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Cardiac Failure Review Volume 2 • Issue 2 • Winter 2016

Volume 2 • Issue 2 • Winter 2016

www.CFRjournal.com

Cognitive Decline in Heart Failure: More Attention is Needed Jelena Cˇelutkiene, Ar uˉnas Vaitkevi Cˇius, Silvija Jakštiene and Dalius Jautužis

Should We Let Sleeping Dogs Lie? Controversies of Treating Central Sleep Apnoea in HFrEF Following the SERVE-HF Study Ali Vazir, Kostantinos Bronis and Simon Pearse

The Role of Cardiovascular Magnetic Resonance Imaging in Heart Failure Mark A Peterzan, Oliver J Rider and Lisa J Anderson

Complementary and Synergic Role of Combined Beta-blockers and Ivabradine in Patients with Chronic Heart Failure and Depressed Systolic Function: A New Therapeutic Option? Maurizio Volterrani and Ferdinando Iellamo

Ivabradine selectively inhibits the If current the sinus node

Sinus node The pacemaker of the heart

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Na+ Ivabradine

f-channel K+ ISSN: 2057-7540

Cerebral microbleeds

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−40 mv −70 mv Ivabradine reduces the slow diastolic depolarisation phase

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Volume 2 • Issue 2 • Winter 2016

www.CFRjournal.com

Editor-in-Chief Andrew JS Coats

William T Abraham

Alexander Lyon

Ali Ahmed

Theresa A McDonagh

The Ohio State University, USA

Imperial College London, UK

Washington DC VA Medical Center, USA

King’s College Hospital, UK

Inder Anand

Kenneth McDonald

John Atherton

Ileana L Piña

University of Minnesota, USA

St Vincent’s Hospital, Ireland

Royal Brisbane and Women’s Hospital, Australia

Montefiore Einstein Center for Heart & Vascular Care, USA

Michael Böhm

Saarland University, Germany

Kian-Keong Poh

National University Heart Center, Singapore

Alain Cohen Solal

Paris Diderot University, France

A Mark Richards

Henry J Dargie

University of Otago, New Zealand

Western Infirmary, Glasgow

Giuseppe Rosano

Carmine De Pasquale

St George’s University of London, UK

Flinders University, Australia

Jose Antonio Magaña Serrano

Frank Edelmann

National Medical Centre, Mexico

Charité University Medicine, Germany

Martin St John Sutton

Michael B Fowler

Hospital of the University of Pennsylvania, USA

Stanford University, USA

Allan D Struthers

Michael Fu

Ninewells Hospital & Medical School, UK

Sahlgrenska University Hospital, Sweden

Michal Tendera

David L Hare

University of Silesia, Poland

University of Melbourne, Australia

Michael Henein

Maurizio Volterrani

Adelino Leite-Moreira

Cheuk Man Yu

IRCCS San Raffaele Pisana, Italy

Heart Centre and Umea University, Sweden University of Porto, Portugal

The Chinese University of Hong Kong, Hong Kong

Managing Editor Lindsey Mathews • Production Jennifer Lucy • Senior Designer Tatiana Losinska Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director Mark Watson •

Editorial Contact Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

Cover image

©7activestudio | www.istockphoto.com

Design Tatiana Losinska

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Radcliffe Cardiology

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 © 2016 All rights reserved ISSN: 2057–7540 • eISSN: 2057–7559

© RADCLIFFE CARDIOLOGY 2016

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Established: March 2015 Frequency: Bi-annual Current issue: Winter 2016

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.

Submissions and Instructions to Authors • •

Structure and Format • •

• •

Cardiac Failure Review is a bi-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.

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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.

• •

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, Lindsey Mathews commeditor@radcliffecardiology.com

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

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

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. ■

© RADCLIFFE CARDIOLOGY 2016

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Contents

Foreword

78

Andrew JS Coats and Giuseppe Rosano

Clinical Practice

79

What the General Practitioner Needs to Know About Their Chronic Heart Failure Patientt

85

Transitional Care to Reduce Heart Failure Readmission Rates in South East Asia

90

Chagas Heart Failure in Patients from Latin America

Frans H Rutten and Joe Gallagher

Wan Xian Chan, Weiqin Lin, and Raymond Ching Chiew Wong

Reinaldo B Bestetti

Heart Failure with Preserved Ejection Fraction

95

Impact of Exercise Training on Peak Oxygen Uptake and its Determinants in Heart Failure with Preserved Ejection Fraction Wesley J Tucker, Michael D Nelson, Rhys I Beaudry, Martin Halle, Satyam Sarma, Dalane W Kitzman, Andre La Gerche and Mark J Haykowksy

102

Haemodynamics of Heart Failure With Preserved Ejection Fraction: A Clinical Perspective Mauro Gori, Attilio Iacovoni and Michele Senni

Comorbidities

106

Cognitive Decline in Heart Failure: More Attention is Needed

110

Depression in Patients with Heart Failure: Is Enough Being Done?

113

Should We Let Sleeping Dogs Lie? Controversies of Treating Central Sleep Apnoea in HFrEF Following the SERVE-HF Study

. . ˇ elutkiene, Aru Jelena C ˉ nas Vaitkevicˇ ius, Silvija Jakštiene and Dalius Jatužis

Amam Mbakwem, Francis Aina and Casmir Amadi

Ali Vazir, Kostantinos Bronis and Simon Pearse

Imaging

115

The Role of Cardiovascular Magnetic Resonance Imaging in Heart Failure Mark A Peterzan, Oliver J Rider and Lisa J Anderson

Therapeutics

123

The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelines

130

Complementary and Synergic Role of Combined Beta-blockers and Ivabradine in Patients with Chronic Heart Failure and Depressed Systolic Function: A New Therapeutic Option?

Ivan Milinkovic´, Giuseppe Rosano, Yuri Lopatin and Petar M Seferovic´

Maurizio Volterrani and Ferdinando Iellamo

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CARDIAC FAILURE REVIEW

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Sustained benefits to the failing heart SIMDAX® is: • a cardioprotective inodilator with a unique triple mechanism of action.1 SIMDAX® offers: • improved hemodynamics2-6 without a significant increase in oxygen consumption,7-8 • reduction of symptoms of acute heart failure,2,3,9,10 • sustained effects.5,9 1. 2. 3. 4. 5.

Papp et al. Int J Cardiol 2012 59(2):82-7. Follath et al. Lancet. 2002;360:196-202. Slawsky et al. Circulation. 2000;102:2222-7. Nieminen et al. J Am Coll Cardiol. 2000;36:1903-12. Kivikko et al. Circulation. 2003;107:81-6.

6. 7. 8. 9. 10.

Lilleberg et al. Eur J Heart Fail. 2007; 9:75-82. Lilleberg et al. Eur Heart J. 1998;19:660-8. Ukkonen et al. Clin Pharmacol Ther. 2000;68:522-31. Mebazaa et al. JAMA. 2007; 297:1883-91. Packer et al. JACC Heart Fail 2013; 1(2):103-11.

For effects of levosimendan on quality of life in Advanced Heart Failure, see Fruhwald S et al. Exp Rev Cardiovasc Ther 2016

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

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

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

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

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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 Georges University of London, UK

W

e have great pleasure in introducing the latest issue of Cardiac Failure Review to our readers. In the last few months the 2016 European Society of Cardiology (ESC)–Heart Failure Association Guidelines for the diagnosis and treatment of acute and chronic heart failure (CHF) were launched at the Heart Failure Association meeting in Florence, Italy. The guidelines have been very well accepted. A notable feature is the prominence now given to the important issue of comorbidities, a theme taken up strongly in this issue of Cardiac Failure Review. Experts cover topics of increasing relevance to the heart failure patient and carer alike as the importance of comorbidities is increasingly recognised, both because the HF population is aging and the frequency of multiple coexisting comorbidities progressively increases. We have an expert review of a very topical issue – given the surprise results of the SERVE-HF trial that studied Autoset maskbased therapy of central sleep apnoea in heart failure with reduced ejection fraction – by Ali Vazir and colleagues. Another crucial area for review includes the crucial role of the primary care practitioner in looking after CHF patients in an article by Frans H Rutten and Joe Gallagher. Two of the most troubling comorbidities that impact particularly older CHF patients are cognitive . ˇ elutkiene and colleagues) and depression (reviewed by Amam Mbakwem and colleagues). decline (reviewed by Jelena C

Given the important changes introduced by the most recent ESC guidelines this year, we also have expert updates on how to combine ivabradine and beta-blockers in HF patients by Maurizio Volterrani and colleagues, and a review of the role of ivabradine and trimetazidine in the new ESC HF guidelines by Petar Seferovic´ and colleagues. We hear also of the importance of transitional care planning if we are to reduce all-too-high rates of readmission during this vulnerable phase in the HF patient’s journey, illustrated with experience from a South East Asian perspective from Wan Xian Chen and colleagues. We also strongly recommend the excellent reviews of other important HF topics including the haemodynamics of heart failure with preserved ejection fraction by Michele Senni and colleagues, and the potential central and periphery benefits of exercise training in this enigmatic condition as reviewed by Mark Haykowsky and colleagues. A condition once confined to the footnotes of developed countries’ textbooks is now being seen with increased frequency, given increased South American migration to Europe and North America, that of Chagas heart failure. This condition is expertly reviewed by Reinaldo Bestetti. Finally, we whole-heartedly recommend the review of the role of cardiovascular magnetic resonance imaging in heart failure by Lisa Anderson, Oliver Rider and Mark Peterzan. We hope you will enjoy reading the whole issue as much as we did in helping assemble it. ■

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© RADCLIFFE CARDIOLOGY 2016

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Clinical Practice

What the General Practitioner Needs to Know About Their Chronic Heart Failure Patient F r a n s H Ru t t e n 1 a n d J o e G a l l a g h e r 2 1. Department of General Practice, Julius Center for Health Sciences and Primary Care, University Medical Center (UMC) Utrecht, Utrecht, The Netherlands; 2. Department of General Practice, Health Research Group, University College Dublin, Dublin, Ireland

Abstract In this article we highlight what general practitioners (GPs) need to know about heart failure (HF). We pay attention to its definition, diagnosis – with risks of under- and over-diagnosis – and the role natriuretic peptides, electrocardiography, echocardiography, but also spirometry. We stress the role of the GP in case finding and risk stratification with optimisation of cardiovascular drug use in high-risk groups. Epidemiological data are provided, followed by discussion of the management aspects and possibilities of cooperative care of patients with chronic HF, focussing on pharmacological treatment, comorbidities and end-of-life care. This article highlights the experience and clinical practice of the authors: specifics of local heart failure management, and the role of the GP, will naturally vary.

Keywords General practitioner, chronic heart failure, primary care, care pathway, diagnostic care, palliative care, co-operative care Disclosure: The authors have no conflicts of interest to declare. Received: 12 September 2016 Accepted: 6 October 2016 Citation: Cardiac Failure Review 2016;2(2):79–84. DOI: 10.15420/cfr.2016:18:1 Correspondence: Frans H Rutten, Julius Center for Health Sciences and Primary Care, UMC Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. E: F.H.Rutten@umcutrecht.nl

“I cannot keep pace with my husband. Is it simply ageing, overweight and my sedentary lifestyle?” This is a common encounter in primary care, bearing in mind that around 16 % of older community-dwelling people experience at least grade 3 shortness of breath according to the Medical Research Council questionnaire (“walk slower than people of the same age because of breathlessness or have to stop for breath when walking at my own pace on the level”).1

up-titration of cardiovascular (CV) drugs of high-risk people from the community, e.g. those with a previous coronary event, hypertension or type 2 diabetes, effectively reduces the development of HF and CV hospitalisations. Early initiation or up-titration of angiotensinconverting enzyme inhibitors (ACE-inhibitors), angiotensin receptor blockers (ARBs) and beta-blockers has been shown to be effective in this group.5,6

Heart failure (HF) is a common syndrome, predominantly occurring in the elderly, with a significant impact on quality of life, high mortality rates and unplanned hospitalisations that place a significant burden on health care systems and budgets in developed countries.2 General practitioners (GPs) play an important role in the disease trajectory of a patient with HF. In particular, GPs have a pivotal role in the diagnostic and palliative phase, and participate in co-operative care with specialist teams in the intervening period.

GPs should be prepared for this transition in care. Here, the authors give a framework for the potential role of GP in HF care throughout the natural history of the condition (see Figure 1).

Three important reasons underlie the gradual shift from hospitalbased care to primary care being seen in many developed countries. First, in the last decade, heart failure with a preserved ejection fraction (HFpEF) is increasing, while the prevalence of heart failure with a reduced ejection fraction (HFrEF) is decreasing. For HFpEF, hospital care is in general not necessary, except in cases with acute exacerbations, and it is characterised by multiple comorbidities, which benefit from generalist care. A second reason is that governments are increasingly shifting chronic disease care to primary care, given international evidence on cost-effectiveness. Studies have shown that if HFrEF patients are adequately up-titrated, the care provided by GPs is as good as that of a HF clinic.3,4 A final reason is that risk stratification with natriuretic peptides and

© RADCLIFFE CARDIOLOGY 2016

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Definition, Diagnosis, Case Finding and Risk Stratification A diagnosis of HF requires a combination of clinical features – such as breathlessness, fatigue and ankle oedema – together with a structural or functional abnormality of the heart that impairs its ability to pump or relax on echocardiography.2,7 Pump failure may be caused by reduced contraction of the left ventricle, measured as a reduced ejection fraction (EF; <40  %). Reduced EF is almost always accompanied by impaired filling of the left ventricle, but in some patients reduced filling dominates whereas the EF is normal. This failure of relaxation of the heart in diastole and reduced filling is termed HF with preserved EF (≥50 %).7 The updated European Society of Cardiology (ESC) guidelines on HF have recently introduced an ‘in-between’ category; HF mid-range EF (HFmrEF; EF 40–49 %), which typically has features of both HFrEF and HFpEF.2 HFrEF is best understood. It typically develops after myocardial infarction, when myocyte loss results in left ventricular (LV) dilatation

Access at: www.CFRjournal.com

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Clinical Practice Figure 1: Potential Role of GP in Heart Failure Care (HF) Throughout the Natural History of the Condition

Prevention

Diagnosis

Optimal management risks factors, e.g. hypertension, type 2 diabetes and hyperlipaedemia

Suggestive symptoms 1. elevated natriuretic peptides: referral for echocardiography 2. Natriuretic peptides below exclusionary cutpoint: consider other disease.

Risk stratification of CV risk patients with natriuretic peptides; guide who may require intensive therapy

Pitfalls spirometry (unrecognized heart failure can give obstructive pattern) ECG helps identify causes or consequences of heart failure e.g. atrial fibrillation

Stable HF Cooperative care with cardiologist in HFrEF and HFmrEF Titration of diuretics and blood pressure control in HFpEF Regularly ECG for QRS width Referral for admission: Exacerbations of HFrEF, HFmrEF, HFpEF:

(suspected) acute HF Pre-hospital: initiate nitrates sl, loop diuretics, possibly opioids and oxygen

End of life care Often patients die with rather than from heart failure often unpredictable for individual patients

Disease trajectory of heart failure

and diminished contraction.7,8 HFpEF may develop after longstanding hypertension, but also in those with obesity and type 2 diabetes.8 Compensatory myocardial stiffening results in reduced filling capacity of the normal sized or even small left ventricle. This leaves a ventricle with an EF in the normal range but a reduced stroke volume.7 Patients with HFpEF may have particularly bothersome symptoms during exercise.7,8

Overdiagnosis and Underdiagnosis Especially in the early stages, the detection of any type of HF is difficult because symptoms and signs are non-specific. Breathlessness, a key symptom of HF, may be confused with chronic obstructive pulmonary disease (COPD), obesity or deconditioning.7 Signs are mostly related to fluid overload and include elevated jugular venous pressure, pulmonary crackles and ankle oedema, but fluid overload may be absent, particularly in patients receiving diuretics for hypertension.2 A displaced or broadened/sustained apex beat is suggestive of HF, but palpation of the apex beat is infrequently performed nowadays in clinical practice.7 Fluid overload (backward failure) and compensation or adaptation of the heart (increased heart rate abnormal apex beat), or reduced oxygen delivery to metabolising tissues (forward failure) may result in symptoms or signs, but these may be hard to recognise, e.g. mild cognitive impairment, muscle fatigue or delayed recovery after exercise. Also, important possible causes (or consequences) of HF may be found on examination, e.g.a cardiac murmur. It should be noted that, especially in early HF, symptoms may be transient rather than present all the time. Other important aspects come from the patient’s history: ischaemic heart disease, particularly prior myocardial infarction, type 2 diabetes and hypertension should trigger the GP to ask for symptoms suggestive of HF. These problems with key clinical features may lead to underdiagnosis, as was clearly shown by the high prevalence rates of unrecognised HF (constituting up to 80  % of all HF cases) in high-risk community populations, e.g. older people with breathlessness, type 2 diabetes or COPD from primary care.9–11 When these patients present to the GP, symptoms that could suggest HF may not be recognised as such or may be confused with other diagnoses, and also not reported by the patients themselves. Moreover, atypical presentation or comorbidities can complicate identification of HF. For instance, in a patient diagnosed with COPD, it may be unclear whether progression of shortness of

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breath is due to COPD or HF.12 Thus, case finding strategies in primary care yield a high proportion of patients with previously unknown HF, and notably HFpEF. This is an important issue when it comes to treatment (see below). On the other hand, overdiagnosis also exists, although this seems to be an issue of less significance in primary care with around 17 % incorrectly labelled with HF.13,14

Risk Stratification Results from two randomised controlled trials (RCTs) provide us with encouraging results that a preventive strategy in high-risk CV patients may be effective.5,6 Both studies showed that ‘asymptomatic’ (or not mentioned symptoms spontaneously) type 2 diabetes patients, and people who have established CV risk factors or disease could be stratified with B-type natriuretic peptides (BNPs). Those with a BNP >50 pg/mL or N-terminal pro-B-type natriuretic peptide (NTproBNP) >125 pg/mL had positive outcomes if intensively treated with renin–angiotensin–aldosterone system (RAAS) inhibitors.5,6 In the St. Vincent’s Screening to Prevent Heart Failure (STOP-HF) trial, this resulted in a reduction in LV dysfunction with or without HF; 5.3 % in the intervention arm compared with 8.7 % in the care as usual group (odds ratio 0.55, p=0.003). Also, the incidence rate of emergency hospitalisation for major CV events decreased by the intervention.5 In the Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients (PONTIAC) trial in which patients were up-titrated to maximal tolerated renin–angiotensin system (RAS) inhibitors and beta-blockers, the primary endpoint hospitalisation/death due to cardiac disease at 2 years was significantly reduced compared with care as usual (hazard ratio 0.35 (95 % CI [0.13–0.98]; p<0.044).6

Respiratory Symptoms and Abnormal Spirometry Symptoms such as breathlessness, cough and wheezing may not necessarily reflect pulmonary disease. HF, and as a result fluid in the lungs, can cause wheezing by the fluid compression from outside the bronchioles. In the case of asthma and COPD, the mainly expiratory obstruction comes from the muscular layer around the bronchioles, or from leucocyte accumulation and inflammation inside the bronchioles, giving the same symptomatology. It is therefore important to consider that wheezing can have a cardiac origin as well. A similar pitfall should be acknowledged with respect to spirometry. In the presence of clinically detectable pulmonary fluid overload, e.g. pulmonary crepitations or ankle oedema, patients with (unrecognised) HF have a greater reduction in forced expiratory volume in 1 second (FEV1) than in the forced vital capacity (FVC).15 Since a diagnosis of COPD is based on ‘obstruction’ with spirometry, operationalised as FEV1/FVC <70  %, patients with (unrecognised) HF may remain undetected and can be labelled as COPD. Thus, overdiagnosis of COPD can occur at the cost of missing HF.15–17 Spirometry should therefore only be performed in stable and euvolemic patients, to prevent overdiagnosis of COPD.15

Additional Tests: Natriuretic Peptides, Electrocardiography and Imaging When HF is suspected on the basis of medical history and signs and symptoms, additional diagnostic investigations are required to exclude HF, or select those who need further testing and identify whether the HF is associated with a reduced or preserved EF. Echocardiography can either be performed right away if a patient is known to have a prior myocardial infarction or atrial fibrillation (AF), or based on the result of natriuretic peptide assays and electrocardiography.2

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The General Practitioner and the Chronic Heart Failure Patient

For primary care, rather low exclusionary cut-off values for natriuretic peptide levels are recommended by the ESC guidelines on HF.2 These are set so that the likelihood of HF is low if values are below the cutoff point.2,18–23 Exclusionary cut-off values of <125 pg/mL for NTproBNP and BNP <35 pg/mL are recommended in the ESC guidelines,2 while the National Institute for Health and Care Excellence (NICE) in the UK recommends 400 pg/mL and 100 pg/mL, respectively.24 When applied in the primary care setting, 125 pg/mL for NTproBNP results in a negative predictive value of over 99 % at the cost of many more echocardiograms than a cut-off value of 400 pg/mL, which has a negative predictive value of about 97  %.18 Missed cases will mainly be those with HFpEF.18 Using low cut-off points for non-acute patients suspected of HF is useful in the light of the lower a priori chance of disease and, most importantly, because of the milder severity of the disease than in acute breathlessness.2,18 It should be noted that in the case of non-acute breathlessness, other causes may underlie elevated NTproBNP levels, including AF, age over 75 years, renal impairment and LV hypertrophy, but not mild-to-moderate COPD.2,7 B-type natriuretic peptides (BNP and NTproBNP) are produced by myocytes in response to increased wall stress, which is in general lower in HFpEF than in HFrEF, in line with Laplace’s law (wall tension=pressure x radius/wall thickness).7 With similarly elevated LV pressures, the wall stress and thus production of B-type NPs is lower in HFpEF because the diameter of the ventricle is smaller and wall thickness higher (concentric remodelling), while in HFrEF the left ventricle is dilated and its wall thinned (eccentric remodelling). Moreover, B-type NPs may normalise in 24 hours and thus BNP and NTproBNP may be in the normal range when measured a day or more after the patient has visited the GP for symptoms of breathlessness during exercise.25,26 If a patient has natriuretic peptide levels above the cut-off values, echocardiography is usually indicated as the next step in the diagnostic process. Open access echocardiography is still not available to most primary care physicians. This could be a useful means to bring earlier diagnosis of HF to primary care. With echocardiography, HFrEF can be distinguished from HFpEF and HFmrEF. For HFrEF, the single measurement of a left ventricular ejection fraction (LVEF) <40  % is widely accepted (preferably seen in combination with a dilated left ventricle).2 For HFpEF, the description and ranges for abnormal parameters is still debated and is currently defined by expert consensus. Most consider a combination of measurements are needed, including: • • • •

a (nearly) normal EF; left atrial enlargement; increased LV mass or wall thickness; and raised LV filling pressures.2,7

Assessing diastolic dysfunction is even more unclear as measuring LV filling non-invasively with echocardiography in particular is difficult.7 Other investigations, such as the electrocardiogram (ECG), chest X-ray and other blood tests other than natriuretic peptides might also be considered in the diagnostic work-up of a patient with possible HF. An ECG is useful to detect possible causes and consequences of HF, such as AF. Chest X-ray is not very helpful, unless in the case of clear fluid overload. In that situation, however, signs and symptoms generally already point in the same direction. Chest X-ray

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is not worthwhile for diagnosing COPD, but may help to diagnose or exclude pulmonary malignancy. 2 Blood tests other than B-type NPs can be useful to rule out precipitating factors such as thyroid disease or anaemia, measure modifiable CV risk factors such as cholesterol and assess baseline liver and renal function prior to initiating treatment. Overall, history taking and investigation of signs and symptoms is very important in primary care. Of additional tests, natriuretic peptides are most informative and valuable.18–20,23 High-risk patients (e.g. type 2 diabetes, COPD) may benefit from risk stratification based on B-type NPs and case finding.

