CFR 4.1

Cardiac Failure Review Volume 4 • Issue 1 • Spring 2018

©Radcliffe Cardiology

Volume 4 • Issue 1 • Spring 2018

www.CFRjournal.com

Optimising Heart Failure Therapies in the Acute Setting Mattia Arrigo, Petra Nijst and Alain Rudiger

Left Ventricular Dysfunction in the Setting of Takotsubo Cardiomyopathy: A Review of Clinical Patterns and Practical Implications Kenan Yalta, Mustafa Yılmaztepe and Cafer Zorkun

Ablation for Atrial Fibrillation in Heart Failure with Reduced Ejection Fraction Jackson J Liang and David J Callans

Identification and Treatment of Central Sleep Apnoea: Beyond SERVE-HF William T Abraham, Adam Pleister and Robin Germany

3D human heart

ISSN: 2057-7540 CFR 4.1_FC.indd All Pages

Plant-based diets to prevent and treat heart failure

Abnormal ECG showing atrial fibrillation, arterial blood pressure and oxygen saturation

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Organised by the Heart Failure Association of the ESC

HEART FA I LU R E including the

2018

World Congress on Acute Heart Failure

2 9 6 2 M AY

VIENNA Heart Failure: classical repertoire, modern instruments

w w w. e s c a r d i o . o r g / h e a r t f a i l u r e

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Volume 4 • Issue 1 • Spring 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

Stanford University, USA

The Ohio State University, USA

National University Heart Center, Singapore

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

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 Henry J Dargie

Carmine De Pasquale

Theresa A McDonagh

Michal Tendera

Kenneth McDonald

Maurizio Volterrani

Ileana L Piña

Cheuk Man Yu

St Vincent’s Hospital, Ireland

Flinders University, Australia

Frank Edelmann

Charité University Medicine, Germany

Hospital of the University of Pennsylvania, USA

Allan D Struthers

King’s College Hospital, UK

Western Infirmary, Glasgow

St George’s University of London, UK

Alexander Lyon

Imperial College London, UK

Paris Diderot University, France

University of Otago, New Zealand

Montefiore Einstein Center for Heart & Vascular Care, USA

Ninewells Hospital & Medical School, UK University of Silesia, Poland IRCCS San Raffaele Pisana, Italy The Chinese University of Hong Kong, Hong Kong

Managing Editor Rosie Scott • Production Helena Clements • 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 Circulation & Commercial Contact David Ramsey david.ramsey@radcliffe-group.com •••

Cover image

credit: medistock © stock.adobe.com / Boxes credit: © www.shutterstock.com

•

Cover design Tatiana Losinska

Cardiology

Lifelong Learning for Cardiovascular Professionals

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 there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

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: Spring 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, Leiah Norcott leiah.norcott@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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© RADCLIFFE CARDIOLOGY 2018

Contents

www.CFRjournal.com

Foreword

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Andrew JS Coats and Giuseppe Rosano

Clinical Syndromes

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What is Heart Failure with Mid-range Ejection Fraction? A New Subgroup of Patients with Heart Failure Sunil K Nadar and Osama Tariq

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Heart Failure with Mid-Range Ejection Fraction and How to Treat It Yuri Lopatin

Left Ventricular Dysfunction in the Setting of Takotsubo Cardiomyopathy: A Review of Clinical Patterns and Practical Implications Kenan Yalta, Mustafa Yılmaztepe and Cafer Zorkun

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Heart Failure in Sub-Saharan Africa Joseph Gallagher, Kenneth McDonald, Mark Ledwidge and Chris J Watson

Treatment

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Pharmacological Interventions Effective in Improving Exercise Capacity in Heart Failure Cristiana Vitale, Ilaria Spoletini and Giuseppe MC Rosano

Iron Therapy in Heart Failure: Ready for Primetime?

Ify R Mordi, Aaron Tee and Chim C Lang

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Ablation for Atrial Fibrillation in Heart Failure with Reduced Ejection Fraction

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Optimising Heart Failure Therapies in the Acute Setting

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Ambulatory Intra Aortic Balloon Pump in Advanced Heart Failure

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Bromocriptine for the Treatment of Peripartum Cardiomyopathy

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Identification and Treatment of Central Sleep Apnoea: Beyond SERVE-HF

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A Review of Plant-based Diets to Prevent and Treat Heart Failure

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Erratum

Jackson J Liang and David J Callans

Mattia Arrigo, Petra Nijst and Alain Rudiger

Syed Yaseen Naqvi, Ibrahim G Salama, Ayhan Yoruk and Leway Chen

Tobias Koenig, Johann Bauersachs and Denise Hilfiker-Kleine

William T Abraham, Adam Pleister and Robin Germany

Conor P Kerley

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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

W

e have great pleasure in introducing the latest issue of Cardiac Failure Review. We have been impressed with the extra information that has flooded in concerning the new classification of heart failure (including for the first time heart failure with mid-range ejection fraction [HFmrEF]) popularised by the influential 2016 European Society of Cardiology and Heart Failure Association Guidelines.1 What we were aiming for by introducing this new classification was twofold: a clearer separation between HFrEF, where many treatments had been proven to be effective and heart failure with preserved ejection fraction (HFpEF) where none had, and the encouragement for further analyses and trials in this new group with left ventricular ejection fraction (LVEF) in the range of 40–49 %. The second aim will take some time to complete in terms of new trials, as these take many years to design and complete. The first part of this, however, has come through brilliantly, with new analyses of both the CHARM programme of Candesartan cilexetil2 and the beta-blocker trialists' meta-analysis group.3 In both cases, we can clearly say now that there is prospective evidence

that mortality and morbidity outcomes are improved by these two treatment classes also in HFmrEF, and we can also say the absence of benefit in HFpEF still remains. Nadar and Tariq in this issue elegantly review the aetiology and pathophysiology of HFmrEF, its clinical profile, the most appropriate diagnosis and the prognosis for these patients. Yuri Lopatin also reviews the therapies available for HFmrEF, noting that doctors are already treating HFmrEF, with multiple registries showing that the rate of prescription of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists and beta-blockers is quite high in patients with HFmrEF, probably because of analyses showing that HFmrEF patients, in contrast to patients with HFpEF, had a benefit in prognosis similar to those with HFrEF when guideline-recommended therapies were tested. In addition to the two examples we quote above, Lopatin also reviews evidence from a post-hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) that revealed a reduction in the primary endpoint (a composite of death from cardiovascular causes, aborted cardiac arrest or HF hospitalisation) in HFpEF patients on the lower end of the ejection fraction spectrum – LVEF 45–49 %, but not when LVEF was >60 % (LVEF <50 %: HR=0.72; LVEF ≥60 %: HR=0.97, p=0.046). This will not be the end of this particular story, because clinicians are already asking whether we should consider patients with stable LVEF in the 40–49 % range differently to those with recovered ejection fraction, where it has increased from levels <40 % after the introduction of effective therapies for HFrEF. As always, more trials and more analyses are needed to answer this important question.

Later in the issue, Yalta and colleagues review the very contemporary issue of the implication of different clinical patterns of left ventricular dysfunction in the setting of Takotsubo cardiomyopathy. They raise the worrying suggestion that, despite apparent recovery in left ventricular function after a bout of Takotsubo, microscopic changes at the cellular level may cause long-term damage to myocardial function, including persistent diastolic dysfunction and subclinical left ventricular systolic dysfunction. The implications of this phenomenon on subsequent symptomatology and prognosis, particularly exercise- or stress-induced complications among Takotsubo cardiomyopathy survivors, is deserving of further study.

Gallagher and colleagues review the emerging crisis of heart failure in sub-Saharan Africa. The co-existence of multiple trends is impacting on this region. Its growing population, the ageing of its population and the rapidly increasing prevalence of atherosclerotic risk factors are making heart failure much more common, adding ischaemic and age-related heart failure to the hitherto more common aetiologies in Africa, such as rheumatic heart disease and endomyocardial fibrosis. This combined with a relative deficiency in access to care and diagnostic techniques, such as echocardiography, which when combined with a patchy availability of guideline-recommended treatments, means that there is much avoidable mortality and morbidity due to heart failure in this region. They highlight the potential future role of more widespread biomarkers to facilitate access decisions to sub-optimally available resources, such as clinical echocardiography, for these patient populations.

DOI: 10.15420/cfr.2018.4.1.FO1

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Foreword

Vitale et al. review which pharmacological interventions we have available to improve the otherwise very limited exercise capacity of some heart failure subjects. This list is not synonymous with treatments that improve prognosis. They conclude, somewhat counterintuitively, if you consider what most doctors consider effective heart failure medication, that the only heart failure drugs recommended in the 2016 European Society of Cardiology heart failure guidelines that have been convincingly shown to increase exercise capacity for heart failure sufferers are ivabradine, trimetazidine and intravenous iron. They then summarise their beneficial effects on HF symptoms, physical performance and quality of life. Intravenous iron is further reviewed in detail by Mordi et al., who conclude that iron deficiency (even without anaemia) is much more common in patients with heart failure than we suspected, and may well be under-diagnosed in routine clinical practice. They summarise the clinical trials of intravenous iron replacement that have shown benefits in exercise capacity and symptoms, and recommend that intravenous iron should be considered in symptomatic heart failure patients with documented iron deficiency (and furthermore, as the guidelines state, that we should investigate heart failure patients for the presence of such iron deficiency). They also highlight that ongoing trials will provide further evidence as to the long-term effects on mortality and hospitalisation of this type of therapy. One word of warning, however; the majority of published studies performed have evaluated ferric carboxymaltose and other forms of intravenous iron and, in particular, oral iron therapy, which might not show the same benefits and therefore cannot be recommended. Whether other intravenous iron preparations provide any benefit, as well as the optimal dose and duration, remains yet to be confirmed, as does whether the benefits will also extend in to HFpEF and HFmrEF populations with iron deficiency.

Other extremely hot topics are reviewed, including the potential for catheter ablation therapy of AF in heart failure after the groundbreaking Catheter Ablation versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and AF (CASTLE-AF) trial,4 and the contemporary role of the therapy of central sleep apnoea (CSA) in heart failure, as reviewed by Abraham et al. Liang and Callans review the increasing dual burdens of AF and heart failure in our ageing population and how the two conditions interact to worsen patient outcomes. They remind us that modern heart failure guidelines recommend the use of the CHA2DS2-VASc and HASBLED risk scores is decision-making around oral anticoagulation, which is usually recommended for stroke prophylaxis in this setting.

Beta-blockers have long been considered the cornerstone of heart failure therapy in patients with HFrEF, yet the beneficial effect of these medications in patients with HFrEF appears to be mitigated by the co-existence of AF. Large meta-analyses have shown that beta-blockers significantly reduce both all-cause mortality and cardiovascular hospitalisations in patients in sinus rhythm, but not AF, despite similar degrees of ventricular rate reduction in both groups. They review ablation studies in heart failure with AF, noting that, to date, the optimal strategy for rhythm control has remained uncertain. A large number of retrospective observational studies and a few randomised controlled trials had suggested catheter ablation may help clinical outcomes in this setting. The CASTLE-AF study is the most recent randomised controlled trial in this setting. The primary endpoint (the composite of all-cause mortality and unplanned hospitalisation for worsening heart failure) was reduced by 38 % (p=0.007) compared to controls, and all-cause mortality was also reduced (13.4 versus 25 %; HR 0.53, 95 % CI [0.32–0.86], p=0.011). They conclude that although more trials are needed, AF ablation should be considered as an adjunctive treatment strategy for patients with HFrEF and AF. Abraham and colleagues review the treatment of CSA in HFrEF patients following the adverse findings in the SERVE-HF trial.5 They conclude that CSA is an important adverse prognostic factor for HFrEF patients, and that quality of life can be improved with treatment with the novel strategy of an implantable phrenic nerve stimulator. Although improving quality of life in heart failure patients is extremely valuable in its own right, we continue to wait for data demonstrating that the improvements in sleep apnoea events, oxygenation and arousals produced by such a device would lead to improvements in cardiovascular outcomes in the HFrEF population.

Arrigo and colleagues introduce us to the management of a complex part of the heart failure clinical story, that of acute heart failure.

After reviewing the clinical features of acute heart failure, they review our management options during the hospital stay and in the crucial early post-discharge period. They review essential early interventions, taking into account clinical presentation, pathophysiological features and any precipitating factors. They stress the important part that comorbidities play in this setting. They recommend individually personalised therapy after a '7-P evaluation': phenotype, pathophysiology, precipitants, pathology, polymorbidity, potential harms and preferences.

Readers are recommended then to consider more specialised topics, such as the article by Naqvi et al. on ambulatory intra aortic balloon pump in advanced heart failure, and that by Koenig and colleagues on the potential for bromocriptine in the treatment of peripartum cardiomyopathy. Lastly, the article by Kerley is helpful for all those doctors, who like us are asked about natural and dietary therapies and their effect in heart failure, in his masterly summary of plant-based diets in the prevention and treatment of heart failure. We hope you enjoy reading our latest issue of Cardiac Failure Review as much as we did in compiling it from the excellent work of our contributors. n 1.

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. DOI: 10.1093/ eurheartj/ehw128; PMID: 27206819.

Lund LH, Claggett B, Liu J, et al. Heart failure with mid-

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range 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 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.

4.

5.

DOI: 10.1093/eurheartj/ehx564; PMID: 29040525.

Marrouche NF, Brachmann J, Andresen D, et al.

Catheter ablation for atrial fibrillation with heart failure.

N Engl J Med 2018;378:417–27. DOI: 10.1056/ NEJMoa1707855.

Cowie MR, Hoehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. New Engl J Med 2015;373:1095–105. DOI: 10.1056/ NEJMoa1506459; PMID: 26323938..

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AUTHOR ‘cilexitil’ has been changed ‘cilexetil’ Please confirm that this modifica is correc

Clinical Syndromes

What is Heart Failure with Mid-range Ejection Fraction? A New Subgroup of Patients with Heart Failure Sunil K Nadar and Osama Tariq Sultan Qaboos University Hospital, Muscat, Oman

Abstract Since the publication of European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure (HF) in 2016, a new class of HF has been defined, namely HF with mildly reduced ejection fraction (HFmrEF). Although the name was new, there had long been awareness of the existence of a grey area between the two established classes of HF: HF with reduced ejection fraction and HF with preserved ejection fraction. Patients between these two classes were previously either excluded from HF studies or were included in the other groups. With the definition of this new group of patients, a door has opened for researchers to further explore their characteristics, treatment and outcomes. In this article we aim to clarify the existing literature on the clinical characteristics and pathophysiology of this newly-defined group of patients.

Keywords Acute and chronic heart failure, left ventricular ejection fraction, heart failure with reduced ejection fraction, heart failure with mid-range ejection fraction, heart failure with preserved ejection fraction Disclosure: The authors have no conflicts of interest to declare.

Received: 30 January 2018 Accepted: 24 March 2018. Citation: Cardiac Failure Review 2018;4(1):6–8. DOI: https://doi.org/10.15420/cfr.2018:7:2 Correspondence: Dr Sunil K Nadar, Senior Consultant Cardiologist, Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman. E: sunilnadar@gmail.com

The latest guidelines on the diagnosis and management of heart failure (HF) published by the European Society of Cardiology (ESC) introduced a new class of HF: HF with mid-range ejection fraction (HFmrEF).1 This was in addition to the previously-defined classes: HF with reduced ejection fraction (HFrEF), in which the left ventricular ejection fraction (LVEF) is below 40 %, and HF with preserved ejection fraction (HFpEF), in which the LVEF exceeds 50 %. Although the terminology is new, it should be remembered that even the previous ESC guidelines on the management of HF, published in 2012, acknowledged the existence of this ‘grey area’ between the two previously-defined groups.2 Therefore, what these new guidelines have done is merely legitimised this grey area as a distinct entity by giving it a name. It is estimated that the proportion of HF patients falling within this intermediate group is 13–24 %.3–5

in this group was in between those in patients with HFpEF and HRrEF. On the other hand, Pascual-Figa et al. recently showed that patients in the intermediate category of HFmrEF match a phenotype closer to the clinical profile of HFrEF, associated with a higher risk of sudden cardiac death and cardiovascular death than patients with HFpEF.6 Still other registries showed that the prognosis of HFmrEF patients is similar to those with HFpEF.7,12

Aetiology and Pathophysiology HF has many underlying pathologies, including both cardiovascular and systemic conditions. Evaluating the specific cause has profound significance in the diagnosis and treatment of different types of HF. Patients with HFpEF or HFrEF have different epidemiological and aetiological profiles. Typically, those with HFpEF are older, female and with a history of hypertension and AF,13 whilst those with HFrEF are comparatively younger and have a higher rate of ischaemic heart disease or cardiomyopathy, diabetes and other cardiovascular risk factors.14

The guideline authors state that the main reason for the introduction of this new group was to give it importance in its own right, as this group of patients are usually not included in either HFpEF or HFrEF trials. However, this new entity is still confusing for many physicians due to overlapping clinical presentation, management and outcomes.

As desired by the guideline authors, subsequent to the publication of these guidelines, there have been many papers on this group of patients, which were mainly new analyses of previous studies, or a re-examination of new data. These studies have shown that patients with HFmrEF exhibit significant differences compared to those with HFrEF and HFpEF.6–8 It is also known that patients with HFrEF and HFpEF have different responses to conventional HF therapies, with the latter generally being less responsive.9–11

The underlying pathophysiology of HFmrEF is not clear, although it appears that it may be associated with both mild systolic and diastolic dysfunction. It has been recognised that a subset of patients with HFrEF previously had HFpEF.15 Thus, this intermediate category could be a group of patients in the HFpEF population who have progressive LV dysfunction.15,16 It could also comprise a subset of patients with HFrEF that has improved with treatment; such patients may be clinically distinct from those with persistently preserved or reduced EF and would have a better prognosis.17

So where do HFmrEF patients fit in? The results have been mixed.

Chioncel et al. recently published their findings on the analysis of the ESC HF Long-Term Registry.8 They found that the long-term mortality rate

It has been hypothesised that HFmrEF is actually a subset of HFpEF in which patients acquire coronary artery disease and are progressing to HFrEF.16 Data from the Organized Program to Initiate Lifesaving

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What is Heart Failure with Mid-Range Ejection Fraction?

Treatment in Hospitalized Patients with HF (OPTIMIZE-HF) and the Acute Decompensated HF Registry (ADHERE) studies have shown the distinct characteristics, management and outcomes of patients with mildly reduced LVEF, distinguishing them from patients with HFrEF and HFpEF.18,19 Patients with HFmrEF have also been shown to have multiple comorbidities. Kapoor et al. have described a higher incidence of diabetes, AF, chronic obstructive pulmonary disease (COPD), anaemia and renal insufficiency in these patients compared with the other HF groups.3 However, patients with HFmrEF have a similar incidence of coronary artery disease to the HFrEF population, are more likely to have hypertension than patients with HFrEF and are more likely to have ischaemic heart disease and diabetes than patients with HFpEF.16

Clinical Profile There is no clear demarcation between HFmrEF and the other two HF entities in terms of clinical presentation. They all have the clinical features of HF as described in the guidelines. HFmrEF has no other specific characteristics on presentation to distinguish it from the other forms. However, patients with HFmrEF have demographic and clinical characteristics that are more similar to those of patients with HFpEF than HFrEF. Cheng and colleagues have shown that, of all the patients hospitalised with HF in the Get With The Guidelines–HF (GWTG-HF) registry, 14 % belonged to the HFmrEF category, and their clinical presentation and demographic characteristics were overlapping with both HFrEF and HFpEF groups, but clearly closer to HFpEF cohort.20 Diagnosis based on clinical signs and symptoms is quite difficult in patients with HFmrEF because of the comorbidities involved, especially if the patient is elderly and has other concomitant issues like COPD.21

Diagnosis and Management All types of HF present with a similar clinical picture, and the distinction between HFrEF, HFpEF and HFmrEF ultimately requires an echocardiogram. In the 2016 ESC guidelines, the diagnostic criteria for HFmrEF include signs and symptoms of HF, an LVEF of 40–49 %, elevated levels of natriuretic peptides and presence of either structural or functional cardiac abnormalities.1 In case of uncertainty, a stress test or invasively measured elevated LV filling pressure may be needed to confirm the diagnosis.

The ESC guidelines do not give specific recommendations for management of HFmrEF, but they suggest that, since patients with HFmrEF have mostly been included in trials of HFpEF, rather than HFrEF, they should be treated with the same management principle as patients with the former, until new evidence is available.1 There is a lack of clinical trials specifically in patients with HFmrEF, and therefore there is a lack of data showing efficacy of specific agents in this patient group. However, recently there have been post hoc analyses of older trials specifically looking at this group. Lund et al. analysed the data from the Candesartan in HF – Assessment

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onikowski P, Voors AA, Anker SD, et al.; ESC Scientific P Document Group. 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.

DOI: 10.1093/eurheartj/ehw128; PMID: 27206819.

McMurray JJ, Adamopoulos S, Anker SD, et al.; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012:

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of Mortality and Morbidity (CHARM) programme.22 They found that candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. Solomon et al., in their analysis of the Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist (TOPCAT) study, showed that spironolactone was effective at the lower levels of LVEF.23 Cleland et al. recently published an individual patient meta-analysis of 11 clinical trials of beta-blockers for HF.24 They found that the use of beta-blockers improved LVEF and prognosis on follow-up in this patient group. These post hoc analyses will help guide our treatments and should form the basis of future prospective trials.

In current clinical practice, compared with HFrEF patients, fewer patients with HFpEF and HFmrEF appear to receive diuretics, betablockers, mineralocorticoid receptor antagonists, and angiotensinconverting enzyme inhibitors or angiotensin receptor blockers.1,11 The American Heart Association recommends to consider aldosterone antagonists in a selected population of patients with HF and LVEF ≥45 %, to decrease hospitalisations, whilst diuretic therapy is recommended to improve symptoms of congestion.25 However, it is recommended that patients be screened for cardiovascular and non-cardiovascular comorbidities, and management of these comorbidities is an integral part of the management of HFmrEF, as it is for HFpEF.26

Prognosis Changes in ejection fraction over time are common and seem to be more important than baseline ejection fraction alone, and patients who progress from HFmrEF to HFrEF have a worse prognosis than those who remain stable or transition to HFpEF.11,14 Mortality rates have been found to be higher among patients with HFrEF, but similar between those with HFmrEF and HFpEF.14 In the OPTIMIZE-HF trial, the mortality rates were 3.9 % for patients with HFrEF, 3.0 % for HFmrEF and 2.9 % for HFpEF.27 A meta-analysis of over 40,000 patients with HF found that the adjusted risk of mortality steadily increased with every 5–10 % decrease in LVEF below 40 % but were not significantly different in the groups with LVEF >40 %.14 On the other hand, the Swedish Heart Failure registry showed that chronic kidney disease was more strongly predictive of mortality in patients with HFmrEF and HFrEF than in patients with HFpEF.28

Conclusions The newly-defined entity HFmrEF has rapidly gained acceptance among physicians and researchers as, although the nomenclature is new, the existence of a different group or grey area between the two established forms of HF was previously known. Despite some similarities with pre-existing HF categories, this intermediate group seems to be a distinct but heterogeneous group. Although there has been research conducted in this group of patients, albeit as part of HFpEF or HFrEF studies, more work needs to be done to understand this form of HF better. We hope, as the ESC guideline authors did, that defining this group of patients and legitimising them with a separate name will spur more research and help us to understand this previously neglected group of patients. n

The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847.

DOI: 10.1093/eurheartj/ehs104; PMID: 22611136.

Kapoor JR, Kapoor R, Ju C, et al. Precipitating clinical factors, heart failure characterization, and outcomes in patients hospitalized with heart failure with reduced, borderline, and preserved ejection fraction. JACC Heart Fail 2016;4:464–72.

DOI: 10.1016/j.jchf.2016.02.017; PMID: 27256749.

Tsuji K, Sakata Y, Nochioka K, et al.; CHART-2 Investigators.

5.

6.

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. DOI: 10.1002/ejhf.807; PMID: 28370829.

Coles AH, Tisminetzky M, Yarzebski J, et al. Magnitude of and prognostic factors associated with 1-year mortality after hospital discharge for acute decompensated heart failure based on ejection fraction findings. J Am Heart Assoc 2015;4:e002303. DOI: 10.1161/JAHA.115.002303; PMID: 26702084.

Pascual-Figal DA, Ferrero-Gregori A, Gomez-Otero I, et al.;

7

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7.

8.

9.

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11.

12.

13.

14.

MUSIC and REDINSCOR I research groups. Mid-range left ventricular ejection fraction: clinical profile and cause of death in ambulatory patients with chronic heart failure. Int J Cardiol 2017;240:265–70. DOI: 10.1016/j.ijcard.2017.03.032; PMID: 28318662.

Guisado-Espartero ME, Salamanca-Bautista P, AramburuBodas Ó, et al.; RICA investigators group. Heart failure with mid-range ejection fraction in patients admitted to internal medicine departments: findings from the RICA registry. Int J Cardiol 2018;255:124–8. DOI: 10.1016/j.ijcard.2017.07.101; PMID: 29305104.

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. DOI: 10.1002/ejhf.813; PMID: 28386917.

Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction.

N Engl J Med 2006;355:251–9. DOI: 10.1056/NEJMoa052256; PMID: 16855265.

Pitt B, Pfeffer MA, Assmann SF, et al.; TOPCAT Investigators.

Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92. DOI: 10.1056/ NEJMoa1313731; PMID: 24716680.

Butler J, Fonarow GC, Zile MR, et al. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail 2014;2:97–112.

DOI: 10.1016/j.jchf.2013.10.006; PMID: 24720916.

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.

DOI: 10.1002/ejhf.945; PMID: 28948683.

Andersson C, Vasan RS. Epidemiology of heart failure with preserved ejection fraction. Heart Fail Clin 2014;10:377–88.

DOI: 10.1016/j.hfc.2014.04.003; PMID: 24975902.

Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).

The survival of patients with heart failure with preserved

8

CFR_Nadar_FINAL.indd 8

15.

16.

17.

18.

19.

20.

21.

22.

or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J 2012;33:1750–7.

DOI: 10.1093/eurheartj/ehr254; PMID: 21821849.

Yu CM, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195–201.

DOI: 10.1161/hc1002.105185; PMID: 11889013.

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. DOI: 10.1002/ejhf.159; PMID: 25210008.

Nadruz W Jr, West E, Santos M, et al. Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes. Circ Heart Fail 2016;9:e002826. DOI: 10.1161/CIRCHEARTFAILURE.115.002826; PMID: 27009553.

Fonarow GC, Abraham WT, Albert NM, et al.; OPTIMIZE-HF Investigators and Coordinators. Prospective evaluation of beta-blocker use at the time of hospital discharge as a heart failure performance measure: results from OPTIMIZE-HF. J Card Fail 2007;13:722–31. DOI: 10.1016/j.cardfail.2007.06.727; PMID: 17996820.

Sweitzer NK, Lopatin M, Yancy CW, et al. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions. Am J Cardiol 2008;101:1151–6. DOI: 10.1016/j.amjcard.2007.12.014; PMID: 18394450.

Cheng RK, Cox M, Neely ML, et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J 2014;168:721– 30. DOI: 10.1016/j.ahj.2014.07.008; PMID: 25440801.

Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 2014;115:79–96. DOI: 10.1161/CIRCRESAHA.115.302922; PMID: 24951759.

Lund LH, Claggett B, Liu J, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and

23.

24.

25.

26.

27.

28.

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.

Solomon SD, Claggett B, Lewis EF, et al.; TOPCAT Investigators.

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.

DOI: 10.1093/eurheartj/ehv464; PMID: 26374849.

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 double-blind randomized trials. Eur Heart J 2018;39:26–35.

DOI: 10.1093/eurheartj/ehx564; PMID: 29040525.

Yancy CW, Januzzi JL Jr., Allen LA, et al. 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2018;71:201–30.

DOI: 10.1016/j.jacc.2017.11.025; PMID: 29277252.

Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59):998–1005.

DOI: 10.1016/j.jacc.2011.11.040; PMID: 22402071.

Abraham WT, Fonarow GC, Albert NM, et al.; OPTIMIZE-HF Investigators and Coordinators. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol 2008;52:347–56. DOI: 10.1016/j.jacc.2008.04.028; PMID: 18652942.

Löfman I, Szummer K, Dahlström 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. DOI: 10.1002/ejhf.821; PMID: 28371075.

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Heart Failure with Mid-Range Ejection Fraction and How to Treat It Yuri Lopatin Volgograd State Medical University, Regional Cardiology Centre, Volgograd, Russia

Abstract The introduction of heart failure (HF) with mid-range ejection fraction (HFmrEF) as a distinct phenotype has achieved its aim of stimulating research into the underlying characteristics, pathophysiology and treatment of HF patients with left ventricular ejection fraction of 40–49 %. Comparison of clinical characteristics, comorbidities, outcomes and prognosis among patients with HF with preserved ejection fraction, HFmrEF and HF with reduced ejection fraction allowed consideration of HFmrEF as an intermediate phenotype, which often resembles HF with reduced ejection fraction more than HF with preserved ejection fraction. The latest findings suggest that patients with HFmrEF seem to benefit from therapies that have been shown to improve outcomes in HF with reduced ejection fraction.

Keywords Heart failure, mid-range left ventricular ejection fraction, prognosis, treatment Disclosure: The author has no conflicts of interest to declare.

Received: 12 February 2018 Accepted: 28 February 2018 Citation: Cardiac Failure Review 2018;4(1):9–13. DOI: https://doi.org/10.15420/cfr.2018:10:1 Correspondence: Yuri Lopatin, Cardiology Department, Volgograd Regional Cardiology Centre, 106, Universitetsky prospekt, Volgograd, Russia. E: yu.lopatin@gmail.com

In 2016, the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC)1 introduced heart failure (HF) with mid-range ejection fraction (HFmrEF) as a distinct phenotype. This distinction was expected to stimulate research on the underlying characteristics, pathophysiology and treatment of patients with HFmrEF. Indeed, in the following 2 years, the number of studies devoted to HFmrEF grew rapidly. Given that in terms of left ventricular ejection fraction (LVEF) HFmrEF (LVEF 40–49 %) occupies an intermediate position between HF with reduced ejection fraction (HFrEF) (LVEF <40 %) and HF with preserved ejection fraction (HFpEF) (LVEF >50 %), the key question is whether patients with HFmrEF represent a distinct pathophysiological entity or a transitional phenotype between HFrEF and HFpEF. The search for an answer to this question continues and will determine the effectiveness of strategies for the management of patients with HFmrEF. This article provides a narrative review of findings from recent observational studies, sub-analyses of clinical trials and analyses of data from large registries that focused on patients with HFmrEF. This review aims to discuss the current state of evidence regarding the essence of HFmrEF and management of patients with HFmrEF.

Terminology Related to Heart Failure with Mid-range Ejection Fraction In 2014, the term HFmrEF was proposed for the first time by Lam and Solomon2 to describe patients with HF and LVEF in the range of 40–49 %, who had been commonly excluded from clinical trials.

Since then, HFmrEF has often been called the ‘middle child’ in the HF family, implying the lack of attention to this phenotype in comparison with its ‘siblings’ HfrEF and HFpEF.2 In the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic HF,1 the term HFmrEF replaced the term ‘grey area’ that had been previously used to refer to HF patients with LVEF of 35–50 % and mild systolic dysfunction.

According to these ESC Guidelines, a positive diagnosis of HFmrEF

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requires the following conditions to be fulfilled: (i) symptoms and/ or signs of HF; (ii) LVEF of 40–49 %; (iii) elevated natriuretic peptides (B-type natriuretic peptide – BNP ≥35 pg/ml or N-terminal pro-B type natriuretic peptide – NT-proBNP ≥125 pg/ml); and (iv) a relevant structural heart disease (left ventricle hypertrophy with left ventricular mass index ≥115 g/m2 for men and ≥95 g/m2 for women) or left atrial enlargement (>34 ml/m2) or diastolic dysfunction (the ratio of mitral peak velocity of early filling – E to early diastolic mitral annular velocity – e’, E/e’ ratio ≥13 and a mean e’ septal and lateral wall <9 cm/sec).1 Similarly, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines3 described patients with LVEF in the range of 40–50 % as an intermediate group, pointing to its certain similarities to the group of patients with HFrEF. Besides that, the 2013 ACC/AHA Guidelines3 acknowledged the existence of borderline HFpEF (HFbEF) (LVEF 41–49 %) and improved HFpEF (LVEF >40 %). Such HF patients are classified as HFpEF patients; only in the first case they fall into a borderline or intermediate group, and in the second case they previously had HFrEF with a later improvement or recovery of LVEF. The recognition of the fact that LVEF often changes over time4,5 determined the appearance of such clarifying definitions as HFmrEF improved (previously HFrEF with LVEF <40 %), HFmrEF deteriorated (previously HFpEF with LVEF >50 %) and HFmrEF unchanged (previously HFmrEF with LVEF 40–50 %)6 (Figure 1). For such definitions, more than one measurement of ejection fraction is required. Nonetheless, in 2017 Lam and Solomon6 recognised that research should focus on finding prognostic differences and responses to therapeutic intervention across the spectrum of EF rather than terminology.

Pathophysiology of Heart Failure with Mid-range Ejection Fraction Limited evidence is currently available with respect to pathophysiological mechanisms of HFmrEF.7 A measurement of 37

Access at: www.CFRjournal.com

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Clinical Syndromes Figure 1: Changes in Left Ventricular Ejection Fraction over Time and Definitions of HFmrEF Deterioration

Deterioration HFmrEF deteriorated

HFrEF (LVEF <40 %)

HFmrEF (LVEF 40–49 %)

HFpEF (LVEF ≥50 %)

HFmrEF improved Recovery

Recovery

HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction.

biomarkers from different pathophysiological domains (myocardial stretch, inflammation, angiogenesis, oxidative stress, haematopoiesis) showed that biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch while biomarker profiles in patients with HFpEF were mainly related to inflammation.8 However, patients with HFmrEF demonstrated an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers.8 Further studies on the pathophysiology of HFmrEF are required.

Prevalence and Clinical Characteristics of Heart Failure with Mid-range Ejection Fraction Based on the results of recently-published clinical studies and analyses of data from registries, patients with HFmrEF may constitute up to one-quarter of all patients with HF.7,9–15 Clinical characteristics of patients with HFmrEF compared with those of patients with HFrEF and HFpEF, which were identified through analyses of data from three large registries,9–12 are presented in Table 1. Despite some similarities in clinical presentation, burden of comorbidities, and quality of life between HFrEF, HFmrEF, and HFpEF, in general, patients with HFmrEF were often characterised as a population of patients with intermediate characteristics between HFrEF and HFpEF. Nevertheless, patients with HFmrEF were usually younger and more likely to be male compared with those with HFpEF. In terms of these characteristics, the HFmrEF group resembles the HFrEF group but, most importantly, HFmrEF is closer to HFrEF with regard to both a higher prevalence of coronary artery disease (CAD) and a greater risk of new cardiac ischaemic heart disease (IHD) events.13 Besides, previous myocardial infarction and revascularisation procedures were more common both in patients with HFmrEF and HFrEF, than in patients with HFpEF.16 However, patients with HFmrEF were more likely to have hypertension and diabetes than those with HFrEF. Moreover, patients with HFmrEF showed a higher prevalence of atrial fibrillation and left ventricular hypertrophy but a lower prevalence of left ventricular and atrial dilation compared to patients with HFrEF.9 It should be noted that HFmrEF patients with atrial fibrillation compared with sinus rhythm were older, had a higher prevalence of hypertension, transient ischaemic attacks or stroke, a longer duration of HF and more severe HF but a lower prevalence of IHD.17 Analyses of the most common precipitating factors for hospitalisation among HF patients revealed high occurrence of respiratory infections, arrhythmias, myocardial ischaemia and medication noncompliance, regardless of the baseline LVEF.14,15 However, the prevalence of these factors as precipitants for

10

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the acute episode among patients with HFmrEF was intermediate compared with HFrEF and HFpEF. Overall, further studies analysing patients’ demographic characteristics, as well as aetiology and clinical presentation of the disease, may improve risk stratification and management of patients with HFmrEF.

Predictors and Prognosis of Heart Failure with Mid-range Ejection Fraction The analysis of pooled data from four community-based longitudinal cohorts identified 200 cases of HFmrEF (10 % of all new HF cases) among 28,820 participants, who were followed for a median of 12 years.18 Among clinical predictors of HFmrEF were such factors as older age, male sex, higher systolic blood pressure, diabetes mellitus and previous myocardial infarction (p<0.01 for all).18 Natriuretic peptides, cystatin-C and high-sensitivity troponin were identified as biomarkers predicting HFmrEF (p<0.01 for all).18 Interestingly, while natriuretic peptides had higher association with the incidence of HFrEF than of HFmrEF, they did not differ in their association with the incidence of HFmrEF compared with HFpEF. The rate of all-cause mortality after the onset of HFmrEF was higher than after the HFpEF (50 and 39 events per 1,000 person-years, respectively, p=0.02), but did not differ from the rate of all-cause mortality of HFrEF (50 and 46 events per 1,000 person-years, respectively, p=0.78).18 Several recently-published analyses of data from clinical registries compared the prognoses of HFrEF, HFmrEF and HFpEF, the results of which were divergent.9,11,19–23 In the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF), 4,953 patients hospitalised with the diagnosis of HF were included.19 Of those, 25 % of the patients who had a documented LVEF (n=3,257) had a diagnosis of HFmrEF. Patients with HFmrEF were more frequently hospitalised due to acute coronary syndrome (38.6 %, p<0.01) or infection (17 %, p<0.01) compared with patients with HFrEF and HFpEF. The most common presentations of HFmrEF were acute pulmonary oedema, acute de novo HF or atrial fibrillation/flutter on admission. Hazard of all-cause in-hospital mortality or 30-day mortality in HFmrEF was statistically significantly lower than in HFrEF (hazard ratio [HR]=0.64, p=0.03) but similar to HFpEF (HR=1.03, p=0.92).

