined to AHF arising from a low cardiac output condition. A few observations highlight the need to improve the identification of patients who really need inotropic support (and perhaps the selection of the most appropriate inotrope for any particular case).13 However, within that qualifying population, inodilators, such as levosimendan, should be the therapy of preference for patients already receiving beta-blockers, those with AHF of ischaemic aetiology and those experiencing cardiorenal syndrome. Aspects of renal function in AHF and AdHF are considered later in this article.

Levosimendan in Acute Heart Failure or Cardiogenic Shock Arising from Acute Coronary Syndromes AHF in the context of acute coronary syndromes (ACS) is an urgent situation that requires early identification and treatment, not least because AHF can deteriorate into CS. Risk factors for the emergence of AHF in ACS include advanced age, previous MI or chronic HF, diabetes, hypertension and female sex. More than 40% of cases of AHF were encountered with episodes of ACS in the EuroHeart Failure Survey II, and the combination of ACS with AHF has been associated with very poor survival prospects.18 The Finnish Acute Heart Failure (FINN-AKVA) study documented an almost twofold higher 30-day mortality in AHF patients with ACS than in nonACS cases (13% versus 8%; p=0.03).20 ACS–AHF was also associated with prolonged hospitalisation and with more costly treatment in the intensive care unit. Similar adverse findings for the interplay between ACS and AHF have been recorded in the CardShock study and other investigations.21 As evidenced by the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, both the incidence of AHF as a complication of ACS and the mortality associated with ACS–AHF have decreased in recent years: between 1996 and 2008, the incidence of AHF as a sequel to ACS declined from 46% to 28% (p<0.001).22 This downward trend has been particularly marked in patients with ST-segment elevation MI and is very likely attributable to a more frequent use of primary percutaneous coronary intervention (PCI), which assures early reperfusion and salvage of jeopardised myocardium, thereby averting the emergence of AHF.23 The use of more high-sensitivity troponin testing to enhance detection of minor evolving ischaemia may also have contributed to this trend. The results of the Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial make a strong case for favouring a culprit-lesion-only strategy in most patients when performing PCI for ACS–AHF.24 The short-term risks associated with longer procedure times, more complex interventions and higher doses of contrast agents seem to outweigh any potential benefits of a multivessel approach.

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Levosimendan in AHF and AdHF There is extensive polypharmacy in ACS–AHF, with widespread use of inotropes, vasopressors and other classes of drugs, but many of these practices are empirical and pragmatic rather than evidence based.20 Formal structured research into the relative merits of different drug therapies in ACS–AHF is lacking and there is insufficient reliable information regarding the comparative efficacy of different agents.25,26 Some broad principles of therapy may nevertheless be identified. Several of these apply with special force to the management of CS, the emergence of which is identified in the 2016 ESC guidelines as warranting consideration of inotrope use.13 The percentage of ACS episodes that progress to CS is relatively low (≤10%), but short-term (in-hospital) mortality in CS is exceptionally high (40% in CardShock, higher in other reports) and CS is the leading cause of death in patients with acute MI.21,23,27

Figure 1: Effect of Levosimendan on Survival Favours Levosimendan Comparator Levosimendan Comparator Study Events Total Events Total Dobutamine cotrolled Dose-finding 1 95 1 20 LIDO 8 103 17 100 SURVIVE 79 664 91 663 Placebo controlled Dose-finding Dose-escalation and withdrawal RUSSLAN REVIVE I REVIVE II Pooled analysis#

the Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure after an Acute Myocardial Infarct (RUSSLAN) trial supports those considerations, as do the findings of a meta-analysis of six studies (n=1,065), which documented improvements in various indices of haemodynamic function in ACS patients treated with IV levosimendan, with no adverse effect on mortality in AHF–CS patients and a strong signal for a survival benefit in AHF–ACS patients (RR 0.74, 95% CI [0.58–0.93]; p=0.01).33,34 The Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial compared levosimendan and dobutamine in AHF.25 For the subset of patients who had acute MI as a cause of AHF, mortality in both treatment groups was two to three times that in the non-ischaemic subset and 31-day mortality was 4% lower in the levosimendan ACS–AHF group (28% versus 32%), a notable, although not statistically significant, survival gain. It has been proposed that levosimendan may be considered in four clinical AHF–CS scenarios based on a patient’s haemodynamic status and Killip classification.25 In the lower Killip classes, and in patients with relatively well-sustained blood pressure (systolic >110 mmHg), levosimendan may be used as monotherapy to enhance urinary output if the response to diuretics is inadequate. In the more advanced stages with pulmonary oedema or frank CS, levosimendan may be combined with a vasopressor such as noradrenaline to augment cardiac output and raise blood pressure. When vasopressors are used to support blood pressure there should be a strong presumption for noradrenaline over adrenaline, based on data from a head-to-head controlled comparison in CS and findings from CardShock.35,36

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95% CI (0.01; 3.23) (0.21; 1.01) (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

The management of CS includes haemodynamic support with inotropes and vasopressors to increase cardiac output and blood pressure in order to restore tissue perfusion. Inotropes as a broad class are endorsed to support the circulation of patients who are demonstrably hypotensive and/or hypoperfused despite adequate filling pressures. This circumscribed indication reflects concerns that conventional adrenergic inotropes (and PDE-3 inhibitors) increase cellular energy demands and oxygen consumption in a situation of ischaemic compromise and may exert undesirable tachycardic or pro-arrhythmic effects. Levosimendan, by virtue of its calcium-sensitising action, does not exert untoward effects of this kind to the same degree and, moreover, exhibits antistunning and condition effects that may be relevant and advantageous in states of ischaemia.28–32 The survival benefit of levosimendan in

RR 0.21 0.46 0.87

0.5 1

Relative Risk Ratio (95% CI)

Meta-analysis of the results of the phase II and III clinical trials considered in the regulatory process. These trials included the Dose-finding study by Slawsky et al.,72 the Dose-escalation and withdrawal study by Nieminen et al.,73 the LIDO study by Follath et al.,74 the RUSSLAN study by Moiseyev et al.,33 the SURVIVE study by Mebazaa et al.75 and the REVIVE I and II studies by Packer et al.76 Pooled statistics were calculated using the Cochran–Mantel– Haenszel test, controlling for the study. Graphic rendition from data by Pollesello et al.15

The combination of vasopressors plus inodilators may offer better short-term prognosis than vasopressor therapy alone (HR 0.66, 95% CI [0.55–0.80]). This proposition is based on a pooled analysis from three observational studies and requires confirmation in a suitably powered randomised controlled trial.37 The Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF) registry, which contributed data to this analysis, indicated within a single dataset of reasonable size (n=4,953) that inodilatation as delivered by levosimendan was associated with substantially better survival than inopressors or adrenergic inotropes (Figure 2).38 This identifies, subject to confirmation, a niche for levosimendan, which may be used in combination with noradrenaline as an alternative to dobutamine. Of note in this context, the blood pressure-lowering effect of levosimendan does not appear to require excessive increases in vasopressor dosage in CS.39 Because its inotropic effect is independent of beta-adrenoceptor stimulation, levosimendan is an appropriate haemodynamic support for ACS–AHF or CS patients on chronic beta-blocker therapy. All inotropes and vasopressors should be used at the lowest dose and for the shortest time possible. Levosimendan should be administered at an individualised infusion rate in the range 0.05–0.2 µg/kg/min. Loading dose is to be used when in need for immediate effect, and if systolic blood pressure exceeds 100 mmHg. Ideally, the infusion rate should be closely monitored and individualised in dependency of tolerability and haemodynamic response. Hypovolaemia and/or hypokalemia must be corrected before and during treatment. The effects of a 24-hour infusion of levosimendan persist for up to 2 weeks due to the longlasting effect of its active metabolite, but the haemodynamic effects may be longer. Thereafter, treatment may safely be repeated.

Levosimendan in Advanced Heart Failure Patients with AdHF suffer from severe and persistent symptoms that are often intractable to recommended drug therapies; they typically have marked limitation of exercise capacity and accompanying impaired QoL and are likely to have undergone repeated hospitalisations.40 AdHF is also widely associated with progressive deterioration in the function of multiple organ systems, including the kidneys and liver. AdHF may affect up to 10% of patients with HF and this prevalence may be

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Advanced Heart Failure Figure 2: In-hospital Mortality Rates of Inotropes

Figure 3: Effects of Levosimendan and Dobutamine in Chronic Heart Failure

60 Epinephrine

p=NS

In-hospital mortality (%)

Norepinephrine 40

30 Dopamine

RBF

p=NS

Dobutamine

Diuretics Whole cohort

Levosimendan Vasodilators 5

p<0.012

eGFR

Days In the ALARM-HF registry, use of the inodilator levosimendan was linked with a notably lower mortality rate than traditional adrenergic inotropes. Graphic rendition from data by Mebazaa et al.38

Change from baseline (%)

expected to increase in future because of growth in the HF population and improved survival among AdHF patients. Some published studies and some preliminary observations on the physiological effects of levosimendan in AdHF provide a starting point for an appraisal of the drug’s use in this context. A series of recent studies has examined the impact of levosimendan treatment on the lungs, heart and skeletal muscle.41–43 Collectively, these studies provided evidence that single-dose levosimendan administration to AdHF patients was accompanied by: • improved peak oxygen uptake and amelioration of ventilation efficiency; • reduced brain natriuretic peptide (BNP); • increased cardiac output at rest and during exercise; • improved lung mechanics and diaphragm function; • restoration of the normal function of alveolar capillary cells (but not of alveolar capillary gas diffusion); and • improved oxygen delivery to the muscle and muscle oxygen utilisation. The Heart Failure Association of the ESC reviewed its definition of AdHF in 2018.44 In our collective opinion, this revised definition provides the best available starting point for a consideration of treatment options, with the proviso that it is not a guideline and that it offers neither classes of recommendation nor formal, structured levels of evidence. Heart transplantation (HTx) remains the definitive intervention in AdHF and delivers very good outcomes.45 However, donor shortage limits this option to a minority of patients who must be carefully selected from those who are simultaneously at high risk of dying without a transplant and who may be expected to have good prognosis after receiving a donor heart.46 For the many patients rendered ineligible for HTx by virtue of age and/or co-morbidities or by the absence of a donor heart, longterm mechanical circulatory support (MCS) with continuous flow left

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Increase of eGFR by levosimendan, but not dobutamine, in patients with chronic heart failure.69 Percentage changes from baseline in cardiac index, renal blood flow and eGFR after administration of IV levosimendan or dobutamine. CI = cardiac index; RBF = renal blood flow. Purple bars = levosimendan; blue bars = dobutamine. From data by Lannemyr et al.69

ventricular assist devices (LVADs) may now be a valid alternative destination therapy (DT). About half of the >2,500 LVADs implanted annually in the US are intended as DT measures. Contemporary registries report good survival with LVADs as DT (78% and 68% at 1 and 2 years, respectively between 2013 and 2016 in the International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support [INTERMACS] registry).47 Complication rates with MCS remain tangible, but the risk of death, disabling stroke and device reoperation has been substantially reduced with the advent of newer devices.48,49 Many AdHF patients falling outside the parameters for HTx or MCS receive inotropes to stabilise their haemodynamic status and relieve symptoms. Repeated scheduled infusions of drugs, such as dobutamine or PDE-3 inhibitors, should be avoided because of concerns about malignant arrhythmias and increased mortality.50–52 In contrast, the intermittent use of levosimendan has been shown to be safe and well tolerated; neither the LEVO-Rep nor LIONHEART randomised controlled trials produced indications of increases in all-cause mortality or sudden cardiac death during four and six cycles, respectively, of levosimendan therapy.53,54 In addition, levosimendan offers persistent haemodynamic improvement thanks to a pharmacologically active metabolite with a long half-life. A survival effect of intermittent levosimendan has not been demonstrated in a properly powered randomised controlled trial, but the results of the Pulsed Infusions of Levosimendan in Outpatients With Advanced Heart Failure (Levo-Rep) and Intermittent IV Levosimendan in Ambulatory Advanced Chronic Heart Failure Patients (LION-HEART) trials make a persuasive case for further evaluation of levosimendan

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Levosimendan in AHF and AdHF Table 1: Molecular Targets and Pharmacological Effects of Levosimendan

Table 2: Indications for IV Vasoactive Drugs in Clinical Scenarios in Heart Failure

Molecular Targets

Pharmacological Effects

Clinical Setting

Agent

• Calcium sensitisation of the contractile apparatus by selective binding to calcium saturated cardiac troponin C

• Inotropy without increase of calcium transient and oxygen consumption • Anti-stunning effect

Increased pulmonary artery pressure

• Levosimendan • Milrinone

Need for beta-blocker

• Levosimendan • Milrinone

• Opening of the ATP-sensitive potassium channels on the smooth muscle of the vasculature

• Vasodilation (including coronary arteries) • Increase of end-organ perfusion

Hypotension

• Dobutamine • Norepinephrine • Dopamine

Worsening renal function

• Opening of the mitochondrial ATPsensitive potassium channels

• Cardioprotection and organ protection • Anti-ischaemic effect

• Levosimendan • Dobutamine • Dopamine

Ischaemic disease

• Levosimendan • Dobutamine

in this context.53,54 The Repetitive Levosimendan Infusion for Patients With Advanced Chronic Heart Failure (LeoDOR) trial is currently recruiting patients for this purpose (NCT03437226). This multicentre randomised controlled trial is designed to explore the safety and efficacy of repetitive levosimendan infusions (seven cycles at 0.2 µg/kg/min for 6 hours every 2 weeks or five cycles at 0.1 µg/kg/min for 24 hours every 3 weeks) administered to AdHF patients following a recent HF-related hospitalisation. As many as 80% of AHF hospitalisations are the product of acuteon-chronic deterioration in haemodynamic status; this may include cases where AHF is superimposed on AdHF.40 As was exemplified in the findings of the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) study, congestion and dyspnoea precede the emergence of AHF; more generally, haemodynamic congestion precedes symptomatic congestion, which in turn precedes hospitalisation for AHF.55 As described by Zile et al. and conceptualised by Adamson, the phase of presymptomatic congestion may precede the emergence of overt clinical symptoms by several days to weeks.56,57 The existence of this period of preclinical decline represents an opportunity for intervention that may avert unplanned hospitalisation due to haemodynamic crisis. Given that repeat hospitalisation for AHF is associated with progressively deteriorating survival prospects, identifying and exploiting this opportunity for pre-emptive treatment is clearly in the interests of patients. Observations on the feasibility of pre-symptomatic intervention to avert hospitalisation add weight to observations in the LEVO-Rep and LION-HEART trials that use of intermittent levosimendan in outpatients with AdHF was associated with marked improvement in event-free survival (LEVO-Rep) or a reduction in HF hospitalisation (LION-HEART).53,54,58,59 A recent metaanalysis of six studies of intermittent levosimendan in chronic HF has produced an estimated risk ratio of 0.40 (95% CI [0.27–0.59]; p<0.00001), with consistency of effect in all the contributing studies.60

Differential Renal Effects of Levosimendan Kidney dysfunction is encountered in a substantial proportion of patients with AHF or AdHF.61 In this setting, it is usually secondary to impaired cardiac function, conforming to the definition of type 1 cardiorenal syndrome (CRS). Various pathophysiological mechanisms contribute to kidney damage in CRS, including hypoperfusion, renal venous congestion and neurohormonal activation.