When to Refer a Patient The decision to refer a patient will depend on the individual expertise of the GP and the organisation of the health care system. Most guidelines advocate an initial specialist assessment to make the formal diagnosis of HF. Once a definitive diagnosis is reached, specialists may initiate HF medication or this may be done by the GP. Consideration of device therapy is usually done at the specialist level based on parameters including EF and widening of the QRS on the ECG. Referral for rehabilitation may also be via specialist or GP teams.

Prevention of Heart Failure The 2013 European Society of Hypertension/ESC guidelines for the management of arterial hypertension state that hypertension is the most important attributable risk factor for developing HF.27,28 Preventing HF is the largest benefit associated with blood pressurelowering drugs. This was seen in treatment with diuretics, betablockers, ACE inhibitors and ARBs.29 The elderly are no exception.30 Thus, adequately addressing high blood pressure in primary care is important to prevent development of HF. Optimal treatment of other CV risk factors such as hypercholesterolaemia and type 2 diabetes through pharmacological and lifestyle interventions is also important to prevent HF. Timely management of myocardial infarction to reduce muscle loss may also help to reduce the number of patients developing LV dysfunction in the longer term.

What is the Prevalence of Heart Failure? Although, the ESC guidelines on HF mention a prevalence of 1–2 % in the general population, a recent systematic review suggests that it is closer to 4 %.2,31 Reports based on hospitalised patients suggest that around 50 % of the patients have HFpEF and 50 % have HFrEF, with a time trend towards an increase in HFpEF.32,33 Population prevalence data among adults aged 65 years or over living in the community with HF found that around 75 % had HFpEF and 25 % had HFrEF.34

What is the Prognosis? The prognosis of HF, a chronic progressive disease, depends on the point in time the diagnosis is made (early or late in the disease trajectory) and thus the severity of the disease. Around one in 10 will have died five years after diagnosis, rising to around one in three for cases first detected during hospitalisation.7,35,36 As a comparison, the five year mortality of colon cancer is around one in three.

How Should Heart Failure be Managed? Lifestyle interventions, pharmacological therapies, devices and multidisciplinary disease management programmes can relieve symptoms, improve prognosis and optimise quality of life of patients

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Clinical Practice with HFrEF.2 For HFpEF, clear mortality-reducing drugs are not yet available. Based on expert opinion, it is recommended to use loop diuretics to keep the patient euvolemic with careful titration, encourage aerobic exercise, optimise blood pressure control and control of heart rate in AF.2,37 From a health care system viewpoint, it is also important to manage costs, which can particularly be achieved by preventing hospital admissions where possible.38 It is vital that patients with HF, and their carers where applicable, understand their condition and are actively involved in management decisions, and to encourage self-care. eHealth strategies may be supportive in this regard. Patients should be encouraged to avoid overuse of salt, follow a healthy diet, adhere to prescribed drugs and do regular exercise. For patients with more advanced HFrEF, interventions such as daily weighing and fluid restriction (<1,500  mL/day) may be required. In patients with an EF <35  % after optimising therapy, an implantable cardioverter-defibrillator (ICD) may be considered to prevent sudden death. In those with an EF <35  % and QRS duration >130 ms, cardiac resynchronisation therapy might be considered by the cardiologist.2 Pharmacological therapies are the mainstay of treatment in HF and will be more closely considered below.

Pharmacological Treatment Loop diuretics are essential to relieve symptoms, particularly in acute situations, for HFrEF, HFmrEF or HFpEF. Most patients once stabilised still require ongoing diuretics, although often at a lower dosage. These are the only drugs that can adequately remove fluid from the body in those with congestion. In those with HFrEF, up-titration of ACE inhibitors (or ARB when ACE inhibitors are not tolerated; dry cough in up to 5  % of cases) and beta-blockers should follow. Additionally, mineralocorticoid receptor antagonists (MRAs), such as spironolactone or eplerenone can also be added in patients who remain symptomatic.2 Diuretic use may be temporarily discontinued or reduced if patients are up-titrated with RAS inhibitors and beta-blockers, but the majority of patients will need to continue taking diuretics at some level. If after this combination of therapies, patients still have symptoms, or have a LVEF <35  % and a broad QRS complex on the ECG, and/or a LVEF <30 %, further management should be done by the cardiologist (such as the fitting of cardiac synchronisation devices or ICD). If symptoms (New York Heart Association [NYHA] class II–IV) still persist despite the use of these three drugs plus diuretics, some patients may benefit from ivabradine, which slows heart rate through a mechanism independent of beta-blockers, if they are in sinus rhythm, LVEF <35 % and their heart rate is >70 beats/min.2 As already mentioned, patients with HFpEF benefit from adequate titration of diuretics, which can give important symptom relief.2 Drugs acting on the RAS that yield good results in HFrEF, such as ACE inhibitors and ARBs, have not shown clear benefits in HFpEF.39–41 MRAs, however, may play a role in the future. In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, the MRA spironolactone was compared with placebo. Overall, it did not reduce the incidence of the composite of death from CV causes, aborted cardiac arrest or hospitalisation for the management of HF (HR 0.89; 95  % CI [0.77–1.04]), but it did lower the incidence of first and total number of HF hospitalisations.

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Also, an interaction by inclusion stratum and region was seen, with no favourable effects in Russia/Georgia (HR 1.10; 95 % CI [0.79–1.51]), but a favourable profile was seen on the primary outcome in the US, Argentina and Brazil (HR 0.82; 95  % CI [0.69–0.98]) where most included patients that had an elevated natriuretic peptide level at inclusion.42 Thus, the TOPCAT trial does not give conclusive evidence on the use of spironolactone in HFpEF, but it may hint at a benefit for patients with elevated natriuretic peptide levels.

Novel Treatment Option A new drug class has recently emerged for the management of patients with HF with reduced EF. The so-called angiotensin receptor neprilysin inhibitor (ARNI) class currently has one drug available for clinical use. Sacubitril-valsartan (formerly known as LCZ696), exerts a dual action; it consists of an ARB (valsartan) and a neprilysin inhibitor (which inhibits the enzyme that breaks down active BNP). It acts to reduce sympathetic tone, aldosterone levels and sodium retention, through inhibition of the overactive RAS by an ARB while simultaneously potentiating the effect of the protective vasoactive neuropeptide BNP through neprilysin inhibition. Sacubitril-valsartan (formerly known as LCZ696), was evaluated in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial in comparison with enalapril 10 mg twice daily.43 After 27 months of follow-up, the trial was stopped early due to positive interim results. In symptomatic patients with HFrEF (LVEF <40  %, BNP >150 pg/mL, mean age 63.8 years), who were treated with ACE inhibitor or ARB, and other background HF therapies such as beta-blockers and MRAs, the absolute risk of the composite of CV mortality and hospitalisation for HF was reduced by 4.7  % (21.8 versus 26.5  %, relative risk reduction 20  %) with sacubitril-valsartan versus enalapril in HFrEF patients on optimal HF background therapy. All-cause mortality was 17.0 % with the ARNI as compared with 19.8 % with enalapril, yielding a hazard ratio of 0.84 (95 % CI [0.72–1.31]; p<0.001).43 It should be noted that relative to primary care practice, included patients were relatively young and 21 % were female. Moreover, as a consequence of a run-in phase in the trial design, only patients who could tolerate ACE inhibitor and ARB were enrolled. Indeed, not many adverse effects were reported. Data from the Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) trial comparing sacubitril-valsartan with valsartan in HFpEF, showed that ARNI reduced NT-proBNP levels, left atrial volume index and increased the estimated glomerular filtration rate (eGFR), more so than with valsartan alone, independent of its systolic blood pressure-lowering effect.44 The potential benefit of an ARNI in HFpEF is investigated further in the ongoing Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients with Preserved Ejection Fraction (PARAGON) trial. Sacubitril-valsartan may not be prescribed by GPs in the following years, but this may change in the future.

Renal Function Managing patients with HF requires careful monitoring and prescribing. In particular, balancing the use of (loop) diuretics and their adverse effect on kidney function can be challenging. To help safely manage these patients, prerenal dysfunction should be distinguished from post-

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renal dysfunction. In prerenal dysfunction, the patient is dehydrated, due to the use of too high a dosage of diuretics, which causes the blood pressure in the kidney to be too low to filtrate. On the other hand, in post-renal dysfunction, there is too much fluid (venous congestion) and consequently too much venous pressure on the kidney. Both situations lead to decreased kidney function, more so with venous congestion. Practically, this means that patients who are overloaded should receive diuretics and this can have a beneficial effect on kidney function. GFR may even increase as a result. Caution is needed where the patient is already on diuretic treatment – giving too high a dose can lead to kidney under-perfusion and thus further deterioration in renal function. Urea and GFR together with a check of the patient’s fluid status by physical examination using parameters such as postural drop in blood pressure can help to monitor and adjust diuretic dosing. It is important to ensure that patients are not on other medications, which can adversely affect renal function and decrease effectiveness of diuretics such as nonsteroidal anti-inflammatory drugs.

Patients (EMPA-REG OUTCOME) showed that empagliflozin (an inhibitor of sodium-glucose cotransporter [SGLT-2] in the kidney) added to metformin for glucose-lowering had beneficial prognostic CV effects (CV mortality, non-fatal myocardial infarction and non-fatal stroke) compared with placebo in patients with diabetes and CV disease.46 Subgroup analysis has suggested that the benefit was consistent for patients with and without HF.47 AF and HF are both common in older people and often co-occur. Up to 50 % of those with AF may have HF, and because B-type NP is also elevated by AF itself, echocardiography should be considered to detect or exclude co-existing HF in those presenting with AF. In patients with HFrEF and AF, a recent individual patient data (IPD) meta-analysis of landmark HFrEF trials with betablockers showed that in general, those with HFrEF and AF seem not to benefit, while those in sinus rhythm do.48 Further research will provide us an answer whether this effect is related to the heart rate achieved with beta-blockers in those with HFrEF and AF.

Organisation of Care Acute Heart Failure When a patient presents with acute shortness of breath, high respiratory rate and lung crackles, immediate hospitalisation is required. However, in such suspected acute HF (AHF) cases, the following steps can be considered by the GP before the ambulance arrives, but only if they have the equipment, expertise and feel confident to do so: • When systolic blood pressure >110 mmHg: sublingual nitroglycerin for immediate relief of breathlessness through venodilatation. • Furosemide 40 mg intravenously (iv), and in those already on a loop diuretic an even higher dosage may be used, while awaiting the ambulance and the cardiologist (note that furosemide needs about 20 minutes to work). • When oxygen saturation <92  %: titrate oxygen administration to achieve an oxygen saturation >92 %. This can be vital for immediate survival, but should not be provided routinely in those with oxygen saturations >92  %. This is because oxygen administration can cause vasoconstriction and a reduction in cardiac output. In COPD, hyperoxygenation may also increase the ventilation–perfusion mismatch, suppressing ventilation leading also to hypercapnia. • When severely agitated: 5 mg morphine slowly iv can help reduce dyspnoea through venodilatation. • Some pre-hospital systems may use continuous positive airways pressure to help improve oxygenation and reduce respiratory distress.

Heart Failure, Non-cardiac Comorbidities and Atrial Fibrillation GPs have a particularly important role in overseeing the overall health status of patients. They are the physicians most aware of non-cardiac comorbid conditions. Treating such co-morbidities may improve HF symptoms. It should be noted, however, that effects of improving symptoms compared with improving prognosis may need to be carefully balanced. For instance, the Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial showed that addressing central sleep apnoea, which is common in HFrEF with mask ventilation improved symptoms, but prognosis was worse.45 Importantly, cardioselective beta-blockers may be prescribed in patients with comorbid COPD. In those with comorbid type 2 diabetes, metformin is the preferred drug. Recently, the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus

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Various examples of co-operative care have been developed across Europe. Often patients with HFrEF are managed in the hospital outpatient clinic for 3–6 months after diagnosis, to titrate medication to optimal doses. Hospital and community-based HF nurses can play an invaluable role in management and education of patients. Although current guidelines recommend outpatient follow-up in specialised HF clinics, the optimal duration of these programmes has not been established, nor whether all or only high-risk patients would benefit. The randomised Danish NorthStar trial compared extended follow-up of stable patients on optimal medical therapy in the HF clinic with referral back to the GP.3 After a median follow-up of 2.5 years, no differences were seen in time to death or hospital admission with a CV problem (HR 1.17; 95  % CI [0.95–1.45]; p=0.149 HF outpatient clinics versus GPs), nor in any of the secondary outcomes of mortality, HF admission, quality of life, number of days admitted and number of admissions.3 Also, high-risk patients, as identified by NT-proBNP >1,000 pg/mL did not benefit from follow-up in a HF clinic, as compared with referral to their GP.3 The Dutch Comparative Study on Guideline Adherence and Patient Compliance in Heart Failure Patients (COACH-2) study also found no difference between follow-up in primary care versus in a HF clinic, in the number of deaths and CV hospital admissions. Guideline adherence was assessed by the guideline adherence indicator (GAI-3) as well as patient adherence (medication possession ratio [MPR]), and no differences were observed after 12 months.4 Both studies conclude that HFrEF patients can be referred back to primary care after initial management in hospital. The COACH-2 study group points out that, given the complexity of the HF syndrome and its comorbidities, close collaboration between health care providers is crucial to provide optimal, integrated care.

The Role of the General Practitioner in End-of-Life Care Special attention should be dedicated to the last phase of life of HF patients. In a Dutch study, most elderly patients with HF (mean age 82.3 years) did not visit the cardiology outpatient clinic frequently in their last year of life (0.4 times), while home visits by the GP were more important (12.1 visits in last year).49 Of note, in the Netherlands, most (55.9  %) HF patients passed away at home or in a home for the elderly. Among those who died in hospital (32.6  %), only a small part died on the cardiology ward (5.8  % of total). Thus, most patients die

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Clinical Practice with, not of, HF. Causes of death in this study were sudden death (28 %), progressive HF (23 %), cancer (20 %) or other causes (29 %).49 It is important to realise that there is tremendous individual variation in the disease trajectory of HF. One cannot know when the palliative phase starts; patients generally do not follow a gradual downward path. Some feel and function quite well and die suddenly, while others may follow an upward path after a period of poor quality of life. Diverse and multiple

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comorbidities further complicate the disease trajectory, warranting regular monitoring. Thus, the GP plays a crucial role and should lead the end-of-life care of patients with HF.

Conclusion HF is a complex condition of increasing prevalence that requires the input of GPs as well as specialist services to ensure patients receive best care across the disease spectrum, from prevention to end-of-life care. ■

18. Taylor CJ, Roalfe AK, Tait L, et al. Observational longitudinal cohort study to determine progression to heart failure in a screened community population: the Echocardiography Heart of England Screening Extension (ECHOES-X) study. BMJ open 2014;4 :e005256. DOI: 10.1136/bmjopen-2014005256 19. Zaphiriou A, Robb S, Murray-Thomas T, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart Fail 2005;7 (4):537–41. DOI: 10.1016/j.ejheart.2005.01.022; PMID: 15921792 20. Fuat A, Murphy JJ, Hungin AP, et al. The diagnostic accuracy and utility of a B-type natriuretic peptide test in a community population of patients with suspected heart failure. Br J Gen Pract 2006;56 (526):327–33. PMID: 16638247; PMCID: PMC1837840 21. Nielsen LS, Svanegaard J, Klitgaard NA, Egeblad H. N-terminal pro-brain natriuretic peptide for discriminating between cardiac and non-cardiac dyspnoea. Eur J Heart Fail 2004;6 (1):63–70. DOI: 10.1016/j.ejheart.2003.10.003; PMID: 15012920 22. Gustafsson F, Steensgaard-Hansen F, Badskjaer J, et al. Diagnostic and prognostic performance of N-terminal ProBNP in primary care patients with suspected heart failure. J Card Fail 2005;11 (5 Suppl):S15–20. PMID: 15948095 23. Kelder JC, Cowie MR, McDonagh TA, et al. Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis. Heart 2011;97 (12):959–63. DOI: 10.1136/hrt.2010.220426; PMID: 21478382 24. National Institute for Health and Care Excellence. Chronic heart failure: management of adults with chronic heart failure in primary and secondary care (partial update) (Clinical guideline 108). 2010. Available at: www.nice.org.uk/CG108 (10 October 2016). 25. Mottram PM, Haluska BA, Marwick TH. Response of B-type natriuretic peptide to exercise in hypertensive patients with suspected diastolic heart failure: correlation with cardiac function, hemodynamics, and workload. Am Heart J 2004;148 :365–70. DOI: 10.1016/j.ahj.2004.02.012; PMID: 15309010 26. Maisel AS, Shah KS, Barnard D, et al. How B-Type Natriuretic Peptide (BNP) and Body Weight Changes Vary in Heart Failure With Preserved Ejection Fraction Compared With Reduced Ejection Fraction: Secondary Results of the HABIT (HF Assessment With BNP in the Home) Trial. J Card Fail 2016;22 :283–93. DOI: 10.1016/j.cardfail.2015.09.014; PMID: 26433086 27. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34 :2159–219. DOI: 10.1093/eurheartj/eht151; PMID: 23771844 28. Tocci G, Sciarretta S, Volpe M. Development of heart failure in recent hypertension trials. J Hypertens 2008;26 :1477–86. DOI: 10.1097/HJH.0b013e3282fe1d3d; PMID: 18551026 29. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood pressure lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362 :1527–35. PMID: 14615107 30. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358 (18):1887–98. DOI: 10.1056/NEJMoa0801369; PMID: 18378519 31. van Riet EE, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail 2016;18 (3):242–52. DOI: 10.1002/ejhf.483; PMID: 26727047 32. Owen 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