The Get With The Guidelines®-HF (GWTG-HF) Registry20 included 39,982 patients from the US hospitalised with HF; of those, 8.2 % had HFbEF. The 5-year mortality rate was similar in patients with HFrEF, HFbEF and HFpEF (75.3 %, 75.7 % and 75.6 %, respectively). Patients with HFbEF had a slightly higher re-admission rate than those with HFpEF (85.7 % and 84.0 %, respectively, adjusted HR=1.05, p=0.03).

In the RICA Registry,21 2,753 patients admitted with HF to Spanish internal medicine units were included; of those, 10.2 % had HFmrEF. Patients with HFrEF had statistically significantly higher 1-year mortality compared with patients with HFmrEF and HFpEF (28 % versus 20 % and 22 %, respectively, p<0.01). However, there was no difference between the three groups in 30-day and 1-year re-admission rates.

In the REDINSCOR II Registry,22 16 % of patients admitted to Spanish cardiology services with decompensated or de novo HF (n=1,420) had HFmrEF. Over a 1-year prospective follow-up, HRrEF, HFmrEF and

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Heart Failure with Mid-Range Ejection Fraction Table 1: Clinical Characteristics of Patients with HFmrEF (HFbEF) Compared to Patients with HFrEF and HFpEF GWTG-HF10

Age (years)

SwedeHF11,12

ESC-HF-LT9

HFrEF

HFbEF

HFpEF

HFrEF

HFmrEF

HFpEF

HFrEF

HFmrEF

HFpEF

(n=15,716)

(n=5,626)

(n=18,897)

(n=23,402)

(n=9,019)

(n=9,640)

(n=5460)

(n=2,212)

(n=1,462)

79.0

81.0

82.0

72.0

74.0

77.0

64.0

64.2

68.6

Female gender (%)

40.0

50.5

76.3

29.0

39.0

55.0

21.6

31.5

47.9

BMI (kg/m2)

25.7

26.5

27.4

26.0

27.0

28.0

27.8

28.6

28.4

Systolic blood pressure (mmHg)

132.0

142.0

144.0

124.0

131.0

133.0

121.6

126.5

131.0

Heart rate (BPM)

82.0

81.0

79.0

74.0

73.0

74.0

72.9

73.2

72.5

NYHA class III/IV (%)

–

–

–

45.6

31.2

38.4

30.6

18.4

20.3

Hypertension (%)

73.1

77.9

81.3

56.0

64.0

72.0

55.6*

60.1*

67.0*

Diabetes mellitus (%)

39.3

41.5

40.6

27.0

27.0

28.0

32.3

30.5

29.3

Coronary artery disease (%)

58.0

56.7

44.9

54.0

53.0

42.0

48.6

41.8

23.7

Smoking (%)

11.2

Atrial fibrillation (%)

36.1

Lung disease (%)

26.7‡

Chronic kidney disease (%)

8.7

60.0**

55.0**

60.0**

12.7

10.7

8.1

†

51.0

58.0

63.0

18.3

22.3

32.2

29.6‡

31.4‡

28.0

30.0

35.0

15.2§

11.6§

14.0§

20.9

21.1

19.6

45.0

48.0

56.0

19.5

16.5

19.9

Anaemia (%)

16

21.3

22.4

31.0

35.0

41.0

–

–

–

Stroke or TIA (%)

15.8

17.1

17.4

–

–

–

9.4

8.3

9.8

†

40.2

7.6 †

40.6

Hypertension treatment; †Atrial fibrillation or flutter; ‡COPD or asthma; §COPD; **current or previous. COPD = chronic obstructive pulmonary disease; HFbEF = borderline heart failure with preserved ejection fraction; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; TIA = transient ischaemic attack. *

HFpEF groups showed no statistically significant differences in allcause mortality, cause of death or HF re-admission. In all three groups, the most frequent cause of death was refractory HF, followed by death due to non-cardiovascular causes.

The ESC Heart Failure Long-Term Registry9 collected 1-year follow-up data in 9,134 ambulatory HF patients; of those, 24.2 % had HFmrEF. There was no statistically significant difference in 1-year all-cause mortality among patients with HFrEF and HFpEF (8.8 % versus 6.3 %, p<0.01). Patients with HFmrEF experienced an intermediate level of 1-year all-cause mortality (7.6 %), which did not differ from patients with HFrEF (p=0.07) and HFpEF (p=0.17). Non-cardiovascular mortality was higher in patients with HFmrEF and HFpEF (27.8 % and 30.7 %, respectively) compared with HFrEF (20.1 %); however, this difference was not statistically significant (p=0.06). The percentages of patients hospitalised for HF in the HFrEF group was statistically significantly higher than in the HFmrEF and HFpEF groups (14.6 %, 8.7 %, and 9.7 %, respectively, p<0.01).9 In the Swedish Heart Failure Registry,11 all-cause mortality of 42,061 hospitalised and ambulatory HF patients, 21 % of which had HFmrEF, was analysed at 30 days, 1 year and 3 years of follow-up. All-cause mortality in the overall cohort was numerically but not statistically significantly higher between patients with HFmrEF and HFpEF at all time points, while it was considerably and significantly higher in HFrEF compared with HFpEF (p<0.01 for interaction) at all time points.

Nevertheless, 3-year mortality was higher in HFmrEF than in HFpEF in the presence of CAD (HR=1.11), but not in the absence of CAD (HR 1.02, p<0.01 for interaction).

Two Spanish prospective registries (Network for the Study of Heart Failure [REDINSCOR I] and the MUerte Súbita en Insuficiencia Cardíaca

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(MUSIC)23 included 3,446 ambulatory HF patients with a median followup of 41 months. Of those, 13.3 % had HFmrEF. The observed all-cause mortality was statistically significantly higher in the group of HFrEF than in HFmrEF and HFpEF, which had comparable rates (33.0 %, 27.8 %, and 28.0 %, respectively, p=0.01). The risk of cardiovascular death, HF death or sudden cardiac death did not differ between HFmrEF and HFrEF. However, patients with HFmrEF were at a higher risk of cardiovascular death (sub-hazard ratio=1.71, p=0.01) and sudden cardiac death (subhazard ratio=2.73, p=0.04) than patients with HFpEF. The differences in the above-mentioned results could potentially be explained by the features of the HF patients included in these registers (acute, stable HF or their mix), as well as different periods of follow-up.

Further studies are required to determine a long-term prognosis in HFmrEF patients.

Left Ventricular Ejection Fraction Transitions and Prognosis in Heart Failure Patients with Mid-range Ejection Fraction As discussed in the introduction, LVEF in HF patients quite often shifts from one category to another, which reasonably raises the question about the transitional status of HFmrEF between HFpEF and HFrEF rather than it being a distinct phenotype of HF. Indeed, in the Swedish Heart Failure Registry,16 more than one-third of HFmrEF patients experienced worsening of EF during the follow-up, whereas approximately one-quarter improved their EF. Of note, patients with IHD in general, and new IHD events in particular, were more likely to experience worsening of EF and less likely to experience improvement in EF.16 In the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) study,13 HFmrEF at registration transitioned to HFpEF and HFrEF by 44 % and 16 % at 1 year, respectively. At 1 year, HFmrEF patients had mortality comparable to that of HFpEF patients,

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Clinical Syndromes Table 2: Use of Cardiovascular Medications and Devices in Patients with HFmrEF as Reported in Recent Analyses of Data from Clinical Registries SwedeHF11

GWTG-HF20

CHART-213

TIME-CHF24

MUSIC/REDINSCOR I23

REDINSCOR II22

RICA21

‡

79

ACEi/ARB (%)

84

64.7

80.0

90.7

87.2

72.4

Beta-blockers (%)

86

78.5‡

63.8

73.1

76.7

71.8‡

71.0

MRAs (%)

24

11.9‡

29.3

33.3

40.0

45.0‡

41.0

ARNI (%)

NA

NA

NA

NA

NA

NA

NA

Ivabradine (%)

NA

NA

NA

NA

NA

NA

1.0

Diuretics (%)

74

46.5‡

63.3

NA

NA

NA

NA

Loop diuretics (%)

NA

NA

NA

89.8

76.7

NA

93.0

Thiazides (%)

NA

NA

NA

NA

NA

NA

14.0

†

‡

Digoxin (%)

16

14.8

NA

13.9

16.8

NA

25.0

Anticoagulation therapy (%)

38

31.9‡

NA

NA

NA

NA

53.0

Statins (%)

48

55.4*

39.6

NA

59.1

NA

NA

27.0

Platelet inhibitors (%)

53

45.4

NA

30.2

NA

41.0

Nitrates (%)

17

18.4†

NA

32.4

NA

NA

NA

CRT (%)

0.9

11.5

1.8

NA

4.6

NA

NA

ICD (%)

1.3

3.9

3.9

2.8

7.0

NA

NA

Vasodilators (%)

NA

15.8‡

NA

NA

NA

NA

29.0

†

§

Lipid-lowering medications; on admission; discharge medication; aspirin; ACEi = angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; CHART-2 = Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study; CHF = trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure; CRT = cardiac resynchronisation therapy; GWTG-HF = The Get With The Guidelines-HF Registry; HFmrEF = heart failure with mid-range ejection fraction; ICD = implantable cardioverter-defibrillator; MRA = mineralocorticoid receptor antagonist; NA = data not available; REDINSCOR II - Red Espan˜ola de Insuficiencia Cardiaca researchers; RICA – Spanish National Registry on Heart Failure; SwedeHF = Swedish Heart Failure Registry; TIME-MUSIC/REDINSCOR I - MUerte Súbita en Insuficiencia Cardíaca/Network for the Study of Heart Failure.

*

†

‡

§

which was better than that in HFrEF patients. However, patients with HFmrEF at registration had increased mortality if they transitioned to HFrEF at 1 year. Similar data were obtained from the Washington University Heart Failure Registry.7 In this registry, the majority of patients (73 %) had HFmrEF improved (prior LVEF <40 %), 17 % had a deteriorated HFmrEF (prior LVEF >50 %), and 10 % remained stable in HFmrEF (prior LVEF 40–50 %). Herewith, patients with improved HFmrEF had significantly (p<0.01) better clinical outcomes (death, cardiac transplantation, HF hospitalisation, cardiac hospitalisation) relative to matched patients with HFrEF and to HFmrEF deteriorated patients.7 Meanwhile, clinical outcomes of the HFmrEF deteriorated subgroup of patients did not differ from the outcomes of matched HFpEF patients.

It appears that the transition of LVEF from HFrEF to HFmrEF is associated with a better prognosis than stable HFmrEF, but patients who deteriorate from HFpEF to HFmrEF have a slightly worse prognosis than patients with stable HFmrEF. Further studies are needed to confirm this observation.

Management of Heart Failure Patients with Mid-range Ejection Fraction Due to the fact that some HFmrEF patients have been included in trials focused on HFpEF patients, the current ESC Guidelines on HF1 recommend therapies for HFmrEF on the basis of the evidence for HFpEF rather than that for HFrEF. Along with that, diuretics are recommended in congested patients with HFmrEF to alleviate symptoms and signs.1 Nevertheless, the rate of prescription of HF classic disease-modifying agents, especially, such as angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs) and beta-blockers, is quite high in patients with HFmrEF. The use of cardiovascular medications and devices in

12

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patients with HFmrEF as it was presented in the recently published analyses of data from registries is summarised in Table 2. Several analyses showed that HFmrEF patients, in contrast to patients with HFpEF, had a benefit in prognosis similar to those with HFrEF when guideline recommended therapies were used.11,13,25–27 In the CHART-2 study,13 prognostic impacts of ACEis, ARBs, MRAs, betablockers, statins, calcium channel blockers and diuretics in HFmrEF patients were different from those in HFpEF patients, but were almost comparable to those in HFrEF patients.13 The use of beta-blockers was positively associated with improved mortality in HFmrEF and HFrEF, but not in HFpEF patients.13 Diuretics had a negative prognostic impact in HFmrEF and HFrEF, but not in HFpEF patients, whereas statin use was associated with reduced mortality in HFpEF, but not in HFmrEF or HFrEF.13 Similar findings were obtained in the analysis of the Swedish Heart Failure registry,11 beta-blocker therapy was associated with reduced 1-year mortality in HFmrEF with CAD (HR=0.74, p=0.01) but not in HFmrEF without CAD (HR=0.99, p=0.94). ACEis and ARBs were effective in reducing the risk of death regardless of the presence or absence of CAD (HR=0.67 and HR=0.59, respectively). It should be noted that in this study diuretics demonstrated a negative impact on survival in HFmrEF patients.

The benefit of beta-blockers in HFmrEF patients was confirmed in an individual patient-level analysis of 11 major double-blind randomised trials.24 Beta-blockers improved mortality in sinus rhythm but not in patients with atrial fibrillation in all EF categories except LVEF ≥50 %.

The post hoc analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT)25 revealed a reduction in the primary endpoint (a composite of death from

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Heart Failure with Mid-Range Ejection Fraction cardiovascular causes, aborted cardiac arrest, or HF hospitalisation) in HFpEF patients on the lower end of the EF spectrum – LVEF 45–49 %, but not when LVEF was above 60 % (LVEF <50 %: HR=0.72; LVEF ≥60 %: HR=0.97, p=0.046).

The recently-published post hoc analysis of the CHARM Programme (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity)26 determined a similar statistically significant improvement in the primary outcome (cardiovascular death or HF hospitalisation) for candesartan versus placebo both in patients with HFrEF and HFmrEF (HR=0.82, p<0.001 and HR=0.76, p<0.02, respectively), but not in HFpEF (HR=0.95, p=0.57).

Interestingly, a reduction of NT-proBNP levels in patients with HFmrEF during routine care was associated with a lower risk of all-cause death or HF hospitalisation.28 However, whether NT-proBNP changes will predict drug efficacy is yet to be clarified.

Currently, new prospective, adequately designed and powered studies that would confirm the benefits of modern HF therapies in patients with HFmrEF are needed. The most pragmatic approach appears to be

1.

onikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines P 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. DOI: 10.1002/ejhf.592; PMID: 27207191.

2. 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. DOI: 10.1002/ejhf.159; PMID: 25210008.

3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:147–239. DOI: 10.1016/j.jacc.2013.05.019; PMID: 23747642.

4. Dunlay SM, Roger VL, Weston SA, et al. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail 2012;5:720–6. DOI: 10.1161/CIRCHEARTFAILURE.111.966366; PMID: 22936826.

5. Clarke CL, Grunwald GK, Allen LA, et al. Natural history of left ventricular ejection fraction in patients with heart failure.

Circ Cardiovasc Qual Outcomes 2013;6:680–6. DOI: 10.1161/ CIRCOUTCOMES.111.000045; PMID: 24129973.

6. Lam CS, Solomon SD. Fussing over the middle child heart failure with mid-range ejection fraction. Circulation 2017;135:1279–80. DOI: 10.1161/ CIRCULATIONAHA.117.027324; PMID: 28373521.

7. Rastogi A, Novak E, Platts AE, et al. Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction. Eur J Heart Fail 2017;19:1597–1605. DOI: 10.1002/ejhf.879; PMID: 29024350.

8. Tromp J, Khan MA, Mentz RJ, et al. Biomarker profiles of acute heart failure patients with a mid-range ejection fraction. JACC Heart Fail 2017;5:507–17. DOI: 10.1016/j.jchf.2017.04.007; PMID: 28624483.

9. 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. DOI: 10.1002/ejhf.813; PMID: 28386917.

10. Cheng RK, Cox M, Neely ML, et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J

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11.

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20.

an analysis of treatment effects across the entire EF spectrum, especially in patients with EF <50 % (HFrEF and HFmrEF). Furthermore, such an underlying cause of HFmrEF as CAD will have to be taken into account because the importance of pharmacological and invasive strategies for improving prognosis in this category of patients is well known.

Conclusion It can be already argued that the introduction of HFmrEF as a separate phenotype of HF has achieved its aim of drawing attention to HFmrEF, given the increased number of published studies. The comparison of the clinical characteristics, comorbidities, outcomes and prognosis among patients with HFpEF, HFmrEF and HFrEF allowed consideration of HFmrEF as an intermediate phenotype, which often resembles HFrEF more than HFpEF. Moreover, HFmrEF can dynamically transit into HFpEF or HFrEF, suggesting that HFmrEF represents a transitional status between HFpEF and HFrEF rather than an independent entity of HF. Much less is known about the underlying pathophysiological mechanisms of HFmrEF. New studies are needed not only to improve our understanding of the pathophysiology of HFmrEF, but also to identify effective therapeutic strategies. The latest findings on the beneficial effects of therapies for HFrEF in HFmrEF patients are promising. n

2014;168:721–30. DOI: 10.1016/j.ahj.2014.07.008; PMID: 25440801.

Koh AS, Tay WT, Teng THK, et al. A comprehensive populationbased characterization of heart failure with mid-range ejection fraction. Eur J Heart Fail 2017;19:1624–34. DOI: 10.1002/ ejhf.945; PMID: 28948683.

Löfman I, Szummer K, Dahlström 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. DOI: 10.1002/ejhf.821; PMID: 28371075.

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. DOI: 10.1002/ejhf.807; PMID: 28370829.

Kapoor JR, Kappor R, Ju C, et al. Precipitating clinical factors, heart failure characterization and outcomes in patients hospitalized with heart failure with reduced, borderline and preserved ejection fraction, JACC Heart Fail 2016; 4:464–72. DOI: 10.1016/j.jchf.2016.02.017; PMID: 27256749.

Guisado-Espartero ME, Salamanca-Bautista P, Aramburu-Bodas Ó et al. Heart failure with mid-range ejection fraction in patients admitted to internal medicine departments: Findings from the RICA Registry. Int J Cardiol 2018: pii: S0167-5273(17)30729-5.

DOI: 10.1016/j.ijcard.2017.07.101; PMID: 29305104.

Vedin O, Lam CS, Koh AS, et al. Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail 2017;10:e003875. DOI: 10.1161/ CIRCHEARTFAILURE.117.003875; PMID: 28615366.

Sartipy U, Dahlström U, Fu M, et al. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2017;5:565–74. DOI: 10.1016/j. jchf.2017.05.001; PMID: 28711451.

Bhambhani V, Kizer JR, Lima JAC van der Harst P, et al.

Predictors and outcomes of heart failure with mid-range ejection fraction. Eur J Heart Fail 2017: DOI: 10.1002/ejhf.1091; PMID: 29226491.

Farmakis D, Simitsis P, Bistola V, et al. Acute heart failure with mid-range left ventricular ejection fraction: clinical profile, in-hospital management, and short-term outcome. Clin Res Cardiol 2017;106:359–68. DOI: 10.1007/s00392-016-1063-0; PMID: 27999929.

Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year

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outcomes. J Am Coll Cardiol 2017;70:2476–2486. DOI: 10.1016/j. jacc.2017.08.074; PMID: 29141781.

Guisado-Espartero ME, Salamanca-Bautista P, AramburuBodas Ó, et al. Heart failure with mid-range ejection fraction in patients admitted to internal medicine departments: Findings from the RICA Registry. Int J Cardiol 2018; 255:124–128. DOI: 10.1016/j.ijcard.2017.07.101; PMID: 29305104.

Gomez-Otero I, Ferrero-Gregori A, Varela Román A, et al.

Mid-range ejection fraction does not permit risk stratification among patients hospitalized for heart failure. Rev Esp Cardiol 2017;70:338–46. DOI: 10.1016/j.rec.2016.11.016; PMID: 28011188.

Pascual-Figal DA, Ferrero-Gregori A, Gomez-Otero I, et al.

Mid-range left ventricular ejection fraction: Clinical profile and cause of death in ambulatory patients with chronic heart failure. Int J Cardiol 2017;240:265–70. DOI: 10.1016/j. ijcard.2017.03.032; PMID: 28318662.

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. 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;37:455–62. DOI: 10.1093/eurheartj/ehv464; PMID: 26374849.

Lund LH, Claggett B, Liu J, et al. Heart failure with mid-range 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.

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 2017;19:1586–96. DOI: 10.1002/ ejhf.798; PMID: 28295985.

Savarese G, Hage C, Orsini N, et al. Reductions in N-terminal pro-brain natriuretic peptide levels are associated with lower mortality and heart failure hospitalization rates in patients with heart failure with mid-range and preserved ejection fraction. Circ Heart Fail 2016;9:e003105. DOI: 10.1161/ CIRCHEARTFAILURE.116.003105; PMID: 28029640.

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Clinical Syndromes

Left Ventricular Dysfunction in the Setting of Takotsubo Cardiomyopathy: A Review of Clinical Patterns and Practical Implications Kenan Yalta, Mustafa Yılmaztepe and Cafer Zorkun Trakya University, Cardiology Department, Edirne, Turkey

Abstract Takotsubo cardiomyopathy (TTC) is primarily regarded as a form of acute and transient myocardial disease with a variety of characteristic wall-motion abnormalities. Importantly, a significant portion of TTC cases generally present with variable degrees of acute left ventricular (LV) dysfunction with or without clinical HF. On the other hand, LV dysfunction in the setting of TTC has been universally and exclusively considered as a synonym for systolic dysfunction, potentially overlooking other forms of myocardial pathologies, including transient diastolic dysfunction, in this setting. More interestingly, recent observations suggest that TTC, despite its macroscopic recovery, may not always manifest as a fully reversible phenomenon, suggesting persistence of microscopic changes at the cellular level to some degree.

In clinical practice, these residual changes might largely account for the evolution of certain pathologies, including persistent diastolic dysfunction and subclinical LV dysfunction with variable symptomatology (particularly those arising during high levels of myocardial workload, including exercise, etc.) among TTC survivors. Within this context, the present review aims to highlight various clinical patterns and implications of LV dysfunction in the setting of TTC, and to provide basic information regarding morphological and mechanistic characteristics of wall-motion abnormalities in this setting.

Keywords Takotsubo cardiomyopathy, systolic dysfunction, diastolic dysfunction, persistent diastolic dysfunction, subclinical dysfunction, clinical heart failure, prognostic implications, therapeutic implications Disclosure: The authors have no conflicts of interest to declare.

Received: 27 December 2017 Accepted: 14 February 2018 Citation: Cardiac Failure Review 2018;4(1):14–20. DOI: https://doi.org/10.15420/cfr.2018:24:2 Correspondence: Kenan Yalta MD, Trakya University, Cardiology Department, Edirne, Turkey. E: kyalta@gmail.com

In the past decades, takotsubo cardiomyopathy (TTC) has emerged as a specific form of acute and transient myocardial disease, predominantly affecting postmenopausal women in the clinical setting.1–4 In general, myocardial involvement in this setting appears to harbour a regional pattern particularly extending beyond the territory of a single coronary artery (and usually without concomitant significant coronary artery disease [CAD]).2,4,5 Mechanistically, sympathetic hyperstimulation attributable to a variety of external and internal stressors has been regarded as the fundemental trigger of TTC evolution.3,5–8 Despite the lack of consensus on the definitive diagnosis of TTC, a variety of diagnostic criteria (e.g. Mayo and Gothenburg) have been previously proposed.1,8,9 Among these, the Gothenburg criteria suggest a variety of diagnostic hallmarks, including reversible wall -motion abnormalities, frequently in response to a stressful trigger; absence of other potential causes associated with these abnormalities (e.g. ischaemia and tachycardia); and a disproportionately low elevation of cardiac troponin (i.e. no or mild elevation).8,9 More recently, the European HF Association has also suggested additional clinical findings, including ECG changes and elevation of natriuretic peptides, for the diagnosis of TTC, along with recommending that hyperadrenergic conditions (including pheochromocytoma) no longer be considered as exclusion criteria.1 In general, acute coronary syndromes (ACS) and TTC appear to have a close analogy based on their clinical characteristics, including symptomatology and ECG, which suggests the urgent need for coronary angiogram to reach a final diagnosis.3,10 On the other hand,

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since TTC primarily emerges as a myocardial disease with an acute onset, it may also present with HF symptoms and signs, instead or on top of ACS-like admission characteristics. Therefore, this phenomenon should also be differentiated from a variety of acute HF syndromes, including myocarditis, that might even be more challenging in clinical practice.1,3 Acute HF in patients with TTC might, to a large extent, be attributable to left ventricular (LV) dysfunction, characterised by systolic and/or diastolic dysfunction, along with certain specific complications including LV outflow tract (LVOT) obstruction arising in various degrees and durations. Accordingly, the present paper aims to highlight the morphological and mechanistic characteristics of LV involvement in the setting of TTC, with a particular emphasis on clinical aspects of LV dysfunction in this setting.

Takotsubo Cardiomyopathy-associated Wallmotion Abnormalities Morphological Types In clinical practice, TTC generally presents with a variety of regional and transient cardiac wall -motion abnormalities (mostly akinesia and rarely hypokinesia) that may, in certain settings, elicit a significant decline in cardiac function.8,9 Among these, LV apical akinesia along with a basal hyperkinesia pattern has been described as the classical and most common variant (comprising about 50–80 % of cases) , primarily characterised by an apical ballooning appearance on LV imaging.1,8,9 However, other less common variants involving LV basal (inverted TTC), midventricular and lateral segments have also been increasingly

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Takotsubo Cardiomyopathy and Left Ventricular Dysfunction reported.1,9 Moreover, TTC may present with biventricular or isolated right ventricular (RV) involvement in about one-third of cases , and may even emerge as a global or focal LV dysfunction. Interestingly, a gradual upward trend in the incidences of these atypical variants has been reported.9 Importantly, myocardial involvement in this setting usually appears to be circumferential and extends beyond the territory of a single coronary artery, demonstrating a sharp transition to the normal or hyperkinetic territories, possibly, in part, due to the anatomical distribution and varying involvement of cardiac sympathetic branches.1,24 These wallmotion abnormalities, along with potential complications (LVOT obstruction, etc.), are generally diagnosed on invasive LV angiogram or transthoracic echocardiogram (TTE). On the other hand, cardiac MRI using late gadolinium enhancement may be more valuable in certain settings, including RV involvement and, particularly, formefruste manifestations that might mimic acute myocarditis or ACS.1,3 These techniques are also of utmost value to monitor gradual recovery of wall-motion abnormalities.1 Regardless of the location, these wallmotion abnormalities generally normalise within hours to weeks, largely depending on the clinical severity of TTC attack, and a complete recovery at 12 weeks is highly likely.1,11

Mechanistic and Molecular Basis Several theories have been suggested regarding the pathogenesis of transient wall-motion abnormalities in the setting of TTC. Systemic and/or local catecholamine surge along with a regional heterogeneity in cathecholamine sensitivity is the most popular and extensively investigated theory.1,8,12 Evolution of similar wall-motion abnormalities in response to iatrogenic and hormonal triggers associated with sympathetic hyperstimulation also substantiate this theory.13,14 On the other hand, the exact mechanisms underlying excess cathecholamine toxicity in this setting have yet remained to be established. One such mechanism might be attributable to the supply–demand mismatch in oxygen and adenosine triphosphate (ATP) levels potentially leading to a state of metabolic shutdown, along with a significant decline in contractile functions at the myocellular level.8 Moreover, adrenergic hypersensitivity (and hence detrimental effects) may also appear to be potentiated in the setting of enhanced myocardial wall stress associated with sympathetic hyperstimulation or other causes.8 Within this context, even though the theories of macro- and microvascular dysfunction generally fail to fully explain the evolution of specific wall-motion abnormalities in the setting of TTC,15,16 myocardial ischaemia may potentially have a facilitating impact, and may decrease the threshold for the emergence of contractile dysfunction owing to impaired myocardial metabolism and energetics in this setting.8 Similarly, oestrogen deficiency may also be proposed, at least, to have a contributory role, largely through induction of endothelial dysfunction, for example.5 Excess cathecholamine toxicity along with severe energy depletion (and hence metabolic shutdown) also appear to be associated with a variety of corresponding histopathological changes at the myocellular level. Accordingly, myocardial biopsies obtained from acute TTC cases were previously found to have large areas of intracytoplasmic glycogen; damaged mitochondria (indicative of energy deprivation); quantitative and qualitative derangement of myocyte proteins (actin, titin, etc.); extracellular matrix enlargement harbouring interstitial fibrosis (increased collagen-1 and fibronectin); and myocyte disarray (as shown through connexin-43 labelling); however, there were no signs of cellular necrosis or apoptosis.17 These abnormal changes associated

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with myocardial dysfunction (both systolic and diastolic) were also shown to significantly normalise in the recovery phase of TTC. On the other hand, altered LV geometry associated with enhanced myocardial wall stress might exclusively lead to the emergence of characteristic wall-motion abnormalities, suggesting a purely mechanical basis of TTC in certain settings.6,18–20 Circumferential wall stress (CWS) within the myocardium is well known to be associated with intraventricular pressure, chamber diameter and wall thickness.18,20 Accordingly, LV geometric changes, including septal hypertrophy and small LV cavity (usually due to hypertrophic cardiomyopathy or hypertensive heart disease) might potentially account for acute and substantial increments in intraventricular gradient, eventually giving rise to the evolution of apical ballooning (largely due to enhanced apical intraventricular pressure and hence CWS).18,19 Besides the substantial impact of intraventricular pressure gradient, relative enhancement of CWS in the apical in comparison to the basal segments might also be ascribed to the minor alterations in chamber diameters and wall thicknesses of the apical segments.20 Importantly, CWS increase in the apical segments may be persistent in nature and, as mentioned previously, may potentially create a milieu for adrenergic hypersensitivity within these segments. More interestingly, a recent study using cardiac MRI to measure LV wall stress in patients with TTC suggested that elderly women might have more pronounced end-systolic and end-diastolic wall stresses in response to hypertension due to stressful triggers, which may partly explain the specific age and gender predilection of TTC.21 Lastly, the beta-2 adrenoceptor/inhibitory G protein activation theory was recently suggested to specifically explain the evolution of apical akinesia due to TTC.8,22 According to this theory, excessive levels of adrenaline (but not noradrenaline) in the setting of acute stress potentially hyperstimulate beta-2 adrenoreceptors predominantly localised in the apical regions, which, in turn, activates the inhibitory G protein leading to a reduction in cyclic adenosine monophosphate levels, and hence contractile dysfunction, in these regions.8,22 However, the theory fails to explain the genesis of wall-motion abnormalities in the regions other than the apices, and it needs to be tested through further studies.

In summary, the pathogenesis of transient wall -motion abnormalities in the setting of TTC appears to be a quite unique process with a complex and multifaceted nature, with multiple factors implicated (adrenergic surge, changes in adrenoceptor sensitivity and enhanced myocardial wall stress, etc.), usually in various combinations. Importantly, these wall -motion abnormalities might give rise to the evolution of acute HF characterised by significant systolic and/or diastolic dysfunction in a portion TTC cases.

Left Ventricular Dysfunction and Clinical Heart Failure: An Ominous Duo in Patients with Takotsubo Cardiomyopathy In general, it might not be as rare to encounter significant LV dysfunction and acute HF in patients with TTC as was considered previously. A previous retrospective analysis reported an HF incidence of 45 % on admission among patients with TTC.2 Moreover, 20 % of HF cases also suffered cardiogenic shock in this study. It is noteworthy that TTC, in contrast to the consensus on its favourable nature,23 may be associated with acute systolic and/or diastolic dysfunction on admission or during hospital stay, indicating particular management strategies.1 As described later in this article, the combination of LV dysfunction and clinical HF seems to have a much worse prognosis

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Clinical Syndromes Table 1: Potential Causes of Systolic Dysfunction in the Setting of Takotsubo Cardiomyopathy a

Takotsubo cardiomyopathy variants extensively involving left ventricle Decreased compensatory hypercontractility of the residual segmentsb Co-existing acute coronary syndrome or, rarely, myocarditis3,10 Pre-existing systolic dysfunction Acute LV outflow tract obstruction, and other rare mechanical complicationsc aSystolic dysfunction refers to an LV ejection fraction below normal reference values on LV imaging (echocardiogram, etc.). bLargely due to bystander conditions, including significant coronary artery disease affecting non-involved segments. cWhen associated with reduced cardiac output. LV = left ventricular.

than subclinical LV dysfunction in the acute setting. On the other hand, the Gothenburg criteria suggest the presence of normal or near-normal cardiac output and LV filling pressures as supportive findings for the diagnosis of TTC.8 This potentially implies that HF associated with LV dysfunction should not be regarded as a routine finding in patients with TTC. Therefore, alternative causes of acute HF should also be considered beforehand in the clinical setting.

Systolic Dysfunction: Potential Causes and Implications In the setting of TTC, acute HF due to LV systolic dysfunction, as determined by low LV ejection fraction (LVEF) values (below normal limits on TTE or other imaging modalities, including LV angiogram, MRI, etc.) has been regarded as the most common complication (in 12–45 % of cases) that warrants urgent diagnosis and proper management.1,2

a new-onset TTC in these patients who already have segmentary or global wall-motion abnormalities.24 Traditionally, TTC and ACS appear to have a significant intersecting zone in terms of their clinical findings.3 Nevertheless, they should not always be regarded as mutually exclusive entities , even if coronary imaging suggests ACS/TTC co-existence in certain settings.10 A variety of clinical factors, including severe systemic inflammation on admission, an existing physical stressor and presence of spontaneous coronary artery dissection on coronary imaging, were recently suggested to predict this co-existence in clinical practice.10 Therefore, a co-existing ACS might contribute to, or even account for, the evolution of systolic dysfunction in certain TTC patients. Similarly, co-existing myocarditis, as the primary or secondary pathology, might also account (though much more rarely) for the significant systolic dysfunction in certain patients.3 As expected, LV systolic function in TTC patients with a co-existing ACS or chronic myocardial disease (e.g. cardiomyopathy), as opposed to those with TTC in isolation, does not completely normalise even after full recovery of TTC. Lastly, mechanical complications, including acute LVOT obstruction and acute mitral regurgitation (mostly due to systolic anterior motion or apical tethering of subvalvular structures), along with very rarely encountered myocardial perforations, such as ventricular septal rupture (<1 % of cases),1,11,25–27 may also be regarded as specific forms of systolic dysfunction in patients with TTC. Potential causes of systolic dysfunction in the setting of TTC are summarised in Table 1. Among the mechanical complications, acute LVOT gradient merits further mention.

Acute Left Ventricular Outflow Tract Obstruction

Since LV systolic dysfunction in patients with TTC mostly evolves acutely, without pulmonary or systemic adaptive mechanisms, it generally presents with signs and symptoms of clinical HF, including dyspnoea, hypotension, pulmonary rales, etc.2 Importantly, there is also a strong correlation between the degree of acute systolic dysfunction and the severity of HF symptoms in a significant portion of TTC cases (as opposed to the setting of chronic cardiomyopathy and its symptomatology). On the other hand, cases with borderline systolic dysfunction ( LVEF >40–45 %) may remain clinically silent in terms of HF symptomatology. Conversely, it seems more reasonable to consider clinical HF as a highly probable scenario rather than an unpredictable complication in TTC patients with lower LVEF values (LVEF <40 %).2 Within this context, a retrospective analysis suggested that low LVEF (<40 %), presence of a physical stressor and advanced age (>70 years) as independent predictors of clinical HF in patients with TTC.2 However, this study grossly focused on the overall evolution of clinical HF that might also have risen because of the acute diastolic dysfunction.

Acute LVOT gradient (generally ranging between 20 and 140 mm Hg) has been considered a specific form of LV dysfunction generally encountered in up to 25 % of patients with TTC.1,11,26 In other terms, it may potentially be labelled as a form of systolic HF when associated with a reduction in cardiac output along with haemodynamic compromise. LVOT gradient in this setting is largely associated with the hypercontraction pattern of basal LV segments usually characteristic of the typical TTC variant, and is usually accompanied by systolic anterior motion and mitral valve regurgitation.1,25 Accordingly, a recent study demonstrated typical TTC incidences of 100 % and 78 % in TTC patients with and without an LVOT gradient, respectively.25 More importantly, the incidence of clinical HF was strikingly higher in TTC patients with a LVOT gradient as compared with those without in this study (78 % versus 28 %). In general, a LVOT gradient of >25 mmHg is regarded to have haemodynamic significance, and a value of ≥40 mmHg poses a high risk in clinical practice.1

Mechanistically, it seems likely that LV systolic dysfunction in patients with TTC might be attributable to a variety of factors, including extensive TTC-induced wall-motion abnormalities; decreased compensatory hypercontractility of the residual myocardial segments (due to bystander CAD,1 etc.); pre-existing myocardial disease;11 concomitant acute conditions (including ACSs)10 and mechanical complications.1,11 In general, evolution of systolic dysfunction is largely attributable to the direct impact of acutely evolving and extensive wall-motion abnormalities in TTC cases with previously normal or nearnormal cardiac function. However, a portion of cases might already harbour a pre-existing myocardial disease that might clinically worsen because of a superimposing TTC. In other terms, a TTC attack might potentially account for an acute exacerbation of a chronic myocardial disease. On the other hand, it may be quite challenging to diagnose

On the other hand, the issue of whether LVOT gradient in the setting of TTC appears to serve as the cause or consequence of characteristic wall-motion abnormalities remains controversial.11,26 Even though mechanical factors (e.g. acute increases in intraventricular gradient) per se might serve as the fundamental contributor to the evolution of wall -motion abnormalities in certain settings,18,19 it seems more likely that LVOT gradient is a fully reversible complication usually arising during the early course of TTC.11,25,27 More interestingly, LVOT gradient might rarely emerge as a late-onset phenomenon with a persistent or permanent nature in the setting of TTC as well.27–29 Mechanistically, evolution of this phenomenon was previously ascribed to the TTCinduced temporal changes in LV geometry in the setting of a background myocardial disease, including hypertrophic cardiomyopathy.27 However, late-onset LVOT gradient, as opposed to its early onset counterpart,

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Takotsubo Cardiomyopathy and Left Ventricular Dysfunction generally presents with classical symptoms of aortic stenosis (angina, dyspnea, etc.) rather than acute haemodynamic compromise.

