CFR 4.2 by Radcliffe Cardiology

Cardiac Failure Review Volume 4 • Issue 2 • Summer 2018

©Radcliffe Cardiology

Volume 4 • Issue 2 • Summer 2018

www.CFRjournal.com

Heart Failure with Mid-range Ejection Fraction: Lessons from CHARM Lars H Lund

Calming the Nervous Heart: Autonomic Therapies in Heart Failure Peter Hanna, Kalyanam Shivkumar and Jeffrey L Ardell

Frailty in Heart Failure: Implications for Management Cristiana Vitale, Ilaria Spoletini and Giuseppe MC Rosano

Imaging of Valvular Heart Disease in Heart Failure Tomaz Podlesnikar, Victoria Delgado and Jeroen J Bax

Multidetector computer tomography in pre-transfemoral aortic valve implantation planning ISSN: 2057-7540 CFR 4.2_FC.indd All Pages

Residual mitral regurgitation

Tortuous bilateral iliofemoral arteries

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ESC future congresses Covering the full spectrum of cardiology

ESC Congress Munich 2018 25-29 August

Where the world of cardiology comes together

ALL TOPICS Munich, Germany 25-29 August 2018

EuroEcho 2 0 Imaging 1 8 exercise and sport | valvular heart disease

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of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the ESC. www.escardio.org/EACVI

In conjunction with the 43rd Annual Meeting of the ESC Working Group on Cardiac Cellular Electrophysiology

INTERVENTION London, United Kingdom 9-11 September 2018

CARDIAC IMAGING Milan, Italy 5-8 December 2018

ACUTE CARDIAC CARE Malaga, Spain 2-4 March 2019

EuroHeartCare

EuroCMR 2019

Annual Congress of the Council on Cardiovascular Nursing and Allied Professions

extending the clinical value of cmr through quality and evidence

HEART RHYTHM Lisbon, Portugal 17-19 March 2019

2019

EuroPrevent European Congress on Preventive Cardiology

2-4 May 2019

Milan, Italy

2-4 May

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KEY FIGURES: 3 Days, 20 Sessions, 50 international faculty members, 200 abstracts, 500 delegates, 40 countries represented, 1 congress!

17th Annual Meeting

KEY DEADLINES: Abstract Submission: 10 January Early Registration fee: 27 February Late Registration fee: 2 April

on Cardiovascular Magnetic Resonance (CMR) of the European Association of Cardiovascular Imaging (EACVI)

11-13 April 2019 Lisbon, Portugal

www.escardio.org/EACVI www.escardio.org/EuroHeartCare #euroheartcare

NUCLEAR CARDIOLOGY AND CARDIAC CT Lisbon, Portugal 12-14 May 2019

#EuroCMR

NURSING Milan, Italy 2-4 May 2019

CARDIAC MAGNETIC RESONANCE Venice, Italy 2-4 May 2019

www.escardio.org/europrevent #europrevent

PREVENTION Lisbon, Portugal 11-13 April 2019

Heart Failure

Wo r l d Co ng ress o n Acute Hear t Failure

2019

2 5 -2 8 M AY AT H E N S g r e e c e

Organised by the Heart Failure Association of the ESC

heart failure from alpha to omega

www.escardio.org/heartfailure

INTERVENTION Paris, France 21-24 May 2019

Untitled-2 1

HEART FAILURE Athens, Greece 25-28 May 2019

BASIC SCIENCE Budapest, Hungary Spring 2020

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Volume 4 • Issue 2 • Summer 2018

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, Roma, 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, Roma, Italy

William T Abraham

Michael B Fowler

Kian-Keong Poh

Ali Ahmed

National University Heart Center, Singapore

Stanford University, USA

The Ohio State University, USA

Michael Fu

Sahlgrenska University Hospital, Sweden

A Mark Richards

Washington DC VA Medical Center, USA

Inder Anand

David L Hare

Giuseppe Rosano

John Atherton

Michael Henein

Jose Antonio Magaña Serrano

Heart Centre and Umea University, Sweden

National Medical Centre, Mexico

Adelino Leite-Moreira

Martin St John Sutton

St George’s University of London, UK

University of Melbourne, Australia

University of Minnesota, USA Royal Brisbane and Women’s Hospital, Australia

Michael Böhm

University of Porto, Portugal

Saarland University, Germany

Alain Cohen Solal

Hospital of the University of Pennsylvania, USA

Alexander Lyon

Allan D Struthers

Theresa A McDonagh

Michal Tendera

Kenneth McDonald

Maurizio Volterrani

Ileana L Piña

Cheuk Man Yu

Imperial College London, UK

Paris Diderot University, France

Henry J Dargie

Ninewells Hospital & Medical School, UK

King’s College Hospital, UK

Western Infirmary, Glasgow

Carmine De Pasquale

University of Silesia, Poland

St Vincent’s Hospital, Ireland

Flinders University, Australia

Frank Edelmann

Charité University Medicine, Germany

University of Otago, New Zealand

IRCCS San Raffaele Pisana, Italy

Montefiore Einstein Center for Heart & Vascular Care, USA

The Chinese University of Hong Kong, Hong Kong

Managing Editor Rosie Scott • Production Aashni Shah • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing Director Leiah Norcott • Commercial Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O’Neill •••

Editorial Contact Rosie Scott rosie.scott@radcliffe-group.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffe-group.com •••

Cover image

credit: medistock © stock.adobe.com

•

Cover design Tatiana Losinska

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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 © 2018 All rights reserved ISSN: 2057–7540 • eISSN: 2057–7559

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Established: March 2015 Frequency: Tri-annual Current issue: Summer 2018

Aims and Scope • 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.

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

Editorial Expertise 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.

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.

Submissions and Instructions to Authors • 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

Reprints All articles included in Cardiac Failure Review are available as reprints. Please contact the Publishing Director, Liam O’Neill liam.oneill@radcliffe-group.com

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

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

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Cardiac Failure Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

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

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Contents

www.CFRjournal.com

Foreword

Andrew JS Coats and Giuseppe Rosano

Diagnosis

Heart Failure with Mid-range Ejection Fraction: Lessons from CHARM

Advances in Imaging and Heart Failure: Where are we Heading?

Imaging of Valvular Heart Disease in Heart Failure

Lars H Lund

Santhi Adigopula and Julia Grapsa

Tomaz Podlesnikar, Victoria Delgado and Jeroen J Bax

Pathophysiology

Heartâ&#x20AC;&#x201C;brain Interactions in Heart Failure

Calming the Nervous Heart: Autonomic Therapies in Heart Failure

Nadja Scherbakov and Wolfram Doehner

Peter Hanna, Kalyanam Shivkumar and Jeffrey L Ardell

Therapy

Metabolic Modulation of Cardiac Metabolism in Heart Failure Giuseppe MC Rosano and Cristiana Vitale

Co-Morbidities

104

Frailty in Heart Failure: Implications for Management

107

Exercise Training in Heart Failure Patients With Persistent Atrial Fibrillation: a Practical Approach

Cristiana Vitale, Ilaria Spoletini and Giuseppe MC Rosano

Justien Cornelis, Jonathan Myers, Hein Heidbuchel, Christiaan Vrints and Paul Beckers

Clinical Syndromes

112

Postpartum Cardiomyopathy and Considerations for Breastfeeding Laura Kearney, Paul Wright, Sadeer Fhadil and Martin Thomas

ÂŠ RADCLIFFE CARDIOLOGY 2018

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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, our readers, Volume 4.2 of Cardiac Failure Review. Heart failure with mid-range ejection fraction, HFmrEF, formally introduced into the definition of heart failure phenotypes by the 2016 ESC Heart Failure Guidelines,1 has been the subject of intense investigation and analysis since its launch as a concept. One of these outcomes has been the re-analysis of existing clinical trial databases to establish what treatments can be said to be effective also in HFmrEF in addition to HFrEF. Although what we would like are prospective randomized controlled trials specifically designed to test the hypothesis that a particular treatment would beneficially effect HFmrEF, such trials are unlikely to occur soon, if at all. Until then, the best we can get is detailed analysis of individual patient data, including all outcome trials that included HFmrEF patients without bias. In this issue, Lars Lund of Stockholm explores evidence from the CHARM programme of the effectiveness of Candesartan Cilexetil in the therapy of HFmrEF. In a recently published analysis,2 Lund and colleagues showed the effect of Candesartan when used to treat HFmrEF. He

summarised data from observational studies and registries suggesting the prevalence of HFmrEF out of all heart failure (HF) subtypes varied between 10 and 24%. This HFmrEF cohort similarly comprised 17% of the CHARM programme, showing it was within the range of what is seen in the community. In CHARM, despite lower mortality rates in HFmrEF compared to HFrEF, the primary outcome for candesartan versus placebo was similar with a hazard ratio (95% confidence interval) of 0.82 (0.75–0.91, p<0.001) in HFrEF compared to 0.76 (0.61–0.96), p=0.02) in HFmrEF, which was distinctly different to what was seen in HFpEF (0.95 [0.79–1.14] p=0.57). Similar results were seen for recurrent HF hospitalization, with incidence rate ratios of 0.68 (0.58–0.80, p<0.001) for HFrEF and 0.48 (0.33–0.70, p<0.001) for HFmrEF, compared to 0.78 (0.59–1.03, p=0.08) for HFpEF. Taken together with similar analyses for beta-blockers3 and a subgroup report of the effect of spironolactone in TOPCAT,4 this is beginning to suggest that HFmrEF should be treated the same as HFrEF, albeit noting that the evidence for spironolactone is considerably weaker than the other two, because it is a sub-analysis of a single trial, and one that itself was not statistically significant for benefit as designed. We have an article from the Cleveland Clinic that reviews modern advances in imaging in heart failure. The authors stress developments they see emerging in modern imaging in HF. They predict an expansion of the use of echocardiography in assessing two aspects of importance in modern HF management: diastolic function and exercise-induced changes in ventricular function. They also update us on the usefulness of multi-detector computed tomography and cardiovascular magnetic resonance. They offer a review of what they coin “molecular imaging”, in which radionuclide imaging, using either positron emission tomography (PET) or single-photon emission computed tomography, can be used for characterization of tissue function in myocardial disorders, including 123I-labeled MIBG, as a marker of adrenergic function to risk stratify patients for risk of ventricular arrhythmic sudden cardiac death (SCD), and the progression of HF autonomic dysfunction. Another important area is the accurate assessment of coronary flow reserve with stress myocardial perfusion PET. Lastly, they introduce the exciting future world of hybrid imaging and 3D printing. Cardiac hybrid or fusion imaging combines imaging modalities to enhance functional and structural detail, as well as helping guide interventional procedures with immediately updated images peri-procedure. Based on hybrid imaging, and with the addition of advanced polymer technologies to make realistic tissue “feel”, 3D printing may in future allow careful planning of complex procedures, and aid in teaching and objective credentialing of practical competence in procedures. We have two articles on the emerging field of the heart–brain–nerve axis in HF. Scherbakov and Doehner review heart–brain interactions in HF, such as the effects of HF on the brain, including cardio-embolic and low perfusion pressure effects, the impairment of higher cortical and brain stem functions (cognitive impairment, sympathetic over-activation, neuro-cardiac reflexes), as well as treatment-related interactions, including drug- and device-related interactions. Peter Hanna and colleagues at the UCLA Neurocardiology Program review the field of autonomic reflex targeted therapies for HF. HF is characterized by significant and potentially mechanistically important DOI: 10.15420/cfr.2018.4.1.FO1

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Foreword

autonomic imbalance with increased sympathetic and reduced parasympathetic drive. Despite the success of pharmacological manipulation of the disordered neurohormonal axis, neuromodulation of similar abnormalities in autonomic control of the heart have as yet been very poorly studied, despite mechanistic and pre-clinical studies suggesting significant potential benefit in pursuing these strategies. The small number of clinical trials to date have delivered inconsistent results, which the authors put down to inadequate understanding of the structural and functional organization of the cardiac nervous system. Simple things such as appreciating the importance that the site of stimulation or inhibition of a complex neural network system may have on the outcome of neuromodulation or its stimulation parameters (intensity, frequency, duration and on–off effects) and the background cardioneural pathologic substrate. They conclude that it is highly likely that the optimum neuromodulation approach may require a much more sophisticated fine-tuning, even down to individually personalised approaches as patients' disease progresses. They review many possible approaches and summarise the extent to which these can be said to have shown promise or “proof of concept”. These include vagus nerve stimulation with the aim of increasing parasympathetic tone and restoring integrated cardiac reflex function. This has had variable clinical trial success so far in the ANTHEM-HF, NECTAR-HF and INOVATE HF studies. Spinal cord stimulation (SCS), which already has FDA approval as a therapy for chronic pain syndrome and refractory angina, suppresses the release of cardiac-related afferent neurotransmitters, thereby modulating sympathetic preganglionic neural activity and reducing sympatho-excitation within the intra-thoracic extra-cardiac ganglia. It is suggested to show cardioprotective effects in animal models of myocardial ischaemia and infarction and in HF. Two clinical studies, SCS HEART and DEFEAT-HF, leave the field unproven to date. Baroreflex activation therapy also has a past history; this time as a treatment for resistant hypertension and refractory angina. Through electrical stimulation of the baroreceptor afferent fibres, central sympathetic outflow is reduced, while parasympathetic tone is augmented. Preclinical studies in HF have produced evidence of proof-of-concept in myocardial infarction-induced HF. Human clinical trials include Hope for Heart Failure (HOPE4HF) of 146 patients HFrEF patients with improved NYHA functional class, QOL and 6MWT, with a reduction in NT pro-BNP. This will be followed by the BeAT-HF trial. Renal denervation, initially evaluated for refractory hypertension, also has been shown to have potentially useful effects in animal and early human studies in HF, including the REACH-Pilot study and Symplicity HF. Stellate ganglionectomy, a form of cardiac sympathetic denervation (CSD), was also initially proposed as a treatment for angina and ventricular arrhythmias. One prospective, randomized pilot study has evaluated CSD for heart failure. None of the trials to date in this whole field, however, can be considered large enough to evaluate the potential of the field, but it is highly likely we will see more electro-therapeutic neuromodulatory approaches for disease treatment in the future, given the importance of autonomic dysfunction in the pathophysiology of HF. Vitale and colleagues in two articles review the important topic of frailty complicating cases of HF in the older patient population and the potential of the metabolic agent trimetazidine. Frailty is a complex clinical syndrome very common in patients with HF, and is associated with dramatically impaired quality of life and prognosis. Vitale and colleagues summarise what we know and gives directions of where future potential treatments may lie. In “Metabolic modulation of cardiac metabolism in heart failure: the role of trimetazidine”, Rosano and Vitale review the metabolic changes that affect both cardiac and skeletal muscles in HF. Abnormalities of high-energy phosphate production both contribute to symptoms and via reflex effects and direct myocardial effects can exacerbate the progression of HF. They summarise metabolic therapy in HF, with a particular focus on trimetazidine. Such agents can partially correct cardiac substrate metabolism directly, and have been shown able to improve symptoms, functional capacity and prognosis in HF on top of guideline-directed medical therapy. Last but certainly not least, there are topical expert reviews of three specialist sub-topics in HF: exercise training in HF complicated by atrial fibrillation, HF complicated by pulmonary hypertension and postpartum cardiomyopathy, with special consideration of the impact on breastfeeding. We have pleasure in recommending this, the latest issue of Cardiac Failure Review. n

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(27):2129–200. DOI: 10.1093/ eurheartj/ehw128; PMID: 27206819.

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Lund LH, Claggett B, Liu J, et al. Heart failure with midrange ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail 2018; DOI: 10.1002/ejhf.1149; PMID: 29431256; epub ahead of press. Cleland JGF, Bunting KV, Flather MD, et al. Beta-blockers in Heart Failure Collaborative Group. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection

fraction: an individual patient-level analysis of doubleblind randomized trials. Eur Heart J 2018;39(1):26–35. DOI: 10.1093/eurheartj/ehx564; PMID: 29040525. Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 2016; 37(5):455–62. DOI: 10.1093/eurheartj/ehv464; PMID: 26374849.

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Diagnosis

Heart Failure with Mid-range Ejection Fraction: Lessons from CHARM Lars H Lund Cardiology Unit, Department of Medicine, Karolinska Institutet, and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden

Abstract The newly defined category of heart failure (HF) with mid-range ejection fraction (HFmrEF; EF 40–49 %) is beginning to be characterised but little is known about the potential for treating it. Trials and observational studies suggest that standard therapy for HF with reduced ejection fraction (HFrEF; EF <40 %) may also offer some benefit to patients with EF ≥40 %; however, any difference between its effects on HFmrEF and true HF with preserved ejection fraction (HFpEF) have until now not been explored. This study summarises randomised trial data from the CHARM programme that suggest that candesartan may improve outcomes in HFmrEF.

Keywords Heart failure, mid-range ejection fraction, preserved ejection fraction, outcomes, candesartan, angiotensin receptor blocker Disclosure: LHL: present work: none; unrelated to present work: grants to author’s institution: AstraZeneca, Novartis; consulting: AstraZeneca, ViforPharma, Novartis, Merck, Relypsa, Boehringer Ingelheim. Funding: LHL was supported by grants for a broad HFpEF research programme from the Swedish Research Council (grant 201323897-104604-23), the Swedish Heart Lung Foundation (grant 20150063) and Stockholm County Council (grants 20090556 and 20110120). Received: 7 March 2018 Accepted: 9 May 2018 Citation: Cardiac Failure Review 2018;4(2):70–2. DOI: https://doi.org/10.15420/cfr.2018.11.2 Correspondence: Lars H Lund, Department of Cardiology, N305, Karolinska Institutet and Karolinska University Hospital, 117 76 Stockholm, Sweden. E: lars.lund@alumni.duke.edu

The cut-off values for “normal” ejection fraction (EF) are poorly defined. The EchoNoRMAL study suggested a lower boundary of 49–57 %.1 The American Society of Echocardiography and European Association of Cardiovascular Imaging consider a normal EF and normal range (±2 SD) as 62 % (52–72 %) in men and 64 % (54–74 %) in women.2 By these criteria, an EF of 40–49 % would not be considered normal. However, there is considerable uncertainty and even controversy around the newly defined heart failure (HF) category of “HF with midrange ejection fraction” (HFmrEF; EF 40–49 %). The 2016 European Society of Cardiology HF guidelines introduced this term for HF with EF in the middle range of 40–49 %, which is between HF with reduced EF (HFrEF; <40 %) and preserved EF (HFpEF; ≥50 %) EF.3,4 While the purpose of creating this category was to identify an area in need of further research, it has led to some confusion regarding how to classify and, more importantly, how to treat patients with HFmrEF. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Programme studied patients with symptomatic heart failure across the entire spectrum of EF. In CHARMPreserved, which enrolled patients with LVEF >40 %, candesartan did not significantly reduce cardiovascular death or HF hospitalisation (unadjusted HR 0.89 [95 % CI 0.77–1.03], p=0.118; covariate adjusted 0.86 [0.74–1.0], p=0.051). However, it was effective in HFrEF and, in CHARM-Overall, there was no heterogeneity with respect to EF (p=0.33). Recently, we specifically studied HFmrEF in CHARM and tested the hypothesis that candesartan improves outcomes in HFmrEF.5

HFmrEF made up about 10 % of incident HF in a US community-based study.12 In prevalent HF, it represents 24 % in the European Society of Cardiology Heart Failure Long-Term Registry,8 21 % of the Swedish HF Registry (SwedeHF),11 and 13 % of a multi-ethnic Singapore and New Zealand cohort.13 While many characteristics in HFmrEF are intermediate between HFrEF and HFpEF, many others – especially the higher prevalence of ischaemic heart disease – suggest that HFmrEF is distinctly more similar to HFrEF.6 In CHARM, HFmrEF accounted for 17 % of patients. It was indeed intermediate between HFrEF and HFpEF with regard to history of hypertension, New York Heart Association (NYHA) class, and BMI. However, HFmrEF appeared similar to HFrEF regarding the most important characteristics, e.g. lower age, male sex predominance, lower systolic blood pressure, less AF, and more ischaemic heart disease and a history of MI, consistent with other emerging analyses.14

HFmrEF Outcomes: More Similar to HFpEF In CHARM, over a mean follow-up of 2.9 years overall, there were: 15.9, 8.5, and 8.9 primary events (cardiovascular deaths or first HF hospitalisations) per 100 patient-years in HFrEF, HFmrEF and HFpEF respectively; and 20.0, 10.8, and 11.1 recurrent HF hospitalisations per 100 patient-years respectively. The incidence rates for first HF hospitalisation, cardiovascular (CV) death and all-cause death were comparable in HFmrEF and HFpEF and lower in HFmrEF and HFpEF than in those with HFrEF.

HFmrEF Characteristics: Similar to HFrEF HFmrEF is often referred to as an “intermediate” phenotype that may represent a “transition phase”, but several reports over the past year suggest that this is overly simplistic6–11.

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While the characteristics of HFmrEF are distinctly more similar to HFrEF, the syndrome appears milder in HFmrEF, so the CV risk appears lower.

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HFmrEF in CHARM Figure 1: Effect of Candesartan on All Outcomes by Ejection Fraction as a Continuous Variable CV death and HF hospitalisation

Treatment effect (rate ratio)

HF hospitalisation 2

p for trend=0.34 overall p=0.15

p for trend=0.53 overall p=0.14

1.5

0.8

0.6

All-cause hospitalisation 2 Treatment effect (rate ratio)

CV death 2

All-cause death 2

p for trend=0.42 overall p=0.34

p for trend=0.036 overall p=0.11

1.5

0.8

0.6

Ejection fraction

HF hospitalisation 2

1.5

p for trend=0.17 overall p=0.37

Ejection fraction

p for trend=0.50 overall p=0.48

Ejection fraction

The figures show unadjusted incidence rate ratios and 95 % confidence intervals for the candesartan treatment effect for the six outcomes according to ejection fraction as a continuous variable. The range shaded in blue is the HFmrEF range. The red arrow indicates the EF at which the 95 % CI for the hazard ratio for candesartan versus placebo was no longer <1.0. CV = cardiovascular; HF = heart failure. Modified from Lund et al., 2018,5 with permission from Wiley.

Candesartan Appears Effective in HFmrEF In CHARM, the incidence rates for the primary outcome for candesartan versus placebo were 14.4 versus 17.5 per 100 patient-years (HR [95 % CI] 0.82 [0.75–0.91], p<0.001) in HFrEF; 7.4 versus 9.7 per 100 patientyears (0.76 [0.61–0.96] p=0.02) in HFmrEF; and 8.6 versus 9.1 per 100 patient-years (0.95 [0.79–1.14] p=0.57) in HFpEF. For recurrent HF hospitalisation, the incidence rate ratios were 0.68 (0.58–0.80), p<0.001; 0.48 (0.33–0.70), p<0.001; and 0.78 (0.59–1.03), p=0.08, respectively.

However, the resemblance between HFmrEF and HFrEF and the benefits suggested in the post-hoc analyses of CHARM, TOPCAT and the betablocker meta-analysis may make clinicians reluctant to randomise patients in the HFmrEF range, and the variability of EF measurements may make it difficult to identify patients with HFmrEF reliably.

Conclusion The recent analysis from CHARM suggests that:

Figure 1 shows unadjusted treatment effects for each outcome according to continuous EF (spline). The hazard ratios and upper 95 % CIs were all below 1.0, indicating benefit with candesartan, up to and beyond EF ~50 % for the primary composite and first HF hospitalisation outcomes, and up to EF ~60 % for the recurrent HF hospitalisations outcome.

• H FmrEF resembles HFrEF regarding most clinical characteristics, in particular a history of myocardial infarction. • HFmrEF resembles HFpEF with respect to a lower risk of HF and CV events, suggesting HFmrEF is a milder syndrome than HFrEF. • Candesartan may reduce CV and HF events in HFmrEF to the same extent as in HFrEF.

Candesartan reduced CV death, all-cause death and all-cause hospitalisation only at the lower end of the EF spectrum. The potential efficacy of HFrEF therapy also in HFmrEF has been hinted at in observational studies,15,16 in the TOPCAT trial with spironolactone,17 as well as in a meta-analysis of 11 randomised trials with beta-blockers.18

EF may change over time and there is inherent variability in EF measurements, which makes identification of patients with HFmrEF difficult; nonetheless, this condition is not infrequently encountered and it needs to be addressed.

Taken together, these data provide a rationale for future studies of generic, inexpensive treatments in HFmrEF, something that can be done at low cost and high efficiency in pragmatic trial settings.19

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The treatment effect finding in CHARM should be interpreted with caution because this was a post-hoc analysis; nonetheless, it suggests that interventions known to be effective in HFrEF have potential and should be explored also in HFmrEF. n

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Diagnosis 1.

chocardiographic Normal Ranges Meta-Analysis of E the Left Heart Collaboration. Ethnic-specific normative reference values for echocardiographic LA and LV size, LV mass, and systolic function: the EchoNoRMAL Study. JACC Cardiovasc Imaging 2015;8:656–65. https://doi.org/10.1016/ j.jcmg.2015.02.014; PMID: 25981507. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–70. https://doi.org/10.1093/ehjci/jev014; PMID: 25712077. Lam CS, Solomon SD. The middle child in heart failure: heart failure with mid-range ejection fraction (40–50 %). Eur J Heart Fail 2014;16:1049–55. https://doi.org/10.1002/ejhf.159; PMID: 25210008. 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. Lund LH, Claggett B, Liu J, et al. Heart failure with midrange ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail 2018. https://doi.org/10.1002/ejhf.1149; PMID: 29431256; epub ahead of press. Vedin O, Lam CSP, Koh AS, et al. Significance of ischemic heart disease in patients with heart failure and preserved,

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midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail 2017;10: e003875. https://doi.org/10.1161/ CIRCHEARTFAILURE.117.003875; PMID: 28615366. Lofman I, Szummer K, Dahlstrom U, et al. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail 2017;19:1606–14. https://doi.org/10.1002/ejhf.821; PMID: 28371075. Chioncel O, Lainscak M, Seferovic PM et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2017;19:1574–85. https://doi.org/10.1002/ejhf.813; PMID: 28386917. Sartipy U, Dahlstrom U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2017;5:565–74. https://doi. org/10.1016/j.jchf.2017.05.001; PMID: 28711451. Tsuji K, Sakata Y, Nochioka K et al. Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study. Eur J Heart Fail 2017;19:1258–69. https://doi.org/10.1002/ejhf.807. PMID: 28370829. Koh AS, Tay WT, Teng THK et al. A comprehensive population-based characterization of heart failure with mid-range ejection fraction. Eur J Heart Fail 2017;19:1624–34. https://doi.org/10.1002/ejhf.945; PMID: 28948683. Bhambhani V, Kizer JR, Lima JA et al. Predictors and outcomes of heart failure with mid-range ejection fraction. Eur J Heart Fail 2018;20:651–9. https://doi.org/10.1002/ejhf.1091; PMID: 29226491. Lam CSP, Gamble GD, Ling LH et al. Mortality associated with heart failure with preserved vs. reduced ejection fraction in a

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prospective international multi-ethnic cohort study. Eur Heart J 2018;39:1770–80. https://doi.org/10.1093/eurheartj/ehy005. PMID: 29390051. Rickenbacher P, Kaufmann BA, Maeder MT et al. Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME–CHF). Eur J Heart Fail 19:1586–96. https://doi.org/10.1002/ ejhf.798; PMID: 28295985. Lund LH, Benson L, Dahlstrom U, Edner M. Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA 2012;308:2108–17. https://doi.org/10.1001/ jama.2012.14785; PMID: 23188027. Lund LH, Benson L, Dahlstrom U, Edner M, Friberg L. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312:2008–18. https://doi.org/10.1001/ jama.2014.15241; PMID: 25399276. Solomon SD, Claggett B, Lewis EF et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 2016;37:455–62. https://doi.org/10.1093/eurheartj/ ehv464; PMID: 26374849. Cleland JGF, Bunting KV, Flather MD et al. Beta–blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39:26–35. https://doi.org/10.1093/eurheartj/ehx564. PMID: 29040525. Lund LH, Oldgren J, James S. Registry-based pragmatic trials in heart failure: current experience and future directions. Curr Heart Fail Rep 2017;14:59–70. https://doi.org/10.1007/s11897017-0325-0; PMID: 28247180.

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Diagnosis

Advances in Imaging and Heart Failure: Where are we Heading? Santhi Adigopula 1,2 and Julia Grapsa 1,2 1. Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland Clinic Lerner School of Medicine, Ohio, USA; 2. Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, United Arab Emirates

Abstract Advanced cardiac imaging, following technological advances, has progressed significantly; it now serves as a diagnostic as well as a prognostic tool. Heart failure patients demand constant follow-up with baseline imaging such as echocardiography or more advanced imaging such as stress imaging. Imaging guides treatment as well as interventional procedures for the improvement of heart failure patients. This review aims to summarise the latest imaging techniques in heart failure diagnosis and treatment.

Keywords Heart failure, imaging, echocardiography, stress, prognosis, diagnosis Disclosure: The authors have no conflicts of interest to declare. Received: 22 January 2018 Accepted: 28 June 2018 Citation: Cardiac Failure Review 2018;4(2):73–7. DOI: https://doi.org/10.15420/cfr.2018.5.2 Correspondence: Santhi Adigopula, MD, Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Al Maryah island, PO 112412, Abu Dhabi, United Arab Emirates. E: adigopula.santhi@gmail.com

The increasing prevalence of heart failure requires the establishment of new imaging techniques that are able to diagnose early and guide treatment. With an estimated 825,000 new cases annually in the US, the heart failure burden will continue to rise and is expected to exceed 8 million by 2030.1

• l eft atrial volume index >34 ml/m2, or left ventricular mass index ≥115 g/m2 for males and ≥95 g/m2 for females; • average E/e’ >14; • annular e’ velocity : septal e’ <7 cm/s and lateral e’ <10 cm/s; and • peak tricuspid regurgitant velocity >2.8 m/s.

Echocardiography

Pulmonary pressures are of crucial importance as they are an indirect marker of significant diastolic dysfunction in patients with even normal LVEF.11 When the ejection fraction is reduced or where there is a confounding factor such as volume overload, other parameters are useful for the assessment of LV filling pressures.

Left Ventricular Function: The New Definition of Mid-Range Ejection Fraction Heart Failure Echocardiography is a first-line bedside tool for the diagnosis of heart failure patients and the assessment of prognosis, 2,3 with ejection fraction (EF) having been the cornerstone of heart failure definition.2 During the last decade, left ventricular (LV) EF has been employed to describe the new entity of mid-range EF heart failure (HFmrEF) as being an LVEF of 41–49 %.3 It is now clear that patients with HFmrEF represent a grey area,4,5 with recent data from major trials6,7 demonstrating that patients with HFmrEF behave similarly to those with heart failure with reduced EF (HFrEF), in terms of both prognosis and response to therapy. As a result of the new definition, more light has been shed on diastolic dysfunction and its role in the development of heart failure.

Exercise stress test and diastolic dysfunction In patients with shortness of breath and grade 1 diastolic dysfunction at rest, diastolic stress testing is crucial in diagnosis and prognosis (Figure 1). It is usually performed with a treadmill or supine bicycle. The test is considered positive if all the following three criteria are met during exercise:9,10 • average E/e’ >14 or septal E/e’ ratio >15; • peak tricuspid regurgitant velocity >2.8 m/s; and • septal e’ velocity <7 cm/s.