33. Gerber Y, Weston SA, Redfield MM, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med 2015;175 :996–1004. DOI: 10.1001/jamainternmed.2015.0924; PMID: 25895156; PMCID: PMC4451405 34. Mureddu GF, Agabiti N, Rizzello V, et al. Prevalence of preclinical and clinical heart failure in the elderly. A population-based study in Central Italy. Eur J Heart Fail 2012;14 :718–29. DOI: 10.1093/eurjhf/hfs052; PMID: 22562498 35. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients with heart failure with preserved 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 36. Boonman-de Winter LJ, Hoes AW, Cramer MJ, et al. Prognosis of screen-detected heart failure with reduced and preserved ejection fraction in patients with type 2 diabetes. Int J Cardiol 2015;185 :162–4. DOI: 10.1016/j.ijcard.2015.03.120; PMID: 25796002 37. Pandey A, Parashar A, Kumbhani D, et al. Exercise training in patients with heart failure and preserved ejection fraction: A meta-analysis of randomized controlled trials. Circ Heart Fail 2015;8 :33–40. DOI: 10.1161/CIRCHEARTFAILURE.114.001615; PMID: 25399909; PMCID: PMC4792111 38. Stewart S, Jenkins A, Buchan S, et al. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail 2002;4 (3):361–71. PMID: 12034163 39. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27 :2338–45. DOI: 10.1093/eurheartj/ehl250; PMID: 16963472 40. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359 :2456–67. DOI: 10.1056/NEJMoa0805450; PMID: 19001508 41. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARMPreserved Trial. Lancet 2003;362 :777–81. DOI: 10.1016/S01406736(03)14285-7; PMID: 13678871 42. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370 (15):1383–92. DOI: 10.1056/NEJMoa1313731; PMID: 24716680 43. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371 (11):993–1004. DOI: 10.1056/NEJMoa1409077; PMID: 25176015 44. Jhund PS, Claggett B, Packer M, et al. Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur J Heart Fail 2014;16 (6):671–7. DOI: 10.1002/ejhf.76; PMID: 24692284 45. Yogasundaram H, Oudit GY. Increased mortality Associated With Adaptive Servo-Ventilation Therapy in Heart Failure Patients With Central Sleep Apnea in the Halted SERVEHF Trial. Can J Cardiol 2015;31 (9):1202–3. DOI: 10.1016/j. cjca.2015.07.712; PMID: 26321438 46. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373 (22):2117–28. DOI: 10.1056/ NEJMoa1504720; PMID: 26378978 47. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J 2016;37 (19):1526–34. DOI: 10.1093/eurheartj/ ehv728; PMID: 26819227; PMCID: PMC4872285 48. Kotecha D, Holmes J, Krum H, et al. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individualpatient data meta-analysis. Lancet 2014;384 :2235–43. DOI: 10.1016/S0140-6736(14)61373-8; PMID: 25193873 49. Rutten FH, Heddema WS, Daggelders GJ, Hoes AW. Primary care patients with heart failure in the last year of their life. Fam Pract 2012;29 (1):36–42. DOI: 10.1093/fampra/cmr047; PMID: 21810902

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Clinical Practice

Transitional Care to Reduce Heart Failure Readmission Rates in South East Asia W a n X ia n C ha n , We i q i n L i n , a n d Ra y m o n d Ch i n g Ch i e w Wo n g Cardiac Department, National University Heart Centre, Singapore

Abstract Heart failure (HF) is an emerging public health problem due to increasing hospitalisations, readmissions and direct healthcare costs. Transitional care (TC) aims to improve multidisciplinary care coordination in HF and provides a streamlined strategy to ensure discharge success. This article reviews the different TC models and interventions in HF, and compares their strengths, weaknesses and efficacies. Notably, a nurse-led TC model under the direct administration of a dedicated multidisciplinary team appears to be the superior model of care. The emerging use of remote technology to track patient progress adds value, as human resources are scarce. Several knowledge gaps are highlighted in this article. The authors share their local institutional TC experience and discuss its early impact on HF care.

Keywords Heart failure, transitional care, multidisciplinary care coordination, South East Asia, models of care Disclosure: The authors have no conflicts of interest to declare. Received: 26 May 2016 Accepted: 17 August 2016 Citation: Cardiac Failure Review 2016;2(2):85–9. DOI: /10.15420/cfr.2016:9:2 Correspondence: Assistant Professor Chan Wan Xian, Cardiac Department, National University Heart Centre, Singapore, 5 Lower Kent Ridge Road, 119074 Singapore; E: wan_xian_chan@nuhs.edu.sg

Southeast Asian nations are increasingly facing a higher burden of cardiovascular risk factors,1 which in turn correlate with a propensity towards cardiac-related diseases including heart failure (HF). In Singapore, HF is the most common cardiac cause of hospitalisation, accounting for 17 % of all cardiac admissions.2 In 2015, public hospitals recorded in excess of 5,700 unique HF admissions.3 The objectives of this paper are to describe unique transitional interventions used in our programme to reduce HF readmissions, to discuss the impact of resource utilisation, and draw comparisons with published literature on transitional care (TC).

rates. The role of TC is to bridge gaps in patient management during the transition from acute hospital care to home and community care. A review of existing, varied TC programmes revealed common intervention themes and strategies, including early admission assessment, medication reconciliation, patient education, caregiver inclusion, telephone follow-up, home visits, handovers to post-hospital care providers and early follow-up.10 Nurses are the main healthcare providers in most TC models. Table 2 shows the strengths, weaknesses and efficacies of the different TC models and interventions.11–19

Nurse-led TC Programme

Scope of the Problem: HF Hospitalisation and Readmissions Ng et al. reported a rising trend in incident HF admissions among those aged >65 years between 1991 and 1998, the final 3 years showing an acute rise, with admission rates per 10,000 population rising from 85.4 in 1991 to 110.3 in 1998.4 Subsequent publications from local institutions have highlighted the current burden of cardiac comorbidities and prevailing HF event rates (Table 1).5 –8 The mean ages of HF patients in these publications ranged from 65.0 to 68.7 years. Common comorbidities included diabetes mellitus (48.5–62.0  %), hypertension (53.5–79.0 %) and coronary artery disease (46.8–83.1 %). By 2014, pooled data from three public institutions in Singapore showed that HF readmission rates were 18 %, the average length of stay was 5.2 days per admission, and in-hospitalisation mortality was 4 % (unpublished source).

TC Models in HF There are multiple challenges in caring for patients with advanced cardiovascular diseases.9 Unmet needs in this group affect readmission

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The Canadian Partners in Care for Congestive Heart Failure model evaluated the efficacy of a TC programme on top of the usual posthospital care to improve patients’ quality of life and reduce readmission rates.24 In this model, TC nurses provided further services to cater to unmet needs, utilising: supportive care for self-management; links between hospital and home nurses; and balance of care between patient, family and professional care providers. Patients were given a comprehensive workbook and educational maps, providing patients and their caregivers with knowledge about post-discharge selfcare. They were also provided with information and resources to formulate systems for social/community support. Prior to discharge, the TC nurse sent a nursing transfer letter to the community nurse, highlighting the patient’s clinical status and management needs. A routine post-discharge phone call was also made by the TC nurse to check on progress. The strengths of this programme lies in patient/caregiver empowerment and the provision of a single point of contact (the TC nurse), should the need arise. It also provides smoother transfer

Access at: www.CFRjournal.com

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Clinical Practice Table 1: Summary of Most Recently Available Published Data From Singaporean Institutions Highlighting the Burden of Cardiac Comorbidities and Prevailing Heart Failure Event Rates Authors Cohort

Study Design Sample Average Male Ethnicity Size (n) Age (%) (%) (Years)

Leong

Hospital-

Observational

et al24

based

prospective

Seow

Hospital-

et al25

based

Lee

Hospital-

et al26

based

Retrospective

Retrospective

Omar

Programme- Retrospective

et al27

based

173

225

668

154

68.7

68.5

66.0

65.0

51.4

56.4

67.4

54.0

Risk Factors Present (%)

Chinese: 52.0 Diabetes: 50.3 Indian: 10.4

CAD: 46.8

Other: 4.1

Hypertension: 67.6

AF: 16.5 Chinese: 60.0 Diabetes: 52.1 Indian: 14.7

CAD: 83.1

Malay: 24.0

Hypertension: 53.5

Other: 1.3 Chinese: 72.0 Diabetes: 48.5

Mortality

Drugs (%)

Comments

20.8 % in

ACE-I/ARB

35.8 % of cohort had

1 year

LVEF ≤45 %

67.5 % in

ACE-I 79.1;

All had LVEF ≤40.

5 years

BB 6.2

More deaths in females than males

In 24 months:

ACE-I/ARB

(75.3 % versus 62.7 %) 17 % had LVEF >40. Indians had a higher

Indian: 10.9

CAD: 68.5

Chinese: 14.3 % 86.5;

Malay: 17.1

Hypertension: 72.6

Malay: 27 %s

BB 66.6

Indian: 18.6 % None in 6

ACE-I/ARB 96; High usage of

months

BB 70

Chinese: 56.0 Diabetes: 62 Indian: 17.0

CAD: 63

Malay: 26.0

Hypertension: 79

death rate

guideline-based drugs

Other: 1.0 ACE-I = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BB = beta-blocker; CAD = coronary artery disease; LVEF = left ventricular ejection fraction.

Table 2: Strengths, Weaknesses and Efficacies of Different Transitional Care Models and Interventions Programme/ Intervention Partners in Care for Congestive Heart Failure11 (nurse-led)

Strength • Seamless transfer of nursing care from hospital to community

Weaknesses • Less focused on psychosocial issues

Efficacies • Improved quality of life scores

• Manpower-intensive

• Fewer emergency department

• Single point of contact for the patient

visits

• Comprehensive post-discharge

• No difference in admissions12

services available Bridge model

• Focused on psychosocial issues

(social worker-led)

• Addresses caregiver well-being

• Less focused on the medical/ nursing needs of the patient

• Increased attendance at physician follow-up appointments • No difference in caregiver stress levels • No difference in admission rate and mortality13

Structured telephone support

• Easy to organise and cost-effective

• Lack of true physical contact

• Reduced hospitalisation

• Allows for a constant channel

• Largely dependent on truthful reporting

• No difference in

of communication between patient

by the patient

mortality14–16

and healthcare providers • Less intrusive Telemonitoring

• Able to remotely monitor a variety of physiological parameters • Empowers medical team to remotely

• Dependent on device stability

• Measurement of weight,

• Might involve invasive devices

blood pressure, heart rate

• Devices are generally costly

and rhythm does not reduce

act on deviations of parameters • Less manpower-intensive than home visitation

hospitalisation rates • Equivocal in reducing mortality17,19 • Use of CardioMEMS™ (St. Jude Medical) pulmonary artery pressure monitor reduced hospitalisation rates18

of care from hospital to the community. This model is manpower intensive, however, with less focus on patients’ psychosocial issues. Patients being managed under the TC programme had better Minnesota Living with Heart Failure Questionnaire scores and significantly fewer emergency department (ED) visits at 6 and 12 weeks post discharge. There was a trend towards fewer patient admissions under this TC programme.

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Social Worker-led TC Programme The bridge model, devised by the Illinois Transitional Care Consortium, is a social worker-led, post-discharge intervention programme targeting unmet biopsychosocial needs. 12 In a randomised trial conducted by the Consortium, the TC programme, termed the Enhanced Discharge Planning Program (EDPP), was compared against usual care for patients with high social risks for readmission. On top

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Figure 1: Singaporian Institutional Approach to the Transitional Care (TC) of Heart Failure (HF) Patients Evaluation by TC nurse and HF cardiologist prior to discharge Low risk

• 1–2 admissions within a year • No functional issues • No care issues

Moderate risk Patient meets 1 or more of the following criteria: • 2–3 admissions within a year • Functional decline on admission • Concern over care at home

High risk Patient meets 1 or more of the following criteria: • 3 or more admissions within a year • Functional decline during hospitalisation • Care issues at home/no caregiver after discharge

Develop individualised care plans (Early post discharge HF clinic and telemonitoring devices will be arranged prior to discharge if necessary) Low risk

Moderate risk

High risk

• Provide patients with a phone number for the ward so they can call for advice when necessary • TC nurse to call patient within 48 hours of discharge if they are not being transferred to a community hospital or nursing home Home visit when appropriate within a week post discharge if patient verbally consents

Home visit when appropriate within 48 hours post discharge if patient verbally consents

Fortnightly multidisciplinary meeting • • • •

TC nurses, HF cardiologist, physiotherapist, pharmacist, medical social worker and care co-ordinator to attend Discuss patient care plan and review progress Depending on care needs, arrange early post-discharge HF clinic appointment and telemonitoring device Initiate appropriate referral to community care services (home rehabilitation, community day care and befriender services)

of regular hospital care, patients on the EDPP underwent detailed psychosocial assessment as inpatients. Patients’ post-discharge care needs were identified and relevant community partners and resources were identified and engaged prior to discharge. A postdischarge phone call by the EDPP social worker was made on the second post-discharge day to check on the patient’s progress. This social worker-led model has a strong emphasis on psychosocial issues, even addressing caregiver well-being but provides less focus on medical and nursing needs than the nurse-led programme. Patients on the EDPP were more likely to return for scheduled physician follow-up appointments; however, there were no statistical differences in patient/ caregiver stress, readmission rates within 30 days and mortality.

Structured Telephone Support Structured telephone support (STS) involves contacting the patient after discharge to provide them with continuing education on his or her condition, assess symptoms and check on medication compliance. According to the DIAL trial, a randomised trial of telephone intervention in HF, patients in the STS arm were less likely to die from or be admitted for HF compared to patients receiving standard care.13 A Cochrane review on the effect of STS intervention including 16 trials involving 5,613 patients showed a significant reduction in HF admissions but a non-significant reduction in mortality rates.14 A separate meta-analysis of 13 randomised STS trials, however, showed a significant reduction in mortality rates for HF patients receiving STS over standard care.15 The strengths of STS lie in its ease of organisation and costeffectiveness. It allows for a constant channel of communication

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between the patient and healthcare providers, without being as intrusive as home visits. The drawback is that there is a lack of true physical contact and information is largely dependent on truthful reporting by patients or caregivers.

Telemonitoring With the advancement in remote monitoring technology, telemedicine has emerged as a key player in the field of post-discharge care. Telemonitoring has the ability to remotely monitor a variety of physiological parameters, empowering healthcare providers to remotely act on deviations of parameters. In the Trans-European Network-Home-Care Management System trial, telemonitoring was shown to reduce 1-year mortality rates; however there was no effect on hospitalisation rates.16 In the Telemedical Interventional Monitoring in Heart Failure trial, patients with New York Heart Association (NYHA) class II/III HF were stratified into two groups: physician-led remote monitoring or standard care. The trial did not show any difference between the two strategies in relation to improving mortality or hospitalisation rates.17 The invasive Chronicle® device (Medtronic Inc), which was implanted in the right-hand side of the heart to measure right ventricular pressure, was not approved for use by the US Food and Drug Administration as the Continuous Haemodynamic Monitor in Patients with Advanced Heart Failure (COMPASS-HF) trial did not show a reduction in HF events in the device group.18 However, in the CardioMEMS™ Heart Sensor Allows Monitoring in Pressure to Improve Outcomes in NYHA Class Heart Failure Patients (CHAMPION) trial, active titration of diuretic doses based on pulmonary artery pressure readings transmitted by the CardioMEMS device was associated with decreased rates of hospitalisation.19

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Clinical Practice Figure 2: Impact of Transitional care (TC) Programme in Heart Failure Patients on All-cause Readmission, Emergency Department (ED) Visits and Length of Inpatient Stay

support available to patients. Quality improvement strategies are also important to improve and integrate the work processes involved in care coordination.23

A

Local Institutional Experience and Evidence

Three Months Pre and Post Implementation

–54 %

20

A TC programme for HF patients was initiated at our institution in April 2014. The purpose of the service was to enable the smooth transition of care plans from hospital discharge to home and to improve patients’ medical, functional and social care status in the community setting post discharge.

18.52

Pre-TC

18

Post-TC

16 14

Counts

12 10

8.44

8 6

–50 %

4

2.05

2 0

1.02

Readmissions (n)

–44 % 1.90

1.07

ED visits (n)

Length of stay (days)

Outcome B

Six Months Pre and Post Implementation

–40 %

25

Counts

Care components are individualised to patients’ care needs depending on their risk groups. Not all HF patients enrolled in TC receive all care components.

22.74

Pre-TC Post-TC

20

15

13.75

10 –38 % 5

0

2.74

1.70

Readmissions (n)

TC was applied to newly-diagnosed HF patients, those with recurrent readmissions, as well as HF patients experiencing functional decline or social issues. Patients were risk-stratified into low, moderate or high risk of post-discharge readmission depending on the number of readmissions in a year, degree of functional decline and level of care support (Figure 1). Care components of the HF transitional service include: post-discharge telephone interviews and hotline; nurse-led home care visits; early post-discharge HF clinic; and telemonitoring of weight with medication titration.

–27 % 2.58

1.89

ED visits (n)

Length of stay (days)

In order to correctly titrate patients’ medication, patients who are likely to clinically benefit from weight monitoring are supplied with a weighing machine on discharge. This remote monitoring system transmits readings to the hospital’s database. Weight monitoring is also offered to patients in the outpatient clinic who do not require other TC interventions, such as home visits. The nurses review the readings daily and titrate diuretic dosages based on the readings and telephone communications of each patient’s clinical condition.

Outcome Source: Data on file, corresponding author Dr Wan Xian Chan.

The drawbacks of telemonitoring include the cost of monitoring devices, dependence on device stability and lack of direct contact with the patient. This limits communication to address psychosocial issues with patients and caregivers.

Regional Experience in TC Efforts to implement TC in the management of HF patients are uncommon in Asia. A recent randomised trial of a nurse-led TC programme for HF patients in Hong Kong demonstrated no significant differences in event-free survival, hospital readmission or mortality between the TC and usual care groups.20

Current Recommendations Both the American College of Cardiology and the European Society of Cardiology recommend effective systems of care coordination to provide HF patients with comprehensive multidisciplinary care plans from the beginning to the end of their healthcare journey.7,8 In the scientific statement from the American Heart Association,23 effective care coordination requires the optimisation of communication among healthcare providers in multiple disciplines, identifying patients at high risk of unfavourable outcomes, adequately training the healthcare professionals involved and assessing health-related quality of life measures to enhance the psychological and social

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All patients on the programme who are at moderate or high risk have their status reviewed during a fortnightly multidisciplinary meeting. Following this, their care plans are adjusted according to their needs. Our programme enrolled 60 HF inpatients and nine outpatients between April 2014 and September 2015. We observed a 50  % decrease in readmissions, 44  % decrease in ED visits and 54 % reduction in length of stay when we compared these parameters 3 months before and after HF TC management (Figure 2a). The decrease in readmissions (−38  %), ED visits (−27  %) and duration of hospitalisation (−40  %) was sustained 6 months after enrolment for the 53 patients remaining in the programme (Figure 2b). By then, seven patients had been discharged from the TC programme. For the remote weight monitoring intervention, which included the outpatients, there was a significant reduction in HF readmission (−31  %) and duration of hospital stay (−31  %) for the 6 months post-recruitment.

Implications for Future Practice and Research into HF Care TC is important in the provision of patient-centric, coordinated care meeting the multi-faceted needs of HF patients. Current HF TC practices, interventions and patient populations targeted are heterogeneous, however, and no clear guidelines for clinical applications can be drawn

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from existing data.17 Research into interventional TC models should enhance and augment the delivery of care to provide consistently good clinical outcomes in a cost-effective manner. Patient-centric outcomes, such as quality of life, functional status and patient satisfaction, are important to patients and caregivers and further research efforts are needed within the wider context of the healthcare system. As effective transition of care should aim to reduce societal costs, the cost-effectiveness of and cost-savings introduced by TC models are important outcomes to evaluate. The application of innovative technologies in HF care started with telemedicine using remote monitoring technology8 and pulmonary artery-guided management with a wireless implantable haemodynamic monitoring system. 13 Further research into and applications of innovative technologies could augment current HF TC strategies. The future of TC programmes in HF clearly lies in a multidisciplinary approach with: • nurse-led structured telephone support combined with home visits (scheduled depending on patients’ and caregivers’ needs); • general physician-led remote medical consultations to adjust medications and care plans (to address functional and psychosocial issues); • multidisciplinary support from medical social workers, physiotherapists, occupational therapists, dieticians and pharmacists, depending on patients’ care needs; • the application of remote monitoring devices, if applicable;

World Health Organization. Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva, World Health Organization 2009. Available at: www.who.int/healthinfo/global_burden_disease/ GlobalHealthRisks_report_full.pdf (accessed 7.9.16) 2. Ministry of Health. 2015. Top 10 conditions of hospitalisation. Available at: https://www.moh.gov.sg/content/moh_web/ home/statistics/Health_Facts_Singapore/Top_10_Conditions_ of_Hospitalisation.html (accessed 7.9.16) 3. Singapore Ministry of Health. 2016. Heart failure. Available at: https://www.moh.gov.sg/content/moh_web/home/ costs_and_financing/hospital-charges/Total-Hospital-Bills-Bycondition-procedure/heart_failure.html (accessed 7.9.16) 4. Ng TP, Niti M. Trends and ethnic differences in hospital admissions and mortality for congestive heart failure in the elderly in Singapore, 1991 to 1998. Heart 2003;89:865–70. PMID: 12860859 5. Leong KT, Goh PP, Chang BC, et al. Heart failure cohort in Singapore with defined criteria: clinical characteristics and prognosis in a multi-ethnic hospital-based cohort in Singapore. Singapore Med J 2007;48:408–14. PMID: 17453098 6. Seow SC, Chai P, Lee YP, et al. Heart failure mortality in Southeast Asian patients with left ventricular systolic dysfunction. J Card Fail 2007;13:476–81. DOI: 10.1016/j. cardfail.2007.03.010; PMID: 17675062 7. Lee R, Chan SP, Chan YH, et al. Impact of race on morbidity and mortality in patients with congestive heart failure: a study of the multiracial population in Singapore. Int J Cardiol 2009;134:422–5. DOI: 10.1016/j.ijcard.2007.12.107; PMID: 18372060 8. Omar AR, Suppiah N, Chai P, et al. Efficacy of communitybased multidisciplinary disease management of chronic heart failure. Singapore Med J 2007;48:528–31. PMID: 17538751 9. Albert NM, Paul S, Murray M. Complexities of care for patients and families living with advanced cardiovascular diseases: overview. J Cardiovasc Nurs 2012;27:103–13. DOI: 10.1097/JCN.0b013e318239f4dd; PMID: 22210145 10. Albert NM, Barnason S, Deswal A, et al. Transitions of care in heart failure: a scientific statement from the American Heart 1.