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Renal dysfunction has repeatedly been shown to be one of the most adverse prognostic indicators for patients with HF and to be linked with prolonged hospitalisation.62–65 Therefore, pharmacological and non-pharmacological interventions for AHF or AdHF need to be shaped by the ambition to preserve or rectify renal perfusion, the deterioration of which underlies the emergence of kidney dysfunction. The use of inodilators or inotropes to avert or correct CRS may be particularly apt in patients with low blood pressure or hypoperfusion and the specific effects of levosimendan on renal vasculature and haemodynamics highlight its potential in these cases.66–68 Those effects include selective vasodilation of the renal glomerular afferent arterioles, thereby enhancing renal filtration directly as well as via its effect on cardiac output. Lannemyr et al. recently reported that both levosimendan (loading dose of 12 µg/kg for 10 minutes, then infusion at 0.1 µg/kg/min for 65 minutes; n=16) and dobutamine (continuous infusion started at 5.0 µg/kg/min for 10 minutes, then 7.5 µg/kg/min for 65 minutes; n=16) improve systemic haemodynamics and renal blood flow to a similar extent in patients with chronic HF (mean baseline left ventricular ejection fraction 27%) and impaired renal function (mean eGFR <80 ml/min/1.73 m2).69 However, only levosimendan increased eGFR (Figure 3), supporting the proposition that levosimendan causes selective vasodilation of afferent renal arterioles whereas dobutamine dilates both afferent and efferent vessels. These data indicate that the similarity of effect on systemic haemodynamic indices may not translate into correspondingly favourable effects on renal perfusion and signal that levosimendan may be a preferred inotropic agent for the management of CRS in the setting of low-output AHF or AdHF. Case studies reviewed at Heart Failure 2019 illustrate that levosimendan may also be appropriate as part of a bridge to transplant strategy for preserving renal function in patients with AdHF and restrictive cardiomyopathy. A series of 35 repeat courses of levosimendan therapy delivered over 20 months was associated with large and sustained improvements in a series of indicators of renal function, including creatinine, N-terminal pro-BNP and the need for oral potassium supplementation. This intervention brought creatinine levels, the most responsive and most quickly reacting indicator of haemodynamic effects on kidney function in CRS, into the normal range for six consecutive months before further clinical deterioration necessitated HTx. These experiences are consistent with an earlier

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Advanced Heart Failure report of long-term improvement in renal function in a prospective study of 40 patients with AdHF treated with levosimendan while awaiting HTx.70

Conclusion The appropriate, effective and successful use of IV vasoactive drugs in AHF and AdHF is founded on accurate assessment of the aetiology of decompensation and the broader patient profile. Where congestion or hypertension predominate, and patients present with either fluid accumulation or fluid redistribution, the management emphasis should favour vasodilators and diuretics to unload the heart and mobilise fluid. Inotropes and/or vasopressors are indicated for ‘wet and cold’ patients

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who exhibit inadequate peripheral perfusion despite adequate filling status. These patients usually present with low blood pressure (systolic <90 mmHg), but it should be kept in mind that hypoperfusion is not synonymous with hypotension; hypoperfusion may not always be followed by significant hypotension, as in the presence of sympathetic overactivation causing peripheral vasoconstriction. Levosimendan is an inodilator with a unique pharmacology (Table 1), and may be appropriate for similar patients with higher blood pressure if they are refractory to vasodilator and diuretic therapy.71 A series of clinical scenarios warranting the use of inotropes/inodilators and/or vasopressors is shown in Table 2 and illustrates the wide-ranging utility of levosimendan as an intervention in these situations. n

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infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 2002;23:1422–32. https://doi. org/10.1053/euhj.2001.3158; PMID: 12208222. Shang G, Yang X, Song D, et al. Effects of levosimendan on patients with heart failure complicating acute coronary syndrome: A meta-analysis of randomized controlled trials. Am J Cardiovasc Drugs 2017;17:453–63. https://doi.org/10.1007/ s40256-017-0237-0; PMID: 28597399. Levy B, Clere-Jehl R, Legras A, et al. Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2018;72:173–82. https://doi. org/10.1016/j.jacc.2018.04.051; PMID: 29976291. Tarvasmäki T, Lassus J, Varpula M, et al. Current real-life use of vasopressors and inotropes in cardiogenic shock— adrenaline use is associated with excess organ injury and mortality. Crit Care 2016;20:208. https://doi.org/10.1186/ s13054-016-1387-1; PMID: 27374027. Pirracchio R, Parenica J, Resche Rigon M, et al. The effectiveness of inodilators in reducing short term mortality among patients with severe cardiogenic shock: a propensitybased analysis. PLoS One 2013;8:e71659. https://doi. org/10.1371/journal.pone.0071659; PMID: 23977106. Mebazaa A, Parissis J, Porcher R, et al. Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med 2011;37:290–301. https://doi. org/10.1007/s00134-010-2073-4; PMID: 21086112. Russ MA, Prondzinsky R, Christoph A, et al. Hemodynamic improvement following levosimendan treatment in patients with acute myocardial infarction and cardiogenic shock. Crit Care Med 2007;35:2732–9. https://doi.org/10.1097/00003246200712000-00010; PMID: 17893627. Braunwald E. Heart failure. JACC Heart Fail 2013;1:1–20. https:// doi.org/10.1016/j.jchf.2012.10.002; PMID: 24621794. Mushtaq S, Andreini D, Farina S, et al. Levosimendan improves exercise performance in patients with advanced chronic heart failure. ESC Heart Fail 2015;2:133–41. https://doi. org/10.1002/ehf2.12047; PMID: 27708855. Campodonico J, Mapelli M, Spadafora E, et al. Surfactant proteins changes after acute hemodynamic improvement in patients with advanced chronic heart failure treated with levosimendan. Respir Physiol Neurobiol 2018;252–253:47–51. https://doi.org/10.1016/j.resp.2018.03.007; PMID: 29548887. Magrì D, Brioschi M, Banfi C, et al. Circulating plasma surfactant protein type B as biological marker of alveolar-capillary barrier damage in chronic heart failure. Circ Heart Fail 2009;2:175–80. https://doi.org/10.1161/ CIRCHEARTFAILURE.108.819607; PMID: 19808337. 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. Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth Adult Heart Transplantation Report-2018; Focus Theme: Multiorgan Transplantation. J Heart Lung Transplant 2018;37:1155–68. https:// doi.org/10.1016/j.healun.2018.07.022; PMID: 30293612. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016;35:1–23. https://doi.org/10.1016/j. healun.2015.10.023; PMID: 26776864. Kirklin JK, Xie R, Cowger J, et al. Second annual report from the ISHLT Mechanically Assisted Circulatory Support Registry. J Heart Lung Transplant 2018;37:685–91. https://doi.org/10.1016/j. healun.2018.01.1294; PMID: 29550146. Mehra MR, Goldstein DJ, Uriel N, et al. Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 2018;378:1386–95. https://doi.org/10.1056/ NEJMoa1800866; PMID: 29526139. Kormos RL, Cowger J, Pagani FD, et al. The Society of Thoracic Surgeons Intermacs Database Annual Report: Evolving Indications, Outcomes, and Scientific Partnerships. Ann Thorac Surg 2019;107:341–53. https://doi.org/10.1016/j. athoracsur.2018.11.011; PMID: 30691584.

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Levosimendan in AHF and AdHF 50. Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients with severe heart failure: a systematic review and metaanalysis of randomised controlled trials. Intensive Care Med 2012;38:359–67. https://doi.org/10.1007/s00134-011-2435-6; PMID: 22160239. 51. Amsallem E, Kasparian C, Haddour G, et al. Phosphodiesterase III inhibitors for heart failure. Cochrane Database Syst Rev 2005;1:CD002230. https://doi. org/10.1002/14651858.CD002230.pub2; PMID: 15674893. 52. Metra M, Eichhorn E, Abraham WT, et al. Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials. Eur Heart J 2009;30:3015–26. https://doi. org/10.1093/eurheartj/ehp338; PMID: 19700774. 53. Altenberger J, Parissis JT, Costard-Jaeckle A, et al. Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial. Eur J Heart Fail 2014;16:898–906. https://doi.org/10.1002/ejhf.118; PMID: 24920349. 54. Comín-Colet J, Manito N, Segovia-Cubero J, et al. Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial. Eur J Heart Fail 2018;20:1128–36. https://doi.org/10.1002/ejhf.1145; PMID: 29405611. 55. Ambrosy AP, Pang PS, Khan S, et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial. Eur Heart J 2013;34:835–43. https://doi. org/10.1093/eurheartj/ehs444; PMID: 23293303. 56. Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 2008;118:1433–41. https://doi.org/10.1161/ CIRCULATIONAHA.108.783910; PMID: 18794390. 57. 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/s11897-0090039-z; PMID: 19948098. 58. Abraham WT, Adamson PB, Bourge RC, et al. Wireless

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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. Costanzo MR, Stevenson LW, Adamson PB, et al. Interventions linked to decreased heart failure hospitalizations during ambulatory pulmonary artery pressure monitoring. JACC Heart Fail 2016;4:333–44. https:// doi.org/10.1016/j.jchf.2015.11.011; PMID: 26874388. Silvetti S, Belletti A, Fontana A, et al. Rehospitalization after intermittent levosimendan treatment in advanced heart failure patients: a meta-analysis of randomized trials. ESC Heart Fail 2017;4:595–660. https://doi.org/10.1002/ehf2.12177; PMID: 28834396. Reid R, Ezekowitz JA, Brown PM, et al. The prognostic importance of changes in renal function during treatment for acute heart failure depends on admission renal function. PLoS One 2015;10:e0138579. https://doi.org/10.1371/journal. pone.0138579; PMID: 26380982. Fonarow GC, Adams KF Jr, Abraham WT, et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA 2005;293:572–80. https://doi.org/10.1001/ jama.293.5.572; PMID: 15687312. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006;113:671–8. https://doi. org/10.1161/CIRCULATIONAHA.105.580506; PMID: 16461840. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006;47:1987–96. https://doi. org/10.1016/j.jacc.2005.11.084; PMID: 16697315. Agostoni P, Corrà U, Cattadori G, et al. Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: a multiparametric approach to heart failure prognosis. Int J Cardiol 2013;167:2710–8. https://doi. org/10.1016/j.ijcard.2012.06.113; PMID: 22795401. Zager RA, Johnson AC, Lund S, et al. Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Renal Physiol 2006;290:F1453–62. https://doi. org/10.1152/ajprenal.00485.2005; PMID: 16418300. Rehberg S, Ertmer C, Vincent JL, et al. Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock. Crit Care Med 2010;38:2016–23. https://doi.

org/10.1097/CCM.0b013e3181ef4694; PMID: 20657271. 68. Grossini E, Molinari C, Pollesello P, et al. Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs. J Pharmacol Exp Ther 2012;342:376–88. https://doi.org/10.1124/jpet.112.193961; PMID: 22566668. 69. Lannemyr L, Ricksten SE, Rundqvist B, et al. Differential effects of levosimendan and dobutamine on glomerular filtration rate in patients with heart failure and renal impairment: A randomized double-blind controlled trial. J Am Heart Assoc 2018;7:e008455. https://doi.org/10.1161/ JAHA.117.008455; PMID: 30369310. 70. Zemljic G, Bunc M, Yazdanbakhsh AP, et al. Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. J Card Fail 2007;13:417–21. https://doi.org/10.1016/j. cardfail.2007.03.005; PMID: 17675054. 71. Bouchez S, Fedele F, Giannakoulas G, et al. Levosimendan in acute and advanced heart failure: an expert perspective on posology and therapeutic application. Cardiovasc Drugs Ther 2018;32:617–24. https://doi.org/10.1007/s10557-018-6838-2; PMID: 30402660. 72. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 2000;102:2222–7. https://doi.org/10.1161/01.CIR.102.18.2222; PMID: 11056096. 73. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 2000;36:1903–12. https://doi.org/10.1016/S07351097(00)00961-X; PMID: 11092663. 74. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002;360:196–202. https://doi. org/10.1016/S0140-6736(02)09455-2; PMID: 12133653. 75. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297:1883–91. https://doi.org/10.1001/jama.297.17.1883; PMID: 17473298. 76. Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013;1:103–11. https://doi.org/10.1016/j.jchf.2012.12.004; PMID: 24621834.

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Left Ventricular Assist Device Support Complicates the Exercise Physiology of Oxygen Transport and Uptake in Heart Failure Erik H Van Iterson Section of Preventive Cardiology and Rehabilitation, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, US

Abstract Low-output forward flow and impaired maximal exercise oxygen uptake (VO2 max) are hallmarks of patients in advanced heart failure. The continuous-flow left ventricular assist device is a cutting-edge therapy proven to increase forward flow, yet this therapy does not yield consistent improvements in VO2 max. The science of how adjustable artificial forward flow impacts the exercise physiology of heart failure and physical O2 transport between the central and peripheral systems is unclear. This review focuses on the exercise physiology of axial continuous-flow left ventricular assist device support and the impact that pump speed has on the interactive convective and diffusive components of whole-body physical O2 transport and VO2.

Keywords Chronic heart failure, Fick principle, exercise intolerance, aerobic exercise capacity, left ventricular assist device, mechanical circulatory support Disclosure: The author has no conflicts of interest to declare. Received: 17 April 2019 Accepted: 15 July 2019 Citation: Cardiac Failure Review 2019;5(3):162–8. DOI: https://doi.org/10.15420/cfr.2019.10.2 Correspondence: Erik H Van Iterson, Cardiac Rehabilitation, Section of Preventive Cardiology and Rehabilitation, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, JB1 Cleveland, OH 44195, US. E: vanitee@ccf.org 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.

The maximal exercise oxygen uptake (VO2 max) response physiologically reflects the clinical status of patients with low-output left heart failure (HF). The failure of VO2 max to rise above 12 ml/kg/min is a hallmark of deteriorated clinical status, impaired oxidative metabolic capacity and indicates advanced medical therapy is required to prolong life.1,2 The continuous-flow left ventricular assist device (cf-LVAD) is a progressive cutting-edge therapy increasingly recommended to end-stage patients for the management of signs and symptoms of HF, including impaired VO2 max.1–7 Contemporary evidence also suggests that while cf-LVAD support extends life, intentional device optimisation methods, including pump-speed modification during exercise, yield ambiguous and often confusing interpretations of VO2.1,4–7,8–13 Without the assurance that VO2 will increase post-implantation, it remains uncertain which key elements, beyond enhanced forward flow, contribute to VO2 and oxidative metabolic capacity in cf-LVAD recipients.8–16 What has yet to be examined in depth is how the exercise physiology of VO2 and physical O2 transport between the central and peripheral systems are impacted by artificial forward flow. This article examines the physical elements of exercise physiology that should be considered when evaluating the aerobic exercise capacity of patients in advanced HF who are dependent on axial cf-LVAD support. As adjustable forward flow is a key feature of cf-LVAD therapy, particular emphasis is placed on the impact that pump speed has on the physical and physiological features of whole-

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body O2 transport and exercise VO2. Although studies have tested the effect of centrifugal cf-LVAD support on VO2, this research is not reviewed herein as the literature is too complex for a combined discussion involving axial flow devices. The unique mechanical and physiological properties of centrifugal versus axial flow require special consideration when interpreting the impact pump-speed optimisation methods can have on VO2.17–19

Mass and Local Oxygen Transport The prominent and integrative failure of heart rate, stroke volume, preload and afterload, arterial pressure and systemic vascular resistance prevent cardiac output (Q) and physical O2 transport from intrinsically and reliably accommodating sudden changes in the oxidative metabolic demand of skeletal muscles in cf-LVAD candidates. These physiological interactions are highly complex. Even after the introduction of mechanical circulatory support, patients are not immune from physical O2 transport limitations that will impact VO2.3,8–16,20–23 Despite similar patient phenotypes, physical haemodynamic constraints and modest margins for physiological adaptation due to advanced whole-body disease, cf-LVAD therapy considerably reduces the debilitating physical consequences of HF in select recipients.3,8–11,13–16,20–23 However, it is not only physical contributions from classical determinants of central haemodynamics that are involved in such changes. Peripheral haemodynamics and the local and micro-level O2 transport environment play an underappreciated

Left Ventricular Assist Devices and the Exercise Physiology of Oxygen Transport role in affecting aerobic exercise capacity, as demonstrated by the signs and symptoms of patients with refractory HF, including the worsening maximal VO2 seen in some patients post-implant.3,16,24–30

Figure 1: Relationships between Cardiac Output, Arteriovenous Oxygen Content Difference and Oxygen Uptake during Sub-anaerobic Threshold Exercise High cf-LVAD pump speed

Haemodynamics: Convective and Conductive (Diffusive) Oxygen Transport

Current data suggest that while the mechanised central circulation undoubtedly works to recover part of the impaired native forward flow, this action alone cannot be assumed to translate to and coincide with equivalent and interactive improvements in DO2, DMO2 and/or VO2.3,8–11,14,15,20–23 Examining the nature of convective and conductive O2 transport relationships will be crucial in better understanding VO2, how to optimise pump speeds and where to focus when evaluating limitations in exercise.24–29