Diastolic Assessment and the Value of Exercise Testing By returning to the basics, two important echocardiographic features are important in heart failure patients: an accurate evaluation of diastolic function8 and the value of exercise testing.9,10

Evaluation of diastolic dysfunction at rest Accurate assessment of the degree of diastolic dysfunction is a prerequisite for a heart failure assessment. During diastology assessment, mitral E and annular E’ velocities should be recorded as well as peak velocity of tricuspid regurgitant jet from multiple windows.8 The key structural alterations during diastolic dysfunction in patients with normal EF are:8

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Strain Echocardiography Impaired global longitudinal strain (GLS) is common among HFpEF patients, indicating the presence of covert systolic dysfunction despite normal LVEF.13 Furthermore, impaired strain has been associated with biomarkers of wall stress and collagen synthesis and diastolic dysfunction.13 Longitudinal ventricular strain has been correlated independently to peak VO2 in patients with reduced and preserved EF and has been superior in identifying patients with reduced exercise capacity. There is a significant relationship between diastolic function and GLS, confirming a coupling between diastolic and longitudinal systolic function in HFpEF.14

Access at: www.CFRjournal.com

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Diagnosis Figure 1: Basic Principles of Stress Echocardiography

Stress imaging

Stress echocardiography

Exercise testing

Assess dynamic component of

Clarify symptoms status Loading conditions and

valvular abnormalities

ventriculo-arterial coupling

Use in cath lab: to unmask

Unmask subclinical myocardial

diastolic dysfunction in cases

dysfunction

of pulmonary hypertension

Contraindications:

Dobutamine stress echo in low flow

• Clear indication for valve surgery

low gradient aortic stenosis:

• Uncontrolled hypertension • Arrhythmias

Differentiates true severe from

• Physical/mental disability

pseudosevere aortic stenosis

• Systemic disease: unable to perform exercise Stop if: • 85 % predicted heart rate • Typical chest pain • Shortness of breath, dizziness, hypotension, significant ventricular arrhythmia or muscular exhaustion

Figure 2: Speckle Tracking in Amyloidosis

findings raise awareness among physicians to perform early strain echocardiography in patients on chemotherapy such as anthracyclines. As demonstrated in the literature,17 GLS greater than −17.45 % obtained after 150 mg/m2 of anthracycline therapy is an independent predictor of future anthracycline-induced cardiotoxicity.

Anteroseptal

-10 Anterior

Septal -15

-7

–11 -12

-18

-25

-18

-22 -11 -5

Right Heart -19

-26

-13 -7

-14

Inferior

Lateral

-7

Posterior Typical pattern of apical sparing compatible with amyloidosis.

Unique strain patterns may guide the diagnosis in certain cardiomyopathies such as the apical sparing of longitudinal strain in amyloidosis (Figure 2).15 Furthermore, strain has emerging and valuable input in the early detection of chemotherapy-related cardiotoxicity.16 Peak systolic GLS appears to be the best measure. A 10–15 % early reduction in GLS by speckle-tracking echocardiography during therapy appears to be the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or heart failure. Latest

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Left atrial strain is also an emerging imaging index that highlights stiffness, and the latter has been associated with left atrial dysfunction and its associated prognosis in patients with heart failure.18 It also helps indirectly to raise a suspicion of fibrosis, especially in patients with a predisposition to develop AF.19

Imaging modalities have demonstrated significant progress in terms of imaging of the right heart. We employ new software for right ventricular reconstruction, while right atrial dimensions either by measuring the volume or by measuring more complex indices such as the sphericity index, have been associated with functional outcomes and a particular prognosis in patients with pulmonary hypertension (Figure 3).20 In patients with heart failure, as mentioned above, the assessment of pulmonary pressures either at rest or during exercise are of prognostic value. Furthermore, right ventricular area strain is now associated with functional outcomes and with prognostic markers in patients with pulmonary hypertension.21

Multidetector CT Cardiac CT imaging aims to employ the latest technology22,23 together with ECG gating in order to reduce scan time and radiation exposure. Multidetector CT (MDCT) can measure infarct size with accurate correlation to measurements obtained through cardiac MRI (CMR)

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Imaging in Heart Failure and can be a valuable alternative to CMR in patients with non-MRI conditional pacemakers or defibrillators.22,24

Figure 3: Advanced Echocardiography

Coronary calcium scan is a reliable test to screen for coronary artery disease and has been integrated in clinical practice as a risk stratification imaging marker, especially in subgroups such as renal patients.23 Furthermore, dual-source CT can evaluate LV dyssynchrony, myocardial scar and coronary venous anatomy in patients undergoing cardiac resynchronisation therapy.24 Time to maximal wall thickness and inward wall motion measured with MDCT has been associated with the prediction of major adverse cardiac events.25 One step beyond the morphological assessment of coronary arteries, dual-source CT combines coronary artery anatomy and myocardial perfusion imaging (MPI). An emerging modality, stress myocardial CT perfusion imaging with adenosine may detect haemodynamically significant coronary lesions,26,27 with data comparable to that from CMR and single-photon emission CT (SPECT). Wang et al. performed a 30-patient feasibility study of adenosine-stress dynamic MPI with 128-MDCT dual-source CT for detecting flow-obstructing stenosis.26 A larger and multi-centre study by Meinel et al. proved that myocardial perfusion CT has incremental value in predicting clinical risk factors and detecting coronary artery stenosis compared with coronary CT angiography CCTA.28

Real-time 3D Echocardiography of the right ventricle in a 35-year-old female patient with idiopathic pulmonary arterial hypertension.

Figure 4: Multidetector CT in Pre-transfemoral Aortic Valve Implantation Planning

Computational fluid dynamics measures fractional flow reserve (FFR), and this method (CT-FFR) has also been validated against invasive FFR in patients with stable coronary artery disease.29,30 Adding FFR measurement may add in favour of invasive angiography, as an CT-FFR of â&#x2030;¤0.80 has been a better predictor of revascularisation or major adverse cardiac events than severe stenosis on a coronary CT angiogram.30 In electrophysiology, 3D reconstruction of cardiac structures from CT data sets has revolutionised the understanding of left atrial anatomy and greatly facilitated the development of novel atrial ďŹ brillation ablation approaches.19 CT also tends to guide pulmonary vein isolation during ablation of atrial fibrillation procedures.31 Finally, CT has a key role in evolving interventional procedures such as trans-catheter aortic valve implantation, where annulus can be accurately measured to size the valve as well as the distance of coronary ostia.32 Accurate aortic annulus measurement is critical to identify the appropriate valve prosthesis size (Figure 4). Aortic root MDCT also allows prediction of the angulation of the root angiogram, which facilitates the angiographic procedure by reducing the number of root injections.33 MDCT is also fundamental in the evaluation of size, tortuosity and calcification of peripheral arteries, from the aortic valve down to the femoral arteries, and guides the selection of appropriatesize catheters during the procedure.34

Cardiovascular Magnetic Resonance CMR has emerged as a superior imaging modality in the noninvasive assessment of heart failure, adding to the diagnosis, when conventional imaging modalities such as echocardiography fail to specify the aetiology, but also CMR has a vital role in prognosis and in guiding treatment decisions.35,36 CMR has several advantages when compared with other imaging modalities, due to accuracy, reproducibility, larger field of view, no radiation, and the ability to characterise myocardial tissue. It allows

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Significant calcification of the mitral annulus, mitral and aortic valves.

comprehensive evaluation of ventricular size and function to establish the cause of heart failure, determine myocardial perfusion and viability and mechanical dyssynchrony, and evaluate pericardial disease.35 CMR is recognised as the gold standard method for the quantification of ventricular volumes. Velocity-encoded CMR37 may quantify mitral diastolic flow and diastolic longitudinal myocardial lengthening velocity of the LV base. CMR precontrast T1 of infarcted tissue is significantly correlated with regional diastolic circumferential strain rate.38 For patients with intermediate pretest likelihood of CAD, vasodilator stress CMR is used to detect perfusion defects, and dobutamine stress CMR is used to assess for wall motion abnormalities, combined with quantitating deformation with strain-encoded CMR to improve accuracy over visual assessment on cine imaging.39,40 Late gadolinium enhancement (LGE) imaging is fundamental to differentiate between ischaemic and non-ischaemic cardiomyopathy. Full-thickness infarcts as assessed by LGE-CMR had been shown to correlate inversely with the likelihood of segmental and global

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Diagnosis Figure 5: Cardiac Magnetic Resonance in Heart Failure

Figure 6: Cardiac MRI in Amyloidosis

Mildly reduced left ventricular ejection fraction: 46 %. Left ventricular basal to mid-lateral epicardial and pericardial delayed contrast enhancement, reflecting fibrosis. pericardial enhancement also extends anteriorly.

Late gadolinium enhancement (LGE) images typically show circumferential subendocardial contrast enhancement or bilateral septal subendocardial LGE with dark mid-wall (zebra pattern).

functional recovery post revascularisation.40,41 Dilated non-ischaemic cardiomyopathy is characterised by mid-wall distribution of LGE, and the presence independently predicts major adverse cardiovascular events, including hospitalisation for decompensated heart failure, sudden and non-cardiac sudden death, malignant ventricular arrhythmias and all-cause mortality (Figure 5).42

The presence of both coronary microvascular and diastolic dysfunction was associated with a markedly increased risk of heart failure events.

CMR is the primary non-invasive imaging modality for the assessment of suspected myocarditis in clinically stable patients, by evaluating LV function.43–45 In patients with heart failure and possible iron overload, CMR with T2* provides definitive diagnosis. CMR in cardiac amyloidosis typically reveals increased myocardial gadolinium enhancement (global, sub-endocardial or transmural), short T1, rapid blood pool wash-out and suboptimal myocardial nulling.15 As a summary, CMR aids in diagnosis, risk stratification, treatment guidance and prognosis from the wealth of information obtained through myocardial tissue characterisation using T1, T2 and T2* mapping sequences and quantitative volumetric analysis (Figure 6). Future research in 3D LGE, strain imaging and diffusion tensor CMR is ongoing and offers promise to improve diagnostic accuracy and reproducibility.

Hybrid Imaging and 3D Printing Cardiac hybrid or fusion imaging combines imaging modalities, and this advanced imaging technique sheds light on anatomical and functional information. It provides additional information in heart failure patients who are complex patients requiring imaging of coronary arteries, assessment of myocardial viability, and evaluation of valvular abnormalities in combination with haemodynamic alterations. Hybrid imaging with CT can guide interventional procedures like revascularisation, cardiac resynchronisation therapy and structural heart valve disease interventions (transcatheter aortic valve implantation, MitraClip, left atrial appendage occlusion in heart failure patients with AF).49,50 SPECT/CT and PET/CT may improve the diagnostic accuracy for ischaemic heart disease in patients with heart failure, allow the determination of functionally relevant coronary stenosis and guide targeted revascularisation in the elevated-risk population. Based on hybrid imaging, 3D printing allows careful planning of complex procedures and aims to minimise complications and improve outcomes.51 n

Molecular Imaging In heart failure, the autonomic nervous system is disrupted, initially with upregulation of the sympathetic nervous system to compensate for a failing heart and, over time, downregulation of cardiac receptors. Radionuclide imaging, using either PET or single-photon emission CT (SPECT), has been the modality most commonly used for human molecular imaging, Molecular imaging allows tissue characterisation in myocardial disorders at molecular, subcellular and cellular levels. It has the potential for assessing the severity of heart failure and for monitoring treatment effects. 123I-labelled MIBG, as a marker of adrenergic neuron function, could play an important role in the risk stratification of heart failure patients.46 A major focus has been on the ability of 123I-MIBG imaging to risk-stratify patients for risk of ventricular arrhythmic sudden cardiac death, and thereby guide the use of an ICD.46 As cardiac autonomic innervation is more closely related to underlying mechanisms of arrhythmias than LVEF, MIBG imaging should better determine the need for an ICD.46,47 Furthermore, emerging studies highlight the role of coronary flow reserve with stress myocardial perfusion PET as an independent predictor of diastolic dysfunction and adverse effects, especially hospitalisation of heart failure patients with preserved EF. 48

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Clinical Perspective • T his review highlighted the latest advances in cardiac imaging and, specifically, their implementation in the diagnosis and management of heart failure. • The clinical decision pathway is very well described in the latest guidelines.3 • Echocardiography is the first-line imaging modality, especially because it can be portable even in the intensive care environment. It may be complemented by other modalities, chosen according to their ability to answer specific clinical questions and taking account of contraindications to and risks of specific tests. • The reliability of clinical outcomes and the management strategy are highly dependent on the imaging modality, the operator and centre experience. Guidelines3 are bringing together the latest studies and indicate clinical algorithms on when and how each imaging modality may be used. Despite this, there is an ongoing need for randomised clinical trials to specify indications and limitations of each modality.

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Imaging in Heart Failure

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2017;18:392–401. https://doi.org/10.1093/ehjci/jew223; PMID: 28064155. von Roeder M, Rommel KP, Kowallick JT, et al. Influence of left atrial function on exercise capacity and left ventricular function in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging 2017;10:e005467. https://doi.org/10.1161/CIRCIMAGING.117.006785; PMID: 28790126. Tan TC, Koutsogeorgis ID, Grapsa J, et al. Left atrium and the imaging of atrial fibrosis: catch it if you can! Eur J Clin Invest 2014;44:872–81. https://doi.org/10.1111/eci.12305; PMID: 25066356. Grapsa J, Gibbs JS, Cabrita IZ, et al. The association of clinical outcome with right atrial and ventricular remodelling in patients with pulmonary arterial hypertension: study with real-time three-dimensional echocardiography. Eur Heart J Cardiovasc Imaging 2012;13:666–72. https://doi.org/10.1093/ ehjci/jes003; PMID: 22294683. Smith BC, Dobson G, Dawson D, et al. Three-dimensional speckle tracking of the right ventricle: toward optimal quantification of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 2014;64:41–51. https://doi. org/10.1016/j.jacc.2014.01.084; PMID: 24998127. Le Polain de Waroux JB, Pouleur AC, Goffinet C, et al. Combined coronary and late-enhanced multidetector computed tomography for delineation of the etiology of left ventricular dysfunction: comparison with coronary angiography and contrast-enhanced cardiac magnetic resonance imaging. Eur Heart J 2008;29:2544–51. https://doi.org/10.1093/eurheartj/ehn381; PMID: 18762553. Winther S, Svensson M, Jørgensen HS, et al. Prognostic value of risk factors, calcium score, coronary CTA, myocardial perfusion imaging, and invasive coronary angiography in kidney transplantation candidates. JACC Cardiovasc Imaging 2018;11:842–54. https://doi.org/10.1016/j.jcmg.2017.07.012; PMID: 28917674. Behar JM, Rajani R, Pourmorteza A, et al. Comprehensive use of cardiac computed tomography to guide left ventricular lead placement in cardiac resynchronization therapy. Heart Rhythm 2017;14:1364–72. https://doi.org/10.1016/j. hrthm.2017.04.041; PMID: 2847951. Truong QA, Szymonifka J, Picard MH, et al. Utility of dualsource computed tomography in cardiac resynchronization therapy-DIRECT study. Heart Rhythm 2018. https://doi. org/10.1016/j.hrthm.2018.03.020; PMID: 29572087; epub ahead of print. Wang Y, Qin L, Shi X, et al. Adenosine-stress dynamic myocardial perfusion imaging with second-generation dualsource CT: comparison with conventional catheter coronary angiography and SPECT nuclear myocardial perfusion imaging. AJR Am J Roentgenol 2012;198:521–9. https://doi. org/10.2214/AJR.11.7830; PMID: 22357991. Bettencourt N, Chiribiri A, Schuster A, et al. Direct comparison of cardiac magnetic resonance and multidetector computed tomography stress-rest perfusion imaging for detection of coronary artery disease. J Am Coll Cardiol 2013;61:1099–107. https://doi.org/10.1016/ j.jacc.2012.12.020; PMID: 23375929. Meinel FG, Pugliese F, Schoepf UJ, et al. Prognostic value of stress dynamic myocardial perfusion CT in a multicenter population with known or suspected coronary artery disease. Am J Roentgenol 2017;208:761–9. https://doi.org/10.2214/ AJR.16.16186; PMID: 28177653. Nakanishi R, Budoff MJ. Noninvasive FFR derived from coronary CT angiography in the management of coronary artery disease: technology and clinical update. Vasc Health Risk Manag 2016;12:269–78. https://doi.org/10.2147/VHRM.S79632; PMID: 27382296. Lu MT, Ferencik MF, Roberts RS, et al. Noninvasive FFR derived from coronary CT angiography. Management and outcomes in the PROMISE trial. JACC Cardiovasc Imaging 2017;10:1350–8. https://doi.org/10.2147/VHRM.S79632; PMID: 27382296. Ang R, Hunter RJ, Baker V, et al. Pulmonary vein measurements on pre-procedural CT/MR imaging can predict difficult pulmonary vein isolation and phrenic nerve injury during cryoballoon ablation for paroxysmal atrial fibrillation. Int J Cardiol 2015;195:253–8. https://doi.org/10.1016/j. ijcard.2015.05.089; PMID: 26048388. Ismail TF, Cheasty E, King L, et al. High-pitch versus conventional cardiovascular CT in patients being assessed for transcatheter aortic valve implantation: a real-world appraisal. Open Heart 2017;4:e000626. https://doi.org/10.1136/ openhrt-2017-000626; PMID: 28878951. Nasis A, Mottram PM, Cameron JD, Seneviratne SK. Current and evolving clinical applications of multidetector cardiac CT in assessment of structural heart disease. Radiology 2013;267:11–25.

https://doi.org/10.1148/radiol.13111196; PMID: 23525715. 34. K urra V, Kapadia SR, Tuzcu EM, et al. Pre-procedural imaging of aortic root orientation and dimensions: comparison between X-ray angiographic planar imaging and 3-dimensional multidetector row computed tomography. JACC Cardiovasc Interv 2010;3:105–13. https://doi.org/10.1016/j. jcin.2009.10.014; PMID: 20129578. 35. Webb J, Fovargue L, Tøndel K, et al. The emerging role of cardiac magnetic resonance imaging in the evaluation of patients with HFpEF. Curr Heart Fail Rep 2018;15:1–9. https://doi.org/10.1007/s11897-018-0372-1; PMID: 29404975. 36. Su MY, Lin LY, Tseng YH, et al. CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF. JACC Cardiovasc Imaging 2014;7:991–7. https://doi.org/10.1016/j. jcmg.2014.04.022; PMID: 25240451. 37. Rathi VK, Biederman RW. Expanding role of cardiovascular magnetic resonance in left and right ventricular diastolic function. Heart Fail Clin 2009;5:421–35. https://doi.org/10.1016/j. hfc.2009.02.005; PMID: 19564017. 38. Azarisman SM, Carbone A, Shirazi M, et al. Characterisation of myocardial injury via T1 mapping in early reperfused myocardial infarction and its relationship with global and regional diastolic dysfunction. Heart Lung Circ 2016;25:1094–106. https://doi.org/10.1016/j.hlc.2016.03.011; PMID: 27210302. 39. Le TT, Huang W, Bryant JA, et al. Stress cardiovascular magnetic resonance imaging: current and future perspectives. Expert Rev Cardiovasc Ther 2017;15:181–89. https://doi.org/10.108 0/14779072.2017.1296356; PMID: 28256176. 40. Pontone G, Andreini D, Guaricci AI, et al. The STRATEGY study (stress cardiac magnetic resonance versus computed tomography coronary angiography for the management of symptomatic revascularized patients): resources and outcomes impact. Circ Cardiovasc Imaging 2016;9:e005171. https://doi. org/10.1161/CIRCIMAGING.116.005171; PMID: 27894070. 41. Child NM, Das R. Is cardiac magnetic resonance imaging assessment of myocardial viability useful for predicting which patients with impaired ventricles might benefit from revascularization? Interact Cardiovasc Thorac Surg 2012;14:395–8. https://doi.org/10.1093/icvts/ivr161; PMID: 22279116. 42. Halliday BP, Cleland JGF, Goldberger JJ, Prasad SK. Personalizing risk stratification for sudden death in dilated cardiomyopathy: the past, present, and future. Circulation 2017;136:215–31. https://doi.org/10.1161/ CIRCULATIONAHA.116.027134; PMID: 28696268. 43. Wei S, Fu J, Chen L, Yu S. Performance of cardiac magnetic resonance imaging for diagnosis of myocarditis compared with endomyocardial biopsy: a meta-analysis. Med Sci Monit 2017;23:3687–96. https://doi.org/10.12659/MSM.902155; PMID: 28755532. 44. Mayr A, Klug G, Feistritzer HJ, et al. Myocardial edema in acute myocarditis: relationship of T2 relaxometry and late enhancement burden by using dual-contrast turbo spinecho MRI. Int J Cardiovasc Imaging 2017;33:1789–94. https://doi. org/10.1007/s10554-017-1170-7; PMID: 28528429. 45. Gaikwad N, Butler T, Maxwell R, et al. Late gadolinium enhancement does occur in Tako-tsubo cardiomyopathy – a quantitative cardiac magnetic resonance and speckle tracking strain study. Int J Cardiol Heart Vasc 2016;12:68–74. https://doi.org/10.1016/j.ijcha.2016.07.009; PMID: 28616546. 46. Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res 2004;95:754–63. https://doi.org/10.1161/01. RES.0000145047.14691.db; PMID: 15486322. 47. Buxton AE, Lee KL, Hafley GE, et al. Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease: lessons from the MUSTT study. J Am Coll Cardiol 2007;50:1150–7. https://doi.org/10.1016/j. jacc.2007.04.095; PMID: 17868806. 48. Taqueti VR, Solomon SD, Shah AM, et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur Heart J 2017;39:840–9. https://doi.org/10.1093/eurheartj/ehx721; PMID: 29293969. 49. Gaemperli O, Kaufmann PA, Alkadhi H. Cardiac hybrid imaging. Eur J Nucl Med Mol Imaging 2014;41:S91–103. https://doi. org/10.1007/s00259-013-2566-9; PMID: 24658682. 50. Truong QA, Gewirtz H. Cardiac PET-CT for monitoring medical and interventional therapy in patients with CAD: PET alone versus hybrid PET-CT? Curr Cardiol Rep 2014;16:460. https://doi. org/10.1007/s11886-013-0460-5; PMID: 24464305. 51. Qian Z, Wang K, Liu S, et al. Quantitative prediction of paravalvular leak in transcatheter aortic valve replacement based on tissue-mimicking 3D printing. JACC Cardiovasc Imaging 2017;10:719–31. https://doi.org/10.1016/j.jcmg.2017.04.005; PMID: 28683947.

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Diagnosis

Imaging of Valvular Heart Disease in Heart Failure Tomaz Podlesnikar, Victoria Delgado and Jeroen J Bax Heart and Lung Centre, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

Abstract Valvular heart disease (VHD) and heart failure (HF) are major health issues that are steadily increasing in prevalence in Western populations. VHD and HF frequently co-exist, which can complicate the accurate diagnosis of the severity of valve stenosis or regurgitation and affect decisions about therapeutic options. Transthoracic echocardiography is the first-line imaging modality to determine left ventricular (LV) systolic function, to grade valvular stenosis or regurgitation and to characterise the mechanism underlying valvular dysfunction. 3D transoesophageal echocardiography, cardiovascular magnetic resonance and cardiac CT are alternative imaging modalities that help in the diagnosis of patients with HF and VHD. The integration of multimodality cardiovascular imaging is important when deciding whether the patient should receive transcatheter aortic valve repair and replacement therapies. In this article, the use of multimodality imaging to diagnose and treat patients with VHD and HF is reviewed.

Keywords Heart failure, valvular heart disease, aortic stenosis, mitral regurgitation, echocardiography, computed tomography, cardiovascular magnetic resonance Disclosure: The Department of Cardiology at the Leiden University Medical Center received unrestricted research grants from Biotronik, Medtronic, Boston Scientific and Edwards Lifesciences. VD has received speaker fees from Abbott Vascular. Received: 1 April 2018 Accepted: 28 June 2018 Citation: Cardiac Failure Review 2018;4(2):78–86. DOI: https://doi.org/10.15420/cfr.2018.16.1 Correspondence: Jeroen J Bax, Heart and Lung Centre, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. E: j.j.bax@lumc.nl

Heart failure (HF) is a rapidly growing public health problem with an estimated prevalence of more than 26 million people worldwide.1 In developed countries the prevalence is 1–2 % peaking at ≥10 % among people aged over 70 years.2 In the US, the lifetime risk of developing HF is 20 % among people aged 40 years or older.3 Diagnosing the underlying cause of HF is central to the choice of appropriate treatment. Significant valvular heart disease (VHD; moderate and severe) was found in 14 % of patients who were referred for echocardiography due to suspected HF.4 Among patients with moderate and severe native VHD included in the Euro Heart Survey, 69.8 % presented with HF symptoms and the most frequent valvular lesions were aortic stenosis (AS) and mitral regurgitation (MR).5 Cardiac imaging plays a central role in determining the mechanism and the severity of VHD as well as the degree of accompanying left ventricular (LV) remodelling and systolic dysfunction. The primary dilemma for patients with VHD and HF is to determine whether the LV dysfunction is due to the disease of the valve or the ventricle. In patients with AS and HF symptoms, LV systolic dysfunction is usually secondary to the valve disease, while in patients with HF and functional MR, LV systolic dysfunction and remodelling are primary and are responsible for mitral valve malcoaptation. Furthermore, LV dimensions and ejection fraction (LVEF) are key parameters to indicate the need for valve surgery.6–8 With advances in percutaneous valve interventions – transcatheter aortic valve replacement (TAVR) and percutaneous transcatheter mitral valve repair, several other imaging parameters need to be evaluated to assess feasibility and predict therapeutic success. Echocardiography is the primary imaging modality and may be complemented by cardiac CT and cardiovascular magnetic resonance (CMR) when additional

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anatomical or functional information is needed. This review article focuses on the use of multimodality imaging to evaluate patients with HF and the most prevalent VHD – MR and AS – and how to decide the optimal intervention.

Mitral Regurgitation in Heart Failure Significant (moderate and severe) MR is among the most common VHD, with an estimated prevalence of 1.7 % in the US peaking at 9.3 % in people older than 75 years of age.9 In one study involving 70,043 patients with suspected HF referred for echocardiography, MR of any severity was found in 12.5 % and moderate or severe MR in 3.1 % of patients.4 MR is classified as primary (organic) if there is primary structural abnormality of any component of the mitral valve apparatus (leaflets, chordae tendineae, papillary muscles or mitral annulus). The most common aetiologies include degenerative disease, rheumatic disease and endocarditis.10,11 In contrast, secondary (functional) MR results from LV dilation and dysfunction whereas the components of the mitral valve were originally normal. The main causes of secondary MR are ischaemic heart disease and dilated cardiomyopathy.10,11 Patients with severe primary MR commonly present with no or minimal symptoms.12 In contrast, HF is always present in secondary MR.13 In a large retrospective study including 1,256 patients with ischaemic and non-ischaemic cardiomyopathy, any grade of secondary MR was present in 73 % and 24 % had severe MR.13 Patients with HF and significant MR are usually evaluated using transthoracic and transoesophageal echocardiography. The underlying mechanism (primary versus secondary) and the severity of MR are systematically analysed. Grading of MR is based on a multiparametric

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Valvular Heart Disease and Heart Failure Table 1: Echocardiographic Criteria for the Definition of Severe Mitral Regurgitation Signs of Severe Mitral Regurgitation

Strengths

Limitations

Primary

Secondary

Valve morphology

Flail leaflet, ruptured papillary muscle, severe retraction, large perforation

Severe tenting, poor • 3D echocardiography provides detailed leaflet coaptation views of the MV, including surgical view

LV and LA size

Dilated

• N ormal size almost excludes severe chronic primary MR

• Non-specific in secondary MR • Can be within the normal range in acute severe MR or in smaller people

Colour flow regurgitant jet*

Large central jet or eccentric wall-impinging jet of variable size

• Rapid qualitative assessment • Good for screening for MR • Evaluates the spatial orientation of the regurgitant jet

• D ependent on haemodynamic and technical variables • May underestimate the severity in eccentric jets

Continuous-wave Doppler signal of regurgitant jet

Holosystolic, dense, triangular

• Easy to use

• Triangular signal is insensitive • Signal density is gain dependent

Flow convergence

Large throughout systole (≥1 cm at a Nyquist limit of 30–40 cm/sec)

• Rapid qualitative assessment • Can be used in eccentric jets • Absence of PISA is usually a sign of mild MR

• PISA size is affected by: • Multiple jets • Non-circular regurgitant orifices (common in secondary MR) • Non-holosystolic MR

Vena contracta width (mm)* ≥7 (>8 for average between apical twoand four-chamber views)

• L ess dependent on hemodynamic and technical factors (e.g. pulse repetition frequency) • Can be applied in eccentric jets

• Challenging in • Multiple jets • Non-circular regurgitant orifices (common in secondary MR) • Non-holosystolic MR

Pulmonary vein flow

Minimal to no systolic flow/systolic flow Reversal

• S ystolic flow reversal in ≥1 pulmonary vein is specific for severe MR

• Insensitive • Not accurate if MR jet is directed into the sampled vein • Blunting of the systolic wave in AF, elevated LA pressure

Mitral inflow

E-wave dominant (≥1.5 m/s6; ≥1.2 m/s10)

• Easy to use • Dominant A-wave inflow pattern virtually excludes severe MR

• N on-specific (high E waves in secondary MR, AF and MS)

2D EROA (mm2)†

≥40

≥206

PISA method • Main method of MR quantification • Practical calculation • Can be used in eccentric jets

PISA method • PISA size affected by several factors (see flow convergence) • Error in PISA radius is squared

Regurgitant volume (mL)†

≥60

≥306

Volumetric method • Valid with multiple and eccentric jets • Valid in non-holosystolic MR

Volumetric method • Not valid for concomitant AR • Cumbersome, training needed • Errors in measurements can combine in the final results

Regurgitant fraction (%)10

≥50

• A ccounts for low-flow conditions (common in secondary MR)

• Errors in measurements of each parameter (regurgitant volume, LV end-diastolic volume) can magnify in the final results

Qualitative • A bsence of specific signs does not exclude severe MR

Semi-quantitative

Quantitative

AF = atrial fibrillation; AR = aortic regurgitation; CW = continuous wave; EROA = effective regurgitant orifice area; LA = left atrium; LV = left ventricle; MR = mitral stenosis; MR = mitral regurgitation; MV = mitral valve; PISA = proximal isovelocity surface area. *At a Nyquist limit 50–70 cm/sec. †European guidelines recommend lower thresholds for severe secondary MR compared with the American guidelines. Source: Baumgartner, et al.,6 2017; Zoghbi, et al., 2017.10c

approach which includes qualitative, semi-quantitative and quantitative parameters (Table 1).6,10 It is important to note that the evaluation of MR severity is significantly influenced by the LV loading conditions and the systemic blood pressure.14 In people with HF, decreased transmitral pressure gradients – due to lower systemic blood pressure and high left atrial (LA) pressures – result in lower velocity regurgitant jets, which appear small on Doppler

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colour flow images.10 Furthermore, vena contracta and flow convergence assume circular geometry at the regurgitant jet orifice. In secondary MR, the regurgitant orifice is frequently crescent in shape, and vena contracta, regurgitant volume and effective regurgitant orifice area (EROA) calculated using the proximal isovelocity surface area (PISA) method may therefore significantly underestimate the severity of MR.10

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Diagnosis

Valvular Heart Disease and Heart Failure

Figure 1: 3D Vena Contracta Area in Secondary Mitral Regurgitation

A: Apical left ventricular long axis view showing restriction and severe tenting of both mitral valve leaflets (upper image); the coaptation depth (CD, yellow arrow) was 1.5 cm and the bend in the body of the anterior mitral leaflet (yellow arrowhead) demonstrated tethering by the secondary chordae (known as the seagull or hockey stick sign). Bottom image shows prominent colour flow Doppler regurgitant jet. B: Multi-planar reconstruction of the 3D colour flow Doppler dataset across the regurgitant orifice. Note the highly crescentic shape of the vena contracta (bottom right image), which involved the whole coaptation line from the anterolateral to the posteromedial mitral valve commissure. 3D vena contracta area (VCA) of 0.9 cm2 (yellow dotted line) was in the range of severe mitral regurgitation.15