Diastolic Dysfunction: The Forgotten Tale in Takotsubo Cardiomyopathy In clinical practice, clinicians rarely focus on potential mechanisms, diagnostic algorithms or the clinical relevance of diastolic dysfunction in the setting of TTC. This attitude is largely based on the general misconception that considers existing diastolic dysfunction in this setting only as an innocent bystander, rather than a clinical phenomenon with important implications. In general, acute diastolic dysfunction arises in a significant portion of cases with TTC in various degrees and durations.6,30–33 Accordingly, in a recent study primarily focusing on the long-term prognostic impact of LV dysfunction in patients with TTC, the prevalence of diastolic dysfunction on admission was reported to be as high as 53 % (108 of 205 cases).31 Among these, the majority of patients (65 of 108) were found to have a mild degree of diastolic dysfunction (mitral E/A ratio <0.8, E/e′ ratio < 8, deceleration time >200 ms and normal left atrial [LA] filling pressure [grade I]34), with only a minority (13 of 108) having severe diastolic dysfunction (E/A ratio ≥2, increased LA filling pressure and deceleration time <160 ms [grade III]). In contrast with an asymptomatic nature of mild diastolic dysfunction at rest,34 moderate and severe degrees (grade II and III; pseudonormalisation and restrictive pattern on TTE, respectively) are more likely to elicit symptoms and signs of diastolic HF even at rest, and particularly in a more pronounced manner when they evolve acutely, as in the setting of TTC. Temporally, diastolic dysfunction arising after a TTC attack may be transient, persistent or even permanent.

Transient Diastolic Dysfunction In the setting of TTC, this form of diastolic dysfunction is generally considered to arise in close temporal correlation with reversible segmentary wall-motion abnormalities in terms of its time of onset and duration.33 However, clear-cut mechanisms of this phenomenon remain to be fully established. At the myocellular level, both contraction and relaxation largely mediate their effects through a variety of common molecular targets, including interaction of myofilaments that are primarily governed by an energy-dependent, active process.31,35 Consistent with this, any severe metabolic shutdown of diverse aetiology at the cellular level (excess cathecholaminergic toxicity, etc.)8 is expected to elicit myocardial stunning or severe myocardial failure, substantially compromising both systolic and diastolic function in a simultaneous manner. In TTC hearts with full-blown myocardial stunning rather than hypokinesia in the affected region, the particular phase of cardiac cycle in which the myocardial stunning takes place is also of crucial importance in terms of emergence as well as severity of acute diastolic dysfunction. For instance, myocardial stunning at the mid- or end-systolic phase (frozen in a “neither contracting nor relaxed” state) is more likely to elicit significant diastolic dysfunction as compared with that occurring in the end-diastolic phase.

Interestingly, diastolic dysfunction might be associated not only with impaired active relaxation but also with enhanced passive LV stiffness in patients with TTC. Accordingly, LV diastolic stiffness was shown to be significantly higher, along with reduced atrial contribution to LV volume, during late diastole in a population of 24 TTC patients compared with a control group,36 possibly as a result of TTC-induced histopathological changes such as interstitial fibrosis, 16 along with morphological changes in LV architecture, including shape distortion. Of note, noninvolved segments might also contribute to diastolic dysfunction,

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possibly due to the hypercontraction pattern within these segments potentially leading to reduced relaxation, particularly in the presence of increased heart rate. Regardless of putative mechanisms, clinicians mostly consider diastolic dysfunction in this setting as a transient phenomenon; accordingly, a recent study has demonstrated complete recovery of diastolic function (as measured with conventional and tissue Doppler indices) in close correlation with systolic function in a population of 28 patients with TTC.33

Persistent or Permanent Diastolic Dysfunction: An Intricate and Multifaceted Phenomenon It seems quite surprising that TTC, a phenomenon universally renowned for its apparently fully reversible nature, might be associated with persistent (or even permanent) diastolic dysfunction that potentially extends far beyond the recovery of its characteristic wall -motion abnormalities. Within this context, a previous study, in which cardiac MRI was used to evaluate serial changes in systolic and diastolic function in TTC patients, clearly demonstrated the relative persistence of diastolic dysfunction (as measured with indices including LV peak filling time and LA emptying volume) in comparison to systolic dysfunction (as measured with LVEF) at the time of discharge.32 However, both diastolic and systolic function were reported to fully recover on follow-up. This implies that diastolic dysfunction, despite its ultimate normalisation, may tend to demonstrate a significantly slower and more delayed recovery pattern compared with systolic dysfunction in patients with TTC. This notion is in line with a recent study that demonstrated improvement of diastolic function in only 28 % of cases in the recovery phase (mean 38±16 days after admission) , with the rest (72 %) having unchanged or worsening diastolic function.31 Importantly, persistent diastolic dysfunction in isolation might also be regarded as a trigger of acute HF, and hence not just an innocent bystander in TTC patients. Accordingly, a case of acute HF (arising 1 month after recovery from a TTC attack) due to persistent diastolic dysfunction was previously reported as the first case in the literature,37 suggesting the particular clinical relevance of this phenomenon.

Mechanistically, persistent or permanent diastolic dysfunction seems to be a more complex and multifaceted phenomenon compared with its transient counterpart.38,39 Microstructural changes, including enlargement of the extracellular matrix and interstitial fibrosis,17,40 which are generally considered transient, might, to some degree, outlast the acute stage of TTC, and might even persist indefinitely.38,39 Besides these residual microstructural changes,39 persistent RV involvement might also have a pivotal role in the evolution of persistent or permanent diastolic dysfunction, largely through ventricular interdependence and TTC-induced temporal changes in cardiac macrostructure, including LV geometry.6,38 However, pre-existing diastolic dysfunction seems to be the most likely aetiology given the advanced age of the TTC population.31,38 Table 2 demonstrates the potential mechanisms of transient and persistent (permanent) diastolic dysfunction in patients with TTC.

Management of Left Ventricular Dysfunction Since LV dysfunction in this setting is regarded as a fully reversible phenomenon (at least to systolic function at rest), supportive measures have been the mainstay of therapy in clinical practice.1,11 Renin–angiotensin system (RAS) blockers, beta-blockers (preferably metoprolol and carvedilol based on preclinical studies)41,42 have been generally recommended in the acute setting.1,11 On the other hand, the recent European HF Association position statement recommended

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Clinical Syndromes Table 2: Potential Mechanisms of Transient and Persistent (Permanent) Diastolic Dysfunction in Patients with Takotsubo Cardiomyopathy

Reversible interstitial changesb

Residual interstitial changesb

LV diastolic filling) may be the fundamental strategy in TTC cases with diastolic HF in isolation or in combination with systolic HF. In general, severe diastolic dysfunction (with a restrictive pattern) with or without life-threatening symptomatology (pulmonary oedema, haemodynamic compromise) appears to be a quite rare phenomenon.31 In the long term, agents with proven mortality benefit, including nebivolol, may be specifically preferred, particularly in elderly TTC patients with persistent or permanent diastolic dysfunction.48

Vigorous hypercontraction pattern of the non-involved segmentsa

Temporal changes in LV geometry associated with late-onset diastolic dysfunction

Left Ventricular Dysfunction as a Risk Stratifier: Shorand Long-term Impacts on Prognosis

Morphological changes in LV architecture, including transient shape distortion

Persistent right ventricular involvementc

Transient

Persistent (Permanent)

Metabolic shutdown with severe myocellular energy depletiona

Pre-existing diastolic dysfunction

Predominantly associated with impaired active relaxation. bPredominantly associated with enhanced chamber stiffness. cPossibly through ventricular interdependence.

LV = left ventricular. a

their use exclusively in patients with a LVEF of < 45 %.1 However, in case of an emerging clinical systolic HF, these agents (regardless of initial LVEF values) should be initiated, at least until recovery. Diuretics and nitroglycerin may also be recommended , largely for symptomatic relief, after exclusion of LVOT obstruction.11 Severe forms of acute HF (significant pulmonary oedema, hypotension, etc.), with or without cardiogenic shock due to primary pump failure, generally mandate the use of mechanical support devices such as extracorporeal membrane oxygenation and LV assist devices, all serving as bridge-to-recovery strategies.11,43 On the other hand, the use of intra-aortic balloon counterpulsation (IABP) in this setting is controversial, and is not routinely recommended based on its neutral results in recent trials.1 Importantly, cathecholaminergic inotropes (dobutamine, isoprenaline, adrenaline, etc.) are strictly contraindicated because they do more harm than good and might worsen the clinical status in this setting, largely due to their paradoxical adverse impact on myocardial function.1,44 On the other hand, non-cathecholaminergic inotropes, including levosimendan, might serve as a safer and efficient alternative to manage severe HF in this setting.45,46 In the setting of acute significant LVOT obstruction (with a gradient of ≥40 mmHg along with a systolic blood pressure of <110 mmHg), the initiation of selective alpha-1 agonists, including phenylephrine and beta-blockers (including short-acting intravenous ones), along with the use of intravenous fluids, may be the preferred strategy.1,11 On the other hand, an existing severe pulmonary oedema and/or cardiogenic shock should initially warrant the urgent use of mechanical support until the mitigation or recovery of LVOT obstruction. Importantly, all inotropic agents and IABP are generally considered to be contraindicated because of their significant potential to aggravate the gradient.11 Therefore, even before initiating levosimendan (the only indicated inotrope for the management of severe primary pump failure in TTC patients)45,46 an existing significant LVOT gradient (accompanying or accounting for the severe clinical status) should be definitively ruled out beforehand.

Currently, there exists no ideal therapy for the management of diastolic dysfunction; accordingly, many agents that work well in subjects with systolic HF generally fail or do not work efficiently in those with diastolic HF, particularly in terms of hospitalisation and mortality rates.47 This notion might, to a large extent, apply to the setting of TTC as well.

Symptomatic relief (diuretics, etc.) along with, where possible, rate control with beta-blockers, for example, (and hence enhancement of

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In the recent European HF Association position statement, a variety of clinical parameters , including advanced age (≥75 years ), an LVEF value of <35 %, pulmonary oedema, an LVOT gradient of >40 mmHg, systolic blood pressure of <110 mmHg and other life-threatening mechanical or arrhythmogenic complications, have been suggested as the major high-risk factors in the acute setting of TTC.1 This potentially denotes that LV functions and associated haemodynamic indices might be regarded as the most crucial determinants of short-term prognosis, possibly associated with the majority of adverse events, including in-hospital deaths among patients with TTC. However, the prognostic impact of clinical LV dysfunction (in combination with symptoms and signs) seems to be more substantial compared with subclinical LV dysfunction in the acute phase.

On the other hand, little is known about the long-term prognostic impact of transient LV dysfunction in this setting.1 It is well known that adverse myocardial remodelling (characterised by late-onset and gradual changes including compensatory hypertrophy, ultimately leading to a progressive and insidious decline in systolic function)49 generally evolves in survivors of ACS, myocarditis, etc., with significant myocardial injury, and appears to be associated with poor prognosis in these patients. However, such a limited duration of systolic dysfunction, as in the setting of TTC, can not be considered a trigger of adverse myocardial remodelling, which generally evolves and progresses within months to years after the initial insult.

In contrast, LV dysfunction extending beyond the acute stage might have long-term consequences in the setting of TTC; accordingly, persistence of diastolic along with systolic dysfunction (LVEF <50 %) in the recovery stage of TTC (38±16 days) was suggested to be associated with both cardiac and non-cardiac adverse events over a median period of 2 years in a retrospective analysis.31 These authors primarily suggested pre-existing diastolic dysfunction and associated patient-related factors, such as frailty, as the potential mechanisms of long-term adverse events. In particular, cardiovascular events (including arrhythmogenesis) in the long term may be associated, to some degree, with persistent myocardial changes, including interstitial fibrosis, in TTC patients, mostly arising as part of an ongoing clinical LV dysfunction.6,31 Within this context, use of RAS blockers (up to 1 year after recovery) was previously suggested to improve prognosis, largely owing to the favourable impact of these agents on myocardial microstructure.11 However, potential TTC recurrences (in 5–22 % of cases within 5 years), as well as comorbidities including malignancy,1,50 have been generally considered as the fundamental determinants of long-term prognosis in TTC patients.

Importantly, frequent TTC recurrences might theoretically be associated with cumulative pathological changes within the myocardium, even leading to adverse remodelling in rare instances. Within this

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Takotsubo Cardiomyopathy and Left Ventricular Dysfunction context, beta-blockers and sympathetic ganglion blockade, as well as psychological (and cognitive behavioural) treatment and certain yoga practices, may improve long-term prognosis in selected cases, possibly through prevention of future TTC recurrence and, correspondingly, abortion of cumulative myocardial changes, to some degree.1,27,51–53 These preventative implications appear to be based on the strong association between acute autonomic discharge and TTC, and may also be substantiated by the recent evidence of a lower prevalence of diabetes mellitus among TTC cases, potentially suggesting the protective role of diabetes-induced sympathetic neuropathy against TTC evolution.51–53

Figure 1: Clinical Course of LV Dysfunction in the Setting of Takotsubo Cardiomyopathy

TTC in acute stage

Systolic dysfunction in isolation1,3,10,11,24–26

Combined systolic and diastolic dysfunction

Subclinical Left Ventricular Dysfunction: A Subtle Phenomenon with Significant Impact on Quality of Life Among Takotsubo Cardiomyopathy Survivors A portion of cases remote from the index TTC event may continue to suffer a variety of symptoms, including reduced exercise capacity, palpitation and angina, even with fully recovered systolic and diastolic function, as measured with conventional TTE indices.1,54 On the other hand, these patients were generally found to have abnormal tissue Doppler parameters, including impaired myocardial deformation indices (LV global, circumferential and longititunal strain) compared with controls.54,55 In a recent, interesting study of 37 cases with a TTC history and 37 control subjects, a significant portion of cases (88 %) were reported to have symptoms of HF after a median duration of 20 months after the index TTC attack, including fatigue, breathlessness and angina, despite normal LVEF values on TTE.54 Accordingly, these patients, compared with controls, had significantly impaired exercise capacity on exercise testing (decreased peak levels of O2 consumption: 24±1.3 vs 31±1.3 ml/kg/min, p<0.001), as well as reduced global longitutinal (–17±1 vs –20±1 %, p=0.006) and apical circumferential strain rates (–16±1.0 vs –23±1.5 %, p<0.001). Moreover, these patients were also found to have impaired myocardial energetic status, as demonstrated by a reduced phosphocreatine/ATP ratio (1.3±0.1 vs 1.9±0.1, p<0.001) compared with control subjects.

These findings may imply that even though macroscopic normalisation, as demonstrated with conventional TTE indices, generally appears to be obvious, recovery at the myocellular level may not be complete, with persistence of dysfunction, to some degree, in cellular components (mitochondria, contractile proteins, etc.) probably on a parallel with the clinical severity of the index event in a significant portion of TTC survivors. In other terms, some sort of myocardial dysfunction (systolic and/or diastolic) arising during cycles of enhanced myocardial workload (exercise, hypertensive attacks, etc.), largely because of the residual dysfunction in myocardial energy metabolism and contractile reserve, may account for this poorly understood phenomenon.

Myocardial failure on exercise may also be verified with the use of certain tools, including diastolic stress testing56 and dobutamine stress echocardiogram, in these patients.

Beta-blockers may be of particular benefit for symptomatic improvement in this setting.1 In addition, agents such as trimetazidine and ranolazine, which primarily target improvement of cellular energy metabolism, and hence myocardial ischaemia, were recently suggested as promising adjunctive options for the management of HF.57 Accordingly, TTC survivors with persistent symptomatology may be the ideal candidates for such therapeutic strategies in clinicalpractice.

Importantly, since future TTC attacks might further aggravate sublinical LV dysfunction, prevention of TTC recurrences is also of paramount

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Diastolic dysfunction in isolation17,31,33,35,36

Systolic and diastolic functions within normal limits

Following the acute stage

Subclinical LV dysfunction1,54

Full recovery

Persistent (permanent) diastolic dysfunction6,31,32,37–39

LV = left ventricle; TTC = takotsubo cardiomyopathy.

importance in this setting. Within this context, (besides the wellknown effects of beta-blockers, psychological therapy, etc.), isoflurane (an anaesthetic agent) was recently found to be effective both in the prevention and attenuation of TTC-induced LV dysfunction in experimental studies.58,59 However, further studies are still warranted to discover novel agents with preventive features and disease-specific actions (targeted therapy) in the setting of TTC. Figure 1 demonstrates the general clinical course of various patterns of LV dysfunction in patients with TTC.

Conclusion In clinical practice, a significant proportion of patients with TTC present with LV dysfunction (with or without clinical HF) that may be regarded as an umbrella term, primarily constituting a variety of clinical patterns with diverse characteristics and implications in the short and long term. Accordingly, systolic dysfunction (defined as a resting LVEF below the normal reference values on imaging modalities) generally emerges as a fully reversible pathology, primarily serving as an important determinant of prognosis in the acute setting.

Moreover, transient diastolic dysfunction, in isolation or in combination with systolic dysfunction, may also add to the symptomatology and, to some extent, prognosis of TTC in the acute setting. On the other hand, recent observations suggest that TTC, despite the gross recovery of LV function on LV imaging, may not always be considered a fully reversible phenomenon, as demonstrated by the persistence of certain pathologies, including diastolic dysfunction and subclinical LV dysfunction, in a significant proportion of cases. Moreover, these persistent and subtle changes may have the potential to significantly influence long-term prognosis, as well as quality of life in TTC survivors.

Unfortunately, there exists no specific targeted therapy for the management of acute and/or residual LV dysfunction in the setting of TTC, and the use of supportive measures is generally indicated as the

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Cardiol 2017;244:84–5. DOI: 10.1016/j.ijcard.2017.06.103; PMID: 28784455.

Rolf A, Nef HM, Möllmann H, et al. Immunohistological basis of the late gadolinium enhancement phenomenon in tako-tsubo cardiomyopathy. Eur Heart J 2009;30:1635–42. DOI: 10.1093/eurheartj/ehp140; PMID: 19389788.

Izumi Y, Okatani H, Shiota M, et al. Effects of metoprolol on epinephrine-induced takotsubo-like left ventricular dysfunction in non-human primates. Hypertens Res 2009;32:339–46. DOI: 10.1038/hr.2009.28; PMID: 19300450.

Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation 2012;126:697–706.

DOI: 10.1161/CIRCULATIONAHA.112.111591; PMID: 22732314.

Donker DW, Pragt E, Weerwind PW, et al. Rescue extracorporeal life support as a bridge to reflection in fulminant stress-induced cardiomyopathy. Int J Cardiol 2012;154:e54–6.

Redmond M, Knapp C, Salim M, et al. Use of vasopressors in Takotsubo cardiomyopathy: a cautionary tale. Br J Anaesth 2013;110:487–8. DOI: 10.1093/bja/aes586; PMID: 23404978.

Padayachee L. Levosimendan: the inotrope of choice in cardiogenic shock secondary to takotsubo cardiomyopathy?

Heart Lung Circ 2007;16(Suppl 3):S65–70.

Karvouniaris M, Papanikolaou J, Makris D, Zakynthinos E. Sepsis-associated takotsubo cardiomyopathy can be reversed with levosimendan. Am J Emerg Med 2012;30:832.e5–7.

Jeong EM, Dudley SC Jr. Diastolic dysfunction. Circ J 2015;79:470–7. DOI: 10.1253/circj.CJ-15-0064; PMID: 25746522.

Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–25. DOI: 10.1093/eurheartj/ehi115; PMID: 15642700.

Yilmaz A, Yalta K, Turgut OO, et al. Clinical importance of elevated CK-MB and troponin I levels in congestive heart failure. Adv Ther 2006;23:1060–7. DOI: 10.1007/BF02850226.

Song BG, Hahn JY, Cho SJ, et al. Clinical characteristics, ballooning pattern, and long-term prognosis of transient left ventricular ballooning syndrome. Heart Lung 2010;39:188–95.

DOI: 10.1016/j.hrtlng.2009.07.006; PMID: 20457338.

Gowdar S, Syal S, Chhabra L. Probable protective role of diabetes mellitus in takotsubo cardiomyopathy: a review.

Vessel Plus 2017;1:129–36.

Madias JE. Low prevalence of diabetes mellitus in patients with Takotsubo syndrome: A plausible “protective” effect with pathophysiologic connotations. Eur Heart J Acute Cardiovasc Care 2016;5:164–70.

Chhabra L. Brain–heart disconnection: a protective effect of diabetes mellitus in Takotsubo Cardiomyopathy. Am J Cardiol 2016;117:1858.

Scally C, Rudd A, Mezincescu A, et al. Persistent long-term structural, functional, and metabolic changes after stressınduced (Takotsubo) Cardiomyopathy. Circulation 2017; DOI: DOI: 10.1161/CIRCULATIONAHA.117.031841; epub ahead of press.

Kim SA, Jo SH, Park KH, et al. Functional recovery of regional myocardial deformation in patients with Takotsubo Cardiomyopathy. J Cardiol 2017;70:68–73. DOI: 10.1016/j. jjcc.2016.09.006; PMID: 27889396.

Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277–314.

DOI: 10.1016/j.echo.2016.01.011; PMID: 27037982.

Steggall A, Mordi IR, Lang CC. Targeting metabolic modulation and mitochondrial dysfunction in the treatment of heart failure. Diseases 2017;5:pii;E14. DOI: 10.3390/diseases5020014.

Redfors B, Oras J, Shao Y, et al. Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo). Int J Cardiol 2014;176:815–21. DOI: 10.1016/j. ijcard.2014.08.025; PMID: 25156846.

Oras J, Redfors B, Ali A, et al. Early treatment with isoflurane attenuates left ventricular dysfunction and improves survival in experimental Takotsubo. Acta Anaesthesiol Scand 2017;61:399– 407. DOI: 10.1111/aas.12861; PMID: 28185263.

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Clinical Syndromes

Heart Failure in Sub-Saharan Africa Joseph Gallagher, 1 Kenneth McDonald, 2 Mark Ledwidge 2 and Chris J Watson 3 1. gHealth Research Group, University College, Dublin, Ireland; 2. Heartbeat Trust, Dun Laoghaire Co, Dublin, Ireland; 3. Centre for Experimental Medicine, Queens University, Belfast, Northern Ireland

Abstract Heart failure is a growing problem in sub-Saharan Africa. This arises as the prevalence of risk factors for cardiovascular disease rises, life expectancy increases and causes of heart failure more common in Africa, such as rheumatic heart disease and endomyocardial fibrosis, continue to be a significant issue. Lack of access to diagnostics is an issue with the expense and technical expertise required for echocardiography limiting access. Biomarker strategies may play a role here. Access to essential medicines is also limited and requires a renewed focus by the international community to ensure that appropriate medications are readily available, similar to that which has been implemented for HIV and malaria.

Keywords Heart failure, Africa, echocardiography, essential medicines, natriuretic peptides Disclosure: The authors have no conflicts of interest to declare.

Received: 22 January 2018 Accepted: 15 February 2018 Citation: Cardiac Failure Review 2018;4(1):21–4. DOI: https://doi.org/10.15420/cfr.2018:4:1 Correspondence: Joe Gallagher, gHealth Research Group, University College Dublin, Belfield, Dublin 4, Ireland. E: jgallagher@ucd.ie

Patients with heart disease in Africa commonly present with heart failure both for admission to hospital1 and in the outpatient setting.2 Recent data suggests that, in line with high-income countries, heart failure with preserved ejection fraction is also becoming more common.3 Data from the 12 clinical studies performed before 2005 in eight sub-Saharan Africa (SSA) countries have shown that up to 75 % of cases of heart failure were non-ischaemic in origin.1,4 A recent study showed that patients with heart failure in Africa were the youngest (mean [SE] = 53 [0.4] years), most likely to be illiterate (43 %), lack health insurance (66 %) and medication insurance (67 %), and most likely to be in New York Health Association functional class IV (21 %) compared with those from Asia, the Middle East and South America.5 Over the past several years a shift in the cardiovascular disease profile has been observed, which was reflected by recent clinical trial data derived from the largest multicentre registry for heart failure in Africa.

The sub-Saharan Africa Survey of Heart Failure (THESUS-HF)6 study characterised the causes, treatment and short-term outcome in 1006 Africans from nine SSA countries. Compared with data from prior to 2005, it highlighted hypertension as a rising cause of heart failure (from 23 % to 43 %), an increasing importance of cardiomyopathies (from 20 % to 29 %), a reduced recognition of rheumatic heart disease (from 22 % to 17 %), and a rise in ischaemic heart disease (from 2 % to 8 %) in the aetiology of heart failure.4 Recent studies that have specifically looked for evidence of ischaemic heart disease have shown a higher prevalence than previously reported. A case-control study from Kenya recently suggested that ischaemic heart disease was the second most common cause of heart failure.7 This is in line with the changing demographics in Africa and rise in risk factors, such as hypertension, diabetes and obesity (Table 1).

There are also causes of heart failure that are significantly more prevalent in Africa and rarely found outside low-income countries, such as rheumatic heart disease, endomyocardial fibrosis and HIV-related cardiomyopathy.

© RADCLIFFE CARDIOLOGY 2018

CFR_Gallagher_FINAL.indd 21

Rheumatic heart disease, caused by infection with group A Streptococcus, has been virtually eliminated in high-income countries but continues to be a significant problem in Africa. The prevalence of clinically silent rheumatic heart disease (21.1 per 1000 people; 95 % CI [14.1–31.4]) was about seven to eight times higher than that of clinically manifest disease (2.7 per 1000 people; 95 % CI [1.6–4.4]).20 A recent study demonstrated the young age of patients with this condition (median age of 28 years) had a female preponderance (66.2 % female) and up to a quarter had evidence of left ventricular dysfunction.21 Prevention of progression of valvular disease is currently based on regular penicillin prophylaxis.

Endomyocardial fibrosis is characterised by deposition of fibrous tissue on the endocardial surfaces and is the most common cause of restrictive cardiomyopathy. Its cause is unknown and there are no specific treatments for it. It is commonest within 15 degrees either side of the equator and commonly affects the young. A screening study in rural Mozambique showed a prevalence of 19.8 % with the highest prevalence among those aged 10–19 years.22 The pathophysiology of heart failure in HIV-infected persons is multifactorial and intimately related to the presence of traditional risk factors for coronary artery disease, myocardial inflammation, myocardial fibrosis, coronary artery disease and pericardial disease. The advent of antiretroviral therapy led to a dramatic reduction in this condition and, similar to heart failure of other aetiologies, heart failure with preserved ejection fraction is the most prevalent form of HIV-related cardiomyopathy in the era of highly-active antiretroviral therapy.23,24

Diagnosis of Heart Failure The diagnosis of heart failure can pose significant challenges in Africa due to lack of access to appropriate diagnostics. Internationally, at least,

Access at: www.CFRjournal.com

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Q5

Clinical Syndromes Table 1: Aetiology of Heart Failure in Sub-Saharan African Countries in the 21st Century Study

Country

Study Size and Duration

Prevalence/Epidemiology

Kingue et al. 20059

Cameroon

167 patients, single-centre, 3-year descriptive study

Main aetiologies of heart failure: hypertension (54.5 %), cardiomyopathies (26.3 %), rheumatic heart disease (24.6 %), valvular heart diseases (24.6 %), ischaemic heart disease (2.4 %)

Amoah et al. 200010

Ghana

572 patients, single-centre, 4-year prospective study

Main causes of heart failure: hypertension (21.3 %), rheumatic heart disease (20.1 %), cardiomyopathy (16.8 %), congenital heart disease (9.8 %) and coronary artery disease (10.0 %) Commonest rheumatic valvular lesion: mitral regurgitation (78.0 %) Commonest cardiomyopathies: dilated cardiomyopathy (67.7 %), endomyocardial fibrosis (22.9 %), hypertrophic cardiomyopathy (9.4 %)

Oyoo et al. 199911

Kenya

91 patients, single-centre, crosssectional study

Main causes of heart failure: rheumatic heart disease (32.0 %), cardiomyopathy (25.2 %), hypertensive heart disease (17.6 %), pericardial disease (13.2 %), cor pulmonale (7.7 %), ischaemic heart disease (2.2 %), congenital heart disease (2.2 %)

Soliman et al. 200812

Malawi

3,908 patients, single-centre, 5-year registry

Main causes of heart failure: valvular heart disease (mainly rheumatic heart disease; 34 %), hypertensive heart disease (24 %), cardiomyopathies (19 %), pericardial diseases (14 %), congenital heart disease (4 %), arrhythmias (4 %), other CVD (1 %)

Kennedy et al. 201313

Malawi

250 children with an abnormal echocardiogram, single-centre, 2-year registry

Main causes of heart failure: 55.6 % congenital heart disease (24 % ventricular septal defect, 10 % tetralogy of Fallot, 7.2 % patent ductus arteriosus) and 44.4 % acquired heart disease (22.4 % rheumatic heart disease, 13.6 % dilated cardiomyopathy)

Karaye et al. 201314

Nigeria

2 centres, 1-year registry of all patients Centre 1: patronised by high-income earners; Centre 2: patronised by lowincome earners

Most common heart disease: hypertensive heart disease (56.7 %; more common in Centre 1), dilated cardiomyopathy (15.2 %) Second most common heart disease: ischaemic heart disease (8.7 %; more common in Centre 2) Third most common heart disease: rheumatic heart disease (8.3 %), peripartum cardiomyopathy (4.3 %; exclusively found in Centre 2)

Familoni et al. 200715

Nigeria

82 patients, single-centre, 3-year descriptive study

Main causes of heart failure: hypertension (43.4 %), dilated cardiomyopathy (28.0 %), rheumatic heart disease (9.8 %), endomyocardial fibrosis (2.24 %), cor pulmonale (3.7 %), ischaemic heart disease (8.5 %), other (3.5 %)

Thiam et al. 200316

Senegal

170 patients, single-centre, 6-month prospective study

Main causes of heart failure: hypertension (45.0 %), rheumatic heart disease (34.0 %), diabetes mellitus (11.8 %) Main aetiologies on ECG: LV hypertrophy (63.5 %), AF (16.6 %), valvular heart diseases (45.0 %), hypertension (34.0 %), unspecified (6.0 %)

Ismail et al. 200717

Uganda

65 patients, single centre

Main causes of heart failure: dilated cardiomyopathy (47.7 %), rheumatic heart disease (35.4 %), cor pulmonale (4.6 %), ischaemic heart disease (4.6 %), endomyocardial fibrosis (1.5 %), pericardial disease (1.5 %), other (4.6 %)

Sliwa et al. 200818

South Africa

844 patients (from 4,162 CVD patients, 85 % native Africans), single-centre, 1-year population study

Main causes for heart failure: hypertension (33.3 %), dilated cardiomyopathy (35.1 %), cor pulmonale (26.7 %), ischaemic heart disease (9.1 %), rheumatic heart disease (7.9 %), valvular heart disease (8 %)

Dokainish et al. 20165

Africa

1,294 outpatients Nigeria (383 patients), South Africa (169 patients), Sudan (501 patients), Uganda (151 patients), Mozambique (90 patients)

Main causes for heart failure: hypertensive heart disease (35 %), ischaemic cardiomyopathy (20 %), idiopathic dilated cardiomyopathy (15 %), rheumatic valvular heart disease (7 %)

Abebe et al. 20163

Ethiopia

850 patients admitted with acute heart failure

Main causes for heart failure: ischaemic heart disease (15.8 %), hypertensive heart disease (16.0 %), valvular heart disease (40.1 %), dilated cardiomyopathy (12.5 %), cor pulmonale (4.5 %), others (10.3 %)

Makubi et al. 201619

Tanzania

411 patients >18 years of age from inpatient and outpatient setting

Medical history of: hypertension (47 %), dilated cardiomyopathy (23 %), ischaemic heart disease (10 %), diabetes (12 %), valve disease (1 %)

CVD = cardiovascular disease. Adapted from Glezeva, et al., 2015.8

six heart failure score methodologies based on symptoms and signs have been developed to help diagnose and assess the prevalence of heart failure in the non-hospitalised patient.25 These generally include clinical history and examination, and chest X-ray at a minimum. A number of these criteria26â&#x20AC;&#x201C;28 were established before non-invasive techniques for assessing systolic and diastolic dysfunction became

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CFR_Gallagher_FINAL.indd 22

widely available. However, although the scores are useful in detecting manifest heart failure, objective measurements of cardiac function, such as echocardiography, appear necessary to reduce the false positive rate and accurately detect early stages of heart failure25 and are now an essential part of European and North American guidelines on the diagnosis of heart failure.29,30,3 However, echocardiography is

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Heart Failure in Sub-Saharan Africa not widely available in Africa, where a reported survey in Kenya and Uganda showed functional and staffed radiography, ultrasound and ECG were available in less than half of hospitals in Kenya and Uganda combined; this did not specifically address echocardiography.31 It has also been demonstrated that training nurses and mid-level providers in simplified echocardiographic protocols can be an effective strategy to improve heart failure diagnosis and management in SSA, but equipment remains relatively expensive for such resource-poor settings and training can be an issue.32 In the absence of sufficient resources, an effective approach to perform large-scale risk-profiling of patients would be the implementation of a point-of-care diagnostic test throughout SSA that could be used nationwide when echocardiography facilities are not available or readily accessible. Biomarker diagnostic tests are easy to perform as they do not require specific medical expertise and can be performed in any location as point-of-care tests, and are therefore practical in rural community settings that have limited access to hospitals or medical centres.

The use of natriuretic peptides (NPs) as a tool to rule out heart failure has been implemented in high-income countries33 with success and these tests are also now available as point-of-care tests, which may prove a useful strategy in Africa. NPs are protein biomarkers with established clinical significance for diagnosis and prognosis of cardiovascular disease and heart failure.34 Among them B-type natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-proBNP) have consistently been shown to have the best diagnostic, prognostic and therapeutic clinical benefits in relation to both acute and chronic heart failure.34–36 NPs have also been shown to be superior to echocardiography parameters in risk stratification in hypertension.37 The strength of using inexpensive BNP and NT-proBNP tests for risk stratification of patients with high-risk factors for heart failure was also demonstrated by several clinical studies, including the recently published St Vincent’s Screening to Prevent Heart Failure Study (STOP-HF)38 and the NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) study.39 These studies used BNP and NT-proBNP, respectively, to identify a high-risk cohort in a group of individuals with cardiovascular disease or risk factors. By targeting care to these individuals (mostly through enhanced use of renin–angiotensin–aldosterone system modifying therapies and betablockers, which are also the keystone therapies in the management of heart failure with reduced ejection fraction, these studies were able to achieve a significant reduction in new onset heart failure and other major adverse cardiovascular events.

In low- and middle-income countries where access to expensive and technical cardiac imaging is likely to remain limited and confined to large population centres there is a potential for NPs to aid in the diagnosis and management of heart failure, particularly in combination with point-of-care echocardiography.

1.

2.

3.

amasceno A, Cotter G, Dzudie A, et al. Heart failure D in sub-Saharan Africa: time for action. J Am Coll Cardiol 2007;50:1688–93. DOI: 10.1016/j.jacc.2007.07.030; PMID: 17950152.

Tefera YG, Abegaz TM, Abebe TB, Mekuria AB. The changing trend of cardiovascular disease and its clinical characteristics in Ethiopia: hospital-based observational study. Vasc Health Risk Manag 2017;13:143–51. DOI: 10.2147/VHRM.S131259; PMID: 28461753.

Abebe TB, Gebreyohannes EA, Tefera YG, Abegaz TM. Patients with HFpEF and HFrEF have different clinical characteristics but similar prognosis: a retrospective cohort study. BMC Cardiovasc Disord 2016;16:232. DOI: 10.1186/s12872-016-0418-9;

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4.

5.

6.

Management of Stable Heart Failure Following diagnosis, it is important that access to appropriate medical therapies is available for patients with heart failure. The World Health Organization has targeted that medicines to prevent recurrent cardiovascular disease be available in 80 % of communities and used by 50 % of eligible individuals by 2025. However, a recent analysis of the Prospective Urban Rural Epidemiology Study (PURE) data sought to determine the availability of four key cardiovascular medications: aspirin, statin, angiotensin-converting enzyme (ACE) inhibitor and beta-blockers.40 It found that all four medications were available in 62 % of urban and 37 % of rural communities in lower middle-income countries, and in 25 % of urban and one of 30 (3 %) rural communities in low-income countries. The four cardiovascular disease medicines were potentially unaffordable for 0.14 % of households in high-income countries (14 of 9,934 households) but unaffordable for 60 % of lowincome countries studied.40 A survey of Kenya and Uganda showed that ACE inhibitors were only available in 51 % of Kenyan and 79 % of Ugandan hospitals. Almost one-third of the hospitals in each country had a stock-out of at least one of the medication classes in the prior quarter.31 A study looking at medication availability in Uganda showed that ACE inhibitors were available in 22.2 % of health facilities overall, varying from 75 % of hospitals to significantly less in health centres (0–75 % depending on area) and private clinics (36.5 %) (p<0.001).41

Prognostic Variables A recent analysis of the Symptoms and Signs of Heart Failure at Admission and Discharge and Outcomes in the Sub-Saharan Acute Heart Failure (THESUS-HF) data demonstrated that in acute heart failure patients in SSA, symptoms and signs of heart failure improve throughout admission, and simple assessments, including oedema, rales, oxygen saturation, respiratory rate, and asking the patient about general well-being, are valuable tools in patients’ clinical assessments.42 Interestingly echocardiographic parameters had limited prognostic benefit. Heart rate and left atrial size predicted death within 60 days or readmission. Heart rate, left ventricular posterior wall thickness in diastole, and presence of aortic stenosis were associated with the risk of death within 180 days. Echocardiographic variables, especially those of left ventricular size and function, were not found to have additional predictive value in patients admitted for acute heart failure.43

Conclusion Heart failure in SSA is an increasing issue. There is a need to explore new diagnostic strategies that are implementable in low-income countries with a predominantly rural population. There is also a need to explore management strategies and, in particular, medication supply.

Further research is also required in conditions particular to the African region, such as rheumatic heart disease and endomyocardial fibrosis, to ensure these conditions can be effectively managed. n

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Mayosi BM. Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa. Heart 2007;93:1176–83. DOI: 10.1136/ hrt.2007.127746; PMID: 17890693.

Dokainish H, Teo K, Zhu J, et al. Heart failure in Africa, Asia, the Middle East and South America: the INTER-CHF study. Int J Cardiol 2016;204:133–41. DOI: 10.1016/j.ijcard.2015.11.183; PMID: 26657608.

Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012;172:1386–94.

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Glezeva N, Gallagher J, Ledwidge M, et al. Heart failure in subSaharan Africa: review of the aetiology of heart failure and the role of point-of-care biomarker diagnostics. Trop Med Int Health 2015;20:581–8. DOI: 10.1111/tmi.12461; PMID: 25598183.