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Despite obvious links between the rise in oxidative metabolic demand of skeletal muscle and increase in Q (with subcomponents) during exercise, Q only represents a portion of the contribution of physical O2 transport to VO2. Convective O2 delivery (DO2) to skeletal muscle, microcirculation and hundreds of square meters of capillary surface area required for O2 diffusion (DMO2) – the other major component of O2 transport – is also greatly dependent on physical chemistry. The O2-carrying capacity of blood and arterial O2 content (CaO2), both of which are signalled by oxyhaemoglobin (O2Hb) dissociation curve dynamics, play pivotal roles in facilitating the physical elements of VO2.24–28,31–33 Indeed, the confluence of cardiovascular system contributions to O2 transport is estimated to account for at least 70% of aerobic exercise capacity.31 Thus, it is not by unilaterally increasing total Q that tissue-specific peripheral haemodynamics, DO2 and DMO2 successfully meet the rapid and maximal O2 needs of mitochondria and related processes.24,26,28,34–36 For most adults, the ‘bulk O2 flow’ response (i.e. Q) to physical exertion does not typically limit exercise until high-metabolic-demand phases are achieved (i.e. the isocapnic buffering period is reached or exceeded); nor should it be expected that DO2 itself limits aerobic exercise.24,25,33,34,37–39

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Ca-vO2 (ml/dl) Fick principle relationships between cardiac output (Q) as a function of calculated skeletal muscle arteriovenous oxygen content difference (Ca-vO2); and the relationship of both these variables to oxygen uptake (VO2). Q and VO2 are group means for patients in advanced heart failure dependent on continuous-flow left ventricular device performing pump-speeddependent mirrored bouts of constant-load cycle exercise set at 60% of VO2 max.10 Orange triangle: exercise at a fixed pump speed of 11,000 rpm (Q = 6.69 l/min; VO2 = 0.71 l/min). Purple circle: exercise at a fixed pump speed of 9,000 rpm (Q = 5.91 l/min; VO2 = 0.67 l/ min). The difference in Q was significant (p=0.014), whereas the difference in VO2 was non-significant (p=0.241). Red dotted line: critical O2 extraction ratio (O2 ER = VO2 /DO2 ) is ≈70–75%, coinciding with the physiological need to stop exercising. cf-LVAD = continuous flow left ventricular assist device; DO2 = oxygen delivery; Q = cardiac output; VO2 = oxygen uptake. Source: Apostolo et al. 2018.10

capillaries, resulting in exaggerated outward fluid flux, reduced inward fluid flux and a physical barrier to O2 transport.43–45

Optimising Fixed Pump Speed Submaximal Exercise Vignati et al. and, more recently, Apostolo et al. from the same group have comprehensively studied the impact of cf-LVAD speed (maximum rpm 12,000; flow rate 7 l/min) on upright aerobic exercise performance.9,10 Fick principle calculations were used to study how total Q (via inert gas rebreathing) changed as a function of adjustments in arteriovenous O2 content difference (Ca-vO2). For 15 patients who performed two mirrored bouts of sub-anaerobic threshold constantload cycle exercise (mean 35 W), decreased pump speed from 11,000 rpm to 9,000 rpm translated into down-and-right-shifted coupling between Ca-vO2 and VO2 without affecting heart rate (Figure 1).10 This also means that Fick principle-derived VO2 isopleths (e.g. 1.25 l/min in Figure 1), can be taken to suggest increased Q from low-to-high pump speed is perhaps unnecessary given that VO2 was not impacted by pump speed while remaining proportionate to Ca-vO2.10 The varying sensitivities of Q, Ca-vO2 and VO2 to pump speed dynamics further suggests that within the rpm ranges studied, not only does the rate of forward O2 flow differential have a negligible impact on sub-anaerobic threshold VO2, but it is also possible that harm can be caused when pump speed is increased beyond that required to meet oxidative metabolic demand and overcome afterload.40–42 Excessive central-to-peripheral haemodynamic redistribution can overload hydrostatic pressure in the arterial and venous ends of skeletal muscle

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Based on what is already known about Starling forces and the determinants of O2 diffusion at the alveolar–capillary membrane interface, poor filtration and uncontrolled capillary hydrostatic pressure alongside imbalanced preload sensitivity to changes in afterload could be expected to result in or exacerbate the accumulation of peripheral interstitial fluid.46–53 Here, even a relatively small rise in capillary hydrostatic pressure, particularly at the venous end, would disrupt interstitial fluid balance.47,52 Measured changes in arterial pressure during exercise are also unlikely to be sensitive enough in cf-LVAD recipients to detect incremental changes in peripheral interstitial fluid accumulation that would limit DMO2. While this hypothesis has yet be tested in cf-LVAD recipients, the implication of rapid interstitial fluid accumulation is that the resulting physical barrier reduces DMO2 and leads to inadequate O2 transport to the mitochondria for oxidative phosphorylation.46–50 Thus, in the acute setting, it can be hypothesised that limitations to aerobic exercise in cf-LVAD recipients can be physical at the peripheral level and partly reversible by optimisation of pump speed relative to work-rate.

When No Increase in Submaximal VO2 is Beneficial Based on available data, it is unclear whether pump speed-mediated increases in sub-anaerobic threshold VO2 for a fixed work-rate are beneficial.10 When patients performed mild-to-moderate intensity

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Advanced Heart Failure Figure 2: Relationships between Cardiac Output, Arteriovenous Oxygen Content Difference and Oxygen Uptake comparing Sub-anaerobic Threshold Exercise with Maximal Exercise High cf-LVAD pump speed

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Ca-vO2 (ml/dl) Right-most orange triangle: exercise at a fixed pump speed of 11,000 rpm (Q = 5.9 l/min; VO2 = 0.84 l/min). Right-most purple circle: exercise at a fixed pump speed of 9,000 rpm (Q = 5.3 l/min; VO2 = 0.79 l/min). Differences in Q (p<0.01) and VO2 (p=0.01) were significant. However, there was no significant difference for Ca-vO2 at different pump speeds (15.7 ml/dl at 9,000 rpm and 15.1 ml/dl at 11,000 rpm). Ca-vO2 = arteriovenous oxygen content difference; cf-LVAD = continuous flow left ventricular assist device; Q = cardiac output; VO2 = oxygen uptake. Source: Vignati et al. 20179 and Apostolo et al. 2018.10

exercise they did not demonstrate pump speed reliance, and hence O2 flow-dependent reliance, on physical O2 transport (e.g. Q) for VO2.10 This result is consistent with the findings for healthy adults.24,25 During sub-anaerobic threshold exercise, cellular and biochemical pathways involving the mitochondria and oxidative phosphorylation primarily drive VO2.24,25 Thus, since no appreciable differences in sub-anaerobic threshold VO2 occurred with the change from low to high pump speed,10 it is possible that despite the potential to deliver more O2 on a rapid basis via cf-LVAD support, the metabolic necessity for O2 can still in part be regulated, even in severely advanced HF. Numerous exercise studies across disciplines also report that the amount of excess VO2 for a given work-rate is key for assessing aerobic exercise capacity.54–60 A high VO2:W ratio (i.e. >10 ml/min VO2 per W) signals an inappropriate ‘gain’ in VO2 closely linked to metabolic inefficiency and supra-reliance on substrate-level phosphorylation for energy regeneration.54–60 This means that although the sub-anaerobic threshold VO2 is not significantly impacted by pump speed, the ‘gain’ in VO2 (calculated herein) increases at high versus low pump speed (20.3 versus 19.0 ml/min/W, respectively), suggesting exercise metabolic efficiency is slightly better when performed at lower pump speed.10 Thus, while the ‘gain’ in VO2 for both pump settings was greater than expected for comparable healthy adults,54–60 the interpretability of VO2 within any phase of exercise can be improved when evaluated relative to power.

Maximal Exercise When maximal exercise data are plotted with submaximal data, see Figure 2, it appears that the insensitivity of VO2 to physical O2 transport

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However, the impact of pump speed on coupling between VO2 and Ca-vO2 did not differ at maximal versus sub-anaerobic threshold exercise.9,10 The exact reasons for why VO2 demonstrated higher sensitivity to Q as opposed to Ca-vO2 at maximal exercise (ΔVO2 52 ml/min; p=0.01) cannot be independently explained by pump speed. The same pump speed settings were used for both exercise intensities.9 Maximal heart rate also did not differ between pump speeds, consistent with the heart rate responses reported in HeartMate II studies.8,12 Thus, peripheral haemodynamics, oxidative metabolic demand and skeletal muscle O2 transport mechanisms should not be overlooked as key interactive features linking pump speed and forward flow to changes in VO2 at maximal exercise.

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during mild-to-moderate intensity exercise does not persist to maximal stress.9,10 At maximal exercise there was a better balance between Q and VO2, which coincided with a high pump speed (11,000 rpm). This observation is consistent with the increased VO2 max linked to ‘responsive’ residual left ventricular function (indicated by a resting left ventricular ejection fraction ≥40%) at high pump speed (9,000 rpm) in the HeartMate II treadmill studies.12

Without reviewing additional data it can only be hypothesised that as oxidative metabolic demand of skeletal muscle rises towards maximal exertion in cf-LVAD recipients – coinciding with increased skeletal muscle pump activity, speed and frequency of venous return and exercise power – so does skeletal muscle recruitment.9,10,12,61 Therefore, increased total metabolic demand plus greater muscle recruitment should demonstrate a closer association with high rather than low pump speed assuming there is also negligible residual left ventricular function. As such, understanding the relationship between metabolically active skeletal muscle relative to total Q reveals the potential impact the microcirculation can have on DO2, DMO2, Ca-vO2, VO2 and exercise capacity.29,62 The evaluation of cf-LVAD recipients’ aerobic exercise capacity should include an integrated assessment highlighting the extent of multilevel (un)coupling across pump speed, forward flow, VO2, exercise power, skeletal muscle availability and recruitment.

Skeletal Muscle Recruitment and Maximal Exercise The ability to recruit skeletal muscle during aerobic exercise involves the collateral recruitment and perfusion of capillaries. In comparison to rest, the larger total capillary surface area available during exercise allows skeletal muscle to accommodate increased Q, and with this a greater potential for maximising physical O2 transport. Viewing the collective differences between maximal Q, VO2 and Ca-vO2 as exercise capacity and clinical status worsen from Weber class A to D (Figure 3), a widening of Ca-vO2 reflects not only the peripheral response to oxidative metabolic demand, but also information concerning the inseparable links between Q and active skeletal muscle that allow DO2 and DMO2 to serve as physical determinants of VO2.63,64 Thus, when the recipient (i.e. skeletal muscle) of enhanced forward flow is appropriately responsive (e.g. capillaries are recruited), cf-LVAD support can be highly effective for improving aerobic exercise capacity. Unfortunately, for most end-stage patients, the capacity for proper Ca-vO2 expansion relative to increasing oxidative metabolic demand is compromised by skeletal muscle disease(s). This clinical phenotype is not unique to advanced stage HF and can include cachexia, capillary rarefaction, low capillary surface area reserve, small type I-to-II muscle

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Left Ventricular Assist Devices and the Exercise Physiology of Oxygen Transport Figure 3: Relationships Between Cardiac Output, Arteriovenous Oxygen Content Difference and Oxygen Uptake in Heart Failure Patients with Reduced Ejection Fraction Performing Maximal Exercise

Figure 4: Physical and Physiological O 2 Transport Contribution to Maximal Exercise Oxygen Uptake Described by Fick’s First Law and Fick Principle Fick Principle convective line, V02 ideal Hb

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Ca-vO2 (ml/dl) Heart failure severity worsens from Weber class A to D according to the following maximal exercise VO2 criteria: A = >20 ml/kg/min; B = 16–20 ml/kg/min; C = 10–15 ml/kg/min; and D = <10 ml/kg/min.63,64 Overall, as heart failure severity worsens maximal cardiac output (Q) decreases. In order for maximal VO2 to increase, VO2 is forced to become more reliant on the expansion of Ca-vO2. Importantly, cf-LVAD support does not appear to markedly improve total Q when compared with similar severity Weber class D patients without cf-LVAD support; instead, the cf-LVAD plays a significant role in allowing the widening of Ca-vO2 and increase in maximal VO2 at both pump speeds. Ca-vO2 = arteriovenous oxygen content difference; cf-LVAD = continuous flow left ventricular assist device; Q = cardiac output; VO2 = oxygen uptake. Source: Apostolo et al. 2018.10

fibre ratios and, in most cases, a composite of these.64–70 Therefore, with the high likelihood that skeletal muscle pathophysiology progressively worsens in the lead-up to cf-LVAD support, ‘peripheral’ components of HF reinforce the view that whole-body physical O2 transport and aerobic exercise capacity can only be partially restored with artificial forward flow. Indeed, beyond cf-LVAD support alone, post-implantation participation in cardiac rehabilitation – including regular aerobic and strength training exercise – can lead to significant improvements in VO2 max.3,16,22,23

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The Wagner model demonstrates how the physical and physiological O2 transport contribution to maximal exercise VO2 is the result of interactions between the conductive (i.e. diffusive) movement of O2 described by Fick’s first law (VO2 = DMO2 × [PO2 − PmO2]) and the convective movement of O2 described by the Fick principle (VO2 =1.34 × Q × Hb × Sa-vO2).27,28,38,73 This model illustrates that VO2 is subject to impairments in either DMO2 or DO2 or, in most cases, a combination of both. Taken further, because of how DO2 is derived, it also clear that factors (i.e. the alkaline Bohr effect and Haldane effect) influencing the oxyhaemoglobin dissociation curve also impact VO2. This is illustrated by comparing maximal VO2 responses as a result of DO2 constrained to the same Q but corrected for haemoglobin content values reported for cf-LVAD patients.8,9,12 Data plotted for the diffusional movement of O2 (straight grey lines) reflect group means at maximal exercise for both heart failure with reduced ejection fraction and controls.74 The impact of cf-LVAD speed, as well as the type of pump speed increase on O2 transport, DO2 and VO2 are represented by low versus high fixed comparisons9 and fixed versus incremental comparisons.8,12 cf-LVAD = continuous flow left ventricular assist device; DMO2 = oxygen diffusion; DO2 = oxygen delivery; Hb = haemoglobin; PmO2 = mitochondrial partial pressure of oxygen; PO2 = partial pressure of oxygen; Q = cardiac output; Sa-vO2 = arteriovenous oxygen saturation difference; VO2 = oxygen uptake. Source: Jung et al. 2014,8 Vignati et al. 2017,9 Noor et al. 201212 and Esposito et al. 2010.74

Is an Increase in Maximal VO2 an Improvement? The acute ‘benefit’ of high pump speed on VO 2 max may be outweighed by the negative impact long-term excessive rapid blood flow can have on shortened O2 microcirculatory transit times, imbalanced Starling forces and dysregulated hydrostatic and osmotic pressure gradients. Similar to what has been reported for the cardiopulmonary circulation, it can be hypothesised that for optimal coupling between Q, DO 2 and D MO2 to occur in skeletal muscle, blood transit time needs to allow O 2 to diffuse from the O 2-rich microcirculation, across the membrane barrier, to the O 2-poor interstitial fluid and finally the mitochondria.27,29,51,71 In the absence of an adequate capillary-to-interstitial partial pressure of oxygen (PO2) gradient, O2 microcirculatory transit time and capillary

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surface area, it would be nearly impossible for DMO2, O2 transport to mitochondria and oxidative phosphorylation to occur. This is because high hydrostatic pressure of the interstitial space, precipitated by capillary flooding secondary to excessive pump speed, would prevent DMO2. Moreover, if pump speed is too rapid to allow arterial reservoirs to fill, the impact the skeletal muscle pump has on shuttling venous return will be marginalised.72 This will result in progressively worsening preload to overcome high left-heart afterload.53 Thus, while transient low-to-high shifts in pump speed may temporarily increase VO2 max, whether this symbolises physiological adaptation, what is considered a sustainable ‘improvement’ in aerobic exercise capacity and the associated clinical benefit should be interpreted with caution.8–10,12

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Advanced Heart Failure Figure 5: Effect of Incrementally Increased Pump-speed on Relationships Between Cardiac Output, Arteriovenous Oxygen Content Difference and Oxygen Uptake During Maximal Exercise Agostoni class A

High pump speed

Agostoni class B Low pump speed

Agostoni class C Weber class B

Incremental pump speed (Jung et al.)

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Incremental pump speed (Fresiello et al.)

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Ca-vO2 (ml/dl) An extension of Figure 3 with additional data reported in Jung et al.8 (yellow diamond) and Fresiello et al.13 (inverted green triangle), who tested whether incremental increases in cf-LVAD speed during upright cycle cardiopulmonary exercise testing was associated with greater maximal VO2 compared with that which occurs at fixed pump speed matched for exercise intensity. Only data for the exercise bout performed with the incremental increase in pump speed could be calculated using the Fick principle and plotted based on physiologically plausible values. See text for an explanation of why only data for incremental pump speed tests are plotted. Ca-vO2 = arteriovenous oxygen content difference; cf-LVAD = continuous flow left ventricular assist device; DMO2 = oxygen diffusion; VO2 = oxygen uptake. Source: Jung et al. 20148 and Fresiello et al. 201613.