With the development of 3D echocardiography, the vena contracta area can be directly visualised using multiplanar reformation planes across the regurgitant orifice and measured by planimetry (Figure 1). Zeng et al15 proposed definition of severe MR to have a cut-off value of 3D vena contracta area as ≥0.41 cm2. In patients with functional MR, the 3D vena contracta area has been shown to be significantly larger than the 2D PISA-derived EROA (0.39 ± 0.17 cm2 versus 0.27 ± 0.11 cm2 respectively; p<0.001), resulting in an average 27 % underestimation of the EROA by the PISA method compared with the 3D vena contracta area.15 The assessment of the severity of MR with colour flow Doppler echocardiography is based on instantaneous peak flow rates and is therefore reliable only when there is little temporal variation of MR during the cardiac cycle. However, secondary MR is often dynamic, peaking in early and late systole and improving during mid systole when LV pressures are at their maximum.16 In such circumstances, MR should be quantified with volumetric methods, which account for the whole systole. In the absence of aortic regurgitation or intracardiac shunt, the difference between stroke volume measured at the mitral annulus (LV inflow) and the LV outflow tract (LV outflow) equals MR volume. Volumetric method is frequently used with CMR.6,7 The preferred method to quantify MR with CMR is to use phase contrast CMR to subtract the aortic forward flow from the LV stroke volume, assessed by planimetry of the LV short-axis cine images (Figure 2).10

Selecting Interventions for Mitral Regurgitation After establishing the diagnosis of symptomatic severe secondary MR, the type of valve intervention is based upon the degree of LV functional impairment, evidence of myocardial viability and the ability to perform revascularisation. When revascularisation is indicated, surgical intervention should be considered.6,8 However, the preferred type of surgical treatment, i.e. mitral valve repair by means of restrictive

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annuloplasty or chordal-sparing valve replacement, is not agreed upon. European guidelines recommend mitral valve repair as the preferred method, while mitral valve replacement may be considered in patients with echocardiographic risk factors for residual or recurrent MR (Table 2).6,17 In contrast, American guidelines recommend chordalsparing mitral valve replacement for severely symptomatic patients (New York Heart Association class III–IV) with chronic severe ischaemic MR.8 This recommendation is based on the results of a randomised control trial that showed a higher rate of moderate or severe MR recurrence at 2 years follow-up in patients who underwent mitral valve repair compared with patients who underwent chordal-sparing mitral valve replacement (58.8 % versus 3.8 %, p<0.001), leading to higher incidence of HF and repeat hospitalisations in the mitral valve repair group.18 When revascularisation is not indicated, the decision between surgery and percutaneous edge-to-edge repair is made based on the degree of LV dysfunction and the surgical risk. When the surgical risk is low and LVEF is more than 30 %, surgery may be considered, while percutaneous edge-to-edge repair is preferred for patients presenting with high surgical risk or LVEF lower than 30 % despite optimal medical management, including pharmacological treatment and cardiac resynchronisation therapy.6 In the US, percutaneous edge-to-edge repair is currently not approved for clinical use in secondary MR.8 For successful surgical and percutaneous mitral valve repair in secondary MR, accurate LV assessment, including LV volumes, LVEF and sphericity index, is mandatory, accompanied by geometric assessment of the MV apparatus (tenting area, coaptation depth, leaflet angles and inter-papillary muscle distance). Transthoracic and transoesophageal echocardiography are the primary modalities, although detailed information can also be obtained with cardiac CT and CMR. Table 2 summarises the echocardiographic criteria that suggest increased risk of MR recurrence after mitral valve repair as

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Valvular Heart Disease and Heart Failure Figure 2: Cardiovascular Magnetic Resonance to Quantify Mitral Regurgitation

A 74-year old patient with heart failure symptoms had inconsistent grading of the severity of mitral regurgitation (MR) with echocardiography and was referred for cardiovascular magnetic resonance (CMR). A: Left ventricular systolic cine images show prominent MR jet (yellow arrowheads). MR was caused by mitral annular dilatation, secondary to severe left atrial dilatation. The patient had a long-lasting history of paroxysmal atrial fibrillation. B: Left ventricular forward stroke volume (AoSV) was measured with phase contrast CMR in the ascending aorta, just above the aortic valve. Panel C: Total left ventricular stroke volume (LVSV) was obtained using planimetry of the short-axis cine images as the difference between left ventricular end-diastolic volume (LVEDV; left image) and left ventricular end-systolic volume (LVESV; right image). Since the patient had no aortic regurgitation, the difference between the LVSV and AoSV was equal to mitral regurgitant volume (MRVol). The regurgitant fraction (RF) was calculated by dividing MRvol by LVSV. The results (MRVol 20 mL; RF 25 %) clearly ruled out severe MR, which was further supported by normal left ventricular volumes.

well as unfavourable anatomical conditions for percutaneous edgeto-edge repair with a MitraClip® device (Abbott Vascular, Menlo Park, CA, US).17 In patients with secondary MR who are undergoing surgery, successful repair is less likely in the presence of severe mitral valve tethering with coaptation depth >1 cm, systolic tenting area >2.5 cm2, posterior mitral leaflet angle >45° and distal anterior mitral leaflet angle >25°.17,19 Furthermore, global and regional LV remodelling, indicated by LV end-diastolic dimension >65 mm, end-systolic dimension >51 mm, systolic sphericity index >0.7 and interpapillary muscle distance >20 mm predict a lower likelihood of successful mitral valve repair.17,20 A leaflet coaptation depth >11 mm and coaptation length <2 mm challenge the percutaneous edge-to-edge mitral valve repair since these parameters indicate advanced LV remodelling with

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excessive tethering of the mitral leaflets.17 Large regurgitant orifices often require implantation of more than one MitraClip to reduce MR. Short posterior leaflet, cleft, severe annular calcification and calcification in the grasping area are other anatomical conditions that challenge percutaneous edge-to-edge repair.17 Peri-procedural transoesophageal echocardiography is crucial to perform successful percutaneous implantation of a MitraClip device (Figure 3).

Aortic Stenosis in Heart Failure: Diagnosis and Assessment of Severity The LV pressure overload caused by AS increases LV wall stress and as a consequence the LV responds with myocyte hypertrophy to maintain a normal LVEF. However, this response is counterproductive in the

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Diagnosis Table 2: Unfavourable Anatomical Conditions for Successful Surgical and Percutaneous Edge-To-Edge Repair in Secondary Mitral Regurgitation Surgical Repair

Percutaneous Repair

Parameters Related to Mitral Valve Tethering Coaptation depth >1 cm

Coaptation depth >11 mm

Systolic tenting area >2.5 cm2

Coaptation length <2 mm

Posterior mitral leaflet angle >45°

Severe asymmetric tethering

Distal anterior mitral leaflet angle >25°

Large (>50 %) inter-commissural extension of regurgitant jet

Parameters related to left ventricular remodelling LV end-diastolic diameter >65 mm

Severe annular dilatation

LV end-systolic diameter >51 mm

Severe left ventricular remodelling

End-systolic inter-papillary muscle distance >20 mm Systolic sphericity index >0.7 Unfavourable anatomical conditions specific for percutaneous edge-to-edge repair –

Short posterior leaflet

–

Calcification in the grasping area

–

Severe annular calcification

–

Cleft

LV = left ventricular. Source: De Bonis, et al., 2016.17

Figure 3: Transoesophageal Echocardiography During MitraClip Implantation: Guiding the Intervention (A–C) and the Assessment of Procedural Results (D,E).

A: Transseptal puncture. Arrows point at the tenting of the interatrial septum before the puncture in two simultaneous perpendicular image planes. B: Opening of the Mitraclip device in the left atrium. C: The MitraClip implantation – orienting the device arms perpendicular to the leaﬂets (arrows) is essential for successful grasping of the mitral valve. D: Three MitraClips* were implanted in a patient with severe secondary mitral regurgitation. E: Assessment of residual mitral regurgitation. F: Transmitral gradient measurement for the evaluation of post-implant mitral valve stenosis.

long term and causes LV diastolic dysfunction, myocardial ischaemia in the subendocardium, increased myocardial fibrosis (reactive and replacement) and eventually LV systolic dysfunction.21 Clinically, patients with severe AS may present with dyspnoea, chest pain and syncope. The prevalence of HF among patients with severe AS varies largely based on the definition of HF (e.g. reduced LVEF and presence of symptoms) and the characteristics of people included in the studies. In one large cohort study (n=79,043) involving people with HF symptoms

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referred for echocardiography, mild-to-severe AS was found in 10.1 % and moderate or severe AS in 3.2 %.4 Furthermore, in the Euro Heart Survey, 19.3 % of people with severe AS undergoing surgical aortic valve replacement (SAVR) had LVEF <50 %.5 In a more contemporary study of 42,776 patients with AS undergoing SAVR included in the German Aortic Valve Registry, LVEF <50 % was present in 26.6 % of the patients.22 Data from the American Transcatheter Valve Therapy (TVT) Registry showed a 25.6 % prevalence of reduced LVEF (<45 %) among 42,988 patients undergoing TAVR.23

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Valvular Heart Disease and Heart Failure Table 3: Echocardiographic Criteria for the Definition of Severe AS Severe AS

Common Mistakes in the Assessment

Recommendations to Avoid Mistakes in

of LFLG AS

the Assessment of LFLG AS

• U nderestimation of peak velocity and mean gradient: • Misalignment of the ultrasound beam with the AS jet • High blood pressure

• M ultiple acoustic windows to determine the highest velocity • Parallel ultrasound beam alignment with the direction of flow • Perform the measurements when patient has normal blood pressure

Peak velocity (m/s)

≥4.0

Mean gradient (mmHg)

≥40

AVA (cm2) by continuity equation (LVOT area × LVOT VTI)

<1.0

• Underestimation of LVOT area: • Elliptical shape of LVOT • Calcifications • Sigmoid septum • Diastolic measurements • Underestimation of LVOT VTI: • PW Doppler sample volume placed too apically

• S ystolic LVOT diameter in ≥3 beats (sinus rhythm) and in ≥5 beats (irregular rhythm) • 3D planimetric measurement of the LVOT area (3D TEE, CT) • PW Doppler sample volume should be in the middle of LVOT just below the flow convergence where smooth velocity curve is obtained

AVAi (cm2/m2)

<0.6

• Underestimation in obese patients

• I mportant measure in children, adolescents, small adults

Velocity ratio (LVOT velocity/ peak velocity)

<0.25

• U nderestimation of LVOT velocity or peak velocity

• M ultiple acoustic windows to determine the highest peak velocity • Parallel ultrasound beam alignment with the direction of flow • Perform the measurements when patient has normal blood pressure • PW Doppler sample volume should be in the middle of LVOT just below the flow convergence where smooth velocity curve is obtained

AS = aortic stenosis; AVA = aortic valve area; AVAi = indexed aortic valve area; CT = computed tomography; LFLG = low-flow low-gradient; LVOT = left ventricular outflow tract; PW = pulsed wave; TEE = transoesophageal echocardiography; VTI = velocity time integral. Source: Baumgartner, et al., 2017.24

Doppler echocardiography is the preferred technique for the assessment of the severity of AS. The primary hemodynamic parameters defining severe AS with echocardiography are the peak jet velocity ≥4 m/s, mean transvalvular pressure gradient ≥40 mmHg and aortic valve area (AVA) by continuity equation <1 cm2 (Table 3).24 In the majority of patients, these criteria coincide. However, up to 30 % of patients may show low peak jet velocity and transaortic valve gradient with an AVA <1 cm2.25 This is frequently observed among patients with LVEF <50 %, the so-called classical low-flow, low-gradient severe AS. Low-dose dobutamine stress echocardiography is the primary diagnostic method to differentiate between true severe AS and pseudo-severe AS in patients with reduced LVEF.24 In patients with true severe AS, an IV infusion of low-dose dobutamine will increase the LV contractility and stroke volume leading to an increase in mean transvalvular gradient while the AVA will remain narrow (Figure 4). In contrast, pseudo-severe AS is diagnosed when the increase in LV contractility and stroke volume is accompanied by an increase in AVA of more than 1 cm2 (Figure 5). While patients with true severe low-flow, low-gradient AS should undergo prompt aortic valve intervention, the course of action for patients with pseudo-severe AS is less clear. Fougeres et al.26 demonstrated comparable survival of patients with pseudo-severe AS to that of propensity-matched patients with systolic HF and no evidence of VHD. However, this has recently been challenged by another study that demonstrated a very high risk for clinical events (defined as the composite of all-cause death, aortic valve replacement and HF hospitalization) among patients with HF and moderate AS.27 Furthermore, in a retrospective analysis of 1,090 people with moderate AS and LVEF ≤50 %, aortic valve surgery was associated with a higher 5-year survival compared with people who had medical

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therapy.28 While current guidelines do not recommend aortic valve intervention in HF patients with moderate AS, this view might change after the results of the ongoing international, multicentre, randomised trial TAVR UNLOAD, which has been designed to compare the efficacy and safety of transfemoral TAVR in addition to optimal HF therapy vs HF therapy alone in HF patients with moderate AS.29 In patients without contractile reserve, defined as failure to increase stroke volume >20 % during dobutamine stress echocardiography, the assessment of aortic valve calcification burden with cardiac CT may help to estimate the severity of AS (Figures 4, 5).24 Aortic valve calcium score is quantified using the Agatston method and expressed in arbitrary units (AU).30 Cueff et al.31 demonstrated a good overall correlation between the degree of aortic valve calcification and hemodynamic parameters of AS severity assessed by: the AVA (r=-0.63, p<0.001); indexed AVA (r=-0.67, p<0.001); mean gradient (r=0.78, p<0.001); and peak velocity (r=0.79, p<0.001). The proposed cut-off value of 1,651 AU yielded a 93 % sensitivity and 75 % specificity in grading AS severity in patients with classical low-flow, low-gradient AS. Clavel et al.32 proposed different cut-off values to define severe AS for men and women as 2,065 AU and 1,274 AU, respectively. The joint European and American recommendations for the assessment of AS consider the aortic valve calcium score as a continuum – a very high calcium score suggests severe AS and a low calcium score suggests severe AS is unlikely (Table 4).24

Treatment Options for Aortic Stenosis Current therapeutic options for patients with severe AS and HF are conservative medical therapy, SAVR and TAVR. The Europe and US Class 1 recommendation for patients with symptomatic high-

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Diagnosis Figure 4: Classical Low-flow, Low-gradient Severe Aortic Stenosis

A: A 75-year old male with ischaemic cardiomyopathy, reduced left ventricular ejection fraction (32 %) and low cardiac output. At rest, echocardiography showed calcified aortic valve with severely narrowed valve area <1.0 cm2, while peak velocity and mean gradient were in the range of moderate aortic stenosis. B: During low-dose dobutamine stress echocardiography peak jet velocity and mean gradient increased ≥4.0 m/s and ≥40 mmHg respectively and the aortic valve area remained <1.0 cm2, revealing true severe aortic stenosis. Furthermore, an increase in cardiac output demonstrated left ventricular contractile reserve. C: CT showed a tricuspid aortic valve with high calcium score, suggesting high likelihood of severe aortic stenosis. AU = arbitrary units; AVA = aortic valve area; CI = cardiac index; Mean gr = mean gradient; SVi = stroke volume index; Vmax = peak velocity.

Figure 5: Pseudo-severe Low-flow, Low-gradient Aortic Stenosis

A: An 80-year old male with dilated cardiomyopathy, reduced left ventricular ejection fraction (21 %) and low cardiac output. At rest, echocardiography showed calcified aortic valve with an area <1.0 cm2 (suggesting severe aortic stenosis), while peak velocity and mean gradient were representative of mild aortic stenosis. B: During low-dose dobutamine stress echocardiography, the peak jet velocity and mean gradient marginally increased and the aortic valve area increased >1.0 cm2, revealing pseudo-severe aortic stenosis. C: CT showed tricuspid aortic valve with low calcium score, suggesting non-severe aortic stenosis. AU = arbitrary units; AVA = aortic valve area; CI = cardiac index; Mean gr = mean gradient; SVi = stroke volume index; Vmax = peak velocity.

gradient severe AS is that there is no lower LVEF limit for aortic valve intervention since LV function is likely to improve after relief of stenosis.6,7 The Class 1 recommendation for symptomatic severe AS patients with an LVEF <50 % is that they should undergo SAVR.6,7

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In patients with classical low-flow, low-gradient severe AS with reduced LVEF, aortic valve intervention is indicated when dobutamine stress echocardiography shows evidence of LV contractile reserve. This is the Class 1 recommendation in European guidelines and

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Valvular Heart Disease and Heart Failure Table 4: Calcium Score by Computed Tomography in Grading of Aortic Stenosis Men

Women

Severe aortic stenosis very likely

≥3,000

≥1,600

Severe aortic stenosis likely

≥2,000

≥1,200

Severe aortic stenosis unlikely

<1,600

<800

Figure 6: CT in Pre-procedural Assessment for Transcatheter Aortic Valve Replacement (TAVR)

Source: Baumgartner, et al., 2017.24

Table 5: Imaging-derived Characteristics that Guide the Decision between TAVR and SAVR in Patient at Increased Surgical Risk Favours TAVR Favours SAVR Peripheral arteries anatomy favourable for transfemoral TAVR

Unfavourable access (any) for TAVR

Porcelain aorta

Expected patient-prosthesis mismatch

Short distance between coronary ostia and aortic valve annulus

Size of aortic valve annulus out of range for TAVR

Aortic root morphology unfavourable for TAVR

Valve morphology (bicuspid, degree of calcification, calcification patter) unfavourable for TAVR

Presence of thrombi in aorta or left ventricle

SAVR = surgical aortic valve replacement; TAVR = transcatheter aortic valve replacement. Source: Baumgartner, et al., 2017.6

Class 2a in American guidelines.6,7 An intervention should also be considered in patients without LV contractile reserve, particularly when the CT calcium score is high (Class IIa recommendation in European guidelines, while American guidelines stress the importance of individualised decisions in these high-risk patients).7,8 Tribouilloy et al.33 demonstrated that patients with low-flow, lowgradient severe AS without contractile reserve experience high operative mortality, but SAVR was associated with better outcomes compared with patients who were treated conservatively. Only symptomatic patients with severe comorbidities, in whom aortic valve intervention is unlikely to improve survival or quality of life, should be treated with medical therapy.6 The choice of the intervention in patients with symptomatic severe AS and HF should be made by the specialist heart team and should take into account the patient’s cardiac and extracardiac characteristics, the individual risk of surgery, the feasibility of TAVR, as well as the local experience and outcome data.6,8 Table 5 lists the imaging-derived characteristics that guide the decision to choose TAVR or SAVR. Multi-slice CT has become the imaging modality of choice for pre-procedural evaluation of TAVR candidates in most centres due to its low invasiveness and comprehensive evaluation.6 It allows assessment of the size and the shape of the aortic annulus, its distance to the coronary ostia, the distribution of calcifications and the dimensions of the aortic root, which is of paramount importance to determine feasibility of TAVR and to choose appropriate prosthesis

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A: Double oblique transverse view of a calcified tricuspid aortic valve. B: Planimetry of the aortic annulus. The posterior part of the annulus was severely calcified (arrow), increasing the likelihood of aortic rupture in case of an oversized TAVR prosthesis implantation or post-dilatation with an oversized balloon. C: The calcification extended from the aortic annulus into the left ventricular outflow tract towards the anterior mitral valve leaflet (arrow). D: Measurement of the distance between left main coronary artery and the aortic annulus (arrow). A calcified plaque in the left coronary artery is visible (arrowhead). E: Tortuous bilateral iliofemoral arteries. F: Multi-planar reconstruction revealed only mildly calcified right iliofemoral artery with adequate lumen diameter to allow for transfemoral TAVR.

size (Figure 6). However, if CT is contraindicated, for example, if the patient has severely impaired renal function, 3D transoesophageal echocardiography can be used to determine the aortic annulus size. It is important to remember that the obtained annulus dimensions with 3D transoesophageal echocardiography are smaller than those measured with cardiac CT and the echocardiographic accuracy can be reduced in heavily calcified aortic valves.34,35 Cardiac CT also allows assessment of the peripheral arteries to determine feasibility of transfemoral access, which is the least invasive TAVR approach, used in the majority of patients.23,36 Cardiac CT allows detailed visualisation of iliofemoral arteries and aorta with the assessment of size, tortuosity, degree of calcification and plaque burden (Figure 6). For currently available TAVR delivery catheters, a 6–6.5 mm minimal luminal vessel diameter of femoral arteries is considered acceptable.37 In case of contraindications to CT, invasive angiography or, less commonly, CMR angiography might be employed.

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Diagnosis Conclusion Accurate grading of valvular lesion and reliable assessment of LV dysfunction is of paramount importance when deciding the most appropriate therapy for patients with VHD and HF. Transthoracic echocardiography is the first-line imaging modality to quantify LV systolic function and grade of valvular stenosis and regurgitation, as well as characterising the mechanism of valvular dysfunction. However, in HF patients, quantification of valvular dysfunction remains challenging

avarese G, Lund LH. Global public health burden of heart S failure. Card Fail Rev 2017;3:7–11. https://doi.org/10.15420/ cfr.2016:25:2; PMID: 28785469. 2. 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. 3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52. https://doi. org/10.1161/CIR.0b013e31829e8807; PMID: 23741057. 4. Marciniak A, Glover K, Sharma R. Cohort profile: prevalence of valvular heart disease in community patients with suspected heart failure in UK. BMJ Open 2017;7:e012240. https://doi.org/10.1136/bmjopen-2016-012240; PMID: 28131996. 5. Lung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231–43. PMID: 12831818. 6. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739-91. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619. 7. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:2440–92. https:// doi.org/10.1161/cir.0000000000000029; PMID: 24589852. 8. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 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 Clinical Practice Guidelines. Circulation 2017;135:e1159–e95. https://doi.org/10.1161/ cir.0000000000000503; PMID: 28298458. 9. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S01406736(06)69208-8; PMID: 16980116. 10. Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 2017;30:303–71. https://doi.org/10.1016/j.echo.2017.01.007; PMID: 28314623. 11. Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14:611-44. https://doi.org/10.1093/ ehjci/jet105; PMID: 23733442. 12. Avierinos JF, Tribouilloy C, Grigioni F, et al. Impact of ageing on presentation and outcome of mitral regurgitation due to flail leaflet: a multicentre international study. Eur Heart J

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13.

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25.

and the use of other imaging techniques such as 3D transesophageal echocardiography, CMR and CT is needed to determine whether valve stenosis and regurgitation are severe. The integration of multimodality cardiovascular imaging is even more important when assessing suitability for transcatheter valve repair and replacement therapies. CT has become the key imaging modality for pre-procedural evaluation of patients undergoing TAVR, and 3D transoesophageal echocardiography is crucial to guide percutaneous edge-to-edge mitral valve repair. n

2013;34:2600-9. https://doi.org/10.1093/eurheartj/eht250; PMID: 23853072. Rossi A, Dini FL, Faggiano P, et al. Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 2011;97:1675–80. https://doi.org/10.1136/hrt.2011.225789; PMID: 21807656. Yoran C, Yellin EL, Becker RM, et al. Dynamic aspects of acute mitral regurgitation: effects of ventricular volume, pressure and contractility on the effective regurgitant orifice area. Circulation 1979;60:170-6. PMID: 445720. Zeng X, Levine RA, Hua L, et al. Diagnostic value of vena contracta area in the quantification of mitral regurgitation severity by color Doppler 3D echocardiography. Circ Cardiovasc Imaging 2011;4:506–13. https://doi.org/10.1161/ circimaging.110.961649; PMID: 21730026. Hung J, Otsuji Y, Handschumacher MD, et al. Mechanism of dynamic regurgitant orifice area variation in functional mitral regurgitation: physiologic insights from the proximal flow convergence technique. J Am Coll Cardiol 1999;33:538–45. PMID: 9973036. De Bonis M, Al-Attar N, Antunes M, et al. Surgical and interventional management of mitral valve regurgitation: a position statement from the European Society of Cardiology Working Groups on Cardiovascular Surgery and Valvular Heart Disease. Eur Heart J 2016;37:133–9. https://doi.org/10.1093/ eurheartj/ehv322; PMID: 26152116. Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation. N Engl J Med 2016;374:344–53. https://doi. org/10.1056/NEJMoa1512913; PMID: 26550689. Kongsaerepong V, Shiota M, Gillinov AM, et al. Echocardiographic predictors of successful versus unsuccessful mitral valve repair in ischemic mitral regurgitation. Am J Cardiol 2006;98:504–8. https://doi. org/10.1016/j.amjcard.2006.02.056; PMID: 16893706. Braun J, Bax JJ, Versteegh MI, et al. Preoperative left ventricular dimensions predict reverse remodeling following restrictive mitral annuloplasty in ischemic mitral regurgitation. Eur J Cardiothorac Surg 2005;27:847–53. https://doi.org/10.1016/j. ejcts.2004.12.031; PMID: 15848325. Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009;373: 956-66. https://doi.org/10.1016/s0140-6736(09)60211-7; PMID: 19232707. Fujita B, Ensminger S, Bauer T, et al. Trends in practice and outcomes from 2011 to 2015 for surgical aortic valve replacement: an update from the German Aortic Valve Registry on 42 776 patients. Eur J Cardiothorac Surg 2018;53: 552–9. 10.1093/ejcts/ezx408; PMID: 29190355. Carroll JD, Vemulapalli S, Dai D, et al. Procedural experience for transcatheter aortic valve replacement and relation to outcomes. J Am Coll Cardiol 2017;70:29–41. https://doi. org/10.1016/j.jacc.2017.04.056; PMID: 28662805. Baumgartner HC, Hung J, Bermejo J, et al. Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging 2017;18:254–75. https://doi.org/10.1093/ehjci/jew335; PMID: 28363204. Minners J, Allgeier M, Gohlke-Baerwolf C, et al. Inconsistencies of echocardiographic criteria for the grading of aortic valve stenosis. Eur Heart J 2008;29:1043–8. https://doi.

org/10.1093/eurheartj/ehm543; PMID: 18156619. 26. F ougeres E, Tribouilloy C, Monchi M, et al. Outcomes of pseudo-severe aortic stenosis under conservative treatment. Eur Heart J 2012;33:2426–33. https://doi.org/10.1093/eurheartj/ ehs176; PMID: 22733832. 27. van Gils L, Clavel MA, Vollema EM, et al. Prognostic implications of moderate aortic stenosis in patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2017;69:2383–92. https://doi.org/10.1016/j.jacc.2017.03.023; PMID: 28494976. 28. Samad Z, Vora AN, Dunning A, et al. Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction. Eur Heart J 2016;37:2276–86. https://doi.org/10.1093/eurheartj/ehv701; PMID: 26787441. 29. Spitzer E, Van Mieghem NM, Pibarot P, et al. Rationale and design of the Transcatheter Aortic Valve Replacement to UNload the Left ventricle in patients with ADvanced heart failure (TAVR UNLOAD) trial. Am Heart J 2016;182:80–8. https://doi.org/10.1016/j.ahj.2016.08.009; PMID: 27914503. 30. Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–32. PMID: 2407762. 31. Cueff C, Serfaty JM, Cimadevilla C, et al. Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction. Heart 2011;97:721–6. https://doi.org/10.1136/ hrt.2010.198853; PMID: 20720250. 32. Clavel MA, Messika-Zeitoun D, Pibarot P, et al. The complex nature of discordant severe calcified aortic valve disease grading: new insights from combined Doppler echocardiographic and computed tomographic study. J Am Coll Cardiol 2013;62:2329–38. https://doi.org/10.1016/j. jacc.2013.08.1621; PMID: 24076528. 33. Tribouilloy C, Levy F, Rusinaru D, et al. Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. J Am Coll Cardiol 2009;53:1865–73. https://doi.org/10.1016/j.jacc.2009.02.026; PMID: 19442886. 34. Ng ACT, Delgado V, van der Kley F, et al. Comparison of aortic root dimensions and geometries before and after transcatheter aortic valve implantation by 2-and 3-dimensional transesophageal echocardiography and multislice computed tomography. Circ-Cardiovasc Imag 2010;3:94–102. https://doi.org/10.1161/ Circimaging.109.885152; PMID: WOS:000273736000013. 35. Podlesnikar T, Prihadi EA, van Rosendael PJ, et al. Influence of the quantity of aortic valve calcium on the agreement between automated 3-dimensional transesophageal echocardiography and multidetector row computed tomography for aortic annulus sizing. Am J Cardiol 2018;121:86–93. https://doi.org/10.1016/j. amjcard.2017.09.016; PMID: 29096883. 36. Walther T, Hamm CW, Schuler G, et al. Perioperative Results and Complications in 15,964 Transcatheter Aortic Valve Replacements: Prospective Data From the GARY Registry. J Am Coll Cardiol 2015;65:2173–80. https://doi.org/10.1016/j. jacc.2015.03.034; PMID: 25787198. 37. Bax JJ, Delgado V, Bapat V, et al. Open issues in transcatheter aortic valve implantation. Part 2: procedural issues and outcomes after transcatheter aortic valve implantation. Eur Heart J 2014;35:2639–54. https://doi.org/10.1093/eurheartj/ ehu257; PMID: 25062953.

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Pathophysiology

Heart–brain Interactions in Heart Failure Nadja Scherbakov 1,2 and Wolfram Doehner 1,2,3 1. Centre for Stroke Research Berlin, Charité University Hospital, Berlin, Germany; 2. German Centre for Heart and Cardiovascular Research (DZHK), Partner Site Berlin, Charité University Hospital, Berlin, Germany; 3. Division of Cardiology and Metabolism, Department of Cardiology, Charité University Hospital, Berlin, Germany

Abstract Heart failure (HF) is a complex disease with a growing incidence worldwide. HF is accompanied by a wide range of conditions which affect disease progression, functional performance and contribute to growing healthcare costs. The interactions between a failing myocardium and altered cerebral functions contribute to the symptoms experienced by patients with HF, affecting many comorbidities and causing a poor prognosis. This article provides a condensed version of the 2018 position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association. It addresses the reciprocal impact on HF of several pathological brain conditions, including acute and chronic low perfusion of the brain, and impairment of higher cortical and brain stem functions. Treatment-related interactions – medical, interventional and device-related – are also discussed.

Keywords Heart failure, neuro-cardiac reflexes, cerebral perfusion, cognitive impairment Disclosure: Dr Scherbakov has no conflicts of interest to declare. Dr Doehner has received personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sphingotec, Vifor Pharma, and ZS Pharma as well as research support from Sanofi, Vifor Pharma and ZS Pharma. Received: 7 March 2018 Accepted: 9 May 2018 Citation: Cardiac Failure Review 2018;4(2):87–91. DOI: https://doi.org/10.15420/cfr.2018.14.2 Correspondence: Wolfram Doehner, Center for Stroke Research Berlin, CSB and Department of Cardiology, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E: wolfram.doehner@charite.de

Heart failure (HF) is a complex clinical syndrome with more than 15 million diagnosed cases worldwide.1,2 Characterised by structural or functional impairment of ventricular filling or ejection fraction (EF) 3, HF is frequently accompanied by multiple comorbidities. Brain disorders, including stroke, mental disturbances and cognitive impairment are distinct from the comorbidities traditionally related to HF and require specific management. Both organs are linked by multiple feedback signals, and the discovery of bi-directional interactions of failing heart and neuronal signals has led to the concept of the cardio-cerebral syndrome in HF.4 This article provides a condensed version of the recently published position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association and details several pathophysiological and functional aspects of the heart–brain interactions in HF (Figure 1).5

Stroke and Cerebral Perfusion in Patients with Heart Failure Stroke is one of the leading causes of mortality and disability in adult life and had a global incidence rate of more than 10 million in 2013.6,7 Patients with HF have an increased risk for stroke,8 and it contributes to morbidity and mortality in this patient group.9 In the populationbased Framingham Heart Study, the relative risk of stroke in people with HF was four-fold higher for men and three-fold higher for women compared with patients without HF.8 The prevalence of stroke did not differ between patients with HF with preserved ejection fraction (HEpEF) and those with HF with restricted ejection fraction (HFrEF) and ranged between 2.4 and 5.8 % for HFrEF and between 3.8 and 7.4 % for HFpEF in clinical trials.10–12 This overall reduction in risk may be related to the treatment of the disease and initiation of stroke prevention measures.