Kingue S, Dzudie A, Menanga A, et al. [A new look at adult chronic heart failure in Africa in the age of the Doppler echocardiography: experience of the medicine

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individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care. Health Technol Assess 2009;13:1–207.

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Maisel A, Mueller C, Adams K, Jr., et al. State of the art: using natriuretic peptide levels in clinical practice. Eur J Heart Fail 2008;10:824–39. DOI: 10.1016/j.ejheart.2008.07.014; PMID: 18760965. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316–22.

DOI: 10.1016/S0140-6736(03)13976-1; PMID: 12892964.

Clerico A, Fontana M, Zyw L, et al. Comparison of the diagnostic accuracy of brain natriuretic peptide (BNP) and the N-terminal part of the propeptide of BNP immunoassays in chronic and acute heart failure: a systematic review. Clin Chem 2007;53:813–22. DOI: 10.1373/clinchem.2006.075713; PMID: 17384013.

Gallagher J, Watson C, Zhou S, et al. B-type natriuretic peptide and ventricular dysfunction in the prediction of cardiovascular events and death in hypertension. Am J Hypertens 2018;31:228–34.

DOI: 10.1093/ajh/hpx153; PMID: 29036547.

Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptidebased screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA 2013;310:66–74. DOI: 10.1001/ jama.2013.7588; PMID: 23821090.

Huelsmann M, Neuhold S, Resl M, et al. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. J Am Coll Cardiol 2013;62:1365–72. DOI: 10.1016/j.jacc.2013.05.069; PMID: 23810874.

Khatib R, McKee M, Shannon H, et al. Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and lowincome countries: an analysis of the PURE study data. Lancet 2016;387:61–9. DOI: 10.1016/S0140-6736(15)00469-9; PMID: 26498706.

Musinguzi G, Bastiaens H, Wanyenze RK, et al. Capacity of health facilities to manage hypertension in Mukono and Buikwe districts in Uganda: challenges and recommendations.

PloS One 2015;10:e0142312. DOI: 10.1371/journal. pone.0142312; PMID: 26560131.

Sani MU, Cotter G, Davison BA, et al. Symptoms and signs of heart failure at admission and discharge and outcomes in the sub-Saharan acute heart failure (THESUS-HF) registry.

J Card Fail 2017;23:739–42. DOI: 10.1016/j.cardfail.2016.09.016; PMID: 27664511 Sani MU, Davison BA, Cotter G, et al. Echocardiographic predictors of outcome in acute heart failure patients in sub-Saharan Africa: insights from THESUS-HF. Cardiovasc J Afr 2017;28:60–7. DOI: 10.5830/CVJA-2016-070; PMID: 28262911.

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Treatment

Pharmacological Interventions Effective in Improving Exercise Capacity in Heart Failure 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 Heart failure (HF) is characterised by exercise intolerance, which substantially impairs quality of life (QOL) and prognosis. The aim of this review is to summarise the state of the art on pharmacological interventions that are able to improve exercise capacity in HF. Ivabradine, trimetazidine and intravenous iron are the only drugs included in the European Society of Cardiology HF guidelines that have consistently been shown to positively affect functional capacity in HF. The beneficial effects on HF symptoms, physical performance and QOL using these pharmacological approaches are described.

Keywords Exercise tolerance, heart failure, intravenous iron, ivabradine, trimetazidine Disclosure: The authors have no conflicts of interest to declare.

Received: 7 February 2018 Accepted: 7 March 2018 Citation: Cardiac Failure Review 2018;4(1):25–7. DOI: https://doi.org/10.15420/cfr.2018:8:2 Correspondence: Giuseppe Rosano, Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, via della Pisana 235, 00163 Rome, Italy.

E: giuseppe.rosano@sanraffaele.it

Exercise intolerance is a typical symptom of heart failure (HF), impairing patients’ ability to perform activities of daily living and affecting quality of life (QOL).1 Chronic HF is characterised by a progressive reduction in exercise capacity, increasing fatigue and shortness of breath.2 In addition, exercise intolerance is often accompanied by increased blood pressure and chronotropic incompetence.1 According to European Society of Cardiology (ESC) guidelines on HF,1 the goals of treatment are to improve functional capacity and QOL, as well as clinical status, in order to prevent hospital admission and reduce mortality. For these reasons, pharmacological and nonpharmacological interventions have been developed to improve exercise capacity in HF. According to ESC guidelines, exercise training is an integral component of the management of patients with this HF.1 In fact, there is considerable evidence that exercise not only is safe but also leads to physical and psychological benefits in HF patients.3 As for pharmacological intervention, in past decades this has been mainly focused on improving mortality and morbidity, and has added little to exercise capacity and QOL in people with HF. Interventions with effects on exercise capacity have not been considered in the therapeutic algorithm of HF, mainly because early interventions such as flosequinan and ibopamine have been associated with neutral or unfavourable outcomes.4,5 However, more recently, it has become evident that drugs with a positive effect on functional capacity may also positively affect prognosis in HF. With this in mind, the aim of this review is to summarise the state of the art on pharmacological interventions that are able to improve exercise capacity in HF.

Intravenous Iron Iron deficiency is a common comorbidity of HF, affecting up to 50 % of patients.6–8 It can lead to anaemia and/or skeletal muscle dysfunction

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without anaemia in HF patients. Iron is a critical component of peroxide- and nitrous oxide-generating enzymes that are critical for mitochondrial function. As a consequence of iron insufficiency, impaired oxygen transport occurs, altering the metabolism of cardiac and skeletal muscle. Owing to these effects on skeletal muscle, iron deficiency is associated with reduced exercise capacity and poor prognosis. In fact, increased morbidity and mortality is associated with this condition.7 For these reasons, the ESC guidelines indicate that ferric carboxymaltose (FCM; intravenous iron) should be considered in symptomatic patients (serum ferritin <100 μg/l, or serum ferritin 100–299 μg/l with transferrin saturation <20 %).1 This recommendation is based on evidence showing that treatment with intravenous FCM decreases symptoms and improves functional capacity and QOL in HF patients.

Earlier studies suggested that in anaemic patients with chronic HF, iron alone (without erythropoietin) increased haemoglobin count, reduced symptoms and improved exercise capacity.9,10 In patients with moderate-to-severe congestive HF and chronic kidney insufficiency, improvements in New York Heart Association (NYHA) class and echocardiographic indices were observed.10 Consistently with this, a double-blind, randomised, placebo-controlled study in anaemic patients with chronic HF and renal insufficiency demonstrated that FCM reduced N-terminal probrain natriuretic peptide (NT-proBNP) levels, and that this reduction was associated with an improvement in exercise capacity as well as left ventricular ejection fraction (LVEF), NYHA functional class, renal function and QOL.11 In addition, the Effect of FCM on Exercise Capacity in Patients with Iron Deficiency and Chronic HF (EFFECT-HF) study further clarified that FCM led to repletion of iron stores and improved HF severity and QOL.12

Access at: www.CFRjournal.com

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Treatment A single-blind, randomised controlled study demonstrated that FCM improved exercise tolerance, functional class and HF symptoms in patients with chronic HF and evidence of abnormal iron metabolism, with these effects being more evident in anaemic patients.13 Independently of the presence of anaemia, the Ferinject Assessment in Patients with Iron Deficiency and Chronic HF (FAIR-HF) trial showed the benefits of FCM on symptoms, functional capacity and QOL, with an acceptable side-effect profile.14 The Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic HF (CONFIRM-HF) trial showed that the observed improvements in functional capacity, symptoms and QOL were also associated with a decreased risk of hospitalisation for worsening HF at 1 year.15 Two meta-analyses in iron-deficient patients with systolic HF indicated that FCM improved HF symptoms, outcomes, exercise capacity and QOL,16 and that this intervention was associated with a reduction in recurrent cardiovascular hospitalisations.17 On the other hand, the recent Iron Repletion Effects on Oxygen Uptake in HF (IRONOUT-HF) trial, conducted in patients with HF and reduced ejection fraction (HFrEF) and iron deficiency, showed that high-dose oral iron did not improve exercise capacity over 16 weeks.18 These results suggest that oral intake does not provide adequate replacement of iron in HF patients.

Three recently initiated double-blind, placebo-controlled clinical trials (AFFIRM-AHF, FAIR-HF2 and HEART-FID) will investigate the effects of intravenous FCM versus placebo on morbidity and mortality outcomes and will further clarify the impact of intravenous FCM supplementation on functional capacity and clinical outcomes.

Ivabradine The efficacy of ivabradine in HF is now well established.19–22 ESC guidelines indicate ivabradine for the treatment of HFrEF patients who are in sinus rhythm and who cannot tolerate a beta-blocker, and for those who already receive an angiotensin-converting enzyme inhibitor, a beta-blocker and a mineralocorticoid receptor antagonist and are still symptomatic.1 Clinical trials have demonstrated that ivabradine effectively improves functional capacity in patients with HFrEF. The carvedilol, ivabradine or their Combination on Exercise Capacity in Patients with HF (CARVIVA HF) trial found that ivabradine, alone or in combination with carvedilol, was more effective than carvedilol alone in improving exercise tolerance and QOL in HF patients. 21 Patients receiving carvedilol and ivabradine in combination had better exercise performance than those receiving carvedilol alone. The effects of ivabradine on exercise capacity were associated with an improvement in isokinetic strength compared to carvedilol, and with a significant reduction in fatigue index. These data are in agreement with a subanalysis of the Systolic HF Treatment with the If Inhibitor Ivabradine Trial (SHIFT), conducted in 1944 patients, in which health-related QOL was found to be inversely associated with clinical events.19 Treatment with ivabradine was associated with improvements in QOL scores and better outcomes, due to the improvement in exercise capacity and symptoms.

These studies suggest that combined ivabradine and beta-blocker therapy is associated with a better functional capacity than

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beta-blockers alone, and that combination therapy provides better QOL than beta-blocker monotherapy.23 Furthermore, the combination of carvedilol and ivabradine leads to better control of heart rate and exercise capacity than uptitration of beta-blocker monotherapy.

Furthermore, the addition of ivabradine to carvedilol in patients in sinus rhythm, ischaemic HF and heart rate ≥70 BPM was found to lead to a shorter beta-blocker uptitration period, higher final beta-blocker dose, greater heart rate reduction and better exercise capacity.22 Most of the effects of ivabradine on functional capacity are related to the haemodynamic improvements provided by ivabradine in HF, and not only through heart rate reduction.24 In fact, ivabradine provides an anti-remodelling effect, improves left ventricular structures and function, and reduces NT-proBNP levels.25 When compared with beta-blockers, ivabradine, for the same degree of heart rate reduction, does not impair the neuromuscular junction, thereby affecting muscular contraction. For all these reasons, ivabradine is effective in improving functional capacity, relieving symptoms and increasing QOL in patients with HF.26 These effects also translate into prognostic benefits.

Trimetazidine Trimetazidine is a relatively old agent but relatively new in the treatment of HF. It has been shown to improve LVF, exercise capacity and prognosis in patients with mainly ischaemic HF.27–31 Trimetazidine improves cardiac metabolism by inhibiting free fatty acid oxidation and improving glucose utilisation. This metabolic switch leads to a greater production of high-energy phosphate per mol of oxygen and, therefore, to more energy for contraction.

This improved metabolic efficiency translates into greater efficiency of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase and of the actin–myosin interactions.32,33 Several studies have shown that modulation of myocardial metabolism with trimetazidine and drugs acting on the same metabolic pathway, such as perhexiline, may improve left ventricular remodelling and prognosis in patients with HFrEF. Although metabolic modulators have been used in clinical practice for decades, they have been only recently introduced in HF management.

Metabolic agents improve cardiac metabolism without altering haemodynamics.34 Among metabolic agents acting on cardiac myocytes, only perhexiline and trimetazidine are available for clinical use. Trimetazidine is the metabolic agent with the most data in patients with HF, while only a few reports, mainly preclinical, are available for perhexiline.

In chronic HF, trimetazidine improves LVF, normalises myocardial metabolism and improves endothelial dysfunction.35–37 A collaborative, multicentre study has shown that trimetazidine improves mortality in patients with HFrEF.31 A meta-analysis investigating the effects of trimetazidine as add-on treatment in patients with chronic HF demonstrated that the agent improves clinical symptoms and cardiac function, reduces hospitalisations for cardiac causes, and decreases serum levels of BNP and C-reactive protein.30 Finally, there is evidence that modified trimetazidine may yield fewer benefits than the original form in terms of LVEF enhancement, which may be because of the difference in pharmacokinetics.38,39

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Drugs to Improve Exercise in Heart Failure Randomised clinical trials confirmed the efficacy of trimetazidine in patients with HF. Beneficial effects include improvements in NYHA functional class, exercise tolerance, QOL, LVEF and cardiac volume.31,35,40–42 A meta-analysis of 955 HF patients concluded that trimetazidine therapy significantly reduces left ventricular end-systolic volume and improves NYHA functional class and exercise duration, as well as decreasing allcause mortality, cardiovascular events and hospitalisation rates.43 The 2016 ESC guideline indicates that trimetazidine may be considered for the treatment of stable angina pectoris with symptomatic HFrEF, when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (effective anti-anginal treatment, safe in HF), class IIb, level of evidence A.1 This recommendation is based on the body of evidence suggesting that trimetazidine may improve NYHA functional capacity, exercise duration and LVF in patients with HFrEF.

1.

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McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology.

Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. DOI: 10.1093/ eurheartj/ehs104; PMID: 22611136.

Piepoli MF, Conraads V, Corrà U, et al. Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation. Eur J Heart Fail 2011;13:347–57. DOI: 10.1093/eurjhf/hfr017; PMID: 21436360.

Packer M, Narahara KA, Elkayam U, et al. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J Am Coll Cardiol 1993;22:65–72. DOI: 10.1016/0735-1097(93)90816-J; PMID: 8509565.

Hampton JR, van Veldhuisen DJ, Kleber FX, et al. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators. Lancet 1997;349:971–7. DOI: 10.1016/ S0140-6736(96)10488-8; PMID: 9100622.

Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–82. DOI: 10.1016/j.ahj.2013.01.017; PMID: 23537975.

Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241–51.

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Cleland JG, Zhang J, Pellicori P, et al. Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure. JAMA Cardiol 2016;1:539–47.

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Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol 2006;48:1225–7. DOI: 10.1016/j. jacc.2006.07.015; PMID: 16979010.

Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency.

J Nephrol 2008;21:236–42. PMID: 18446719 Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol 2007;50:1657–65. DOI: 10.1016/j.jacc.2007.07.029; PMID: 17950147. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al.

EFFECT-HF Investigators. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation 2017;136:1374–83. DOI: 10.1161/ CIRCULATIONAHA.117.027497; PMID: 28701470.

Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observerblinded trial. J Am Coll Cardiol 2008;51:103–12. DOI: 10.1016/j. jacc.2007.09.036; PMID: 18191732.

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Conclusions A substantial body of evidence for their beneficial effects supports the use of ivabradine, trimetazidine and intravenous iron to improve functional capacity and prognosis in HF.23 In particular, treatment with ivabradine up to 7.5 mg twice daily has been found to improve functional parameters and exercise capacity in HF patients,21 with improvements in QOL scores and better outcomes. Similarly, treatment with trimetazidine is associated with improvements in exercise tolerance, NYHA functional class, QOL, LVEF and cardiac volume.

Intravenous FMC has been found to improve exercise capacity, functional class, HF severity and symptoms, and QOL, as well as reducing hospitalisation rates for worsening HF. Ongoing trials will further clarify the impact of intravenous FCM supplementation on functional capacity and clinical outcomes. n

14. A nker SD, Comin Colet J, Filippatos G, et al. FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48.

DOI: 10.1056/NEJMoa0908355; PMID: 19920054.

15. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.

CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.

Eur Heart J 2015;36:657–68. DOI: 10.1093/eurheartj/ehu385; PMID: 25176939.

16. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail 2016;18:786–95. DOI: 10.1002/ ejhf.473; PMID: 26821594.

17. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018;20:125–33. DOI: 10.1002/ ejhf.823; PMID: 28436136.

18. Lewis GD, Malhotra R, Hernandez AF, et al. NHLBI Heart Failure Clinical Research Network. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317:1958–66.

DOI: 10.1001/jama.2017.5427; PMID: 28510680.

19. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J 2011;32:2395–404. DOI: 10.1093/eurheartj/ehr343; PMID: 21875859.

20. Swedberg K, Komajda M, Böhm M, et al. SHIFT investigators.

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.

DOI: 10.1016/S0140-6736(10)61198-1; PMID: 20801500.

21. Volterrani M, Cice G, Caminiti G, et al. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF trial). Int J Cardiol 2011;151:218– 24. DOI: 10.1016/j.ijcard.2011.06.098; PMID: 21764469.

22. Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to β-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study.

Adv Ther 2015;32:108–19. DOI: 10.1007/s12325-015-0185-5; PMID: 25700807.

23. Milinković I, Rosano G, Lopatin Y, Seferović PM. The role of ivabradine and trimetazidine in the new ESC HF guidelines.

Card Fail Rev 2016;2:123–9. DOI: 10.15420/cfr.2016:13:1; PMID: 28785466.

24. Rosano GM, Vitale C, Volterrani M. Heart rate in ischemic heart disease. The innovation of ivabradine: more than pure heart rate reduction. Adv Ther 2010;27:202–10. DOI: 10.1007/ s12325-010-0030-9; PMID: 20495895.

25. Pereira-Barretto AC. Cardiac and hemodynamic benefits: mode of action of ivabradine in heart failure. Adv Ther 2015;32:906–19. DOI: 10.1007/s12325-015-0257-6; PMID: 26521191.

26. Sarullo FM, Fazio G, Puccio D, et al. Impact of “off-label” use of ivabradine on exercise capacity, gas exchange, functional class, quality of life, and neurohormonal modulation in patients with ischemic chronic heart failure. J Cardiovasc Pharmacol Ther 2010;15:349–55.

DOI: 10.1177/1074248410370326; PMID: 20940450.

27. Lim WY, Woldman S. Pharmacological management of chronic heart failure: old drugs, new drugs and new indications. Br J Hosp Med (Lond) 2013;74:C18–22. DOI: 10.12968/hmed.2013.74.

Sup2.C18; PMID: 23411909.

28. Zhao Y, Peng L, Luo Y, et al. Trimetazidine improves exercise tolerance in patients with ischemic heart disease: a metaanalysis. Herz 2016;41:514–22. DOI: 10.1007/s00059-015-43922; PMID: 26668006.

29. Z hang 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. DOI: 10.1016/j.jacc.2011.11.027; PMID: 22381427.

30. Zhou X, Chen J. Is treatment with trimetazidine beneficial in patients with chronic heart failure? PLoS One 2014;9:e94660.

DOI: 10.1371/journal.pone.0094660; PMID: 24797235.

31. 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. DOI: 10.1016/j.ijcard.2012.09.123; PMID: 23073279.

32. 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.

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33. Zemljic G, Bunc M, Vrtovec B. Trimetazidine shortens QTc interval in patients with ischemic heart failure. J Cardiovasc Pharmacol Ther 2010;15:31–6. DOI: 10.1177/1074248409354601; PMID: 19966175.

34. Palaniswamy C, Mellana WM, Selvaraj DR, Mohan D. Metabolic modulation: a new therapeutic target in treatment of heart failure. Am J Ther 2011;18:e197–201. DOI: 10.1097/ MJT.0b013e3181d70453; PMID: 20393344.

35. 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. DOI: 10.1016/j.ehj.2004.06.034; PMID: 15474696.

36. 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. DOI: 10.1016/j.jacc.2006.03.060; PMID: 16949492.

37. Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect. Eur Heart J 2007;28:1102–8. DOI: 10.1093/ eurheartj/ehm071; PMID: 17456483.

38. Barré J, Ledudal P, Oosterhuis B, et al. Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure.

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39. Génissel P, Chodjania Y, Demolis JL, et al. Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers. Eur J Drug Metab Pharmacokinet 2004;29:61–8.

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40. 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. DOI: 10.1136/ hrt.2003.031310; PMID: 15657223.

41. Rosano GM, Vitale C, Sposato B, et al. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study.

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42. Sisakian H, Torgomyan A, Barkhudaryan A. The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy.

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43. Gao D, Ning N, Niu X, et al. Trimetazidine: a metaanalysis of randomised controlled trials in heart failure.

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Treatment

Iron Therapy in Heart Failure: Ready for Primetime?

Ify R Mordi, Aaron Tee and Chim C Lang Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK

Abstract There is an increasing awareness of the prevalence of iron deficiency (ID) in patients with heart failure (HF) and its contributory role in the morbidity and mortality of HF. It is important to note that many HF patients have ID without being anaemic, hence it is vital to screen for ID even in patients with haemoglobin within the normal laboratory range. This review summarises the pathophysiology and epidemiology of ID in HF before discussing the evidence for iron replacement therapy in HF patients. Finally, it discusses the ongoing large outcome trials evaluating iron replacement in HF.

Keywords Heart failure, iron deficiency, iron replacement, exercise capacity, cardiovascular outcomes Disclosure: AT and CCL have no conflicts of interest to declare. IM is supported by a NHS Education for Scotland/Chief Scientist Office Post-Doctoral Clinical Lectureship (PCL 17/07).

Received: 29 January 2018 Accepted: 28 March 2018 Citation: Cardiac Failure Review 2018;4(1):28–32. DOI: https://doi.org/10.15420/cfr.2018:6:2 Correspondence: Professor Chim C Lang, Division of Molecular and Clinical Medicine, University of Dundee, Mailbox 2, Ninewells Hospital & Medical School, Dundee, DD1 9SY. E: c.c.lang@dundee.ac.uk

Despite advances in the management of heart failure (HF), a significant burden of mortality and morbidity remains.1 This, combined with the ever-escalating costs of novel drug development, has led to an increased focus on the treatment of comorbidities in order to improve outcomes. As a chronic condition, it is increasingly recognised that HF is actually an iron-deficient state, and is highly prevalent, similar to patients with chronic kidney disease and chronic rheumatological conditions in whom iron therapy is an established part of management. In this review article, we discuss the epidemiology and pathophysiology of iron deficiency (ID) in HF and the current evidence for its utility.

can be deleterious, causing cardiac and liver toxicity, as well as oxidative stress.5 The average oral intake of iron is around 10–20 mg/day, and around 1–2 mg is absorbed in the duodenum. There is no pathway for iron excretion; however, around 1–2 mg/day is lost through other mechanisms, such as skin desquamation and bleeding.6 Once absorbed, intracellular iron exists in the ferrous form (Fe2+), while extracellular iron is in the ferric form (Fe3+). Iron is described as either stored (as ferritin within the liver, bone marrow and spleen) or utilised (circulating and intracellular iron).7 Circulating iron is bound to transferrin, which delivers iron to tissues for utilisation or storage, while most intracellular iron is within haemoglobin.

Iron Metabolism

Pathophysiology and Epidemiology of Iron Deficiency in Heart Failure

Iron is an important micronutrient that is required by every cell in the body for metabolism. It has a number of important roles that contribute to metabolic health. First, iron is able to transfer between the ferrous (Fe2+) and ferric (Fe3+) states, allowing it to act as a catalyst for important biochemical reactions.2 Iron is a component of haemoglobin and thus plays a key role in tissue oxygenation. It is also a component of myoglobin, which is an oxygen-binding protein found in skeletal muscle and myocytes, allowing oxygen release in hypoxic conditions.3 In addition to being a constituent of haemoglobin, iron plays a key role in erythropoiesis, via hepcidin, which is produced in the liver and regulates iron absorption in the gastrointestinal tract and iron release from reticuloendothelial tissue. ID leads to a reduction in maturation of haematopoietic cells and resistance to erythropoietin, a renally produced cytokine that increases red blood cell development.4 Iron is also a key component of mitochondria, and hence is vital for myocyte energy production. Given these key functions, it is clear to see why targeting ID is an attractive proposition.

It is important to note that total body iron is regulated within a narrow therapeutic window and iron overload, such as in haemochromatosis,

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The prevalence of ID in HF patients has been reported as being up to 50 %, even in patients without anaemia.8–10 The pathophysiology of ID with HF specifically is likely to be multifactorial. When ID is found in patients with HF, it is important not to overlook other causes, such as gastrointestinal ulceration or malignancy. The prevalence of these conditions in patients with ID means that gastrointestinal investigation is often required as first-line to exclude sinister causes.11 There may be simple factors, such as blood loss due to antiplatelet or anticoagulant therapy, leading to iron loss. Importantly though, the use of these medications has not been shown to be correlated with reduced ferritin in HF patients, suggesting that this is not the primary cause of ID.8,9 Malabsorption (and consequent reduced nutrition) may also play a role. A reduction in appetite from chronic illness may lead to a reduction in dietary iron intake. Additionally, gut interstitial oedema can lead to a poorly functioning gastrointestinal tract and reduced oral iron uptake. Liver congestion may also play a role. The chronic inflammatory state associated with HF leads to increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6). Inflammation induces the synthesis of hepcidin, which leads

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Iron Therapy in Heart Failure to reduction in the release of stored iron.12 Intriguingly, while most chronic inflammatory diseases are associated with higher levels of hepcidin, studies in HF patients have actually shown that worse HF is associated with lower levels of hepcidin and does not appear to correlate with IL-6 in this group of patients.13,14 This may be in part due to elevated levels of erythropoietin associated with worse HF and is associated with the suppression of hepicidin.15 In a study of explanted hearts, iron stores within the hearts of HF patients due for cardiac transplant were found to be depleted compared to healthy controls.16 Furthermore, a reduction in soluble transferrin receptor was found in response to increased levels of aldosterone and noradrenaline, which are commonly elevated in HF.

Diagnosis of Iron Deficiency It is important to note that many HF patients have ID without being anaemic, hence it is vital to screen for ID, even in patients with haemoglobin within the normal laboratory range. The gold standard for the assessment of total body iron stores and diagnosis of ID is bone marrow aspiration with Prussian blue staining. However, this is clearly not practical in the routine setting, particularly if repeated testing is required. The use of serum markers is much more common.

Typically, two parameters are used in the assessment of ID: ferritin and transferrin saturation.

Although ferritin is a predominantly intracellular storage molecule, some is able to enter the systemic circulation and can therefore be measured. In stable patients, serum ferritin has been shown to correlate well with overall iron stores measured by bone marrow aspirate.17,18 Traditionally, the normal range for serum ferritin is 30–300 µg/l; however, ferritin is an acute-phase protein and therefore is increased in inflammatory states. For this reason, in most HF studies and in the most recent European Society of Cardiology HF guidelines, serum ferritin <100 µg/l has been used to diagnose absolute ID.19 Absolute ID relates to a state where there is truly insufficient iron.

Transferrin levels are usually low. However, low transferrin levels are not necessary for a diagnosis of ID in those in whom serum ferritin is <100 µg/l. Functional ID is defined as a serum ferritin level of 100–300 µg/l and a transferrin saturation of <20 %. In this setting, while the available iron stores are potentially sufficient to meet the body’s physiological demands, they cannot be transported from the intracellular compartment to the circulation. Transferrin saturations are reduced in inflammatory states but they are much less affected than serum ferritin.20 Serum iron levels can also be measured. Levels vary widely, even from hour to hour, so it is recommended that serum iron levels should not be used for the assessment of ID.21 A recent study by Grote Beverborg et al. compared a variety of iron-associated biomarkers against the gold standard of bone marrow biopsy in 42 patients with HF and found that transferrin saturation ≤19.8 % or serum iron ≤13 µmol/l actually had better diagnostic performance than the current definition using serum ferritin, and also had independent prognostic significance in in 387 outpatients with HF.22 One test that has recently been proposed for the diagnosis of ID is serum-soluble transferrin receptor (ssTR) level, which is not affected by inflammation and appears to correlate very well with iron status, being more sensitive but less specific than serum ferritin (although ferritin cut-offs varied within the meta-analysis from which these data were derived).23,24 Despite showing promise, this test is not widely available. There has

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not yet been any definite incremental benefit to using ssTR above traditional measures of iron status, hence at present serum ferritin and transferrin saturations remain the most useful diagnostic tests.

Consequences of Iron Deficiency The presence of ID in HF has been shown to have a number of clinical implications. Figure 1 summarises the pathophysiological consequences of ID in HF. ID has been associated with adverse outcomes in several cohorts, including hard outcomes, such as mortality and major adverse cardiovascular events, and softer outcomes, such as quality of life (QoL). In a study of 157 HF patients

by Okonko et al., the presence of ID was associated with an over threefold increase in mortality independent of haemoglobin.9 Additionally, non-anaemic patients with ID had double the risk of mortality compared to anaemic patients without ID, suggesting that ID is an independent risk factor in congestive HF patients. These results were replicated in a multicentre international cohort of 1,506 HF patients, with Klip et al. reporting that ID was associated with increased N-terminal pro brain-type natriuretic peptide (NT-proBNP) and worse New York Heart Association (NYHA) class, as well as being an independent predictor of mortality. Several other studies have also shown that ID is an independent predictor of mortality in HF patients.10,25,26 ID has been shown to be independently associated with exercise capacity in HF patients. In a large study of 443 patients with HF who underwent cardiopulmonary exercise testing, patients with ID had lower peak oxygen consumption (VO2 max) and increased ventilator response to exercise compared to those without ID, representing a reduction in exercise capacity.27 When combined with anaemia, the effects seem to be magnified.28 However, absolute ID appears to be independently associated with reduced exercise capacity.29 ID appears to have an impact of QoL in HF patients. Several studies have shown that ID is independently associated with a reduction in QoL, as measured by the Minnesota Living with Heart Failure Questionnaire.30,31 ID has also been shown to affect response to cardiac resynchronisation therapy. In a study 541 patients who underwent cardiac resynchronisation therapy implantation, the prevalence of ID was 56 %. Those with ID had less symptomatic improvement and a lower extent of reverse remodelling than those without ID.32 The presence of ID was also associated with increased mortality and HF hospitalisation independent of the presence of anaemia. One recent small study reported that in addition to a non-left bundle branch block ECG pattern, ID was an independent predictor of response to cardiac resynchronisation therapy in 48 HF patients (defined as reduction in left ventricular end-systolic volume <15 % or increase in VO2 max >10 %).33 Most studies have focused on HF with reduced ejection fraction (HFrEF). In acute HF, ID appears to be associated with both short- and intermediate-term risk of mortality.34 The presence of absolute (but not functional) ID has been shown to be independently associated with an increased risk of readmission within 30 days in a study of 693 patients admitted to hospital with acute HF.35 Interestingly, in this study over half of the patients had HF with preserved ejection fraction (HFpEF).

The adverse effects of ID are less well described in HFpEF; however, in the large multicentre study by Klip et al. there was no significant

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Treatment Figure 1: Definition and Clinical Implications of Iron Deficiency in Heart Failure

Iron deficiency Absolute: Serum ferritin <100 μg/l Relative: Serum ferritin 100–300 μg/l and transferrin saturation <20 %

• Mitochondrial dysfunction • Oxidative stress • Cellular apoptosis • Reduced myocardial efficiency

• Reduced quality of life • Reduced exercise capacity • Impaired cognition • Increased hospitalisation • Increased mortality

interaction between ejection fraction and the impact of ID (p=0.3), although this may have been due to numbers as only 13 % of the patients included had preserved ejection fraction.8 More recently a study of 1,197 patients, including 229 with HF with mid-range ejection fraction and 72 with HFpEF, found that ID was associated with lower exercise capacity and increased mortality regardless of left ventricular ejection fraction (LVEF).36 These results suggest that iron replacement may be of benefit in HFpEF and acute HF patients as well as HFrEF patients, and have led to the growing interest in iron replacement to improve outcomes.

Iron Replacement Therapy in Heart Failure Issues with Oral Iron Replacement Oral iron therapy, most commonly given as ferrous sulphate or ferrous fumarate, is relatively inexpensive and widely used. However, there are limitations with oral administration, not least the low gastrointestinal absorption of iron and its limited tolerability. This intolerance is produced, at least in part, by oxidative damage of the mucosal boundary when iron is oxidised from Fe2+ to Fe3+.37 This causes sideeffects such as constipation, diarrhoea and dyspepsia in up to 60 % of patients prescribed oral iron. Additionally, oral iron can take a long time to replenish iron stores, particularly if there is ongoing iron loss at the same time.

It appears that oral iron is unlikely to be efficacious in HF patients.

A recently-published randomised trial by Lewis et al. evaluated 225 patients with HFrEF and ID (absolute or functional) who were given 16 weeks of oral iron or placebo and found no difference in exercise capacity (peak VO2 or 6-minute walk test), NT-proBNP or Kansas City Cardiomyopathy Questionnaire.38 In addition to this, there was minimal improvement in iron stores in the group given iron, suggesting that oral iron replacement is unlikely to be of benefit. A much smaller trial randomised 18 patients with ID anaemia to receive intravenous (IV) iron (iron sucrose 200 mg weekly for 5 weeks), oral iron (ferrous sulphate 600 mg/day for 8 weeks) or oral placebo and found that although there was no significant difference in the increase in haemoglobin between the groups, VO2 only increased in the group given IV iron.39 The results from these trials are consistent with prior trials where oral iron has been given with erythropoietin or darbepoetin, where in the groups given oral iron therapy alone there have been no significant improvements in exercise capacity or symptoms.40,41 Given these results, focus has now switched to IV iron replacement.

patients given IV iron sucrose for up to 17 days and found that there was an improvement in exercise capacity and some symptomatic benefit.42 The first randomised trial of IV iron, performed in 40 patients

by Tobili et al., reported a reduction in NT-proBNP in HF patients with ID anaemia and renal impairment, as well as improvements in LVEF, 6-minute walk test and symptoms.43 These results were further extended to include non-anaemic patients by Okonko et al., who again found an improvement in exercise capacity and symptoms after 16 weeks of IV iron compared to placebo.44 The largest trial reported to date was the Ferinject® Assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study.45 This was a randomised trial of 459 patients with HF (LVEF <45 %) and ID (absolute or functional) with haemoglobin in the 95–135 g/l range randomised to ferric carboxymaltose or placebo. The study met its primary endpoint, with those patients receiving IV iron significantly more likely to have improved self-reported Patient Global Assessment at 6 months (50 % versus 28 %, p<0.001). There were also significant improvements in NYHA class and 6-minute walk test.

These results were independent of the presence of anaemia. These results were replicated in the Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) trial, a study of 304 patients with HF and ID in which participants were randomised to IV ferric carboxymaltose or placebo. The CONFIRM-HF trial authors reported significant improvements in 6-minute walk test, NYHA class and QoL, as well as time to first hospitalisation.46 Most recently, the Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Chronic Heart Failure and Iron Deficiency (EFFECT-HF) trial evaluated 172 patients with HF and ID and also suggested an improvement in peak VO2 with IV iron replacement.47 However, there were issues with missing data in this study.

Two meta-analyses of randomised trials of IV iron in HF patients with ID have been performed recently to summarise the results of these trials: a standard meta-analysis of five randomised trials including 509 patients and 342 controls,48 and an individual patient data meta-analysis including 504 patients and 335 controls.49 These studies have suggested a significant reduction in all-cause mortality, cardiovascular hospitalisation and HF hospitalisation with IV iron, as well as significant improvements NYHA class, 6-minute walk test and symptom questionnaire scores.

The weight of evidence from these randomised trials has led several guideline groups to recommend the consideration of IV iron therapy, (see Table 1). Nevertheless, evidence is still awaited from large outcome trials to determine the long-term prognostic benefit of IV iron replacement in HF. Several of these trials are currently ongoing, (see Table 2), and are likely to report in the near future. Positive results are likely to lead to stronger guideline recommendations to implement IV iron replacement in routine clinical practice.

Future Directions and Conclusions Intravenous Iron Replacement: Current Evidence and Guidelines IV iron replacement avoids the gastrointestinal tract, improving absorption of iron. While oral iron therapy appears to be ineffective in HF patients with ID, there is an increasing amount of evidence suggesting that IV iron replacement is beneficial. Several small trials have suggested a potential benefit of IV iron in HF patients. Bolger et al. reported on 16

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As well as investigating the potential benefit of IV iron on mortality in HF, there are several other questions that remain. First, while the majority of iron replacement studies in HF have included HFrEF patients, whether IV iron replacement is of benefit in HFpEF is unclear. The ongoing FAIR-HFpEF trial will provide further insight on this (NCT03074591). Second, the efficacy and safety of IV iron replacement in the in-patient setting in acute HF is unknown. Third,

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Iron Therapy in Heart Failure Table 1: Current Guideline Recommendations for Intravenous Iron in Heart Failure Body

Year

Recommendation

Class/Level of Evidence

2016

IV iron (ferrous carboxymaltose) should be considered in symptomatic HFrEF and ID (absolute or functional)

IIa/A

American College of Cardiology/American Heart Association50

2017

IV iron might be reasonable in patients with NYHA class II–III and ID (absolute or functional)

IIb/B

Scottish Intercollegiate Guidelines Network51

2016

Consider IV iron in those with NYHA class III and LVEF ≤45 % or NYHA class II and LVEF ≤40 %, ID and haemoglobin 9.5–13.5 g/dl

Recommended/1++ (high-quality metaanalyses, systematic reviews of RCTs, or RCTs with a very low risk of bias)

European Society of Cardiology

19

HFrEF = heart failure with reduced ejection fraction; ID = iron deficiency; IV = intravenous; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; RCT = randomised controlled trial. The National Institute for Health and Care Excellence updated guideline for HF is due to be published in 2018; there is no mention of iron deficiency in the most recent guideline (2010).52

Table 2: Ongoing Large Outcome Trials of Intravenous Iron in Heart Failure Study

FAIR-HF2

Affirm-AHF

HEART-FID

IRONMAN

ClinicalTrials.gov Registration Number

NCT03036462

NCT02937454

NCT03037931

NCT02642562

Actual Start Date

7 February 2017

3 April 2017

15 March 2017

August 2016

Estimated Completion Date

October 2020

June 2019

January 2021

February 2021

HF Duration

Chronic

Acute

Chronic

Chronic

Primary Outcome(s)

Combined HF hospitalisations and CV death

Combined HF hospitalisations and CV death

• Death at 1 year • HF hospitalisation at 1 year • Change in 6-minute walk time at 6 months

Combined HF hospitalisations and CV death

Duration of Follow-up

At least 1 year

1 year

1 year

Minimum 2.5 years from last patient recruited

Intervention

Ferric carboxymaltose

Ferric carboxymaltose

Ferric carboxymaltose

Iron (III) isomaltoside 1,000

Amount of Iron

1,000 mg IV bolus followed by optional 500–1,000 mg within first 4 weeks (up to a total of 2,000 mg), followed by 500 mg every 4 months except when haemoglobin is >16.0 g/dl or ferritin is >800 µg/l

First dose is undiluted bolus injection.