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11.

12.

13.

14.

15.

16.

17.

• the involvement of community care services (community or home rehabilitation, home nursing care, home hospice care) to support patients’ care needs in the long term. The coordination of care for HF patients and caregivers encompassing hospital discharge and holistic management at home as well as the employment of community care services to meet care needs is required. This could potentially reduce HF hospital admissions, improve patients’ quality of life and satisfaction with care, and empower patients to make self-care decisions.

Conclusion Published data from institutions in Singapore5–8,24 suggest that incident admissions due to HF in Southeast Asia are rising, and patients admitted for HF are younger with higher mortality rates. Conversely, there is an urgent need to improve quality of care throughout the continuum of the disease, with its unpredictable trajectory of clinical events and multidisciplinary care needs. Through the implementation of transitional HF care in our institution, we reconstructed the care coordination and workflow pathways, overcame barriers that disrupted seamless care delivery, and optimised health system operations. TC in this patient group requires patient-centric, multidisciplinary care coordination from hospital to home to community in the longterm, applied in a cost-effective manner and enhanced by the use of innovative technologies. Further research is needed to augment current TC practices. ■

Association. Circ Heart Fail 2015;8:384–409. DOI: 10.1161/ HHF.000000000000000; PMID: 25604605 Harrison MB, Browne GB, Roberts J, et al. Quality of life of individuals with heart failure: a randomized trial of the effectiveness of two models of hospital-to-home transition. Med Care 2002;40:271–82. PMID: 12021683 Altfeld SJ, Shier GE, Rooney M, et al. Effects of an enhanced discharge planning intervention for hospitalized older adults: a randomized trial. Gerontologist 2013;53:430–40. DOI: 10.1093/geront/gns109; PMID: 22961467 GESICA investigators. Randomized trial of telephone intervention in chronic heart failure: DIAL trial. BMJ 2005;331:425. DOI: 10.1136/bmj.38516.398067.E0 Inglis SC, Clark RA, McAlister FA, et al. Which components of heart failure programmes are effective? A systematic review and meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of chronic heart failure management in 8323 patients: abridged Cochrane Review. Eur J Heart Fail 2011;13:1028–40. DOI: 10.1093/eurjhf/hfr039; PMID: 21733889; PMID: 16061499 Feltner C, Jones CD, Cené CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med 2014;160:774–84. DOI: 10.7326/M14-0083; PMID: 24862840 Cleland JG, Louis AA, Rigby AS, et al; TEN-HMS Investigators. Noninvasive home telemonitoring for patients with heart failure at high risk of recurrent admission and death: the Trans-European Network-Home-Care Management System (TEN-HMS) study. J Am Coll Cardiol 2005;45:1654–64. DOI: 10.1016/j.jacc.2005.01.050; PMID: 15893183 Koehler F, Winkler S, Schieber M, et al; Telemedical Interventional Monitoring in Heart Failure Investigators. Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study. Circulation 2011;123:1873–80. DOI: 10.1161/ CIRCULATIONAHA.111.018473; PMID: 21444883

18. Abraham WT, Stevenson LW, Bourge RC, et al; CHAMPION Trial Study Group. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016;387:453–61. DOI: 10.1016/ S0140-6736(15)00723-0; PMID: 26560249 19. Bourge RC, Abraham WT, Adamson PB, et al; COMPASS-HF Study Group. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study. J Am Coll Cardiol 2008;51:1073–9. DOI: 10.1016/j.jacc.2007.10.061; PMID: 18342224 20. Yu DS, Lee DT, Stewart S, et al. Effect of nurse-implemented transitional care for Chinese individuals with chronic heart failure in Hong Kong: a randomized controlled trial. J Am Geriatr Soc 2015;63:1583–93. DOI: 10.1111/jgs.13533; PMID: 26289684 21. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 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:e147–239. DOI: 10.1016/j.jacc.2013.05.019; PMID: 23747642 22. McMurray JJ, Adamopoulos S, SD Anker, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787–847. DOI: 10.1093/eurheartj/ ehs104; PMID: 22611136 23. Albert NM, S Barnason, Deswal A, et al. Transitions of care in heart failure: a scientific statement from the American Heart Association. Circ Heart Fail 2015;8:384–409. 10.1161/ HHF.0000000000000006 24. Atherton JJ, Hayward CS, Wan Ahmad WA, et al. Patient characteristics from a regional multicenter database of acute decompensated heart failure in Asia Pacific (ADHERE International-Asia Pacific). J Card Fail 2012;18:82–8. DOI: 10.1016/j.cardfail.2011.09.003; PMID: 22196846

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Chagas Heart Failure in Patients from Latin America Re i n a l d o B B e s t e t t i Department of Medicine, University of Ribeir��o Preto, Ribeirão Preto, Brazil

Abstract Physicians working in Europe and the United States should suspect Chagas heart failure in every patient coming from Latin America with chronic heart failure. Diagnosis should be confirmed by positive serology. Right bundle branch block and left anterior fascicular block on 12-lead electrocardiogram, enlarged cardiac silhouette with no pulmonary congestion on chest X-ray and left ventricular apical aneurysm on echocardiography are the distinctive features of this condition. The clinical course is poorer than that of non-Chagas heart failure; however, medical treatment is similar. Implantable cardioverter-defibrillators are useful in the primary and secondary prevention of sudden cardiac death. Cardiac resynchronisation therapy can be given to patients on optimal medical therapy and with lengthened QRS complex. Heart transplantation is the treatment of choice for patients with end-stage Chagas heart failure.

Keywords Chagas disease, heart failure, heart transplantation, implantable cardioverter-defibrillator, sudden cardiac death Disclosure: The author has no conflicts of interest to declare. Received: 28 June 2016 Accepted: 30 September 2016 Citation: Cardiac Failure Review 2016;2(2):90–4. DOI: 10.15420/cfr.2016:14:2 Correspondence: Reinaldo B Bestetti, Director of the Medical School, University of Ribeirão Preto, Av. Costabile Romano, 2201, Ribeirão Preto, 14096-900, Brazil. E: rbestetti44@gmail.com

More than a century after its discovery, Chagas disease still is a major health problem in Latin America, with 5.7 million people in 21 countries being affected by it.1 Moreover, about 70 million people are at risk of acquiring the illness.1 Cases of Chagas disease are now found globally; there are more than 400,000 immigrants with this disease living in Europe (mainly in Spain, Italy and France) and the United States.2 The consequence of this is that the annual global (direct plus indirect) cost of the disease is in the region of US $7.2 billion, which is more than the cost of the majority of cancers.3 Chagas disease is caused by the protozoan Trypanosoma cruzi, which is transmitted to humans through the faeces of insect vectors known as triatomine bugs. About 20  % of patients develop chronic cardiomyopathy within 20 years of initial diagnosis by positive serology test.1 Chagas cardiomyopathy can clinically manifest as precordial chest pain,4 thromboembolism,5 cardioembolic stroke,6 intraventricular conduction disturbances, atrioventricular block, ventricular dysrhythmias,7 sudden cardiac death (SCD)8 or chronic heart failure (CHF).9 Chagas heart failure has several peculiarities that distinguish it from other forms of heart failure. Physicians must therefore be alert to how to deal with Chagas heart failure to ensure patients receive the best treatment for this condition. This overview is intended to provide insights into how to recognise and treat patients living in non-endemic countries who have Chagas heart failure.

Epidemiology Up to 14 % of patients in areas where Chagas disease is endemic have Chagas heart failure.7 This percentage is higher than the 2  % seen in a cohort of Chagas disease patients from a non-endemic

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area.10 Where the disease is endemic, asymptomatic left ventricular dysfunction affects 3–39 % of patients with chronic Chagas disease11 and precedes CHF;12 in non-endemic areas, the prevalence of this abnormality is 4 %.10 Given the epidemiology of Chagas disease, clinicians faced with immigrants from Latin America should have a high degree of suspicion for heart failure in those with positive serology. Figure 1 provides a simplified care pathway. An echocardiographic study should be undertaken to detect early myocardial dysfunction in this patient population.

The Distinctive Clinical Picture Chagas heart failure is the consequence of reduced left ventricular ejection fraction (LVEF).9 In general, dyspnoea is the predominant symptom. Following this inaugural symptom, pedal oedema supervenes, and the clinical picture of right-sided heart failure ensues. Isolated right-sided heart failure, although rare, can be observed in patients with Chagas heart failure. It sometimes precedes the appearance of left-sided heart failure. In the presence of bi-sided heart failure, physical examination may suggest that right-sided heart failure predominates.13 This means that a patient with anasarca and left ventricular systolic dysfunction, for example, may have no dyspnoea. In patients with mild symptoms, especially in those in New York Heart Association (NYHA) Class II, precordial chest may simulate coronary artery disease (CAD).4 Coronary angiography can be performed to rule out concomitant obstructive CAD, but this is normal in the vast majority of cases.14 Abnormalities in myocardial perfusion scintigraphy can be observed in the absence of concomitant obstructive CAD in

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Chagas heart failure patients, thus suggesting derangement of the coronary microvasculature. Physical examination usually reveals a high frequency of splitting of the second heart sound, as first noted by Chagas.15 This is associated with the presence of right bundle branch block (RBBB) on 12-lead electrocardiogram (ECG). Isolated liver enlargement heralding the appearance of right-sided heart failure can also be detected on physical examination.16

Figure 1: A Simplified Care Planning Pathway for Clinicians Faced with Immigrants from Latin America with Chagas Disease

Positive Trypanosoma cruzi serology

12-lead ECG

Another finding not observed at the same magnitude in non-Chagas disease heart failure is the presence of cardiac arrhythmias on physical examination.17 Atrial fibrillation is observed in up to 30  % of patients with this condition18,19 and premature contractions (ventricular in origin in the vast majority of cases) occur in about 50  % of patients.18 It is important to emphasise that the prevalence of atrial fibrillation is higher in patients with Chagas heart failure than in those from a general, unselected population;20 about three-quarters of patients with Chagas heart failure will have cardiac arrhythmia on physical examination.

Peculiarities of Subsidiary Tests RBBB and left anterior fascicular block are found in about 40  % of patients with Chagas heart failure, which is higher than that seen in CHF due to other types of cardiomyopathy.17,18,21 The association between RBBB and left anterior fascicular block, which is more frequent in patients with Chagas cardiomyopathy,22 should alert physicians to the possibility of Chagas heart failure. In contrast, the prevalence of left bundle branch block (LBBB), which is frequently found in patients with non-Chagas cardiomyopathy,23 is lower in Chagas heart failure.17,18,21 Such electrocardiographic peculiarities should raise suspicion of Chagas disease aetiology in patients with CHF coming from an endemic area. On chest X-ray it is common to see an impressive cardiomegaly with no evidence of congestion, a finding observed as far back as 1945.13 This is probably a consequence of the concomitant right ventricular involvement usually observed in patients with Chagas heart failure. Such a characteristic should prompt physicians to consider this diagnosis in patients from an area where Chagas is endemic. On echocardiographic study, about 37  % of patients with Chagas cardiomyopathy have segmental wall motion abnormalities similar to those found in patients with ischaemic cardiomyopathy.18 In such circumstances, it is mandatory to rule out the diagnosis of CADinduced cardiomyopathy. Another distinctive finding is the presence of apical left ventricular aneurysm in the absence of CAD, which affects about 21 % of patients with Chagas cardiomyopathy22 and is therefore highly suggestive of Chagas disease.24 This finding may help physicians diagnose patients who have emigrated from an endemic area and is very important because apical left ventricular aneurysm is associated with SCD in patients with this condition,25 probably because the abnormality is the site from which malignant ventricular arrhythmias may arise.8 Twenty-four-hour Holter monitoring can reveal complex premature ventricular contractions, particularly non-sustained ventricular tachycardia (NSVT). Holter monitoring reveals NSVT in up to 50  % of patients with Chagas heart failure,26 a much higher frequency than observed in patients with non-Chagas heart failure.27 NSVT is heralded by the presence of premature ventricular contractions on resting ECG.28 This is of the utmost importance because about

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24-hour Holter

Chest X-ray

Echocardiography

LVSD detected

Medical management

CRT

ICD

Heart transplantation LVSD = left ventricular systolic dysfunction; CRT = cardiac resynchronisation therapy; ICD = implantable cardioverter defibrillator.

10  % of Chagas disease patients with NSVT progress to sustained ventricular tachycardia,29 which in about 24  % of cases degenerates into ventricular fibrillation and SCD.30 Clearly, the presence of NSVT in a young patient with CHF from an endemic area should raise the diagnostic possibility of Chagas heart failure. Twelve-lead ECG and Holter monitoring can detect complete atrioventricular block. Chagas disease is the leading cause of complete atrioventricular block in areas where the disease is endemic;31 it was found in about 10  % of patients seen in one referral centre for the treatment of Chagas disease.32 In other referral centres specialised in heart failure treatment, however, the frequency of pacemakers in patients with Chagas heart failure is as high as 50 %.33 The presence of CHF and advanced atrioventricular block in young patients from an endemic area should therefore alert the physician to a diagnosis of Chagas cardiomyopathy.

Clinical Course The clinical course of Chagas heart failure is relentless, with an annual mortality approaching 20  %.34 Predictors of mortality are NYHA Functional Class IV, LVEF, hyponatremia, lack of beta-blocker therapy and digoxin use.34 Life expectancy for patients with CHF secondary to Chagas cardiomyopathy is poorer than that observed in patients with mild to moderate CHF secondary to idiopathic dilated cardiomyopathy,21 ischaemic cardiomyopathy18 and hypertensive cardiomyopathy.17 Thromboembolism is a constant threat for patients with Chagas heart failure, particularly pulmonary embolism. It has a considerable impact on the clinical course of the disease. In severe CHF, right-sided cardiac thrombosis is found in about 58 % of patients, and half will experience pulmonary thromboembolism.35 Cerebrovascular accidents are also

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Clincial Practice a clinical problem, affecting about 11  % of patients.36 In those with milder forms of the syndrome, the risk of death from cerebrovascular accidents is high, at about 42 %.26 Patients with Chagas heart failure are at risk of thromboembolic phenomena due to the high prevalence of mural thrombosis, therefore physicians should routinely screen such patients for intracavitary thrombus and provide timely anticoagulation.

Treatment There is no evidence base supporting the treatment of patients with Chagas heart failure; Chagas disease is one of the most important but neglected diseases in the world. Treatment of this condition therefore mainly relies on the experience of physicians dealing with this syndrome.

Medical Diuretics, particularly furosemide, have successfully been used to decongest systemic and/or pulmonary circulation, and no deleterious effect has been observed.9 When furosemide alone is unable to relieve symptoms at a mean daily dosage of 160 mg/day, hydrochlorothiazide can be added.9 In cases of hyponatremia, water restriction has proven useful. A combination of spironolactone plus enalapril has also shown to be of benefit in patients with Chagas heart failure.37 Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers have been used in patients with Chagas heart failure without detrimental effect.37 Enalapril increased LVEF and decreased left ventricular systolic diameter on echocardiography, decreased cardiac silhouette on chest X-ray, and decreased brain natriuretic peptide serum levels in patients with this condition.37 Captopril 150 mg/day improved functional status and decreased urinary catecholamine levels as well as premature ventricular contractions on 12-lead ECG.38 Beta-blockers have been found to have a beneficial effect. Carvedilol 50 mg/day increased LVEF when it was <45 %.37 Metoprolol 50 mg/day induced improvement in clinical status, decreased noradrenaline serum levels, and increased systemic arterial pressure and LVEF on echocardiography.39 A sub-analysis of a prospective randomised trial performed on 25 patients showed increased survival in patients with Chagas heart failure.40 A longitudinal cohort study has demonstrated that metoprolol or carvedilol, even in small daily doses (carvedilol >9.75 mg), are associated with improved survival.41 Finally, the use of beta-blockers may have been responsible for the decrease in mortality observed in patients with Chagas heart failure in recent years.42 When the combination of ACEIs and beta-blockers provokes symptomatic systemic arterial hypotension, and the target dose of each agent cannot be reached, it has been suggested that the ACEI should be decreased and the target dose of beta-blocker be given.9 Digoxin produces a decrease in renin–angiotensin system activity43 and an improvement in haemodynamic profile44 when administered acutely to patients with Chagas heart failure. Nonetheless, the chronic use of digoxin is an independent predictor of mortality in such patients,34 probably due to digoxin intoxication. Increased digoxin levels have been detected in about 55 % of patients with Chagas heart failure;45 therefore serum levels should be measured when digoxin is given to patients with this condition. It is important to emphasise that the suggestions for treating patients with Chagas heart failure with diuretics, mineralocorticoid antagonists,

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ACEIs, beta-blockers and digoxin are in line with the European Society of Cardiology guidelines for the treatment of patients with non-Chagas heart failure.46 Aetiological treatment with benznidazole has no effect in patients with mild Chagas heart failure. In the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT) trial, which included about 2,854 Chagas disease patients – 17  % of whom had left ventricular systolic dysfunction – benznidazole showed no benefit over placebo in terms of morbidity and mortality. Aetiological treatment should not therefore be given to patients with Chagas heart failure.47

Non-surgical Device Therapy SCD occurs in about 46 % of patients with Chagas heart failure.25 In >90 % of cases, SCD is caused by ventricular tachycardia degenerating into ventricular fibrillation or direct ventricular fibrillation.8 These conditions have a prevalence of 20 % in patients with severe Chagas heart failure (LVEF <35  %).48 Cardinalli-Neto et al.48 observed that patients with Chagas heart failure have a higher incidence of repetitive ventricular tachycardia and/or ventricular fibrillation than those with non-Chagas heart failure.48 These repetitive arrhythmias lead to shock occurrence in primary SCD prevention with an implantable cardioverter defibrillator (ICD). Shock occurrence was appropriate in all situations, affecting about 23% of patients; all Chagas heart failure patients could therefore be considered for ICDs.49 Amiodarone therapy has been associated with an unfavourable prognosis in patients with Chagas heart failure;50 moreover, in patients with mild Chagas heart failure (LVEF 45.8 ± 11.2  %) amiodarone is an independent predictor of inducible ventricular tachycardia on electrophysiological study.51 Patients with Chagas heart failure and a LVEF <35 % may therefore be suitable for primary prevention of SCD because their clinical profile is similar to that in patients with nonChagas heart failure suitable for ICD treatment. ICDs also appear to be of value in the secondary prevention of SCD. The number ICD shocks and episodes of ventricular tachycardia or ventricular fibrillation are higher in Chagas disease than in non-Chagas disease patients with milder forms of CHF.52 ICD implantation has shown that the risk of arrhythmia recurrence is high in patients with mild CHF;30,53 moreover, left ventricular diastolic diameter, a marker of SCD,25 is also a predictor of appropriate shock therapy in patients with mild CHF secondary to Chagas cardiomyopathy.54 ICD therapy also seems to decrease the number of SCDs in patients with mild Chagas heart failure.55 In a cohort of patients receiving ICD therapy compared with historical control patients taking amiodarone, ICD decreased all-cause mortality and SCD in patients with this condition.56 Thus, physicians dealing with patients with Chagas heart failure and ventricular tachycardia/ventricular fibrillation should refer such patients to receive ICD therapy for the secondary prevention of SCD. The efficacy of cardiac resynchronisation therapy (CRT) in the setting of Chagas heart failure is not completely clear in view of the paucity of studies. Silva et al. studied the effects of CRT in patients receiving right ventricular pacing and observed an increase in LVEF and an improvement in functional status.57 Araujo et al.58 reported an increase in LVEF and a decrease in left ventricular systolic volume. The European Society of Cardiology guidelines have recently recommended CRT for non-Chagas heart failure patients with a QRS duration >150 msec and a non-LBBB. These guidelines also recommend patients

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with non-LBBB and a QRS duration between 130 and 149 msec be considered for CRT.46 Taking into account that about 16 % of patients with Chagas heart failure will have LBBB, almost half of them will have non-LBBB17,18,21 and the beneficial effects obtained with CRT in such patients make it reasonable to suggest CRT for selected patients with this condition.