Linking Convective and Diffusive Oxygen Transport DMO2 at skeletal muscle during exercise, as it relates to VO2, can be closely estimated using Fick’s first law.27,28,38,73 The equation VO2 = DMO2 × (PO2 − PmO2) suggests the intra- to extra-capillary flux of O2 is directly proportional to its conductance coefficient constant and a known PO2 gradient between the capillaries and mitochondria (PmO2).27,28,38,73 The foundational Wagner model for physical O2 transport was the first to illustrate how DMO2 integrates with elements underlying the Fick principle (VO2 = 1.34 × Q × Hb × arteriovenous oxygen saturation difference) and the O2Hb dissociation curve to jointly compose VO2.27,28,38,73 The interdependence of such relationships, where VO2 is derived using both the Fick principle and Fick’s first law, are plotted together in Figure 4 as a function of the expected change in skeletal muscle PO2 accompanying maximal exercise (capillary [PcO2], PvO2 or mixed venous [PmvO2]) .27,28,38,73 The DMO2 and DO2 lines intersect closely, representing the total physical contribution of O2 transport to aerobic exercise capacity, regardless of patient type.12,27,28,38,73 Indeed, if maximal exercise DMO2 (mean 12.6 ml/min/mmHg) is set at levels reported for HF without cf-LVAD74, the point where DMO2 (grey hashed line) and DO2 (blue and red curved lines) intersect for

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cf-LVAD (Figure 4) illustrates failing DMO2 and DO2 together but not separately physically limit VO2.8–10 Given the Fick principle, the direct impact that O2Hb association and dissociation capacity have on DO2 and subsequently DMO2 is also apparent. This physical chemistry factor is capable of predetermining the VO2 ceiling, irrespective of pump speed and total Q.12,27,28,75,76 To illustrate this point, the DO2 curves (light purple, teal and dark purple) corrected for haemoglobin (mean 11.2 g/dl, 11.5 g/dl and 12.9 g/dl) demonstrate a clear downward shift from the ideal DO2 curve (dark teal) reflecting normal haemoglobin (15.0 g/dl; Figure 4).8,9,12 The ensuing differences in VO2 reflect the robust influence of the O2Hb dissociation curve independent of haemodynamic differences, since Q was set at the same fixed constant for DO2 curves. If DMO2 increases towards levels reflective of healthy controls (mean 18.5 ml/min/mmHg; grey dotted line in Figure 4), it becomes apparent that improving DMO2 by increasing capillary unit and surface area recruitment could compensate for low DO2 and facilitate a rise in VO2.74 However, the promise of this compensatory mechanism means it is unlikely that further increases in DMO2 are plausible for cf-LVAD recipients if the level for HF reported in Esposito et al. even slightly overestimates what could be expected for more severe HF.74 This is because the critical exercise termination thresholds for the O2 extraction ratio (O2ER = VO2/DO2 ≈ 70–75%) and PO2 for capillary and femoral venous blood (<25 mmHg) align vertically at the intersection of the HF DMO2 line and DO2 curves.71,77 Thus, all of this collectively suggests that true maximal VO2 was achieved by cf-LVAD recipients in reviewed studies and no further increase in DMO2 could be expected to safely occur.

Does Incremental Pump Speed Improve Exercise Capacity? In contrast to optimising the cf-LVAD for exercise using a fixed pump speed,9,12 a number of studies have tested whether modifying pump speed (HeartMate II maximal rpm = 15,000; flow = 10 l/min) between fixed and incremental settings impacts maximal VO2 and Q.8,11,13 In Figure 5, separate upright cycle maximal exercise data for incremental pump speeds of +200 rpm/min and +400 rpm/2 min (maximal mean for both = 10,843 rpm) suggest similar VO2, cf-LVAD flow, Ca-vO2, heart rate and W responses.8,13 Conversely, the study by Fresiello et al. reported that pump speed type had no effect on VO2, whereas Jung et al. identified an increased VO2 response associated with incremental pump speed, consistent with observations made by Apostolo et al.8,10,13 Interestingly, Fick principle data for VO2 (1.22 and 1.27 l/min) and cf-LVAD flow (6.0 and 6.2 l/min) could not be plotted for fixed tests at 9,371 and 9,357 rpm as values calculated for Ca-vO2 were atypically high (20.3 and 20.5 ml/dl, respectively).8,13 Even when considering that the effects of the O2Hb dissociation curve and variability in reported data are not accounted for by calculating Ca-vO2 using means, it is physiologically unlikely that Ca-vO2 was supra-responsive and mixed venous O2 saturation drastically reduced during fixed versus incremental studies. Based on available data and the Fick principle, it can only be hypothesised that subtle contributions from native Q during fixed tests makes up for lower cf-LVAD flow while reducing Ca-vO2 to more plausible levels. Native Q may make different contributions to gross flow depending on pump speed type and right and left heart interactions involving unique cf-LVAD sensitivity to preload and afterload, as briefly discussed below.

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Left Ventricular Assist Devices and the Exercise Physiology of Oxygen Transport Right Heart Considerations when Interpreting cf-LVAD Contributions to Aerobic Exercise Capacity In lieu of a strong body of evidence to support the current understanding of right heart function during exercise testing in cf-LVAD recipients, in silico studies suggest the cf-LVAD exhibits a considerably lower preload sensitivity than the intact human heart.53,78 On the other hand, simulations demonstrate that, within a given patient, left heart preload sensitivity lessens as afterload increases whereas left heart afterload sensitivity is nominally impacted by changes in preload.53 All of this means that, while right ventricular function and preload have a clear impact on cf-LVAD function, proposed associations between preload and afterload suggest the strongest interactions occur when the afterload is highest.6,53,79 However, afterload, even in cases of advanced stage HF, does not necessarily peak at maximal exercise or relate to whether native left ventricular function is able to contribute to ‘normal’ aortic valve function.8,12,80–82 Classical resting evaluations of right heart function may not fairly indicate the heart’s ability to perform under conditions where the active skeletal muscle pump and drop in afterload have favourable influences on haemodynamics. On a real-time basis, non-physiological elements confound what is understood about the influence right heart function has on left heart forward flow and VO2. For example, low preload sensitivity during exercise has implications for cf-LVAD haemodynamics because the presence of high afterload must be offset by adequate venous circulation and right ventricular function in order to decrease the chance of ‘suckdown’.53,78 This also means factors, such as gravity and

ehra MR, Canter CE, Hannan MM, et al. The 2016 M International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant 2016;35:1–23. https://doi.or/10.1016/ j.healun.2015.10.023; PMID: 26776864. Corra U, Agostoni PG, Anker SD, et al. Role of cardiopulmonary exercise testing in clinical stratification in heart failure. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:3–15. https://doi. org/10.1002/ejhf.979; PMID: 28925073. Adamopoulos S, Corra U, Laoutaris ID, et al. Exercise training in patients with ventricular assist devices: a review of the evidence and practical advice. A position paper from the Committee on Exercise Physiology and Training and the Committee of Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:3–13. https://doi.org/10.1002/ejhf.1352; PMID: 30474896. Cook JL, Colvin M, Francis GS, et al. Recommendations for the use of mechanical circulatory support: ambulatory and community patient care: a scientific statement from the American Heart Association. Circulation 2017;135:e1145–58. https://doi.org/10.1161/CIR.0000000000000507; PMID: 28559233. 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. Birati EY, Jessup M. Left ventricular assist devices in the management of heart failure. Card Fail Rev 2015;1:25–30. https://doi.org/10.15420/CFR.2015.01.01.25; PMID: 28785427. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015;34:1495–504. https://doi.org/10.1016/ j.healun.2015.10.003; PMID: 26520247. Jung MH, Hansen PB, Sander K, et al. Effect of increasing pump speed during exercise on peak oxygen uptake in heart failure patients supported with a continuous-flow left ventricular assist device. A double-blind randomized study. Eur J Heart Fail 2014;16:403–8. https://doi.org/10.1002/ejhf.52; PMID: 24464845. Vignati C, Apostolo A, Cattadori G, et al. LVAD pump speed increase is associated with increased peak exercise cardiac output and VO2, postponed anaerobic threshold and improved ventilatory efficiency. Int J Cardiol 2017;230:28–32. https://doi. org/10.1016/j.ijcard.2016.12.112; PMID: 28038810.

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body position, which directly affect the venous circulation must be taken into account when evaluating exercise and right heart function in cf-LVAD recipients.40,83–86 Collective effects associated with venous return, right ventricular function, skeletal muscle pump activity and left heart afterload are likely to have less of an impact on how cf-LVAD support integrates with native Q and gross physical O2 transport during supine exercise in comparison to the upright position.40,83–86 Caution should be taken when translating (semi)supine studies to the upright position, particularly when evaluating the combined effects of right ventricular function, native Q and cf-LVAD support on the various subcomponents of physical O2 transport and aerobic exercise capacity.

Conclusion The physiological concepts proposed in this review suggest that for cf-LVAD pump speed transitions to be effective and safely impact VO2 and aerobic exercise capacity, the rapidity of the pump must not be set so the rate of forward flow grossly exceeds skeletal muscle oxidative metabolic demand, microcirculatory net filtration capacity and exercise work-rate. The unique role skeletal muscle plays in accommodating and facilitating physical O2 transport and performing oxidative metabolism highlights the therapeutic role that cardiac rehabilitation and aerobic exercise training can have on maximising the benefit of cf-LVAD support. Clinical and mechanistic studies are needed to explore and test the validity of the proposed links between pump speed, forward flow, whole-body physical O2 transport, and the physical and physiological features of skeletal muscle when oxidative metabolic demand is expected to be highest, during maximal exercise.

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Co-morbidities

Sodium–Glucose Cotransporter-2 Inhibitors and Heart Failure Prevention in Type 2 Diabetes Muhammad Shahzeb Khan 1 and Javed Butler 2 1. Department of Medicine, Cook County Hospital, Chicago, Illinois, US; 2. Department of Medicine, University of Mississippi, Jackson, Mississippi, US

Abstract Diabetes and heart failure (HF) are closely linked, with one causing a worse prognosis in the other. The majority of anti-hyperglycaemic agents primarily reduce risk of ischaemic microvascular events without targeting the mechanisms involved for diabetes cardiomyopathy and HF. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a novel class of glucose-lowering agents that have consistently reduced HF hospitalisations, unlike other agents. The authors discuss the current evidence and highlight possible future directions for the role of SGLT2 inhibitors in HF prevention.

Keywords SGLT2 inhibitors, heart failure, diabetes, empagliflozin, canagliflozin, cardiovascular outcome trials Disclosure: JB has received research support from the NIH, Patient-Centered Outcomes Research Institute and the EU. He serves as a consultant for Abbott, Adrenomed, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, CVRx, Innolife, Janssen, LinaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, V-Wave and Vifor. MSK has no has no conflicts of interest to declare. Received: 3 July 2019 Accepted: 21 September 2019 Citation: Cardiac Failure Review 2019;5(3):169–72. DOI: https://doi.org/10.15420/cfr.2019.06.R1 Correspondence: Javed Butler, Department of Medicine, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, US. E: jbutler4@umc.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 non-commercial purposes, provided the original work is cited correctly.

In 2008, the European Medicines Agency and US Food and Drug Administration (FDA) issued industry guidance stating that all future novel glucose-lowering agent trials must undergo routine cardiovascular risk evaluation either before approval or as a postmarketing commitment.1 This mandated that all cardiovascular endpoint committees prospectively adjudicate all major adverse cardiovascular events, including cardiovascular death, non-fatal MI and stroke, occurring across Phase II and III diabetes trials. However, the statement did not specifically mention heart failure (HF) as an endpoint. HF is the second most common cardiovascular presentation of diabetes after peripheral arterial disease.2 In people with diabetes, mortality from HF constitutes a large proportion of overall mortality. Moreover, approximately 40% of hospitalised HF patients have concomitant diabetes, a trend that is expected to increase even further.3–5 Both diabetes and HF are closely linked, with one causing a worse prognosis in the other. The majority of anti-hyperglycaemic agents primarily reduce the risk of ischaemic microvascular events without targeting the mechanisms involved for diabetes cardiomyopathy and HF. Some glucose-lowering agents, such as thiazolidinediones and saxigliptin, have been linked to increased risk of incident HF and HF hospitalisations.6,7 Other drugs, such as liraglutide, have shown overall cardiovascular benefit without specifically improving outcomes in established HF patients.8 However, unlike other anti-hyperglycaemics, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a novel class of glucose-lowering agents that have consistently reduced HF hospitalisations.9–15 This class of medication works by selectively inhibiting SGLT2, thus causing decreased renal absorption of glucose.

Multiple studies have shown that SGLT2 inhibitors are associated with weight loss and blood pressure reduction in addition to glycaemic control.16 In this article, we discuss the current evidence and highlight the future direction for SGLT2 inhibitors in HF prevention.

Evidence from Randomised Clinical Trial and Observational Data There are three completed cardiovascular safety trials for SGLT2 inhibitors: EMPAgliflozin cardiovascular outcome event trial in type 2 diabetes – Removing Excess Glucose (EMPA-REG OUTCOME), CANagliflozin cardioVascular Assessment Study (CANVAS) and Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58).9,11,12 In EMPA-REG OUTCOME, 7,020 people with diabetes and established cardiovascular disease were randomised to empagliflozin or placebo.9 The primary endpoint of the trial – major adverse cardiovascular events – was significantly reduced (HR 0.86; 95% CI [0.74–0.99]; p=0.04) in the empagliflozin arm. HF hospitalisation was an undefined secondary outcome. Compared with placebo, empagliflozin significantly reduced the risk of HF hospitalisations (4.1% versus 2.7%; HR 0.65; 95% CI [0.50–0.85]) and composite outcome of HF hospitalisations and cardiovascular death (5.7% versus 8.5%; HR 0.66; 95% CI [0.55–0.79]; p<0.001). Consistent benefit in HF hospitalisation was observed in all subgroups including age, race, estimated glomerular filtration rate (eGFR) and baseline medications for HF. Empagliflozin was also beneficial across a spectrum of HF patients.17 The results of these trials led to empagliflozin being approved by the FDA in 2016 for the prevention of major adverse cardiovascular events in people with

Access at: www.CFRjournal.com

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Co-morbidities Table 1: Baseline Characteristics of the Three Sodium–Glucose Cotransporter-2 Inhibitor Trials Trial

Drug

Year

Haemoglobin

Excluded HF

HF (%)

HF Outcome

A1c (%)

eGFR Cut-off for Inclusion Criterion (ml/min/1.73 m2)

EMPA-REG OUTCOME9

Empagliflozin

2015

7,020

8.1

HF hospitalisation

≥30

CANVAS

Canagliflozin

2017

10,142

8.2

HF hospitalisation

≥30

DECLARE-TIMI 5812

Dapagliflozin

2018

17,160

8.3

NYHA class IV

HF hospitalisation + CVD

≥60*

*Creatinine clearance based on Cockroft–Gault equation. eGFR = estimated glomerular filtration rate; HF = heart failure; NYHA = New York Heart Association; SGLT2 = sodium–glucose cotransporter-2.

Table 2: Hospitalisation for Heart Failure and Cardiovascular Death Stratified by Presence of Heart Failure and Atherosclerotic Cardiovascular Disease at Baseline Trials

HF Hospitalisation + CV Death, HR [95% CI]

EMPA-REG OUTCOME CANVAS11 DECLARE-TIMI 58

HF at Baseline

No HF at Baseline

ASCVD at Baseline

No ASCVD at Baseline

0.72 [0.52–1.04]

0.63 [0.51–0.78]

0.66 [0.55–0.79]

0.61 [0.46–0.80]

0.87 [0.72–1.06]

0.77 [0.65–0.92]

0.83 [0.58–1.19]

0.79 [0.63–0.99)

0.84 [0.72–0.99)

0.83 [0.71–0.98]

0.84 [0.67–1.04]

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HF = heart failure; NR = not reported.

diabetes.18 However, no specific recommendation was given for HF prevention, as HF was not one of the primary endpoints. In the CANVAS trial,10,142 people with diabetes and high cardiovascular risk were randomised to canagliflozin or placebo.11 The primary endpoint was major adverse cardiovascular events, which was significantly reduced in the canagliflozin group (HR 0.86; 95% CI [0.75–0.97]; p<0.001 for non-inferiority; p=0.02 for superiority). Canagliflozin was also associated with a significant reduction in the risk of HF hospitalisation (5.5 versus 8.7 per 1,000 patient-years; HR 0.67; 95% CI [0.52–0.87]). Subgroup analyses showed that patients with baseline HF derived a greater benefit in terms of cardiovascular death and HF hospitalisations.