Study treatment dose (ml) to be determined by the patient’s body weight and haemoglobin value at respective visits

15 mg/kg (maximum 750 mg).

Two doses seven days apart (maximum combined dose of 1,500 mg). Repeated every 6 months as indicated by iron indices

20 mg/kg

Estimated Enrolment

1,200

1,100

3,014

1,300

Important Inclusion Criteria

• Patients with chronic HF present for at least 12 months • Confirmed presence of iron deficiency • Serum haemoglobin of 9.5–14.0 g/dl

• Current hospitalisation for an episode of acute HF • Iron deficiency • LVEF <50 % within 12 months prior to randomisation

• Stable HF (NYHA II–IV) on maximally-tolerated background therapy • LVEF ≤35 % • Haemoglobin >9.0 g/dl and <13.5 g/dl (females) or <15.0 g/ dl (males) • Serum ferritin <100 ng/ml or 100–300 ng/ml with TSAT <20 %.

• Either documented hospitalisation for HF within 12 months of enrolment or elevated natriuretic peptides

• LVEF <45 % • NYHA class II–IV • Iron deficient, defined as TSAT <20 % and/or ferritin <100 μg/l • Current or recent HF hospitalisation within 6 months for HF or elevated natriuretic peptides

Affirm-AHF = Study to Compare Ferric Carboxymaltose with Placebo in Patients with Acute Heart Failure and Iron Deficiency; CV = cardiovascular; FAIR-HF2 = Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality; HEART-FID = Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure with Iron Deficiency; HF = heart failure; IRONMAN = Intravenous Iron Treatment in Patients with Heart Failure and Iron Deficiency; LVEF = left ventricular ejection fraction; NYHF = New York Heart Failure; TSAT = transferring saturation.

whether alternative methods for the diagnosis of ID, such as ssTR, provide any benefit over and above ferritin and transferrin saturations has not been fully evaluated. Fourth, the majority of published studies performed have evaluated ferric carboxymaltose; whether other IV iron preparations provide any benefit, as well as the optimal dose and duration, are yet to be confirmed.

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In conclusion, ID is common in patients with HF, and may well be underdiagnosed in routine clinical practice. Several trials of IV iron replacement have suggested benefits on exercise capacity and symptoms, so IV iron should be considered in symptomatic HF patients with ID. Several ongoing trials will provide further evidence as to the long-term effects of such treatment on mortality and hospitalisation. n

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38. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

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39. Beck-da-Silva L, Piardi D, Soder S, et al. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol 2013;168:3439–42.

DOI: 10.1016/j.ijcard.2013.04.181; PMID: 23680589.

40. Palazzuoli A, Silverberg D, Iovine F, et al. Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Am Heart J 2006;152:1096 e9–15. DOI: 10.1016/j.ahj.2006.08.005; PMID: 17161060.

41. Ghali JK, Anand IS, Abraham WT, et al. Randomized doubleblind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation 2008;117:526–35. DOI: 10.1161/CIRCULATIONAHA.107.698514; PMID: 18195176.

42. Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol 2006;48:1225–7.

DOI: 10.1016/j.jacc.2006.07.015; PMID: 16979010.

43. Toblli JE, Lombrana A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol 2007;50:1657–65. DOI: 10.1016/j.jacc.2007.07.029; PMID: 17950147.

44. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol 2008;51:103–12.

DOI: 10.1016/j.jacc.2007.09.036; PMID: 18191732.

45. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48.

DOI: 10.1056/NEJMoa0908355; PMID: 19920054.

46. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.

Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015;36:657–68.

DOI: 10.1093/eurheartj/ehu385; PMID: 25176939.

47. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation 2017;136:1374–83.

DOI: 10.1161/CIRCULATIONAHA.117.027497; PMID: 28701470.

48. Jankowska EA, Tkaczyszyn M, Suchocki T, et al.

Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail 2016;18:786–95.

DOI: 10.1002/ejhf.473; PMID: 26821594.

49. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018;20:12–33.

DOI: 10.1002/ejhf.823; PMID: 28436136.

50. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/ HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70:776–803.

DOI: 10.1016/j.jacc.2017.04.025; PMID: 28461007.

51. Scottish Intercollegiate Guidelines Network. SIGN 147: Management of chronic heart failure. 2016. Available at: www. sign.ac.uk/assets/sign147.pdf (accessed 4 April 2018).

52. National Institute for Health and Care Excellence. CG108: Chronic heart failure in adults: management. 2010. Available at: www.nice.org.uk/guidance/cg108 (accessed 4 April 2018).

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Treatment

Ablation for Atrial Fibrillation in Heart Failure with Reduced Ejection Fraction Jackson J Liang and David J Callans Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

Abstract AF and heart failure with reduced ejection fraction (HFrEF) frequently coexist. Catheter ablation is an increasingly utilised treatment strategy for patients with AF and can be safely performed and is effective in achieving sinus rhythm for patients with HFrEF. Successful ablation may result in improved LV function, clinical heart failure status, quality of life and possibly even mortality. This review summarises the literature analysing efficacy, safety and outcomes of AF ablation for patients with HFrEF.

Keywords Atrial fibrillation, cardiomyopathy, catheter ablation, heart failure, outcomes Disclosure: The authors report no relevant conflicts of interest.

Received: 15 January 2018 Accepted: 27 February 2018 Citation: Cardiac Failure Review 2018;4(1):33–7. DOI: https://doi.org/10.15420/cfr.2018:3:1 Correspondence: David J Callans, MD, FHRS, Professor of Medicine, Hospital of the University of Pennsylvania, 9 Founders Pavilion – Cardiology, 3400 Spruce St, Philadelphia, PA, 19104, USA. E: david.callans@uphs.upenn.edu

As the population ages, the incidence of both AF and heart failure (HF) will continue to increase. By the year 2030, there will be an estimated >12 million patients with AF and >8 million patients with HF.1,2 A significant proportion of patients with HF have reduced (<50 %) left ventricular ejection fraction (heart failure with reduced ejection fraction, HFrEF) and the coexistance of AF in patients with AF and HFrEF has been associated with worse outcomes. Patients with HFrEF are predisposed to developing AF since neurohormonal changes and increased LV filling pressures can lead to LA dilation and fibrosis, facilitating AF progression. The development of AF in patients with severe HF is associated with a multitude of negative endpoints compared with patients without AF, including lower functional class, worse peak oxygen consumption, decreased cardiac output and worse mitral and tricuspid regurgitation.3

Medical Therapy for AF in Heart Failure with Reduced Ejection Fraction Patients Guidelines recommmend the use of beta-blockers, angiotensinconverting enzyme inhibitors, angiotensin II recepter blockers, aldosterone antagonists and, more recently, angiotensin receptor– neprilysin inhibitors as medical therapy for patients with symptomatic HFrEF, and these medications are associated with improved mortality.9 Patients with AF and HFrEF have a significantly higher risk of stroke or systemic embolism, as well as overall mortality compared with patients with both AF and HF with preserved ejection fraction (HFpEF) or without HF.10 As such, the presence of HF merits one point with the CHADS2 and CHA2DS2-VASc risk scores and thus oral anticoagulation is usually recommended for stroke prophylaxis, as per guidelines.11

Beta-blockers New-onset AF in patients with HF has also been associated with increased mortality and HF hospitalisations.4 Determining whether AF is a major driver of HF versus simply a marker of worsening HF is important to identify which patients are likely to derive the most benefit from a rhythm control strategy. After adjusting for concomitant risk factors and comorbid conditions, the majority of randomised controlled trials have found that AF is not an independent predictor of mortality in patients with HF. The presence of AF in patients with HFrEF can potentially worsen HF symptoms in several ways. First, the loss of atrial kick during AF can result in decreased LV filling and, therefore, cardiac output. Second, the irregularity of the ventricular response during AF is associated with reduction in cardiac output, a phenomenon that appears to be independent of heart rate.5 Prolonged periods of uncontrolled tachycardia with rapid AF have been well known to result in tachycardia-induced cardiomyopathy, and left ventricular ejection fraction (LVEF) may recover in some patients with adequate rate control.6 Finally, atrial structural changes may occur in the setting of persistent AF, in some cases leading to mitral annular dilation and resultant “atrial functional mitral regurgitation”, which can be reversible with restoration of sinus rhythm.7,8

© RADCLIFFE CARDIOLOGY 2018

CFR_Liang_FINAL.indd 33

Beta-blockers have long been considered the cornerstone of HF therapy in patients with reduced LVEF. However, the beneficial effect of these medications in patients with HFrEF appears to be mitigated by the coexistance of AF.12 Studies have suggested that the survival benefit with beta-blockers in HFrEF is limited only to those patients who are in sinus rhythm.13,14 Large meta-analyses assessing thousands of patients from clinical trials comparing beta-blockers and placebo in patients with HFrEF and sinus rhythm with AF have shown that beta-blockers significantly reduce both all-cause mortality and cardiovascular hospitalisations in patients in sinus rhythm but not AF, despite similar degrees of ventricular rate reduction in both groups.14,15

Anti-arrhythmic Drugs Due to potential for pro-arrhythmia, the choice of anti-arrhythmic drugs for AF is limited to amiodarone and dofetilide in patients with HFrEF, as per the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines.11 Dronedarone is contraindicated in patients with New York Heart Association (NYHA) class III–IV HF or severe LV dysfunction (LVEF <40 %) as its use has been associated with increased early mortality due to HF worsening.16

Access at: www.CFRjournal.com

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Treatment Figure 1: Ablation Lesion Set for Circumferential Pulmonary Vein Isolation

Posterior (A) and anterior (B) projections of the left atrium on the 3-dimensional electroanatomical map showing circular ablation lesions delivered around both sets of pulmonary veins (pink, red and blue circles). The smaller yellow and orange circles in (B) are sites where pacing resulted in diaphragmatic stimulation, delineating the course of the right phrenic nerve.

Vaughan–Williams classification class Ic agents have negative inotropic effects and should thus be avoided in patients with HFrEF.11 Sotalol should also be avoided in patients with HFrEF due to increased likelihood of torsades de pointes, particularly in patients with concomitant renal failure.11 Dofetilide was studied in the Danish Investigations of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure (DIAMOND-CHF) trial, which randomised 1,518 patients with HF and LV dysfunction to dofetilide versus placebo. The study showed that dofetilide was more effective in converting AF to sinus rhythm and maintaining sinus rhythm compared with placebo and dofetilide reduced the risk of HF hospitalisation (RR 0.75, 95 % CI [0.63– 0.89]).17 Although there was no overall difference in mortality compared with placebo among all patients, a post hoc analysis suggested significant reduction in mortality among patients with normal baseline QTc treated with dofetilide compared with patients randomised to placebo.18 Amiodarone is the most effective anti-arrhythmic drug (AAD) to maintain sinus rhythm, but is also associated with several side effects with long-term use including multiple organ toxicities that may as a result actually increase likelihood of non-cardiac mortality, as was suggested by the Sudden Cardiac Death in Heart Failure Trial (SCDHeFT), which included patients with NYHA class III HF.19,20 The Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial randomised 1,376 patients to rate control versus rhythm control (>80 % with amiodarone) and showed that rhythm control was associated with an increased rate of hospitalisation and no mortality benefit.21

Catheter Ablation for AF in Heart Failure with Reduced Ejection Fraction Maintainence of sinus rhythm has been associated with improved mortality and decreased all-cause and heart failure hospitalisations in patients with AF and HFrEF.22 However, the optimal strategy for rhythm control remains controversial. Since the efficacy of AADs remains suboptimal in patients with HFrEF, catheter ablation has become an increasingly utilised treatment strategy. The decision of whether to perform catheter ablation in patients with HFrEF should be individualised, weighing the potential long-term benefits of successful ablation against the risks of intra-procedural complications.

Importantly, certain individual patient characteristics such as larger left atrial volume may predict AF recurrence after ablation.23 There is a growing body of literature supporting AF ablation for patients with HFrEF, with a large number of retrospective observational studies and several randomised controlled trials in addition to many

34

CFR_Liang_FINAL.indd 34

meta-analyses. Based on these data, the 2017 Heart Rhythm Society/ European Heart Rhythm Association/European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm Society/Latin American Society of Cardiac Stimulation and Electrophysiology expert consensus statement on AF ablation recommends that it is reasonable to use similar indications for AF ablation in selected patients with HF as for patients without HF (class IIa, level of evidence B-R). 24 The optimal ablation strategy for patients with HFrEF remains controversial.

Achievement of electrical pulmonary vein isolation (PVI) (Figure 1) should be performed for all AF ablations (class I, level of evidence A) and may be adequate especially in patients with paroxysmal AF. However, especially among patients with non-paroxysmal forms of AF, the benefit additional ablation with lesions sets such as empirical linear ablation, posterior wall isolation and targeting of non-pulmonary vein triggers, complex fractionated atrial electrograms or rotors remains unclear. Prior prospective studies (in non-HFrEF patients) have not shown benefit of additional empirical linear ablation or targeting of complex fractionated atrial electrograms on top of PVI alone in patients with non-paroxysmal AF.25,26

Observational Studies of AF Ablation in Heart Failure with Reduced Ejection Fraction There have been numerous retrospective observational studies examining outcomes of catheter ablation for AF in patients with HFrEF.27–47 Although most these studies are single-centre experiences with relatively small (<100 patients) sample sizes, ablation has been shown to be relatively safe in patients with HFrEF and successful ablation has in general been associated with improved LVEF, improved quality of life and functional capacity.27 Table 1 summarises the findings of these observational studies.

Prospective Randomised Controlled Trials of AF Ablation in Heart Failure with Reduced Ejection Fraction Most randomised controlled trials have demonstrated overall benefit with ablation.48–53 However, there has been one notable exception: a study by MacDonald et al. published in 2011 randomised 41 patients with persistent AF and HFrEF (LVEF <35 %, NYHA class II–IV) to AF ablation versus medical therapy and found no difference in LVEF improvement, N-terminal pro-brain natriuretic peptide level, 6-minute walk distance or quality of life.54 Importantly, in this study, only 50 % of patients remained in sinus rhythm at 6 months and there was a 15 % complication rate in the ablation group.

Khan et al. randomised 81 patients with HFrEF (LVEF ≤40 % and NYHA class II–III) to AF ablation versus AV nodal ablation and biventricular pacing and showed that at 6 months, those randomised to AF ablation had improved questionnaire scores, longer 6-minute walk distance and higher LVEF.48 Jones et al. randomised 52 patients with LVEF ≤35 % and persistent AF to ablation versus rate control.49 Overall, 88 % of patients in the ablation group were in sinus rhythm at the end of the study (68 % single procedure success). The primary endpoint of peak oxygen consumption was significantly higher in the ablation group. Furthermore, significant improvements in Minnesota score and B-type natriuretic peptide (BNP) level were seen in the ablation group as well as a non-significant trend towards benefit in 6-minute walk distance and LVEF.49 In the Catheter Ablation versus Medical Treatment of Atrial Fibrillation in Heart Failure (CAMTAF) trial, Hunter et al. randomised 50 patients with persistent AF and LVEF <50 % to ablation versus rate control. At 6 months,

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AF ablation for HFrEF Table 1: Summary of Observational Studies of AF Ablation in Patients with Heart Failure with Reduced Ejection Fraction (HFrEF) Study

Sample size

Comparison arm

(ablation group)

Mean

Follow-up

Single

Multiple

Improvement

LVEF (%)

(months)

procedure

procedure

in LVEF (%)

Other comments

success (%)

success (%)

Chen 200428

377 (94)

Normal LVEF controls

36

14

52

73

+5

Improved QOL

Hsu 200429

116 (58)

Normal LVEF controls

35

12

50

78

+22

Improved QOL, exercise capacity, LV dimensions

Tondo 200630

105 (40)

Normal LVEF controls

33

14

55

87

+13

Improved QOL, exercise capacity

Gentlesk 200731

366 (67)

Normal LVEF controls

42

20

55

86

+14

Efremidis 200832

13 (13)

–

36

9

62

–

+16

Nadamanee 200833 129 (129)

Improved LV dimensions

–

31

27

58

79

+10

Lutomsky 200834

70 (18)

Normal LVEF controls

41

6

50

–

+10

De Potter 201035

72 (36)

Normal LVEF controls

41

16

50

64

+8

Choi 201036

30 (15)

HF treated medically 37

16

46

73

+13

Cha 201137

368 (111)

Normal LVEF, diastolic dysfunction controls

35

13

–

75

+21

Anselmino 201338

196 (196)

–

40

46

45

62

+10

Calvo 201339

658 (97)

Normal LVEF controls

40

6

70

83

+12

Nedios 201440

138 (69)

Normal LVEF controls

31

28

40

65

+15

Kosiuk 201441

73 (73)

–

37

40

37

–

+4

Lobo 201542

31 (31)

–

45

20

51

77

+14

Bunch 201543

2403 (267)

Matched HFrEF with AF but ablation; and HFrEF with no AF

27

60

39

–

+16

Rillig 201544

80 (80)

–

35

72

35

57

+21

Kato 2016

18 (18)

–

26

21

11

61

+11

Yanagisawa 201646 54 (54)

–

39

6

65

65

+10

Reduction in BNP

Normal LVEF controls

34

43

26

65

+12

Reduction in cardiac death

45

Ullah 2016

47

1273 (171)

Improved LV dimensions and mitral regurgitation

Reduction in ICD therapies

Reduction in death and hospitalisation

BNP = B-type natriuretic peptide; ICD = implantable cardioverter defibrillator; LVEF = left ventricular ejection fraction; QOL = quality of life. Adapted and modified, with permission, from Verma et al.25

those randomised to ablation had 81 % freedom from recurrent AF off AADs and improved LVEF, peak oxygen consumption and Minnesota score compared with the rate control arm.50 in the Ablation versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted Device (AATAC) trial, Di Biase et al. randomised 203 patients with persistent AF, dual-chamber or biventricular implantable cardioverter defibrillator (ICD) and HFrEF (LVEF ≤40 % and NYHA class II–III) to ablation versus amiodarone.51 The primary endpoint was AF recurrence and secondary endpoints were all-cause mortality and unplanned hospitalisations. Despite a wide range of single-procedure success rates between centres (29–61 %), those randomised to ablation were more likely to be in sinus rhythm after single and multiple procedures. Over 2 years of follow-up, the ablation group had lower rates of hospitalisation (31 versus 57 %,

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p<0.001) and mortality (8 versus 18 %, p=0.037) compared with those randomised to amiodarone.51 In the Catheter Ablation versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERAMRI) trial, Prabhu et al. randomised 68 patients with persistent AF and LVEF ≤45 % to ablation versus rate control and found that the ablation group were more likely to have improved LVEF.52 They also demonstrated that absence of late gadolineium enhancement on pre-procedural MRI predicted greater improvement in LVEF and normalisation of LVEF at 6 months. Catheter Ablation versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) is the most recent randomised controlled trial, where patients with paroxysmal or persistent AF and HFrEF (<35 %) and ICD (with home monitoring capability) were randomised to either ablation or conventional medical therapy for

35

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Treatment Table 2: Summary of Randomised Controlled Trials of Patients with Heart Failure with Reduced Ejection Fraction (HFrEF) treated with AF Ablation Mean

Follow-up

Single

Multiple

Improvement

LVEF (%)

(months)

procedure

procedure

in LVEF (%)

success (%)

success (%)

AVJ, CRT

27

6

68

88

+8

Improved 6MWD and Minnesota score

MacDonald 201154 41 (22)

Rate control

36

12

40

50

+4

High rate of complications (%)

Jones 201349

52 (26)

Rate control

22

12

68

88

+11

Improved Minnesota score, BNP, peak oxygen consumption

Hunter 201450

366 (67)

Rate control

42

20

38

81

+8

Improved Minnesota score, peak oxygen consumption

Di Biase 201651

203 (102)

Amiodarone

29

24

–

70

+8

Improved Minnesota score. Lower mortality and hospitalisation rates

Prabhu 201752

66 (33)

Rate control

32

6

56

–

+18

Absence of LGE predicted LVEF improvement in ablation group

CASTLE-AF 201753,55

363 (179)

Medical therapy (32% on AAD, mostly amiodarone)

32

60

–

–

+8

Lower mortality and heart failure hospitalisation

Study

Sample size

Comparison arm

(ablation group) Khan 200848

81 (41)

Other comments

AVJ = AV junction ablation; BNP = B-type natriuretic peptide; CRT = cardiac resynchronization therapy; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; 6MWD = 6-minute walk distance. Adapted and modified, with permission, from Verma et al.25

AF.55 The primary endpoint was a composite of all-cause mortality and unplanned hospitalisation for worsening HF. Over median follow-up of 37.8 months, those randomised to ablation were significantly less likely to experience the composite primary endpoint (28.5 % versus 44.6; HR 0.62, 95 % CI [0.43–0.87]; p=0.007) than controls. Those in the ablation group were also less likely to meet the secondary endpoints of all-cause mortality (13.4 % versus 25 %; HR 0.53, 95 % CI [0.32–0.86]; p=0.011) or HF hospitalisation (20.7 % versus 35.9 %; HR 0.56, 95 % CI [0.37–0.83]; p=0.004) than controls.

Table 2 summarises the major randomised controlled trials comparing catheter ablation with medical therapy.

rhythm over long-term follow-up.56 AF ablation resulted in significant improvement in LVEF (13 %) and reduction in BNP (620 pg/ml). Wilton et al. included eight studies of 1,851 patients in their meta-analysis comparing efficacy and safety of AF ablation in patients with reduced verses normal left ventricular systolic function.57 Freedom from recurrent AF after a single procedure was achieved in 28–55 % of patients with HFrEF; although allowing for multiple procedures, this number increased to 64–96 % (mean 1.4 procedures). There was no difference in rates of complications between groups and there was an 11 % improvement in LVEF in patients in the HFrEF group after AF ablation.

Conclusion Meta-analyses of AF Ablation in Heart Failure with Reduced Ejection Fraction A number of meta-analyses have examined the benefit, efficacy and safety of catheter ablation for patients with HFrEF, all of which have suggested AF ablation to be safe, effective and beneficial in this patient population.56–59 Anselmino et al. pooled data for 1,838 patients from 26 studies (randomised controlled trials, clinical trials and observational studies) and found that over mean follow-up of 23 months, there was a 4.2 % complication rate and 60 % of patients maintained sinus

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Significant interplay exists between AF and HFrEF. Catheter ablation can be safely performed and is effective in maintaining sinus rhythm in patients with HFrEF, although multiple ablations may be necessary to achieve long-term freedom from AF. Successful ablation may result in improved LV function, clinical heart failure status and quality of life, as evidenced by lower BNP levels and improved peak oxygen consumption, Minnesota score and 6-minute walk distance. As such, AF ablation should be considered as an adjunctive treatment strategy for patients with HFrEF. n

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Packer DL, Prutkin JM, Hellkamp AS, et al. Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: analysis from the sudden cardiac death in heart failure trial. Circulation 2009;120:2170–6. DOI: 10.1161/ CIRCULATIONAHA.109.853689 PMID: 19917887.

Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–77. DOI: 10.1056/NEJMoa0708789 PMID: 18565859.

Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) substudy.

Circulation 2001;104:292–296. DOI: 10.1161/01.CIR.104.3.292 PMID: 11457747.

Njoku A, Kannabhiran M, Arora R, et al. Left atrial volume predicts atrial fibrillation recurrence after radiofrequency ablation: a meta-analysis. Europace 2018;20:33–42.

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Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275–e444. DOI: 10.1016/j.hrthm.2017.05.012 PMID: 28506916.

Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl

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26. D ixit S, Marchlinski FE, Lin D, et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287–94.

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27. Verma A, Kalman JM, Callans DJ. Treatment of patients with atrial fibrillation and heart failure with reduced ejection fraction. Circulation 2017;135:1547–63. DOI: 10.1161/ CIRCULATIONAHA.116.026054 PMID: 28416525.

28. Chen MS, Marrouche NF, Khaykin Y, et al. Pulmonary vein isolation for the treatment of atrial fibrillation in patients with impaired systolic function. J Am Coll Cardiol 2004;43:1004–9.

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29. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;351: 2373–83. DOI: 10.1056/NEJMoa041018 PMID: 15575053.

30. Tondo C, Mantica M, Russo G, et al. Pulmonary vein vestibule ablation for the control of atrial fibrillation in patients with impaired left ventricular function. Pacing Clin Electrophysiol 2006;29:962–70. DOI: 10.1111/j.1540-8159.2006.00471.x PMID: 16981920.

31. Gentlesk PJ, Sauer WH, Gerstenfeld EP, et al. Reversal of left ventricular dysfunction following ablation of atrial fibrillation.

J Cardiovasc Electrophysiol 2007;18:9–14. DOI: 10.1111/j.15408167.2006.00653.x PMID: 17081210.

32. Efremidis M, Sideris A, Xydonas S, et al. Ablation of atrial fibrillation in patients with heart failure: reversal of atrial and ventricular remodelling. Hellenic J Cardiol 2008;49:19–25.

PMID: 18350778.

33. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol 2008;51:843–9. DOI: 10.1016/j. jacc.2007.10.044 PMID: 18294570.

34. Lutomsky BA, Rostock T, Koops A, et al. Catheter ablation of paroxysmal atrial fibrillation improves cardiac function: a prospective study on the impact of atrial fibrillation ablation on left ventricular function assessed by magnetic resonance imaging. Europace 2008;10:593–9. DOI: 10.1093/europace/ eun076 PMID: 18385123.

35. De Potter T, Berruezo A, Mont L, et al. Left ventricular systolic dysfunction by itself does not influence outcome of atrial fibrillation ablation. Europace 2010;12:24–9. DOI: 10.1093/ europace/eup309 PMID: 19880855.

36. Choi AD, Hematpour K, Kukin M, et al. Ablation vs medical therapy in the setting of symptomatic atrial fibrillation and left ventricular dysfunction. Congest Heart Fail 2010;16:10–4.

DOI: 10.1111/j.1751-7133.2009.00116.x PMID: 20078622.

37. Cha YM, Wokhlu A, Asirvatham SJ, et al. Success of ablation for atrial fibrillation in isolated left ventricular diastolic dysfunction: a comparison to systolic dysfunction and normal ventricular function. Circ Arrhythm Electrophysiol 2011;4:724–32.

DOI: 10.1161/CIRCEP.110.960690 PMID: 21747059.

38. Anselmino M, Grossi S, Scaglione M et al. Long-term results of transcatheter atrial fibrillation ablation in patients with impaired left ventricular systolic function. J Cardiovasc Electrophysiol 2013;24:24–32. DOI: 10.1111/j.15408167.2012.02419.x PMID: 23140485.

39. Calvo N, Bisbal F, Guiu E, et al. Impact of atrial fibrillationinduced tachycardiomyopathy in patients undergoing pulmonary vein isolation. Int J Cardiol 2013;168:4093–7.

DOI: 10.1016/j.ijcard.2013.07.017 PMID: 23890896.

40. Nedios S, Sommer P, Dagres N, et al. Long-term follow-up after atrial fibrillation ablation in patients with impaired left ventricular systolic function: the importance of rhythm and rate control. Heart Rhythm 2014;11:344–51. DOI: 10.1016/j. hrthm.2013.12.031 PMID: 24374320.

41. Kosiuk J, Nedios S, Darma A, et al. Impact of single atrial fibrillation catheter ablation on implantable cardioverter defibrillator therapies in patients with ischaemic and nonischaemic cardiomyopathies. Europace 2014;16:1322–6.

DOI: 10.1093/europace/euu018 PMID: 24532559.

42. Lobo TJ, Pachon CT, Pachon JC, et al. Atrial fibrillation ablation in systolic dysfunction: clinical and echocardiographic outcomes. Arq Bras Cardiol 2015;104:45–52.

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Rillig A, Makimoto H, Wegner J, et al. Six-year clinical outcomes after catheter ablation of atrial fibrillation in patients with impaired left ventricular function. J Cardiovasc Electrophysiol 2015. DOI: 10.1111/jce.12765 PMID: 26217925.

Kato K, Ejima K, Fukushima N, et al. Catheter ablation of atrial fibrillation in patients with severely impaired left ventricular systolic function. Heart Vessels 2016;31:584–92. DOI: 10.1007/ s00380-015-0635-7 PMID: 25633056.

Yanagisawa S, Inden Y, Kato H, et al. Decrease in B-type natriuretic peptide levels and successful catheter ablation for atrial fibrillation in patients with heart failure. Pacing Clin Electrophysiol 2016;39:225–34. DOI: 10.1111/pace.12788 PMID: 26596862.

Ullah W, Ling LH, Prabhu S, et al. Catheter ablation of atrial fibrillation in patients with heart failure: impact of maintaining sinus rhythm on heart failure status and long-term rates of stroke and death. Europace 2016;18:679–86. DOI: 10.1093/ europace/euv440 PMID: 26843584.

Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778–85. DOI: 10.1056/NEJMoa0708234 PMID: 18946063.

Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013;61:1894–903. DOI: 10.1016/j. jacc.2013.01.069 PMID: 23500267.

Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 2014;7:31–8. DOI: 10.1161/CIRCEP.113.000806 PMID: 24382410.

Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC Multicenter Randomized Trial. Circulation 2016;133:1637–44. DOI: 10.1161/ CIRCULATIONAHA.115.019406 PMID: 27029350.

Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI Study. J Am Coll Cardiol 2017;70:1949–61.

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Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF (CASTLE-AF). https:// clinicaltrialsgov/show/NCT00643188 (Accessed 13 January 2018).

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Treatment

Optimising Heart Failure Therapies in the Acute Setting Mattia Arrigo, 1 Petra Nijst 2 and Alain Rudiger 3 1. Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; 2. Department of Cardiology, Ziekenhuis Oost Limburg Genk, Genk, Belgium; 3. Cardiosurgical Intensive Care Unit, University Hospital Zurich, Zurich, Switzerland

Abstract Acute heart failure (AHF) is a life-threatening condition requiring immediate treatment. The initial therapy should take into account the clinical presentation, pathophysiology at play, precipitating factors and underlying cardiac pathology. Particular attention should be given to polymorbidity and the avoidance of potential iatrogenic harm. Patient preferences and ethical issues should be integrated into the treatment plan at an early stage. The average survival of AHF patients is 2 years and the most vulnerable period is the 3-month time window directly after discharge. Reducing both persistent subclinical congestion and underutilisation of disease-modifying heart failure therapies as well as ensuring optimal transitions of care after hospital discharge are essential in improving outcomes for AHF patients.

Keywords Acute heart failure, cardiogenic shock, pathophysiology, treatment, precipitating factors, vulnerable phase Disclosure: MA has received lecture fees from Orion Pharma Ltd. PN has no conflicts of interest to declare. AR has received lecture fees from Orion Pharma Ltd and AOP Orphan Pharmaceuticals AG. Received: 27 November 2017 Accepted: 1 February 2018 Citation: Cardiac Failure Review 2018;4(1):38–42. DOI: https://doi.org/10.15420/cfr.2017:21:1 Correspondence: Mattia Arrigo, Acute Cardiology and Heart Failure Unit, Department of Cardiology, University Heart Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E: mattia.arrigo@usz.ch

Heart failure is a clinical syndrome induced by cardiac abnormalities resulting in reduced cardiac output and/or elevated intra-cardiac enddiastolic pressures and causing symptoms that are often accompanied by typical physical signs.1 Demographic changes, improved treatment of several acute cardiac disorders, such myocardial infarction, arrhythmia and congenital heart disease, and increased long-term survival of patients with reduced left ventricular systolic function have led to a dramatic increase in the number of patients living with heart failure.

support, mechanical ventilation and percutaneous revascularisation).1,6,7 Moreover, since AHF is a life-threatening condition, initial treatment should be started as soon as possible, ideally within 30–60 min after hospital admission, as this is associated with better outcomes.6–8 The initial treatment should then be tailored and optimised according to a 7-P evaluation: phenotype, pathophysiology, precipitants, pathology, polymorbidity, potential harm and preferences (Figure 1).9

Phenotype Acute heart failure (AHF) is defined as new-onset or worsening of symptoms and signs of heart failure.1 AHF is the most frequent cause of unplanned hospital admission in patients aged 65 years or older and is characterised by significant in-hospital mortality and frequent readmissions.2,3 Outcomes of AHF remain globally poor.4,5 Independent of ejection fraction, the average survival after hospitalisation for AHF is 2 years, with the most vulnerable phase being in the months directly after discharge from hospital. Despite significant achievements in the treatment of chronic heart failure, all trials targeting AHF with short-term in-hospital therapies have had disappointing or at most neutral endpoints. Thus, the optimal strategy for improving longterm outcomes in patients admitted with AHF should be revisited.

Optimisation, personalisation and continuation of (A)HF treatment after hospital discharge seem crucial to achieving the best outcomes.

This article reviews the principles of optimisation and personalisation of AHF treatment during the hospital stay and early outpatient phase.

Triage and the Initial 7-P Evaluation Patients presenting with (suspected) AHF should undergo rapid triage to exclude cardiogenic shock, respiratory failure, myocardial infarction and/or arrhythmia and receive the appropriate level of monitoring and specific treatments (e.g. pharmacological/mechanical haemodynamic

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The initial evaluation should include the assessment of the clinical phenotype based on symptoms or signs of peripheral hypoperfusion (forward failure) and/or systemic congestion (backward failure).

However, given the limited sensitivity and specificity of clinical assessment, additional confirmatory tests may be required, such as biomarkers, echocardiography, lung ultrasound or chest X-ray, to exclude differential diagnoses.

The vast majority of AHF patients are well perfused but congested (warm-wet), while only a minority are hypoperfused (either cold-wet or cold-dry). Hypoperfusion defines cardiogenic shock, the most severe clinical presentation of AHF, which accounts for only about 10 % of AHF cases. However, the treatment of these patients is often more difficult and is associated with 5- to 10-fold higher in-hospital mortality compared to normally perfused cases.4,10 Systemic congestion, in contrast, is widespread and results from the combination of fluid accumulation and redistribution due to a change in vascular compliance, with variable proportions according to the clinical scenario. Fluid accumulation is found predominantly in cases of acute decompensation in chronic heart failure with reduced systolic function, while fluid redistribution mostly occurs in new-onset AHF patients with preserved systolic function and/or systemic inflammation.

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Optimising Heart Failure Therapies

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During the third step, triggers of AHF should be identified. AHF may be precipitated by several factors that may coexist, such as myocardial ischaemia, arrhythmias, infections, uncontrolled hypertension and non-compliance with medical prescriptions.2,19,20 In patients presenting with cardiogenic shock, myocardial infarction is by far the most common precipitant.10 The aims when identifying precipitants are to detect treatable causes (see below) and provide prognostic information. AHF precipitated by an acute coronary syndrome or infection is associated with poorer outcomes; whereas outcomes tend to be better in AHF precipitated by atrial fibrillation or uncontrolled hypertension.2,20,21

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More frequently, AHF consists of acute decompensation of chronic heart failure (ADHF) and is caused by progressive fluid accumulation.

Indeed, persistent neurohumoral activation impairs renal sodium excretion, resulting in sodium and then fluid accumulation.17 The classical congestive cascade includes subclinical stages characterised by increased cardiac filling and venous pressures (haemodynamic congestion), followed by redistribution of fluids into the lungs and visceral organs (organ congestion) and finally to overt symptoms and signs of volume overload (clinical congestion) (Figure 2).11 Although clinical and organ congestion usually follows haemodynamic congestion, the correlation between hydrostatic pressure and oedema formation is weak. Indeed, chronic sodium accumulation in heart failure impairs the function of the interstitial glycosaminoglycan network, reducing its capacity to buffer additional sodium and maintain low interstitial compliance.18 Consequently, interstitial oedema formation may occur even in the presence of mildly elevated hydrostatic pressures and vascular capacitance may change, causing increased cardiac filling pressures without increments in vascular or total body fluid.

Phenotype

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As already mentioned, systemic congestion is the central feature of AHF and results from the combination of fluid accumulation and redistribution induced by neurohumoral activation in the presence of cardiac dysfunction.11 Hypoperfusion manifests only in the most severe forms of AHF (cardiogenic shock) in the presence of severely impaired cardiac output.12 In patients without a previous history of symptomatic heart failure (de novo AHF), AHF mostly occurs secondary to a sudden deterioration in cardiac function – due to myocardial infarction, severe myocarditis or acute valve regurgitation, for example – causing fluid redistribution and, in severe forms, peripheral hypoperfusion.3 These patients have no or only minor increases in body weight before hospital admission. Fluid redistribution and loss due to sweating, perspiratio insensibilis or diuretic therapy can cause intravascular hypovolaemia and insufficient preload. Consequent sympathetic activation induces transient vasoconstriction leading to rapid volume displacement from the peripheral and splanchnic venous systems to the pulmonary circulation.13,14 A mismatch in the ventricular– arterial coupling relationship, with increased afterload and decreased venous capacitance (increased preload), is the primary alteration in hypertensive AHF.15,16

Figure 1: The 7-P Initial Evaluation of Acute Heart Failure Patients

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The second step in the evaluation of AHF patients should focus on understanding the leading pathophysiology at play. AHF can be a consequence of arrhythmia (with and without atrio- or interventricular asynchrony), anatomical defects, incompetent valves, impaired myocardial contractility, pathological myocardial relaxation, hampered ventricular filling and/or excessive cardiac afterload.