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Several risk factors for stroke in patients with HF have been established. A hypercoagulable state, with activated coagulation and disturbances in proteolytic systems,13 reduced blood flow, inflammation and endothelial dysfunction, has been implicated in the development of systemic cardioembolic events in HF including stroke. Further factors such as low flow patterns due to an enlarged left atrium14 or reduced contractility of the left ventricle (LV) with apical akinesia or aneurysm represent additional risk factors of intracardiac thrombosis and, consequently, embolic stroke in patients with HF.15,16 Incidence reported in 10 small-scale observational case-control studies show wide variations in the incidence of thrombo-embolic events with a range of 1.4–12.5 % in HF patients including those with atrial fibrillation (AFib) and those receiving oral anticoagulation therapy.17 Further risk factors such as small vessel disease and large artery atherosclerosis are common in people with ischaemic HF.18 In patients with carotid artery stenosis, reduction of perfusion pressure due to systolic HF may result in a greater volume of ischaemic lesion.19 In addition, a cerebral lesion may remain clinically undetected as a so-called “silent” infarction. The prevalence of silent cerebral infarctions is comparably high in HF cohorts ranging between 27 and 63 %,20,21 which is higher than in age-matched subjects without HF.22 Silent cerebral infarctions and other structural brain damages, such as increased white matter hyperintensities24 or grey matter loss,24 are frequently found in imaging tests for HF patients with cognitive dysfunction and dementia.25 While the benefit of antithrombotic therapy in the context of AFib is clearly established regardless of the presence of HF, there is no

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Pathophysiology Figure 1: Heart and Brain Interactions in Heart Failure.

Cerebral perfusion

Higher cortical function

• Acute disruption of blood flow • Chronic low perfusion

• Mood disorders • Cognitive dysfunction

Peripheral reflexes

Ageing, risk factors (hypertension, diabetes, hyperlipoproteinaemia), arterial atherosclerosis

Lower cerebral function

• Afferent signals

• Sympathetic activation • Neuro-cardiac reflexes (ergoreflex, baroreflex, chemoreflex)

Disease-specific interaction

Treatment-related interaction

• Infectious diseases • Hypothyroidism • Transthyretin amyloidosis • Alcoholism • Chemotherapy • Sarcoidosis • Takotsubo syndrome • Chagas disease • Friedreich’s ataxia • Storage diseases

• Cardiac medication • Non-cardiac medication • Device therapy • Revascularisation • Advanced surgical therapies • Behaviour-related interventions (exercise, smoking, nutrition)

Source: Doehner, et al., 2018.5 Used with permission from Wiley.

adequate antithrombotic therapy for stroke prevention in HF patients with maintained sinus rhythm. The Warfarin versus Aspirin in Patients with Reduced Cardiac Ejection Fraction (WARCEF) trial revealed no overall difference between warfarin and aspirin in preventing ischaemic stroke in HF patients with a mean reduced left ventricular ejection fraction of 24.7 % (±7.5) and sinus rhythm.26 A reduced risk of ischaemic stroke after warfarin was equalised by the increased risk of major bleeding. A borderline significant benefit of warfarin on the primary outcome (ischaemic stroke, haemorrhagic stroke or death from any cause) was observed only after 4 years. The analysis of two smaller randomised controlled trials, the Heart Failure Long-term Antithrombotic Study (HELAS)27 and Warfarin/Aspirin Study of Heart Failure (WASH),28 demonstrated no benefit for patients with HF having antithrombotic therapy compared with placebo regarding vascular events and mortality.29 Accordingly, a position paper from a European Society of Cardiology working group does not support the routine use of warfarin in patients with HF and sustained sinus rhythm.17 It should be noted, however, that the risk–benefit ratio might be significantly improved with the introduction of novel anticoagulant (NOAC) therapies, and the results from the WARCEF trial may be outdated. While stroke represents an acute case of low cerebral perfusion, chronic low cerebral perfusion may manifest in a series of structural cerebral alterations of grey and white matter damage in HF

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patients.30,31 Vascular auto-regulation of the cerebral vasculature (the Bayliss effect) enables maintenance of normal perfusion even with severely elevated blood pressure and it protects the brain against blood pressure peaks. Regional hypoperfusion may occur at low perfusion pressures, and chronic low perfusion may account for metabolic impairment, structural decrease and eventual functional decline of brain areas involved in autonomic, neuropsychological and cognitive control.32 Regional vascular recruitment is modulated by functional activity and local oxygen demands and is locally controlled by a range of factors addressed by the ‘neurovascular unit’, a heterogeneous structure composed of different cell types including astrocytes, pericytes, endothelial cells of the blood brain barrier, microglia and neurons.33 Regional hypoperfusion has been observed in multiple brain areas in people with HF, largely lateralised towards the right side in the occipital, temporal, frontal and parietal regions.34 Bilateral areas of reduced blood flow were observed in the prefrontal cortex, frontal white matter, anterior corpus callosum, thalamus, hippocampus, amygdala and occipital cortex. The decreased regional perfusion may contribute to the autonomic, mood and cognitive regulatory deficits observed in HF. Further, impaired perfusion of multiple brain areas involved in the control of vision, language and speech have been observed that could explain the respective deficits in HF patients.34

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Heart–brain Interactions in Heart Failure Higher Cortical Function in Patients with Heart Failure There are two patterns of cognitive problems in HF that are recognised in clinical practice: a chronic, progressive decline in cognitive ability and an acute change in cognition associated with decompensated HF. Cognitive decline in executive function, attention, episodic memory, language, psychomotor speed and visuospatial ability is typical for patients with HF, with differences between HFrEF and HFpEF.35,36 Accelerated cognitive decline may result from chronic hypoperfusion over the long-term course of HF. The prevalence of early-onset cognitive impairment ranging from 25–74 % has been observed in patients with HF, and is associated with early death, loss of functional independence, worse adherence to therapy and decreased quality of life.37,38,39,40 Delirium, a common sequela of decompensated HF, is associated with prolonged hospital stays and increased mortality.41 Despite its high rate and severe clinical impact, the relationship between acute delirium and HF has not been studied in detail. Cognitive decline is also observed in patients with acute decompensating HF (ADHF), and one study has shown that cognitive performance with respect to memory, perceptual speed, and executive control was affected more severely in 20 patients with ADHF compared with 20 patients with stable chronic HF.42 Another clinical trial demonstrated that 80 % of 744 patients with ADHF had cognitive impairment in at least one of the cognitive domains, such as processing speed, memory and executive function.43 A correlation between cognition and markers of haemodynamic performance (left ventricular EF and N-terminal prohormone of brain natriuretic peptide) as well as inflammation (C-reactive protein) suggests that hypotensive blood pressure and haemodynamic failure plays a role in cognitive impairment.42 Mood and anxiety disorders in HF have been investigated in several clinical trials, and depression in patients with HF has become a major focus of research in recent years. Clinical studies have observed that depression is associated with poor quality of life, lower treatment adherence, greater morbidity and mortality, increased hospitalisation and higher healthcare costs for patients with HF.44,45,46 The aggregated prevalence of depression in patients with chronic HF is 21.5 %47 compared with 2.3–4.7 % in the general population.48,49 Elevated prevalence has been linked to more severe functional class and differences were observed between patients with New York Heart Association class 2 and 3 HF. However, data reporting the prevalence of depression are variable because of the use of different assessment methods, the heterogeneity of cohorts and the wide range of depression symptoms. Anxiety is another frequently encountered disorder in HF patients with a prevalence ranging from 9–53 %.50 Anxiety in people with HF is related to older age, low level of education, poor socioeconomic status, previous psychiatric disease, decreased quality of life, multiple hospitalisations, increased natriuretic peptide levels and impaired functional capacity.51 Depression and anxiety appeared as independent predictors of all-cause mortality in a meta-analysis of 31 studies with 1–3 years’ follow-up.50 Treatment of depression with selective serotonin reuptake inhibitors for people with HF has not been successful and the results of two major randomised controlled trials (SADHART52 and MOOD-HF53) did not show significant improvement in depression scores and HF outcomes. However, in observational small-scale studies, effective management of HF-related physical symptoms improved anxiety and depression scores significantly.54 Disease management programmes and aerobic exercise seem to be

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as effective as drug therapy,55 and repeated visits from nurses and routine contact calls from healthcare staff to give education and care support were found to reduce hospital readmissions and increase quality of life.56

Peripheral Reflexes and Brain Stem Function The impact of the central nervous system on vegetative control of the cardiovascular system is not fully understood. Cardiovascular signals from chemo-, baro- and ergoreceptors trigger afferent signals to the autonomic nervous system (ANS) control centres that provide efferent sympathetic and parasympathetic signals to form baro-, metabo- or chemoreflex circuits. Imbalanced neuroendocrine activation and control of the myocardium and circulation is fundamental in HF pathophysiology and is a driving force of disease progression and high mortality. Peripheral chemoreceptor hypersensitivity characterised by increased sympathetic drive and hyperventilation is predictive of poor outcome in patients with chronic HF.57 During exercise, the contribution of the muscle ergoreceptors to autonomic, hemodynamic, and respiratory responses among patients with HF has been shown to be enhanced compared with control subjects,58 leading to hyperventilation and intolerance of exercise.59 In addition, reduced values of the autonomic markers (heart rate variability and baroreflex sensitivity) were associated with increased mortality after myocardial infarction.60 The ANS is an important target for research into HF therapies.61 Impaired signals between the heart, the cortex and brain stem caused by low perfusion might lead to alterations of the ANS with increased sympathetic tonus, parasympathetic withdrawal and impaired neurocardiac reflexes.30,32,62 Indeed, regional cerebral blood flow to the frontal cortex fails to rise in HF patients during exercise when compared with healthy controls.63 Experimental and clinical studies have also shown an association between stroke and increased levels of catecholamines and/or abnormal autonomic control of heart rate (heart rate variability) and arterial baroreflex sensitivity.64,65 The activation of the sympathetic nervous system, especially after injury involving the insular cortex, promotes the development of AFib, ventricular arrhythmias and abnormalities in QT interval.66,67 Alterations in blood pressure, heart rate and breathing control that derive from a reduction in baroreflex sensitivity and a concomitant increase in peripheral and central chemosensitivity, lead to a pattern of reflex instability. This pattern, known as Cheyne-Stokes respiration, is observed in advanced HF and manifests as central sleep apnoea. The Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure (SERVE-HF) trial found an increased mortality rate in participants which highlights the importance of this mechanism when central sleep apnoea in patients with advanced HFrEF was treated with adaptive servo-ventilation.68 The mechanism may be related to the adverse hemodynamic effects of positive airway pressure in HFrEF patients with low EF although the exact mechanism remains uncertain.

Treatment-related Interactions Treatment-related interactions within the heart–brain axis can be categorised as medical, interventional or device-related. High prevalence of comorbidities in patients with HF accompanied by polypharmacy and age-related pathophysiological changes may affect the efficacy of guideline therapies. Thus, in older patients with HF, the side-effects of lowering blood pressure and the subsequent cerebral hypoperfusion might result in cognitive decline, falls and depression.69,70 However, hypertension treatment has been shown to

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Pathophysiology reduce the risk of death and admission to hospital in a meta-analysis investigating more than 13,000 patients with HFrEF in sinus rhythm.71 In patients receiving device therapy, an increase in symptoms of depression and anxiety during the initial weeks after implantation have been shown.72,73 These symptoms fade, especially in patients who have a favourable response to the therapy, such as cardiac resynchonisation, and cognitive performance improves. Nevertheless, receiving a shock from an implantable cardioverter-defibrillator (ICD) can lead to emotional dysfunction, anxiety and depression during the following month.72,73 Almost 20 % of patients with an ICD suffer posttraumatic stress disorder due to a history of cardiac arrest, device implantation and ICD shock, and cognitive behavioural therapy can potentially improve outcomes.73 The beneficial effect of exercise on functional status and outcome in patients with HF has been shown in several clinical trials. A wide

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range of mechanisms, including indirect effects via cerebral signals such as improved sympatho-vagal balance and attenuated activation of ergo- and metaboreflexes, enhancing cerebral haemodynamics, or even cortical, anti-depressive effects of exercise might contribute to physical and functional improvement in patients with HF.74–76

Conclusion HF is a complex clinical syndrome that involves all organs and systems of the body and it is associated with multiple comorbidities. Bi-directional interactions between failing myocardium and brain dysfunction contribute to the symptoms that patients with HF present with and they account for comorbidities such as stroke, impaired ANS functions, sleep apnoea, cognitive impairment or depression. Neurocardiac feedback signals significantly promote disease progression and cause a poor prognosis in patients with HF. A better understanding of interactions within the heart–brain axis is needed to improve management and prognosis of HF patients. n

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Pathophysiology

Calming the Nervous Heart: Autonomic Therapies in Heart Failure Peter Hanna, Kalyanam Shivkumar and Jeffrey L Ardell David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA

Abstract Heart failure (HF) is associated with significant morbidity and mortality. The disease is characterised by autonomic imbalance with increased sympathetic activity and withdrawal of parasympathetic activity. Despite the use of medical therapies that target, in part, the neurohormonal axis, rates of HF progression, morbidity and mortality remain high. Emerging therapies centred on neuromodulation of autonomic control of the heart provide an alternative device-based approach to restoring sympathovagal balance. Preclinical studies have proven favourable, while clinical trials have had mixed results. This article highlights the importance of understanding structural/functional organisation of the cardiac nervous system as mechanistic-based neuromodulation therapies evolve.

Keywords Neurocardiology, cardiac nervous system, neuromodulation, autonomic therapy, heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 4 July 2018 Accepted: 18 July 2018 Citation: Cardiac Failure Review 2018;4(2):92–8. DOI: https://doi.org/10.15420/cfr.2018.20.2 Acknowledgement: Work was supported by the NIH: Grants U01EB025138 (JLA and KS), HL71830 (JLA), HL084261 (KS) & OT2OD023848 (KS & JLA). Correspondence: Jeffrey L Ardell, UCLA Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, 100 UCLA Medical Plaza, Suite 660, Los Angeles, CA 90095. E: jardell@mednet.ucla.edu

Heart failure (HF) is associated with significant morbidity and mortality, and the burden of disease is rising.1 Despite improved survival – partly a result of advances in medical therapy, coronary interventions and ICD – the mortality rate remains high and relatively stagnant.2 Moreover, advanced HF is associated with impaired quality of life (QOL), which is reflected in the significant number of hospitalisations and increased healthcare costs. The aetiologies of HF are varied but autonomic dysfunction is a hallmark. Imbalance in the complex and dynamic interactions between the sympathetic and parasympathetic efferent limbs of the autonomic nervous system (ANS) is not only reactive to HF as a means of maintaining homeostasis, but also a contributor to HF progression. The interplay between multiple levels of the hierarchy for cardiac control (Figure 1) ultimately results in excessive sympathetic responses with corresponding withdrawal of parasympathetic tone. Furthermore, depressed arterial baroreflex regulation, a major contributor to reflex control of cardiac and peripheral vascular function, is associated with poor survival.3–5 For additional details regarding the pathophysiology of the ANS in HF, we refer the reader to recent articles on the subject.6–8 Medical approaches to treating autonomic dysfunction in HF focus on reducing the overactive sympathetic nervous system through the blockade of the beta-adrenergic or renin–angiotensin–aldosterone systems. However, despite improvements in pharmacologic approaches, treatment of HF remains challenging.9,10 Neuromodulation therapy to restore sympathovagal balance in HF has garnered increasing interest in recent years. Emerging therapies in this area include vagus nerve stimulation (VNS), spinal cord stimulation (SCS), baroreflex activation therapy (BAT), renal denervation (RDN) and stellate ganglionectomy (Figure 2). Here, we summarise the current data in animal models and clinical studies on these autonomic therapies in HF as well as challenges to the implementation of these treatment modalities.

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Approach to Cardiac Neuromodulation When considering the application of bioelectric therapies for cardiac disease, three main concepts of neurocardiology merit discussion.11 Firstly, neural control of cardiac function is exerted through the interactions between central and peripheral components of the cardiac ANS (Figure 1).8 Secondly, the aforementioned interactions may be weakened or strengthened depending on the level of the cardiac neuraxis and the characteristics of the underlying cardiac pathology.12–14 Such neural remodelling is critically dependent on abnormal afferent input.7,8,15,16 Lastly, as the neuromodulation acts on axons of passage, associated neural networks (above and below site of intervention) and the heart itself, the outcome of neuromodulation depends on the stimulation parameters, the location within the neuraxis in which therapy is applied and the cardioneural pathologic substrate against which the therapy is applied. It is highly likely that the optimum neuromodulation approach may be different depending on the status of the patient and that even within a given patient, therapy will need to be adjusted with time, as is already done for pharmacologic approaches.

Vagus Nerve Stimulation VNS devices were initially developed and approved for use in the treatment of epilepsy and refractory depression.17–22 Interest in VNS has expanded to treatments for visceral disorders and for cardiac pathologies.8,22,23 The central premise of VNS is to increase parasympathetic tone and to restore reflexes that mitigate adrenergic inputs to the heart (Table 1). Additionally, VNS is cardioprotective because it limits cardiomyocyte apoptosis and inflammation.24–26 It also protects the heart by altering substrate use within the heart muscle itself.27,28 At the molecular level, VNS may improve survival through the reduction in connexin 43 loss and promotion of electrical stability.29

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Autonomic Therapies in Heart Failure When delivered to the cervical vagosympathetic trunk, VNS activates both ascending (afferent) and descending (parasympathetic efferent) projections (Figure 2). The cardiac nervous system works in a push push-back; fashion. Functional cardiac responses to afferent activation are engaged at lower stimulus intensities leading to withdrawal of centrally derived parasympathetic tone with the potential to modify sympathetic activity (Figure 3). As stimulus intensity is increased, parasympathetic efferents are engaged with expected decreases in regional cardiac function (Figure 3); excessive parasympathetic stimulation can lead to rebound effects during the off-phase of intermittent VNS.30–32 When ascending and descending projections within the cervical vagus are activated in a ‘balanced’ fashion, multiple levels of the cardiac neuraxis are engaged with little or no change in basal cardiac function – we refer to this as the neural fulcrum.30,33,34 The major effects of VNS delivered at this operating point are placing restraints on aberrant reflex processing within the peripheral neural networks of the intrinsic cardiac nervous system, rendering myocytes stress-resistant and exerting anti-adrenergic effects on the heart itself.8 Animal studies have demonstrated the efficacy of chronically implantable VNS device therapy in sudden cardiac death and HF. In an acute ischaemia model in dogs with healed MI, chronic right cervical VNS protected against VF.35 Chronic VNS at the right cervical vagus nerve stymied the progression of HF in a canine high-rate pacing model and dramatically improved LVF and survival in a rat model of HF.26,36 Chronic VNS, both left and right, was likewise effective in maintaining cardiac function in guinea pig models of chronic MI and pressure overload.27,28 The Autonomic Neural Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) study evaluated the use of a VNS system (Demipulse® Model 103 pulse generator and Perennia FLEX® Model 304 lead; Liva Nova, Houston, TX, USA) in patients with HF.37 Its stimulation protocol used titration to the neural fulcrum (as defined above and depicted in Figure 3). Sixty patients with New York Heart Association (NYHA) functional class II–III symptoms, left ventricular ejection fraction (LVEF) ≤40 % and LV end-diastolic diameter (LVEDD) ≥50 mm to <80 mm underwent randomisation for implantation at either the left (n=31) or right (n=29) cervical vagus nerve. Regarding the primary safety endpoint of incidence of procedure- and devicerelated adverse events, one patient died 3 days after an embolic stroke that occurred during implantation. An additional 20 serious adverse events occurred, but none of these were attributed to the VNS system or its implantation. There were statistically significant improvements in the primary efficacy endpoints of LVEF and LV endsystolic volume (LVESV) as well as the secondary efficacy endpoints of LV end-systolic diameter (LVESD), heart rate variability and 6-minute walk test (6MWT). Although there was a trend for improved efficacy outcomes with right as opposed to left VNS, CIs were wide, and there were no statistically significant differences in most efficacy parameters or safety profiles. Subsequent 12-month follow-up on 49 of the initial 60 patients showed that improvements persisted during longer follow-up and that the device implantation remained safe.38 While this study focused on HF with reduced ejection fraction (HFrEF), the ANTHEM-HF with preserved ejection fraction (HFpEF) study seeks to evaluate the safety and efficacy of right cervical VNS in patients with HFpEF and HF mid-range ejection fraction using a similar stimulation protocol and with at least 12-month follow-up.39 Results should be available in late autumn 2018.

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Figure 1: Structural and Functional Organisation of the Cardiac Autonomic Nervous System

Telencephalon

Forebrain control

Hypothalamus

Hypothalamic control

Upper brainstem

Brainstem control Efferent Systems

AFFERENT SYSTEMS

Nodose Spinal reflexes

Spinal cord

lntrathoracic reflexes

DRG

Cardio-cardiac reflexes Sympathetic Parasympathetic

Heart

Concept 1: Neural control of cardiac function involves a multi‐tier hierarchy of interdependent reflexes. Concept 2: There are inherent and acquired factors that impact the progression of cardiac disease. Concept 3: Neuromodulation based therapies impact multiple levels of control. The three major concepts of neuromodulation are displayed in the context of the cardiac autonomic nervous system. DRG = dorsal root ganglion; ICN = intrinsic cardiac nervous system. Adapted from Shivkumar et al., 2016 with permission.7

In contrast to the results from ANTHEM-HF, two other recent studies using VNS produced more neutral effects, at least with respect to objective outcomes such as echocardiographic parameters. The NEural Cardiac TherApy foR HF (NECTAR-HF) study was a randomised, shamcontrolled trial that evaluated the utility of VNS using the Precision Spectra™ system (Boston Scientific; St Paul, MN, USA).40 In this study, 96 patients with NYHA functional class II–III symptoms, LVEF ≤35 % and LVEDD ≥55 mm were randomised to VNS or control (device implanted but VNS off) in a 2:1 ratio for a 6-month period. Stimulation intensity was titrated, as tolerated, with a target of 20 Hz, a duty cycle of 16.7 %, a pulse width of 300 µs and a proposed maximal current intensity of 4 mA. However, primarily because of off-target effects, stimulus intensity was ~1.4 mA, which is in the region below the neural fulcrum and sub-threshold for optimal stimulation (Figure 3).40 In an analysis of 87 of the 96 patients implanted with available data, there was no statistically significant change in the primary endpoint of LVESD. Regarding adverse events, one patient died in the postoperative period from a pulmonary embolism, and there were three patient deaths between randomisation and 6 months as a result of worsening HF or HF complications. Of the 96 patients in the initial 6-month study, 91 patients were evaluated for a total of 18 months. All devices were activated after the initial 6-month period. Those in the group that crossed over from the control group to VNS activation had decreases in LVESV without significant changes in LVESD and LVEF.41 The INcrease Of VAgal TonE in Heart Failure (INOVATE-HF) trial evaluated the CardioFit system (BioControl Medical, Yehud, Israel) in

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Pathophysiology Figure 2: Intervention Sites within the Cardiac Autonomic Nervous System for the Treatment of Heart Failure Higher centres Carotid body chemoreceptors

Petrosal ganglia

Medulla

Carotid sinus baroreceptors DRG Aff. soma

C1-L5

Nodose Aff. soma

Aortic arterial baroreceptors

LCN

Muscle

Spinal cord

T1-T4

Brainstem Aortic chemoreceptors

Afferent soma

lntrathoracic Extracardiac ganglia Sympath Efferent soma

T6-L2

LCN

Kidney Sympath Efferent soma

Neurite

β1

Chymase Ang I

Parasym Efferent soma

Ang II

Afferent soma

Neurite

Gi Heart

AC ATP

Intrinsic cardiac ganglionated plexus

cAMP

Aff = afferent; b = beta-adrenergic receptor; C = cervical; DRG = dorsal root ganglion; Gi = inhibitory G-protein; G-protein; Gs = stimulatory; L = lumbar; LCN = local circuit neuron; M = muscarinic receptor; T = thoracic. The lightning symbol denotes site of stimulation while ‘x’ indicates location of denervation. Stellate ganglionectomy interrupts a portion of afferent and efferent fibres to the heart. Adapted from Ardell et al., 2016 with permission.8

Table 1: Targets of Autonomic Therapies in Heart Failure within the Cardiac Neuraxis VNS

SCS

BAT

RDN

Stellate

Activation of vagal efferents

Reduce afferent input

Activation of carotid sinus baroreceptor afferent fibres

Reduce renal afferent input

Reduce afferent input

Modulate intrathoracic cardiocardiac reflexes

Modulate spinal cord sympathetic reflexes (preganglionic)

Reduce central sympathetic outflow

Reduce renal efferent output

Interrupt preganglionic sympathetic outflow to heart

Activation of ascending afferents to modulate central reflexes

Blunt extracardiac sympathetic reflexes

Increase central parasympathetic outflow

Reduce central sympathetic outflow

Blunt extracardiac sympathetic reflexes

Render myocytes stressresistant

Blunt intrinsic cardiac nervous system reflexes

Render myocytes stressresistant

Ganglionectomy

Targets

BAT = baroreceptor activation therapy; RDN = renal denervation; SCS = spinal cord stimulation; VNS = vagus nerve stimulation.

advanced HF.42 This system used a combination of R-wave triggered VNS pulse delivery with a putative afferent blockade component. In this study, 707 chronic HF patients with NYHA functional class III symptoms and LVEF ≤40 % were randomised to VNS or continued medical therapy in a 3:2 ratio and were followed for a mean of 16 months. Four weeks after implantation, patients in the VNS group underwent stimulation intensity adjustment with a target of 3.5–5.5 mA. Figure 3 illustrates the position of this stimulation protocol in relation to the overall VNS response surface. While the secondary endpoint outcomes of NYHA functional class, QOL and 6MWT improved in the VNS group, the primary efficacy endpoint – a composite of death or HF hospitalisation and/or IV diuretic use – occurred more often in the VNS group than in the control group. The trial achieved the co-primary safety endpoint

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with a rate of freedom from procedure- and system-related events of 90.6 %. The study was negative in that VNS did not reduce the rate of death or HF events in chronic HF patients.

Spinal Cord Stimulation SCS is a Food and Drug Administration-approved therapy for chronic pain syndrome and refractory angina. High thoracic SCS has been used for the treatment of angina caused by coronary artery disease since the 1980s.43–47 Rather than being solely restricted to the spinal cord, SCS is now thought to act at multiple points within the cardiac neuraxis (Table 1).8,48 SCS suppresses the release of cardiac-related afferent neurotransmitters within the dorsal horn of the spinal cord, modulates sympathetic preganglionic neural activity, reduces

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Null HR Response "Neural Fulcrum"

-30 -45 -60

HR Reduction Zone

0.5 1.0 1.5 2.0 2.5 3.0 3.5 A)

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-50 -40 -30 -20 -10 0 30

0 -15

rum

lc l Fu

ura

As the baroreceptor reflex is involved in blood pressure regulation, BAT was developed as a potential treatment for resistant hypertension.60–63 Its utility has also been demonstrated in angina.64,65 Baroreceptors are stretch receptors located in the carotid sinus and aortic arch whose soma are contained within the petrosal and nodose ganglia, respectively. Baroreceptors transmit information regarding arterial pressure centrally (Figure 2). As part of a negative feedback reflex control mechanism, sympathetic and parasympathetic outflows are thereby modulated (Table 1). In HF, baroreceptor sensitivity is reduced with increased sympathetic activity, which may be mediated, in part, by elevated angiontensin II levels.16 Through electrical stimulation of the baroreceptor afferent fibres, central sympathetic outflow is reduced while parasympathetic tone is augmented.8,66 In that regard, in the Device-based Therapy in Hypertension Trial (DEBuT-HT), 45 patients with refractory hypertension undergoing implantation of a carotid stimulator Rheos® System (CVRx; Minneapolis, MN, USA) had significant blood pressure drop at 2-year follow-up.67

CardioFit & INOVATE-HF

HR Augmentation Zone

ity ns

Baroreflex Activation Therapy

NECTAR-HF 30

electrode lead Medtronic Model 3777/3877 (Medtronic; Minneapolis, MN, USA) was implanted in the epidural space with stimulation applied to levels T2–T4 at 50 Hz for 12 h/day. The primary objective of the study was to evaluate the LVESV index (LVESVi). At 6-month follow-up, there was no significant difference in LVESVi. As SCS exhibits a memory function of approximately 45 minutes for maintained efficacy in the offphase, future studies should restrict time of the off-phase to less than 1 hour to maximise the potential for effective control of the cardiac nervous system.59

ANTHEM-HF

Therapeutic Target Zone

Two clinical studies have evaluated the efficacy of SCS in HF. Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART) was a non-randomised, open-label pilot study of 22 patients with NYHA functional class III symptoms and LVEF 20–35 % with ICD on stable, optimal medical therapy with LVEDD of 55–80 mm.57 Seventeen patients underwent implantation of the Eon Mini™ Neurostimulation System (St Jude Medical; Plano, Texas, USA) at levels T1–3 with SCS parameters of 24 h/day, frequency of 50 Hz and pulse width of 200 µs. The primary efficacy endpoint was a composite of six parameters, of which there was significant improvement in NYHA class, QOL, peak maximum oxygen consumption, LVEF and LVESV but not in N-terminal prohormone- (NT pro-) BNP. In terms of safety, there were no deaths or device-device interactions at 6 months. The Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure (DEFEAT-HF) study was a prospective, multi-centre randomised, parallel, single-blind, controlled trial that included 81 patients with NYHA functional class III symptoms, LVEF ≤35 %, QRS duration <120 ms and LVEDD ≥55 mm.58 An eight-

Figure 3: Clinical Application of the Vagus Nerve Stimulation Neural Fulcrum

Heart rate (% change

sympatho-excitation within the intrathoracic extracardiac ganglia and blunts the intrinsic cardiac nervous system reflex response to cardiac stressors (Figure 2).49 SCS has additional cardioprotective effects including reducing arrhythmia burden and apoptosis, while improving contractile function.50–53 In a rabbit model of transient acute ischaemia, SCS reduces infarct size through inhibition of cardiac adrenergic neurons.54 In canine models of healed MI and pacinginduced HF, SCS improved contractile function and reduced the risk of ventricular arrhythmias, plasma brain natriuretic peptide (BNP) and norepinephrine levels.53,55 SCS has also been shown to improve contractile function and myocardial oxygen consumption in a porcine model of MI-induced HF.56

18 14 16 10 12 ) Z 8 (H y 6 uenc Freq RCV

Percent heart rate change during VNS active phase

The chronotropic response surface is plotted with the stimulation parameters used in the NEural Cardiac TherApy foR HF (NECTAR-HF) study, the Autonomic Neural Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) study and the INcrease Of VAgal TonE in Heart Failure (INOVATE-HF) trial. The yellow-shaded region on heart rate response surface approximates the neural fulcrum. HR = heart rate; VNS = vagus nerve stimulation; RCV = right cervical vagus. Adapted from Ardell et al., 2017 with permission.30

Preclinical studies in HF have produced proof-of-concept for BAT efficacy. In a canine model of MI-induced HF, BAT was shown to increase LVEF, reduce LVESV, LV end-diastolic pressure and circulating plasma norepinephrine, as well as normalising expression of cardiac beta1-receptors, beta-adrenergic receptor kinase and nitric oxide synthase.68 On histologic examination, there was reduced fibrosis and hypertrophy. BAT has also been shown to improve survival in a pacinginduced HF canine model.69 The first-in-man pilot study was a single-centre, open-label study involving 11 patients with NYHA functional class III symptoms, LVEF <40 % on optimal medical therapy and ineligible for cardiac resynchronisation therapy (CRT) who underwent BAT for 6 months.70 This study demonstrated safety with only one hospital- and procedurerelated complication of anaemia requiring transfusion with no further sequelae. Patients had reductions in muscle sympathetic nerve activity and improvement in baroreflex sensitivity, LVEF, NYHA class, QOL and 6MWT. In addition, there was a decreased rate of HF hospitalisations compared with the 12-month period prior to BAT system implantation. The Barostim neo system (CVRx), which has approval in Europe, has been evaluated in the Barostim Hope for Heart Failure (HOPE4HF) trial. This randomised controlled trial included 146 patients with NYHA functional class II symptoms and LVEF ≤35 %.71 Patients who underwent BAT improved in NYHA functional class, QOL, 6MWT, and had a reduction in NT pro-BNP. There was a trend towards reduction in HF hospitalisations. However, there were no changes in echocardiographic parameters, including LVEF. Given the evidence that CRT reduces the sympathovagal imbalance in HF, a subsequent analysis demonstrated that the most pronounced effect of BAT was in patients not treated with CRT.72,73 This study will be followed by the Baroreflex Activation Therapy® for Heart Failure BeAT-HF) trial, which seeks to randomise 480 patients with NYHA functional class III symptoms and LVEF ≤35 %. Primary outcomes will be cardiovascular and HF mortality and the

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Pathophysiology safety endpoint will be major adverse neurological and cardiovascular events at 6 months.