(CVD-REAL), comprising more than 300,000 newly diagnosed diabetes patients, compared those who were initiated on SGLT2 inhibitors with those receiving any other glucose-lowering therapy. SGLT2 inhibitors led to an almost 40% relative reduction in HF hospitalisation compared with other therapies.13 A consistent benefit was seen in mortality and HF hospitalisation across the spectrum of patients, including those with or without HF at baseline. Moreover, a network meta-analysis suggested that SGLT2 inhibitors have 99.6% probability of being the most effective anti-hyperglycaemic agent for reducing the risk of HF hospitalisation.19 Table 3 shows the main HF outcomes from the realworld observational data of SGLT2 inhibitors.

Mechanism for Benefit In the recent DECLARE-TIMI 58 trial, which evaluated 17,160 patients, dapagliflozin also significantly reduced the risk of HF hospitalisation (6.2 versus 8.5 per 1,000 patient years; HR 0.73; 95% CI [0.61–0.88]).12 Approximately 4% of patients had HF with reduced ejection fraction (HFrEF) at baseline. Dapagliflozin was shown to reduce the composite endpoint of cardiovascular death/HF hospitalisation more in patients with HFrEF (HR 0.62; 95% CI [0.45–0.86]) compared to those without HFrEF (HR 0.88; 95% CI [0.76–1.02]; p-interaction 0.046). The borderline non-significant results in the non-HFrEF patients were mainly driven by cardiovascular death as in the subgroup analysis; dapagliflozin decreased HF hospitalisation both in patients with HFrEF (HR 0.64; 95% CI [0.43–0.95]) and without HFrEF (HR 0.76; 95% CI [0.62–0.92]). However, the statistically significant reduction in cardiovascular death was observed only in the HFrEF group (HR 0.55; 95% CI [0.34–0.90]). The DECLARE-TIMI 58 trial was unique compared with the previous two trials because it enrolled more patients without known atherosclerotic cardiovascular disease (n=10,186) and was the first trial to include HF hospitalisation as the co-primary endpoint. The baseline HF rate in all three trials was <15%. Table 1 shows baseline characteristics of the three SGLT2 inhibitor trials, and Table 2 shows detailed HF outcomes.

The cardioprotective effects offered by SGLT2 inhibitors cannot be solely attributed to glycaemic control. Several mechanisms for the beneficial effect of SGLT2 inhibitors in regards to HF have been proposed and are highlighted in Figure 1. First, SGLT2 inhibitors have a direct effect on cardiac metabolism by increasing hepatic neogenesis of ketone bodies, which serve as the alternate fuel for a hypertrophied and failing heart.20 Second, SGLT2 inhibitors are believed to inhibit myocardial and renal sodium–hydrogen exchanger 3, leading to modification of intracellular calcium and thus prevention of HF-associated remodelling.21 Third, improvement in renal function and interstitial volume regulation by SGLT2 inhibitors may also contribute to improvement in HF risk.22 Finally, SGLT2 inhibitors cause osmotic diuresis through glycosuria and natriuresis, which may help in optimising loading conditions of the myocardium. SGLT2 inhibitors have also been shown to significantly reduce blood pressure and biomarkers of arterial stiffness, which can lead to better oxygen consumption of the heart.20–22 These mechanisms – aside from glycaemic control – also suggest a role for the use of SGLT2 inhibitors solely for HF prevention, regardless of diabetes status.

Effect on Subgroups These clinical trial data are further supported by the real-world evidence from observational studies.13–15 The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors study

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In the early SGLT2 inhibitor trials, the benefit for major adverse cardiovascular events seemed to be higher in patients with established atherosclerotic cardiovascular disease, although formal heterogeneity

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SGLT2 Inhibitors and HF Prevention Table 3: Observational Data for Mortality and Hospitalisation for Heart Failure Stratified by Heart Failure at Baseline Studies

Mortality, HR [95% CI]

HF Hospitalisation, HR [95% CI]

HF at Baseline

No HF at Baseline

HF at Baseline

No HF at Baseline

CVD-REAL13

N/A

0.56 [0.50–0.63]

N/A

0.61 [0.48–0.78]

0.77 [0.67–0.88]

0.60 [0.49–0.73]

0.75 [0.60–0.94]

0.60 [0.42–0.86]

N/A

0.62 [0.44–0.87]

0.63 [0.42–0.95]

CVD-REAL-2

Patorno et al.15

HF = heart failure; N/A = not applicable.

was not shown. This led to the American and European guidelines recommending the use of SGLT2 inhibitors in people with diabetes and atherosclerotic cardiovascular disease.23,24 However, a recent meta-analysis including data from EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58 showed that SGLT2 inhibitors reduce HF hospitalisations regardless of the presence of HF or atherosclerotic cardiovascular disease at baseline.25 There was an approximately 30% relative risk reduction for HF hospitalisation in both the subgroups. Interestingly, the benefit for major adverse cardiovascular events was only limited to patients with baseline atherosclerotic cardiovascular disease. Thus, data suggest that SGLT2 inhibitors are especially beneficial for HF over a broad spectrum of patients with diabetes. Studies have also demonstrated that the beneficial effect of SGLT2 inhibitors on HF hospitalisation is similar in males and females.26

Figure 1: Possible Mechanisms for Heart Failure Prevention Through Sodium–Glucose Cotransporter-2 Inhibitors

Improved cardiac metabolism

Prevention of HF with SGLT2 inhibition

Reno-protective Effects of SGLT2 Inhibitors A possible explanation for SGLT2 inhibitors reducing HF hospitalisations, regardless of the presence of HF or atherosclerotic cardiovascular disease at baseline, is the reno-protective effects of SGLT2 inhibitors coupled with natriuresis. There are four studies that have assessed the effect of SGLT2 inhibitors on renal outcomes: the Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE), EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58. EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58 were primarily designed as cardiovascular outcome trials with a range of pre-specified exploratory and post hoc renal outcomes. The CREDENCE trial, published in 2019, was the first study to specifically determine the effect of SGLT2 inhibitors on renal outcomes in patients with already-established diabetic kidney disease.27 The primary composite outcome of the CREDENCE trial was doubling of serum creatinine, end-stage renal disease or mortality due to cardiovascular or renal cause. The relative risk of the primary outcome was 30% lower in the SGLT2 inhibitor group compared with the placebo group (event rates of 43.2 and 61.2 per 1,000 patient-years, respectively; RR 0.70; 95% CI [0.59–0.82]; p=0.00001). On pooling results from all the four studies, SGLT2 inhibitors were shown to decrease the risk of dialysis, transplantation or mortality due to renal disease by approximately one-third.28 SGLT2 inhibitors were also shown to decrease the risk of acute kidney injury by 25%. Results from each of the individual studies on various renal endpoints are shown in Table 4. Moreover, significant evidence of benefit was apparent for all eGFR subgroups, , including for patients with a baseline eGFR <45 ml/min/1.73 m2. 28 An eGFR rate of ≥30 ml/ min/1.73 m2 was an inclusion criterion for all four studies apart from DECLARE-TIMI 58, in which a creatinine clearance of ≥60 ml/min was used. Similar to the HF effect, the reno-protective effect was robust in both patients with and without atherosclerotic cardiovascular disease. It is known that patients with lower eGFR are at higher

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Optimise loading conditions of the heart

Reduction in interstitial oedema

Improved renal function

Obstruction of cardiac sodium– hydrogen exchange

HF = heart failure; SGLT2 = sodium–glucose cotransporter-2. Source: Khan and Butler 2019.32 Reproduced with permission from John Wiley and Sons.

risk for HF hospitalisation, and thus SGLT2 inhibitors conferring reno-protection and natriuresis could be the main contributing mechanism for HF prevention. 29,30

Current Position and Future Direction In the current guidelines published by the American Diabetes Association and European Association for the Study of Diabetes, metformin remains the first-line treatment for people with diabetes, with SGLT2 inhibitors as the second-line therapy.31 Given the absence of any mortality or cardiovascular benefit with metformin, future studies should investigate the role of SGLT2 inhibitors as a first-line therapy.32 Moreover, the role of SGLT2 inhibitors in stage D HF patients remains unknown. Considering that stage D HF patients often do not tolerate HF therapy, SGLT2 inhibitors might be an attractive alternative.33 Although SGLT2 inhibitors have shown substantial improvement in HF outcomes, data collected need to be further expanded to include ejection fraction and New York Heart Association (NYHA) class, allowing for more specific subgroup analyses. Moreover, endpoints apart from HF hospitalisation should be considered, such as emergency department visits and urgent office visits. A recent systematic review has highlighted significant gaps regarding HF data capture in novel glucose-lowering therapy trials.34 Apart from EMPA-REG OUTCOME,

171

Co-morbidities Table 4: Effects of SGLT2 Inhibitors on Renal Outcomes Study

AKI, RR

ESRD, RR

Substantial Loss of

[95% CI]

Kidney Function, ESRD

With Preserved Ejection Fraction (EMPEROR-Preserved; NCT03057951) and 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]; NCT03036124).

or Death Due to Renal Cause, RR [95% CI] CREDENCE27

0.85 [0.64–1.13]

0.68 [0.54–0.86]

0.66 [0.53–0.81]

EMPA-REG OUTCOME9

0.76 [0.62–0.93]

0.60 [0.18–1.98]

0.54 [0.40–0.75]

CANVAS11

0.66 [0.39–1.11]

0.77 [0.30–1.97]

0.53 [0.33–0.84]

DECLARETIMI 5812

0.69 [0.55–0.87]

0.31 [0.13–0.79]

0.53 [0.43–0.66]

AKI = acute kidney injury; ESRD = end-stage renal disease; SGLT2 = sodium–glucose cotransporter-2.

none of the SGLT2 inhibitor trials provided details of how HF was defined at baseline. EMPA-REG OUTCOME defined HF using a query for cardiac failure through the Medical Dictionary for Regulatory Activities. None of the trials reported brain natriuretic peptide data, ejection fraction or degree of optimisation in patients who had baseline HF. Moreover, no trial commented on outcome data once the patient had incident HF. There are three on-going trials that will further evaluate the role of SGLT2 inhibitors for HF treatment, irrespective of diabetes status – EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced; NCT03057977), EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure

S Food and Drug Administration. Diabetes mellitus – U evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at: https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/ diabetes-mellitus-evaluating-cardiovascular-risk-newantidiabetic-therapies-treat-type-2-diabetes (accessed 25 September 2019). 2. Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018;379:633–44. https://doi. org/10.1056/NEJMoa1800256; PMID: 30110583. 3. Sharma A, Green JB, Dunning A, et al. Causes of death in a contemporary cohort of patients with type 2 diabetes and atherosclerotic cardiovascular disease: insights from the TECOS trial. Diabetes Care 2017;40:1763–70. https://doi. org/10.2337/dc17-1091; PMID: 28986504. 4. Sharma A, Zhao X, Hammill BG, et al. Trends in noncardiovascular comorbidities among patients hospitalized for heart failure. Circ Heart Fail 2018;11:e004646. https://doi. org/10.1161/CIRCHEARTFAILURE.117.004646; PMID: 29793934. 5. Dei Cas A, Khan SS, Butler J, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail 2015;3:136–45. https://doi.org/10.1016/j. jchf.2014.08.004; PMID: 25660838. 6. Komajda M, McMurray JJV, Beck-Nielsen H, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J 2010;31:824–31. https://doi. org/10.1093/eurheartj/ehp604; PMID: 20118174. 7. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. https://doi. org/10.1056/NEJMoa1307684; PMID: 23992601. 8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. https://doi.org/10.1056/NEJMoa1603827; PMID: 27295427. 9. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 10. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526–34. https://doi.org/10.1093/ eurheartj/ehv728; PMID: 26819227. 11. 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. 12. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med

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EMPEROR-Reduced and EMPEROR-Preserved will randomise patients to empagliflozin or placebo with cardiovascular death and HF-related hospitalisation as the primary endpoint. Similarly, DAPA-HF will randomise patients to dapagliflozin or placebo with cardiovascular death and HF-related hospitalisation as the primary endpoint. Inclusion criteria include established HFrEF (NYHA class II–IV) and ejection fraction ≤40%. There is also an on-going trial evaluating ertugliflozin in diabetes patients with vascular disease: Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease ([VERTIS CV]; NCT01986881). VERTIS CV is expected to enrol 8,000 patients with a primary outcome of time to first occurrence of major adverse cardiovascular event (cardiovascular death, non-fatal MI or stroke). Secondary endpoints include HF-related hospitalisation. If these trials show improvement in HF outcomes with SGLT2 inhibitors, it would represent a paradigm shift in management of HF. While we await results from these trials, it is important to acknowledge that we already have strong evidence that SGLT2 inhibitors provide benefit for primary HF prevention in people with diabetes. Given the robust data and dire public health consequences of concomitant diabetes and HF, clinicians should consider initiating SGLT2 inhibitors for HF prevention at least in diabetes patients, regardless of their HbA1c and atherosclerotic disease status.

2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. Cavender MA, Norhammar A, Birkeland KI, et al. SGLT-2 inhibitors and cardiovascular risk: an analysis of CVD-REAL. J Am Coll Cardiol 2018;71:2497–506. https://doi.org/10.1016/j. jacc.2018.01.085; PMID: 29852973. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 Study. J Am Coll Cardiol. 2018;71:2628–39. https://doi.org/10.1016/j.jacc.2018.03.009; PMID: 29540325. Patorno E, Goldfine AB, Schneeweiss S, et al. Cardiovascular outcomes associated with canagliflozin versus other nongliflozin anti diabetic drugs: population based cohort study. BMJ 2018;360:k119. https://doi.org/10.1136/bmj.k119; PMID: 29437648. Khan MS, Usman MS, Siddiqi TJ, et al. Effect of canagliflozin use on body weight and blood pressure at one-year followup: a systematic review and meta-analysis. Eur J Prev Cardiol 2019;26:1680–2. https://doi.org/10.1177/2047487319829940; PMID: 30755019. Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME trial. Eur Heart J 2018;39:363–70. https://doi.org/10.1093/eurheartj/ehx511; PMID: 29020355. US Food and Drug Administration. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. Available at: https:// www.fda.gov/news-events/ press-announcements/fda-approves-jardiance-reducecardiovascular-death-adults-type-2-diabetes (accessed 25 September 2019). Kramer CK, Ye C, Campbell S, Retnakaran R. Comparison of new glucose-lowering drugs on risk of heart failure in type 2 diabetes: A network meta-analysis. JACC Heart Fail 2018;6:823–30. https://doi.org/10.1016/j.jchf.2018.05.021; PMID: 30196071. Mizuno Y, Harada E, Nakagawa H, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism 2017;77:65–72. https://doi.org/10.1016/j.metabol.2017.08.005; PMID: 29132539. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Med 2017;130 (suppl 6):S30–S39. https://doi.org/10.1016/j. amjmed.2017.04.009; PMID: 28526184. Marti CN, Gheorghiade M, Kalogeropoulos AP, et al. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 2012;60:1455–69. https://doi.org/10.1016/j. jacc.2011.11.082; PMID: 22999723. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37:2315–81. https://doi.org/10.1093/

eurheartj/ehw106; PMID: 27222591. 24. A merican Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care 2018;41(suppl 1):S73–85. https:// doi.org/10.2337/dc18-S008; PMID: 29222379. 25. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892. 26. Yamani N, Usman MS, Akhtar T, et al. Sodium–glucose co-transporter 2 inhibitors for the prevention of heart failure in type 2 diabetes: A systematic review and metaanalysis. Eur J Prev Cardiol 2019:2047487319841936. https://doi. org/10.1177/2047487319841936; PMID: 30966822. 27. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Eng J Med 2019; 380;2295–306. https://doi.org/10.1056/NEJMoa1811744; PMID: 30990260. 28. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019. https://doi.org/10.1016/S22138587(19)30256-6; PMID: 31495651; epub ahead of press. 29. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587–97. https://doi.org/10.1161/ CIRCULATIONAHA.113.005081; PMID: 24334175. 30. Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752–72. https://doi.org/10.1161/ CIRCULATIONAHA.116.021887; PMID: 27470878. 31. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. Diabetologia 2018;61:2461–98. https://doi.org/10.1007/s00125-018-4729-5; PMID: 30288571. 32. Khan MS, Butler J. Heart failure prevention with sodium– glucose cotransporter 2 inhibitors. J Diabetes 2019;11:601–4. https://doi.org/10.1111/1753-0407.12932; PMID: 31044514. 33. Sharma A, Cooper LB, Fiuzat M, et al. Antihyperglycemic therapies to treat patients with heart failure and diabetes mellitus. JACC Heart Fail 2018;6:813–22. https://doi. org/10.1016/j.jchf.2018.05.020; PMID: 30098964. 34. Greene SJ, Vaduganathan M, Khan MS, et al. Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. J Am Coll Cardiol 2018;71:1379–90. https://doi.org/10.1016/j.jacc.2018.01.047; PMID: 29534825.