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ADHF = acute decompensated heart failure; AHF = acute heart failure; SCD = sudden cardiac death. Adapted from Arrigo et al., 2017.9

Pathology The initial treatment of AHF should be started as soon as possible according to the clinical presentation. However, understanding of the underlying cardiac pathology is essential for providing optimal specific therapy and estimating prognosis. For example, giant cell myocarditis requires aggressive immunosuppressive therapy, while severe mitral regurgitation caused by papillary muscle rupture requires cardiac surgery.22 Moreover, end-stage ischaemic heart disease without reversible ischaemia and viability may display significantly lower recovery potential than peripartum cardiomyopathy.23 Infiltrative heart disease may involve other organ systems. Immediate echocardiography is recommended in patients presenting with cardiogenic shock or de novo AHF.1,6

Polymorbidity AHF is a syndrome causing organ dysfunction, mainly of the lungs and abdominal organs.24–26 Historically, renal and hepatic dysfunctions in heart failure have been considered the consequence of visceral hypoperfusion, but more recent data have shown that venous congestion is the strongest haemodynamic determinant of renal and hepatic dysfunction in AHF.27,28 Assessment of organ dysfunction – in particular severe renal and kidney failure – as well as other conditions causing relative contraindications to diagnostics or treatment – such as allergy, pregnancy or active bleeding – are crucial in deciding on optimal diagnostic modalities and treatments to be delivered. Rapid assessment of frailty is recommended in geriatric patients, since it affects overall outcome.29,30 Metabolic disturbances, such as diabetes or thyroid disease, anaemia and iron deficiency should be assessed and optimised.

Potential Harm It is crucial to consider the risk of iatrogenic harm associated with diagnostics and treatment in every medical decision made. This is even more important in the treatment of AHF patients – a population

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Treatment Figure 2: The Typical Cascade of Systemic Congestion Euvolaemia

Haemodynamic congestion

Increased filling pressures

–30

–20

Organ congestion

Intrathoracic impedance change

Increased weight

Clinical congestion

Symptoms

–10

0

Days preceding hospitalisation for heart failure Modified from Adamson, 2009.49 Published with permission from Springer Nature.

of older, critically-ill, polymorbid subjects.31 For example, indiscriminate use of diagnostics (e.g. coronary angiography) and monitoring (e.g. pulmonary artery catheter) may expose patients to severe vascular or radiological complications; excessive use of inotropic agents in the absence of evidence of peripheral hypoperfusion is associated with arrhythmia and excess mortality.32,33

Patient Preferences The seventh part of the initial evaluation of AHF patients should focus on patient preferences and ethical issues. Discussion with the patient (if feasible) or with relatives about resuscitation directives and treatment options may be time-consuming but is crucial to avoid overtreatment.

Importantly, long-term options, such as mechanical assist devices or transplantation, and the wishes of the patient need to be evaluated early rather than late, particularly in AHF patients with the potential for rapid deterioration. In the absence of long-term therapeutic options, palliation and supportive care should be offered to patients. Relatives should be advised of these options if patients are not in a position to consent.34

Treatment at Hospital Admission Correctly deciding which phenotype/pathophysiology predominates is critical in determining which treatment strategy should be used.35 At hospital admission, AHF patients displaying evidence of congestion should receive decongestive treatment such as vasodilators and/or diuretics.8,36 While diuretics are mainly used in the presence of fluid overload, vasodilators are administered to reduce filling pressures in the presence of fluid redistribution and preserved systolic blood pressure (>110 mmHg; more cautiously between 90 and 110 mmHg).

Decongestive therapy should be started as soon as possible and titrated according to clinical response.8 Notably, decongestive therapy should be continued beyond the improvement of symptoms and clinical evidence of organ congestion and maintained until euvolaemia is achieved (Figure 2).

The use of inotropes should be restricted to patients in cardiogenic shock due to impaired myocardial contractility, since their inappropriate use is associated with increased morbidity and mortality.37 In cases of persistent haemodynamic instability despite escalating doses of inotropes, mechanical circulatory support such as veno–arterial extracorporeal life support and percutaneous left-ventricular assist devices should be considered before irreversible organ failure has established.7 In severe pulmonary oedema causing hypoxia, high-flow oxygen therapy, non-invasive or invasive mechanical ventilation are required to ensure oxygenation.

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In addition to decongestive therapy, initial management should include specific treatments directed towards decompensation triggers and the underlying cardiac disorders. In particular, early coronary angiography with revascularisation is recommended in AHF precipitated by acute coronary syndrome. Antiarrhythmic treatment and/or electrical cardioversion are recommended in AHF precipitated by arrhythmia.

Rapid initiation of antimicrobial therapy is recommended for AHF precipitated by infection/sepsis. Sometimes, percutaneous or surgical treatment of structural heart disease is required to achieve durable stabilisation. Finally, patients should be maintained on oral diseasemodifying heart failure treatment whenever possible.1 After delivery of the initial treatment, continuous reassessment of clinical response and patient allocation in terms of level of care should be ensured. The level of care (discharge home, observation, ward, telemetry or intensive/intermediate care unit) should integrate symptom severity, precipitating factors, haemodynamic and respiratory status, the degree of congestion and biomarkers (i.e. natriuretic peptides, troponin, renal function and serum lactate) and the patient’s general condition. Most patients require hospital admission, about half of them to intensive or intermediate care units. Low-risk patients with good response to initial therapy may be considered for early discharge.

Treatment Before Discharge and the First Outpatient Visit The optimal time-point for discharging hospitalised AHF patients may be difficult to determine due to the need to balance patient preferences, healthcare resources and the risk of adverse outcomes.

Indeed, the risk of death is high during hospitalisation for AHF but is even higher during the immediate post-discharge period, which usually lasts 2–3 months and is known as the vulnerable phase.38 Therefore, optimal transitions of care after hospital discharge may be even more important than the delivery of appropriate treatments during hospitalisation in reducing adverse outcomes in AHF patients.

Since the causes of the vulnerable phase remain controversial, identification of patients at particularly high risk of adverse outcomes after hospital discharge is particularly challenging. A combination of pathophysiological disorders and lack of follow up seems to contribute to the high mortality and readmission rates observed. Several risk scores using multiple clinical variables have been developed, but most of them are complex and lack accuracy. Cardiovascular biomarkers added to clinical parameters may reveal active sub-clinical processes, providing valuable insights into the pathophysiology of the vulnerable phase and increasing prognostic accuracy. In the future, a comprehensive multi-marker strategy reflecting different activated pathways in heart failure (myocardial stress, myocyte injury, neurohumoral activation, inflammation, oxidative stress, matrix remodelling and systemic congestion) may increase the precision of biomarker-guided prognostication.39 Even more importantly, the prognostic information derived from a single or multi-marker strategy may be translated into therapeutic decisions and personalisation of follow up, improving patient outcomes.

Persistent subclinical congestion may contribute to the high rates of death and readmission observed after hospital discharge.40 Indeed, despite a global improvement in symptoms during hospital stay, a relevant proportion of patients still display markedly elevated natriuretic peptides at discharge. This discordance between few symptoms and high natriuretic peptide concentrations suggests

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Optimising Heart Failure Therapies persistent haemodynamic congestion. Some studies have reported an association between pre-discharge levels of natriuretic peptides and subsequent risk of death or readmission.41 Based on these data, titration of decongestive therapy based only on symptoms and signs may be insufficient and should include additional parameters, such as biomarkers and/or echocardiography.42,43 Underutilisation of disease-modifying heart failure therapies such as betablockers, renin–angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists is prevalent and may further promote adverse events after hospital discharge.5,44 Beta-blocker discontinuation during hospitalisation is associated with detrimental effects on short-term mortality and readmission.45 Very recently, a large propensity scorematched cohort study showed an association between beta-blocker or RAS inhibitor treatment at hospital discharge and a 40–50 % relative risk reduction in 90-day mortality.44 It showed an additional 25–50 % relative risk reduction with combined beta-blocker and RAS inhibitor therapy at hospital discharge compared to either treatment alone.44 The early benefits were present in both reduced and preserved ejection fraction and persisted at 1-year follow up. In the same study, no significant benefit was found with early mineralocorticoid receptor antagonist administration. In beta-blocker-intolerant patients, early administration of ivabradine might be considered to reduce readmissions during the vulnerable phase.46 Current European Society of Cardiology guidelines recommend initiation or continuation of disease-modifying heart failure therapies during hospitalisation in all AHF patients with reduced ejection fraction unless contraindicated.1 Similarly, evaluation of the patient to determine whether a cardiac device (implantable cardiac defibrillator and/or cardiac resynchronisation therapy) is indicated and, if so, planning for its implantation should not be overlooked.

Furthermore, hospital discharge should occur only after precipitating factors of AHF have been adequately treated and resolved. This point includes revascularisation for myocardial infarction, antiarrhythmic therapy for arrhythmias, antimicrobial treatment for infection, antihypertensive therapy for hypertension and patient education for non-compliance with recommendations. Patient education, home-based measurement of body weight and blood pressure, and early contact with

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Rudiger A, Harjola V-P, Müller A, et al. Acute heart failure: clinical presentation, one-year mortality and prognostic factors. Eur J Heart Fail 2005;7:662–70. DOI: 10.1016/j. ejheart.2005.01.014; PMID: 15921809.

Follath F, Yilmaz MB, Delgado JF, et al. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med 2011;37:619–26. DOI: 10.1007/s00134-010-2113-0; PMID: 21210078.

Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol 2017;70:2476–86. DOI: 10.1016/j. jacc.2017.08.074; PMID: 29141781.

Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on pre-hospital and early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine – short version. Eur Heart J 2015;36:1958–66. DOI: 10.1093/eurheartj/ehv066; PMID:

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7.

8.

9.

10.

11.

12.

13.

14.

15.

healthcare providers have all been proposed to reduce readmission rates; however, these interventions have produced inconsistent results. Early detection of increasing congestion with intrathoracic impedance monitoring and implantable haemodynamic monitoring, e.g. with the CardioMEMS™ HF System (St Jude Medical), have shown promising results in trials but concerns about their cost-effectiveness has prevented their widespread introduction in clinical practice.47,48 Finally, hospital discharge should be planned to allow inclusion of all patients into a comprehensive, post-discharge care programme.

If this is not feasible because of limited resources, entry to such a programme should be restricted to those with high-risk feature, such as markedly elevated natriuretic peptides, abnormal systolic blood pressure, persistent hyponatraemia and recurrent readmissions.38 Outpatient visits to a general practitioner and heart failure clinic should be scheduled before hospital discharge to ensure appropriate follow up. In our centres, we usually plan a visit to the general practitioner within 1 week and a visit to the heart failure clinic within 2–3 weeks after discharge.

During early outpatient visits, assessment and optimisation of volume status (including the comparison of natriuretic peptide concentration with pre-discharge values), up-titration of disease-modifying heart failure treatment and evaluation of cardiac device indication should be performed. After bridging the vulnerable phase, optimisation of oral disease-modifying treatments and regular follow-up visits should be continued on an individual basis.

Conclusion The initial therapy of AHF should be personalised based on clinical phenotype, the pathophysiology at play, precipitants identified and underlying cardiac pathology. Particular attention should be given to polymorbidity, including organ dysfunction, and the avoidance of potential iatrogenic harm. Patient preferences and ethical issues should be integrated into the treatment plan at an early phase. Before hospital discharge, persistent subclinical congestion and underutilisation of disease-modifying heart failure therapies should be addressed and appropriate follow up ensured. n

25998514.

Mebazaa A, Tolppanen H, Mueller C, et al. Acute heart failure and cardiogenic shock: a multidisciplinary practical guidance.

Intensive Care Med 2016;42:147–63. DOI: 10.1007/s00134-0154041-5; PMID: 26370690.

Matsue Y, Damman K, Voors AA, et al. Time-to-furosemide treatment and mortality in patients hospitalized with acute heart failure. J Am Coll Cardiol 2017;69:3042–51. DOI: 10.1016/j. jacc.2017.04.042; PMID: 28641794.

Arrigo M, Rudiger A. Acute heart failure: from pathophysiology to optimal treatment. Cardiovascular Medicine 2017;20:229–35.

Harjola V-P, Lassus J, Sionis A, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock.

Eur J Heart Fail 2015;17:501–9. DOI: 10.1002/ejhf.260; PMID: 25820680.

Arrigo M, Parissis JT, Akiyama E, Mebazaa A. Understanding acute heart failure: pathophysiology and diagnosis. Eur Heart J Suppl 2016;18(suppl G):G11–8. DOI: 10.1093/eurheartj/suw044.

Rudiger A. Understanding cardiogenic shock. Eur J Heart Fail 2015;17:466–7. DOI: 10.1002/ejhf.265; PMID: 25858545.

Cotter G, Metra M, Milo-Cotter O, et al. Fluid overload in acute heart failure – re-distribution and other mechanisms beyond fluid accumulation. Eur J Heart Fail 2008;10:165–9. DOI: 10.1016/j.ejheart.2008.01.007; PMID: 18279771.

Francis GS, Siegel RM, Goldsmith SR, et al. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med 1985;103:1–6. DOI: 10.7326/0003-4819-103-1-1; PMID: 2860833.

Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22. DOI: 10.1056/NEJM200101043440103;

PMID: 11136955.

16. V iau DM, Sala-Mercado JA, Spranger MD, et al. The pathophysiology of hypertensive acute heart failure. Heart 2015;101:1861–7. DOI: 10.1136/heartjnl-2015-307461; PMID: 26123135.

17. Mullens W, Verbrugge FH, Nijst P, Tang WHW. Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur Heart J 2017;38:1872–82. DOI: 10.1093/eurheartj/ ehx035; PMID: 28329085.

18. Nijst P, Verbrugge FH, Grieten L, et al. The pathophysiological role of interstitial sodium in heart failure. J Am Coll Cardiol 2015;65:378–88. DOI: 10.1016/j.jacc.2014.11.025; PMID: 25634838.

19. Fonarow GC, Abraham WT, Albert NM, et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern Med 2008;168:847–54. DOI: 10.1001/archinte.168.8.847; PMID: 18443260.

20. Arrigo M, Tolppanen H, Sadoune M, et al. GREAT Network.

Effect of precipitating factors of acute heart failure on readmission and long-term mortality. ESC Heart Fail 2016; 3:115–21. DOI: 10.1002/ehf2.12083; PMID: 27812386.

21. Rudiger A, Streit M, Businger F, et al. The impact of infections on critically ill acute heart failure patients: an observational study. Swiss Med Wkly 2010;140:w13125. DOI: 10.4414/ smw.2010.13125.

22. Ekström K, Lehtonen J, Kandolin R, et al. Long-term outcome and its predictors in giant cell myocarditis. Eur J Heart Fail 2016;18:1452–8. DOI: 10.1002/ejhf.606; PMID: 27407025.

23. Bauersachs J, Arrigo M, Hilfiker-Kleiner D, et al.

Current management of patients with severe acute peripartum cardiomyopathy: practical guidance from the Heart Failure Association of the European Society of

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Cardiology Study Group on peripartum cardiomyopathy.

Eur J Heart Fail 2016;18:1096–105. DOI: 10.1002/ejhf.586; PMID: 27338866.

Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol 2008;52:1527–39. DOI: 10.1016/j. jacc.2008.07.051; PMID: 19007588.

Nikolaou M, Parissis J, Yilmaz MB, et al. Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure. Eur Heart J 2013;34:742–9. DOI: 10.1093/eurheartj/ehs332; PMID: 23091203.

Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013;62:485–95. DOI: 10.1016/j. jacc.2013.04.070; PMID: 23747781.

Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589–96. DOI: 10.1016/j.jacc.2008.05.068; PMID: 19215833.

Ishihara S, Gayat E, Sato N, et al. Similar hemodynamic decongestion with vasodilators and inotropes: systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure. Clin Res Cardiol 2016;105:971–80. DOI: 10.1007/s00392-016-1009-6; PMID: 27314418.

Teixeira A, Arrigo M, Tolppanen H, et al. Management of acute heart failure in elderly patients. Arch Cardiovasc Dis 2016;109:422– 30. DOI: 10.1016/j.acvd.2016.02.002; PMID: 27185193.

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. DOI: 10.1016/j.jacc.2013.09.070; PMID: 24291279.

Singer M, Glynne P. Treating critical illness: the importance of first doing no harm. PLoS Med 2005;2:e167. DOI: 10.1371/ journal.pmed.0020167; PMID: 15971943.

Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014;40:1795–815. DOI: 10.1007/s00134-014-3525-z; PMID: 25392034.

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inotropes. Intensive Care Med 2015;41:912–5. DOI: 10.1007/ s00134-015-3659-7; PMID: 25605474.

Nieminen MS, Dickstein K, Fonseca C, et al. The patient perspective: quality of life in advanced heart failure with frequent hospitalisations. Int J Cardiol 2015;191:256–64. DOI: 10.1016/j.ijcard.2015.04.235; PMID: 25981363.

Verbrugge FH, Grieten L, Mullens W. New insights into combinational drug therapy to manage congestion in heart failure. Curr Heart Fail Rep 2014;11:1–9. DOI: 10.1007/s11897013-0174-4; PMID: 24218088.

Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of highdose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998;351:389–93. DOI: 10.1016/S0140-6736(97)08417-1; PMID: 9482291.

Mebazaa A, Parissis J, Porcher R, et al. Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med 2011;37:290–301. DOI: 10.1007/ s00134-010-2073-4; PMID: 21086112.

Greene SJ, Fonarow GC, Vaduganathan M, et al. The vulnerable phase after hospitalization for heart failure. Nat Rev Cardiol 2015;12:220–9. DOI: 10.1038/nrcardio.2015.14; PMID: 25666406.

Demissei BG, Cotter G, Prescott MF, et al. A multimarker multi-time point-based risk stratification strategy in acute heart failure: results from the RELAX-AHF trial. Eur J Heart Fail 2017;19:1001–10. DOI: 10.1002/ejhf.749; PMID: 28133908.

Ambrosy AP, Pang PS, Khan S, et al. EVEREST Trial Investigators. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial. Eur Heart J 2013;34:835–43. DOI: 10.1093/eurheartj/ehs444; PMID: 23293303.

Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004;43:635–41. DOI: 10.1016/j.jacc.2003.09.044; PMID: 14975475.

42. A rrigo M, Truong QA, Onat D, et al. Soluble CD146 Is a novel marker of systemic congestion in heart failure patients: an experimental mechanistic and transcardiac clinical study. Clin Chem 2017;63:386–93. DOI: 10.1373/clinchem.2016.260471; PMID: 28062630.

43. Kubena P, Arrigo M, Parenica J, et al. GREAT Network. Plasma levels of soluble CD146 reflect the severity of pulmonary congestion better than brain natriuretic peptide in acute coronary syndrome. Ann Lab Med 2016;36:300–5. DOI: 10.3343/ alm.2016.36.4.300; PMID: 27139601.

44. Gayat E, Arrigo M, Littnerova S, et al. GREAT Network. Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: a propensity-score matched study. Eur J Heart Fail 2017;18:613. DOI: 10.1002/ejhf.932; PMID: 28849606.

45. Prins KW, Neill JM, Tyler JO, et al. Effects of beta-blocker withdrawal in acute decompensated heart failure: a systematic review and meta-analysis. JACC Heart Fail 2015;3:647–53. DOI: 10.1016/j.jchf.2015.03.008; PMID: 26251094.

46. Komajda M, Tavazzi L, Swedberg K, et al. SHIFT Investigators.

Chronic exposure to ivabradine reduces readmissions in the vulnerable phase after hospitalization for worsening systolic heart failure: a post-hoc analysis of SHIFT. Eur J Heart Fail 2016;18:1182–9. DOI: 10.1002/ejhf.582; PMID: 27210035.

47. Hindricks G, Taborsky M, Glikson M, et al. IN-TIME Study Group. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014;384:583–90. DOI: 10.1016/S01406736(14)61176-4; PMID: 25131977.

48. Abraham WT, Adamson PB, Bourge RC, et al. CHAMPION Trial Study Group. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. DOI: 10.1016/S01406736(11)60101-3; PMID: 21315441.

49. Adamson PB. Pathophysiology of the transition from chronic compensated and acute decompensated heart failure: new insights from continuous monitoring devices. Curr Heart Fail Rep 2009;6:287–92. DOI: 10.1007/s11897-009-0039-z; PMID: 19948098.

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Ambulatory Intra Aortic Balloon Pump in Advanced Heart Failure Syed Yaseen Naqvi, 1 Ibrahim G Salama, 2 Ayhan Yoruk 1 and Leway Chen 1 1. Department of Cardiology, Advanced Heart Transplant Program, University of Rochester Medical Center, Rochester, USA; 2. Department of Internal Medicine, Unity Hospital, Rochester, USA

Abstract Cardiac transplantation is the gold standard treatment for patients with advanced congestive heart failure that is refractory to maximal medical therapy. However, donor heart availability remains the major limiting factor, resulting in a large number of patients waiting long periods of time before transplantation. As a result, mechanical circulatory support devices have been increasingly used as a ‘bridge’ in order to sustain organ function and stabilise haemodynamics while patients remain on the transplant waiting list or undergo left ventricular assist device surgery. Intra aortic balloon pumps (IABP) are commonly used for temporary circulatory support in patients with advanced heart failure. IABP is traditionally placed percutaneously through the transfemoral artery approach. The major limitation with this approach is ambulatory restriction that can promote deconditioning, particularly in situations of prolonged circulatory support.

A subclavian/axillary artery approach IABP insertion allows patients to be ambulatory during the pre-transplant period. In this review, we aim to summarise the physiology of IABP, the evidence for its use in advanced CHF and the efficacy and safety of subclavian artery IABP insertion.

Keywords Intra aortic balloon pump, advanced heart failure, mechanical circulatory support, subclavian artery intra aortic balloon pump, left ventricular assist device, cardiac transplantation Disclosure: The authors report no conflicts of interest.

Received: 21 November 2017 Accepted: 14 February 2018 Citation: Cardiac Failure Review 2018;4(1):43–5. DOI: https://doi.org/10.15420/cfr.2018:22:1 Correspondence: Syed Yaseen Naqvi, Department of Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA. E: syed_naqvi@urmc.rochester.edu

Heart failure is a progressive and fatal disease that affects more than 23 million people worldwide, and will affect more than 8 million people in the USA by 2030.1,2 Despite major advancements in medical and device treatments for heart failure in recent decades, the incidence of heart failure continues to rise. This epidemic has a major impact on patient quality of life, while imposing heavy costs on the healthcare system. According to the American College of Cardiology/American Heart Association, advanced congestive heart failure (CHF) is referred to as stage D when patients continue to have symptoms at rest despite optimal guideline directed medical therapy.3 In the USA, more the 250,000 patients suffer from advanced CHF refractory to maximal medical therapy.4 The most recent guidelines update reiterate that cardiac transplantation remains the gold standard therapy for patients with stage D heart failure.5 However, donor heart availability remains the major limiting factor, resulting in a large number of patients waiting long periods of time before transplantation.6 As a result, mechanical circulatory support (MCS) devices have been increasingly used in the acute setting as a ‘bridge’ in order to sustain organ function and stabilise haemodynamics while patients remain on the transplant waiting list or undergo left ventricular assist device (LVAD) surgery. These MCS devices include intra aortic balloon pumps (IABPs), Impella® (ABIOMED) micro-axial flow catheters, and TandemHeart® (Cardiac Assist) centrifugal flow pumps. IABPs are commonly used for temporary circulatory support in patients with advanced heart failure.7–9 IABP is traditionally placed percutaneously through the transfemoral artery approach. The major limitation with this approach is ambulatory

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restriction that can promote deconditioning, particularly in situations of prolonged circulatory support. This restriction is frequently seen in advanced CHF patients waiting long periods of time prior to cardiac transplantation. A subclavian artery approach IABP insertion is an alternative to femoral artery IABP, which allows patients to be ambulatory during the pre-transplant period. In this review, we aim to summarise the physiology of IABP, the evidence for its use in advanced CHF, and the efficacy and safety of subclavian artery IABP insertion.

Physiological Principles of Intra Aortic Balloon Pumps An IABP is usually placed in a retrograde fashion through the femoral artery and is positioned distal to the left subclavian artery in the descending thoracic aorta. Inflating and deflating the balloon in synchrony with the heart rate helps augment diastolic blood pressure and theoretically can increase coronary arterial perfusion, thereby augmenting myocardial oxygen delivery.10 During systole, the balloon quickly deflates thereby reducing afterload and therefore decreasing myocardial oxygen consumption and workload.11 Volume shifting of approximately 40 ml per heart beat by the IABP increases left ventricular stroke volume and cardiac output by up to 1 litre per minute, with the largest increases seen in patients with severely reduced cardiac output.12 Patients who continue to have evidence of endorgan dysfunction, haemodynamic compromise or right ventricular overload despite IABP therapy usually require MCS with higher cardiac output, such as the Impella device.

Access at: www.CFRjournal.com

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Treatment Figure 1: Ambulatory Patient with Left Axillary Artery IABP, Inserted in the Cardiac Catheterisation Laboratory, Awaiting Heart Transplantation and Able to Participate in Physical Therapy

daily living.21 This study suggests that patients who have IABP support are generally more unwell and less mobile, which is likely to further exacerbate patient deconditioning. Long-term IABP support has been shown to be effective as a bridge to LVAD implantation in critically ill end-stage CHF patients and was not associated with increased haemorrhagic complications.7 Patients with mild cardiogenic shock can be adequately supported long-term with IABP until LVAD or heart transplant surgery; however, those with severe cardiogenic shock usually cannot maintain adequate organ perfusion with IABP support.

These patients with severely reduced cardiac indices usually require MCS with higher flow rates, such as the Impella axial flow pump.

Ambulatory Intra Aortic Balloon Pumps A technique of transthoracic IABP insertion has been previously described, predominantly with the use of a short conduit (usually dacron) to allow placement of the IABP in the ascending aorta, axillary or subclavian artery.2 This insertion method was first described by Mayer in patients with aortoiliac occlusive disease.23 More recently, this technique has been further refined, allowing patients to have an IABP placed percutaneously via the upper extremity in the cardiac catheterisation laboratory by either interventional cardiologists or cardiac surgeons (Figure 1). The trans-brachial artery insertion method has been shown to be safe and effective in unstable CAD patients prior to urgent coronary artery bypass surgery.24,25 Multiple studies have shown the effectiveness of ambulatory IABP in advanced heart failure patients waiting for advanced heart failure therapies, namely LVAD implantation or heart transplantation.26–30

IABP = Intra aortic balloon pump.

Intra Aortic Balloon Pumps versus Left Ventricular Assist Device as Mechanical Circulatory Support in Advanced Heart Failure Recent clinical trials have failed to show a clear benefit of IABP support among patients with acute myocardial infarction, cardiogenic shock or high-risk percutaneous coronary intervention.13–15 However, despite these findings, IABP remains the most widely used MCS with more than 50,000 implants per year in the US alone.16 IABP support has been shown to be safe and effective in patients with acute decompensated dilated cardiomyopathy as an urgent method of cardiac support to maintain adequate organ perfusion until cardiac transplant or destination LVAD.17 Current guidelines assign a Class IIa recommendation for the use of MCS in carefully selected patients with stage D CHF as a ‘bridge to recovery’ or ‘bridge to decision’.3 Currently, with the widespread availability of LVAD, approximately 50 % of patients are supported with such devices at the time of cardiac transplantation.18 Continuous-flow LVAD has been shown to improve survival, functional capacity and quality of life in most patients.19,20 However, LVADs have been shown to have similar perioperative mortality, length of hospital stay, renal failure requiring dialysis or early acute rejection compared to IABPs in patients undergoing heart transplant.21 At the time of listing for transplant, patients who underwent IABP support (compared to LVAD) had significantly higher serum creatinine, lower BMI, lower proportion of blood type O and more functional impairment requiring full assistance with activities of

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Estep et al. studied 50 patients with end-stage CHF undergoing left axillary-subclavian artery IABP support as a bridge to heart transplantation.26 Of these 50 patients, the majority (84 %) underwent successful heart transplantation with an excellent (90 %) 90-day posttransplant survival. The most commonly encountered minor adverse event was IABP malposition, occurring in 44 % of patients, which was easily rectified with fluoroscopic adjustment.26 All of these patients were allowed to sit upright and 16 patients were able to ambulate to receive dedicated physical therapist-assisted ambulation sessions to prevent deconditioning. The remaining 34 patients had nursing-guided ambulation. This study showed significant improvements in both renal and liver function and decreases in pulmonary hypertension before and after IABP insertion.26 The median time of ambulatory IABP support was 15 days in patients who underwent heart transplantation alone, with maximum support duration of 152 days in one patient who underwent dual heart-lung transplantation.26 Another similar study

by Tanaka et al. showed a 93 % success rate with subclavian artery IABP as a bridge to transplant, with no mortality related to the balloon pump.30 These two studies clearly highlight the safety and efficacy of long-term use of ambulatory IABP in the advanced CHF population as a bridge to transplant or LVAD.

Complications of Intra Aortic Balloon Pumps A large study of almost 17,000 patients found that major complications associated with IABP insertion is low at 2.6 %.31 These major complications included severe bleeding, major acute limb ischaemia, balloon leak, IABP failure, and death. Limb ischaemia generally occurs secondary to a low femoral artery stick (usually in the profunda or superficial femoral artery) resulting in complete arterial occlusion due to the small calibre of the branches of the common femoral artery. If this occurs, the IABP needs to be removed and placed in the contralateral limb. Arterial dissection or visceral ischaemia (renal or spinal cord) has also been reported.32,33 Despite these complications,

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Ambulatory Intra Aortic Balloon Pump in Advanced CHF the incidence of femoral IABP-related mortality is very low at 0.5 %.31 In a prospective study of 80 patients with decompensated advanced CHF, the use of subclavian IABP is well tolerated with no increased mortality and few side effects.30 The commonly encountered complications of subclavian IABP are need for balloon pump repositioning (30 %), haematoma (5 %), infection (2 %) and subclavian artery thrombosis (1 %).30 Interestingly, there were no distal thromboembolic events with the subclavian IABP, making it safer than femoral IABP. In comparison to LVAD, IABP has much fewer complications. The disadvantages to LVAD, making it a more high-risk intervention compared to IABP, include obligate repeat sternotomy or rarely lateral thoracotomy, acquired von Willebrand disease, increased bleeding risk and greater risk of allosensitisation.34,35

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Conclusion IABPs are commonly used for temporary circulatory support in patients with advanced heart failure, particularly as a bridge to heart transplant or LVAD. Ambulation and physical conditioning of such patients are often paramount when awaiting major surgery and recovery; ambulatory restriction can be detrimental in cases of prolonged circulatory support. Through continued innovation and advancement in the field of heart failure and circulatory support, improvement in clinical care, as well as patient quality of life, is selfevident. As the use of ambulatory IABP becomes more prevalent, future studies should aim to measure its impact on health-related quality of life, as it may be useful in assessing the effectiveness of such acute interventions. n

coronary intervention: a randomized controlled trial. JAMA. 2010;304:867–74. DOI: 10.1001/jama.2010.1190; PMID: 20736470.

Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. New Engl J Med 2012;367:1287–96. DOI: 10.1056/NEJMoa1208410; PMID: 22920912.

Unverzagt S, Buerke M, de Waha A, et al. Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock. Cochrane Database Syst Rev 2015(3):Cd007398. DOI: 10.1002/14651858.CD007398.pub3; PMID: 25812932.

Stretch R, Sauer CM, Yuh DD, Bonde P. National trends in the utilization of short-term mechanical circulatory support. J Am Coll Cardiol 2014;64:1407–15. DOI: 10.1016/j.jacc.2014.07.958; PMID: 25277608.

Norkiene I, Ringaitiene D, Rucinskas K, et al. Intra-aortic balloon counterpulsation in decompensated cardiomyopathy patients: bridge to transplantation or assist device.

Interact Cardiovasc Thorac Surg 2007;6:66–70. DOI: 10.1510/ icvts.2006.140160; PMID: 17669772.

Lund LH, Khush KK, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report 2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant 2017;36:1037–46. DOI: 10.1016/j.healun.2017.07.019; PMID: 28779893.

Starling RC, Naka Y, Boyle AJ, et al. Results of the postU.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2011;57:1890–8. DOI: 10.1016/j.jacc.2010.10.062; PMID: 21545946.

Rogers JG, Aaronson KD, Boyle AJ, et al. Continuous flow left ventricular assist device improves functional capacity and quality of life of advanced heart failure patients. J Am Coll Cardiol 2010;55:1826–34. DOI: 10.1016/j.jacc.2009.12.052; PMID: 20413033.

Castleberry AW, DeVore AD, Southerland KW, et al. Assessing consequences of intra-aortic balloon counterpulsation vs. left ventricular assist devices at the time of heart transplantation. ASAIO J 2016;62(3):232–9. DOI: 10.1097/ MAT.0000000000000329; PMID: 26735554.

Burack JH, Uceda P, Cunningham JN. Transthoracic intraaortic balloon pump: A simplified technique. Ann Thorac Surg 1996;62:299–301. PMID: 8678671.

Mayer JH. Subclavian artery approach for insertion of intraaortic balloon. J Thorac Cardiovasc Surg 1978;76:61–3. PMID: 661368.

Onorati F, Bilotta M, Pezzo F, et al. Transbrachial insertion of a 7.5-Fr intra-aortic balloon pump in a severely atherosclerotic patient. Crit Care Med 2006;34:2231–3. DOI: 10.1097/01.

CCM.0000229884.94475.DB; PMID: 16775570.

25. B undhoo S, O’Keefe PA, Luckraz H, Ossei-Gerning N. Extended duration of brachially inserted intra-aortic balloon pump for myocardial protection in two patients undergoing urgent coronary artery bypass grafting. Interactive cardiovascular and thoracic surgery. 2008;7:42–4. DOI: 10.1510/ icvts.2007.167650; PMID: 18045829.

26. Estep JD, Cordero-Reyes AM, Bhimaraj A, et al. Percutaneous placement of an intra-aortic balloon pump in the left axillary/subclavian position provides safe, ambulatory longterm support as bridge to heart transplantation. JACC Heart Fail 2013;1:382–8. DOI: 10.1016/j.jchf.2013.06.002; PMID: 24621970.

27. Cochran RP, Starkey TD, Panos AL, Kunzelman KS. Ambulatory intraaortic balloon pump use as bridge to heart transplant. Ann Thorac Surg 2002;74:746–51. PMID: 12238834.

28. Umakanthan R, Hoff SJ, Solenkova N, et al. Benefits of ambulatory axillary intra-aortic balloon pump for circulatory support as bridge to heart transplant. J Thorac Cardiovasc Surg 2012;143:1193–7. DOI: 10.1016/j.jtcvs.2012.02.009; PMID: 22365064.

29. Russo MJ, Jeevanandam V, Stepney J, et al. Intra-aortic balloon pump inserted through the subclavian artery: A minimally invasive approach to mechanical support in the ambulatory end-stage heart failure patient. J Thorac Cardiovasc Surg 2012;144:951–5. DOI: 10.1016/j.jtcvs.2012.03.007; PMID: 22520721.

30. Tanaka A, Tuladhar SM, Onsager D, et al. The subclavian intraaortic balloon pump: a compelling bridge device for advanced heart failure. Ann Thorac Surg 2015;100:2151–7.

DOI: 10.1016/j.athoracsur.2015.05.087; PMID: 26228596.

31. Ferguson J, Cohen M, Freedman R, et al. The current practice of intra-aortic balloon counterpulsation: results from the Benchmark Registry. J Am Coll Cardiol 2001;38: 1456–62.

PMID: 11691523.

32. Rastan A, Tillmann E, Subramanian S, et al. Visceral arterial compromise during intra-aortic balloon counterpulsation therapy. Circulation 2010;122:S92–9. DOI: 10.1161/ CIRCULATIONAHA.109.929810; PMID: 20837932.

33. de Agustin JA, de Diego JJ, Nunez-Gil IJ, et al. Aortic dissection caused by intra-aortic balloon pumping. Eur Heart J 2014;35:1718. DOI: 10.1093/eurheartj/ehu010; PMID: 24497342.

34. Drakos SG, Stringham JC, Long JW, et al. Prevalence and risks of allosensitization in HeartMate left ventricular assist device recipients: the impact of leukofiltered cellular blood product transfusions. J Thorac Cardiovasc Surg 2007;133:1612–9. DOI: 10.1016/j.jtcvs.2006.11.062; PMID: 17532964.

35. Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010;56:1207–13. DOI: 10.1016/j.jacc.2010.05.016; PMID: 20598466.

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Treatment

Bromocriptine for the Treatment of Peripartum Cardiomyopathy Tobias Koenig, Johann Bauersachs and Denise Hilfiker-Kleiner Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

Abstract Peripartum cardiomyopathy (PPCM) is a life-threatening, pregnancy-associated heart disease that develops towards the end of pregnancy or in the first months following delivery in previously healthy women. Understanding of the pathophysiology has progressed in recent years, highlighting an oxidative-stress mediated cleavage of the nursing hormone prolactin into a toxic 16-kDa prolactin fragment as a major factor driving the disease. The 16-kDa prolactin fragment induces detrimental but potentially reversible effects on heart function.

Bromocriptine, a clinically-approved drug to block prolactin release, was initially tested in a PPCM mouse model where it efficiently prevented the onset of PPCM. Consequently, this treatment concept was transferred to and successfully used in humans as a bench-tobedside approach. Encouraging proof-of-concept studies led to a randomised trial that further strengthens the role of bromocriptine in addition to standard heart failure therapy in clinical practice. The aim of this article is to summarise this novel and disease-specific medical treatment, along with current knowledge on the epidemiology and pathophysiology of PPCM.

Keywords Peripartum cardiomyopathy, bromocriptine, prolactin, heart failure, pregnancy Disclosure: The authors have no conflicts of interest to declare.