Renal Denervation RDN was initially evaluated in the context of refractory hypertension.74,75 Its efficacy is predicated on interrupting axons (afferent and efferent) projecting along renal arteries (Table 1). The electrode catheter is positioned just proximal to the origin of the second-order renal artery branch with four to eight lesions administered circumferentially along the length of each of the two arteries (Figure 2). Surgical RDN has been shown to have salutary effects in HF in rat and canine models.76–79 Following initially promising results in the Symplicity hypertension (Symplicity HTN-2) trial of catheter-based RDN in hypertension,74 RDN was evaluated in HF. The Renal Artery Denervation in Chronic Heart Failure-pilot (REACH-pilot) study demonstrated the safety of RDN in seven patients with HFrEF on optimal medical therapy and significantly improved 6MWT.80 The REACH study is an on-going prospective, double-blinded randomised study on the safety and effectiveness of RDN in 100 HFrEF patients. The Symplicity HF trial was a feasibility study that evaluated 39 patients with NYHA functional class II-III symptoms and LVEF <40 % on optimal medical therapy with mildly impaired renal function. In the study, one patient did experience renal artery occlusion that may have been related to the RDN procedure.81 The study showed significant reductions in NT pro-BNP without significant changes in LVEF, 6MWT, or estimated glomerular filtration rate. A major complication identified within the Symplicity trials was that substantial variability in efficacy was related to inadequate focus on the extent and verification of axon ablation from the renal artery. Future studies should be designed to assess efficacy at onset and during the course of therapy. A more recent pilot study randomised 60 HF patients with LVEF ≤40 % and NYHA functional class II–IV symptoms to RDN plus optimal medical therapy versus optimal medical therapy alone.82 No adverse effects were identified, and significant improvements were noted in the primary efficacy endpoint of LVEF at 6 months and in secondary endpoints of NYHA functional class, NT pro-BNP, heart rate and Short Form 36 health survey questionnaire in the RDN group.

Stellate Ganglionectomy Cardiac sympathetic denervation (CSD) via stellate ganglionectomy in cardiovascular disease was initially proposed as a treatment for angina in 1899 and has since demonstrated efficacy in reducing angina and ventricular arrhythmias.83–86 The procedure involves the removal of the lower half of the stellate ganglia through the T2–T4 thoracic ganglia as a means of disrupting afferent and sympathetic postganglionic efferent fibres to the heart. Left CSD (LCSD) has been most commonly

enjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and B Stroke Statistics–2018 Update: A Report From the American Heart Association. Circulation 2018;137:e67–e492. https://doi. org/10.1161/CIR.0000000000000558; PMID: 29386200. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292:344–50. https://doi.org/10.1001/ jama.292.3.344; PMID: 15265849. Mortara A, La Rovere MT, Pinna GD, et al. Arterial Baroreflex Modulation of Heart Rate in Chronic Heart Failure. Circulation 1997;96:3450. https://doi.org/10.1161/01.CIR.96.10.3450; PMID: 9396441. La Rovere MT, Bigger JT, Jr., Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998;351:478–84. https://doi.org/10.1016/S01406736(97)11144-8; PMID: 9482439. Nolan J, Batin PD, Andrews R, et al. Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure. Circulation 1998;98:1510. https://doi.org/10.1161/01.

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performed, although recent data suggest improved effectiveness in ventricular arrhythmia with bilateral approaches.84 A prospective, randomised pilot study has evaluated LCSD for HF.87 In this study, Conceição‐Souza et al. randomised 15 patients with LVEF ≤40 % in sinus rhythm with resting heart rate >65 BPM and on optimal medical therapy to continued medical therapy with left stellate ganglionectomy versus medical therapy alone. The study showed no complications attributed to the surgery and mild improvement in LVEF, 6MWT and Minnesota Living with Heart Failure Questionnaire. A large randomised study evaluating LCSD in systolic HF is currently enrolling.88

Challenges to Autonomic Therapies in Heart Failure Several challenges to neuromodulation in HF help explain why success in preclinical studies has not translated into clinical benefit in human studies. In particular, just as target dosing of oral medications is critical in conventional therapy for HF, so too are the bioelectric stimulation parameters and protocols. Many trials employed distinct stimulation parameters with respect to frequency, current pulse width and duty cycle, often with minimal mechanistic justification. Cardiac disease is a dynamic process; neuromodulation is too. As a patient’s sympathovagal balance shifts during the course of the disease process, changes in stimulation parameters may be warranted. It is much more than ‘set and forget’. Future studies should also consider relevant biomarkers in assessing engagement of the neural elements and the effects on end-organ function. With such biomarkers, the potential for effective closed-loop systems can become a reality. Autonomic imbalance plays a crucial role in the pathophysiology of HF. While pharmacologic therapies affect the ANS, limited effectiveness with these approaches has led to interest in applying neuromodulation to HF treatment. VNS has been the most extensively studied modality and the clinical trials have had mixed results, although with the caveat that stimulation parameters may not have been appropriate. Clinical studies in SCS and RDN have had similarly variable results so far. BAT has shown some promise in a pilot study, and we look forward to the results from an on-going clinical trial regarding its efficacy. Neurovisceral science holds great promise in emerging therapies for myriad disease states. To move forwards, it is crucial to understand the structure and function of the ANS and the organs that it targets. It is with anticipation that we await critical aspects of this puzzle. Its various components are being revealed by programmes such as the National Institutes of Health (NIH) – Stimulating Peripheral Activity to Relieve Conditions (SPARC) portfolio, a programme committed to furthering knowledge of nerve-organ interactions and advancing development of neuromodulatory approaches for disease treatment. n

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J Clin Invest 2007;117:289–96. https://doi.org/10.1172/JCI30555; PMID: 17273548. 26. Zhang Y, Popović ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail 2009;2:692–9. https://doi.org/10.1161/CIRCHEARTFAILURE.109.873968; PMID: 19919995. 27. Beaumont E, Southerland EM, Hardwick JC, et al. Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction. Am J Physiol Heart Circ Physiol 2015;309:H1198–206. https://doi.org/10.1152/ ajpheart.00393.2015; PMID: 26276818. 28. Beaumont E, Wright GL, Southerland EM, et al. Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig. Am J Physiol Heart Circ Physiol 2016;310:H1349–59. https://doi.org/10.1152/ ajpheart.00939.2015; PMID: 26993230. 29. Ando M, Katare RG, Kakinuma Y, et al. Efferent vagal nerve stimulation protects heart against ischemiainduced arrhythmias by preserving connexin43 protein. Circulation 2005;112:164–70. https://doi.org/10.1161/ CIRCULATIONAHA.104.525493; PMID: 15998674. 30. Ardell JL, Nier H, Hammer M, et al. Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control. J physiol 2017;595:6887–903. https://doi.org/10.1113/JP274678; PMID: 28862330. 31. Hill M, Wallick D, Martin PJ, Levy MN. Effects of repetitive vagal stimulation on heart rate and on cardiac vasoactive intestinal polypeptide efflux. Am J Physiol 1995;268:H1939– H46. https://doi.org/10.1152/ajpheart.1995.268.5.H1939; PMID: 7771543. 32. Hill MR, Wallick DW, Martin PJ, Levy MN. Frequency dependence of vasoactive intestinal polypeptide release and vagally induced tachycardia in the canine heart. J Auton Nerv Syst 1993;43:117–22. https://doi.org/10.1016/01651838(93)90348-X; PMID: 8326095. 33. Ardell JL, Rajendran PS, Nier HA, et al. Central-peripheral neural network interactions evoked by vagus nerve stimulation: functional consequences on control of cardiac function. Am J Physiol Heart Circ Physiol 2015;309:H1740–H52. https://doi.org/10.1152/ajpheart.00557.2015; PMID: 26371171. 34. Yamakawa K, Rajendran PS, Takamiya T, et al. Vagal nerve stimulation activates vagal afferent fibers that reduce cardiac efferent parasympathetic effects. Am J Physiol Heart Circ Physiol 2015;309:H1579–H90. https://doi.org/10.1152/ ajpheart.00558.2015; PMID: 26371172. 35. Vanoli E, De Ferrari GM, Stramba-Badiale M, et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68:1471–81. https://doi.org/10.1161/01.RES.68.5.1471; PMID: 2019002. 36. Li M, Zheng C, Sato T, et al. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 2004;109:120–4. https://doi.org/10.1161/01. CIR.0000105721.71640.DA; PMIS: 14662714. 37. Premchand RK, Sharma K, Mittal S, et al. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail 2014;20:808–16. https://doi. org/10.1016/j.cardfail.2014.08.009; PMID: 25187002.

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38. P remchand RK, Sharma K, Mittal S, et al. Extended FollowUp of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study. J Card Fail 2016;22:639–42. https://doi.org/10.1016/j.cardfail.2015.11.002; PMID: 26576716. 39. DiCarlo LA, Libbus I, Kumar HU, et al. Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study. ESC Heart Fail 2018;5:95– 100. https://doi.org/10.1002/ehf2.12241; PMID: 29283224. 40. Zannad F, De Ferrari GM, Tuinenburg AE, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J 2015;36:425–33. https://doi.org/10.1093/eurheartj/ehu345; PMID: 25176942. 41. De Ferrari GM, Stolen C, Tuinenburg AE, et al. Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. Int J Cardiol 2017;244:229–34. https://doi.org/10.1016/j. ijcard.2017.06.036; PMID: 28663046. 42. Gold MR, Van Veldhuisen DJ, Hauptman PJ, et al. Vagus Nerve Stimulation for the Treatment of Heart Failure: The INOVATE-HF Trial. J Am Coll Cardiol 2016;68:149–58. https://doi. org/10.1016/j.jacc.2016.03.525; PMID: 27058909. 43. Jessurun GA, DeJongste MJ, Hautvast RW, et al. Clinical follow‐ up after cessation of chronic electrical neuromodulation in patients with severe coronary artery disease: a prospective randomized controlled study on putative involvement of sympathetic activity. Pacing Clin Electrophysiol 1999;22:1432–9. https://doi.org/10.1111/j.1540-8159.1999.tb00346.x; PMID: 10588144. 44. Fanciullo GJ, Robb JF, Rose RJ, Sanders JH. Spinal cord stimulation for intractable angina pectoris. Anesth Analg1999;89:305–6. https://doi.org/10.1097/00000539199908000-00009; PMID: 10439736. 45. Brodison A, Chauhan A. Spinal-cord stimulation in management of angina. Lancet 1999;354:1748–9. https://doi. org/10.1016/S0140-6736(99)00296-2; PMID: 10577633. 46. Murphy DF, Giles KE. Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 1987;28:365–8. https:// doi.org/10.1016/0304-3959(87)90070-4; PMID: 3494978. 47. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci 2008;138:9–23. https://doi.org/10.1016/j.autneu.2007.11.001; PMID: 18083639. 48. Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. Int Rev Neurobiol 2012;107:87–119. https://doi. org/10.1016/B978-0-12-404706-8.00006-1; PMID: 23206679. 49. Ardell JL. Mechanisms of spinal cord neuromodulation for heart disease. Nat Rev Cardiol 2016;13:127–8. https://doi. org/10.1038/nrcardio.2016.8; PMID: 26843288. 50. Ardell JL, Cardinal R, Beaumont E, et al. Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation. Auton Neurosci 2014;186:38–44. https://doi.org/10.1016/j.autneu.2014.09.017; PMID: 25301713. 51. Gibbons DD, Southerland EM, Hoover DB, et al. Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias. Am J Physiol Regul Integr Comp Physiol 2012;302:R357–R64. https://doi.org/10.1152/ ajpregu.00535.2011; PMID: 22088304. 52. Southerland EM, Gibbons DD, Smith SB, et al. Activated cranial cervical cord neurons affect left ventricular infarct size and the potential for sudden cardiac death. Auton Neurosci 2012;169:34–42. https://doi.org/10.1016/j.autneu.2012.03.003; PMID: 22502863. 53. Lopshire JC, Zhou X, Dusa C, et al. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation 2009;120:286–94. https://doi.org/10.1161/ CIRCULATIONAHA.108.812412; PMID: 19597055. 54. Southerland EM, Milhorn DM, Foreman RD, et al. Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic neurons. Am J Physiol Heart Circ Physiol 2007;292:H311–H7. https://doi.org/10.1152/ ajpheart.00087.2006; PMID: 16920800. 55. Issa ZF, Zhou X, Ujhelyi MR, et al. Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a postinfarction heart failure canine model. Circulation 2005;111:3217–20. https://doi.org/10.1161/ CIRCULATIONAHA.104.507897; PMID: 15956128. 56. Liu Y, Yue W-S, Liao S-Y, et al. Thoracic Spinal Cord Stimulation Improves Cardiac Contractile Function and Myocardial Oxygen Consumption in a Porcine Model of Ischemic Heart Failure. J Cardiovasc Electrophysiol 2012;23:534–40. https://doi. org/10.1111/j.1540-8167.2011.02230.x; PMID: 22151312. 57. Tse HF, Turner S, Sanders P, et al. Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART study): first-in-man experience. Heart rhythm 2015;12:588–95. https://doi.org/10.1016/j.hrthm.2014.12.014; PMID: 25500165. 58. Zipes DP, Neuzil P, Theres H, et al. Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure: The DEFEAT-HF Study. JACC Heart Fail 2016;4:129–36. https://doi.org/10.1016/j.jchf.2015.10.006; PMID: 26682789. 59. Armour J, Linderoth B, Arora R, et al. Long-term modulation of the intrinsic cardiac nervous system by spinal cord

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neurons in normal and ischaemic hearts. Auton Neurosci 2002;95:71–9. https://doi.org/10.1016/S1566-0702(01)00377-0. PMID: 11873770. Krum H, Sobotka P, Mahfoud F, Böhm M, Esler M, Schlaich M. Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system. Circulation 2011;123:209–15. https://doi.org/10.1161/ CIRCULATIONAHA.110.971580; PMID: 21242507. Heusser K, Tank J, Engeli S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 2010;55:619–26. https://doi.org/10.1161/ HYPERTENSIONAHA.109.140665; PMID: 20101001. Neistadt A, Schwartz SI. Effects of electrical stimulation of the carotid sinus nerve in reversal of experimentally induced hypertension. Surgery 1967;61:923–31. PMID: 6026140. Schwartz SI, Griffith LS, Neistadt A, Hagfors N. Chronic carotid sinus nerve stimulation in the treatment of essential hypertension. Am J Surg 1967;114:5–15. https://doi. org/10.1016/0002-9610(67)90034-7; PMID: 6026450. Braunwald E, Epstein SE, Glick G, et al. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. N Engl J Med 1967;277:1278–83. https://doi.org/10.1056/ NEJM196712142772402; PMID: 5299662. Epstein SE, Beiser GD, Goldstein RE, et al. Treatment of angina pectoris by electrical stimulation of the carotidsinus nerves: Results in 17 patients with severe angina. N Engl J Med 1969;280:971–8. https://doi.org/10.1056/ NEJM196905012801801; PMID: 4888077. Grassi G, Seravalle G, Quarti-Trevano F, et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53:205–9. https://doi.org/10.1161/HYPERTENSIONAHA.108.121467; PMID: 19124679. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–8. https://doi.org/10.1016/j.jacc.2010.03.089; PMID: 20883933. Sabbah HN, Gupta RC, Imai M, et al. Chronic Electrical Stimulation of the Carotid Sinus Baroreflex Improves Left Ventricular Function and Promotes Reversal of Ventricular Remodeling in Dogs With Advanced Heart Failure. Circ Heart Fail 2011;4:65–70. https://doi.org/10.1161/CIRCHEARTFAILURE.110.955013; PMID: 21097604. Zucker IH, Hackley JF, Cornish KG, et al. Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure. Hypertension 2007;50:904–10. https://doi.org/10.1161/HYPERTENSIONAHA.107.095216; PMID: 17846349. Gronda E, Seravalle G, Brambilla G, et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail 2014;16:977–83. https://doi.org/10.1002/ejhf.138; PMID: 25067799. Abraham WT, Zile MR, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction. JACC Heart Fail 2015;3:487–96. https://doi. org/10.1016/j.jchf.2015.02.006; PMID: 25982108. Zile MR, Abraham WT, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail 2015;17:1066–74. https://doi.org/10.1002/ejhf.299; PMID: 26011593. DeMazumder D, Kass DA, O’Rourke B, Tomaselli GF. Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling. Circ Res 2015;116:1691–9. https://doi.org/10.1161/ CIRCRESAHA.116.305268; PMID: 25733594. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903–9. https://doi.org/10.1016/S01406736(10)62039-9; PMID: 21093036. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81. https://doi.org/10.1016/S01406736(09)60566-3; PMID: 19332353. Dibona GF, Sawin LL. Role of renal nerves in sodium retention of cirrhosis and congestive heart failure. Am J Physiol 1991;260:R298–R305. https://doi.org/10.1152/ ajpregu.1991.260.2.R298; PMID: 1996717. Villarreal D, Freeman RH, Johnson RA, Simmons JC. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol 1994;266:R1599– R604. https://doi.org/10.1152/ajpregu.1994.266.5.R1599; PMID: 8203638. Nozawa T, Igawa A, Fujii N, et al. Effects of long-term renal sympathetic denervation on heart failure after myocardial infarction in rats. Heart Vessels 2002;16:51–6. https://doi. org/10.1007/s380-002-8317-8; PMID: 11833842. Souza D, Mill J, Cabral A. Chronic experimental myocardial infarction produces antinatriuresis by a renal nervedependent mechanism. Braz J Med Biol Res 2004;37:285–93. https://doi.org/10.1590/S0100-879X2004000200017; PMID: 14762585.

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Pathophysiology 80. D avies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol 2013;162:189–92. https://doi.org/10.1016/j.ijcard.2012.09.019; PMID: 23031283. 81. Hopper I, Gronda E, Hoppe UC, et al. Sympathetic response and outcomes following renal denervation in patients with chronic heart failure: 12-month outcomes from the SYMPLICITY HF Feasibility Study. J Card Fail 2017;23:702–7. https://doi.org/10.1016/j.cardfail.2017.06.004; PMID: 28645757. 82. Chen W, Ling Z, Xu Y, et al. Preliminary effects of renal denervation with saline irrigated catheter on cardiac systolic function in patients with heart failure: a prospective,

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randomized, controlled, pilot study. Catheter Cardiovasc Interv 2017;89:E153–E61. https://doi.org/10.1002/ccd.26475; PMID: 27143319. 83. Jonnesco T. Angine de poitrine gukrie par la resection du sympathique cervico‐thoracique. Bull Acad Med. 1920;84:1920. 84. Vaseghi M, Barwad P, Corrales FJM, et al. Cardiac sympathetic denervation for refractory ventricular arrhythmias. J Am Coll Cardiol 2017;69:3070–80. https://doi. org/10.1016/j.jacc.2017.04.035; PMID: 28641796. 85. Schwartz PJ, Snebold NG, Brown AM. Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol 1976;37:1034–40. https:// doi.org/10.1016/0002-9149(76)90420-3; PMID: 1274864.

86. F rancois-Franck C. Signification physiologique de la résection du sympathique dans la maladie de Basedow, l’épilepsie, l’idiotie et le glaucome. Bull Acad Med Paris. 1899;41:565–94. 87. Conceição‐Souza GE, Pêgo‐Fernandes PM, Cruz FdD, et al. Left cardiac sympathetic denervation for treatment of symptomatic systolic heart failure patients: a pilot study. Eur J Heart Fail 2012;14:1366–73. https://doi.org/10.1093/ eurjhf/hfs132; PMID: 23099357. 88. Chin A, Ntsekhe M, Viljoen C, et al. Rationale and design of a prospective study to assess the effect of left cardiac sympathetic denervation in chronic heart failure. Int J Cardiol 2017;248:227–31. https://doi.org/10.1016/j.ijcard.2017.08.012; PMID: 28864134.

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Therapy

Metabolic Modulation of Cardiac Metabolism in Heart Failure Giuseppe MC Rosano and Cristiana Vitale Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy

Abstract Heart failure (HF) is associated with metabolic changes that cause a progressive impairment of cardiac and skeletal muscle high-energy phosphate production. As a consequence of the impaired cardiac metabolism, other processes are activated in the failing heart that further exacerbate the progression of HF. The reduced production of high-energy phosphates has important implications for both systole and diastole in HF with both preserved and reduced left ventricular function. The aim of this review is to summarise the state-of-the-art on metabolic therapy in HF with a particular focus on trimetazidine. Metabolic agents optimise cardiac substrate metabolism without exerting negative haemodynamic effects. In particular, as studies with metabolic agents modulating cardiac metabolism have consistently demonstrated, this approach is effective in improving symptoms, functional capacity and prognosis in people with HF when added to optimal medical therapy. Therefore, the modulation of cardiac metabolism is an important therapeutic approach to the treatment of HF, especially in patients where it is of ischaemic or metabolic origin. Although further studies are needed, metabolic agents might be a new, effective strategy for the treatment of HF.

Keywords Heart failure, metabolism, cardiac metabolism, pharmacology, treatment, prognosis Disclosure: The authors have no conflicts of interest to declare. Received: 12 April 2018 Accepted: 15 July 2018 Citation: Cardiac Failure Review 2018;4(2):99–103. DOI: https://doi.org/10.15420/cfr.2018.18.2 Correspondence: Cristiana Vitale, Centre for Clinical & Basic Research IRCCS San Raffaele Pisana, via della Pisana, 235, 00163 Rome, Italy. E: giuseppe.rosano@gmail.com

Heart failure (HF) affects 1–2 % of the population in developed countries and absorbs a significant amount of human and economic resources.1–3 It is a complex syndrome, characterised by a spectrum of symptoms and signs ranging from minimal loss of normal functional capacity to more severe symptoms refractory to medical therapy. It may be associated with different aetiologies and varying degrees of systolic and/or diastolic cardiac impairment. Recently, understanding of the complex metabolic processes associated with the development of HF has been growing.4 As a consequence, HF is now understood to be a systemic, multi-organ syndrome with metabolic failure the basic mechanism. The failing heart may be defined as ‘an engine out of fuel’.5 Metabolic derangement in HF is not limited to the myocardium but extends to the skeletal muscles and contributes to the deterioration of exercise capacity in these patients, who can experience muscle weakness, fatigue, exercise limitation and dyspnoea, and to disease progression.4 This review will examine the role of metabolic abnormalities in HF and their therapeutic implications, with a focus on the only drug currently available worldwide.

Metabolic Processes in the Normal and Failing Heart At rest, free fatty acid oxidation is the major source of energy for the myocardium. Up to 80 % of high-energy phosphates at rest are produced by the oxidation of free fatty acids. Glucose metabolism provides the remaining quantity of energy. The heart stores

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glucose as glycogen to be used during increased metabolic demands since glucose utilisation is 20–30 % more metabolic efficient than free fatty acid oxidation in producing high-energy phosphates per mole O2.6 At rest, the myocardium uses 15–20 % of its maximal oxidative capacity and adapts substrate utilisation during increased demand.6 A net increase in glucose and lactate uptake and utilisation without change in free fatty acid metabolism has been demonstrated during low to moderate intensity exercise.7–9 However, when the metabolic requirements of the myocardium exceed the limits of its metabolic reserve, an aerobic limit is reached. This threshold is higher when glucose is used as substrate rather than fatty acids. Maladaptive energetics play an important role in the pathophysiology of the failing heart. HF is a ketosis-prone state as blood ketone bodies are increased in this syndrome. Blood ketone bodies and free fatty acid levels are higher during fasting and remain higher after glucose infusion in patients with chronic HF than controls.10 The blood levels of blood ketone bodies are related to the severity of cardiac dysfunction and neurohormonal activation in HF.11 A possible cause for these metabolic derangements in HF is myocardial insulin resistance that develops early in HF which limits the utilisation of glucose and favours the increased utilisation of free fatty acids for ketogenesis. All these changes lead to a reduction in the production of high-energy phosphates and therefore to a metabolically inefficient heart.

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Therapy Figure 1: Cardiac Metabolism Pathways Lactate

Nonesterified fatty acids

Glucose

Cell membrane

Lactate

GLYCOLYSIS

Cytosol Fatty Acyl-CoA

Pyruvate Outer mitochondrial membrane

CPT–I Fatty acyl-carnitine CAT

Inner mitochondrial membrane

NAD+ + CoA-SH PDH

CPT–II Fatty Acyl-CoA

NADH

Mitochondrial matrix

Acetyl-CoA

Fatty acid beta-oxidation

CO2

Citric acid cycle

Cardiac metabolism showing the different metabolic pathways of glucose and non-esterified fatty acids in the cytosol and at the mitochondria level.

Therefore, in HF metabolic changes add to the main causes of the disease favouring its progression and reducing functional capacity. In some conditions, such as diabetes, metabolic derangements leading to inefficient production of high-energy phosphates may constitute the main cause of the disease and may also be responsible for the altered diastolic function observed in most patients with HF with preserved ejection fraction. Other metabolic abnormalities, ranging from testosterone deficiency to a metabolic shift favouring catabolism and impairment in skeletal muscle mass and function, occur in patients with HF and may heighten the metabolic changes occurring in the glycolytic pathway.12 Changes in glucose utilisation lead to a deficiency in high-energy phosphate availability and reserve, and impaired contractility and relaxation.13 Furthermore, other processes, such as structural remodelling and oxidative stress, are also activated as a consequence of the metabolic derangements. All these metabolic alterations are defined as ‘metabolic remodelling’, i.e. remodelling of cardiac energy metabolism, which causes a decrease in energy production and a switch in energy substrate use. Therefore, metabolic remodelling contributes to the progression of HF and to it becoming worse causing progressive loss of myofibrillar content and shape and size of mithocondria (Figure 1).14,15 The reduction in skeletal and cardiac muscle production of high-energy phosphates leads to a progressive decline in both diastolic and systolic function and to the progression of left ventricular remodelling in a metabolic vicious circle.14 The metabolic changes induce maladaptive cellular changes, with decreases in mitochondrial cristae, cellular size, myofibrillar content and actino-myosin coupling. Therefore, interventions aimed at improving cardiac and skeletal muscle metabolism by optimising cardiac metabolism and improving high-energy phosphate production may be a complementary effective approach to the treatment of HF.16

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Treatment of HF with Metabolic Agents Neurohormonal antagonists, such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers or mineralocorticoid receptor antagonists, should be used to modify the progression of systolic dysfunction and to improve the prognosis of patients with chronic HF.17 Diuretics are used in combination with these drugs to relieve symptoms and signs of congestion. However, despite advances in pharmacotherapy for HF with newer drugs such as ivabradine and sacubitril/valsartan, the prognosis of patients with HF remains poor. Cardiac inotropes that increase cardiac energy consumption have been found to have negative effects on long-term prognostis. These effects may be related to the exhaustion of high-energy phosphates leading to an insufficient handling of Ca2+ favouring arrhythmias. The modulation of cardiac metabolism with drugs to promote the preferential use of glucose and non-free fatty acid substrates by the mitochondria to increase metabolic efficiency and function of the failing heart was proposed in the late 1990s. However, only recently has enough clinical evidence accumulated to support the rationale and use of this.6 Several agents able to interfere with cardiac metabolism have been proposed in previous decades but, among all the proposed agents, only trimetazidine and perhexiline have been approved for human use. These two drugs, initially approved for the treatment of angina pectoris and myocardial ischaemia, both directly inhibit myocardial fatty acid oxidation and improve regional and global myocardial function. 18 However, while trimetazidine is available worldwide (except in the US where its dossier has never been submitted), carnitine palmitoyltransferase (CPT) inhibitor perhexiline is not available in most countries amid doubts over its safety

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Role of Trimetazidine in Heart Failure profile, although there is growing evidence of its efficacy in HF.19,20 Both drugs directly inhibit FFA oxidation by blocking 3-ketoacylcoenzyme A thiolase (3-KAT), which shifts energy production from FFA to glucose oxidation. Several studies have shown the benefits of these compounds on myocardial function in patients with ischaemic and non-ischaemic HF.16

Figure 2. Cardiac Histology in HF with Reduced Ejection Fraction

Trimetazidine has been more extensively studied in HF. The beneficial effects of trimetazidine in HF are related to improved of phosphocreatine (PCr) and ATP intracellular levels. This is of particular relevance as PCr/ATP levels are a significant predictor of mortality in HF.16 Indeed, trimetazidine has been shown to improve prognosis in patients with HF and reduced ejection fraction in a multicentre retrospective cohort study and in four meta-analyses.21 On this basis, its use in patients with HF has been advocated by many authors and it is supported by current guidelines.16

Efficacy of Metabolic Modulation in HF The beneficial effect of metabolic modulation of cardiac metabolism in HF has been attributed to the shift of energy production from free fatty acid oxidation to glucose oxidation, which leads to increased production of high-energy phosphates and therefore to greater cardiac and skeletal muscle efficiency.22 The metabolic modulation through inhibition of free fatty acid metabolism is associated with an improvement of the cardiac phosphocreatine:ATP ratio by 33 %, which translates into a parallel increase of left ventricular function. This effect is associated with a reduction in the whole-body rate of energy expenditure, which suggests that the effect may be mediated by decreased metabolic demands in peripheral tissues. The decreased peripheral metabolic demands are the consequence of a greater muscular metabolic efficiency leading to reduced oxygen consumption per any given level of exercise. It has been shown that free fatty acid inhibition improves functional capacity and muscular strength in patients with HF, suggesting an effect that goes beyond the modulation of cardiac metabolism.23–32 Several clinical trials have demonstrated that metabolic modulation through inhibition of free fatty acid metabolism improves New York Heart Association (NYHA) HF class, exercise tolerance, quality of life, left ventricular ejection fracture and cardiac volumes in patients with ischaemic and non-ischaemic HF.23–34 More recently, studies have shown that optimising cardiac metabolism with trimetazidine may improve the prognosis of patients with HF. Randomised clinical trials demonstrated the effect of metabolic modulation of cardiac metabolism added to conventional therapy in improving functional class, left ventricular end-systolic volume and ejection fraction in patients with HF of various origins. An international multicentre cohort study on 669 patients with chronic HF21 has shown that the adjunct of trimetazidine to conventional therapy is effective in reducing mortality and hospitalisations, and improves long-term survival in people with HF. However, further prospective trials that are adequately powered to specifically look at mortality are needed. Four meta-analyses of the available randomised controlled trials have consistently shown that trimetazidine ameliorates cardiac function for ischaemic and non-ischaemic HF, reduces mortality, cardiovascular events and hospitalisation.35–41 The first meta-analysis pooled data from 17 RCTs, which included 955 patients with HF and found that treatment with trimetazidine is

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Note myofibrillar content, glycogen accumulation, small rounded mitochondria with reduced cristae and irregular nuclear envelopes.

associated with NYHA class reduction, increased exercise tolerance and improvement of LVEF in patients with HF of both ischaemic and nonischaemic aetiology. The analysis found that the use of trimetazidine reduces rates of cardiovascular events and hospitalisations as well as all-cause mortality in patients with HF. In a second meta-analysis performed by Zhang et al., based on data from 16 RCTs with 884 patients with HF, trimetazidine was shown to improve NYHA class, increase exercise tolerance, improve LVEF and decrease left ventricular end-systolic and end-diastolic diameters; trimetazidine also reduced rates of hospitalisation but not all-cause mortality. An updated meta-analysis by Zhou and Chen that included data from 994 patients with HF from 19 RCTs confirmed the improvement in NYHA class, cardiac volumes and LVEF in patients treated with trimetazidine. This analysis confirmed the reduction in the rate of hospitalisations for HF. More recently, Grajek and Michalak conducted a meta-analysis assessing the effect of trimetazidine on all-cause mortality rates in patients with HF. They included 326 patients from three RCTs who received trimetazidine in addition to standard pharmacological therapy

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Therapy for HF and found a significant reduction in all-cause mortality rate among patients receiving trimetazidine. Because of the clinical evidence on its efficacy, trimetazidine has been included in the ESC/HFA 2016 guidelines for the treatment of HF with reduced ejection fraction for patients with HF of ischaemic aetiology; it is used as add-on to an ACE inhibitor (or an angiotensin receptor blocker if ACE inhibitors are not tolerated), a beta-blocker and a mineralocorticoid receptor antagonist. Finally, new metabolic agents are emerging as promising therapeutic candidates for HF, as reviewed in detail elsewhere.42 Briefly, there is evidence on efficacy and good tolerability of istaroxime, a drug with lusitropic and inotropic digoxin-like properties, in a phase II clinical trial (HORIZON–HF)43 on patients with HF and reduced ejection fraction. Another compound, omecamtiv mecarbil, a direct activator of myocardial myosin ATPase, has been shown in a clinical trial (ATOMIC–AHF)44 to increase systolic ejection time with good safety; it is being tested in an international multicentre phase III clinical study to test its efficacy in reducing cardiovascular events.