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Co-morbidities

Why is Iron Deficiency Recognised as an Important Comorbidity in Heart Failure? Nicole Ebner and Stephan von Haehling Department of Cardiology and Pneumology, University Medical Centre Goettingen, Goettingen, Germany

Abstract There is an increasing awareness of the prevalence of iron deficiency in patients with heart failure (HF), and its contributory role in the morbidity and mortality of HF. Iron is a trace element necessary for cells due to its capacity to transport oxygen and electrons. The prevalence of iron deficiency increases with the severity of HF. For a long time the influence of iron deficiency was underestimated, especially in terms of worsening of cardiovascular diseases and developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and HF showed new insights into the improvement of iron therapy. Additionally, experimental studies supporting the understanding of iron metabolism and the resulting pathophysiological pathways of iron have been carried out. The aim of this mini review is to highlight why iron deficiency is recognised as an important comorbidity in HF.

Keywords Iron deficiency, heart failure, comorbidity Disclosure: The authors have no conflicts of interest to declare. Received: 18 March 2019 Accepted: 21 May 2019 Citation: Cardiac Failure Review 2019;5(3):173–5. DOI: https://doi.org/10.15420/cfr.2019.9.2 Correspondence: Nicole Ebner, University Medical Centre Goettingen, Department of Cardiology and Pneumology, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. E: nicole.ebner@med.uni-goettingen.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.

Iron is an essential trace element that is present in a number of molecular systems, and it is increasingly recognised as an important cofactor for a variety of cell systems.1 It has been acknowledged that iron plays an important role in oxygen transport, as well as in cell growth and proliferation. In recent years, more insight has been gained into iron physiology and the regulation of cellular iron homeostasis.2 Iron deficiency occurs, for example, when the dietary intake is inadequate, during times of digestive blood loss or menstrual periods or during states that excessively increase iron requirements, particularly during childhood growth or pregnancy.2,3 However, in patients with chronic illnesses, iron may become unable to be immobilised as a consequence of chronic inflammation, thus leading to functional iron deficiency. Many studies have shown that iron deficiency is very common in patients with heart failure (HF), and its prevalence increases with increasing New York Heart Association class.4–8

Prevalence and Prognostic Factors of Iron Deficiency A large meta-analysis of major HF trials showed that the prevalence of iron deficiency is nearly 50% in all patients with HF, and that iron deficiency has important prognostic and quality of life implications, irrespective of the presence of anaemia.9–14 However, iron deficiency, whether absolute or functional, is a frequent finding in HF patients also presenting with anaemia, affecting up to 80% of these individuals.15 In humans, intracellular iron is stored as ferritin and reflects body iron stores. However, ferritin is also an acute-phase reactant whose levels may increase during inflammatory processes. Transferrin saturation

reflects the relative amount of transferrin that is loaded with iron. In contrast to ferritin, transferrin is a negative acute-phase reactant. Importantly, neither serum iron nor serum transferrin alone should be used as indicators of iron status.2 In addition, it is important to understand that different cut-off values indicate iron deficiency in healthy individuals and in patients with chronic illness. Approximately half of all patients with HF have either absolute iron deficiency or functional iron deficiency defined as transferrin saturation <20% and serum ferritin 100–300 μg/L, and this finding is only partly associated with the presence of anaemia.2,16,17 Indeed, many HF patients present with iron deficiency, many with anaemia and some of these with both.

Mechanism of Iron Deficiency It is important to understand the mechanisms of iron absorption and distribution. There are two different pathways of iron absorption, one for haem iron across a haem transporter, and another for iron in its ferrous form, across the divalent metal transporter.2,3 Iron absorption across the gut wall is only possible in the ferrous form, and ferric iron that is found in vegetables needs to be reduced before absorption. The cytosolic protein that accumulates iron is ferritin. Ferritin protects cells from iron toxicity and prevents iron from reacting with other cellular constituents.2 Under normal conditions, nearly the total amount of circulating iron is transported by transferrin.13 The amount of iron transported in ferritin is low compared with transferrin-iron.

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Co-morbidities Cohen et al. suggested that serum ferritin is not a major pathway of systemic iron transport, but locally secreted ferritin may play such a role in selected tissues.18 Despite there being some insight, the detailed pathways that enable iron trafficking from the endosome to the mitochondria and to other cellular sites are not well understood.19 Generally, a large number of proteins need iron as a cofactor, and the two major elements that require iron are haem and iron–sulphur (Fe-S) clusters.20 Under iron replete conditions, iron regulatory protein 1 binds Fe-S clusters and acts as an aconitase when Fe-S cluster synthesis is normal. The presence of Fe-S clusters determines the function of the aconitase. Aconitase is an essential enzyme in the citrate cycle that catalyses the reaction from citrate into aconitate, and requires Fe-S clusters as cofactors. When cellular iron levels are low, iron regulatory protein loses aconitase activity, and there is a corresponding reduction in Fe-S cluster synthesis.19 Mitochondrial function requires iron, since iron is a cofactor for haem proteins that are involved in electron transfer, and in adenosine triphosphate and energy production in the cells. The reason why iron may have an effect on HF irrespective of anaemia and haemoglobin values is that iron is an essential constituent of myoglobin, which is found in the cytoplasm, and avidly binds and releases oxygen.20 The absence of iron in the blood of patients with HF may also be reflected as reduced iron load in the bone marrow and in the myocardium.21,22 Interestingly, a subset of patients in whom myocardial transferrin receptor expression was measured showed upregulation of the receptor. Such upregulation hints at iron deficiency inside the myocardium. In addition, left ventricular stiffness was correlated with peak oxygen uptake, but not with the ferritin level or transferrin saturation.23 The symptoms and signs of iron deficiency are partially explained by the presence of anaemia, but experimental evidence suggests that iron itself improves muscle function and exercise capacity in animals without changes in haemoglobin levels.2,24–26

Iron Deficiency and Exercise Capacity Iron deficiency independently relates to exercise intolerance expressed as reduced peak oxygen uptake and augmented ventilatory response to exercise in patients with chronic HF.27,28 This finding emphasises the role of iron as a cofactor in skeletal and cardiac muscle function. A recent study showed that iron is important for muscle function.29 In recent years, different therapeutic possibilities embrace iron replacement by oral or IV routes.9,12,17 The IV route is more effective than the oral route, mostly as a consequence of the limited absorption capacity in the duodenum and due to the side-effects of oral iron therapy that are encountered in up to 20% of all patients treated with oral iron.30 The Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUTHF) trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with HF with a reduced ejection fraction and iron deficiency.31 Current guidelines of the European Society of Cardiology for the diagnosis and treatment of HF state that all patients should be screened for iron deficiency and anaemia, a class I recommendation based on meta-analysis (level of evidence: A, because two large trials, Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure [FAIR-HF] and Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with

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chronic Heart Failure [CONFIRM-HF], published positive results). Patients who remain symptomatic in New York Heart Association classes II–IV benefit from iron supplementation, preferably via the IV route.32 However, it has to be taken into account that the definition of iron deficiency used by the European Society of Cardiology in the current version of the HF guideline has been validated in clinical trials only in patients with HF with reduced ejection fraction. As no validations exists for HF with preserved ejection fraction, it should be regarded with caution in this population.

Ongoing Studies Several studies with intravenous iron are ongoing; for example, the Iron or Placebo for Anaemia in Intensive Care (IRONMAN study) (NCT03037931, NCT03833336, NCT02937454, NCT03218384, NCT02642562). That study will address whether the additional use of IV iron (iron isomaltoside) on top of standard care will improve the outlook for patients with HF and iron deficiency. Other studies are the FAIR trials. The purpose of the FAIR HF2 study is to determine whether intravenous iron supplementation (ferric carboxymaltose) reduces hospitalisation and mortality in patients with iron deficiency and HF (NCT03036462). The FAIR HFpEF study addresses whether treatment with IV iron (ferric carboxymaltose) for patients with HF with preserved ejection fraction and iron deficiency can improve exercise capacity and symptoms while being safe (NCT03074591).

Future Developments In addition to the ongoing studies with the known IV iron treatments, some new IV iron drugs are being tested. For example, ferric bepectate, a new iron drug, was studied in 33 iron‐depleted anaemic patients who had undergone cardiac surgery.33 They were treated with either 200, 500 or 1500 mg ferric bepectate compared with 500 mg ferric carboxymaltose. They showed that with ferric bepectate, the iron excretion in urine was reduced compared with ferric carboxymaltose. Recent results of the FERRIC iron in Heart Failure (FERRIC HF II) trial showed that iron isomaltose was safe and well tolerated in patients with chronic HF and iron deficiency.34 Moreover, they showed that iron isomaltoside was associated with faster skeletal muscle energy measured in the form of adenosine triphosphate and phosphocreatine after 2 weeks, implying better mitochondrial function. Additionally, these results showed that iron per se is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. Augmented skeletal muscle energetics might be an important mechanism by which iron repletion confers benefits in chronic HF. The exact mechanisms by which chronic heart failure patients develop iron deficiency are still not completely understood. Moliner et al. recently showed an interplay between raised sympathetic nervous system activity and systemic iron deficiency in patients with chronic HF and, particularly, with those biomarkers that suggest impaired iron transport (transferrin saturation <20%) and increased iron demand (raised soluble transferrin receptor levels).35 This impressively supports the hypothesis that iron deficiency might not just be a comorbidity, but may also be a key element in the pathophysiological sequence leading to, and promoting the progression of, chronic HF. However, many questions remain and require further research. We look forward to future research to answer important questions about the use of iron agents in HF.36

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26. B layney L, Bailey-Wood R, Jacobs, A et al. The effects of iron deficiency on the respiratory function and cytochrome content of rat heart mitochondria. Circ Res 1976;39:744–748. https://doi.org/10.1161/01.RES.39.5.744; PMID: 184977. 27. Ebner N, Jankowska EA, Ponikowski P. The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure. Int J Cardiol 2016;205:6–12. https://doi.org/10.1016/j. ijcard.2015.11.178; PMID: 26705670. 28. Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2019;108:203–11. https://doi. org/10.1007/s00392-018-1344-x; PMID: 30051186. 29. Dziegala M, Josiak K, Kasztura M, et al. Iron deficiency as energetic insult to skeletal muscle in chronic diseases. J Cachexia Sarcopenia Muscle 2018;9:802–815. https://doi. org/10.1002/jcsm.12314; PMID: 30178922. 30. Altman NL, Patel A. Intravenous iron therapy in heart failure. Heart Fail Clin 2018;14:537–43. https://doi.org/10.1016/j. hfc.2018.06.003; PMID: 30266362. 31. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317:1958–66. https://doi.org/10.1001/jama.2017.5427; PMID: 28510680. 32. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 2016;69:1167. https://doi. org/10.1016/j.rec.2016.11.005; PMID: 27894487. 33. Muñoz M, Olsen PS, Petersen TS, et al. Pharmacokinetics of ferric bepectate – a new intravenous iron drug for treating iron deficiency. Basic Clin Pharmacol Toxicol 2019. https://doi. org/10.1111/bcpt.13219; PMID: 30839153; epub ahead of press. 34. Charles-Edwards G, Amaral N, et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency: the FERRIC-HF II randomized mechanistic trial. Circulation 2019;139:2386–98. https://doi.org/10.1161/CIRCULATIONAHA.118.038516; PMID: 30776909. 35. Moliner P, Enjuanes C, Tajes M, et al. Association between norepinephrine levels and abnormal iron status in patients with chronic heart failure: is iron deficiency more than a comorbidity? J Am Heart Assoc 2019;8:e010887. https://doi. org/10.1161/JAHA.118.010887; PMID: 30760082. 36. Pollock RF, Muduma G. A systematic literature review and indirect comparison of iron isomaltoside and ferric carboxymaltose in iron deficiency anemia after failure or intolerance of oral iron treatment. Expert Rev Hematol 2019;12:129–36. https://doi.org/10.1080/17474086.2019.1575 202; PMID: 30689458.

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Correspondence

Red Cell Volume Distribution Width as Another Biomarker Artemio García-Escobar 1 and Juan Manuel Grande Ingelmo 2 1. Cardiology Service, Severo Ochoa Hospital, Leganes, Madrid, Spain; 2. Head of Cardiology Service, Severo Ochoa Hospital, Leganes, Madrid, Spain

Disclosure: The authors have no conflicts of interest to declare. Citation: Cardiac Failure Review 2019;5(3):176–9. DOI: https://doi.org/10.15420/cfr.2019.13.1 Correspondence: Artemio García-Escobar, Cardiology Service, Severo Ochoa Hospital, Avenue of Orellana without number, 28911, Leganes, Madrid, Spain. E: dr_garciaescobar@hotmail.com

To the Editor, We congratulate Nadar and Shaikh for their excellent review of the use of biomarkers in heart failure (HF), as well as the new biomarkers currently under investigation.1 Red blood cell distribution width (RDW) is a measure of the heterogeneity of distribution of red blood cell size. A high RDW implies a large variation in red blood cell (RBC) size (anisocytosis) and a low RDW implies a more homogeneous population of RBC sizes. RDW is routinely assessed as part of complete blood count and is calculated as RDW = (standard deviation/MCV) × 100, with reference values approximately 11–15%.2 RDW in combination with mean corpuscular volume (MCV) has been used for the classification of anaemias.3 RDW elevation is associated with conditions of impaired haematopoiesis, such as nutritional deficiencies (iron, folate, vitamin B12), some haemoglobinopathies, myelodysplastic syndrome, myelophthisic anaemia (e.g. neoplastic metastases to bone marrow) and liver impairment, as well as in conditions of increased red cell destruction, such as haemolysis, or when different populations of RBC are present, such as after blood transfusion.4 In recent years, many community cohort studies have shown that an increment in RDW is associated with all-cause mortality. The UK Biobank study (n=503,325; HR 3.10, 95% CI [2.57–3.74])5 and the National Health and Nutrition Examination Survey (n=8175) showed that for every 1% increment in RDW, all-cause mortality risk increased by 22% (HR 1.2, 95% CI [1.15–1.30], p<0.001), and that even in nonanaemic participants it remained associated with mortality.6 In addition, patients with high RDW are 1.8 times more likely to develop adverse events after cardiac surgery (OR 0.55, 95% CI [0.365–0.852], p=0.007).7 In another cohort (n=16,631), after non-cardiac surgery, the area under the curve was 0.761 (95% CI [0.736–0.787]) using a cut-off value of RDW 15.7% with a specificity of 89.3% and a negative predictive value of 99% for predicting 30-day mortality.8 In contrast, in another cohort (n=217,567) RDW >14% was associated with metabolic syndrome (OR 1.14; 95% CI [1.07–1.21]; p<0.0001).9 High RDW is an independent predictor for the development of anaemia during hospitalisation due to acute MI in patients without previous anaemia.10 Moreover, RDW >14.9% is associated with increased major bleeding risk (HR 2.41, 95% [CI 1.15–5.02], p=0.02) in non-STsegment elevation MI (NSTEMI). The addition of RDW to the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) bleeding score had a significant integrated reclassification improvement of 10% (95% CI [6–19]; p=0.02).11 Similarly, another study showed that RDW was a predictor of major bleeding and that with the addition of RDW as a continuous variable to the National Cardiovascular Data Registry risk model, net reclassification improvement increased by 17.3% (95% CI [6.7–28]; p=0.02).12 In the Cholesterol and Recurrent Events (CARE) study of patients with hyperlipidaemia and history of MI, baseline RDW was associated with increased risk of all-cause death per percent increase in RDW, and RDW in the highest quartile was associated with MI, stroke and HF.13 In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program (n=2,679) RDW was associated with morbidity and mortality (HR 1.17 per 1 SD increase, p<0.001) and in the Duke Databank (n=2,140) RDW was associated with all-cause mortality (HR 1.47 per 1-SD, p<0.001) in patients with advanced heart failure.14 Secondary analysis from the Justification for the Use of Statins in Prevention (JUPITER) trial revealed that RDW was associated with allcause mortality.15 In the United Investigators to Evaluate Heart Failure (UNITE-HF) registry, elevated troponin T was an independent predictor for all-cause mortality and hospitalisation for HF, and detectable troponin T was directly and independently related to increasing RDW.16 In the Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department (PRIDE) registry, in patients with complaints of dyspnoea to the emergency department, RDW was independently associated with haemoglobin, use of loop diuretics and beta-blockers on presentation but not with nutritional deficiencies; in a multivariable analysis, RDW was a significant independent predictor of 1-year

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Red Cell Volume Distribution Width Table 1: Studies Related to Red Cell Volume Distribution Width and its Association with Heart Failure and All-cause Mortality Author

Cut-off Value

Study Method and Setting

Results and Conclusion

Felker et al.