Received: 11 January 2018 Accepted: 14 February 2018 Citation: Cardiac Failure Review 2018;4(1):46–9. DOI: https://doi.org/10.15420/cfr.2018:2:2 Correspondence: Denise Hilfiker-Kleiner, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

E: hilfiker.denise@mh-hannover.de

Cardiovascular diseases (CVD) are a major cause of complications in pregnancies worldwide, and can be largely attributed to increased cardiovascular risk factors, such as obesity and hypertensive disorders.1 Today, up to 4 % of all pregnancies are complicated by CVD, with increasing frequency.2 Cardiomyopathies – whether inherited or acquired – represent the leading cause of maternal morbidity and mortality in Western industrialised countries.2 Among these, peripartum cardiomyopathy (PPCM) is particularly important because of notable foetal and maternal morbidity and a significant contribution to maternal deaths in previously healthy women.3–5 Early diagnosis and immediate initiation of an appropriate therapy are crucial in improving the prognosis of this life-threatening disease in young women.3,6–11

Definition, Epidemiology and Risk Factors of Peripartum Cardiomyopathy The Study Group on PPCM of the Heart Failure Association (HFA) of the European Society of Cardiology defines PPCM as follows: “Peripartum cardiomyopathy is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. It is a diagnosis of exclusion. The left ventricle may not be dilated but the ejection fraction is nearly always reduced below 45 %.”10 Other causes of heart failure, such as pre-existing cardiomyopathy, pulmonary embolism, amniotic fluid embolism, and myocardial infarction should be ruled out by thorough evaluation of the patient’s history, physical examination and by means of electrocardiography and/or cardiovascular imaging (such as echocardiography or cardiac magnetic resonance imaging).6,8 The course of the disease can range from mild forms with unspecific symptoms, such as exercise intolerance, general discomfort and peripheral oedema, to severe forms with cardiogenic shock, including

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agitation, orthopnoea and lung oedema.8 Increasing awareness and better diagnostic and therapeutic insights have contributed to improved outcomes in PPCM patients over recent years.11–15 If treated according to published recommendations, approximately 50 % of all women recover fully (defined as left-ventricular ejection fraction [LVEF] ≥50 % and New York Heart Association [NYHA] functional class I) whereas an additional 35–40 % recover at least partially (defined as improvement of LVEF ≥10 % and at least one NYHA functional class).12 Delayed diagnosis can negatively influence prognosis in these previously healthy women.

The incidence of PPCM differs widely depending on the ethnic and regional background of women. Interestingly, Africans and African Americans are at a higher risk for developing PPCM, with an estimated incidence of 1:100 in Nigeria, 1:299 in Haiti and 1:1,000 pregnancies in South Africa. Estimated incidences in Caucasian populations range from 1:1,500 in Germany to 1:10,149 in Denmark.4,10,12,16 An increase in incidence rates has been observed in the US in recent years. While the incidence was formerly reported to be one in 3,250 pregnancies, current data estimate an incidence of one in 1,150 pregnancies.15,17 This trend is also observed in Germany. This may be explained by rising maternal age, a higher number of fertility-assisted treatments and the higher incidence of hypertensive disorders of pregnancy. Higher awareness may also contribute to the detection of more cases with mild-to-moderate LV dysfunction. An ongoing, worldwide, multicentre, observational registry as part of the EURObservational Research Program (EORP) was initiated by the Study Group on PPCM of the HFA.18 The aim of the registry (https://www.escardio.org/Research/Registries‑&‑surveys/ Observational‑registry‑programme/PeriPartum‑CardioMyopathy‑ PPCM‑Registry) is to further investigate epidemiological data, patient characteristics and disease-specific outcomes.

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Bromocriptine in Peripartum Cardiomyopathy Biomarkers Clinical characteristics of PPCM resemble those of dilated cardiomyopathy and shared genetic predispositions can be found in approximately 15 % of all cases.19 PPCM is considered an independent entity distinct from other cardiomyopathies.20 Defined biomarkers to distinguish between PPCM and other cardiomyopathies are still largely missing, but careful analyses of the PPCM pathophysiology have enabled the identification of a set of specific diagnostic and prognostic biomarkers.6 The most used and widely available biomarkers are natriuretic peptides (i.e. brain natriuretic peptide [BNP] and NT-proBNP) and – although not specific for PPCM – normal values can exclude acute heart failure immediately.21 Other more specific biomarkers such as interferon-γ (IFN-γ), microRNA-146a (miR-146a), and soluble fms-like tyrosine kinase-1 (sFlt-1) are still under investigation and have not been used in clinical practice yet.22–24 Mebazaa and colleagues recently demonstrated that the concentration of the pro-angiogenic placenta growth factor (PlGF) in PPCM patients and women with acute heart failure was higher compared with non-pregnant women.25 The sFlt-1/ PlGF ratios were lower in PPCM patients than in normal pregnancies without PPCM. Further research is needed to evaluate the role of blocking sFlt-1 or miR-146a, which shows promising results in the experimental setting but has not been tested in women yet.

Bromocriptine Based on the favourable outcomes in PPCM patients, bromocriptine treatment has been widely introduced into clinical practice in Germany.9,12,26,27 Bromocriptine is a semisynthetic ergot alkaloid that is a potent agonist of the transmembrane G-protein-coupled dopamine 2D-receptor and various serotonin receptors in the central nervous system.28 It is administered orally with a very low bioavailability of <10 % because of a considerable first pass metabolism. Bromocriptine is highly bound to albumin (90–95 %), metabolised via the cytochrome P450 system and mainly excreted by the liver.28 It has been successfully used in various diseases such as prolactinoma, galactorrhoea, type 2 diabetes mellitus, acromegaly and Parkinson’s disease for many years.28–31 Recent research supports and encourages the use of bromocriptine in PPCM because of its ability to block prolactin (PRL) release from the pituitary gland.9,12,26,32

Pathophysiology of Peripartum Cardiomyopathy and Experimental Data A combination of increased oxidative stress during late gestation and in the early postpartum period, and high levels of the nursing hormone PRL have been shown to be an important pathophysiological aetiology of PPCM.4,5,10,24,33–35 Under several conditions that cause oxidative stress, cleavage of the 23-kDa PRL to a 16-kDa PRL fragment (also called vasoinhibin) is triggered by proteases, such as cathepsin D and matrix metalloproteinases. This 16-kDa PRL fragment has strong angiostatic, pro-apoptotic and pro-inflammatory effects and destroys blood vessels thereby restricting oxygen and nutrition supply to the heart, ultimately resulting in heart failure. This concept was first demonstrated in 2007 using a mouse model with a cardiomyocyte-specific knockout of the signal transducer and activator of transcription factor-3 (STAT3).34 Absence of STAT3 causes oxidative stress that in turn increases proteolytic enzymes leading to the generation of 16-kDa PRL from full-length PRL. Bromocriptine ultimately salvaged the myocardium from detrimental effects by blocking PRL release from the pituitary gland. Additionally, 16-kDa PRL induces the release of microRNA-146a in endothelial cells, which in turn has detrimental effects on both endothelial cells and cardiomyocytes and consequently negatively

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affects heart function.22 This work has paved the way for the introduction of bromocriptine in current clinical practice.

Bromocriptine: From Bench to Bedside Initially, case reports were published postulating a potential effect on LV function and recovery of bromocriptine when added to standard of care heart failure treatment (SHFT) in acute PPCM.36,37 However, there was some harsh criticism in the face of this new treatment concept considering the impact of bromocriptine on top of SHFT. Two proofof-concept studies suggested a positive effect of an additive therapy with bromocriptine in PPCM patients. Sliwa and colleagues performed a single-centre, randomised, open-label pilot study of women with newly diagnosed PPCM treated by either SHFT alone (n=10) or SHFT plus bromocriptine (n=10) for a total of 8 weeks.26 In short, additive bromocriptine treatment resulted in fewer deaths, fewer patients in NYHA functional class III and IV and fewer patients with persistent LVEF <35 %. Despite the drawback of a rather small cohort and openlabel treatment, the results were encouraging and strongly supported experimental data in clinical practice.

In an analysis of the German PPCM registry from 2013, Haghikia and colleagues also demonstrated a beneficial effect of bromocriptine on outcome in women with PPCM.12 In total, 64 of 96 patients (67 %) were treated with bromocriptine. The number of patients with full recovery did not differ significantly between the groups. Nevertheless, a significantly higher number of patients were classified as improvers (59 of 64 patients; 92 %) in the bromocriptine group compared with patients not treated with bromocriptine (23 of 32; 72 %). The percentage of women experiencing adverse events in the overall cohort (heart transplantation, left ventricular assist device [LVAD] or death) was 9.4 % (9 of 96 women). It should be noted that significantly more women were treated with bromocriptine in the group that did improve during follow-up. Furthermore, there were significantly more patients treated with beta-blockers and angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) in this group. These results further strengthen the beneficial role of the combination of heart failure medication and bromocriptine in PPCM patients.

Based on the experimental insights and the first promising clinical results, a German prospective, randomised and multicentre trial in patients with severe acute PPCM (LVEF ≤35 %) was conducted comparing a short-term regime (bromocriptine 2.5 mg once daily for 7 days) versus a long-term regime (bromocriptine 2.5 mg twice daily for 14 days followed by 2.5 mg once daily for additional 42 days).9 A placebo group was not permitted for ethical reasons. Of 140 patients assessed for eligibility, 63 finally underwent randomisation. The leading cause for exclusion was a LVEF >35 %. The change in LVEF after 6 months was defined as the primary endpoint and assessed by cardiac magnetic resonance imaging. LVEF improved in the short- and long-term bromocriptine group by 21 % and 24 %, respectively. The difference between both groups did not reach statistical significance.

However, in a subgroup analysis of patients with very low LVEF (<30 %), there was a trend towards a better outcome in terms of LVEF in favour of the long-term bromocriptine treatment. Because of the lack of a control group the results of this subgroup (LVEF <30 %) were compared with a cohort not treated with bromocriptine. These data were extracted from the Investigation on Pregnancy-Associated Cardiomyopathy (IPAC) study, which systematically analyses PPCM patients in the US.15 LVEF at randomisation was 28 % (short-term regime), and 29 % (long-term regime) in the bromocriptine trial. In the

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Treatment Figure 1: Scheme for Bromocriptine Treatment of Acute PPCM at Hannover Medical School LVEF ≥ 25 %, no cardiogenic shock, no ICU treatment

Bromocriptine 2.5 mg once daily for 7 days

+

At least prophylactic anticoagulation

LVEF <25 %, and/or RV dysfunction, and/or cardiogenic shock, and/or ICU treatment

Bromocriptine 2.5 mg twice daily for 14 days followed by bromocriptine 2.5 mg once daily for another 42 days

+

At least prophylactic anticoagulation

ICU treatment, cardiogenic shock with invasive ventilation and/or MCS

Start with bromocriptine 2.5 mg twice daily, uptitrate to a maximum of 10–20 mg daily depending on serum prolactin levels until successful suppression of prolactin levels to normal values

+

At least prophylactic anticoagulation

ICU = intensive care unit; LVEF = left ventricular ejection fraction; MCS, mechanical circulatory support (e.g. extracorporeal membrane oxygenation, percutaneous microaxial pump); RV = right ventricle.

IPAC study, baseline LVEF was 35 % overall. In an analysis of those women with LVEF <30 % enrolled in the IPAC study, 37 % of patients had an event or a LVEF <35 % at follow-up. In the bromocriptine trial, one of 37 patients (2.7 %) with an initial LVEF of <30 % did not improve and remained <35 % at follow-up. Of note, no patient experienced an adverse cardiac event in the bromocriptine trial. In the IPAC study, six patients experienced a total of nine major events (death, LVAD, heart transplantation).9,15 It should be noted that only one of 63 patients in the German bromocriptine trial and 30 of 100 patients enrolled in the IPAC study were of black ethnicity. This might have influenced the results as black ethnicity is considered a risk factor for poor recovery and adverse cardiovascular events.15,17 However, the pilot study in South Africa showed a highly favourable outcome in African PPCM patients treated with bromocriptine (10 % mortality and a higher recovery rate in the bromocriptine group compared with 40 % mortality and no recovery in the group not treated with bromocriptine).26 Likewise, the use of bromocriptine was associated with a low rate of relapse in subsequent pregnancies (20 of 34 PPCM patients with African origin).32 These data further support the notion that PPCM patients of African origin seem to benefit from the addition of bromocriptine to SHFT.

Role of Bromocriptine in Subsequent Pregnancies The role of bromocriptine treatment in women entering subsequent pregnancies after an initial diagnosis of PPCM has been unclear until recently. In a retrospective analysis of 34 patients from Germany, Scotland and South Africa, the addition of bromocriptine to SHFT immediately after delivery was associated with an improved outcome compared with patients not receiving bromocriptine.32 While LV function was not different at the time of conception, LVEF was significantly lower at follow-up after delivery and at follow-up in patients who did not receive bromocriptine immediately after delivery.

Safety of Bromocriptine Given that bromocriptine has a negative reputation regarding adverse effects, such as vascular, neurological or psychiatric disorders, safety concerns may arise. Recent research has revealed no evidence of serious adverse events of bromocriptine treatment when used for up to 8 weeks in dosages up to 20 mg daily. In the previouslymentioned randomised German PPCM trial,9 three of 63 patients (4.8 %) experienced adverse events possibly related to bromocriptine treatment. Venous embolism occurred in two patients and peripheral artery occlusion was diagnosed in another patient, all of them

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treated with the short-term regime. No serious adverse event was noticed in the long-term group that was treated for 8 weeks.

Nevertheless, some case reports suggest a potential prothrombotic effect of bromocriptine in postpartum women.38,39 The Hannover group therefore used at least prophylactic anticoagulation in their randomised study and basically in all their PPCM patients treated with bromocriptine.9 Therefore, the importance of anticoagulation (at least prophylactic heparinisation) during bromocriptine treatment should be emphasised.

Treatment Concepts of Peripartum Cardiomyopathy These results have led to the proposal of the so-called BOARD concept (Bromocriptine, Oral heart failure therapy, Anticoagulation, vasoRelaxing agents, and Diuretics) for the treatment of acute PPCM.27 Dose-adjusted bromocriptine should be applied to all PPCM patients depending on the severity of the disease. The bromocriptine treatment scheme of Hannover Medical School is depicted in Figure 1. Additionally, guideline-directed oral heart failure drugs should be initiated and uptitrated to the standard or maximal tolerated dosages in haemodynamically stable patients, including a beta-blocker, an ACE inhibitor/ARB/angiotensin receptor neprilysin inhibitor and a mineralocorticoid receptor antagonist. In acute PPCM with cardiogenic shock, bromocriptine should be added to acute heart failure therapy.8 Detailed treatment recommendations for heart failure patients are given elsewhere.6,8,21 Because of an increased risk of thromboembolic events, anticoagulation in at least prophylactic dosages should be initiated during bromocriptine treatment. In patients with systolic blood pressure >110 mmHg, vasorelaxing agents are recommended.

Diuretics should be used in case of fluid overload.

It is important to note that the beneficial effect of heart failure and PPCMspecific therapy with bromocriptine may be considerably attenuated by the use of catecholamines such as dobutamine in patients with cardiogenic shock.8 Observations from the German PPCM registry suggest that patients treated with dobutamine had adverse outcomes, i.e. died or needed a VAD or a heart transplantation.40 Experimental analyses in mice confirmed toxic effects of beta-1 adrenergic receptor agonists in PPCM, showing that this treatment depleted the heart massively of energy and induced cardiac muscle necrosis.40 These effects are not influenced or salvaged by bromocriptine and/or the generation of 16-kDa PRL. As a consequence, a warning has been issued that catecholamines should be avoided in PPCM patients and alternative therapies, such as the inodilator levosimendan or temporary circulatory support devices should be used.8 In contrast to other forms of cardiomyopathies, such as dilated cardiomyopathy, most PPCM patients have a high potential for partial or even full recovery especially if early and optimal treatment as outlined above is applied. Suboptimal treatment may make the disease worse and can even lead to irreversible heart failure.

Conclusion Taken together, the unique combination of basic, translational and clinical knowledge has led to a novel disease-specific treatment concept – the BOARD therapy regime – that reduces morbidity and mortality in PPCM patients. Treatment with bromocriptine is safe and effective and has contributed to improved prognosis in this still lifethreatening disease. n

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Forster O, Hilfiker-Kleiner D, Ansari AA, et al. Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy. Eur J Heart Fail 2008;10:861–8. DOI: 10.1016/j. ejheart.2008.07.005; PMID: 18768352.

Patten IS, Rana S, Shahul S, et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 2012;485:333-8. DOI: 10.1038/nature11040; PMID: 22596155.

Mebazaa A, Seronde MF, Gayat E, et al. Imbalanced angiogenesis in peripartum cardiomyopathy- diagnostic value of placenta growth factor. Circ J 2017;81:1654–61. DOI: 10.1253/circj.CJ-16-1193; PMID: 28552862.

Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in the treatment of acute severe

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peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation 2010;121:1465–73. DOI: 10.1161/ CIRCULATIONAHA.109.901496; PMID: 20308616.

Arrigo M, Blet A, Mebazaa A. Bromocriptine for the treatment of peripartum cardiomyopathy: welcome on BOARD. Eur Heart J 2017;38:2680–2. DOI: 10.1093/eurheartj/ehx428; PMID: 28934838.

Holt RI, Barnett AH, Bailey CJ. Bromocriptine: old drug, new formulation and new indication. Diabetes Obes Metab 2010;12:1048–57. DOI: 10.1111/j.1463-1326.2010.01304.x; PMID: 20977575.

Biermasz NR, Romijn JA, Pereira AM, Roelfsema F. Current pharmacotherapy for acromegaly: a review. Expert Opin Pharmacother 2005;6:2393–405. DOI: 10.1517/14656566.6.14.2393; PMID: 16259571.

Perez-Lloret S, Rascol O. Dopamine receptor agonists for the treatment of early or advanced Parkinson’s disease. CNS Drugs 2010;24:941–68. DOI: 10.2165/11537810-000000000-00000; PMID: 20932066.

Molitch ME. Diagnosis and treatment of pituitary adenomas: A review. JAMA 2017;317:516–24. DOI: 10.1001/jama.2016.19699; PMID: 28170483.

Hilfiker-Kleiner D, Haghikia A, Masuko D, et al. Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy. Eur J Heart Fail 2017;19; 1723–28.

DOI: 10.1002/ejhf.808; PMID: 28345302.

Haghikia A, Hoch M, Stapel B, Hilfiker-Kleiner D. STAT3 regulation of and by microRNAs in development and disease.

JAKSTAT 2012;1:143–50. DOI: 10.4161/jkst.19573; PMID: 24058763.

Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589–600. DOI: 10.1016/j. cell.2006.12.036; PMID: 17289576.

Hilfiker-Kleiner D, Struman I, Hoch M, et al. 16-kDa prolactin and bromocriptine in postpartum cardiomyopathy. Curr Heart Fail Rep 2012;9:174–82. DOI: 10.1007/s11897-012-0095-7; PMID: 22729360.

Horn P, Saeed D, Akhyari P, et al. Complete recovery of fulminant peripartum cardiomyopathy on mechanical circulatory support combined with high-dose bromocriptine therapy. ESC Heart Fail 2017;4:641–4. DOI: 10.1002/ehf2.12175; PMID: 28744986. de Jong JS, Rietveld K, van Lochem LT, Bouma BJ. Rapid left ventricular recovery after cabergoline treatment in a patient with peripartum cardiomyopathy. Eur J Heart Fail 2009;11:220–2. DOI: 10.1093/eurjhf/hfn034; PMID: 19168522.

Loewe C, Dragovic LJ. Acute coronary artery thrombosis in a postpartum woman receiving bromocriptine. Am J Forensic Med Pathol 1998;19:258–60. DOI: 10.1097/00000433-19980900000012; PMID: 9760093.

Hopp L, Haider B, Iffy L. Myocardial infarction postpartum in patients taking bromocriptine for the prevention of breast engorgement. Int J Cardiol 1996;57:227–32. DOI: 10.1016/S01675273(96)02789-1; PMID: 9024910.

Stapel B, Kohlhaas M, Ricke-Hoch M, et al. Low STAT3 expression sensitises to toxic effects of beta-adrenergic receptor stimulation in peripartum cardiomyopathy. Eur Heart J 2017;38:349–61. DOI: 10.1093/eurheartj/ehw086; PMID: 28201733.

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Identification and Treatment of Central Sleep Apnoea: Beyond SERVE-HF William T Abraham, 1 Adam Pleister 1 and Robin Germany 2 1. Ohio State University, Columbus, OH, USA; 2. University of Oklahoma, Oklahoma City, OK, USA

Abstract Central sleep apnoea (CSA) occurs in a large proportion of HF patients. CSA has clear detrimental effects, resulting in intermittent hypoxia and sympathetic activation, and is associated with significant morbidity and mortality. Treatment options are limited following the results of a recent trial in which adaptive servo-ventilation resulted in an increase in cardiovascular mortality. Ongoing studies utilising other forms of positive airway pressure may provide additional insight into the results of this trial. A new neurostimulation therapy, phrenic nerve stimulation, has offered a new physiological approach to the treatment of CSA. This therapy has resulted in improvements in the severity of disease and quality of life.

Keywords Central sleep apnoea, hypoxia, phrenic nerve stimulation, heart failure Disclosure: WA is a consultant to Respicardia (manufacturer of the phrenic nerve stimulation device discussed); RG is Chief Medical Officer of Respicardia; AP has no conflicts to disclose.

Received: 8 February 2018 Accepted: 15 March 2018. Citation: Cardiac Failure Review 2018;4(1):50–3. DOI: https://doi.org/10.15420/cfr.2018:9:1 Correspondence: William T Abraham, 483 West 12th Avenue, Room 110P-DHLRI, Columbus, OH 43210, USA. E: william.abraham@osumc.edu

Central sleep apnoea (CSA) occurs in approximately one-third of patients with HF and is associated with a significant increase in morbidity and mortality compared to HF patients without CSA.1–3 CSA results in intermittent hypoxia and activation of the renin–angiotensin system, which contributes to worsening HF.4 Symptoms such as fatigue and difficulty concentrating often overlap with the effects of chronic HF. Treatment options are limited. Positive airway pressure (PAP) therapy has been the most commonly utilised but has failed to demonstrate improvements in quality of life (QOL) or HF.5,6 In addition, one form of PAP therapy increased mortality as a secondary endpoint in patients with reduced ejection fraction.6 A recently approved therapy has taken a physiological approach to treatment, stimulating the phrenic nerve to restore a normal breathing pattern.7 This therapy has been demonstrated to improve CSA and QOL.

Prevalence and Patient Presentation The prevalence of CSA in patients with HF and reduced ejection fraction (HFrEF) is well documented and has remained remarkably stable, estimated at 37–51 %, even with guideline-directed medical therapy.1,8,9 There are fewer studies of CSA in people with HF and preserved ejection fraction, but the prevalence in this population remains approximately 30 %.10 The prevalence of CSA increases with the severity of HF, but it also occurs in patients with mild symptoms.4,9 CSA is also common in patients with other cardiovascular diseases; for example, it is found in approximately 31 % of patients with AF and normal LVF.11 Patients with CSA and HF present with different symptoms from those typically seen in obstructive sleep apnoea (OSA), although some overlap exists (Table 1). HF patients with CSA tend to be thinner, older, have atrial arrhythmias and/or have daytime hypocapnoea (pCO2 <38 mmHg).12 Frequent symptoms include fatigue, insomnia and

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poor concentration. Patients may also report paroxysmal nocturnal dyspnoea, headache and nocturnal angina, which are thought to be due to intermittent hypoxia.4,12 Both OSA and CSA are more common in men, although it is unclear why this should be the case with CSA.4 Suspicion for sleep apnoeas should be high in the HF population.

Regardless of the nature of the apnoea (either OSA or CSA), two-thirds of HF patients have sleep apnoea.

It seems reasonable to think that patients with CSA would be aware of their sleep disturbances, especially those in the severe category (apnoea–hypopnoea index [AHI] >30 events/hour). However, an interesting phenomenon in the HF population is that many patients do not recognise daytime sleepiness or report disrupted sleep, even in the presence of objective sleepiness.13,14 Multiple studies have shown a lack of daytime sleepiness in these populations. It has been theorised that this could be due to patients attributing their poor QOL and fatigue to their underlying HF.15 There is also a hypothesis that the increase in sympathetic drive in these patients causes them not to have typical ‘sleepiness’ symptoms, but rather results in a fatigued or hypervigilant state.16 CSA occurs in two primary forms, characterised by either Cheyne– Stokes respiration or non-Cheyne–Stokes respiration.17 In HF patients, the Cheyne–Stokes respiratory pattern is much more common and has a characteristic oscillatory pattern of shallow–deep–shallow breathing (Figure 1). Cheyne–Stokes respiration results from a delay in the respiratory control centre in detecting and responding to changes in carbon dioxide levels in the blood. The full mechanism is complex and still not completely understood; however, a number of factors appear to play a role. First, in patients with a reduced ejection fraction, there can be an increase in blood circulation time, which results

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Treatment of Central Sleep Apnoea in a delay in the time it takes blood to reach the carotid body and peripheral chemoreceptors responsible for detecting and signalling changes in blood carbon dioxide levels. Second, sympathetic activation results in increased chemosensitivity in the carotid body, further delaying the signalling. HF patients often hyperventilate chronically, and pulmonary congestion can activate pulmonary stretch receptors to cause a relative increase in ventilation. Elevated respiration can lead to a decrease in carbon dioxide and generate a signal to stop breathing.4 Regardless of which mechanism begins the cycle, each cycle perpetuates the next, allowing the abnormal breathing pattern to continue throughout the night. Each cycle results in repetitive hypoxia and arousal events, leading to long-term detrimental effects.

Regardless of whether the pattern is Cheyne–Stokes or non-Cheyne– Stokes, the effects of the breathing disorder result in a number of devastating effects to the cardiovascular system. Intermittent hypoxia leads to inflammation, tissue ischaemia and endothelial dysfunction.

Chronically, this results in thrombosis, left ventricular (LV) hypertrophy and adverse remodelling. Each arousal results in a discrete release of norepinephrine. Norepinephrine can lead to cardiac myocyte apoptosis, cardiac arrhythmias, sodium retention and activation of the renin–angiotensin system. Long term, these effects contribute to the downward cycle of HF; therefore, it is not surprising that patients with HF and CSA have an increased risk of recurrent hospitalisation and death (Figure 2).4,12

Therapeutic Options A number of therapeutic approaches have been utilised for the treatment of CSA. Medications such as theophylline and acetazolamide were shown to decrease the number of apnoea and hypopnoea episodes per hour in small studies, and aided significantly in demonstrating the importance of carbon dioxide in the disease process. However, neither medication has been studied in long-term, randomised controlled trials and there are risks in the HF population with these medications.4 Trials with nasal oxygen demonstrated an improvement in the number of episodes, reduced hypoxia and improved QOL, but clinical trial results have not been consistent. In addition, the risk of hyperoxia is increasingly recognised as harmful in patients with cardiovascular disease.18–20 Studies with newer oxygen delivery systems, which maintain a normal oxygen saturation without the resulting hyperoxia, may hold promise in the future. To date, the most widely used therapeutic approach, PAP, was borrowed from the treatment of OSA. Designed to open closed airways, this therapeutic approach can improve the number of events per hour, but can also worsen or unmask CSA in some patients.4,21 PAP therapies have been tested for the treatment of CSA. The largest randomised controlled trial with the use of continuous PAP (CPAP; single level of air pressure delivered throughout the night) was the Canadian CPAP for Patients with CSA and HF (CANPAP) trial.5 This study randomised 258 patients with HFrEF (ejection fraction <40 %) to CPAP therapy versus no CPAP, with a primary endpoint of morbidity and mortality. Following an interim analysis, a decision was made to stop the study due to an early increase in mortality in the treatment group and a slow enrolment. By the time the study was stopped, there was no difference between the treatment and control groups in morbidity or mortality. The study did demonstrate a reduction in AHI of 21 ± 16 events/hour (from a baseline of 40 ± 17 events/hour).5 However, a post hoc analysis showed that patients who responded to CPAP therapy (defined as achieving an AHI <15) had a decreased mortality rate

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Table 1: Characteristics of HF Patients with Central Sleep Apnoea Central Sleep Apnoea

Obstructive Sleep Apnoea

Male

Male

Fatigue

Fatigue

Arrhythmia (atrial and ventricular)

Atrial fibrillation

Nocturia

Nocturia

Lean (lower BMI)

Overweight

Low ejection fraction

Snoring

Recurrent HF hospitalisations

Morning headaches

Decreased exercise tolerance

Depression

compared with both CPAP non-responders and controls.22 However, no prospective studies confirming this finding have been completed to date.

Following the CANPAP trial, a new type of PAP therapy designed to improve the treatment of CSA by adjusting the pressure delivered, called adaptive servo-ventilation (ASV), was developed. It uses both inspiratory and expiratory pressure, and titrates the pressure to maintain a patent airway and adequate air movement. This therapy was studied in a large clinical trial to improve morbidity and mortality.

The Treatment of Predominant CSA by Adaptive Servo Ventilation in Patients With HF (SERVE-HF) trial randomised 1325 patients to ASV plus medical treatment versus medical treatment alone.6 It was an eventdriven trial and completed the full number of events pre-specified.

However, the trial failed its primary endpoint, with no improvement in mortality or morbidity observed. Similarly, there was no improvement in QOL or arousals, even though AHI improved from 31.2 to 6.6 events/ hour (range 0.0–71.9 events/hour). More concerning, cardiovascular mortality, a secondary endpoint, increased in the treatment group (29 versus 24 %; hazard ratio 1.34; 95 % CI [1.09–1.65]; p=0.006). A contraindication was put in place for HFrEF patients by the US Food and Drug Administration (FDA), and the American Academy of Sleep Medicine supported the contraindication in this patient population.23 Recommendations from the FDA, American Association of Sleep Medicine, and two major ASV device manufacturers suggested that patients newly diagnosed with CSA in the setting of HFrEF should not be treated with ASV device therapy. In addition, all current CSA patients with HFrEF currently on ASV therapy would need to be seen in clinic to discuss risks, options and alternatives. Further analysis demonstrated that the increase in mortality was driven by an increase in sudden cardiac death that occurred not only at night but also during the day.24 The SERVE-HF investigators suggested that this unexpected finding could be due to CSA actually being compensatory or that it could be due to the PAP therapy itself.6 CSA may begin as a compensatory mechanism similar to tachycardia; however, chronic intermittent hypoxia and increased sympathetic drive have been demonstrated to be detrimental in HF patients, and thus it is unlikely that CSA is beneficial chronically.25 Alternative theories have included a discussion of the study design itself. The design allowed crossover, and a significant number of patients did switch; 168 ASV recipients stopped therapy and 87 controls left the study, most of whom are suspected to have subsequently started ASV treatment.26 Adherence to the therapy was poor in the

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Treatment Figure 1: Example of Central Sleep Apnea with Cheyneâ&#x20AC;&#x201C;Stokes Respiration

Figure 2: Interaction of Heart Failure (HF) and Central Sleep Apnoea (CSA)

Apnoea (no breathing) or hypopnoea (shallow breathing)

CSA Oxygen deprivation & awakening

Activation of the sympathetic nervous system (fight-or-flight response)

Heart pump stress

Heart failure

Impaired heart function

treatment group, with an average nightly use of 3.7 hours. However, a recently published on-treatment analysis continues to demonstrate the cardiovascular risk of the therapy.27 Also, due to the study design, cardiac implantable electronic device data were not collected, limiting adjudication of the specific cause of death. One signal from the trial was that a Cheyneâ&#x20AC;&#x201C;Stokes breathing pattern was associated with an increased risk of mortality, but there is no clear methodology on how this parameter was determined and no core lab scoring of these data.6 The algorithm of the specific ASV device has been hypothesised to be the cause of the increased mortality.26 One theory is that the specific ASV device utilised in the trial delivered minute ventilations at up to five-times normal in some patients, which could lead to

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metabolic derangements and sudden death.27 Another theory is that the pressures in some patients were much higher than expected, which could increase pressure to the right heart.28 A relationship was noted between lower ejection fraction and an increased risk in mortality.6 While right ventricular (RV) function was not analysed, it often correlates with LV dysfunction. Increased pulmonary pressure on an already weakened right heart could explain the increased mortality in the trial. Chronically increased pulmonary pressures can stress patients with right heart failure, leading to rapid and progressive RV dysfunction and sudden death.25 Following the SERVE-HF Trial, most other research with ASV was stopped. However, the Effect of ASV on Survival and Hospital Admissions in HF (ADVENT-HF) study (ClinicalTrials.gov identifier: NCT01128816), which is examining a type of ASV therapy with an algorithm that should maintain lower pressures, continues. It is enrolling both OSA and CSA patients with a reduced ejection fraction and may give some additional insight into the treatment of CSA. The data and safety monitoring board has reviewed the data several times and has decided to continue the study in both patient groups.29 Another trial, Cardiovascular Outcomes with Minute Ventilation-Targeted ASV Therapy in HF (CAT-HF), enrolled patients acutely hospitalised for HF and placed them on ASV.30 The study used the same device as in SERVE-HF and was stopped early due to the overlap in patient populations once the results of SERVE-HF were reported. However, there were some encouraging data in patients with HF and preserved ejection fraction, although the sample size was very small (n=24).

Regardless of the mechanism, PAP does not address the physiological nature of CSA: the delay in neurological response to alterations in carbon dioxide levels. The FDA recently approved a therapeutic approach to treat CSA by replacing the delayed signalling. Phrenic nerve stimulation uses neurostimulation to stimulate a single phrenic nerve at night, which restores a normal breathing pattern and

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Treatment of Central Sleep Apnoea stabilises carbon dioxide levels.7 The device is fully implantable, with a transvenous lead placed in a vein near one of the phrenic nerves (either the left pericardiophrenic or right brachiocephalic vein). The pulse generator is placed in either the right or left pectoral region, and respiration is monitored either via a sensing lead placed in the azygous vein or by the stimulation lead itself. The unique algorithm of the device allows it to activate automatically at night, when the patient is in a sleeping position, and suspend therapy when the patient sits up.31 A randomised controlled trial of phrenic nerve stimulation therapy versus no stimulation has been conducted.7 A total of 151 patients with CSA were implanted with the device, with 73 randomised to therapy and 78 to no stimulation. The control group had therapy activated after the primary endpoint evaluation at 6 months. The primary effectiveness endpoint was met, with a 41-percentage-point difference between groups (51 versus 11 %) in the proportion of patients achieving a ≥50 % reduction in AHI from baseline to 6 months. All prespecified and hierarchically tested secondary endpoints were met, including improvements in oxygenation (oxygen desaturation index 4 %), arousals, REM sleep and QOL measured by two different metrics: Epworth Sleepiness Scale and Patient Global Assessment.

Safety was closely monitored by independent clinical events committee and a data and safety monitoring board. The primary safety endpoint of freedom from implant-, device- or delivered-therapy-related serious adverse events was achieved in 91 % of patients. Although participants were not required to have HF, 64 % had a history of HF. Owing to the

1.

ldenburg O, Lamp B, Faber L, et al. Sleep-disordered O breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail 2007;9:251–7. DOI: 10.1016/j. ejheart.2006.08.003; PMID: 17027333.

2. Khayat R, Abraham W, Patt B, et al. Central sleep apnea is a predictor of cardiac readmission in hospitalized patients with systolic heart failure. J Card Fail 2012;18:534–40. DOI: 10.1016/j. cardfail.2012.05.003; PMID: 22748486.

3. Khayat R, Jarjoura D, Porter K, et al. Sleep disordered breathing and post-discharge mortality in patients with acute heart failure. Eur Heart J 2015;36:1463–9. DOI: 10.1093/ eurheartj/ehu522; PMID: 25636743.

4. Costanzo MR, Khayat R, Ponikowski P, et al. Mechanisms and clinical consequences of untreated central sleep apnea in heart failure. J Am Coll Cardiol 2015;65:72–84. DOI: 10.1016/j. jacc.2014.10.025; PMID: 25572513.

5. Bradley TD, Logan AG, Kimoff RJ, et al. CANPAP Investigators.

Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025–33. DOI: 10.1056/ NEJMoa051001; PMID: 16282177.

6. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servoventilation for central sleep apnea in systolic heart failure.

N Engl J Med 2015;373:1095–105. DOI: 10.1056/NEJMoa1506459; PMID: 26323938.

7. Costanzo MR, Ponikowski P, Javaheri S, et al. Remedē System Pivotal Trial Study Group. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet 2016;388:974–82. DOI: 10.1016/S0140-6736(16)30961-8; PMID: 27598679.

8. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol 2006;106:21–8. DOI: 10.1016/j.ijcard.2004.12.068; PMID: 16321661.

9. Grimm W, Apelt S, Timmesfeld N, Koehler U. Sleep-disordered breathing in patients with implantable cardioverterdefibrillator. Europace 2013;15:515–22. DOI: 10.1093/europace/ eus356; PMID: 23129543.

10. Bitter T, Faber L, Hering D, et al. Sleep-disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail 2009;11:602–8. DOI: 10.1093/eurjhf/hfp057; PMID: 19468022.

11. Bitter T, Langer C, Vogt J, et al. Sleep-disordered breathing in patients with atrial fibrillation and normal systolic left ventricular function. Dtsch Arztebl Int 2009;106:164–70. DOI: 10.3238/arztebl.2009.0164; PMID: 19578392.

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close relationship between HF and CSA, the HF subgroup was carefully studied in light of the results of SERVE-HF. Importantly, no trend of an increase in cardiovascular mortality was seen, although the trial was not powered to evaluate this outcome. Given that phrenic nerve stimulation does not employ PAP therapy to treat CSA, the possible negative effects of PAP therapy noted above should be avoided with phrenic nerve stimulation. Importantly, the FDA approved the use of phrenic nerve stimulation in moderate to severe CSA in adult patients, without regard for the presence of HF or ejection fraction, making phrenic nerve stimulation the only approved treatment in the US for CSA in HF patients with ejection fraction ≤45 %.

Conclusion CSA clearly has chronic and detrimental effects on HF patients. While symptoms may be difficult to identify, there is clear benefit in QOL with treatment of CSA using phrenic nerve stimulation, but this has not been observed with other therapies. It is common for patients not to articulate their symptoms or attribute symptoms of CSA to their HF, which delays diagnosis and treatment of CSA. CSA results in chronic sympathetic nervous system activation and hypoxia. While it is logical that treatment of CSA will be able to decrease the significant morbidity and mortality associated with sleep apnoea, no therapy to date has demonstrated improvements in cardiovascular outcomes.

However, this does not mean the disease should not be treated.

Improving QOL in HF patients is extremely valuable while we wait for data demonstrating that improvements in sleep apnoea events, oxygenation and arousals lead to improvements in cardiovascular outcomes in this population. n

12. B ekfani T, Abraham WT. Current and future developments in the field of central sleep apnoea. Europace 2016;18:1123–34.

DOI: 10.1093/europace/euv435; PMID: 27234869.

13. Hastings PC, Vazir A, O’Driscoll DM, et al. Symptom burden of sleep-disordered breathing in mild-to-moderate congestive heart failure patients. Eur Respir J 2006;27:748–55. DOI: 10.1183/09031936.06.00063005; PMID: 16585081.