With the exception of potential reactivation of the disease, the posttransplant complications (rejection, infection, neoplasia and cardiac allograft vasculopathy) in Chagas HT recipients are similar to those found in non-Chagas HT recipients.60 In Bestetti et al.’s experience, the incidence of infection is lower in Chagas than in non-Chagas HT recipients.61

Heart Transplantation

T. cruzi infection reactivation prevalence varies from 27 to 90 %, with a mean prevalence of around 35 %, and can be confounded with rejection in about 43 % of cases. Reactivation can be found from 1 to the 24 months post-HT.65 Mycophenolate mofetil appears to be a risk factor for T. cruzi reactivation.61,66 Reactivation is treated with benznidazole or nifurtimox, and mortality is very low (0.7 %),62 even in cases with central nervous system involvement.67 Clearly, HT is a formal indication for the treatment of end-stage Chagas heart failure.

The prognosis for Chagas disease patients on the heart transplant waiting list is worse than that of non-Chagas disease patients.59 Heart transplantation (HT) is the treatment of choice for patients with this condition. Patients with an annual mortality higher than around 70  % should be considered for HT. Such patients are those with persistent NYHA Class IV, LVEF <30 %, on inotropic support, that have a maximal oxygen consumption rate <10 ml/kg/min, electric storm, hyponatremia along with LVEF <31 %, are not taking beta-blockers and those using digoxin.60

Cell Therapy Aetiological treatment for HT candidates with Chagas disease is not usually recommended because it is ineffective in precluding the reactivation of acute Chagas disease in the HT recipient.61,62 In the case of inadvertent HT from an infected to an uninfected patient, however, the case is different. Blood and tissues should be closely monitored for signs of the parasite for at least for 2 years post transplant and, if found, aetiological treatment should be started as soon as possible.63 Morbidity in the perioperative period is similar to that found in nonChagas disease centres in Brazil. Mortality in Brazil varies from 9 to 22 % because of the widespread unavailability of mechanical circulatory support;60 however a study of 11 patients in the United States showed a 6-month mortality of 18  %, consistent with results from South America, which is not significantly different.64

1.

Anonymous. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wky Epidemiol Rec 2015;90 :33–44. PMID: 25671846 2. Pinazo MJ, Miranda B, Rodrigues-Villar C, et al. Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas. Transplant Rev 2011;25 :91–101. DOI: 10.1016/j.trre.2010.12.002; PMID: 21530219 3. Lee BY, Bacon KM, Bottazzi ME, et al. Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis 2013;13 :342–8. DOI: 10.1016/S14733099(13)70002-1; PMID: 23395248 4. Bestetti RB, Restini CB. Precordial chest pain in patients with chronic Chagas disease. Int J Cardiol 2014;176 :309–14. DOI: 10.1016/j.ijcard.2014.07.112; PMID: 25127335 5. Samuel J, Oliveira M, Correa De Araujo RR, et al. Cardiac thrombosis and thromboembolism in chronic Chagas’ heart disease. Am J Cardiol 1983;52 :147–51. PMID: 6858902 6. Carod-Artal FJ, Gascon J. Chagas disease and stroke. Lancet Neurol 2010;9 :533–42. doi: 10.1016/S1474-4422(10)70042-9; PMID: 20398860 7. Gonçalves JGF, Silva VJD, Borges MCC, et al. Mortality indicators among chronic Chagas patients living in an endemic area. Int J Cardiol 2010;143 :235–42. DOI: 10.1016/ j.ijcard.2009.02.011; PMID: 19336269 8. Bestetti RB, Cardinalli-Neto A. Sudden cardiac death in Chagas’ heart disease in the contemporary era. Int J Cardiol 2008;131 :9–17. doi: 10.1016/j.ijcard.2008.05.024; PMID: 18692919 9. Bestetti RB, Theodoropoulos TA, Cardinalli-Neto A, et al. Treatment of chronic systolic heart failure secondary to Chagas heart disease in the current era of heart failure therapy. Am Heart J 2008;156 :422–30. DOI: 10.1016/ j.ahj.2008.04.023; PMID: 18760121 10. Sabino EC, Ribeiro AL, Salemi VMC, et al.; National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II), International Component. Ten-year incidence of Chagas cardiomyopathy among asymptomatic Trypanopsoma cruzi-seropositive former blood donors. Circulation 2013;127 :1105–15. DOI: 10.1161/ CIRCULATIONAHA.112.123612; PMID: 23393012 11. Bestetti RB, Furlan-Daniel RA. The treatment of chronic

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12.

13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

A randomised trial of intracoronary injection of autologous bone marrow-derived mononuclear cells versus placebo in patients with severe Chagas heart failure has shown no benefit in comparison to placebo.68 This therapy should therefore not be given to patients with this condition.

Conclusion Chagas heart failure has differences in clinical features, subsidiary tests and course that distinguish it from non-Chagas heart failure. The treatment, however, is similar to that available for non-Chagas heart failure. Physicians dealing with this disease should be aware of the differences in presentation and similarities in treatment to ensure patients with this condition are correctly diagnosed receive the best treatment. ■

heart failure secondary to Chagas cardiomyopathy in the contemporary era. Int Cardiovasc For J 2016;7 :19–25. DOI: http://dx.doi.org/10.17987/icfj.v7i0.217 Petti MA,  Viotti R,  Armenti A,  et al. Predictors of heart failure in chronic chagasic cardiomyopathy with asymptomatic left ventricular dysfunction. Rev Esp Cardiol 2008;61 :116–22. DOI: 10.1016/S1885-5857(08)60086-9 Dias E, Laranja FS, Nobrega G. Doença de Chagas. Mem Inst O Cruz 1945;43 :495–581. Carvalho G, Rassi S, Bastos JM, et al. Asymptomatic coronary artery disease in chagasic patients with heart failure: prevalence and risk factors. Arq Bras Cardiol 2011;97 :408–12.  PMID: 22011801 Bestetti RB, Restini CB, Couto LB. Carlos Chagas discoveries as a drop back to scientific construction of chronic Chagas heart disease. Arq Bras Cardiol  2016;107 :63–70. DOI: 10.5935/ abc.20160079; PMCID: PMC4976958 Barros LC. Estudo clínico do aparelho cardiovascular no período terciário da Tripanosomose Americana. Rev Hosp Clin 1948;3 :155–82. Bestetti RB, Otaviano AP, Fantini JP, et al. Prognosis of patients with chronic systolic heart failure: Chagas disease versus systemic arterial hypertension. Int J Cardiol 2013;168 :2990–1. DOI: 10.1016/j.ijcard.2013.04.015; PMID: 23642596 Vilas Boas LG, Bestetti RB, Otaviano AP, et al. Outcome of Chagas cardiomyopathy in comparison to ischemic cardiomyopathy. Int J Cardiol  2013;167 :486–90. DOI: 10.1016/ j.ijcard.2012.01.033; PMID: 22365646 Abuhab A, Trindade E, Aulicino GB, et al. Chagas’ cardiomyopathy: the economic burden of an expensive and neglected disease. Int J Cardiol 2013;168 :2375–80. DOI: 10.1016/j.ijcard.2013.01.262; PMID: 23465560 Dias JCP, Kloetzel K. The prognostic value of the electrocardiographic features of chronic Chagas disease. Rev Inst Med S Paulo 1968;10 :158–62. PMID: 4982469 Barbosa AP, Cardinalli Neto A, Otaviano AP, et al. Comparison of outcome between Chagas cardiomyopathy and idiopathic dilated cardiomyopathy. Arq Bras Cardiol 2011;97 :517–25. DOI: 10.1590/S0066-782X2011005000112  Bestetti RB, Muccillo G. Clinical course of Chagas’ heart disease: a comparison with dilated cardiomyopathy. Int J Cardiol 1997;60 :187–93. PMID: 9226290

23. Rolande DM, Fantini JP, Cardinalli Neto A, et al. Prognostic determinants of patients with chronic systolic heart failure secondary to systemic arterial hypertension. Arq Bras Cardiol 2012;98 :76–84. PMID: 22159402 24. Oliveira JS, Mello De Oliveira JA, Frederigue U Jr, et al. Apical aneurysm of Chagas’s heart disease. Br Heart J 1981;46 :432–7. 25. Bestetti RB, Dalbo CM, Arruda CA, et al. Predictors of sudden cardiac death for patients with Chagas’ disease: a hospital-derived cohort study. Cardiology  1996;87 :481–7. PMID: 8904674 26. Carrasco HA, Parada H, Guerrero L, et al. Prognostic implications of clinical, electrocardiographic and hemodynamic findings in chronic Chagas’ disease. Int J Cardiol 1994;43 :27–38. PMID: 8175216 27. Bardy GH, Lee KL, Mark DB, et al.; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352 :225–37. DOI: 10.1056/ NEJMoa043399; PMID: 15659722 28. Rassi Jr A, Rassi AG, Rassi SG, et al. Arritmias ventriculares na doença de Chagas. Particularidades diagnósticas, prognósticas e terapêuticas. Arq Bras Cardiol 1995;65 :377–87. 29. Silva RMFL, Távora MZP, Gondin FAA, et al. Predictive value of clinical and electrophysiological variables in patients with chronic chagasic cardiomyopathy and nonsustained ventricular tachycardia. Arq Bras Cardiol 2000;75 :41–7. PMID: 10983018 30. Cardinalli-Neto A, Greco OT, Bestetti RB. Automatic implantable cardioverter-defibrillators in Chagas heart disease patients with malignant ventricular arrhythmias. Pacing Clin Electrophysiol 2006;29 :467–70. DOI: 10.1111/j.15408159.2006.00377.x; PMID: 16689840 31. Costa R, Rassi A, Leão MIP. Clinical and epidemiologic characteristics of patients with Chagas disease submitted to permanent cardiac pacemaker implantation. Rev Bras Cir Cardiovasc 2004;19 :107–14. DOI: 10.1590/S010276382004000200003  32. Sierra-Johnson J, Olivera-Mar A, Monteón-Padilla VM, et al. Panorama epidemiológico de la cardiopatia chagásica crônica em México. Rev Saude Publica 2005;39 :754–60. DOI: 10.1590/S0034-89102005000500009  33. Parra AV, Bestetti RB, Cardinalli-Neto A, et al. Impact of right ventricular pacing on patients with Chagas cardiomyopathy with

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Clincial Practice chronic systolic heart failure. Int J Cardiol 2012;154:219–20. 34. Theodoropoulos TA, Bestetti RB, Otaviano AP, et al. Predictors of all-cause mortality in chronic Chagas’ heart disease in the current era of heart failure therapy. Int J Cardiol 2008;128 :22–9. DOI: http://dx.doi.org/10.1016/ j.ijcard.2011.10.043 35. Arteaga-Fernández E, Barretto AC, Ianni BM, et al. Cardiac thrombosis and embolism in patients having died of chronic Chagas cardiopathy. Arq Bras Cardiol 1989;52 : 189–92. PMID: 6858902 36. Espinosa R,  Carrasco HA,  Belandria F,  et al. Life expectancy analysis in patients with  Chagas’  disease: prognosis after one decade (1973–1983). Int J Cardiol  1985;8 :45–56. PMID: 3997291 37. Botoni FA, Poole-Wilson PA, Ribeiro ALP, et al. A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas cardiomyopathy. Am Heart J 2007;153 :544. e1–8. DOI: 10.1016/j.ahj.2006.12.017; PMID: 17383291 38. Roberti RR, Martinez EE, Andrade JL, et al. Chagas cardiomyopathy and captopril. Eur Heart J 1992;13 :966–70. PMID: 1644089 39. Davila DH, Angel F, Bellabarba GA, et al. Effects of metoprolol in chagasic patients with severe congestive heart failure. Int J Cardiol 2002;85 :255–60. PMID: 12208592 40. Issa VS, Amaral AF, Cruz FD, et al. Beta-blocker therapy and mortality of patients with Chagas cardiomyopathy. A subanalysis of the REMADHE prospective trial. Circ Heart Fail 2010;3 :82–8. DOI: 10.1161/CIRCHEARTFAILURE.109.882035; PMID: 19933408 41. Bestetti RB, Otaviano AP, Cardinalli-Neto A, et al. Effects of b-blockers on outcome of patients with Chagas’ cardiomyopathy with chronic heart failure. Int J Cardiol 2011;151 :205–8. DOI: 10.1016/j.ijcard.2010.05.033; PMID: 20591516 42. Barretto ACP, Del Caerlo CH, Cardoso JN, et al. Mortality in heart failure is going down even in patients with inotropics (abstract). Eur J Heart Fail 2009;7 :66. 43. Khoury AM, Davila DF, Bellabarba G, et al. Acute effects of digitalis and enalapril on the neuro-hormonal profile of chagasic patients with severe heart failure. Int J Cardiol 1996;57 :21–9. PMID: 8960939 44. Manço JC, Gallo-Jr L, Godoy RA, et al. Efeitos hemodinâmicos na Cardiopatia Chagásica Crônica. Arq Bras Cardiol 1974;27:25–35. 45. Ferrari SJ, Bestetti RB, Cardinalli-Neto A, et al. Digoxin serum levels in patients with Chagas cardiomyopathy heart failure. Rev Soc Med Trop 2010;43 :496–9. PMID: 21085856 46. Ponikowski P, Voors AA, Anker SD, et al.; Authors/Task Force Members; Document Reviewers. 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

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Failure Association (HFA) of the ESC. Eur Heart J 2016;37 : 2129–200. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819 47. Morillo CA, Marin-Neto JÁ, Avezum A, et al.; BENEFIT Investigators. Randomized trial of benzonidazole for chronic Chagas cardiomyopathy. N Engl J Med 2015;373:1295–306. DOI: 10.1056/NEJMoa1507574; PMID: 26323937 48. Cardinalli-Neto A, Nakazone MA, Grassi LV, et al. Implantable cardioverter-defibrillator therapy for primary prevention of sudden cardiac death in patients with severe Chagas cardiomyopathy. Int J Cardiol 2011;150 :94–5. DOI: 10.1016/ j.ijcard.2011.03.036; PMID: 21497920 49. Pereira FTM, Rocha EA, Monteiro MPM, et al. Long-term follow-up of patients with chronic Chagas disease and implantable cardioverter-defibrillator. Pacing Clin Electrophysiol 2014;37 :751–6. DOI: 10.1111/pace.12342; PMID: 24467488 50. Ayub-Ferreira SM, Mangini S, Issa VS, et al. Mode of death of non Chagas heart disease: comparison with other etiologies. A subanalysis of the REMADHE prospective trial. Plos Negl Trop Dis 2013;7 :e2176. DOI: 10.1371/journal.pntd.0002176; PMID: 23638197 51. Cardinalli-Neto A, Lorga-Filho AM, Silva EF, et al. Clinical predictors of inducible sustained ventricular tachycardia during electrophysiologic study in patients with chronic Chagas heart disease. IJC Heart & Vasculature 2015;9 :85–8. DOI: 10.1016/j.ijcha.2015.10.001 52. Barbosa MPT, Rocha MOC, Oliveira AB, et al. Efficacy and safety of implantable cardioverter-defibrillators in patients with Chagas disease. Europace 2013;15 :957–62. DOI: 10.1093/ europace/eut011; PMID: 23376978 53. Martinelli-Filho M, de Siqueira SF, Moreira H, et al. Probability of occurrence of life-threatening ventricular arrhythmias in Chagas disease versus non-Chagas disease. Pacing Clin Electrophysiol 2000;23 :1944–6. PMID: 11139963 54. Martinelli M, de Siqueira SF, Sternick EB, et al. Long-term folow-up of Implantable Cardioverter-Defibrillator for secondary prevention in Chagas heart disease. Am J Cardiol 2012;110 :1040–5. 55. Cardinalli-Neto A, Bestetti RB, Cordeiro JA, et al. Predictors of all-cause mortality for patients with chronic Chagas heart disease receiving implantable cardioverter defibrillator therapy. J Cardiovasc Electrophysiol 2007;18 :1236–40. DOI: 10.1016/j.amjcard.2012.05.040; PMID: 22727179 56. Galli WL, Sarabanda AV, Baggio JM, et al. Implantable cardioverter-defibrillators for treatment of sustained ventricular arrhythmias in patients with Chagas heart disease: comparison with a control group treated with amiodarone. Europace 2014;16 :674–80. DOI: 10.1093/ europace/eut422; PMID: 24481778 57. Silva RT, Martinelli-Filho M, Lima CE, et al. Functional behavior of patients with conventional pacemakers undergoing cardiac resynchronization. Arq Bras Cardiol 2008;90 :138–43. PMID:

18392387 58. Araújo EF, Chamlian EG, Peroni AP, et al. Cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy: long-term follow up. Rev Bras Cir Cardiovasc 2014;29 :31–6. PMID: 24896160 59. Bertolino ND, Villafanha DF, Cardinalli-Neto A, et al. Prognostic impact of Chagas’ disease in patients awaiting heart transplantation. J Heart Lung Transplant 2010;29 : 449–53. DOI: 10.1016/j.healun.2009.10.014; PMID: 20006935 60. Bestetti RB, Theodoropoulos TA. A systematic review of studies on heart transplantation for patients with endstage Chagas’ heart disease. J Card Fail 2009;15 :249–55. DOI: 10.1016/j.cardfail.2008.10.023; PMID: 19327627 61. Bestetti RB, Souza TR, Lima MF, et al. Effects of mycophenolate mofetil-based immunosuppressive regimen in Chagas heart transplant recipients. Transplantation 2007;84 :441–2. 62. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology. Ann Thorac Surg 2001;71 :1833–8. PMID: 11426756 63. Bestetti RB, Lattes R. Chagas disease in cardiothoracic transplantation. In: Mooney ML, Hannan MM, Husain S, et al, eds. ISHLT Monograph Volume 5: Diagnosis and Management of Infectious Disease in Cardiothoracic Transplantation and Mechanical Circulatory Support . Philadelphia: Elsevier, 2011: 305–12. 64. Kransdorf EP, Czer SC, Luthringer DJ, et al. Heart transplantation for Chagas cardiomyopathy in the United States. Am J Transplant 2013;13:3262–8. DOI: 10.1111/ajt.12507; PMID: 24165397 65. Bocchi EA, Giovanni E, Mocelin AO, et al. Heart transplantation for chronic Chagas disease. Ann Thor Surg 1996;61 :1727–33. DOI: 10.1097/QCO.0000000000000088; PMID: 25023742 66. Bacal F, Silva CP, Bocchi EA, et al. Mycophenolate mofetil increased Chagas disease reactivation in heart transplant patients: comparison between two different protocols. Am J Transplant 2005;5 :2017–21. DOI: 10.1111/j.16006143.2005.00975.x; PMID: 15996254 67. Bestetti RB, Rubio FG, Ferraz Filho JR, et al. Trypanosoma cruzi infection reactivation manifested by encephalitis in a Chagas heart transplant recipient. Int J Cardiol 2013;163:e7–8. DOI: 10.1016/j.ijcard.2012.06.102 68. Santos RR, Rassi S, Feitosa G, et al.; Chagas Arm of the MiHeart Study Investigators. Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized trial of cell therapy in cardiopathies study): a multicentre randomized trial. Circulation 2012;125 :2454–61. DOI: 10.1161/ CIRCULATIONAHA.111.067785; PMID: 22523306

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Heart Failure With Preserved Ejection Fraction

Impact of Exercise Training on Peak Oxygen Uptake and its Determinants in Heart Failure with Preserved Ejection Fraction W esley J T uc k er, 1 Mic ha el D N e l s o n , 1 Rh y s I B e a u d r y , 1 M a r t i n H a l l e , 2 S a t y a m S a r m a , 3 , 4 Da la ne W K it zm a n , 5 A n d r e L a G e r c h e 6 a n d M a r k J H a y k o w k s y 1 , 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

Abstract Heart failure with preserved ejection (HFpEF) accounts for over 50  % of all HF cases, and the proportion is higher among women and older individuals. A hallmark feature of HFpEF is dyspnoea on exertion and reduced peak aerobic power (VO2peak) secondary to central and peripheral abnormalities that result in reduced oxygen delivery to and/or utilisation by exercising skeletal muscle. The purpose of this brief review is to discuss the role of exercise training to improve VO2peak and the central and peripheral adaptations that reduce symptoms following physical conditioning in patients with HFpEF.