RDW 15.2

CHARM cohort (n=2,679) and Duke Databank cohort (n=2,140), endpoint all-cause mortality. Patients with chronic HF with reduced and preserved LVEF. Median follow-up 34 months

CHARM death or HF hospitalisation: n=952, mean RDW 15.2. Patients without death or HF hospitalisation had a mean RDW of 14.4. The multivariable model showed RDW was predictive of adverse outcomes (HR 1.17 per 1 SD increase, 95% CI [1.10–1.25]; p<0.0001) Duke Databank death: n=368. The multivariable model showed RDW remained associated with mortality (HR 1.29 per 1 SD increase, 95% CI [1.16–1.43]; p<0.0001)

RDW ≥13.8

CARE study (n=4,111) Patients with hyperlipidaemia and a history of MI. Endpoint all-cause mortality and cardiovascular events. Median follow-up 59.7 months

RDW was associated with an increased risk of all-cause death (n=376; adjusted HR per % increase in RDW 1.14; 95% CI [1.05–1.24]; p=0.002) The adjusted risk of mortality in the highest quartile of RDW ≥13.8 was 1.78 (95% CI [1.28–2.47]; p=0.002) compared with the referent group (first quartile RDW 10.9–12.6%) RDW highest quartile had adjusted HR for experiencing MI of 1.43 (95% CI [1.03–1.99]; p=0.033) compared with the RDW lowest quartile RDW highest quartile had adjusted HR for experiencing the composite outcome of coronary death or nonfatal MI of 1.56 (95% CI [1.17–2.08]; p=0.001) compared with those with the lowest quartile Risk of stroke was increased in the highest quartile compared with the lowest quartile (adjusted HR 2.58, 95% CI [1.47–4.55]; p=0.004)

RDW >14.4

Consecutive patients hospitalised with acute HF (n=628). Endpoint all-cause mortality and anaemia status. Followup 38.1 months

Patients who died (n=209) had higher RDW 15 (13.8–16.1) versus 14.2 (13.3–15.3); p<0.001 and lower haemoglobin 12.3 ± 1.77 versus 12.8 ± 1.76; p=0.001. Multivariable Cox proportional hazards model RDW remained a risk factor (per %, HR 1.072, CI 95% [1.023–1.124]; p=0.004). Patients with RDW >14.4 (above the median) had lower survival time (logrank <0.001) and higher risk of death in the long-term follow-up (HR 1.89, 95% CI [1.40–2.55]; p<0.001). Higher RDW was associated with higher risk of death in patients with anaemia (n=263) (per %, HR 1.057, 95% CI [1.006–1.112]; p=0.029) and without anaemia (per %, HR 1.287, 95% CI [1.147–1.445]; p<0.001)

RDW ≥15.2

Patients with systolic HF (n=195). Primary endpoint all-cause mortality, hospital readmission due to worsening HF, assessment of 19 biochemical variables. Follow-up median of 14.5 months. T1 RDW ≤13.9%, T2 >13.9 – <15.2% and T3 ≥15.2%.

Died (n=43). RDW was higher in patients who died 15.9 (14.5–17.6) compared with those who lived 14.3 (13.6–15.3); p<0.001. In a multivariate model adjusted for NT-proBNP and other clinical covariates of HF death, RDW was an independent predictor of all-cause mortality (HR 1.61 per 1 SD increase; p<0.0001) Highest RDW T compared with lowest RDW T had high: soluble transferrin receptor 5.9 nmol/l (4.7–7.2) versus 2.3 (2.7–4.3; p<0.001); EPO 14.1 U/ml (7.9–25.7) versus 8.9 (4.9–15.2; p=0.002); IL-6 14.59 pg/ml (8.52–25.32) versus 6.62 (3.88–12.35, p=0.001); TNF-RI 6.93 ng/ml (4.22–10.68) versus 4.61 (3.42–6.69; p=0.007); TNF-RII 5.07 ng/ml (3.75–6.68) versus 3.4 (2.34– 4.57; p<0.001). Also had low iron 10 µmol/l (6.64–13.7) versus 15.4 (10.9– 19.4), transferrin saturation 16% (10–20) versus 23% (18–28), prealbumin 0.18 g/l (0.14–0.24) versus 0.26 (0.21–0.30, p<0.001), eGFR 55 (38–77.5) versus 75 (59–95), albumin 39 g/l (36–42) versus 43 (40.5–45; p<0.001), total cholesterol 3.62 mmol/l (2.95–4.14) versus 4.21 (3.81–5.31; p<0.001)

RDW 15.2

UNITE-HF biomarker registry (n=254). Anaemia in outpatients with HF. Follow-up 1.9 ± 0.9 years. Endpoint all-cause mortality, hospitalisation due to HF, assessment of troponin T and indices of haematological function. Detectable troponin T (n=39). Median detectable troponin T 0.042 ng/ml; 59% (n=23) had values >0.03 ng/ml

Crude 1-year mortality 11.9% (n=55). Elevated troponin T was an independent predictor for all-cause mortality and all-cause hospitalisation for HF (HR 3.72, 95% CI [2.10–6.59], p<0.001) and (HR 3.88, 95% CI [2.43–6.19]; p<0.001) Direct relationship between RDW and elevated troponin T (RDW per unit increase OR 1.51, 95% CI [1.21–1.89], p<0.001). Patients with detectable troponin T compared with undetectable troponin had higher RDW 15.2 (14.2–17.2) versus 13.9 (13–15.1); p<0.001, had lower haemoglobin 11.9 (11.3–13.8) versus 13.6 (12.4–14.9); p=0.002, iron 55 µg/dl (44–72) versus 72 (50–99) p=0.009 and total iron binding capacity saturation 16.5 (12.5–21.5) versus 23 (15–30); p=0.005

RDW ≥14.9

PRIDE study (n=205). Consecutive patients with complaints of dyspnoea to the emergency department. Endpoint all-cause mortality. Followup of 1 year. RDW quartiles (Q): Q1 <13.8%, Q2 13.8–14.8%, Q3 14.9–16.2% and Q4 >16.2%

RDW was independently associated with haemoglobin (p<0.0019), the use of loop diuretics (p=0.006) and beta-blockers (p=0.015) on presentation, but not with folate ((p=0.59) or vitamin B12 deficiencies (p=0.99), recent transfusion (p=0.56) or C-reactive protein (p=0.57). Log-transformed RDW values independently predicted mortality (HR 1.03, 95% CI [1–1.06]; p=0.04), died (n=63). In a multivariable Cox’s proportional hazards analysis RDW was an independent predictor of 1-year outcome in acute HF (HR 1.03 per 1% increase in RDW; 95% CI [1.02–1.07]; p=0.04)

200714

Tonelli et al. 200813

Pascual-Figal et al. 200919

Förhécz et al. 200920

Adams et al. 201016

Van Kimmenade et al. 201017

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Correspondence Van Craenenbroaeck

RDW 14.7

Subanalysis of FAIR-HF study (n=415). Endpoint assess NYHA functional class and 6MWT after intravenous iron repletion. Follow-up 24 weeks

Baseline RDW was higher in anaemic RDW 15.2 (14–16.8%) versus nonanaemic patients RDW 14.2% (13.4–15.4%) p<0.0001. NYHA class III had higher RDW 14.75 (13.8–16.5) versus NYHA class II RDW 14 (13.2–15%) p<0.0001. Treatment with ferric carboxymaltose decreased RDW leves in patients with elevated base line C-reactive protein levels ≥3 mg/l (n=147, p for interaction 0.007), whereas in patients with normal baseline C-reactive protein levels this effect was not significant (p for interaction 0.17). The increase in 6MWT distance was significantly correlated with a decrease in RDW (r=−0.25; p<0.0001)

201515

Women: RDW 15.3 Men: RDW 14.9

Secondary analysis from JUPITER (n=17,197). Patients without a history of cardiovascular disease. Endpoint all-cause mortality. Median follow-up 1.9 years. Ts in women (n=6,568): RDW T1 13.1 (12.7–13.5); T3 15.3 (14.7–16.1) T in men (n=10,629): RDW T1 12.9 (12.6–13.2); T3 14.9 (14.4–15.8)

In a multivariable analysis, the RDW was associated with all-cause mortality (T3 versus T1: HR 1.46, 95% CI [1.12–1.89]; T2 versus T1: HR 0.97, 95% CI [0.74–1.28]; p=0.002)

Sotiropoulos

RDW >16.6

Consecutive patients hospitalised due to acute HF without acute coronary syndrome or need of intensive care (n=402). Endpoint all-cause mortality at 1 year after admission. RDW Qs: Q1 12.2–14.2, Q2 14.3–15.2, Q3 15.3–16.6 and Q4 16.7–32.1

Increasing RDW quartile was an independent predictor of 1-year all-cause mortality (HR 1.66, 95% CI [1.02–2.8]), died (n=114) Kaplan–Meier analysis including all patients showed a graded increased probability of mortality with increasing quartile of RDW (p=0.0004) Patients with LVEF ≥50% showed a graded increased probability of mortality with rising RDW quartile (p=0.0195)

et al. 201323

Horne et al.

et al. 201618

6MWT = 6-minute walk test; eGFR = estimated glomerular filtration rate; EPO = erythropoietin; HF = heart failure; IL-6 = interleukin-6; LVEF = left ventricular ejection fraction; Q = quartile; RDW = red blood cell distribution width; T = tertile; TNF-RI = tumour necrosis factor-alpha receptor I; TNF-RII = tumour necrosis factor-alpha receptor II.

mortality and haemoglobin was not.17 In patients with acute HF, those with high RDW received loop diuretics and oral anticoagulation more often, and high RDW was associated with increased all-cause mortality in patients with preserved left ventricular ejection fraction (LVEF).18 In patients with acute HF, baseline RDW level was associated with a higher risk of death in long-term follow-up regardless of haemoglobin levels and anaemia status.19 In a study of patients with systolic HF, researchers analysed biomarkers of ineffective erythropoiesis, inflammation and undernutrition.20 Patients with >15.2% RDW had low levels of iron, transferrin saturation, prealbumin, albumin, total cholesterol and estimated glomerular filtration rate, and high levels of soluble transferrin receptor, erythropoietin, interleukin-6 (IL-6), tumour necrosis factor-alpha receptor (TNF-R) I and TNF-R II, increased RDW was a predictor of all-cause mortality. The correlations between high RDW with inflammation, ineffective erythropoiesis, undernutrition and impaired renal function support the understanding of why high RDW is associated with adverse outcomes in HF.20 The Study of Anemia in a Heart Failure Population (STAMINA-HFP) showed high RDW was predictive of mortality and hospitalisation. In addition, increasing RDW correlated with decreasing haemoglobin, increasing IL-6 and impaired iron mobilisation.21 In contrast, RDW is a parameter with a sensitivity of 94% for iron deficiency, and an RDW value within the reference interval can be used to exclude iron deficiency in cases in which the serum ferritin concentration does not accurately reflect the iron stores owing to severe tissue damage, as in inflammation or malignancy.22 In the Ferinject Assessment in Patients with Iron Deficiency and Chronic HF (FAIR-HF) study, a subanalysis revealed that high RDW was associated with decreased transferrin saturation and increased C-reactive protein, and that treatment with IV ferric carboxymaltose in iron-deficient chronic HF patients decreased RDW (Table 1).23 Belonje et al. showed that in patients hospitalised for HF, those with higher erythropoietin levels at baseline were independently related to increased mortality at 18 months (HR 2.06, 95% CI [1.4–3.04]; p<0.01).24 Ycas et al. showed that the largest changes in RDW (change in RDW >2%) were observed after following diagnoses of acute renal failure, septicaemia, acute post-haemorrhagic anaemia, pulmonary insufficiency and pleural effusion, suggesting that RDW is a biomarker of ineffective erythropoiesis and possibly hypoxaemia.25 Hypoxia affects the regulation of erythropoiesis; hypoxia-induced factor-1-alpha may enhance or replace the effect of glucocorticoids on burstforming unit-erythroid self-renewal and production of colony-forming unit-erythroid and the erythroblasts are enhanced approximately 170-fold.26 RDW is a parameter included in routine full blood count. It is feasible, quick and easy to obtain at the bedside, and is becoming a handy prognostic marker in patients with HF, indicating the advance of ineffective erythropoiesis, impaired ability to utilise available iron, inflammation and hypoxia. The European Society of Cardiology HF guidelines suggest the use of IV ferric carboxymaltose for patients with iron deficiency (serum ferritin <100 µg/l or ferritin 100–299 µg/l and transferrin saturation <20%) with an indication IIa-A.27 RDW could also be used as a marker of response to iron substitution in patients with HF.

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Nadar SK, Shaikh MM. Biomarkers in routine heart failure clinical care. Card Fail Rev 2019;5:50–6. https://doi. org/10.15420/cfr.2018.27.2; PMID: 30847246. 2. Evans TC, Jehle D. The red blood cell distribution width. J Emerg Med 1991;9(Suppl 1):71–4. PMID:1955687. 3. Bessman JD, Gilmer PR Jr, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol 1983;80:322–6. https://doi.org/10.1093/ajcp/80.3.322; PMID: 6881096. 4. Ford J. Red blood cell morphology. Int J Lab Hematol 2013;35:351–7. https://doi.org/10.1111/ijlh.12082; PMID:23480230. 5. Pilling LC, Atkins JL, Kuchel GA, et al. Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years. PLos One 2018;13:e0203504. https://doi.org/10.1371/journal. pone.0203504; PMID:30212481. 6. Patel KV, Ferrucci L, Ershler WB, et al. Red blood cell distribution width and the risk of death in middle-aged and older adults. Arch Intern Med 2009;169:515–23. https://doi.org/10.1001/archinternmed.2009.11; PMID:19273783. 7. Aydınlı B, Demir A, Güçlü CY, et al. Hematological predictors and clinical outcomes in cardiac surgery. J Anesth 2016;30:770–8. https://doi.org/10.1007/s00540-0162197-y; PMID:27282623. 8. Abdullah HR, Sim YE, Sim YT, et al. Preoperative red cell distribution width and 30-day mortality in older patients undergoing non-cardiac surgery: a retrospective cohort observational study. Sci Rep 2018;8:6226. https://10.1038/ s41598.018-24556-z; PMID:29670189. 9. Sanchez-Chaparro MA, Calvo-Bonacho E, GonzalezQuintela A, et al. Higher red blood cell distribution width is associated with the metabolic syndrome: results of the Ibermutuamur Cardiovascular RIsk assessment study. Diabetes Care 2010;33:e40. https://doi.org/10.2337/dc091707; PMID:20190288. 10. Salisbury AC, Amin AP, Reid KJ, et al. Red blood cell indices and development of hospital-acquired anemia during acute myocardial infarction. Am J Cardiol 2012;109:1104–10. https://doi.org/10.1016/j. amjcard.2011.11.045; PMID:22264598.