14. Redeker NS, Muench U, Zucker MJ, et al. Sleep disordered breathing, daytime symptoms, and functional performance in stable heart failure. Sleep 2010;33:551–60. PMID: 20394325.

15. Javaheri S. Heart Failure. In: Kushida C (ed) The Encyclopedia of Sleep, vol. 3. Waltham, MA: Academic Press, 2013; 374–86.

16. Taranto Montemurro L, Floras JS, Millar PJ, et al. Inverse relationship of subjective daytime sleepiness to sympathetic activity in patients with heart failure and obstructive sleep apnea. Chest 2012;142:1222–8. DOI: 10.1378/chest.11-2963; PMID: 23303285.

17. Flinta I, Ponikowski P. Relationship between central sleep apnea and Cheyne–Stokes respiration. Int J Cardiol 2016;206(Suppl):S8–12. DOI: 10.1016/j.ijcard.2016.02.124; PMID: 26961739.

18. Campbell AJ, Ferrier K, Neill AM. Effect of oxygen versus adaptive pressure support servo-ventilation in patients with central sleep apnoea–Cheyne Stokes respiration and congestive heart failure. Intern Med J 2012;42:1130–6.

DOI: 10.1111/j.1445-5994.2011.02623.x; PMID: 22032285.

19. Sasayama S, Izumi T, Matsuzaki M, et al. Improvement of quality of life with nocturnal oxygen therapy in heart failure patients with central sleep apnea. Circ J 2009;73:1255–62. DOI: 10.1253/circj.CJ-08-1210; PMID: 19448327.

20. Sepehrvand N, Ezekowitz JA. Oxygen therapy in patients with acute heart failure: friend or foe? JACC Heart Fail 2016;4:783–90.

DOI: 10.1016/j.jchf.2016.03.026; PMID: 27289409.

21. Liu D, Armitstead J, Benjafield A, et al. Trajectories of emergent central sleep apnea during CPAP therapy. Chest 2017;152:751–60. DOI: 10.1016/j.chest.2017.06.010; PMID: 28629918.

22. Arzt M, Floras JS, Logan AG, et al. CANPAP Investigators.

Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial

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Aurora RN, Bista SR, Casey KR, et al. Updated adaptive servoventilation recommendations for the 2012 AASM guideline: “the treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses”. J Clin Sleep Med 2016;12:757–61. DOI: 10.5664/jcsm.5812; PMID: 27092695.

Eulenburg C, Wegscheider K, Woehrle H, et al. Mechanisms underlying increased mortality risk in patients with heart failure and reduced ejection fraction randomly assigned to adaptive servoventilation in the SERVE-HF study: results of a secondary multistate modelling analysis. Lancet Respir Med 2016;4:873–81. DOI: 10.1016/S2213-2600(16)30244-2; PMID: 27592224.

Oldenburg O, Coats A. CSA is not beneficial long term in heart failure patients with reduced ejection fraction. Int J Cardiol 2017;227:474–7. DOI: 10.1016/j.ijcard.2016.11.003; PMID: 27825728.

Javaheri S, Brown LK, Randerath W, Khayat R. SERVE-HF: more questions than answers. Chest 2016;149:900–4. DOI: 10.1016/j. chest.2015.12.021; PMID: 26836904.

Woehrle H, Cowie MR, Eulenburg C, et al. Adaptive servo ventilation for central sleep apnoea in heart failure: SERVEHF on-treatment analysis. Eur Respir J 2017;50:1601692. DOI: 10.1183/13993003.01692-2016; PMID: 28860264.

Yamauchi M, Combs D, Parthasarathy S. Adaptive servoventilation for central sleep apnea in heart failure. N Engl J Med 2016;374:689. DOI: 10.1056/NEJMc1515007#SA4; PMID: 26886532.

Lyons OD, Floras JS, Logan AG, et al. ADVENT-HF Investigators.

Design of the Effect of Adaptive Servo-Ventilation on Survival and Cardiovascular Hospital Admissions in Patients with Heart Failure and Sleep Apnoea: the ADVENT-HF trial. Eur J Heart Fail 2017;19:579–87. DOI: 10.1002/ejhf.790; PMID: 28371141.

O’Connor CM, Whellan DJ, Fiuzat M, et al. Cardiovascular outcomes with minute ventilation-targeted adaptive servoventilation therapy in heart failure: The CAT-HF Trial. J Am Coll Cardiol 2017;69:1577–87. DOI: 10.1016/j.jacc.2017.01.041; PMID: 28335841.

Costanzo MR, Augostini R, Goldberg LR, et al. Design of the remedē System Pivotal Trial: a prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea. J Card Fail 2015;21:892–902. DOI: 10.1016/j. cardfail.2015.08.344; PMID: 26432647.

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Treatment

A Review of Plant-based Diets to Prevent and Treat Heart Failure Conor P Kerley Chronic Cardiovascular Disease Management Unit and Heart Failure Unit, St Vincent’s Healthcare Group/St Michael’s Hospital, Dublin, Ireland

Abstract Evidence supporting the role of nutrition in heart failure (HF) incidence and severity is growing. A comprehensive search of online databases was conducted using relevant keywords to identify human studies including diet and HF. Several plant-based diets have consistently been associated with decreased HF incidence and severity, notably the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets. Several other plant-based dietary patterns, including low-fat diets and the rice diet, also show promise. Higher dietary quality, as assessed using different scores, seems to provide protective qualities. Fruit, vegetables, legumes and wholegrains appear to be beneficial, whereas red/processed meats, eggs and refined carbohydrates appear harmful. Some evidence suggests detrimental effects of dairy products and poultry, but more research is needed. There is observational and interventional evidence that a plant-based diet high in antioxidants, micronutrients, nitrate and fibre but low in saturated/trans fats may decrease the incidence and severity of HF. Potential mechanisms for this include decreased oxidative stress, homocysteine and inflammation levels, as well as higher antioxidant defence and nitric oxide bioavailability with gut microbiome modulation. Well-designed randomised, controlled nutrition intervention trials specific to HF are urgently required.

Keywords Heart failure, diet, nutrition, food, dairy, eggs, fish, meat, fruit, vegetables, nuts, wholegrains, carbohydrates Disclosure: The author has no conflicts of interest to declare.

Received: 20 January 2018 Accepted: 7 March 2018 Citation: Cardiac Failure Review 2018;4(1):54–61. DOI: https://doi.org/10.15420/cfr.2018:1:1 Correspondence: Conor P Kerley, Chronic Cardiovascular Disease Management Unit and Heart Failure Unit, St Vincent’s Healthcare Group/St Michael’s Hospital, Dublin, Ireland. E: conorkerley@gmail.com

Heart failure (HF) is a major cause of hospitalisation, morbidity and mortality. Nutritional factors are major contributors to HF precursors, including hypertension, obesity, dyslipidaemia, insulin resistance/ diabetes and systemic inflammation. Multiple landmark trials, including Dietary Approaches to Stop Hypertension (DASH)1 and Prevención con Dieta Mediterránea (PREDIMED),2 have documented the profound effect of nutrition on cardiovascular disease (CVD) incidence/severity.

Most research into HF has focused on pharmacology and devices, with little attention being paid to nutrition.3 Therefore, knowledge regarding the role of nutritional factors in the pathogenesis or treatment of HF is limited3-5 and guidelines typically focus on sodium or fluid restriction.

As nutritional modification is relatively low risk and low cost option, it is an attractive strategy for reducing HF incidence and severity.

This review briefly summarises the evidence of the impact of dietary pattern on HF incidence and severity.

Methods The MEDLINE, CINAHL, EMBASE and Cochrane databases were searched to identify relevant publications up to October 2017.

Keywords used included ‘heart failure’ plus ‘diet’, ‘dietary pattern’, ‘nutrition’, ‘Diet And Reinfarction Trial/DART’, ‘Dietary Approaches to Stop Hypertension/DASH’, ‘Prevención con Dieta Mediterránea/ PREDIMED’, ‘Mediterranean’, ‘low-fat’, or ‘paleo(lithic)’. Bibliographies were searched for further references. All human studies specific to HF (not general CVD or non-HF CVD) were included.

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Articles on salt/sodium or fluid restriction, omega-3/micronutrient supplementation, alcohol and over-/undernutrition (i.e. obesity or malnutrition/cardiac cachexia) were excluded as they were outside the scope of the review. Dietary components, such as fish and eggs, were not excluded but are only discussed briefly as they are not the major focus of this paper.

Results Nutritional factors have long been appreciated to be of importance in CVD. Several epidemiological studies in the past decade have demonstrated a 45–81 % decrease in HF incidence in those following a healthy lifestyle (regular physical activity, healthy dietary pattern, normal BMI, no or moderate alcohol intake and not smoking).6–14 A dose–response relationship was found, with greater adherence to healthy behaviours being associated with a graded reduction in HF incidence. Lifestyle factors, including diet, therefore appear to be important in the primary prevention of HF. As the epidemiological studies included several lifestyle factors, the specific effect of nutrition cannot be elucidated. However, research focusing solely on nutrition and HF has been performed, with the Mediterranean diet (MedDiet) and Dietary Approaches to Stop Hypertension (DASH) being the major dietary patterns studied.

Dietary Approaches to Stop Hypertension DASH was designed to prevent and treat hypertension.1,15 Based on early studies of lower blood pressure in vegetarians, “the diet design goals were to create patterns that would have the blood pressure

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Plant-based Diets to Prevent and Treat Heart Failure lowering benefits of a vegetarian diet, yet contain enough animal products to make them palatable to non-vegetarians”.15 As such, DASH is a plant-based diet rich in carbohydrates and low in fat. It emphasises the consumption of fruit, vegetables, wholegrains and nuts with the addition of some fish, poultry and low-fat dairy products and the minimisation of red meat, sugar and processed foods.

A 2012 cross-sectional study of 6,814 ethnically-diverse adults without CVD reported that greater consistency with DASH was associated with favourable end-diastolic volume, stroke volume and ejection fraction.16 Subsequent separate, large prospective studies reported that greater adherence to DASH was associated with 22 % decreased HF risk in men17 and 37 % decreased risk in women.18 Indeed, a 2013 systematic review and meta-analysis including >144,000 adults reported that a DASH-like diet was associated with significant reductions in CVD incidence, including CHD and stroke (19–21 %), but the greatest risk reduction was against HF (29 %).19 Another prospective observational study conducted in 3,215 women with pre-existing HF found a 16 % decrease in mortality in those with the greatest DASH adherence after 4.6 years.20 A preliminary intervention trial with 375 participants, published in 2003, suggested a natriuretic action of the DASH diet, in conjunction with a hypotensive effect.21 This trial also reported that the DASH diet was more effective with a low sodium content and in hypertensives (compared to normotensives). Follow-up was done in the DASHDiastolic Heart Failure (DASH-DHF) pilot study. DASH-DHF was a non-blinded, non-randomised and non-controlled pilot study of 13 primarily obese, post-menopausal women with HF with preserved ejection fraction that led to three publications. All foods were prepared and served under observation by dieticians in a metabolic kitchen. After 3 weeks there was a mean weight loss of 1.7 kg, which was accompanied by decreases in 24-hour blood pressure, dyspnoea, urinary sodium, brain natriuretic peptide (BNP) and oxidative stress but increases in 24-hour urinary potassium and aldosterone levels as well as a trend towards increased exercise capacity.22 Significant increases in stroke volume, ejection fraction and cardiac contractility were noted as well as significant decreases in arterial elastance, viscoelastic/relaxation and chamber stiffness.23 There were also increases in short-chain acylcarnitines, which correlated with improved left ventricular function,24 suggesting improved myocardial energy utilisation.

A more recent randomised, controlled trial compared DASH to general HF dietary recommendations over 12 weeks in 48 patients with mild to moderate HF.25 Significant increases in large artery elasticity, exercise capacity and quality of life were reported as well as a significant decrease in BNP. All of these changes were achieved without weight loss.

Although the trials lacked investigator blinding, DASH appears to be promising for the prevention and treatment of HF. Based on consistent evidence of benefit in CVD, including HF, DASH has been called “an optimal dietary plan for symptomatic HF”26 and was included in the 2013 American College of Cardiology/American Heart Association CVD risk prevention guidelines (strong recommendation: level 1A).27

Mediterranean Diet Similar to DASH, the MedDiet is a plant-based, carbohydrate-rich, moderate-fat diet. It is characterised by a high intake of vegetables, fruit, wholegrains and nuts with a moderate intake of extra virgin olive

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oil, fish and sometimes wine. It involves a low intake of dairy products, poultry, processed meat, red meat, sugar and processed foods.

The randomised, single-blind Lyon Diet Heart Study tested the hypothesis that a MedDiet would reduce CVD complications in survivors of a first MI compared to usual care plus a prudent Western diet. After 27 months there were eight cases of non-fatal HF (n=303; 1.35 %) in the usual-care group and two cases in the MedDiet group (n=302; 0.33 %).28 In an extended 46-month follow-up, the MedDiet led to a 67 % reduction in the risk of a composite endpoint including HF (p=0.0001).29 A prospective study of 1,000 adults admitted with acute coronary syndrome reported a 7 % decrease in the likelihood of developing left ventricular systolic dysfunction at hospitalisation,12 % reduction in the likelihood of recurrent CVD events, and a trend towards a 10 % lower risk of cardiac remodelling (p=0.06) in those following the MedDiet over 2 years.30 Subsequent large prospective studies reported that MedDiet adherence was associated with decreases in HF incidence of 24 % in healthy adults,31 21 % in healthy women,32 31 % in healthy men33 and 77.4 % in anticoagulated atrial fibrillation patients.34 All of these studies reported that greater adherence conferred greater protection in a dose-dependent manner.31–34 In a recent meta-analysis of six studies (n=10,950), the MedDiet was associated with significant reductions in major vascular events (37 %), coronary events (35 %) and stroke (35 %), but the greatest risk reduction was against HF (70 %).35 Despite these positive results, it should be noted that both the quantity and quality of the available evidence in this meta-analysis was limited and highly variable.

A cross-sectional study conducted in 372 adults with pre-existing HF found that a higher MedDiet score was positively correlated with log skeletal muscle ventricles, left atrial ejection fraction and several measures of ventricular function.36 A prospective study demonstrated a 45 % greater decrease in mortality risk was reported in men who went on to develop HF and had the highest MedDiet adherence compared to those who developed HF and had the lowest adherence.33 In a similar study including 3,215 women with pre-existing HF, after 4.6 years of follow up there was a 15 % decrease in mortality risk in the highest versus lowest quartile of MedDiet adherence (p=0.006).20 Similar to DASH, there is a lack of interventional data. A preliminary analysis of the PREDIMED trial reported decreased plasma N-terminal pro-BNP and oxidised LDL as well as a lower increase in lipoprotein(a) in participants on a MedDiet plus extra virgin olive oil or nuts compared to those on a low to moderate fat diet.37 After 4.8 years, data from PREDIMED demonstrated that the MedDiet plus extra virgin olive oil or nuts had no significant protective effect on HF incidence compared to the low fat diet. However, HF incidence was not significantly lower (22–32 %) in point estimates throughout the trial in the MedDiet group.

The lack of significance may be due to low HF incidence, short follow up and moderate to high baseline adherence to the MedDiet.38 Only one randomised, controlled trial has assessed the effects of the MedDiet on cardiovascular events and mortality. This trial, which included first MI survivors, compared the effects of a MedDiet with a low-fat diet (both with saturated fat ≤7 % calories and dietary cholesterol ≤200 mg/day) with usual care. No significant difference was found between the diets. However, there was significantly increased survival at a median follow-up of 46 months in the MedDiet and low-fat diet groups (84 %) compared to the usual care group (60 %).39

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Treatment DASH Versus the Mediterranean Diet Both dietary patterns are plant-based and low in red/processed meat, refined carbohydrates and processed foods. A prospective study involving 3,215 women with pre-existing HF reported 16 % and 15 % decreases in mortality rates in women with HF with adherence to DASH and the MedDiet, respectively, but these observations were only statistically significant for DASH.20

High-protein Diets There are two interventional trials that have utilised high-protein diets in HF. A small, three-arm trial compared 12 weeks of highprotein, hypoenergetic diet to a standard protein, hypoenergetic diet or a normocaloric American Heart Association-recommended diet among 14 overweight/obese subjects with mild to moderate HF and diabetes. The higher protein diet resulted in significantly greater reductions in weight, body fat, total/LDL cholesterol and triglycerides, as well as significantly greater improvements in exercise capacity, HDL, quality of life and a trend towards increased muscle mass.40 Interestingly, patients in the high-protein group were encouraged to increase their intake of plant- as opposed to animal-based proteins.

A subsequent randomised trial compared the high-protein Nordic Nutrition Recommendation diet to a high protein ‘paleo’ diet (both ad libitum) in 68 overweight postmenopausal women. After 2 years, there were non-significant decreases in weight but significant decreases in left ventricular mass and end diastolic volume in both high-protein groups.41 Conversely, excess dietary protein may be harmful in HF. One pilot intervention trial reported a decrease in stroke volume and cardiac output over time with high-protein diets.42 Further, proteinbound uremic toxins are derived from colonic microbiota metabolism of dietary amino acids, and recent reviews suggest that a low-protein diet may reduce protein-bound uremic toxins with beneficial effects on CVD.,44

The Rice Diet In 2014, two articles were published that recounted Dr Walter Kempner and his rice diet.,46 This diet, which was proposed in the 1940s, consists of white rice, sugar, fruit, fruit juices, vitamins and iron. It provides ~2,000 calories, 20 g protein, 2–3 % fat, 1,000 ml liquid and 150–250 mg sodium daily. High blood pressure and its related symptoms reportedly improved markedly and rapidly in people following the rice diet. A 1949 editorial stated that “results are little short of miraculous […] practically speaking, there is probably no more effective diet for obese decompensated cardiac patients”.47 There has been no original research on the rice diet since 1975,48 but its remarkable reported success combined with similarities to other therapeutic (plant-based and low-sodium) regimens suggest that this may be an interesting concept.

Low-fat Diets Low-fat diets have been and remain the cornerstone of cardiovascular dietary advice. An early, single-blind randomised controlled trial comparing a low-fat diet with added fruit, vegetables, nuts and grain products to a standard low-fat diet in 406 patients with acute MI or unstable angina reported that the supplemented low-fat diet resulted in greater weight loss and significantly increased HDL as well as significantly greater reductions in total/LDL cholesterol, triglycerides, fasting blood glucose, blood pressure, cardiovascular events – including HF incidence – and total mortality after 1 year.49 A more recent controlled trial among subjects after a first MI demonstrated significantly increased survival (84 %) with a low-fat, low saturated fat

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(7 % calories) and low dietary cholesterol (200 mg/day) diet compared to usual care (60 %).39

Low-fat, Plant-based Diet A low-fat, plant-based diet remains the only dietary pattern objectively proven to reverse CHD.,51 This diet has yet to be subjected to a trial specific to HF incidence or outcome. However, an early randomised trial comparing a low-fat, plant-based diet with exercise and stress management to usual care in 46 CHD patients reported significant increases in exercise capacity and left ventricular ejection fraction as well as significant decreases in total cholesterol and angina frequency in the intervention group after just 24 days.52 Subsequent trials from the same group demonstrated that 3 months of the same regimen significantly decreased BMI, LDL, inflammation (C-reactive protein), apolipoprotein-B, angina frequency/severity and physical limitations in subjects with CHD or risk factors.42 It also reduced BMI, body fat, blood pressure, resting heart rate and total/LDL-cholesterol in subjects with impaired left ventricular function while increasing their exercise capacity and quality of life.53 Importantly, these benefits were maintained after 1 year. A follow-up trial in 27 CHD patients with asymptomatic reduced left ventricular ejection fraction reported that, compared to a low-fat, plant-based diet with exercise and stress management, usual care with revascularisation resulted in marked increases in cardiovascular events after 3 months (1,227 %) and 3 years (175 %). However, 88 % of those in the lifestyle change group did not require primary revascularisation at 3 years.54 This 3-year follow-up demonstrates that comprehensive lifestyle changes are achievable, sustainable and effective. Further, a recent case report demonstrated the effects of a plant-based diet in a 79-year-old male with documented triple vessel disease (80–95 % stenosis) and left ventricular systolic dysfunction (ejection fraction 35 %) in the context of progressive dyspnoea. Two months of the diet led to clinicallysignificant reductions in body weight and lipids, with improved exercise tolerance and ejection fraction (+15 %).55

Studies Based on Overall Dietary Quality Alternative Healthy Eating Index The alternative healthy eating index (AHEI) is a nine-component index. It includes vegetables, fruit, nuts, soy protein, cereal fibre and multivitamin use. It is low in trans-fat and alcohol. It also has high ratios of polyunsaturated to saturated fatty acids and of white to red meat.

In a large prospective study, a healthy lifestyle including a high AHEI score was associated with a 77 % reduction in HF incidence.11 Large prospective studies focusing on AHEI score alone observed a 52 % reduction in the risk of HF in women56 and 28 % reduction in HF risk in those with pre-existing CVD or diabetes over 4.5–10-year follow up.57 One of these studies was a prospective analysis of two combined trials of antihypertensive medication. Higher AHEI score had a protective effect regardless of which medications were prescribed (ACE inhibitors or angiotensin II receptor antagonist) or the presence of co-morbidities (CVD or diabetes). This result suggests that diet can be protective in the absence of pharmacology but can also act synergistically.57 This is noteworthy, as an additive benefit of nutrition to pharmacology was reported in one of the first reports of the MedDiet and CVD.29

Dietary Inflammatory Index The dietary inflammatory index was developed to characterise dietary intake, from maximally anti- to pro-inflammatory. A large, cross-sectional study (n=15,693) reported that subjects eating a pro-inflammatory diet

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Plant-based Diets to Prevent and Treat Heart Failure were 30 % more likely to have a circulatory disorder (including HF) compared to those on a less inflammatory diet.58

Dietary Modification Index The dietary modification index score is based on percentage of total energy intake from fat, vegetable and fruit servings, grain servings, percentage of energy intake from saturated fat, percentage of energy intake from trans-fat and dietary cholesterol intake. There was a significant (39 %) decrease in HF risk in women in the highest compared to the lowest dietary modification index quintile in a large prospective study with 10-year follow up.56

Dietary Risk Score The dietary risk score is based on food items that are considered predictive of or protective against CVD. Foods predictive of CVD include meat, salty snacks and fried foods. Protective foods include fruit, leafy green vegetables and other cooked and raw vegetables. A large, prospective study with 4.5-year follow up observed a 43 % decrease in HF risk in adults with pre-existing CVD or type 2 diabetes in the highest versus the lowest dietary risk score quartile.57

foods rich in mono- and polyunsaturated fats was associated with 51 % reduction in the risk of HF deterioration/death. There was also a trend towards delisting for transplantation due to HF improvement with more frequent consumption of fruit, vegetables and legumes.62

Dietary Fats Cross-sectional studies suggest that fatty acids may have beneficial or detrimental effects, depending on the type of fatty acid. One study reported that HF patients with higher saturated and trans fat intake had higher systemic inflammation (tumour necrosis factor-α).63 Consistent with this, another study reported that plasma trans fatty acids were strongly associated with multiple markers of systemic inflammation as well as BNP levels in HF patients.64 In contrast with this, a study of 651 acute coronary syndrome patients reported a 65 % decrease in the risk of left ventricular systolic dysfunction with exclusive olive oil consumption.65 Conversely, a large prospective study of 15,362 male physicians reported a dose–response association between fried food and HF incidence and a 103 % increase in HF risk in those with the highest versus the lowest levels of fried food consumption.66

Dairy

Evidence Linking Dietary Components with Heart Failure Nutritional research has traditionally focused on single foods or nutrients. Although individual dietary components are not the focus of this review, they are covered here as the effect of a single food or nutrient may be confounded by overall dietary habits and patterns.59 Table 1 provides an overview of the associations of different types of food with HF, and Table 2 lists the association of different dietary components with this condition.

Several studies of dietary patterns that have already been discussed also assessed the effects of individual foods and/or food components.

Multivariate analysis of the Women’s Health Initiative Observational Study suggested that a diet low in cholesterol (p=0.001) and high in fibre (p=0.026) had a protective association with CVD.56 Interestingly, dietary cholesterol is found only in animal products, whereas dietary fibre is found only in unprocessed plant products. In the prospective analysis of AHEI and HF incidence from two combined pharmacology trials, the authors further analysed each component of the AHEI.57 They noted that all types of vegetables, green leafy vegetables, other raw vegetables, fruit, soy protein and nuts were inversely associated with HF incidence; while meat, poultry and eggs were positively associated with increased risk. There was no association with fish.57 A prospective study including 201 women with suspected myocardial infarction reported a 13 % decrease in CVD event risk (including HF) with increased consumption of fibre and a 64 % decrease with increased fruit, vegetable and legume consumption.60 Finally, a 2013 cross-sectional study of 312 HF patients awaiting heart transplantation reported that dietary habits typically considered unhealthy (i.e. infrequent consumption of fruits/vegetables/legumes and frequent intake of foods high in saturated fats) were related to enhanced physical quality of life, but only among overweight and obese patients.61 However, this study contrasts with other evidence and may represent reverse causation, whereby patients with severe HF changed their dietary habits to less healthy ones as opposed to an improved diet causing severe HF. A separate prospective study by the same group involving 318 heart transplant candidates reported that frequent intake of salty foods and saturated fat was associated with a 290 % increase in high-urgency transplantation, whereas frequent intake of

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A cross-sectional study of 86 adults with HF noted that dairy intake was associated with both poorer memory and higher pulsatility index in the medial cerebral artery.67 Consistent with this, a later prospective study noted that dairy was associated with an 8 % increase in HF risk.68 However, a recent systematic review and meta-analysis of prospective studies noted an inverse relationship between biomarkers of dairy intake and HF incidence.69

Eggs Prospective studies have reported an increased incidence of HF associated with egg consumption (28–64 %).68,70,71 However, one of these studies reported no association in women or people with diabetes, and the positive association in men was limited to those consuming more than six eggs weekly.70 Nevertheless, a 2017 metaanalysis reported a 25 % increase in the risk of incident HF in those with the highest compared to the lowest egg consumption.72

Fish There are no randomised trials of fish consumption in HF. Several prospective studies have reported that fish consumption is associated with decreased HF risk.31,73–77 However, further studies have reported no protective effect,79 and two studies have reported a U-shaped association between HF risk/event rates and dietary marine omega-3 fatty acids77 or fish consumption.80 The effect of fish consumption may be influenced by its preparation (fried versus non-fried) and type (oily versus non-oily). For example, fried fish has been associated with reduced ejection fraction, lower cardiac output and higher systemic vascular resistance in older adults81 and prospective studies have reported an increased risk of HF with fried fish consumption.73,76 There are three meta-analyses of fish intake and HF risk, two of which reported an inverse association between HF risk and oily fish consumption,83 and one that reported a positive association with fried fish but no significant associations between intake and HF.84 These seemingly inconsistent observations may be partially related to toxins such as mercury. Alternatively, it is possible that dietary displacement may explain the inconsistencies. For example, if consumed in place of red/processed meat or eggs, fish may appear protective; however, if consumed in place of vegetables or wholegrains, fish may not be protective.

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Treatment Table 1: Association of Foods with Heart Failure Incidence and Severity Decreased

Inconsistent Evidence and/or Increased

Incidence/Severity No Reported Association

Incidence/Severity

Vegetables

Nuts

Meat

Fruit

Poultry

Salty snacks

Soy protein

Dairy

Fried foods

Wholegrains

Oily and white fish

Eggs

Legumes

Fried fish

Extra virgin olive oil

Sweetened beverages

Table 2: Association of Dietary Components with the Incidence and Severity of Heart Failure

existing HF reported that higher lycopene intake was associated with significantly longer cardiac event-free survival.92 Lycopene is a major phytonutrient found in tomatoes and other fresh produce, such as watermelon and papaya.

Several cross-sectional studies have suggested that diverse benefits are associated with greater consumption of fruit and vegetables in those with pre-existing HF. These benefits include decreased inflammation,93 decreased oxidative stress,94 increased ejection fraction95 and improved functional capacity.96

Nuts Despite reported non-HF cardio-protective effects, two independent prospective studies found no association between nut consumption and HF incidence.68,97

Wholegrains Decreased Incidence/Severity

Increased Incidence/Severity

Fibre

Saturated fatty acids

Monounsaturated fat

Trans fatty acids

Polyunsaturated fat

Dietary cholesterol

Dietary nitrate

Sodium

An early prospective study with 19.6-year follow-up period reported a 29 % decrease in HF risk in people consuming seven servings of breakfast cereal weekly compared to none. This protective effect was limited to wholegrain cereals.98 Support for this finding was provided by a subsequent prospective study, which reported a 7 % decrease in HF risk with each additional wholegrain serving.68

Antioxidants (vitamin C, lycopene) Cardioprotective minerals (e.g. magnesium, potassium)

One potentially important aspect of fish is the presence of omega-3 fatty acids. Further, a recent meta-analysis of randomised controlled trials reported that omega-3 fatty acids conferred a benefit in HF.85 A 2017 science advisory from the American Heart Association regarding omega-3 – based mostly on secondary prevention trials in those at high risk of CVD – suggested that individuals with recent MI or current HF may benefit from supplementation.86

Other Carbohydrates In contrast to the protective effect of wholegrains, a large prospective study of men (n=42,400) reported a 23 % increase in HF risk with the consumption of ≥400 ml sweetened beverages daily compared to non-consumers.99 Only a single study has assessed glycaemic index or glycaemic load and HF. The 9-year prospective study of 36,019 healthy adults reported no significant association between dietary glycaemic index or glycaemic load and HF events,100 perhaps suggesting that fibre content and the overall composition of carbohydrates is more important than absolute glycaemic index or glycaemic load.

Meat There are five prospective studies examining the association between meat consumption and HF incidence in separate medium to large, middle-aged cohorts. All of these studies found increased HF risk with meat consumption.31,68,87–89 One study reported a dose–response relationship whereby higher meat consumption seemed to confer higher HF risk,87 while another reported increased HF and non-HF mortality with increased meat consumption.88 However, one study stated that there was no association after multivariate adjustment68 and another that although processed meat increased HF risk, unprocessed red meat was not detrimental.89

Fruit and Vegetables A 2008 prospective study of 14,153 healthy white and AfricanAmerican adults reported that neither fruit nor vegetable consumption had a benefit on HF incidence.68 However, a subsequent larger prospective study (n=34,319) reported a 20 % decrease in HF risk in the highest versus the lowest consumers after multivariate adjustment.90 Interestingly, vegetables (mutually adjusted for fruit) were protective but not total fruit (mutually adjusted for vegetables). However, the consumption of apples, pears and berries and of green leafy vegetables was inversely associated with HF risk in a dose–response manner.90 A retrospective study reported marked decreases in both white blood cell count and HF incidence with increasing tomato consumption.91 Consistent with this, a prospective study among adults with pre-

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Potential Mechanisms of Action Plant-based diets are typically rich in fibre, dietary nitrates and cardioprotective micronutrients such as magnesium, potassium and antioxidants (e.g. vitamin C and lycopene) but low in saturated/trans fat. In contrast, animal foods are typically much lower in nitrate, magnesium, potassium and antioxidants. Therefore plant-based diets may increase antioxidant status and nitric oxide bioavailability and decrease reactive oxygen species, inflammation, homocysteine, blood pressure, hyperglycaemia, obesity, lipids and even atherosclerosis.

Another potential mechanism of action is dietary modulation of the gut microbiome. A series of well-conduced human studies demonstrated that intestinal microbiota metabolise choline/phosphatidylcholine and L-carnitine to produce trimethylamine, which is oxidised to pro-atherogenic trimethylamine-N-oxide (TMAO). 101,102 TMAO levels are elevated in people with HF.103 Further, TMAO levels have been correlated with BNP104 and associated with HF severity102–106 and HF mortality.103,104,106 Foods rich in L-carnitine (e.g. red meat)31,68,87-89 and choline/phosphatidylcholine (e.g. eggs)72 have been linked with HF incidence/severity. TMAO production may also explain the inconsistent effects observed with fish, dairy and poultry (all rich sources of choline). Interestingly, those eating primarily plant-based diets, with limited choline/phosphatidylcholine and L-carnitine ingestion, do not seem to produce significant quantities of TMAO, even after ingestion of

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Plant-based Diets to Prevent and Treat Heart Failure L-carnitine/choline.101 Consistent with the data presented herein, plantbased diets appear to have beneficial effects on the gut microbiome while Western diets that are high in animal products appear to have deleterious effects on the gut.

Specific to HF, the MedDiet has been associated with decreased oxidative stress.35 Further interventional data have reported decreased plasma N-terminal pro BNP levels, lower oxidised LDL and the prevention of lipoprotein(a) increase.37

Discussion There is growing evidence that nutrition might be a critical factor in HF incidence and progression. Although existing research is limited, it appears that plant-based diets high in antioxidants, micronutrients, dietary nitrate and fibre but low in saturated/trans fats and sodium are associated with decreased HF incidence/severity. It is likely that these dietary features contribute to decreased oxidative stress, lower homocysteine levels and reduced inflammation as well as to higher antioxidant defence, nitric oxide bioavailability and gut microbiome modulation. Based on studies such as these and mechanistic data, a 2005 review suggested that certain lifestyle measures – including plant-based diets (moderate to low in bioavailable phosphate) – might modulate parathyroid hormone secretion and reduce left ventricular hypertrophy as well as HF risk.107 Similarly, a 2014 editorial regarding a prospective study of processed/unprocessed red meat consumption and HF risk88

of these studies were large and prospective, they often enrolled limited cohorts, for example male physicians. Many existing studies included only one measurement of dietary intake. These studies can only provide associations as opposed to causation and cannot determine whether participants changed their diet during follow up.

Many studies assessed dietary intake via self-report, which is prone to misreporting.

There is a notable lack of interventional trials regarding HF. Existing interventional trials of plant-based diets in HF have reported improvements in cardiac function, myocardial energetics, functional capacity and quality of life, inferring a remarkable response.

Nevertheless, many existing intervention studies were pilot studies with small samples and short follow up.

Future Recommendations

suggested that plant-rich diets could lower HF incidence and severity.108

The potential role of nutrition in HF prevention and treatment was first suggested in the 1940s.46,47 The field has grown but remains limited. Future studies should take account of HF type and severity, pharmacology and co-morbidities. Adequately-powered sample sizes and relevant follow-up periods with investigator-blinded, randomised and controlled trials are urgently required. Dietary intake should ideally be assessed subjectively (e.g. with a food diary) and objectively (e.g. using nutritional biomarkers). Further, future studies should include women, older people and diverse ethnic groups, which have been largely neglected in existing HF nutritional research.

Limitations

Conclusion

This review has several important limitations. Although individual foods and nutrients were briefly introduced, the focus was on data relating to dietary pattern. Further, although some studies relating to overall CVD and its components (e.g. hypertension) were included, they were only included if HF was specifically mentioned and the overall focus was on data relating specifically to HF. Therefore, it is possible that relevant studies were not included in the review. Evidence regarding salt/sodium or fluid restriction, omega-3/micronutrient supplementation, chocolate, supplements, alcohol, over- or undernutrition and animal/cell model data was omitted. These major topics are outside the scope of this review. Further, studies of nutritional biomarkers were not included.

Considering the relative safety and low cost of dietary intervention, clinical trials are urgently needed to help elucidate the effect of dietary patterns and components on HF incidence and severity. A seminal 1999 editorial regarding the famous Lyon Diet Heart Study stated that “relatively simple dietary changes achieved greater reductions in risk of all-cause and coronary heart disease mortality in a secondary prevention trial than any of the cholesterol-lowering studies to date”.109 The editorial details the cost-effectiveness and high benefitto-risk ratio of dietary manipulation compared to drugs and invasive procedures and concludes that dietary factors must be very important.

The current review suggests that diet is important and, agrees with an expert editorial that states: “in our search for the silver bullet, we have overlooked the silver plate. It is regrettable that we remain so imprecise and ill-informed about a cornerstone in patient care. Diet is important. We can and should know more.”110

Study designs, cohorts and outcome measures were heterogeneous, limiting the ability to make comparisons across studies and draw conclusions. In addition, many of the studies included were pilot studies and may not have been adequately powered to see significance in the outcomes of interest.

Most available data are observational. Although reported observations could be real and are plausible, confounding is possible. Many reports included here were re-analyses of the same cohorts. Although many

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Erratum

Erratum to: Impact of Exercise Training on Peak Oxygen Uptake and its Determinants in Heart Failure with Preserved Ejection Fraction Wesley J Tucker,1 Michael D Nelson,1 Rhys I Beaudry,1 Martin Halle,2 Satyam Sarma,3,4 Dalane W Kitzman,5 Andre La Gerche6 and Mark J Haykowsky1,6 1. College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, Texas, USA; 2. Technical University Munich, Munich, Germany; 3 Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas; 4. University of Texas Southwestern Medical Center, Dallas, Texas, USA; 5. Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; 6. Sport Cardiology, Baker IDI Heart Institute, Melbourne, Victoria, Australia

Citation: Cardiac Failure Review 2018;4(1):62. https://doi.org/10.15420/cfr.2018.4.1.ER

For the paper entitled ‘Impact of Exercise Training on Peak Oxygen Uptake and its Determinants in Heart Failure with Preserved Ejection Fraction’, which appeared in Cardiac Failure Review 2016;2(2):95–101, author attributions read as: ‘Wesley J Tucker, Michael D Nelson, Rhys I Beaudry, Martin Halle, Satyam Sarma, Dalane W Kitzman, Andre La Gerche and Mark J Haykowksy’. The corrected authorship should be ‘Wesley J Tucker, Michael D Nelson, Rhys I Beaudry, Martin Halle, Satyam Sarma, Dalane W Kitzman, Andre La Gerche and Mark J Haykowsky’.

Mark Haykowsky’s name was incorrectly spelled. CFR apologises for the error.

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Supporting life-long learning for cardiovascular professionals Led by Editor-in-Chief Andrew JS Coats and underpinned by an editorial board of world-renowned physicians, Cardiac Failure Review is a peer-reviewed journal that publishes reviews. Available in print and online, Cardiac Failure Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

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