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v an Riet EE, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail 2016;18(3):242–52. https://doi.org/10.1002/ejhf.483. PMID:26727047. Targher G, Dauriz M, Laroche C, et al. In-hospital and 1–year mortality associated with diabetes in patients with acute heart failure: results from the ESC–HFA Heart Failure LongTerm Registry. Eur J Heart Fail 2017;19(1):54–65. https://doi. org/10.1002/ejhf.679. PMID:27790816. 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; PMCID:PMC3033496. Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol 2014;64:1388–1400. https://doi.org/10.1016/j. jacc.2014.04.083. PMID:25257642. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med 2007;356:1140–51. https://doi.org/10.1056/NEJMra063052. PMID:17360992. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 2014;171:2080–90. https://doi.org/10.1111/bph.12475. PMID:24147975; PMCID:PMC3976623. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 1988;82:2017–25. https://doi.org/10.1172/JCI113822. PMID:3198763 PMCID:PMC442784. Abozguia K, Shivu GN, Ahmed I, et al. The heart metabolism: pathophysiological aspects in ischaemia and heart failure. Curr Pharm Des 2009;15:827–35. https://doi. org/10.2174/138161209787582101. PMID:19275646. Weber KT, Janicki JS. The metabolic demand and oxygen supply of the heart: physiologic and clinical considerations. Am J Cardiol 1979;44:722–9. https://doi.org/10.1016/00029149(79)90294-7. PMID: 484502. Lommi J, Koskinen P, Naveri H, et al. Heart failure ketosis. J Intern Med 1997;242:231–8. https://doi.org/10.1046/j.13652796.1997.00187.x. PMID:9350168. Lommi J, Kupari M, Koskinen P, et al. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol 1996;28:665–72. https://doi.org/10.1016/0735-1097(96)00214-8. PMID: 8772754. Nagoshi T, Yoshimura M, Rosano GM, et al. Optimization of cardiac metabolism in heart failure. Curr Pharm Des 2011;17(35):3846–53. https://doi. org/10.2174/138161211798357773. PMID:21933140; PMCID:PMC3271354. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 2013;113:709–24. https://doi.org/10.1161/ CIRCRESAHA.113.300376. PMID:23989714; PMCID:PMC3896379. Heusch G, Libby P, Gersh B, et al. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 2014;383:1933–43. https://doi.org/10.1016/S01406736(14)60107-0. PMID: 24831770; PMCID: PMC4330973. Lopaschuk GD, Ussher JR, Folmes CD, et al. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90:207–58. https://doi.org/10.1152/physrev.00015.2009. PMID:20086077.

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Conclusions HF is associated with a maladaptive cardiac metabolism that impairs cardiac function. Understanding the role of cardiac metabolism in HF will open new therapeutic avenues for patients.39-40 Modulation of cardiac metabolism may be especially beneficial in patients with altered glucose metabolism, where the systemic metabolic derangements have profound effect on myocardial function, increasing the risk of HF and its mortality.41 n

Clinical Perspective • H eart failure is associated with maladaptive cardiac metabolism. • Cardiac metabolism in heart failure is shifted towards the use of less energy-efficient free fatty acids. • Improvement of glucose utilisation by the cardiac cells is associated with improved cardiac function. • Modulation of cardiac metabolism improves left ventricular function and exercise capacity in heart failure.

16. F ragasso G. Deranged cardiac metabolism and the pathogenesis of heart failure. Cardiac Fail Rev 2016;2(1):8–13. https://doi.org/10.15420/cfr.2016:5:2. PMID:28785448; PMCID:PMC5490933. 17. 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 J Heart Fail 2016;18(8):891–975. https://doi.org/10.1002/ejhf.592. PMID:27207191. 18. Lionetti V, Stanley WC, Recchia FA. Modulating fatty acid oxidation in heart failure. Cardiovasc Res 2011;90:202–9. https://doi.org/10.1093/cvr/cvr038. PMID:21289012; PMCID:PMC3078800. 19. Beadle RM, Williams LK, Kuehl M, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail 2015; 3(3):202–11. https://doi.org/10.1016/j.jchf.2014.09.009. PMID: 25650370. 20. Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation 2005;112:3280–8. https://doi. org/10.1161/CIRCULATIONAHA.105.551457. PMID:16301359. 21. Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol 2013;163:320–5. https://doi.org/10.1016/j.ijcard.2012.09.123. PMID:23073279. 22. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580–8. https://doi.org/10.1161/01.RES.86.5.580. PMID:10720420. 23. Vitale C, Wajngaten M, Sposato B, et al. Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J 2004;25:1814– 21. https://doi.org/10.1016/j.ehj.2004.06.034. PMID:15474696. 24. Khan M, Meduru S, Mostafa M, et al. Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. J Pharmacol Exp Ther 2010;333:421–9. https://doi.org/10.1124/ jpet.109.165175. PMID:20167841 PMCID:PMC2872960. 25. Brottier L, Barat JL, Combe C et al. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J 1990;11:207–12. https://doi. org/10.1093/oxfordjournals.eurheartj.a059685. PMID:2318223. 26. Fragasso G, Piatti Md PM, Monti L et al. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J 2003;146:E18. https://doi.org/10.1016/S0002-8703(03)00415-0. PMID: 14597947. 27. Lu C, Dabrowski P, Fragasso G, Chierchia SL. Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol 1998;82:898–901. https://doi.org/10.1016/S00029149(98)00500-1. PMID: 9781975. 28. Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left ventricular function in diabetic

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patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16. https://doi.org/10.1186/1475-2840-2-16. PMID:14641923; PMCID:PMC305354. Fragasso G, Palloshi A, Puccetti P et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol 2006;48:992–8. https://doi.org/10.1016/j.jacc.2006.03.060. PMID:16949492. Di Napoli P, Di Giovanni P, Gaeta MA et al. Beneficial effects of trimetazidine treatment on exercise tolerance and B-type natriuretic peptide and troponin T plasma levels in patients with stable ischemic cardiomyopathy. Am Heart J 2007;154(3):602 e1–5. https://doi.org/10.1016/j. ahj.2007.06.033. PMID: 17719313. Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart 2005;91:161–5. https://doi.org/10.1136/hrt.2003.031310. PMID:15657223; PMCID:PMC1768679. Belardinelli R, Purcaro A. Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001;22:2164–70. https://doi.org/10.1053/ euhj.2001.2653. PMID:11913478. Ferraro E, Giammarioli AM, Caldarola S et al. The metabolic modulator trimetazidine triggers autophagy and counteracts stress-induced atrophy in skeletal muscle myotubes. FEBS J. 2013;280:5094–108. https://doi.org/10.1111/febs.12484. PMID:23953053. Belardinelli R, Lacalaprice F, Faccenda E, Volpe L. Trimetazidine potentiates the effects of exercise training in patients with ischemic cardiomyopathy referred for cardiac rehabilitation. Eur J Cardiovasc Prev Rehabil 2008;15:533–40. https://doi.org/10.1097/HJR.0b013e328304feec. PMID:18797405. Gao D, Ning N, Niu X et al. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart 2011;97:278–86. https://doi.org/10.1136/hrt.2010.208751. PMID:21134903. Zhang L, Lu Y, Jiang H et al. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol 2012;59:913–22. https://doi.org/10.1016/j. jacc.2011.11.027. PMID:22381427. Zhou X, Chen J. Is treatment with trimetazidine beneficial in patients with chronic heart failure? PLoS ONE 2014;9:e94660. https://doi.org/10.1371/journal.pone.0094660. PMID: 24797235; PMCID: PMC4010408. Grajek S, Michalak M. The effect of trimetazidine added to pharmacological treatment on all-cause mortality in patients with systolic heart failure. Cardiology 2015;131:22–9. https://doi. org/10.1159/000375288. PMID:25832112. Milinković I, Rosano G, Lopatin Y, Seferović PM. The Role of ivabradine and trimetazidine in the new ESC HF guidelines. Card Fail Rev 2016;2(2):123–9. PMID:28785466. PMCID:PMC5490945. Lopatin Y. Metabolic therapy in heart failure. Card Fail Rev 2015;1(2):112–17. https://doi.org/10.15420/cfr.2015.1.2.112. PMID:28785443; PMCID:PMC5490953. Kamalesh M, Subramanian U, Sawada S et el. Decreased survival in diabetic patients with heart failure due to systolic dysfunction. Eur J Heart Fail 2006; 8(4):404–8. https://doi.

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org/10.1016/j.ejheart.2005.10.005. PMID:16309953. 42. H eggermont WA, Papageorgiou AP, Heymans S, van Bilsen M. Metabolic support for the heart: complementary therapy for heart failure? Eur J Heart Fail 2016; 18(12):1420–9. https://doi. org/10.1002/ejhf.678. PMID:27813339. 43. Shah SJ, Blair JE, Filippatos GS et al. Effects of istaroxime

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on diastolic stiffness in acute heart failure syndromes: results from the hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure (HORIZON–HF) trial. Am Heart J 2009;157:1035–41. https://doi.org/10.1016/j.

ahj.2009.03.007; PMID:19464414. 44. T eerlink JR, Felker GM, McMurray JJ et al. Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure: the ATOMIC–AHF study. J Am Coll Cardiol 2016;67:1444–55. https://doi.org/10.1016/j.jacc.2016.01.031. PMID:27012405.

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Co-Morbidities

Frailty in Heart Failure: Implications for Management Cristiana Vitale, Ilaria Spoletini and Giuseppe MC Rosano Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy

Abstract Frailty is a complex clinical syndrome associated with ageing and chronic illness, resulting from multiple organ impairment; physiological reserves decrease and vulnerability to stressors increase. The role of frailty in cardiovascular disease has become increasingly recognised. Up to 79% of patients with heart failure are frail. Moreover, frailty is associated with a worse quality of life and poor prognosis. This review summarises the available literature on frailty in HF and highlights indications for its management.

Keywords Heart failure, frailty, ageing, management Disclosure: The authors have no conflicts of interest to declare. Received: 10 June 2018 Accepted: 6 July 2018 Citation: Cardiac Failure Review 2018;4(2):104–6. DOI: https://doi.org/10.15420/cfr.2018.22.2 Correspondence: Cristiana Vitale, Centre for Clinical & Basic Research IRCCS San Raffaele Pisana, via della Pisana, 235, 00163 Rome, Italy. E: cristiana.vitale@sanraffaele.it

Because of the ageing population in industrialised countries, the prevalence of cardiovascular disease has dramatically increased.1 In particular, heart failure (HF) has become a major public health problem and the leading cause of morbidity, hospitalisation and mortality in older people.2,3 Patients with HF, especially the oldest, are often characterised by a “vulnerability status” due to the presence of several comorbidities and impaired functional capacity.4,5 The Cardiovascular Health Study,6 a US longitudinal cohort of older people living in the community, has defined this vulnerability status as the “frail phenotype”. This term indicates elderly people with multiple chronic morbidities, resulting in reduced autonomy in daily life activities.6 Of note, the Cardiovascular Health Study found frailty was associated with clinical cardiovascular disease, most strongly with HF. Indeed, almost half of patients with HF were frail, and this was independent of age or New York Heart Association functional classification. The frail phenotype was defined using five criteria: unintentional weight loss; self-reported exhaustion; low energy expenditure; slow gait speed; and weak grip strength. The study also demonstrated the relationships between frailty, comorbidity and disability found to predict and/or exacerbate each other. Although the precise pathogenesis of frailty in HF has not been fully elucidated, shared pathophysiologic mechanisms may help explain the complex relationships among frailty, comorbidity and disability.7 According to the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults,8 a “dependency cascade” may occur. This term indicates a progressive series of damage across multiple organ systems, ranging from functional decline to disability and death. The most common deficits relate to mobility, strength, balance, motor processing, cognition, nutrition, endurance and physical activity.9 Domains of frailty are shown in Figure 1. As deficits in these domains accumulate, the capacity to cope with distress is diminished, and functional decline worsens.10,11 This self-reinforcing dependency

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cascade may be a consequence of impaired homeostatic maintenance/ repair mechanisms.12 Disorders in neurohormonal, metabolic, immunologic and musculoskeletal systems may lead to an increased catabolic state that is typical of the frail phenotype in HF.4 For these reasons, patients who are frail experience sarcopenia, tissue wasting and cardiac cachexia, with consequent weakness, fatigue and reduced resistance to stressors.13 Therefore, frailty in HF is characterised not only by myocardial failure but also by concomitant metabolic failure.4 Frailty and the above-mentioned associated conditions, i.e. cachexia, sarcopenia and reduced functional capacity, are particularly prevalent in patients with advanced HF.14 It still has to be clarified whether therapies aimed at addressing neurohumoral overactivation and improving haemodynamics and cardiac and muscular metabolism may be effective in ameliorating these conditions.

Prognostic Implications Not only are elderly patients with HF at increased risk of developing frailty, but also frail older adults are more likely to develop new-onset HF.15 Therefore, the relationship between frailty and HF is bidirectional. This is thought to be due to the common underlying mechanisms of inflammation, metabolic dysfunction and hormonal dysregulation.16,17 Older adults with frailty and HF are at increased risk of poor clinical outcomes.15 Observational studies have found frailty to be associated with higher mortality rates and healthcare utilisation, including emergency department visits and hospitalisations, disability, falls and cognitive decline.15,18–22 In elderly patients with chronic HF, the presence of frailty was associated with an increased risk of mortality, hospital readmission and functional decline at one year.23 Furthermore, patients with HF and frailty have a worse quality of life since frailty accelerates the risk of developing a disability.6 The FRAILHF, a prospective cohort study including 450 non-dependent patients aged ≥70 years who had been hospitalised for HF,21 evaluated the

Frailty relationships between the frailty phenotype and associated issues (i.e. comorbidities, coexistent geriatric syndromes, self-care and social support) with clinical, functional and quality-of-life outcomes. The study found that even in non-dependent patients, frailty was a risk factor for early disability, long-term mortality and hospital readmission.20

Figure 1: Overlapping Domains of Frailty

Cognitive defects

Functional impairment

Physical deficits

Assessment and Management of Frailty in HF Recognising the frailty phenotype in patients with HF may help to detect those at risk of poor outcomes (i.e. disability, death, hospitalisation or institutionalisation)23,24 so identify those who need early intervention and close monitoring.25 The recognition of frailty is the first step for an accurate risk stratification and planning a tailored therapeutic plan.26,27 However, several knowledge gaps exist. First, a unique definition of this syndrome in patients with HF is still lacking.26 Second, most trials on HF have excluded elderly patients with comorbidities, who comprise the population at the highest risk of frailty.25 Third, an established frailty approach in HF is still missing. Several measurements have been proposed to assess frailty, and a huge variety of methods and instruments are available.11,28,29 The most widely used tools to assess frailty are Fried’s phenotypic definition of frailty and the frailty index, described in detail elsewhere.3,11,30 There are also self-report questionnaires or instruments based on the assessment of single performances (i.e. single domains of frailty). However, a recent systematic review30 found inconsistencies in frailty measurements and identified that the only consistently represented domain across frailty instruments was physical function/mobility. There is, therefore, a need for a consensus from the scientific community for a standard method – preferably user friendly and not time consuming – that can be used to accurately identify frailty in patients with cardiovascular conditions and reliably predict adverse clinical outcomes. To date, the multidimensional interdisciplinary Comprehensive Geriatric Assessment (CGA) is the most used tool to measure frailty. However, this instrument may not adequately characterise frailty in patients with cardiac conditions. To date, there are no validated frailty instruments specific for HF or other cardiovascular conditions.31,32 A recent systematic review30 identified seven frailty assessment instruments that have been used in HF research so far. Of these seven instruments – the Frailty Phenotype, the Deficit Accumulation Index, the Tilburg Frailty Indicator, the CGA, the Frailty Staging System, the Canadian Health and Ageing Clinical Frailty Scale and the Survey of Health, Ageing and Retirement in Europe Frailty Index – none have been validated for use in HF. Assessing frailty with a validated instrument is a priority, international frailty guidelines recommend.33,34 An accurate assessment of frailty in older patients with HF should include its early identification, consideration of referral to specialists, such as cardiologists, primary care physicians and specialist nurses, and anticipation of care.9 The correct timing for the diagnosis of frailty in HF is yet to be established.35 A recent position paper from acute coronary care specialists suggests that, although challenging, the assessment of frailty should be performed during the acute phase of hospital admission.25 However, at this stage, several confounding factors may influence the detection of frailty. For now, self-reported assessments

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Lack of social support

Mood disorders

Undernutrition

should be preferred, while objective performance measures may be used at discharge.25 In any case, routine assessment of frailty should be part of a holistic management plan in patients with HF.30 Finally, given that health status is reduced in patients with HF and frailty, measuring patient-reported health status is pivotal for cardiovascular conditions, according to the American Heart Association (AHA).36 A position paper from the AHA, American College of Cardiology and American Geriatrics Society states that future guidelines should take into account the assessment of frailty domains as well as chronological age in the management of older patients with HF.37 As most older adults are not frail, chronological age is not a reliable indicator of biological age and health status. Frailty has been found to be a better predictor of age-dependent heart rhythm disorders than age.38 A comprehensive approach to manage frailty in HF should therefore start from a multidimensional assessment.39 The domains should include mobility, strength, balance, motor processing, cognition, nutrition, endurance and physical activity.9,39 According to the European Society of Cardiology guidelines, the management of older adults with HF includes the monitoring of frailty over time, taking into account its reversible causes to prevent increasing frailty.40 In particular, optimisation of symptom control may improve exercise tolerance, with improvements in skeletal muscle function and sarcopenia, which ameliorate functional status.41 Exercise training may reduce the frequency of HF exacerbations and hospitalisations, and improve functional capacity, quality of life and survival in HF patients.42 Hormonal treatment with testosterone has been shown to improve functional capacity and quality of life in elderly patients with HF in both sexes but this therapeutic approach needs to be specifically tested in frail patients with HF.43,44 Therefore, frailty may be a dynamic state when its cardiovascular and non-cardiovascular causes may be reversed.40 In addition, rehabilitative programmes may be used to delay or prevent functional decline. In particular, exercise training has a positive effect on physical function and functional capacity in elderly people who are frail.45

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Co-Morbidities Summary Patients with heart failure (HF), especially the oldest, are often affected by frailty. Frailty involves deterioration in multiple organ systems and ranges from functional decline to disability and death. Identifying the frailty phenotype in HF may help to detect patients at risk of poor outcomes. Multidimensional assessment of frailty should be part of a holistic management plan in HF, but a standard approach is lacking. Further studies should aim to deepen knowledge on frailty in HF, and future guidelines should address its management in depth.

In addition, frailty poses special challenges for patients needing end-of-life care. As reviewed in detail elsewhere,46 palliative care should be provided by an interdisciplinary team, with the aims of relieving symptoms (in particular, pain control) and offering psychological support to patients and caregivers to improve quality of life. Under-nutrition and unintentional weight loss are key issues for these patients.47 Therefore, correction of nutrition is a main component

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ichols M, Townsend N, Scarborough P, et al. Trends N in age-specific coronary heart disease mortality in the European Union over three decades: 1980–2009. Eur Heart J 2013;34:3017–27. https://doi.org/10.1093/eurheartj/eht159; PMID:23801825. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292:344–50. https://doi.org/10.1001/ jama.292.3.344; PMID:15265849. Shinmura K. Cardiac senescence, heart failure, and frailty: a triangle in elderly people. Keio J Med 2016;65:25–32. https://doi. org/10.2302/kjm.2015-0015-IR; PMID:27170235. Joseph SM, Rich MW. Targeting frailty in heart failure. Curr Treat Options Cardiovasc Med 2017;19:31. https://doi.org/10.1007/ s11936-017-0527-5;PMID:28357683. Carlson C, Merel SE, Yukawa M. Geriatric syndromes and geriatric assessment for the generalist. Med Clin North Am 2015;99:263–79. https://doi.org/10.1016/j. mcna.2014.11.003;PMID:25700583 Newman AB, Gottdiener JS, McBurnie MA, et al. Associations of subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci Med Sci 2001;56:M158–66. https://doi.org/10.1093/ gerona/56.3.M158; PMID:11253157. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 2004;59:255–63. https://doi.org/10.1093/gerona/59.3.M255; PMID: 15031310. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006;54:991–1001. https://doi.org/10.1111/j.15325415.2006.00745.x; PMID:16776798. Singh M, Alexander K, Roger VL, et al. Frailty and its potential relevance to cardiovascular care. Mayo Clin Proc 2008;83:1146– 53. https://doi.org/10.4065/83.10.1146; PMID:18828975. Rockwood K, Song X, Mitnitski A. Changes in relative fitness and frailty across the adult lifespan: evidence from the Canadian National Population Health Survey. CMAJ 2011;183:E487–94. https://doi.org/10.1503/cmaj.101271; PMID:21540166. Rajabali N, Rolfson D, Bagshaw SM. Assessment and utility of frailty measures in critical illness, cardiology, and cardiac surgery. Can J Cardiol 2016;32:1157–65. https://doi. org/10.1016/j.cjca.2016.05.011; PMID:27476983. Topinkova E. Aging, disability and frailty. Ann Nutr Metab 2008;52 Suppl 1:6–11. https://doi.org/10.1159/000115340; PMID:18382070. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet 2013;381:752–62. https://doi.org/10.1016/S01406736(12)62167-9; PMID: 23395245. Joyce E. Frailty in advanced heart failure. Heart Fail Clin 2016;12:363–74. https://doi.org/10.1016/j.hfc.2016.03.006; PMID:27371513. Goldwater DS, Pinney SP. Frailty in advanced heart failure: a consequence of aging or a separate entity? Clin Med Insights Cardiol 2015;9:39–46. https://doi.org/10.4137/CMC.S19698; PMID: 26244037 Khan H, Kalogeropoulos AP, Georgiopoulou VV, et al. Frailty and risk for heart failure in older adults: the health, aging, and body composition study. Am Heart J 2013;166:887–94. https://doi.org/10.1016/j.ahj.2013.07.032; PMID:24176445. Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Inflammatory markers and incident heart failure risk in older adults: the health ABC (Health, Aging, and Body Composition) Study. J Am Coll Cardiol 2010;55:2129–37. https://doi.org/10.1016/j.jacc.2009.12.045; PMID:20447537 PMCid:PMC3267799

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of frailty management, although it still remains to be clarified whether vitamin/mineral supplements and/or hormone supplements may be beneficial.45

Conclusions Frailty is a dynamic and potentially reversible state. An accurate assessment may allow a tailored, individualised healthcare programme of management to prevent adverse outcomes in HF. Therefore, a consensual and multidimensional assessment is needed. Future trials should include methods to select and stratify participants with frailty as they are an especially high-risk group.25 Finally, upcoming studies should aim to clarify an age threshold for subjects’ inclusion in future research.48 Managing frailty may help improve quality of life and have a substantial impact on prognosis in HF. Considering the role of frailty in clinical management of HF is therefore pivotal. n

18. B utrous H, Hummel SL. Heart failure in older adults. Can J Cardiol 2016;32:1140–7. https://doi.org/10.1016/j. cjca.2016.05.005; PMID:27476982. 19. McNallan SM, Singh M, Chamberlain AM, et al. Frailty And healthcare utilization among patients with heart failure in the community. JACC Heart Fail 2013;1:135–41. https://doi. org/10.1016/j.jchf.2013.01.002; PMID:23956958. 20. Vidan MT, Blaya-Novakova V, Sanchez E, et al. Prevalence and prognostic impact of frailty and its components in non-dependent elderly patients with heart failure. Eur J Heart Fail 2016;18:869–75. https://doi.org/10.1002/ejhf.518; PMID:27072307. 21. Vidan MT, Sanchez E, Fernandez-Aviles F, et al. Frail–Hf, a study to evaluate the clinical complexity of heart failure in nondependent older patients: rationale, methods and baseline characteristics. Clin Cardiol 2014;37:725–32. https:// doi.org/10.1002/clc.22345; PMID:25516357. 22. Afilalo J, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol 2009;103:1616–21. https://doi.org/10.1016/j. amjcard.2009.01.375; PMID:19463525. 23. Rodriguez-Pascual C, Paredes-Galan E, Ferrero-Martinez AI, et al. The frailty syndrome is associated with adverse health outcomes in very old patients with stable heart failure: a prospective study in six Spanish hospitals. Int J Cardiol 2017;236:296–303. https://doi.org/10.1016/j. ijcard.2017.02.016; PMID:28215465 24. Sternberg SA, Wershof Schwartz A, Karunananthan S, et al. The identification of frailty: a systematic literature review. J Am Geriatr Soc 2011;59:2129–38. https://doi.org/10.1111/ j.1532-5415.2011.03597.x; PMID:22091630. 25. Walker DM, Gale CP, Lip G, et al. Editor’s choice – frailty and the management of patients with acute cardiovascular disease: a position paper from the acute cardiovascular care association. Eur Heart J Acute Cardiovasc Care 2018;7:176–93. https://doi.org/10.1177/2048872618758931; PMID:29451402. 26. Uchmanowicz I, Lisiak M, Wontor R, et al. Frailty syndrome in cardiovascular disease: clinical significance and research tools. Eur J Cardiovasc Nurs 2015;14:303–9. https://doi. org/10.1177/1474515114568059; PMID:25595359. 27. Hill E, Taylor J. Chronic heart failure care planning: considerations in older patients. Card Fail Rev 2017;3:46–51. https://doi.org/10.15420/cfr.2016:15:2; PMID: 28785475 28. Afilalo J, Alexander KP, Mack MJ, et al. Frailty Assessment in the Cardiovascular Care of Older Adults. J Am Coll Cardiol 2014;63:747–62. https://doi.org/10.1016/j.jacc.2013.09.070; PMID:24291279. 29. Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: a review. Eur J Intern Med 2016;31:3–10. https://doi.org/10.1016/j.ejim.2016.03.007; PMID:27039014. 30. McDonagh J, Martin L, Ferguson C, et al. Frailty assessment instruments in heart failure: a systematic review. Eur J Cardiovasc Nurs 2018;17:23–35. https://doi. org/10.1177/1474515117708888; PMID:28471241. 31. Forman DE, Alexander KP. Frailty: a vital sign for older adults with cardiovascular disease. Can J Cardiol 2016;32:1082–7. https://doi.org/10.1016/j.cjca.2016.05.015; PMID:27476987. 32. McDonagh J, Ferguson C, Newton PJ. Frailty assessment in heart failure: an overview of the multi-domain approach. Curr Heart Fail Rep 2018;15:17–23. https://doi.org/10.1007/ s11897-018-0373-0; PMID:29353333. 33. Dent E, Lien C, Lim WS, et al. The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty. J Am Med Dir Assoc 2017;18:564–75. https://doi.org/10.1016/j.jamda.2017.04.018; PMID:28648901. 34. Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: a

call to action. J Am Med Dir Assoc 2013;14:392–7. https://doi. org/10.1016/j.jamda.2013.03.022; PMID:23764209. 35. S utton JL, Gould RL, Daley S, et al. Psychometric properties of multicomponent tools designed to assess frailty in older adults: a systematic review. BMC Geriatr 2016;16:55. https://doi.org/10.1186/s12877-016-0225-2; PMID:26927924. 36. Rumsfeld JS, Alexander KP, Goff DC, Jr, et al. Cardiovascular health: the importance of measuring patient-reported health status: a scientific statement from the American Heart Association. Circulation 2013;127:2233–49. https://doi. org/10.1161/CIR.0b013e3182949a2e; PMID:23648778. 37. Rich MW, Chyun DA, Skolnick AH, et al. Knowledge gaps in cardiovascular care of the older adult population: a scientific statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society. J Am Coll Cardiol 2016;67:2419–40. https://doi.org/10.1016/j. jacc.2016.03.004; PMID:27079335. 38. Cheol Cho H. Age is just a number: frailty better evaluates age-dependent heart rhythm defects. J Physiol 2013;594:6805. https://doi.org/10.1113/JP273370; PMID: 27905134. 39. Gorodeski EZ, Goyal P, Hummel SL, et al. Domain management approach to heart failure in the geriatric patient: present and future. J Am Coll Cardiol 2018;71:1921–36. https://doi. org/10.1016/j.jacc.2018.02.059; PMID:29699619. 40. 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 J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ejhf.592; PMID:27207191. 41. Dharmarajan K, Dunlay SM. Multimorbidity in older adults with heart failure. Clin Geriatr Med 2016;32:277–89. https://doi. org/10.1016/j.cger.2016.01.002; PMID:27113146. 42. Cooper LB, Mentz RJ, Sun JL, et al. Psychosocial factors, exercise adherence, and outcomes in heart failure patients: insights from heart failure: a controlled trial investigating outcomes of exercise training (HF–ACTION). Circ Heart Fail 2015;8:1044–51. https://doi.org/10.1161/ CIRCHEARTFAILURE.115.002327; PMID:26578668. 43. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 2009;54:919–27. https://doi.org/10.1016/j. jacc.2009.04.078; PMID:19712802. 44. Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot doubleblind, randomized, placebo-controlled study. J Am Coll Cardiol 2010;56:1310–6. https://doi.org/10.1016/j.jacc.2010.03.090; PMID:20888520. 45. Lang PO, Michel JP, Zekry D. Frailty syndrome: a transitional state in a dynamic process. Gerontology 2009;55:539–49. https://doi.org/10.1159/000211949; PMID:19346741. 46. Koller K, Rockwood K. Frailty in older adults: implications for end-of-life care. Cleve Clin J Med 2013;80:168–74. https://doi. org/10.3949/ccjm.80a.12100; PMID:23456467. 47. Chin APMJ, de Groot LC, van Gend SV, et al. Inactivity and weight loss: effective criteria to identify frailty. J Nutr Health Aging 2003;7:55–60. 48. Rodriguez-Manas L, Feart C, Mann G, et al. Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definitionconsensus conference project. J Gerontol A Biol Sci Med Sci 2013;68:62–7. https://doi.org/10.1093/gerona/gls119; PMID:22511289.

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Co-Morbidities

Exercise Training in Heart Failure Patients With Persistent Atrial Fibrillation: a Practical Approach Justien Cornelis, 1 Jonathan Myers, 2,3 Hein Heidbuchel, 4,5 Christiaan Vrints 4,5 and Paul Beckers 1,4,5 1. Department of Rehabilitation Sciences and Physiotherapy, University of Antwerp, Wilrijk, Belgium; 2. VA Palo Alto Health Care System, Palo Alto, CA, USA; 3. Stanford University, Stanford, CA, USA; 4. Department of Cardiology, Antwerp University Hospital, Edegem, Belgium; 5. Department of Medicine, University of Antwerp, Wilrijk, Belgium

Abstract Persistent AF is present in at least 20 % of patients with chronic heart failure (CHF) and is related to a poor prognosis and more severe cardiac arrhythmias. CHF and AF share a common pathophysiology and can exacerbate one another. Exercise programmes for people with CHF have been shown to improve aerobic capacity, prognosis and quality of life. Given that patients with both CHF and AF show greater impairment in exercise performance, exercise training programmes have the potential to be highly beneficial. Optimal clinical evaluation using a cardiopulmonary exercise test should be performed before starting a training programme. Heart rate should be calculated over a longer period of time In patients with CHF and AF than those in sinus rhythm. The use of telemetry is advised to measure HR accurately during training. If telemetry is not available, patients can be safely trained based on the concomitant workload. An aerobic exercise training programme of moderate to high intensity, whether or not combined with strength training, is advised in patients with CHF and AF. Optimal training modalities and their intensity require further investigation.