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11. Sánchez-Martínez M, López-Cuenca A, Marín F, et al. Red cell distribution width and additive risk prediction for major bleeding in non-ST-segment elevation acute coronary syndrome. Rev Esp Cardiol (Engl Ed) 2014;67:830–6. https://doi.org/10.1016/j.rec.2013.12.018; PMID:25262129. 12. Fatemi O, Torguson R, Chen F, et al. Red cell distribution width as a bleeding predictor after percutaneous coronary intervention. Am Heart J 2013;166:104–9. https:// doi.org/10.1016/j.ahj.2013.04.006; PMID:23816028. 13. Tonelli M, Sacks F, Arnold M, et al. Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease. Circulation 2008;117:163– 8. https://doi.org/10.1161/CIRCULATIONAHA.107.727545; PMID:18172029. 14. Felker GM, Allen LA, Pocock SJ, et al. Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM program and the Duke Databank. J Am Coll Cardiol 2007;50:40–7. https://doi.org/10.1016/j. jacc.2007.02.067; PMID:17601544. 15. Horne BD, Anderson JL, Muhlestein JB, et al. Complete blood count risk score and its components, including RDW, are associated with mortality in the Jupiter trial. Eur J Prev Cardiol 2015;22:519–26. https://doi. org/10.1177/2047487313519347; PMID:24403296. 16. Adams KF Jr, Mehra MR, Oren RM, et al. Prospective evaluation of the association between cardiac troponin T and markers of disturbed erythropoiesis in patients with heart failure. Am Heart J 2010;160:1142–8. https://doi. org/10.1016/j.ahj.2010.07.033; PMID:21146670. 17. Van Kimmenade RR, Mohammed AA, Uthamalingam S, et al. Red blood cell distribution width and 1-year mortality in acute heart failure. Eur J Heart Fail 2010;12:129–36. https://doi.org/10.1093/eurjhf/hfp179; PMID:20026456. 18. Sotiropoulos K, Yerly P, Monney P, et al. Red cell distribution width and mortality in acute heart failure patients with preserved and reduced ejection fraction. ESC Heart Fail 2016;3:198–204. https://doi.org/10.1002/ ehf2.12091; PMID:27818784. 19. Pascual-Figal DA, Bonaque JC, Redondo B, et al. Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients. Eur J Heart Fail 2009;11:840–6. https://doi.

org/10.1093/eurjhf/hfp109; PMID:19696056. 20. Förhécz Z, Gombos T, Borgulya G, et al. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009;158:659–66. https://doi.org/10.1016/j.ahj.2009.07.024; PMID:19781428. 21. Allen LA, Felker GM, Mehra MR, et al. Validation and potential mechanisms of red cell distribution width as a pronostic marker in heart failure. J Card Fail 2010;16:230–8. https://doi.org/10.1016/j.cardfail.2009.11.003; PMID:20206898. 22. Van Zeben D, Bieger R, Van Wermeskerken RK, et al. Evaluation of microcytosis using serum ferritin and red blood cell distribution width. Eur J Haematol 1990;44:106–9. PMID:2318292. 23. Van Craenenbroaeck EM, Conraads VM, Greenlaw N, et al. The effect of intravenous ferric carboxymaltose on red cell distribution width: a subanalysis of the FAIR-HF study. Eur J Heart Fail 2013;15:756–62. https://doi.org/10.1093/ eurjhf/hft068; PMID:23639779. 24. Belonje AM, Voors AA, Van Der Meer P, et al. Endogenous erythropoietin and outcome in heart failure. Circulation 2010;121:245–51. https://doi.org/10.1161/ CIRCULATIONAHA.108.844662; PMID:20048213. 25. Ycas JW, Horrow JC, Horne BD. Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia? Clin Chim Acta 2015;448:107– 17. https://doi.org/10.1016/j.cca.2015.05.021; PMID:26096256. 26. Hattangadi SM, Wong P, Zhang L, et al. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 2011;118:6258–68. https://doi.org/10.1182/blood2011-07-356006; PMID:21998215. 27. 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). Eur Heart J 2016;37:2129–2200. https://doi.org/10.1093/eurheartj/ ehw128; PMID:27206819.

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Correspondence

Red Cell Distribution Width as a Biomarker for Heart Failure: Still Not Ready for Prime-Time Sunil K Nadar and Mohammed Mujtaba Shaikh Department of Medicine, Sultan Qaboos University Hospital, Oman

Disclosure: The authors have no conflicts of interest to declare. Citation: Cardiac Failure Review 2019;5(3):180–1. DOI: https://doi.org/10.15420/cfr.2019.16.1 Correspondence: Sunil Nadar, Department of Medicine, Sultan Qaboos University Hospital, PO Box 31, Al Khoudh, Muscat 123, Oman. E: sunilnadar@gmail.com

Dear Editor, We would like to thank García-Escobar and Ingelmo for their letter regarding our article on the use of biomarkers in routine clinical care for heart failure.1,2 It was with interest that we read their comments on the use of red cell volume distribution width (RDW) as another biomarker for use in the management of patients with heart failure. As mentioned in their letter, RDW is a measure of heterogeneity of red blood cell (RBC) volume or anisocytosis and not a measure of RBC size or volume itself.3 RDW is a number generated by automated blood count machines. Increased variations in RBC volume – that is, a high RDW, is seen in anaemic states (such as iron deficiency anaemia, sickle cell anaemia, thalassaemia and megaloblastic anaemia), in patients using chemotherapeutic agents, in cardiovascular disease, thyroid disease and myelodysplastic syndromes.3 There has been a considerable amount of research into the use of RDW to assess prognosis in various conditions, given that this variable is readily available. García-Escobar and Ingelmo have extensively reviewed this possibility in their letter. They have also analysed the various studies on RDW and heart failure. We agree that data support the use of RDW as a marker of prognosis in patients with heart failure, other cardiovascular diseases and stroke.4–6 There are various mechanisms that may be involved that could explain how RDW predicts mortality. RDW is a surrogate for iron deficiency and other forms anaemia7 that are known to be associated with a poorer prognosis in heart failure.8 In addition to this, there are correlations between high RDW and inflammation, ineffective erythropoiesis, undernutrition and impaired renal function in patients with heart failure.9 RDW is also a marker of hypoxaemia.10 Patients who are sicker on presentation due to systemic inflammation, chronic anaemia, hypoxia and impaired renal function might therefore have a higher RDW due to the various processes coexisting alongside their heart failure. RDW is thus not a specific test for heart failure but is a non-specific surrogate for the various pathogenetic mechanisms that occur in heart failure or indeed any other chronic disease.11–13 RDW therefore cannot be used for the diagnosis of heart failure and as yet there are no studies demonstrating its role in this capacity. Similarly, there are limited data that can be used to assess the changes that occur in RDW as a result of treatment for heart failure14 and pulmonary embolism.15 The studies to date are small and the one on heart failure is retrospective. The lifespan of RBCs is 100–120 days and it would probably take this long for the RDW to show any significant change. Indeed, after the successful treatment of iron deficiency anaemia with iron supplements, studies have shown that it takes up to 3 months for the RDW to come down to reference levels.16 Extrapolating this to patients with heart failure, a raised RDW might indicate a process that was prevalent up to 3 months prior to the patient’s presentation, rather than reflecting an acute issue. In conclusion, we would like to state that RDW is a marker of a chronic disease process and is not specific to heart failure. It appears to predict prognosis in patients with heart failure. Currently, there are no trials showing what specific cut-off values would reflect worse prognosis, we only have studies showing correlations of higher values (even within normal reference ranges) with worse prognosis. We cannot recommend what course of action a treating clinician should take when presented with a RDW value for a patient with heart failure as there are insufficient data. Therefore, although a great research tool, we cannot at present recommend the use of RDW in routine clinical practice. 1.

3. 4.

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García-Escobar A, Ingelmo JM. Red cell volume distribution width as another biomarker. Card Fail Rev 2019;5:176–9. https://doi.org/10.15420/cfr.2019.13.1. Nadar SK, Shaikh MM. Biomarkers in routine heart failure clinical care. Card Fail Rev 2019;5:50–6. https://doi. org/10.15420/cfr.2018.27.2; PMID: 30847246. Evans TC, Jehle D. The red blood cell distribution width. J Emerg Med 1991;9 Suppl 1:71–4. PMID: 1955687. Felker GM, Allen LA, Pocock SJ, et al. Red cell distribution

Access at: www.CFRjournal.com

width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank. J Am Coll Cardiol 2007;50:40–7. https://doi.org/10.1016/j. jacc.2007.02.067; PMID: 17601544. Tonelli M, Sacks F, Arnold M, et al. Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease. Circulation 2008;117:163– 8. https://doi.org/10.1161/circulationaha.107.727545; PMID: 18172029.

Ani C, Ovbiagele B. Elevated red blood cell distribution width predicts mortality in persons with known stroke. J Neurol Sci 2009;277:103–8. https://doi.org/10.1016/j. jns.2008.10.024; PMID: 19028393. Demir A, Yarali N, Fisgin T, et al. Most reliable indices in differentiation between thalassemia trait and iron deficiency anemia. Pediatr Int 2002;44:612–6. https://doi. org/10.1046/j.1442-200x.2002.01636.x; PMID: 12421257. Beedkar A, Parikh R, Deshmukh P. Heart failure and the

Red Cell Volume Distribution Width iron deficiency. J Assoc Physicians India 2017;65:79–80. PIMD: 29322715. 9. Förhécz Z, Gombos T, Borgulya G, et al. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009;158:659–66. https://doi. org/10.1016/j.ahj.2009.07.024; PMID: 19781428. 10. Ycas JW, Horrow JC, Horne BD. Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia? Clin Chim Acta 2015;448:107–17. https://doi.org/10.1016/j.cca.2015.05.021;PMID: 26096256. 11. Pehlivanlar KM, Oztuna F, Abul Y, et al. Prognostic value of red cell distribution width and echocardiographic

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parameters in patients with pulmonary embolism. Adv Respir Med 2019;87:69–76. https://doi.org/10.5603/ arm.2019.0012; PMID: 31038716. 12. Shi C, Xie M, Li L, et al. The association and diagnostic value of red blood cell distribution width in colorectal cancer. Medicine (Baltimore) 2019;98:e15560. https://doi. org/10.1097/md.0000000000015560; PMID: 31083220. 13. Wang H, Wang J, Huang R, et al. Red blood cell distribution width for predicting significant liver inflammation in patients with autoimmune hepatitis. Eur J Gastroenterol Hepatol 2019;98:e15560. https://doi.org/10.1097/ meg.0000000000001447; PMID: 31107736. 14. Muhlestein JB, Lappe DL, Anderson JL, et al. Both initial red cell distribution width (RDW) and change in RDW

during heart failure hospitalization are associated with length of hospital stay and 30-day outcomes. Int J Lab Hematol 2016;38:328–37. https://doi.org/10.1111/ijlh.12490; PMID: 27121354. 15. Yazici S, Kiris T, Sadik CU, et al. Relation between dynamic change of red cell distribution width and 30-day mortality in patients with acute pulmonary embolism. Clin Respir J 2018;12:953–60. https://doi.org/10.1111/crj.12611; PMID: 28063201. 16. Akarsu S, Taskin E, Yilmaz E, et al. Treatment of iron deficiency anemia with intravenous iron preparations. Acta Haematol 2006;116:51–7. https://doi. org/10.1159/000092348; PMID: 16809890.

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21/02/19 11:29:37

EASE THE CHALLENGE OF TREATING THE FAILING HEART

SIMDAX® GIVES YOU TIME WHEN IT’S NEEDED 1 MOST SIMDAX® is the only inodilator2,3 to provide long lasting hemodynamic benefits3–10 and symptom control3–5,11,12 to patients with acute heart failure and in need of inotropic therapy.

References: 1. Nieminen MS et al. Eur Heart J Suppl. 2017;19(suppl C);C15-C21. 2. Papp Z et al. Int J Cardiol. 2012; 159:82–87. 3. Nieminen MS et al. Heart Lung Vessel. 2013;5(4):227–245. 4. Follath et al. Lancet. 2002;360:196–202. 5. Slawsky et al. Circulation. 2000;102:2222–2227. 6. Nieminen et al. J Am Coll Cardiol. 2000;36:1903–1912. 7. Kivikko et al. Circulation. 2003;107:81–86. 8. Lilleberg et al. Eur J Heart Fail. 2007;9:75–82. 9. Lilleberg et al. Eur Heart J. 1998; 19:660–668. 10. Ukkonen et al. Clin Pharmacol Ther. 2000;68:522–531. 11. Mebazaa et al. JAMA. 2007;297:1883–1891. 12. Packer et al. JACC Heart Fail. 2013;1(2):103–111.

PRODUCT INFORMATION: Simdax 2.5 mg/ml concentrate for solution for infusion. Therapeutic indications Simdax is indicated for the short-term treatment of acutely decompensated severe chronic heart failure (ADHF) in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. Dosage and administration Simdax is for in-hospital use only. It should be administered in a hospital setting where adequate monitoring facilities and expertise with the use of inotropic agents are available. Simdax is to be diluted prior to administration. The infusion is for intravenous use only and can be administered by the peripheral or central route. Dosage: The dose and duration of treatment should be individualised according to the patient’s clinical condition and response. The recommended duration of infusion in patients with acute decompensation of severe chronic heart failure is 24 hours. No signs of development of tolerance or rebound phenomena have been observed following discontinuation of Simdax infusion. Haemodynamic effects persist for at least 24 hours and may be seen up to 9 days after discontinuation of a 24-hour infusion. Experience of repeated administration of Simdax is limited. Experience with concomitant use of vasoactive agents, including inotropic agents (except digoxin) is limited. Monitoring of treatment: Consistent with current medical practice, ECG, blood pressure and heart rate must be monitored during treatment and the urine output measured. Monitoring of these parameters for at least 3 days after the end of infusion or until the patient is clinically stable is recommended. In patients with mild to moderate renal or mild to moderate hepatic impairment monitoring is recommended for at least 5 days. Elderly: No dose adjustment is required for elderly patients. Renal impairment: Simdax must be used with caution in patients with mild to moderate renal impairment. Simdax should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min).

Hepatic impairment: Simdax must be used with caution in patients with mild to moderate hepatic impairment although no dose adjustment appears necessary for these patients. Simdax should not be used in patients with severe hepatic impairment. Children: Simdax should not be administered to children and adolescents under 18 years of age. Contraindications Hypersensitivity to levosimendan or to any of the excipients. Severe hypotension and tachycardia. Significant mechanical obstructions affecting ventricular filling or outflow or both. Severe renal impairment (creatinine clearance <30 ml/min) and severe hepatic impairment. History of Torsades de Pointes. Special warnings and special precautions for use An initial haemodynamic effect of levosimendan may be a decrease in systolic and diastolic blood pressure, therefore, levosimendan should be used with caution in patients with low baseline systolic or diastolic blood pressure or those at risk for a hypotensive episode. More conservative dosing regimens are recommended for these patients. Physicians should tailor the dose and duration of therapy to the condition and response of the patient. Severe hypovolaemia should be corrected prior to levosimendan infusion. If excessive changes in blood pressure or heart rate are observed, the rate of infusion should be reduced or the infusion discontinued. The exact duration of all haemodynamic effects has not been determined, however, the haemodynamic effects, generally last for 7-10 days. This is partly due to the presence of active metabolites, which reach their maximum plasma concentrations about 48 hours after the infusion has been stopped. Non-invasive monitoring for at least 4-5 days after the end of infusion is recommended. Monitoring is recommended to continue until the blood pressure reduction has reached its maximum and the blood pressure starts to increase again, and may need to be longer than 5 days if there are any signs of continuing blood pressure decrease, but can be shorter than 5 days if the patient is clinically stable. In patients with mild to moderate renal or mild to moderate hepatic impairment an extended period of monitoring maybe needed.

Simdax infusion should be used cautiously in patients with tachycardia atrial fibrillation with rapid ventricular response or potentially life-threatening arrhythmias. Interaction with other medicinal products and other forms of interaction Consistent with current medical practice, levosimendan should be used with caution when used with other intravenous vasoactive medicinal products due to a potentially increased risk of hypotension. No pharmacokinetic interactions have been observed in a population analysis of patients receiving digoxin and Simdax infusion. Simdax infusion can be used in patients receiving beta-blocking agents without loss of efficacy. Co-administration of isosorbide mononitrate and levosimendan in healthy volunteers resulted in significant potentiation of the orthostatic hypotensive response. Undesirable effects The most commonly (>1/10) reported adverse reactions include headache, hypotension and ventricular tachycardia. Overdose Overdose of Simdax may induce hypotension and tachycardia. High doses (at or above 0.4 microgram/kg/min) and infusions over 24 hours increase the heart rate and are sometimes associated with prolongation of the QTc interval. Simdax overdose leads to increased plasma concentrations of the active metabolite, which may lead to a more pronounced and prolonged effect on heart rate requiring a corresponding extension of the observation period. Storage Store at 2°C-8°C (in a refrigerator). Do not freeze.

CONTACT INFORMATION: Orion Corporation, Orion Pharma, PO Box 65, FI-02101 ESPOO, FINLAND. Tel. +358 10 4261