Keywords Heart failure with preserved ejection fraction, exercise training, peak aerobic power Disclosure: DWK is funded by NIH grants R01AG18915; P30AG12232. MJH is funded by the Moritz Chair in Geriatrics in the College of Nursing and Health Innovation at the University of Texas at Arlington. The remaining authors have no conflicts of interest to declare. Received: 27 August 2016 Accepted: 10 October 2016 Citation: Cardiac Failure Review 2016;2(2):95–101. DOI: 10.15420/cfr.2016:16:2. Correspondence: Mark J Haykowsky, University of Texas at Arlington, College of Nursing and Health Innovation, 411 S Nedderman Drive, Arlington, Texas 76010, USA. E: mark.haykowsky@uta.edu

Heart failure (HF) is a major healthcare problem associated with high rates of morbidity and mortality.1 Approximately 6 million Americans aged ≥20 years have HF, and it is the leading cause of hospitalisation among older adults with estimated healthcare costs of US$31 billion annually.1,2 HF with preserved ejection fraction (HFpEF) accounts for over 50 % of all HF cases, and unlike HF with reduced ejection fraction (HFrEF), pharmacological, or device-based therapy do not improve survival or quality of life in patients with HFpEF.3,4 The hallmark symptom of HFpEF, even when well compensated and non-oedematous, is impaired exercise tolerance, measured objectively as decreased peak aerobic power (VO2peak).5–8 Specifically, VO2peak is 35  % lower in patients with HFpEF versus age-matched healthy controls secondary to central and peripheral abnormalities that result in reduced oxygen delivery to and/or utilisation by the exercising muscles.7,9-12 A consequence of the reduced VO2peak is that basic (getting dressed) and instrumental (housework, walking to get mail) activities of daily living require near-maximal effort. Given that exercise intolerance is a major independent predictor of hospital readmissions and mortality in HFpEF, a major goal of therapy is to improve VO2peak in patients with HFpEF.13 Prior studies have demonstrated that exercise training is a safe and effective therapy to improve VO2peak, cardiovascular and skeletal muscle function, quality of life and hospital readmission rates in patients with HFrEF.14–24 Furthermore, exercise-based cardiac rehabilitation has been shown to modestly reduce both all-cause and cardiovascular

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mortality rates in HFrEF.19 As a result, in the US example, exercisebased cardiac rehabilitation is covered by Medicare in patients with HFrEF. In contrast, despite numerous studies showing that exercise training is a safe and effective therapy for improving exercise tolerance and quality of life in HFpEF,25–28 exercise-based cardiac rehabilitation is currently not covered by Medicare in patients with HFpEF due to limited data on its effect on survival in this population. In this brief review, we discuss the role of exercise training to improve VO2peak and the central and peripheral adaptations that occur with physical conditioning in patients with HFpEF.

Effects of Exercise Training on Peak Aerobic Power in Heart Failure With Preserved Ejection Fraction To date, eight randomised controlled trials have examined the efficacy of exercise training to improve VO2peak in patients with HFpEF (see Table 1).25–32 Specifically, in five of these studies, moderate-intensity continuous endurance training (MICT) was performed 3–5 days per week for 1–5 months. This exercise prescription is in line with the American Heart Association exercise guidelines for overall cardiovascular health, which recommends at least 30 minutes of moderate-intensity aerobic physical activity (such as walking) at least 5 days per week.33 Two studies incorporated high-intensity interval training (HIIT), consisting of 4–5 intervals performed at 80–95 % peak heart rate for 2–4 minutes interspersed with 2–3 minutes of active recovery, for 1–3 months. Finally, Alves et al.29 estimated VO2peak after 6 months of moderate-

Access at: www.CFRjournal.com

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Heart Failure With Preserved Ejection Fraction Table 1: Randomised Controlled Exercise Intervention Trials in HFpEF Study

Angadi

Group

Age

Female

EF

(n)

(yrs)

(%)

(%)

HIIT (9)

69

11

65

Mode

Freq

Intensity

(d/wk) TM

3

4 x 2–4 min

Duration

Program

(min)

length

16 min HIIT

(wks) 4

Main findings

of peak VO2peak;

et al.

at 80–95 %

DD grade,

201530

HRpeak x

E;

2–3 min active

LAVI, A, E/A, DT;

MICT (6)

72

33

66

TM

3

e’ (septal), E/e’,

50 % HRpeak

IVRT, EF, BAFMD 15–30 min

4

HRpeak

VO2 -

VO2 at VnT,

recovery at 60–70 %

Predictors

VO2peak, VO2 at VnT, DD grade, LAVI, E, A, E/A, DT, e’ (septal), E/e’, IVRT, EF, BAFMD

Edelmann

ET (44)

64

55

67

CYC + RT

et al.

2–3

50–70 %

20-40

12

2

VO2peak

15 reps

wk: 5–12

201125

VO2peak, 6MWD,

inversely

60–65 %

class;

correlated

1RM

procollagen type I;

with E/e’

LVEF, LVMI,

(r = –0.37,

LAVI, E/e’,

NT- proBNP Fu et al.

Con (20)

65

60

66

ET (30)

61

33

58

CYC

3

201626

VO2peak

VnT, e’, QoL, NYHA

5 by 3 min

30

12

VO2peak, peak

=0.002) VO2peak

at 80 %

a–vO2 Diff, cerebral/

correlated

VO2peak x

muscle oxygenation

with peak

3-min active

E/e’, Ve/VCO2;

recovery at

change in

LVEF, LVIDd, LVIDs, perfusion

40 % VO2peak

peak SVI, CI, HR

in frontal lobe (p=0.002) and VL (p=0.04) adjusted r2 =0.4

Kitzman

Con (30)

63

40

57

ET (24)

70

83

61

et al.

Walk /

3

CYC

40–70 %

60

16

HRR

VO2peak, 6MWD,

-

VnT, physical QoL;

201027

rest LV EDV, ESV, EF, LVM, LVM/vol, E, A, DT, IVRT, Norepinephrine, BNP Con (22)

Haykowsky ET (22)

69

91

60

70

82

-

et al.

Walk/

peak HR,

CYC

a–vO2Diff;

2012a 37

peak LV EDV, ESV, SV, CO, SVR

Kitzman

Con (18)

68

94

-

ET (24)

70

72

58

et al.

Walk/

3

CYC/AE

40–70 %

60

16

HRR

84 % of in VO2peak due to a–vO2Diff

VO2peak, peak HR, 6MWD, VnT

201332

physical QOL; carotid arterial stiffness, BAFMD, rest LV EDV, ESV, SV, EF, E, A, DT, IVRT

Kitzman

Con (30)

70

80

56

ET (24)

67*

81 %*

61*

Main effects

VO2peak

et al.

Walk

3

based on

Individualised 60

20

ET: VO2peak,

correlated

201631

HRR

6MWD,

with change

peak

DBP, body

in percent

weight, fat mass,

lean mass

NYHA class;

(r = 0.32, (Continued)

T2

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The Impact of Exercise Training on Peak Oxygen Uptake in HFpEF

Table 1 (Continued): Randomised Controlled Exercise Intervention Trials in HFpEF Study

Group

Age

Female

EF

(n)

(yrs)

(%)

(%)

Mode

Freq

Intensity

(d/wk)

Duration

Program

(min)

length

Main findings

Predictors of peak

(wks) rest LVM, EDV,

VO2 p=0.003)

EF, LAD, E/A,

and change

E, E/e’, arterial

in thigh

stiffness.

SM:IMF ratio (r = 0.27, p=0.02)

CR (24)

-400 kcal/d CR

CR+ ET

-350 kcal/d

(22)

CR + Walk

Main effects CR: VO2peak, 6MWD, leg muscle quality, QoL (KCCQ), rest E/A; peak DBP, body weight, non-bone lean, fat (abdominal, subcut, visceral; thigh subcut), thigh SM; NYHA Class, rest LVM, h/R

Con (22) Smart

ET (12)

67

42

59

CYC

3

et al.

60–70 % VO2peak

201228

30

16

VO2peak; slope;

VE/VCO2

peak HR,

LVEF, CO, E, A, E/A, E, S, E/e’, DT, strain, strain rate Con (13)

62

54

57

increase = decrease; 1RM = one-repetition maximum; 6MWD = six-minute walk distance; A = atrial filling velocity; AE = arm ergometry; a–vO2Diff = arteriovenous oxygen difference; CI = cardiac index; CO = cardiac output; CR = caloric restriction; CYC = cycle; DBP = diastolic blood pressure; DD = diastolic dysfunction grade; DT = deceleration time; E = early filling velocity; e’ = early diastolic velocity of the mitral annulus; E/A = early to atrial filling velocity ratio; E/e’ = early mitral inflow velocity to early diastolic mitral annulus velocity ratio; EDV = end-diastolic volume; EF = ejection fraction; ESV = end-systolic volume; ET = exercise training; Freq = frequency; HFpEF = heart failure and preserved ejection fraction; HIIT = high-intensity interval training; h/R = relative wall thickness; HR = heart rate; HRmax = maximal heart rate; HRpeak = peak heart rate; HRR = heart rate reserve; IMF = intermuscular fat; IVTR = isovolumic relaxation time; KCCQ = Kansas City Cardiomyopathy Questionnaire; LAD = left atrial diameter; LAVI = left atrial volume index; LVEDVI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection fraction; LVIDd = left ventricular internal diameter in diastole; LVIDs = left ventricular internal diameter in systole; LVM = left ventricular mass; LVMI = left ventricular mass index; MICT = moderate-intensity continuous training; NT-proBNP = NYHA, New York Heart Association; QoL = quality of life; Reps = repetitions; S = systolic annular velocity; SM = skeletal muscle; Subcut = subcutaneous; SV = stroke volume; SVI = stroke volume index; TM = treadmill; VE/VCO2 = ventilation to carbon dioxide production slope; VL = vastus lateralis; Vnt = ventilator a threshold; VO2peak = peak oxygen uptake. *Whole group mean; same cohort as Kitzman et al. (2010).

intensity interval training (five 3-min sets of moderate-intensity [70–75 % maximal heart rate] treadmill walking or cycling interspersed with 1-min low-intensity active recovery) in patients with HFpEF. As shown in Figure 1, the increase in VO2peak after training is 2.2 ml/kg/min (~15  %), which is above the clinically meaningful change (1 ml/kg/min or 10  %) in VO2peak for patients with HF.34 The mechanisms responsible for the increased VO2peak may be due to cardiovascular or skeletal muscle adaptations that result in increased oxygen delivery and/or utilisation by the active muscles.

Exercise Training and Cardiac Function The decreased VO2peak in HFpEF is due, in part, to impaired left ventricular (LV) relaxation, increased LV diastolic stiffness3 and decreased cardiac output secondary to blunted chronotropic, ionotropic and vasodilator reserve.5, 6,35 Several studies have assessed changes in resting and exercise cardiac function following exercise training in HFpEF. Kitzman et al.27,31,32 and others28,30 reported that MICT does not change resting LV volumes, morphology or systolic or diastolic function in patients with HFpEF (see Table 1). In contrast, Edelmann et al. reported that MICT

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and supplemental resistance training resulted in a significant decrease in resting left atrial volume index and the ratio of early mitral inflow velocity and mitral annular early diastolic velocity (E/e’).25 Moreover, the increase in VO2peak was inversely related to the improvement in E/e’. Fu et al. extended these findings by showing that HIIT significantly reduced the E/e’ ratio in patients with HFpEF.26 Although these non-invasive measures suggested that exercise training may improve LV filling pressure, Fujimoto et al. found that 1 year of progressive and vigorous endurance exercise training did not change LV compliance in older patients with HFpEF including during cardiac (un)loading manoeuvres.36 Currently, only two studies have compared exercise cardiac function before and after exercise training in patients with HFpEF.26,37 Using 2D echocardiography, Haykowsky et al. measured rest, peak and reserve (peak minus rest) LV volumes and cardiac output and estimated arterial– venous oxygen difference (a–vO2Diff) before and after 16 weeks of MICT in older patients with HFpEF.37 The training-mediated increase in VO2peak was secondary to a significant increase in peak and reserve heart rate and a–vO2Diff with no change in peak or reserve end-diastolic volume, end-systolic volume, stroke volume or cardiac output.

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Heart Failure With Preserved Ejection Fraction Figure 1: Changes in VO 2peak Following ET or Non-exercise Ususal Care (UC) in Patients With HFpEF 30 Pre

∗ 25

Post

# ∗

VO2peak (ml/kg/min)

20

#

#

#

15

10

5

0 MICT

HIIT

Angadi et al. (2015)

UC

ET

Edelmann et al. (2011)

UC

HIIT

Fu et al. (2016)

UC

ET

Kitzman et al. (2010)

UC

ET

Kitzman et al. (2013)

UC

ET

Kitzman et al. (2016)

UC

ET

Smart et al. (2012)

ET = exercise training; HFpEF = heart failure with preserved ejection fraction; HIIT = high-intensity interval training; MICT = moderate-intensity continuous training; VO2peak; peak aerobic power. *p<0.05 within condition; #p<0.05 between conditions.

Using impedance cardiography, Fu et al. measured exercise cardiac output and estimated a–vO2Diff prior to and after 12 weeks of HIIT.26 Similar to the findings by Haykowsky et al.,37 the HIIT-mediated increase in VO2peak was secondary to the increased a–vO2Diff as peak heart rate, stroke volume index and cardiac index were unchanged after training.26 Accordingly, the increased VO2peak after MICT or HIIT appears to be due to non-cardiac peripheral adaptations that result in increased oxygen extraction by the active muscles.9

Exercise Training and Vascular Function Recent evidence suggests that HFpEF is associated with both macrovascular38,39 and microvascular dysfunction,40,41 and that these vascular changes directly relate to exercise intolerance.9,38,39,42 First, patients with HFpEF demonstrate increased arterial stiffness compared with healthy controls as measured by carotid arterial and proximal thoracic aortic distensibility using high-resolution ultrasound and MRI.9,38,39 Second, patients with HFpEF have also been shown to have impaired microvascular function, as measured by laser Doppler imaging coupled with iontophoresis of endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators.40 Together, these impairments are thought to contribute to reduced leg blood flow and leg vascular conductance during exercise.41,43 Interestingly, peripheral artery endothelial function is not significantly different in patients with HFpEF rigorously screened to exclude confounding effects of atherosclerosis compared with healthy agematched controls.42,44 Several investigators have examined the vascular effects of endurance exercise training in older patients with HFpEF.30–32 Kitzman et al. first reported that carotid arterial stiffness and brachial artery flow-mediated dilation (FMD) were not significantly different after 8 or 16 weeks of MICT.32 More recently, Kitzman et al. found that 20

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weeks of MICT did not change carotid–femoral pulse wave velocity (i.e. vascular stiffness).31 Angadi et al. confirmed and extended these findings by showing that brachial artery FMD was unchanged after 4 weeks of MICT or HIIT in older patients with HFpEF (see Table 1).30 Taken together, the few studies performed to date suggest that the benefits of MICT or HIIT likely derive from mechanisms other than alterations in central or peripheral vascular function in clinically stable patients with HFpEF (see Table 1). Future studies are required to examine the change in microvascular function following exercise training in HFpEF.

Changes in Skeletal Muscle Function With Exercise Training in Heart Failure With Preserved Ejection Fraction Patients with HFpEF exhibit multiple skeletal muscle abnormalities, including increased skeletal muscle adiposity, reduced percent of type I (oxidative) fibres and enzymes, decreased capillary:fibre ratio compared with healthy, age-matched controls; these alterations are associated with their severely reduced exercise tolerance.44,45 There is a paucity of studies that have examined the effect of exercise training on skeletal muscle function. Haykowsky et al. demonstrated that 84  % of the increase in VO2peak after MICT was attributed to improved a–vO2Diff.37 Although the mechanisms of improved oxygen extraction were not studied, they may be due to favourable changes in skeletal muscle quality, as MICT does not change skeletal muscle mass.31 Indeed, Fu et al. recently reported that 12 weeks of HIIT significantly increased estimated peak exercise a–vO2Diff and vastus lateralis muscle oxygenation.26 No study to date has examined changes in capillary density, fibre type or oxidative metabolism within skeletal muscle following exercise training. However, pilot work by Bhella et al. using 31phosphate

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The Impact of Exercise Training on Peak Oxygen Uptake in HFpEF

magnetic resonance spectroscopy demonstrated that leg muscle oxidative metabolism was reduced during exercise in a small number (n=2) of patients with HFpEF relative to healthy controls.46 Given that in patients with HFpEF skeletal muscle abnormalities are related to impaired exercise intolerance, future studies are required to examine the role of exercise (endurance and resistance) training to improve skeletal muscle morphology and oxidative capacity.47

Exercise Training-mediated Improvement in Peak Aerobic Power: Role of Training Intensity

14 and 52 weeks). The main finding was that exercise training improved VO2peak (weighted mean difference [WMD] of 2.3 ml/kg/min, 95 % confidence interval (CI) [1.3–3.2]), 6MWD (WMD of 30 min, 95 % CI [4.3–56.0]) and MLHFQ (8.9 points, 95  % CI [3.3–14.0]) compared with usual care. In contrast, cardiovascular drug intervention did not improve VO2peak, 6MWD or MLHFQ compared with placebo or no-treatment. More recent studies have examined the role of exercise training alone or combined with novel non-pharmacological therapy to improve exercise outcomes in patients with HFpEF.

HIIT is characterised by brief, intermittent bursts of vigorous aerobic exercise interspersed with periods of low-intensity active recovery. A recent meta-analysis comparing the effectiveness of HIIT versus MICT for improving VO2peak in HFrEF reported that HIIT is superior to MICT in improving VO2peak (weighted mean difference: 2.1 ml O2/kg/min).48 To date, only two randomised controlled trials have examined the effects of HIIT on VO2peak in HFpEF.26,30

In obese older adults without HF, weight loss via dietary caloric restriction (CR) improves LV mass and diastolic function, exercise capacity, glycaemic control, blood pressure regulation, body composition and skeletal muscle function. 51–56 However, CR is controversial as a treatment for HFpEF, as observational studies suggest that overweight and moderately obese patients with HFpEF survive longer than those who are normal or underweight.57 Therefore, current HFpEF management guidelines do not include diet or CR.58

Angadi and colleagues were the first to compare MICT versus HIIT on peak VO2 in older patients with HFpEF.30 The main finding was that HIIT resulted in a significant increase in peak VO2 (pre: 19.2 versus 21.0 ml/kg/min; p=0.04) with no change after MICT (pre: 16.9 versus 16.8 ml/kg/min; p=0.93).30 Fu et al. measured peak VO2 and its determinants after 12 weeks of HIIT in patients with HFpEF

Kitzman et al. recently compared the effects of 20 weeks of CR or endurance training alone, or in combination, on VO2peak and quality of life in older obese patients with HFpEF (see Table 1).31 Endurance exercise training (+1.2 ml/kg/min VO2) and CR (+1.3 ml/kg/min VO2) significantly increased VO2peak and 6MWD, while the change in VO2peak with combined endurance training and CR were additive

and HFrEF.26 Peak VO2 was significantly higher after HIIT; however, the mechanisms of improvement were dependent on underlying HF phenotype.26 Specifically, peak exercise heart rate, stroke volume index and cardiac index increased significantly with no change in peak a–vO2Diff in patients with HFrEF. Conversely, the increased VO2peak in patients with HFpEF was secondary to the increase in peak a–vO2Diff. Accordingly, the mechanisms responsible for the improvement in VO2peak may differ between patients with HFrEF and HFpEF.

(+2.5 ml/kg/min). Both exercise training and CR also reduced body weight and fat mass, while CR improved leg muscle quality and decreased abdominal and thigh subcutaneous fat. Finally, the change in VO2peak was positively correlated with the change in percent lean mass and the change in thigh muscle to intermuscular fat ratio. Further studies are needed to determine whether these favourable changes in body composition are associated with reduced clinical events in patients with HFpEF.

In summary, short-term HIIT is an effective training stimulus to improve VO2peak; however, the magnitude of improvement (mean change: +2.2 ml/kg/min VO2peak) is similar to that found after MICT (mean change: +1.9 ml/kg/min VO2peak). Currently, it is unknown if HIIT is superior to MICT in increasing VO2peak in studies lasting >3 months; however, a large, multicentre randomised controlled exercise training intervention trial (OptimEx-CLIN study) is currently ongoing to examine the optimal dose and intensity of exercise training (12 months of HIIT versus MICT versus control) to improve VO2peak in patients with HFpEF.49

Dietary inorganic nitrate supplementation, typically in the form of beetroot juice, has emerged as a novel strategy to lower blood pressure, and improve vascular health and exercise performance in patients with hypertension or HF.59–62 Inorganic nitrate, through its conversion to inorganic nitrite, targets nitric oxide delivery to areas of low oxygen content and may be a potential mediator of hypoxic vasodilation for exercising skeletal muscle.62 Furthermore, beetroot juice has been shown to improve exercise efficiency with multiple studies showing less oxygen consumed per unit of work performed.63,64

Novel Interventions in Heart Failure With Preserved Ejection Fraction

Zamani et al. performed a randomised, double-blind crossover study comparing a single dose of inorganic nitrate (12.9 mmol beetroot juice) with an identical nitrate-depleted placebo in 17 patients with HFpEF.62 Beetroot juice increased VO 2peak, total work performed and peak exercise cardiac output and reduced aortic augmentation index and systemic vascular resistance. Eggebeen et al. recently extended these findings by showing that 1 week of daily dosing with beetroot juice significantly improved submaximal aerobic endurance by 24 % and decreased resting blood pressure in older patients with HFpEF. 59 These findings suggest that acute and short-term delivery of dietary inorganic nitrate can increase VO 2peak and submaximal aerobic endurance in patients with HFpEF. Future, large-scale clinical trials are needed to determine whether dietary inorganic nitrate alone or combined with MICT or HIIT improve VO 2peak and its determinants.