Keywords Exercise, training, heart failure, atrial fibrillation, rehabilitation, heart rate Disclosure: The authors have no conflicts of interest or financial ties to declare. Received: 30 April 2018 Accepted: 6 July 2018 Citation: Cardiac Failure Review 2018;4(2):107–11. DOI: https://doi.org/10.15420/cfr.2018.19.2 Correspondence: Justien Cornelis, Department of Rehabilitation Sciences and Physiotherapy, University of Antwerp, CDE S0.22, Universiteitsplein 1, 2610 Wilrijk, Belgium. E: Justien.Cornelis@uantwerpen.be

A hallmark symptom of chronic heart failure (CHF) is exercise intolerance associated with early fatigue and/or dyspnoea with a minimal degree of exertion. It is also associated with a decline in capacity to perform activities of daily living and a diminished quality of life (QoL). Both patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF) have poorer prognostic risk factors, including increased mortality.1 In patients with CHF and persistent AF, exercise performance tends to be more impaired than it is in people in sinus rhythm. This is typically reflected by a decreased peak oxygen uptake (VO2), e.g. 13.4 ml/kg/min in patients with CHF and AF versus 15.2 ml/kg/min in patients with CHF in sinus rhythm.2,3 Concerning exercise performance, lower peak VO2 is an independent predictor of AF, but not the ventilation over carbondioxine (VE/VCO2) slope. Exercise training to increase exercise capacity is important in the management of CHF and could counteract many negative consequences of AF. Moreover, a recent observation from the Women’s Health Study shows that in women with recent AF, risk factors such as obesity, hypertension, smoking and diabetes are predictive for CHF later in life. Countering these risk factors with appropriate therapy such as exercise training, smoking cessation and control of hypertension in AF could help to prevent the development of CHF.4,5

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The general approach to AF management does not differ between people with CHF and other patients, but a few considerations are worth making.6 In this review, we seek to provide practical guidance on cardiac rehabilitation in patients with CHF and AF.

AF in Chronic Heart Failure: Prevalence and Prognosis AF is the most common sustained clinical arrhythmia, with higher incidence and prevalence rates in developed countries, occurring in approximately 3 % of adults aged ≥20 years.6–9 The prevalence of AF rises markedly with age; many modifiable and non-modifiable risk factors underlie AF, including hypertension, CHF, coronary artery disease, valvular heart disease, obesity, type 2 diabetes, cardiomyopathies, congenital heart defects, long-term endurance exercise or chronic kidney disease.6,7,10–12 AF, especially when persistent or permanent, is present in at least 20 % of patients with CHF, with prevalence increasing with severity of the syndrome.13,14 It is associated with a poorer prognosis in patients with than those without CHF,and among patients with a higher incidence of more severe cardiac arrhythmias.1,15 CHF and AF share a common pathophysiology and can exacerbate one another through mechanisms including structural cardiac remodelling, activation of neurohormonal mechanisms and rate-related impairment of left ventricular function.16,17 Since CHF and AF often go hand in

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Co-Morbidities hand,AF will eventually occur in most people with CHF, particularly among older patients with HFpEF.18,19 Moreover, epidemiologic data suggest that people with AF have a 10-fold higher risk of developing CHF than those without AF. While the focus of AF treatment usually involves ablation and optimising pharmacological therapy, these approaches could be insufficient to completely treat this condition. Holistic management of the patient including adequate CHF prevention is needed.19

Exercise Training in Patients with Chronic Heart Failure and AF Physiology of Exercise Training An exercise training programme for healthy individuals improves both central and peripheral determinants of the Fick equation – peak oxygen uptake (VO2) = cardiac output (CO) x arteriovenous O2 difference (a–vO2) – and therefore improves cardiac as well as skeletal muscle function.20 A recent review stated that peak VO2 is approximately 35 % lower in patients with CHF than in healthy subjects, with similar magnitudes of impairment in patients with HFrEF and HFpEF.21 Moreover, AF is associated with lower exercise capacity in both HFrEF and HFpEF.2,3,22 A landmark study of 1,744 patients diagnosed with HFpEF,of whom 239 showed AF, revealed that peak VO2 was significantly lower – 1.8 ml/ kg/min – when AF was present.22 The authors observed that AF was associated with exercise intolerance, increased mortality and impaired contractile reserve. Stroke volume is generally not modifiable with training in CHF and therefore a higher heart rate (HR) may occur in some patients to augment cardiac output.23 Particularly in HFpEF, exercise capacity appears to be largely mediated by inadequate blood flow to the active skeletal muscles secondary to impaired cardiac output.21 In both, HFpEF and HFrEF (particularly the former), the role of peripheral factors such as endothelial function, ergoreflex activation and vasodilatory capacity are important factors underlying exercise intolerance.21,24–26 In these patients, strength training in particular could be effective. In general, the combination of aerobic and strength training will positively modify these central and peripheral determinants of peak VO2.27–30

Clinical Evaluation Before Exercise Training Before cardiac rehabilitation, patients with CHF require a clinical evaluation, optimal pharmacological therapy, risk stratification and treatment of the underlying causes of the condition.31 In addition, the numerous haemodynamic abnormalities in CHF should be considered as they underlie reduced exercise capacity and can therefore be improved by exercise training. Clinically stable patients with CHF are excellent candidates for cardiac rehabilitation. CHF stability should be verified based on daily changes in body weight, symptoms and comorbidities. Before initiating a cardiac rehabilitation programme, a cardiopulmonary exercise test (CPET) with gas exchange analysis should be performed to evaluate safety, exercise capacity and prognosis.32 During a CPET, ECG monitoring. blood pressure recording and, where appropriate, O2 saturation should be performed. Relative and absolute contraindications for CPET and exercise training (Table 1) should be considered.33

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There is no fundamental difference between performing a CPET and initiating cardiac rehabilitation for patients with CHF and AF and those with CHF alone. Although CPET assessment is considered to be the gold standard method for the evaluation of fitness and the function of the cardiorespiratory and muscular systems, in many centres, a graded exercise test is not usually completed with cardiac rehabilitation. If this is the case, alternative assessment methods can be used to obtain the intensity for rehabilitation. These are discussed below. It is important to prescribe exercise in an individualised manner focusing on exercise capacity, QoL, activities of daily living and secondary prevention, as suggested by the International Classification of Functioning, Disability and Health.34 There is no single programme that is best for all patients or even one patient over time.31 Therefore, the clinician should evaluate the patient’s psychosocial, pathophysiologic, environmental and vocational factors and tailor them to the person’s needs and realistic goals. Selecting activities that the patient enjoys is likely to lead to better adherence to physical activities once the rehabilitation programme ends. Involving the patient’s family and taking into account his/her social activities tends to strengthen motivation and increase adherence to the exercise training programme.35 Moreover, the clinician should consider comorbidities, such as respiratory disease, diabetes, obesity and musculoskeletal disorders, when prescribing exercise as they can limit exercise performance. The effect of training is best measured by peak VO2 as it reflects the capacity of the body to transport, use and distribute oxygen. Other criteria to assess training effects can include submaximal performance testing, the ability to perform activities of daily living, improvements in independence and being able to continue working, participate in social activities and the like. These important changes can occur without a significant increase in peak VO2.

Intensity, Duration, Frequency and Modality of Training It should be noted that a fundamental prerequisite for exercise in patients with AF is appropriate HR control, not only at rest but also during exercise. It is beyond the scope of this review to thoroughly discuss the benefits and risks of rate and/or rhythm control in AF. Instead, this review focuses on training principles for patients under optimised pharmacotherapy. Moreover, prior research has shown that more lenient HR control (i.e. accepting rates at rest of up to 110 BPM) does not change outcome compared to more stringent HR control, and is associated with a reduced need for pacemakers.36,37 On the other hand, lenient HR control at rest can lead to rapidly conducted AF which will affect left ventricular function during exercise both acutely and possibly in the long term. In some patients, European Society of Cardiology guidelines recommend a strategy of HR control drugs, possibly combined with a pacemaker, to ensure HR is well controlled under different circumstances, including rehabilitation.38 Intensity, duration, frequency and modality are the main elements of a training programme.30 The ways in which they are applied depend on the patient’s clinical status (Table 2). A training session should start with an appropriate warm-up (e.g. ~10 minutes of callisthenic exercises) and end with a cooling-down period (e.g. ~10 minutes of stretching and breathing exercises). In general, improvements in aerobic capacity are achieved if the patient exercises dynamically (employing large muscle groups using a treadmill or arm ergometer, cycling, stepping or rowing) for at least 30 minutes, three to five times per week at an intensity of 40–80 % of peak VO2.30 This range

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Exercise Training Table 1: Absolute and Relative Contraindications for Cardiopulmonary Exercise Testing and Exercise Training in Patients with Chronic Heart Failure Absolute Contraindications

Relative Contraindications

Acute MI (3–5 days for CPET, within 3 weeks for training)

Left main coronary stenosis or its equivalent

Progressive worsening of exercise tolerance or dyspnoea at rest or on exertion (3–5 days) or uncontrolled heart failure

Severe untreated arterial hypertension at rest (>200 mmHg systolic or (>120 mmHg diastolic)

Significant ischaemia at low rates (±50 W)

Tachyarrhythmia or bradyarrhythmia

Unstable angina

High-degree atrioventricular block

Uncontrolled arrhythmias causing unstable conditions

Hypertrophic cardiomyopathy

New onset atrial fibrillation in CHF

Significant pulmonary hypertension

7. Syncope

Advanced or complicated pregnancy

Active endocarditis, acute myocarditis or pericarditis

Electrolyte abnormalities

Symptomatic moderate to severe aortic stenosis

Orthopaedic impairment that compromises exercise performance

10. Regurgitant valvular heart disease requiring surgery

10. Abnormal increase in body mass over previous 1–3 days in stable CHF

11. Acute pulmonary embolus, infarction or oedema

11. Concurrent continuous or intermittent dobutamine therapy in stable CHF

12. Thrombosis of lower extremities or orthopaedic problems

12. Decrease in systolic blood pressure with exercise in stable CHF

13. Suspected dissecting aneurysm

13. New York Health Association functional class IV

14. Uncontrolled asthma

14. Complex ventricular arrhythmia at rest or appearing with exertion

15. Uncontrolled diabetes

15. Supine heart rate at rest ≥100 bpm in stable CHF

16. Acute systemic illness or fever

16. Pre-existing comorbidities in stable CHF

17. Respiratory failure 18. Desaturation at rest ≤85 % 19. Acute noncardiopulmonary disorder that may comprise exercise 20. Mental impairment or inability to cooperate CHF: chronic heart failure; CPET: cardiopulmonary exercise test. Sources: American Thoracic Society; American College of Chest Physicians, 2003;33 and Gianuzzi et al, 2001.62

depends on the exercise modality, i.e. the time period in interval training or continuous training. In patients with stable CHF, training at 85–95 % peak VO2 has been said to be optimal.39 It should, however, be questioned if performance at these high percentages can be conducted effectively by individual patients considering influencing factors such as motivation and anxiety. It is appropriate to start at a lower intensity for short periods and steadily increase duration and intensity throughout the rehabilitation period (often 3–6 months). The biggest challenge related to exercise prescription is individualising training intensity. To optimally estimate individualised training intensity, peak VO2 should be measured during CPET. The patient then exercises at a percentage of the individual peak VO2 at the corresponding HR. For example, a patient who starts an exercise training programme at 50 % of peak VO2 should exercise at the corresponding HR, typically within a HR range at this intensity ±5 BPM. Another objective method for individualising training intensity involves adopting an intensity commensurate with the respiratory compensation point (RCP) or second ventilatory threshold (VT2).40–42 With increasing exercise intensity and lactic acid production above the first ventilatory threshold (VT1), a point is reached when intracellular bicarbonate is no longer able to adequately counteract exerciseinduced metabolic acidosis. At this point, respiratory alkalosis develops through a VE increase in excess of VCO2, and this is termed VT2 or RCP. Simultaneously, the VE/VCO2 ratio inverts its trend (it increases versus initial decrease), and the VT2 is identifiable as the nadir of the VE/VCO2 versus workload relationship.43 This point is defined as the exercise level at which ventilation increases exponentially relative to the increase in VCO2. At the RCP, the body cannot transport enough

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oxygen to compensate for the accumulating CO2 levels, lactate accumulates and hyperventilation occurs.42 When identifiable, the VT2 is usually attained around 70–80 % peak VO2 and 80–90 % peak HR reached during incremental exercise; it has been suggested that this is related to so-called “critical power”,that is, the upper intensity limit for prolonged aerobic exercise.44–46 CP presents the highest workload sustainable when both VO2 and lactate remain in a steady state.47,48 Independent of peak VO2, the RCP can occur earlier or later, depending on individual efficiency in oxygen delivery and the ability of the body to remove lactate. Because it is difficult to exercise at or beyond the RCP, an individualised training intensity of 90 % RCP is often implemented.42 Independent of the reference value – % peak VO2 or % RCP – it should be noted that in patients with CHF and AF (an estimated 10–30 % of patients with HF), the variation in HR is usually high and a fixed HR for a certain workload often cannot be measured accurately.49 Therefore, during CPET, the HR for a certain workload must be determined using a longer sampling interval (e.g. mean HR for 30 seconds at a given intensity for instance a 50 % peak VO2 or at 90 % RCP). During “constant pulse rate” training, practitioners should be aware that not all equipment or training devices register the HR correctly during exercise when AF is present, since they do not average the HR over a longer sampling interval, for example a period of 1 minute. So, to exercise patients with CHF and AF at a constant pulse rate, telemetry should be used continuously throughout training sessions. If telemetry is not available in the rehabilitation facility, other options can be considered to rehabilitate these patients in a safe, individualised and effective manner. In these circumstances, training at “constant workload” associated with the load at 50 % peak VO2 or 90 % RCP is advised rather than the concomitant HR. The desired effect is that exercise training delays the occurrence of the RCP and therefore HR will be lower and workload

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Co-Morbidities Table 2: Components of the Exercise Prescription for Patients with Chronic Heart Failure and AF Basic Principle of Training Progression: First Increase Duration and Gradually Adjust Intensity Each training session starts with warm-up (5–10 min) and ends with a cooling-down period (5–10 min): callisthenic exercises, breathing exercises or stretching. Intensity Based on Patients’ Clinical Status 1.

Severely debilitated (<10 ml/kg/min peak VO2): 40–50 % peak VO2

Moderate (10–18 ml/kg/min peak VO2): 50–80 % peak VO2

Mild impairment (>18 ml/kg/min peak VO2): 60–80 % peak VO2

Individualised level of intensity: determine 90 % RCP

improves exercise capacity, QoL and performance in activities of daily living in patients with AF.55,56 However, some authors recommend training for patients with CHF at the RCP level (i.e. the upper limit of the moderate to high-intensity range) for periods of 15–30 minutes. While this represents a higher than conventional intensity, it has been demonstrated to be safe.42,57,58 Studies are inconsistent in terms of the effects of long-term vigorous endurance exercise training and highintensity interval training since these forms apply intensities more than 80 % peak VO2 or >90 % RCP, and may be associated with an increased incidence of AF and higher risks.55,56 Given the variability in the ventricular response in AF, it has been recommended that exercise intensity should be targeted at 10 BPM below the HR associated with the referenced criteria.

Borg rating of perceived exertion (6–20 scale): preferably 12–14 Duration Based on Patients’ Clinical Status 1.

Severely impaired functional capacity: 5–10 min, once or several times per day

Moderate to mild impairment: increasing from 15 min (1–2 times per day) to 30 min (3–5 times per week)

Modality 1.

Aerobic continuous training: walking, cycling, rowing and callisthenics, often at an intensity of 50–80 % peak VO2 or 90% RCP.

Strength training: M quadriceps (leg extension), M biceps brachii (arm flexion), M latissimus dorsi (pull down forward), M deltoideus (push up forward), M rhomboides (pull backwards), Mm pectoralis (butterfly), M serratus anterior (chest press), M triceps brachii (arm extension), M trapezius (pull down backwards) = dynamic training of muscle groups at low to moderate intensity (50–70 % of 1RM) with 1–3 sets of 10–15 repetitions.

Interval training: in appropriate patients, a regimen of aerobic exercises in which periods of high intensity (80–90 % peak VO2) are alternated with periods of low to moderate intensity (40–80 % peak VO2). These periods of high intensity can be short (30 s) or long (4 min). Practitioners should take into account that there might be a higher risk of adverse events in the long term.

Combinations of modalities: combining aerobic continuous training or interval training with strength training has superior effects. Often, a higher amount of strength training is done at the start of the training programme. The aerobic part is increased throughout the programme.

RCP = respiratory compensation point; VO2 = oxygen uptake; 1RM = one repetition maximum.

will be higher at the RCP. Deciding an appropriate, individualised training intensity is more challenging when CPET is not available, but intensity can be determined using a percentage of maximal HR achieved, or what is known as the HR reserve or Karvonen formula (maximal HR − resting HR × desired intensity + resting HR). These methods are only reliable in patients in normal sinus rhythm whose measurements of resting and maximal heart rates are precise. More subjective methods include estimation of the perceived exertion using the Borg scale. An intensity at a level between 12 and 14 on the 6–20 scale has been shown to be well tolerated and associated with favourable training responses.50,51 The “talk test”has also been suggested as a valid method to monitor exercise intensity when CPET assessment is not possible.52 It has been suggested that the 6-minute walk test is a simple and reliable test to estimate exercise tolerance in patients with CHF; however, it is not a valid tool for prescribing exercise intensity.53,54 Despite relatively limited literature, available studies are consistent in showing that low to moderate intensity aerobic physical activity

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Recently, the potential superior effects of high-intensity interval training was investigated in trials involving patients with CHF. Despite initial promising results, a more recent, larger trial indicated that high-intensity interval training did not have superior effects on exercise capacity than moderate continuous training.29,59 Moreover, it is suggested that training at high intensity for short periods might raise the risk of hospital readmission in these patients. The question remains whether single bouts of exercise at high intensity are useful, safe, motivating for patients, and practical in CHF. A recent metaanalysis comparing modalities of exercise training in people with CHF (interval versus continuous training, with and without strength training) indicated that no training mode was superior to another in terms of prognosis, exercise capacity and QoL, even though left ventricular function appeared to show greater improvement with interval training.30 More research should be directed toward the most effective training modality in people with CHF. In patients with CHF and AF, implementing high intensities is not recommended at this time. Resistance training was once thought to be strictly contraindicated in patients with CHF. However, it is now widely recommended to restore muscular strength. CHF is known to be a muscle-wasting disease and many affected patients experience weakness of the large muscle groups when they start a cardiac rehabilitation programme. Resistance training has been demonstrated to be safe and to increase exercise capacity (by facilitating peripheral oxygen extraction), reduce blood pressure and increase the capacity to perform activities of daily living.42,58,60 In cardiac rehabilitation programmes, strength training is often combined with aerobic training. As with aerobic training, resistance training should begin slowly and progress gradually according to a patient’s ability.58 Strength training should focus on the major muscle groups and one repetition maximum (1RM) should be tested at initiation. An appropriate technique in patients with CHF and AF might be 10–15 RM testing, which reflects the maximum weight that a person can move 10–15 times. One set of 10–15 repetitions at an intensity of 50–70 % of 1RM is usually appropriate at the beginning of the programme. Sets can then be increased from one to three throughout the period.58,60

Future Directions and Conclusions Throughout the world, key cardiology organisations focusing on prevention have developed recommendations for cardiac rehabilitation programmes.61 Historically, these have focused on patients with coronary artery disease, and recommendations for patients with CHF have been made much more recently. Much less research has looked at other populations with cardiovascular disease; to the best

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Exercise Training of the authors’ knowledge, no recommendations have been made specifically for patients with CHF and AF. Clinical trials comparing exercise training modalities, intensities, frequency and duration for this specific population are lacking. Therefore, the practical guidelines discussed here are based on recommendations for patients with CHF and adjusted based on the available literature and the authors’ clinical experience. Further refinement of exercise training methods, along with evaluating the effects of training on prognosis and QoL in patients with CHF and AF are needed from future randomised trials.

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ang TJ, Larson MG, Levy D, et al. Temporal relations of W atrial fibrillation and congestive heart failure and their joint influence on mortality. Circulation 2003;107:2920–5. https://doi. org/10.1161/01.CIR.0000072767.89944.6E; PMID:12771006. Agostoni P, Emdin M, Corrà U, et al. Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients. Eur Heart J 2008;29:2367–72. https://doi.org/10.1093/ eurheartj/ehn361; PMID: 18682448. Pardaens K, Van Cleemput J, Vanhaecke J, Fagard RH. Atrial fibrillation is associated with a lower exercise capacity in male chronic heart failure patients. Heart 1997;78:564–8. https://doi.org/10.1136/hrt.78.6.564; PMID: 9470871. Chatterjee NA, Chae CU, Kim E, et al. Modifiable risk factors for incident heart failure in atrial fibrillation. JACC Heart Fail 2017;5(8):552–60. https://doi.org/10.1016/j.jchf.2017.04.004; PMID: 28624486. Ko D, Schnabel RB, Trinquart L, Benjamin EJ. The changing landscape of atrial fibrillation. JACC Heart Fail 2017;5:561. https://doi.org/10.1016/j.jchf.2017.05.002; PMID: 28624487. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https:// doi.org/10.1093/eurheartj/ehw210; PMID: 27567408. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation. Am J Cardiol 1998;82:2N–9N. https://doi.org/10.1016/ S0002-9149(98)00583-9; PMID: 9809895. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129:837–47. https://doi. org/10.1161/CIRCULATIONAHA.113.005119; PMID: 24345399. Haim M, Hoshen M, Reges O, et al. Prospective national study of the prevalence, incidence, management and outcome of a large contemporary cohort of patients with incident non‐valvular atrial fibrillation. J Am Heart Assoc 2015;4:e001486. https://doi.org/10.10.1161/JAHA.114.001486; PMID: 25609415. Menezes AR, Lavie CJ, DiNicolantonio JJ et al. Atrial fibrillation in the 21st century. Mayo Clin Proc 2013;88:394–409. https://doi. org/10.1016/j.mayocp.2013.01.022; PMID: 23541013. Oldgren J, Healey JS, Ezekowitz M, et al. Variations in etiology and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: the RE–LY AF registry. Circulation 2013;129:1568–76. https://doi. org/10.1161/CIRCULATIONAHA.113.005451; PMID:24463370 Miller JD, Aronis KN, Chrispin J et al. Obesity, exercise, obstructive sleep apnea, and modifiable atherosclerotic cardiovascular disease risk factors in atrial fibrillation. J Am Coll Cardiol 2015;66:2899–906. https://doi.org/10.1016/j. jacc.2015.10.047; PMID:26718677 De Ferrari GM, Klersy C, Ferrero P et al. Atrial fibrillation in heart failure patients: prevalence in daily practice and effect on the severity of symptoms. Eur J Heart Fail 2007;9:502–9. https://doi.org/10.1016/j.ejheart.2006.10.021; PMID:17174599. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. J Am Coll Cardiol 2003;91:2–8. https://doi.org/10.1016/S00029149(02)03373-8; PMID: 12670636. Singh SN, Poole J, Anderson J, et al. Role of amiodarone or implantable cardioverter/defibrillator in patients with atrial fibrillation and heart failure. Am Heart J 2006;152:974.e7–11. https://doi.org/10.1016/j.ahj.2006.08.012; PMID: 17070171. Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure. Circulation 2009;119:2516–25. https://doi.org/10.1161/ CIRCULATIONAHA.108.821306; PMID:19433768. Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J 2015;36:3250–7. https://doi. org/10.1093/eurheartj/ehv513; PMID: 26419625. Sartipy U, Dahlström U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2017;5:565–74. https://doi. org/10.1016/j.jchf.2017.05.001; PMID: 28711451. Vrints C. Voorkamerfibrillatie en hartfalen: Siamese tweelingen die een teamaanpak vergen. Tijdschrift voor Cardiologie 2017;29:293–5 [in Dutch]. Gilbert-Kawai ET, Wittenberg MD (2014) The Fick equation – oxygen uptake measurement. In: Gilbert-Kawai ET, Wittenberg MD (eds). Essential Equations for Anaesthesia: Key Clinical Concepts for the FRCA and EDA. Cambridge: Cambridge University Press, 2014;94–5. https://doi.org/10.1017/CBO9781139565387.048 Haykowsky MJ, Tomczak CR, Scott JM, et al. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. J Appl

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In conclusion, an exercise training programme of moderate intensity is advised for patients with CHF and AF. Optimal clinical evaluation using CPET should be carried out before a training programme is started. In patients with CHF and AF, the average HR should be calculated over a longer time period than it is in patients in sinus rhythm. The use of telemetry is advised to measure HR accurately during training since most training devices do not estimate HR accurately in patients with AF. If telemetry is not available during training, patients can be safely trained based on the concomitant workload and perceived exertion. n

Physiol 2015;119:739–44. https://doi.org/10.1152/ japplphysiol.00049.2015; PMID: 25911681. Elshazly MB, Senn T, Wu Y, et al. Impact of atrial fibrillation on exercise capacity and mortality in heart failure with preserved ejection fraction: insights from cardiopulmonary stress testing. J Am Heart Assoc 2017;6:pii: e006662. https://doi. org/10.1161/JAHA.117.006662; PMID: 29089343. Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation 2011;123:1010–20. https://doi.org/10.1161/ CIRCULATIONAHA.110.940577; PMID: 21382903. Duscha BD, Schulze PC, Robbins JL, Forman DE. Implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after exercise training. Heart Fail Rev 2008;13:21–37. https://doi.org/10.1007/s10741-007-9056-8; PMID: 17955365. Kitzman DW, Nicklas B, Kraus WE et al. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 2014;306:H1364–70. https://doi.org/10.1152/ ajpheart.00004.2014; PMID: 24658015. Haykowsky MJ, Kitzman DW. Exercise physiology in heart failure and preserved ejection fraction. Heart Fail Clin 2014;10:445–52. https://doi.org/10.1016/j.hfc.2014.04.001; PMID: 24975908. Haykowsky MJ, Timmons MP, Kruger C, et al. Meta-analysis of aerobic interval training on exercise capacity and systolic function in patients with heart failure and reduced ejection fractions. Am J Cardiol 2013;111:1466–9. https://doi. org/10.1016/j.amjcard.2013.01.303; PMID: 23433767. Mandic S, Tymchak W, Kim D et al. Effects of aerobic or aerobic and resistance training on cardiorespiratory and skeletal muscle function in heart failure: a randomized controlled pilot trial. Clin Rehabil 2009;23:207–16. https://doi. org/10.1177/0269215508095362; PMID: 19218296. Ellingsen O, Halle M, Conraads V, et al. High-intensity interval training in patients with heart failure with reduced ejection fraction. Circulation 2017;135:839–49. https://doi.org/10.1161/ CIRCULATIONAHA.116.022924; PMID: 28784833. Cornelis J, Beckers P, Taeymans J, et al. Comparing exercise training modalities in heart failure. Int J Cardiol 2016;221:867–76. https://doi.org/10.1016/j.ijcard.2016.07.105; PMID: 27434363. Myers J. Principles of exercise prescription for patients with chronic heart failure. Heart Fail Rev 2008;13:61–8. https://doi. org/10.1007/s10741-007-9051-0; PMID: 17939037. Myers J, Arena R, Franklin B, et al. Recommendations for clinical exercise laboratories. Circulation 2009;119:3144–61. https://doi.org/10.1161/CIRCULATIONAHA.109.192520; PMID: 17939037. American Thoracic Society, American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:211. https:// doi.org/10.1164/rccm.167.2.211; PMID: 12524257. World Health Organization. International Classification of Functioning, Disability and Health. Geneva; WHO, 2001. Beckers PJ, Denollet J, Possemiers NM, et al. Maintaining physical fitness of patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil 2010;17:660–7. https://doi.org/10.1097/ HJR.0b013e328339ccac; PMID:20389247. Van Gelder IC, Wyse DG, Chandler ML, et al. Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies. Europace 2016;8:935–42. https://doi.org/10.1093/europace/ eul106; PMID: 16973686. Groenveld HF, Crijns HJ, Van den Berg MP, et al. The effect of rate control on quality of life in patients with permanent atrial fibrillation. J Am Coll Cardiol 2011;58:1795–803. https://doi. org/10.1016/j.jacc.2011.06.055; PMID: 23410544 Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https:// doi.org/10.1093/ejcts/ezw313; PMID: 28038729. Ismail H, McFarlane J, Nojoumian AH, et al. Clinical outcomes and cardiovascular responses to different exercise training volumes in heart failure patients. Circulation 2013;128(22 Suppl):A13023; PMID: 23965488. Mezzani A, Hamm LF, Jones AM, et al. Aerobic exercise intensity assessment and prescription in cardiac rehabilitation. Eur J Prev Cardiol 2013;20:442–67. https://doi. org/10.1177/2047487312460484; PMID: 23104970. Conraads VM, Van Craenenbroeck EM, De Maeyer C, et al. Unraveling new mechanisms of exercise intolerance in

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Clinical Syndromes

Postpartum Cardiomyopathy and Considerations for Breastfeeding Laura Kearney, 1 Paul Wright, 2 Sadeer Fhadil 2 and Martin Thomas 2 1. UK Drugs in Lactation Advisory Service; 2. Barts Health NHS Trust, London, UK

Abstract Postpartum cardiomyopathy (PPCM) is a rare condition that develops near the end of pregnancy or in the months after giving birth, manifesting as heart failure secondary to left ventricular systolic dysfunction. Clinical progression varies considerably, with both end-stage heart failure occurring within days and spontaneous recovery seen. Treatment pathways for heart failure are well established, but the evidence about the safety of medicines passed to infants during breastfeeding is scarce and mainly poor; this often leads to an incorrect decision that a mother should not breastfeed. Given its benefits to both mother and infant, breastfeeding should not routinely be ruled out if the mother is taking heart failure medication but the consequences for the infant need to be considered. An informed risk assessment to minimise potential harm to the infant can be carried out using the evidence that is available along with a consideration of drug properties, adverse effects, paediatric use and pharmacokinetics. In most cases, risks can be managed and infants can be monitored for potential problems. Breastfeeding can be encouraged in women with cardiac dysfunction with PPCM although treatment for the mother takes priority with breastfeeding compatibility being the secondary consideration. International research is continuing to establish efficacy and safety of pharmacotherapy in PPCM.

Keywords Postpartum cardiomyopathy, pregnancy, breastfeeding, heart failure medication Disclosure: The authors have no conflicts of interest to declare. Received: 18 May 2018 Accepted: 25 July 2018 Citation: Cardiac Failure Review 2018;4(2):112–18. DOI: https://doi.org/10.15420/cfr.2018.21.2 Correspondence: Laura Kearney, UK Drugs in Lactation Advisory Service, UK E: mailto:laura.kearney@uhl-tr.nhs.uk Acknowledgement: We thank Sarah Fenner for her expert opinion for the risk assessment of levosimendan

Postpartum cardiomyopathy (PPCM) is a diagnosis of exclusion, where patients present with heart failure secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, with no other cause of heart failure identified.1 PPCM is relatively uncommon, affecting between one in 5,000 and one in 10,000 births;2 it is thought to be more prevalent in women aged over 30 years, of black ethnicity, with a history of pre-eclampsia or pregnancyinduced hypertension and those who have had multiple gestations.3 Symptoms can be indistinguishable from those of normal pregnancy, with women presenting with dyspnoea, orthopnoea and reduced exercise capacity. Physical examination, chest X-ray and echocardiography are generally consistent with a diagnosis of heart failure, and levels of brain natriuretic peptide (BNP) and troponin are usually elevated. Clinical progression varies considerably, with some patients advancing to endstage heart failure within a few days of presentation. Similarly, recovery of left ventricular function is variable and can occur spontaneously.1

A recent practical guide on peripartum cardiomyopathy1 considers the use of bromocriptine (in addition to standard therapy for heart failure) depending on the extent of presenting LV function. Bromocriptine will effectively stop lactation and the implications of this should be discussed with the mother should this treatment option be required. Evidence for the effectiveness of bromocriptine in PPCM comes from relatively small studies with many confounding variables. The ongoing EURObservational Programme on PPCM5 is anticipated to provide longer term outcome data and may give clearer insights on the place of bromocriptine in the management of PPCM.