Fukuta et al. recently conducted a meta-analysis of randomised controlled trials on the effect of cardiovascular drugs (eight studies, 1080 patients) or exercise training (five studies, 245 patients) intervention on VO2peak, six-minute walk distance (6MWD) and quality of life (measured with the Minnesota Living with Heart Failure Questionnaire [MLHFQ] total score) in patients with HFpEF.50 The training mode included aerobic exercise (walking, cycling, 20–60 minutes per session, 2–3 days/week) for 12–24 weeks (a substantial portion of participants in the exercise intervention trials were receiving standard HF medications). Cardiovascular drug interventions included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists or betablocker treatment (intervention duration ranged across trials between

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Heart Failure With Preserved Ejection Fraction Training Effects in Related Populations A special mention should be made of a recent observational study by Pathak et al. that demonstrated the efficacy of exercise training in obese patients with atrial fibrillation (AF; LV ejection fraction >40  %, mean average across groups E/E’ ratio = 12.1 and left atrial volume index = 39 ml/m2).65 Although patients with HFpEF were not independently identified in this study, the description of the cohort suggests that many patients likely met criteria for HFpEF. Among patients with obesity and AF, HFpEF is disproportionately represented, as are overlapping risk factors such as hypertension and diabetes (observed in ~75 % and ~25 % of the study cohort, respectively). It is also notable that approximately three-quarters of the cohort had an exercise capacity below expected norms and other measures of diastolic function were frequently abnormal. Thus, it may be reasonable to consider this study cohort under a broad umbrella of HFpEF. Pathak et al. employed a novel intervention that included a tailored exercise programme that incorporated a combination of aerobic and strength exercises (increasing ≥200 min of exercise per week) as part of a dedicated physician-led risk factor management clinic that aggressively treated hypertension, hyperglycaemia, dyslipidaemia, obstructive sleep apnoea and obesity.65 A favourable response to exercise training was defined as an increase in maximal exercise capacity of more than two metabolic equivalent of tasks

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(approximating >20 % improvement) and this was achieved in 127 of the 308 subjects (41 %). This impressive intervention was associated with multiple health benefits including a marked reduction in AF, an improvement in diastolic measures and a reduction in left atrial size. In the absence of clear evidence as to which component of the lifestyle and risk factor intervention was most crucial, this key study reinforces the importance of taking a holistic view to cardiovascular health in addition to exercise training in patients with HFpEF or related risk factors.

Conclusion Patients with HFpEF have severe exercise intolerance secondary to impaired cardiovascular and skeletal muscle function. The few randomised controlled exercise intervention trials performed to date demonstrate that endurance training alone or combined with resistance training is an effective therapy to increase VO2peak secondary to peripheral ‘non-cardiac’ factors that result in increased oxygen extraction by the active muscles. Unlike HFrEF, the mean change in VO2peak with HIIT (2.2 ml/kg/min) is similar to that found after MICT (1.9 ml/kg/min). Finally, exercise training combined with novel non-pharmacological interventions (CR or acute or 1 week of beetroot juice) has also been shown to improve VO2peak and aerobic endurance in patients with HFpEF, while broad-based risk factor interventions may enhance the benefits of exercise. ■

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Heart Failure With Preserved Ejection Fraction

Haemodynamics of Heart Failure With Preserved Ejection Fraction: A Clinical Perspective Ma uro G o r i , A t t i l i o I a c o v o n i a n d M i c h e l e S e n n i Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo, Italy

Abstract Despite the burden of heart failure (HF) with preserved ejection fraction (HFpEF), its pathophysiological mechanisms remain controversial and are likely to be multifactorial. Indeed, it has been suggested that HFpEF may represent “a forest of a variety of trees”, because of heterogeneity in pathophysiological mechanisms involved and phenotypic expression of the disease. A better understanding of HFpEF is crucial for the development of appropriate therapeutic targets. Recent studies on HFpEF have highlighted its particular haemodynamic features, and haemodynamic derangements are critical to both early and advanced stages of the disease. By definition, haemodynamic properties are determined by the result of the dynamic interchange between the heart, vasculature, and autonomic nervous system, which regulate the circulation of blood. Importantly, it has been shown that both intrinsic and extrinsic factors are implicated in the haemodynamic impairments typical of HFpEF patients. Thus, understanding of HFpEF haemodynamics requires consideration of the interplay between both cardiac and non-cardiac factors.

Keywords Heart failure with preserved ejection fraction, haemodynamics, diastolic dysfunction, cardiac factors, extra-cardiac factors Disclosure: The authors have no conflicts of interest to declare. Received: 15 September 2016 Accepted: 11 October 2016 Citation: Cardiac Failure Review 2016;2(2):102–5. DOI: 10.15420/cfr.2016:17:2 Correspondence: Michele Senni, MD, Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. E: msenni@hpg23.it

Despite the burden of heart failure (HF) with preserved ejection fraction (HFpEF),1 its pathophysiological mechanisms remain controversial and are likely to be multifactorial.2,3,4 The lack of a comprehensive paradigm applicable to all patients suggests that haemodynamic derangements responsible for this disorder may be quite heterogeneous. As recently highlighted, haemodynamic features of HFpEF involve both cardiac and extra-cardiac mechanisms. Studies on HFpEF have shown diastolic abnormalities, subtle systolic dysfunction, pulmonary hypertension, right ventricular dysfunction and chronotropic incompetence, in addition to ventricular–vascular mechanisms and abdominal factors. In this short review we highlight and discuss the different mechanisms characterizing HFpEF haemodynamics, which finally lead to elevated left ventricular end diastolic pressure (LVEDP), a common hallmark of this multifaceted syndrome (see Figure 1).

Cardiac Factors in HFpEF Haemodynamics Patients with HFpEF are considered to be predominantly elderly women with hypertension, left atrial enlargement, obesity, and with specific pathophysiological abnormalities in cardiac structure such as myocyte hypertrophy, interstitial fibrosis, inflammation, and microvascular dysfunction. Thus, it has been postulated that the signs and symptoms of HF may be primarily a consequence of progressive abnormalities in diastolic function domains.5 The importance of diastolic left ventricular dysfunction in HFpEF has been confirmed by the majority of invasive and non-invasive haemodynamic studies, which show uniform presence at rest of slow active left ventricle (LV) relaxation and elevated passive LV stiffness.5,6,7,8 Furthermore, it has been demonstrated that elevated diastolic LV stiffness may

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limit cardiac performance during exercise-associated tachycardia or rapid pacing.9 In contrast, Kawaguchi et al, using the multi-beat conductance catheter technique, demonstrated in a small group of patients and controls that ventricular-arterial stiffening was the predominant mechanism underlying elevated LVEDP. However, they did not show differences in relaxation and stiffness in subjects with HFpEF compared with HF-free controls.10 Therefore, other intrinsic mechanisms have been advocated in HFpEF haemodynamics, such as subtle systolic dysfunction, pulmonary hypertension and right ventricular (RV) dysfunction. While left ventricular ejection fraction (LVEF) is the most widely used index of systolic function, applied to distinguish HFpEF from mid-range and reduced LVEF HF patients,11 it is dependent on loading conditions and chamber size. Therefore, it is a poor measure of contractility. Importantly, it has been shown that HFpEF patients – despite the preserved LVEF – have subtle systolic dysfunction at rest, by means of reduced LV strain at echocardiographic imaging, and this dysfunction has prognostic relevance.12,13 Furthermore, it has been suggested that contractile dysfunction may contribute to inadequate myocardial response to efforts, leading to the appearance and aggravation of HF symptoms.14,15 Indeed, a recent study in HFpEF subjects examined cardiac systolic reserve during exercise and found that contractility increases were depressed.16 Therefore, the exercise test may unmask mild deficits in systolic function in HFpEF. Previous studies have also reported a high prevalence of pulmonary hypertension (PH) in HFpEF.17 Importantly, PH portends worse outcome

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substantially improve prediction of long-term mortality in patients with suspected HFpEF.25 Because this technique is mainly used in research institutions, a possible alternative is to perform a fluid challenge at the time of catheterisation, to confirm HFpEF presence,26 and eventually to differentiate PAH from PVH. In fact, a recent study showed that among 207 patients with a suspected diagnosis of PAH, one fifth developed elevated PAWP after a fluid bolus, and were reclassified as having PVH.27 Nonetheless, it is important to remember that approximately 20  % of normal adults may develop PAWP >15 mmHg with acute saline infusion.28 Overall, such data imply that many patients with PH may have an under-recognised component of PVH linked to left-sided HF, which is manifested more under conditions of exertion or volume loading.29 In particular, exercise stress testing or volume challenge are indicated at the time of invasive procedure for patients presenting with PH and normal PAWP who are obese and/or who have a dilated left atrium.30 However, there is not presently enough evidence on standardisation of these procedures. There are no validated cut-off values for a pathological haemodynamic response during exercise or after acute saline infusion that would allow a clear classification of HFpEF. Generating these values by performing diagnostic trials is of major importance, but at present it is difficult to recommend routine exercise haemodynamic testing and/or a volume challenge for clinical practice. Another invasive haemodynamic study has recently shown that RV dysfunction is common in HFpEF and is caused by both RV contractile impairment and afterload mismatch from PH.31 In this study, the factors associated with RV dysfunction were increasing pulmonary artery pressures, atrial fibrillation, male sex and LV dysfunction. It has also been demonstrated that patients with HFpEF display impaired RV reserve during exercise that is associated with high filling pressures and inadequate cardiac output responses.32 These findings highlight the importance of biventricular dysfunction in HFpEF haemodynamics.

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Figure 1: Schematic Representation of HFpEF Haemodynamics

RIGHT VENTRICULAR DYSFUNCTION

Impaired relaxation

PULMONARY HYPERTENSION

actin myosin Ca++

VASCULAR STIFFNESS

DIASTOLIC DYSFUNCTION Stiffness

CARDIAC FACTORS

SUBTLE SYSTOLIC DYSFUNCTION

ABDOMINAL MECHANISMS

EXTRA-CARDIAC FACTORS

in HFpEF patients.18,19 It has been shown that the degree of PH is similar in subjects with HFpEF and HF with reduced ejection fraction (HFrEF), and is largely reversible with acute infusion of sodium nitroprusside. However, the combined potentially greater risk of hypotension or depression of stroke volume suggests that vasodilator-based approaches may not be as broadly applicable to HFpEF as they are to HFrEF.20 Another study has shown that pulmonary artery systolic pressure (PASP) rises along with pulmonary artery capillary wedge pressure (PAWP) in patients with both hypertension and HFpEF.18 However, PASP remains higher in HFpEF, even when adjusting for PAWP, suggesting a pre-capillary component to PH on top of pulmonary venous hypertension (PVH).18 Distinguishing these factors may be difficult. By definition, an elevated PAWP (i.e. >15 mmHg) characterises PVH, while pulmonary arterial hypertension (PAH) is typically associated with a normal PAWP. Of note, estimation of PAWP by non-invasive methods is suboptimal. This is because the most used echocardiographic index of elevated PAWP – E/E’ – has been shown to be only modestly correlated with supine PAWP in patients with unexplained dyspnoea and preserved LVEF and, in general, this index lacks sensitivity.21,22,23 Therefore invasive evaluation currently provides more reliable diagnostic information (see Table 1). Of note, PAWP obtained at the time of right heart catheterisation is influenced by resting conditions and the patient’s volume status at the time of the procedure. Indeed, it has been demonstrated that resting haemodynamics may be normal, while performing right heart catheterisation during supine exercise may unmask a diagnosis of HFpEF.24 Furthermore, invasive exercise testing may

CHRONOTROPIC INCOMPETENCE

LVEDP Rest and / or exercise

HF signs and symptoms HF hospitalization

HFpEF haemodynamics result from the tight interplay of both cardiac and non-cardiac factors. HF = heart failure; HFpEF = heart failure with preserved ejection fraction; LVEDP = left ventricular end diastolic pressure.

Table 1: Haemodynamic Parameters at Rest in Healthy Adults and HFpEF Patients Healthy adults

Early HFpEF

Advanced HFpEF

RAP (mmHg)

0–6

0–8

≥10

Mean PAP (mmHg)

<20

<20

≥25

PAWP (mmHg)

6–15

6–18

≥20

LVEDP (mmHg)

<16

<16

≥16

HFpEF = heart failure with preserved ejection fraction; LVEDP = left ventricular end diastolic pressure; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; RAP = right atrial pressure. Adapted from Andersen et al., 2014.46

Chronotropic incompetence represents another important characteristic of HFpEF, which has been described in approximately 30  % of patients.33,34,35 Indeed, chronotropic reserve is depressed in HFpEF even when compared with older, age-matched controls, independently from rate-lowering medication use. Chronotropic incompetence may help to partially explain why most patients with HFpEF complain of symptoms only during physical exertion. Since the increase in plasma catecholamine with exercise is similar in HFpEF and healthy controls, it has been suggested that chronotropic incompetence may be related to deficits in beta-adrenergic stimulation.33 Additionally, autonomic dysfunction may be a contributing factor, as heart rate recovery is abnormal and baroreflex sensitivity impaired in HFpEF.34

Extrinsic Factors in HFpEF Haemodynamics An alternative model for HF development in HFpEF patients underscores the contribution of non-myocardial factors to systolic and diastolic LV performance. Cardiac function is affected by the net balance between afterload and preload.36 Central aortic stiffness, increasing systolic load and negatively affecting ventricular–vascular coupling, may accelerate HF development in at-risk patients. Of note, aortic stiffness increases with age, particularly in women with hypertension, and is a precursor of incident HF. 37,38 To preserve adequate coupling among the heart and the arterial system, ventricular systolic stiffening also

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Heart Failure With Preserved Ejection Fraction HFpEF Haemodynamics: Critical Appraisal

Figure 2: Differences in Left Ventricular and Left Atrial Pressure Recordings LV

LA

LV + LA LV A-wave LV

LV A-wave

V-wave LV A-wave

LV EDP

LV pre-A LV RFW LVmin

LA

Mean LAP

V

A

LA

X Y

Left panel: LV diastolic pressure recording. Arrows point to LV minimal pressure (min), LV RFW, LV pre-A pressure, A wave rise with atrial contraction and EDP. Middle panel: LA pressure recording showing V- and A-waves marked along with Y and X descent. Right panel: simultaneous LV and LA pressure recording showing differences in LVEDP and LA pressure. LA = left atrial; LV = left ventricular; LVEDP = LV end diastolic pressure; RFW = rapid filling wave. Source: Nagueh SF et al.49 Reproduced with permission from Oxford University Press, ©2016.

increases, and this combined ventricular–vascular stiffening is a hallmark of HFpEF.10,39 This limits LV systolic reserve, increases the cardiac energy demands required to enhance cardiac output, and plays a central role in arterial pressure liability accompanying small changes in LV preload.10 Other extrinsic factors advocated in HFpEF haemodynamics comprise abdominal mechanisms. In many HFpEF patients fluid retention may occur in the abdominal cavity, with bowel congestion leading to endotoxin translocation and systemic inflammation. In the same way, systemic inflammation may also be induced by comorbidities such as obesity, diabetes mellitus or chronic obstructive pulmonary disease that are highly prevalent in these patients, and this has been suggested as a possible cause of myocardial structural and functional alterations.40,41 Of note, the increased neurohormonal activation typical of HF results in venoconstriction, with impaired capacitance function of the splanchnic vasculature. Increased capillary hydrostatic pressure leads to a rise in intra-abdominal pressure and eventually also to organ dysfunction. Indeed, HFpEF is frequently associated with renal impairment, as chronic kidney disease (CKD) occurs in up to two thirds of HFpEF patients and is associated with poor prognosis.42,43,44 There is a bidirectional link between HFpEF and CKD, as it has been shown that venous congestion may lead to CKD and, vice versa, renal impairment begets congestion and HF. Renal impairment causes metabolic derangements and affects circulating factors causing an activated systemic inflammatory state and endothelial dysfunction. This may lead to hypertrophy, myocardial stiffening, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte, finally causing haemodynamic impairments.45

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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 Senni M, Paulus WJ, Gavazzi A, et al. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014;35 :2797–815. DOI: 10.1093/eurheartj/ehu204; PMID: 25104786 D’Elia E, Vaduganathan M, Gori M, et al. Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. Eur J Heart Fail 2015;17:1231–9. DOI: 10.1002/ejhf.430; PMID: 26493383 Shah AM, Pfeffer MA. The many faces of heart failure with preserved ejection fraction. Nat Rev Cardiol 2012;9 :555–6. DOI: 10.1038/nrcardio.2012.123; PMID: 22945329 Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure— abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350 :1953–9. DOI: 10.1056/ NEJMoa032566; PMID: 15128895 Phan TT, Abozguia K, Nallur Shivu G, et al. Heart failure with

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While diastolic dysfunction was originally considered pathognomonic in HFpEF haemodynamics,5,6,7,8,9 abnormalities of active LV relaxation and/or passive stiffness have been described by most but not all invasive haemodynamic studies.10 There are different reasons for these discrepancies, such as heterogeneity in study populations, differences in control groups, the use of invasive or non-invasive studies, or examinations being performed only at rest or also during effort. Additionally, a major challenge to the field is that truly representative experimental models of HFpEF do not exist, and human data – particularly direct myocardial analysis – remain limited, with very small populations having been studied. There are no data from beating muscle or cells from human hearts, and existing animal models fail to capture the complexity of the human disease. Furthermore, it should be emphasised that only left heart catheterisation allows for direct measurement of LVEDP, as well as the kinetics of relaxation and passive chamber stiffness through pressure-volume recordings (PV loops). However, these assessments require highfidelity micromanometer and conductance catheter systems, which are demanding techniques that are not easily reproducible and not widely available in clinical settings. Of note, even though it has been suggested that a high-quality PAWP tracing is just as robust as directly measured LVEDP,46 this assumption is incorrect in the case of LV disease. This is because a strong atrial contribution to LV filling can occur in this condition, which can translate in a LVEDP considerably higher than the mean left atrial pressure and PAWP (see Figure 2).47 Overall, these considerations seem to suggest that diastolic dysfunction may still have a central role in HFpEF haemodynamics, although it may be demanding to prove it in clinical and experimental studies (see Figure 1). Finally, the recognition of diastolic LV dysfunction as the predominant mechanism underlying HFpEF haemodynamics does not necessarily imply that the latter represents the sole contributor to haemodynamic derangements. Indeed, numerous other mechanisms have been recently identified and may play important roles. Among these, both cardiac and extra-cardiac factors should be assessed to adequately interpret HFpEF haemodynamics. However, it should be emphasised that ultimately most of these mechanisms negatively affect LVEDP, which represents the hallmark of HFpEF, together with normal LV dimensions and preserved LVEF. Raised LVEDP justifies HF signs and symptoms, may lead to myocardial ischemia, fibrosis, and structural impairment, and portends adverse prognosis in HFpEF patients. An approach centred on the specific pathophysiological abnormalities in cardiac structure and function, in particular diastolic dysfunction, may be more effective for therapeutic discovery.48 ■

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PMID: 18617626 39. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 2007;115 :1982–90. DOI: 10.1161/ CIRCULATIONAHA.106.659763; PMID: 17404159 40. 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 41. Paulus WJ, Tschöpe C. A Novel Paradigm for Heart Failure with Preserved Ejection Fraction: Comorbidities Drive Myocardial Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation. J Am Coll Cardiol 2013;62 :263–71. DOI: 10.1016/j.jacc.2013.02.092; PMID: 23684677 42. Gori M, Senni M, Gupta DK, et al; PARAMOUNT Investigators. Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction. Eur Heart J 2014;35 :3442–51. DOI: 10.1093/ eurheartj/ehu254; PMID: 24980489 43. Rusinaru D, Buiciuc O, Houpe D, et al. Renal function and long-term survival after hospital discharge in heart failure with preserved ejection fraction. Int J Cardiol 2011;147 :278–82. DOI: 10.1016/j.ijcard.2009.09.529; PMID: 19896733 44. Brouwers FP, de Boer RA, van der Harst P, et al. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community based cohort: 11-year follow-up of PREVEND. Eur Heart J 2013;34 :1424–31. DOI: 10.1093/eurheartj/eht066; PMID: 23470495 45. Ter Maaten JM, Damman K, Verhaar MC, et al. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail 2016;18 :588–98. DOI: 10.1002/ ejhf.497; PMID: 26861140 46. Andersen MJ, Borlaug BA. Invasive hemodynamic characterization of heart failure with preserved ejection fraction. Heart Fail Clin 2014;10:435–44. DOI: 10.1016/ j.hfc.2014.03.001; PMID: 24975907 47. Peverill RE. “Left ventricular filling pressure(s)” - Ambiguous and misleading terminology, best abandoned. Int J Cardiol 2015;191 :110–3. DOI: 10.1016/j.ijcard.2015.04.254; PMID: 25965616 48. Senni M, Gavazzi A, Gheorghiade M, et al. Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart. Eur J Heart Fail 2015;17 :760–3. DOI: 10.1002/ejhf.453; PMID: 26647216 49. Nagueh SF, Smiseth OA, Appleton CP, et al; Houston, Texas; Oslo, Norway; Phoenix, Arizona; Nashville, Tennessee; Hamilton, Ontario, Canada; Uppsala, Sweden; Ghent and Liège, Belgium; Cleveland, Ohio; Novara, Italy; Rochester, Minnesota; Bucharest, Romania; and St. Louis, Missouri. 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. Eur Heart J Cardiovasc Imaging 2016; DOI: 10.1093/ehjci/jew082; PMID: 27422899: epub ahead of press.