Management of acute and stable heart failure in PPCM should focus on control of volume status, dampening neurohormonal responses and reducing the risk of associated thromboembolic and arrhythmic complications.4

The benefits of breastfeeding to both mother and infant are recognised,6 so it is important to protect the breastfeeding relationship wherever possible; advising a mother not to breastfeed because of medicine exposure is not a ‘zero risk’ option to either mother or infant. As well as breast milk being a tailored nutrition source,7,8 other immediate benefits to the infant include immunoprotection7,9 and pain relief for procedures such as heel prick.10 Longer-term benefits to the infant include reduced risk of sudden infant death,11 a lower risk of becoming obese,12,13 and improved cognitive development.14,15 Benefits to the mother include reduced risks of breast cancer,16,17 ovarian cancer,18 type II diabetes19 and hypertension.20

While treatment pathways for heart failure are well established, the implications for infants whose mothers choose to breastfeed while on heart failure pharmacotherapy need to be considered. Appropriate treatment for the mother must be a primary concern, with breastfeeding compatibility a secondary consideration.

Documented evidence for the use of medicines during breastfeeding is largely very poor, if available at all, often leading to an incorrect decision that the mother should not breastfeed. However, any evidence available can be used, along with a consideration of drug properties and pharmacokinetics, to carry out an informed risk assessment. In

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Postpartum Cardiomyopathy and Breastfeeding most cases, medicine use can continue during breastfeeding, and most risks can be managed. On the very rare occasions where breastfeeding cannot be recommended becaues of medicine exposure, an abstinence period will be required to ensure that the medicine has been excreted out of the breast milk compartment. The mother may also be too acutely unwell to physically breastfeed. In either scenario, the mother will need to express her milk to maintain supply so she can start breastfeeding at a later stage if she wishes. If an abstinence period has been recommended due to medicine exposure, expressed milk will need to be discarded. Otherwise, expressed milk can continue to be given to the infant. The licensed use of medicines is set out in their summary of product characteristics. This provides information from the manufacturer on a medicine and conditions attached to its use. A section is included on use in breastfeeding but this is often overcautious and recommendations are based on the lack of evidence, rather than a more considered risk assessment. To date, there is no requirement for manufacturers to conduct studies in breastfeeding since, understandably, it would be unethical to do so. The advice presented in this article takes into account known pharmacokinetic principles, clinical experience to date and, where available, published evidence. Timing of feeds against a given dose is not generally advocated, since there is no evidence to suggest what additional benefit this practice confers, and it can be stressful for a mother to adhere to these conditions, especially when she is taking multiple medicines. Therefore the risk assessments presented within this article represent the overall on-going exposure of the breastfed infant. Advice is offered in supporting breastfeeding wherever possible, but it should be noted this may be contrary to advice given by the manufacturers and would render the product being used outside its product license. Unless otherwise stated, throughout this article, there are no published data for the use of medicines used in PPCM management during breastfeeding. Table 1 provides a useful and concise summary.

Principles of Determining Drug Safety in Breastfeeding Nearly all medicines will pass into breast milk to some extent, although transfer is usually low. Many factors affect milk drug concentration: these can be drug related (dose, bioavailability, lipid solubility, protein binding, molecular weight, pKa, half-life, active metabolites and mechanism of elimination); and maternal related (maternal dose, pharmacogenomics and renal and hepatic function). In addition, the adverse effect profile of the medicine needs to be considered since these can potentially occur in the exposed infant. Common principles are used to help in risk assessment for compatibility of a medicine during breastfeeding include (note this list is not exhaustive): • Protein binding If a drug is highly protein bound, less fraction of the drug is freely available to pass across into breast milk. • Half-life Drugs with longer half-lives have a greater potential to accumulate in the infant, which increases the risk of the infant experiencing side effects. Half-lives of active metabolites also need to be considered.

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• Oral bioavailability If a drug has minimal or low oral bioavailability (for example drugs administered via parenteral routes to achieve good therapeutic concentrations), when the infant ingests the drug orally via breast milk, it will not lead to significant systemic concentrations in the infant. • Lipid solubility Drugs that have high lipid solubility are more likely to pass into breast milk because they are able to pass through the lipid membrane of the alveolar epithelium. • Molecular weight Small molecules are more likely to be able to pass into breast milk via passive diffusion. Larger molecules require other transporting mechanisms or will simply be too big to pass through. It is generally accepted that molecules with a molecular weight above 1,000 will be able to pass through only in small quantities if at all.7 Very large molecules, such as proteins, are generally considered too large to pass through into breast milk, although evidence to the contrary is beginning to emerge.21,22 • Infant age Newborn infants, especially premature infants, have underdeveloped hepatic and renal clearance capacities, which can lead to accumulation. An older infant will have better developed clearance pathways. Additionally, once an infant is being weaned, overall milk consumption (and hence drug exposure) will lessen. • Paediatric use If a drug is used therapeutically in infants, there is experience of its use in the paediatric population, which provides reassurance of the drug’s acceptability in breastfeeding since the level of exposure from breast milk is generally much smaller than that used to achieve a therapeutic effect. The clinical status of the infant needs to be taken into consideration. If an infant is unwell, effects from drug exposure in breast milk need to be considered to avoid a potential deterioration in their condition. A premature infant is far more likely to be vulnerable to effects from medicines because of the increased risk of drug accumulation from underdeveloped clearance capacities. If either of these situations apply, it would be advisable to seek specialist advice since an individual risk assessment on the infant should be carried out. It is usually advised that medicines used during breastfeeding should be at the lowest effective dose for the mother and for the shortest duration possible to minimise exposure of medicines to the infant through breast milk. However, in the treatment of PPCM, the mother should receive the treatment she requires, often with dosing being maximised for optimal effect, with safety in breastfeeding being the secondary consideration.

Pharmacotherapy in Acute Heart Failure Secondary to Postpartum Cardiomyopathy Acute heart failure requires urgent admission to hospital for assessment and offloading of volume, which usually requires both intravenous diuretics and glyceryl trinitrate for vasodilation, both of which are titrated to response and systolic blood pressure. Patients with a low output state or with persistent congestion may need ionotropic agents, namely noradrenaline, dobutamine, milrinone or levosimendan, until organ perfusion is restored and/or congestion reduced. Loop diuretics (furosemide and bumetanide) have favourable pharmacokinetic properties so levels in breast milk are anticipated to be low. They have high protein binding (up to 99 %) and are short acting (half-life of approximately 2 hours).

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Clinical Syndromes Furosemide is considered to be the preferred choice loop diuretic during breastfeeding since it has lower oral bioavailability (60–70 %) than bumetanide (80–95 %); oral bioavailability of furosemide is even lower in neonates.23 Furosemide is also used in full-term neonates from birth.24 Patients with significant fluid overload or failure to achieve adequate diuresis with a single loop diuretic may require the addition of a thiazide diuretic such as bendroflumethiazide or metolazone. As with loop diuretics, the pharmacokinetic profile of thiazides predicts that levels expressed in breast milk would be too low to have an effect in the infant.25 Bendroflumethiazide is the preferred choice, as there is more experience of its use and because of its pharmacokinetic profile (>90 % protein binding and short acting, with a half-life of 3–4 hours).23,26 Although the amounts of loop and thiazide diuretic predicted to cross into breast milk are not thought to be harmful, there is concern that intense diuresis may suppress lactation.27,28 If high doses or combinations are used, the mother’s milk supply should be monitored by ensuring the infant is gaining weight adequately and monitoring the infant for fluid loss, dehydration, and lethargy.25 Vasodilation with glyceryl trinitrate can help to reduce pre and post load in the myocardium and, as such, offers value in resolving symptoms in acute decompensated heart failure. As it has a very short half-life of minutes,23 the drug’s passage into breast milk would not be expected at clinically relevant concentrations. Although shortterm use is considered compatible with breastfeeding, the infant should be monitored for signs of nitrate absorption such as flushing after feeding.25 Where inotropic support is necessary to maintain adequate cardiac output, noradrenaline, dobutamine, milrinone or levosimendan may be used. Noradrenaline is extremely short acting29 with a half-life of 1–2 minutes so breast milk levels would be expected to be very low. In addition, due to negligible oral bioavailability, the infant is not predicted to absorb any from their gastrointestinal tract. There is some concern from animal data that very high doses may interfere with the lactation process itself,30,31 although there is no clinical evidence to support this. Therefore, noradrenaline can be used during breastfeeding without any special precautions. Similarly, dobutamine is considered compatible due to favourable pharmacokinetic properties, including an extremely short half-life of around 2 minutes and negligible oral bioavailability.22

and low protein binding (around 40 %).23,32 Although levosimendan is unlikely to pass across into milk, the active metabolites will, with the potential for drug accumulation in the infant. There is one case report in which levosimendan and the active metabolite (OR–1896) were measured in maternal plasma and breast milk. Levosimendan was not detected in milk or plasma; only the active metabolite was detected in milk (0.08–0.10 ng/ml).33 Because experience of its use is limited, breastfeeding while being exposed to levosimendan must proceed with extreme caution. Although exposure in the mother will be for 24 hours, because of the extended half-life of the active metabolites, the infant will have to be monitored for adverse effects for around a week after cessation of therapy for signs of hypotension, cardiac arrhythmias, hypokalemia, anaemia and gastrointestinal disturbances.23 Expressing and discarding for a short period is not recommended since peak maternal plasma levels will only be reached after 2 days,33 with a lag time for when peak concentrations will enter breast milk. This makes it difficult to calculate when such an abstinence period may be most beneficial, while adding complications for the mother.

Pharmacotherapy in Stable Heart Failure Secondary to PPCM Blockade of the Rennin-angiotensin System Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in those who cannot tolerate an ACE inhibitor have been shown to improve survival in patients with heart failure through their effects on the renin-angiotensin-aldosterone system. They should be started once renal function and haemodynamic stability allow.4

Angiotensin-Converting Enzyme Inhibitors In general, ACE inhibitors have poor bioavailability but are metabolised to active metabolites which have long half-lives.23,32 An exception to this is lisinopril, which does not have an active metabolite and has a shorter half-life than other ACE inhibitors.23 Therefore, although the pharmacokinetic profile of lisinopril appears favourable, there is no data to support its use during breastfeeding. For other ACE inhibitors, where evidence is available, only very small amounts of the parent drug and its active metabolite have been found in breast milk.35,36,37,38,39,40 Enalapril is often the preferred option since it has the most published data supporting its use. One study calculated the level of infant exposure to enalapril as 0.16 % of the maternal weight-adjusted dose.37 Enalapril can also be used therapeutically from birth.24 Other ACE inhibitors can be considered for use during breastfeeding with caution.

Angiotensin II Receptor Blockers Milrinone with a low molecular weight (211) and protein binding (70 %) would suggest passage into breast milk.23 Despite it being given intravenously, it is almost completely absorbed after oral administration23 suggesting the infant will absorb what they are exposed to. Milrinone has a relatively short half-life of 2.3 hours, and is generally given in the acute phase to those unresponsive to other treatments. Because of its pharmacokinetics and adverse effect profile, it is advisable to temporarily disrupt breastfeeding during a milrinone infusion and for 8–10 hours after the infusion has been completed.25 The mother should be encouraged to express and discard breast milk during this time. Levosimendan has good oral bioavailability (85 %)32 and is extensively metabolised, with a short half-life of about one hour although its active metabolites (OR–1855 and OR–1896) have longer half-lives (75–80 hours)

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Angiotensin II receptor blockers (ARBs) have very high protein binding,23 so potentially there is less free drug available to pass into the breast milk compartment. Compared to other ARBs, losartan would be a preferable choice since it undergoes extensive first-pass metabolism, resulting in very low systemic bioavailability of around 33 %.41 In addition, the parent drug and its active metabolite have short half-lives (2 and 9 hours respectively).41 If choice allows for PPCM treatment, an ACE inhibitor would be preferable in terms of breastfeeding. However, if an ARB is required, breastfeeding can proceed with caution.

Angiotensin Receptor Neprilysin Inhibitor (ARNI) The recently marketed angiotensin receptor neprilysin inhibitor (ARNI; sacubitril valsartan) complex has no published data regarding use during breastfeeding. Neither is there any evidence of use during breastfeeding of it component parts individually. After oral

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Postpartum Cardiomyopathy and Breastfeeding administration, the complex readily dissociates. The use of valsartan has been discussed above in the context of ARBs. Sacubitril has favourable pharmacokinetics, with a reasonably short half-life of the parent drug and metabolite (1.4 and 11.5 hours), high plasma protein binding (around 95 %), and relatively low oral bioavailability of both parent and metabolite (60 % and 23 %).42 Therefore, although evidence is lacking, its use should not pose significant risk to the breastfeeding infant. Use of the complex can therefore proceed with caution. With any of the medicines used for blocking the renin-angiotensin system (ACE inhibitors, ARBs or ARNIs), the breastfed infant should be monitored for hypotension (especially in neonates), drowsiness, lethargy, and poor feeding and weight gain. In a newborn infant, renal function should be monitored24,25,41,42,43 In addition, the infant should be monitored for hyperkalemia if sacubitril valsartan is used.42

Mineralocorticoid receptor antagonists Mineralocorticoid receptor antagonists (MRAs) are recommended in patients with heart failure and an ejection fraction of 35 % or less who remain symptomatic despite treatment with beta-blockers and ACE inhibitors. Eplerenone and spironolactone have both been shown to reduce mortality in heart failure.4 Spironolactone is the preferred choice during breastfeeding, although there is only one published case report for its use. This showed that from measured breast milk levels, only negligible amounts of the active metabolite canrenone (0.2 %) would be received by a breastfeeding infant.48 In addition, spironolactone can be used in full term neonates from birth.25 There is no data for the use of eplerenone during breastfeeding, but use would not be expected to pose any significant risk to the infant. Therefore breastfeeding can proceed with caution. As with all diuretics, there is a concern that intense diuresis can affect the milk supply.27,28 Therefore, if high doses or combinations are used, the mother’s milk supply should be monitored by checking if the infant is putting on weight adequately. The infant should also be monitored for fluid loss, dehydration, and lethargy.25

good oral bioavailability (90 %), a comparatively longer half-life (10–12 hours) and moderate lipid solubility.23 It has relatively high renal excretion (50 %),23 which can potentially lead to drug accumulation. However, there is one case report in which bisoprolol levels were measured in breast milk; the levels were undetectable, which is reassuring.49 Carvedilol has a more favourable pharmacokinetic profile during breastfeeding, with very high protein binding (98 %), low oral bioavailability (25 %) due to first-pass metabolism, and a shorter halflife (6 hours).23,50 However, it has high lipid solubility,23,50 suggesting that some passage into breast milk would be expected. Nebivolol is metabolised via cytochrome P450 enzyme CYP2D6, which is subject to genetic polymorphism. This leads to wide inter-patient variability in peak plasma concentrations and elimination half-lives.23 For example, the peak plasma concentration of nebivolol is about 23 times higher in poor metabolisers than extensive metabolisers.51 Although the clinical significance of this remains uncertain,52 it becomes difficult to extrapolate how much nebivolol will transfer into breast milk, and consequently how an infant will respond. However, although nebivolol has high protein binding (98 %), it also has high lipid solubility.23 Overall, passage into breast milk would still be expected. Some studies have potentially implicated beta-blockers in causing adverse effects in breastfed infants,53,54,55 although there have been no reports of this happening directly with bisoprolol, carvedilol or nebivolol. Based on the available evidence, metoprolol succinate would be the choice in breastfeeding if available. If it is not available, carvedilol would be a preferred second choice option, although bisoprolol can be used with caution. The use of nebivolol should be avoided where possible, and should be considered only if other beta-blockers are not suitable. Infants exposed to beta-blockers via breast milk should be monitored for drowsiness, lethargy, beta-blockade (especially bradycardia), and poor feeding and weight gain.

Beta-blockers

Other Pharmacological Treatments

Beta-blockers, given together with ACE inhibitors, are first-line therapy in patients with heart failure, reducing mortality through modulation of neurohormonal activation. Propranolol and metoprolol are usually the preferred choice of beta-blockers during breastfeeding because of available evidence, favourable pharmacokinetic profiles and use in the paediatric population.

Additional therapeutic options may need to be administered to those presenting with PPCM and can be given to patients who remain symptomatic despite optimum therapy with ACE inhibitors, betablockers and MRAs. The following considerations must be taken into account in mothers that are breastfeeding.

Digoxin Comparatively, there is a reasonable amount of evidence to support the use of metoprolol during breastfeeding with no adverse effects reported to date. Only small amounts have been found in breast milk (0.5–2 % of the maternal weight adjusted dose)44,45 and extremely low or undetectable infant serum levels.46,47 Other favourable characteristics include low bioavailability (around 50 %) and a short half-life (3–7 hours), 23 as well as use in infants therapeutically from 1 month. Within the UK, metoprolol succinate is unlicensed and not readily available (unlike the tartrate salt) and, as such, bisoprolol, carvedilol or nebivolol are often preferred options regarding PPCM management. Pharmacokinetically, bisoprolol does not have a favourable profile compared to other beta-blockers: it has very low protein binding (30 %),

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Although digoxin does not have a favourable pharmacokinetic profile, there is evidence to show that in practice, levels found in breast milk are very low. Oral doses of 0.25–0.75 mg daily give breast milk levels ranging from 0.41–1.9 μg/litre.56,57,58,59 In two of these studies, the infant serum level was measured and found to be undetectable in one infant whose mother was taking 0.25 mg daily for 10 days, and 0.2 μg/litre after a 0.75 mg daily dose.57,59 In one study, 11 women were given 0.5 mg intravenous digoxin as a single dose; from the data, it was extrapolated that an infant serum level of only 3 % of the maternal therapeutic dose would be achieved.60 There have been no adverse effects reported in infants exposed to digoxin via breast milk. In addition, digoxin can be used from birth therapeutically.24 Digoxin is therefore considered compatible with breastfeeding and no special monitoring is required.25

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Clinical Syndromes Table 1: Compatibility of Medicines Used in PPCM Management With Breastfeeding Drug

Use in Breastfeeding

Infant Monitoring

Comments

Diuretics Furosemide

Caution

Bumetanide

Caution

Bendroflumethiazide

Caution

Metolazone

Caution

Preferred choice loop diuretic Used in neonates from birth Fluid loss, dehydration, lethargy and adequate weight gain

Preferred choice thiazide diuretic

Inotropes and Vasodilators Noradrenaline

Yes – negligible risk

Nil

Dobutamine

Yes – negligible risk

Nil

Glyceryl trinitrate (short term use)

Caution

Flushing after feeding

No oral bioavailability for the infant

Levosimendan

Extreme caution

Hypotension, cardiac arrhythmias, hypokalemia, anaemia and gastrointestinal disturbances

If given, continue to monitor infant for a week after cessation of therapy

Milrinone

Avoid

Monitoring not required since abstinence period eliminates risk

Concomitant breastfeeding not recommended: express and discard during infusion and for 8–10 hours after

Blockade of the Rennin Angiotensin System ACE* inhibitor

Caution

ARB† (although ACE inhibitor considered firstline)

Caution

Sacubitril valsartan

Caution

Hypotension, drowsiness, lethargy, poor feeding and weight gain. If used in a neonate, monitor renal function

Enalapril considered first-line Losartan considered preferred choice

If sacubitril valsartan used, also monitor for hyperkalemia

Mineralocorticoid Receptor Antagonists Spironolactone

Yes – low risk

Eplerenone

Caution

Fluid loss, dehydration, lethargy and adequate weight gain

Spironolactone considered preferred choice

Beta-blockers Metoprolol

Yes – low risk

Bisoprolol

Caution

Carvedilol

Caution

Nebivolol

Extreme caution

Metoprolol preferred choice (if available), followed by carvedilol Drowsiness, lethargy, beta-blockade (especially bradycardia), poor feeding and weight gain

Other Pharmacological Treatments Digoxin

Yes – negligible risk

No special monitoring required

Hydralazine

Yes – negligible risk

No special monitoring required

Isosorbide dinitrate

Caution

Drowsiness, lethargy, poor feeding and weight gain

Ivabradine

Extreme caution

Bradycardia and arrhythmias, poor feeding and weight gain

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blockers.

Hydralazine Hydralazine is considered compatible with breastfeeding. There is a wealth of experience of its use in the postpartum period and it can be used therapeutically from birth. 24 It has a favourable pharmacokinetic profile – low bioavailability (around 35 %), good protein binding (90 %), and a short half-life (maximum 8 hours).23 One study reported the milk level as 130 μg/l from a hydralazine dose of 30 mg three times daily; this was calculated as the infant being exposed to 13 μg hydralazine per feed.61 In another study of 10 lactating women taking hydralazine doses of between 10 mg and 40 mg, the average milk concentration was 240 nmol/l; the authors calculated that an infant would not be exposed to any more than 25 μg per day. In this study, serum levels were measured in two infants and shown to be only 4–7 % after direct infant therapeutic

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administration.62 Breastfeeding can therefore proceed with no special monitoring requirements.

Isosorbide Dinitrate Isosorbide dinitrate has low molecular weight (236), low protein binding and variable bioavailability (10–90 %).23,32 There is concern that nitrates may cause nitrate intoxication in infants because they are susceptible to methaemaglobinaemia.25 This risk increases with high doses and long-term use24 but is a rare side-effect, even when infants are exposed to isosorbide dinitrate directly.32 Amounts in breast milk are unlikely to present an issue, even with long-term exposure. Isosorbide dinitrate can therefore be used during breastfeeding with caution. Infants should be monitored for drowsiness, lethargy, and poor

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Postpartum Cardiomyopathy and Breastfeeding feeding and weight gain. Flushing is an unlikely side-effect in the infant when used at lower doses longer term.

be reviewed for their suitability in breastfeeding to minimise the risk of harm to the infant, while optimising therapy for the mother.

Ivabradine

Disclaimer

Its molecular weight (467) and protein binding (70 %)23,63 suggest that excretion into breast milk would be expected. However, ivabradine has low oral bioavailability (40 %) due to extensive first pass metabolism.62 Ivabradine has been identified as a teratogen in animal studies, although it is unclear what effect, if any, the potentially low levels in breast milk could have on the developing infant. Until more is known about ivabradine in breast milk, it must be used with extreme caution. The infant should be monitored for bradycardia and arrhythmias, and poor feeding and weight gain.5

The risk assessments provided apply to maternal monotherapy and a healthy infant born at term. When mothers are on combinations of therapies, additive side-effect profiles need to be considered. Should the infant be premature or unwell, or if the mother taking extensive multiple medications, an individual risk assessment is required and specialist advice should be sought. n

Conclusion Management of PPCM in a breastfeeding mother is challenging, given the complexities surrounding diagnosis and pharmacokinetic considerations in breastfeeding. On-going data collection through an international registry aims to provide further details on disease presentation, comorbidities, diagnostic and therapeutic management of patients with PPCM, as well as information on their offspring;9 this will help to clarify efficacy and safety of pharmacotherapy in PPCM. In any case, diagnosis should be made swiftly to allow prompt initiation of treatment. Pharmacokinetic considerations in breastfeeding should

liwa K, Petrie MC, Hilfiker-Kleiner D, et al. Long-term S prognosis, subsequent pregnancy, contraception and overall management of peripartum cardiomyopathy: practical guidance paper from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy. Eur J Heart Fail 2018;20:951–62. https://doi. org/10.1002/ejhf.1178. PMID:29578284. 2. CardiomyopathyUK. Peripartum cardiomyopathy. 2018. Available at: www.cardiomyopathy.org/peripartumcardiomyopathy/intro (accessed 25 July 2018). 3. Arany Z, Elkayam U. Peripartum cardiomyopathy. Circulation 2016;133(14):1397–409. https://doi.org/10.1161/ CIRCULATIONAHA.115.020491. PMID:27045128. 4. 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(27):2129–200. https://doi. org/10.1093/eurheartj/ehw128. PMID:27206819. 5. Sliwa K, Mebazaa A, Hilfiker-Kleiner D et al. Clinical characteristics of patients from the worldwide registry on peripartum cardiomyopathy (PPCM): EURObservational Research Programme in conjunction with the Heart Failure Association of the European Society of Cardiology Study Group on PPCM. Eur J Heart Fail 2017;19:1131–41. https://doi. org/10.1002/ejhf.780. PMID:28271625. 6. Victora CG, Bahl R, Barros AJD et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect (breastfeeding 1). Lancet 2016;387:475–90. https://doi. org/10.1016/S0140-6736(15)01024-7. 7. Lawrence RA, Lawrence RM. Breastfeeding: A Guide for the Medical Profession. 8th ed. Philadelphia: Elsevier, 2016. 8. World Health Organization. Global strategy for infant and young child feeding. 2003. Available at: http://apps.who.int/ iris/bitstream/handle/10665/42590/9241562218.pdf (accessed 25 July 2018). 9. Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93. https://doi. org/10.1590/1806-9282.62.06.584. PMID:27849237. 10. Shah PS, Herbozo C, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain in neonates (review). Cochrane Database Syst Rev 2012;12 Dec. Art No: CD004950. https://doi. org/10.1002/14651858.CD004950.pub3. PMID:23235618. 11. Thompson JMD, Tanabe K, Moon RY et al. Duration of breastfeeding and risk of SIDS: an individual participant data meta-analysis. Pediatrics. 2017;140(5):pii:e20171324. https://doi. org/10.1542/peds.2017-1324. PMID: 29084835. 12. Wallby, T, Lagerberg D, Magnusson M. Relationship between breastfeeding and early childhood obesity: results of a prospective longitudinal study from birth to 4 years. Breastfeed Med 2017;12(1):48–53. https://doi.org/10.1089/bfm.2016.0124.

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Clinical Perspective • D ocumented evidence for the use of medicines during breastfeeding is largely very poor, if available at all, often leading to an incorrect decision that the mother should not breastfeed. • Many factors affect infant drug exposure via breastmilk, including pharmacokinetics, pharmacodynamics, and the clinical condition of mother and infant. All of these factors should be used to assess the risk-benefit of continuing breastfeeding while taking medication. • There are very few medicines in the management of PPCM which truly require a breastfeeding abstinence period. • Currently those presenting with PPCM should be encouraged to breastfeed if they choose to do so, with any risks being managed with adequate infant monitoring.

PMID:27991826. 13. G ilman MW, Rifas-Shiman SL, Camargo CA, Berkey CS et al. Risk of overweight among adolescents who were breastfed as infants. JAMA 2001;285:2461–7. https://doi.org/10.1001/ jama.285.19.2461. PMID:11368698. 14. Quigley MA, Hockley C, Carson C, et al. Breastfeeding is associated with improved child cognitive development: a population-based cohort study. J Epidemiol Community Health 2009;63(Suppl_2):8. https://doi.org/10.1016/j. jpeds.2011.06.035. PMID: 21839469. 15. Victora CG, Horta BL, Loret de Mola C et al. Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil. Lancet Glob Health 2015; 3: e199–205. https://doi.org/10.1016/S2214-109X(15)70002-1. PMID:25794674;PMCID:PMC4365917. 16. Lööf-Johanson M, Brudin L, Sundquist M, Rudebeck CE. Breastfeeding associated with reduced mortality in women with breast cancer. Breastfeed Med 2016;11(6):321–7. https:// doi.org/10.1089/bfm.2015.0094; PMID:27269432. 17. Beral V. Breast cancer and breastfeeding: collaborative reanalysis of individual data. 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002;360:187– 95. https://doi.org/10.1016/S0140-6736(02)09454-0. PMID:12133652. 18. Sung, HK, Ma SH, Choi JY et al. The effect of breastfeeding duration and parity on the risk of epithelial ovarian cancer: a systematic review and meta-analysis. J Prev Med Public Health 2016;49(6):349–66. https://doi.org/10.3961/jpmph.16.066; PMID:27951628 PMCID:PMC5160134. 19. Gunderson EP, Lewis CE, Lin Y et al. Lactation duration and progression to diabetes in women across the childbearing years. JAMA Intern Med 2018;178(3):328–37. https://doi. org/10.1001/jamainternmed.2017.7978. PMID:29340577. 20. Steube AM, Schwarz EB, Grewen K et al. Duration of lactation and incidence of maternal hypertension: a longitudinal cohort study. Am J Epidemiol 2011; 174(10):1147–58. https://doi.org/10.1093/aje/kwr227. PMID:21997568; PMCID:PMC3246687. 21. Baker TE, Cooper SD, Kessler L, Hale TW. Transfer of natalizumab into breast milk in a mother with multiple sclerosis. J Hum Lact 2015;31(2):233–6. https://doi. org/10.1177/0890334414566237. PMID:25586712. 22. Fritzsche J, Pilch A, Mury D, et al. Infliximab and adalimumab use during breastfeeding. J Clin Gastroenterol 2012; 46(8):718–9. https://doi.org/10.1097/MCG.0b013e31825f2807. PMID:22858514. 23. Brayfield A (ed). Martindale: the complete drug reference. London: Pharmaceutical Press. Available at: www.medicinescomplete.com (accessed 25 July 2018).

24. P aediatric Formulary Committee. BNF for children. London: BMJ Group, Pharmaceutical Press and RCPCH Publications. Available at: www.medicinescomplete.com (accessed 25 July 2018). 25. UK Drugs in Lactation Advisory Service (UKDILAS). Lactation safety information. Available at: www.sps.nhs.uk (accessed 25 July 2018). 26. Accord UK. Summary of product characteristics. Bendroflumethiazide tablets BP 2.5 mg. 2015. Available at: www.medicines.org.uk/emc/product/5727/smpc (accessed 25 July 2018). 27. Cominos DC, Van Der Walt A, Van Rooyen AJ. Suppression of postpartum lactation with furosemide. S Afr Med J 1976; 50:251–2. https://doi.org/10.1097/00006254-197611000-00004. PMID:3858. 28. Stout G. Suppression of lactation. Br Med J 1962;1:1150. Letter. PMCID:PMC1958377. 29. Hospira UK. Summary of product characteristics. Noradrenaline (norepinephrine) 1 mg/ml concentrate for solution for Infusion. 2018. Date of revision 05/2018. Available at: www.medicines.org.uk/emc/product/4115/smpc (accessed 25 July 2018). 30. Thomas GB, Cummins JT, Doughton BW et al. Direct pituitary inhibition of prolactin secretion by dopamine and noradrenaline in sheep. J Endocrinol 1989;123:393–402.https:// doi.org/10.1677/joe.0.1230393. PMID:2607250. 31. Song SL, Crowley WR, Grosvenor CE. Evidence for involvement of an adrenal catecholamine in the betaadrenergic inhibition of oxytocin release in lactating rats. Brain Res 1988;457:303–9. https://doi.org/10.1016/00068993(88)90700-7. PMID:2851365. 32. DRUGDEX® System: Klasco RK (cd). DRUGDEX® System. Truven Health Analytics (Greenwood Village, Colorado, updated periodically). Available at: www.micromedexsolutions.com/home/dispatch. 33. Orion Pharma. Summary of product characteristics. Simdax 2.5 mg/ml concentrate for solution for infusion. 2010. www. simdax.com/siteassets/simdax-spc.pdf (accessed 25 July 2018). 34. Benlolo S, Lefoll C, Katchatouryan V, et al. Successful use of levosiemendan in a patient with peripartum cardiomyopathy. Anesth Analg 2004;98:822–4. https://doi.org/10.1213/01. ANE.0000099717.40471.83. PMID:14980944. 35. Huttunen K, Gronhagen-Riska C, Fyhrquist F. Enalapril treatment of a nursing mother with slightly impaired renal function. Clin Nephrol 1989;31:278. Letter. PMID:2544326 36. Rush JE, Snyder DL, Barrish A, Hichens M. Comment on Huttunen K, Gronhagen-Riska C, Fyrquist F. Enalapril treatment of a nursing mother with slightly impaired renal function. Clin Nephrol 31:278. Clin Nephrol 1991;35:234. Letter. PMID:1649713. 37. Redman CWG, Kelly JG, Cooper WD. The excretion of

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38.

39.

40.

41.

42.

43.

44.

45.

46.

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