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Expert Opinion Cognitive Decline in Heart Failure: More Attention is Needed . . J elena Cˇ elutk iene, 1 Aruˉ n a s V a i t k e v i cˇ i u s , 2 S i l v i j a J a k š t i e n e 3 a n d D a l i u s J a t u ž i s 2 1. Department of Cardiovascular Diseases, Vilnius University, Vilnius, Lithuania; 2. Department of Neurology and Neurosurgery, Vilnius University, Vilnius, Lithuania; 3. Department of Radiology, Lithuanian University of Health Sciences, Vilnius, Lithuania

Abstract Cognitive decline is a prevalent condition and independent prognostic marker of unfavourable outcomes in patients with heart failure. The highest prevalence, up to 80 %, is reported in patients hospitalised due to acute decompensation. Numerous factors contribute to cognitive dysfunction in heart failure patients, with hypertension, atrial fibrillation, stroke and impaired haemodynamics being the most relevant. Cerebral hypoperfusion, disruption of blood–brain barrier, oxidative damage and brain-derived cytokines are pathogenic links between heart failure and alteration of cognitive functioning. White matter hyperintensities, lacunar infarcts and generalised volume loss are common features revealed by neuroimaging. Typically affected cognitive domains are presented. Assessment of cognitive functioning, even by simple screening tests, should be part of routine clinical examination of heart failure patients.

Keywords Cognitive impairment, heart failure, adherence, adverse outcomes, cognitive domains, patient self-care Disclosure: The authors have no conflicts of interest to declare. Received: 21 September 2016 Accepted: 13 October 2016 Citation: Cardiac Failure Review 2016;2(2):106–9. DOI: 10.15420/cfr.2016:19:2 Correspondence: Jelena Cˇ elutkiene˙, Santariškiu˛ 2, LT 08661, Vilnius, Vilnius University hospital Santariškiu˛ Klinikos, A corpus, room A229, Vilnius, Lithuania. E: Jelena.celutkiene@santa.lt

To ensure performance of everyday tasks, adherence to treatment regiments, appointments, and following dietary requirements, cognition is crucial.1 Cognitive impairment (CI) is a broad and inclusive term used to describe dysfunction of processes in various cognitive domains, such as attention, memory, judgment, reasoning, decision-making and problem solving, comprehension and production of language.

Prevalence and Pathogenic Mechanisms Evidence is mounting that impaired cardiac function may precipitate early-onset CI. Reported prevalence2–8 of cognitive dysfunction in the heart failure (HF) population parallels the severity of HF, being the highest in the acute decompensation settings (see Table 1). Multiple factors contributing to cognitive decline in HF are presented in Figure 1. Hypertension is found to be independently associated with CI9,10 through compromise in auto-regulation of cerebral blood flow and cerebral ischaemia (see Figure 2). Neuroimaging has revealed structural brain abnormalities (see Figure 3) correlating with reduced cognition. Cognitive impairment has been identified as an important clinical issue in numerous recently conducted studies, though no definite consensus has been achieved so far regarding optimal diagnostics and treatment tools in patients suffering both from HF and CI. There is a definite limitation on this issue in the literature as investigators have used plenty of different tools ranging from simple and fast tests to neuropsychological test batteries, and the assessment of cognition has not been standardised. The common approach should

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be thoroughly investigated and reached using existing data and future clinical studies.

Cognitive Domains and Assessment Tools The severity of CI may range from mild symptoms to advanced dementia. Mild CI is a commonly used definition for a clinical syndrome in which a patient has subjective complaints as well as objective symptoms of cognitive decline (measured by neuropsychological tests), though daily functioning of the patient is mostly intact.11 It is established that patients with mild cognitive impairment have an increased risk of progression to dementia.12,13 Dementia is characterised by a progressive impairment in more than one cognitive domain, and compromised daily functioning is evident. Most of the HF patients suffer from mild impairment in cognition, but some of them may have moderate-to-severe CI.13 Heart failure adversely affects various cognitive domains, including attention, learning ability and working memory, executive functions, and information processing speed (see Figure 4).13–15 Cognitive impairment in HF patients usually fulfils the criteria of vascular CI or vascular dementia.16 Being one of the most important cognitive functions, episodic memory of specific personal events and experiences was demonstrated to slowly decline in HF patients.5,13,14,17 Furthermore, deficits in initial learning as well as delayed information recall were reported in the literature.17 This suggests that CI in HF patients and CI in patients with vascular dementia could share pathophysiological mechanisms.18 Deficits in executive functioning (problem solving, planning, reasoning and flexibility) have a

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Table 1: Reported Prevalence Rate of Cognitive Dysfunction (CD) in Heart Failure Patients Author (year)

Study type

Setting

N

Prevalence

Prevalence of

CD test used

mild CD (%) NA

MMSE

Zuccala et al.2 (1997)

Cross-sectional

Mild–moderate CHF

57

of CD (%) 53

Debette et al. (2007)

Prospective

Hospitalisation for AHF

83

61

30

MMSE

Gure et al.4 (2012)

Cross-sectional

Community (USA)

6,189

39

24

Telephone interview for cognitive

Hajduk et al.5 (2013)

Prospective

Hospitalisation for AHF

577

79

NA

Specific protocol*

3

status (patterned MMSE) Dodson et al.6 (2013)

Prospective

Hospitalisation for AHF

282

47

25

MMSE due to AHF

Levin et al.7 (2014)

Prospective

Hospitalisation for AHF

744

80

32

Specific protocol*

Hyunh et al.8 (2016)

Longitudinal

Hospitalisation for AHF

565

45

NA

MoCA

*Specific bedside protocol: test of immediate and delayed memory (subscale of MoCA), processing speed (Digit Symbol Substitution Test, DSST) and executive function (Controlled Oral Word Association Test [COWA] for verbal fluency). AHF = acute heart failure; CHF = chronic heart failure; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment.

Figure 1: Contributing Factors to Cognitive Dysfunction in Heart Failure STROKE ARTERIAL HYPERTENSION

REDUCED PHYSICAL ACTIVITY UNDERNUTRITION

ATRIAL FIBRILLATION

DEPRESSION MEDICATIONS

CHRONIC OR INTERMITTENT CEREBRAL HYPOPERFUSION • reduced ejection fraction • reduced cardiac output • impaired diastolic filling • low systolic blood pressure

METABOLIC/HUMORAL ABNORMALITIES CO-MORBIDITIES

• atherosclerosis • diabetes • anaemia/iron deficiency

• increased homocysteine • elevated BNP • hyponatraemia • low serum albumin • low testosterone (males)

BNP = brain natriuretic peptide.

strong impact on the patient’s everyday life and are common in cases of frontotemporal and vascular dementia, and are also detected in HF patients.19 Importantly, depression should be considered during the evaluation of patients with HF as a common treatable disorder in elderly persons having chronic diseases. Depression markedly compromises cognitive functioning and treatment adherence in HF patients.9,19 A number of neuropsychological tests for measurement of cognitive functioning are available, yet some of them are time-consuming and require special training. There is a need for tests that are informative, yet short and easy to administer in everyday clinical practice. Currently, there is no consensus regarding the optimal battery of neuropsychological tests to assess patients with HF. Brief screening instruments to administer in an outpatient clinical practice, the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA), are the most widely used screening tests in the literature. Some studies reported an association between the left ventricular ejection fraction and the MMSE scores.2 Both tools are 30-point tests to assess basic cognitive domains, the presence of and severity of CI. Cut-off scores of ≤24 are usually used to diagnose mild CI.20 Though the MMSE and the MoCA are useful tests for screening patients with CI, they could be insufficient in identifying subtle cognitive dysfunction, and more detailed neuropsychological tools may be required.21

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Importance of Cognitive Decline for Prognosis and Self-care Several prospective and cross-sectional studies showed a strong independent association of cognitive deterioration and increase in mortality and readmissions in acute heart failure (AHF) patients.2,6,8,10,22,23 A twofold increase in 30-day death and readmissions,8 almost fivefold rates of 1-year mortality,23 as well as increase in hospitalisation and/or death within 5 years were demonstrated.22 Such association with poor outcomes is observed even in cases of mild CI,8 which frequently remains undiagnosed. Dodson et al. found that patients with unrecognised cognitive decline exhibited a higher 6-month mortality and hospital readmissions.6 Intact memory and executive function are necessary to recognise worsening symptoms, adhere to medication regimens and numerous lifestyle modifications, follow scheduled clinic visits, and comply with dietary recommendations. Even mild cognitive deficits may interfere with adherence to self-care practices.5,24 Memory and executive function impairments are independently associated with worse instrumental activity, especially with a decreased ability to manage medications.9,10,25

Possible Ways to Prevent Cognitive Impairment Evidence of therapeutic methods for prevention and management of cognitive decline in HF is lacking. The primary approach to the management of the HF patients with CI seems to be optimal pharmacotherapy, outlined in the HF guidelines,26 restoring central haemodynamics, as well as correction of vascular risks factors. Several studies demonstrated that patients with mild CI can return to normal cognitive functioning.27 The beneficial influence of HF treatment on cognition processes including angiotensin-converting enzyme inhibitors, diuretics, digoxin, cardiac resynchronisation therapy and heart transplantation were reported.28–31 Clinical trials (such as the Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients with Heart Failure and Preserved Ejection Fraction [PERSPECTIVE] trial; NCT02884206) investigating the impact of treatment with angiotensin receptor neprilysin inhibitors and computerised adaptive cognitive training on cognitive function are ongoing.32 Non-pharmacological measures, such as physical activity, are also important and have been identified to have beneficial effects on cognition as well as protective benefits on brain plasticity in vascular CI and related conditions.33,34 The main task for physicians is to identify patients with early stages of CI in order to start corrective measures as soon as possible and also manage patients at risk of CI.35

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Comorbidities Figure 2: Pathogenic Links of Heart Failure and Cognitive Dysfunction

HEART FAILURE Reduced ejection fraction, cardiac output Impaired diastolic filling Low systolic blood pressure

ARTERIAL HYPERTENSION

CHRONIC/INTERMITTENT CEREBRAL HYPOPERFUSION

HYPOXIA HIF-1

ATRIAL FIBRILLATION, ATHEROSCLEROSIS Brain

Blood VASCULAR REMODELING ENDOTHELIAL DYSFUNCTION

DISRUPTION OF BRAIN−BLOOD BARRIER

METABOLIC/HUMORAL ABNORMALITIES • ↑elevated BNP • hyponatraemia • ↑homocysteine

Brain

OXIDATIVE DAMAGE

STROKES BRAIN-DERIVED CYTOKINES

PROINFLAMMATORY CYTOKINES IL-1, IL-6, TNF-alpha INDIRECT CAUSES • diabetes • depression • anaemia • ↓nutrition, etc.

COGNITIVE DYSFUNCTION BNP = brain natriuretic peptide; HIF-1 = hypoxia inducible factor-1; IL-1 = interleukin-1; IL-6 = interleukin-6; TNF-alpha = tumour necrosis factor-alpha.

Figure 3: Magnetic Resonance Imaging of Structural Brain Abnormalities in Patients with Cognitive Dysfunction

A

B

C

D

A: Confluent hyperintense changes in the periventricular white matter consistent with small vessel ischaemic changes associated with generalised brain volume loss. B: Multifocal chronic small vessel ischaemic changes, predominantly affecting frontal lobes, and associated with a lacunar infarct on the right side. C: Lacunar infarcts bilaterally in the thalami and small vessel ischaemic changes affecting frontal periventricular white matter and associated generalised brain volume loss. D: Haemosiderin staining bilaterally in the thalami and left occipital lobe due to microbleeds.

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Figure 4: Cognitive Domains Typically Affected in Heart Failure Patients

ATTENTION (CONCENTRATION) Focusing the mind on one task at a time, blocking distractions

VISUAL-SPATIAL FUNCTION

Conclusion

PROCESSING SPEED Ability to perform sequences of tasks with smoothness, accuracy and coordination EXECUTIVE FUNCTIONS Decision-making, planning, solving problems, functioning in social structures, adapting to unexpected circumstances REACTION TIME

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

LEARNING

WORKING MEMORY Short-term storage and manipulation of information

Borson S. Cognition, aging, and disabilities: conceptual issues. Phys Med Rehabil Clin N Am 2010;21 :375–82. DOI: 10.1016/j.pmr.2010.01.001; PMID: 20494283 Zuccala G, Cattel C, Manes-Gravina E, et al. Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure. J Neurol Neurosurg Psychiatry 1997;63 :509–12. DOI: 10.1136/jnnp.63.4.509; PMID: 9343133 Debette S, Bauters C, Leys D, et al. Prevalence and determinants of cognitive impairment in chronic heart failure patients. Congest Heart Fail 2007;13 :205–8. DOI: 10.1111/j.1527-5299.2007.06612.x; PMID: 17673872 Gure TR, Blaum CS, Giordani B, et al. The prevalence of cognitive impairment in older adults with heart failure. J Am Geriatr Soc 2012;60 (9):1724–9. DOI: 10.1111/j.15325415.2012.04097.x; PMID: 22882000 Hajduk AM, Lemon SC, McManus DD, et al. Cognitive impairment and self-care in heart failure. Clin Epidemiol 2013;5 :407–16. DOI: 10.2147/CLEP.S44560; PMID: 24187511; PMCID:PMC3810196 Dodson JA, Truong TT, Towle VR, et al. Chaudhry, Cognitive impairment in older adults with heart failure: prevalence, documentation, and impact on outcomes. Am J Med 2013;126 :120–6. DOI: 10.1016/j.amjmed.2012.05.029; PMID: 23331439; PMCID:PMC3553506 Levin SN, Hajduk AM, McManus DD, et al. Cognitive status in patients hospitalized with acute decompensated heart failure. Am Heart J 2014;168 :917–23. DOI: 10.1016/j. ahj.2014.08.008; PMID: 25458656 Hyunh QL, Negishi K, Blizzard L, et al. Mild cognitive impairment predicts death and readmission within 30 days of discharge for heart failure. Int J Cardiol 2016;221 :212–7. DOI: 10.1016/j.ijcard.2016.07.074; PMID: 27404677 Alosco ML, Brickman AM, Spitznagel MB, et al. The independent association of hypertension with cognitive function among older adults with heart failure. J Neurol Sci 2012;323 :216–20. DOI: 10.1016/j.jns.2012.09.019; PMID: 23026535 Ampadu J, Morley JE. Heart failure and cognitive dysfunction. Int J Cardiol 2015;178 :12–23. DOI: 10.1016/j.ijcard.2014.10.087; PMID: 25464210 Lopez OL, Becker JT, Jagust WJ, et al. Neuropsychological characteristics of mild cognitive impairment subgroups. J Neurol Neurosurg Psychiatry 2006;77 :159–65. DOI: 10.1136/ jnnp.2004.045567; PMID: 16103044 Fleisher AS, Sowell BB, Taylor C, et al. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 2007;68 :1588–95. DOI: 10.1212/01. wnl.0000258542.58725.4c; PMID: 17287448 Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail 2007;9 :440–9. DOI: 10.1016/ j.ejheart.2006.11.001; PMID: 17174152

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There are no particular approved medicines for patients with CI in HF. Given that acetylcholinesterase inhibitors and memantine were found to be effective in vascular dementia, a similar effect might be expected in patients with HF, though no formal regulatory approvals have been received.36,37

Cognitive decline is a prevalent condition and an independent prognostic marker of adverse outcomes in patients with HF. Assessment of cognitive functioning, even by simple screening tests, should be part of routine clinical examinations of HF patients. Despite evolving data in clinical practice, CI is still the challenge for clinicians. Future research including cognitive function as a relevant endpoint of HF studies is warranted. Better understanding of pathogenic links between CI and HF including molecular, neuroendocrine, epigenetic and psychosocial factors is needed. It is important to uncover the relationship between cognitive function and HF types and co-morbidities, use of cardiovascular drugs and devices. Furthermore, more randomised and controlled trials should be initiated to provide additional data and implement diagnostic, prevention and management tools for CI in patients with HF. ■

14. Vogels RL, Oosterman JM, van Harten B, et al. Profile of cognitive impairment in chronic heart failure. J Am Geriatr Soc 2007;55 :1764–70. DOI: 10.1111/j.1532-5415.2007.01395.x; PMID: 17727641 15. Pressler SJ, Subramanian U, Kareken D, et al. Cognitive deficits in chronic heart failure. Nurs Res 2010;59 (2):127–39. DOI: 10.1097/NNR.0b013e3181d1a747; PMCID: PMC2922920 16. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2011;42 :2672–713. DOI: 10.1161/STR.0b013e3182299496; PMID: 21778438 17. Mapelli D, Bardi L, Mojoli M, et al. Neuropsychological profile in a large group of heart transplant candidates. PLoS One 2011;6 :e28313. DOI: 10.1371/journal.pone.0028313; PMID: 22180780 18. Moorhouse P, Rockwood K. Vascular cognitive impairment: current concepts and clinical developments. Lancet Neurol 2008;7 :246–55. DOI: 10.1016/S1474-4422(08)70040-1; PMID: 18275926 19. Foster ER, Cunnane DF, Edwards DE, et al. Executive dysfunction and depressive symptoms associated with reduced participation of people with severe congestive heart failure. Am J Occup Ther 2011;65 :306–13. DOI: 10.5014/ ajot.2011.000588; PMID: 21675336 20. Cameron J, Worrall-Carter L, Page K, et al. Screening for mild cognitive impairment in patients with heart failure: Montreal Cognitive Assessment versus Mini Mental State Exam. Eur J Cardiovasc Nurs 2013;12 :252–60. DOI: 10.1177/1474515111435606; PMID: 22514141 21. Hawkins MA, Gathright EC, Gunstad J, et al. The MoCA and MMSE as screeners for cognitive impairment in a heart failure population: a study with comprehensive neuropsychological testing. Heart Lung 2014;43 :462–8. DOI: 10.1016/j.hrtlng.2014.05.011; PMID: 25035250 22. McLennan SN, Pearson SA, Cameron J, Stewart S. Prognostic importance of cognitive impairment in chronic heart failure patients: does specialist management make a difference? Eur J Heart Fail 2006;8 :494–501. DOI: 10.1016/ j.ejheart.2005.11.013; PMID: 16504580 23. Zuccalà G, Pedone C, Cesari M, et al. The effects of cognitive impairment on mortality among hospitalized patients with heart failure. Am J Med 2003;115 :97–103. PMID: 12893394 24. Hughes TF, Snitz BE, Ganguli M. Should mild cognitive impairment be subtyped? Curr Opin Psychiatry 2011;24 :237–42. DOI: 10.1097/YCO.0b013e328344696b; PMID: 21346570 25. Alosco ML, Spitznagel MB, Raz N, et al. Executive dysfunction is independently associated with reduced functional independence in heart failure. J Clin Nurs 2014;23 :829–36. DOI: 10.1111/jocn.12214; PMID: 23650879 26. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart

27.

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33.

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36.

37.

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 Canevelli M, Grande G, Lacorte E, et al. Spontaneous reversion of mild cognitive impairment to normal cognition: a systematic review of literature and meta-analysis. J Am Med Dir Assoc 2016;17 :943–8.DOI: 10.1016/j.jamda.2016.06.020; PMID: 27502450 Almeida OP, Tamai S. Clinical treatment reverses attentional deficits in congestive heart failure. BMC Geriatr 2001;1 :2. DOI: 10.1186/1471-2318-1-2; PMID: 11604103 Hoth KF, Poppas A, Ellison KE, et al. Link between change in cognition and left ventricular function following cardiac resynchronization therapy. J Cardiopulm Rehabil Prev 2010;30 :401–8. DOI: 10.1097/HCR.0b013e3181e1739a; PMID: 20562712 Zuccalà G, Onder G, Marzetti E, et al. Use of angiotensinconverting enzyme inhibitors and variations in cognitive performance among patients with heart failure. Eur Heart J 2005;26 :226–33. DOI: 10.1093/eurheartj/ehi058; PMID: 15618043 Roman DD, Kubo SH, Ormaza SG, et al. Memory improvement following cardiac transplantation. J Clin Expl Neuropsychol 1997;19 :692–7. DOI: 10.1080/01688639708403754; PMID: 9408799 Tang Y, Zhu Z, Liu Q, et al. The efficacy of cognitive training in patients with vascular cognitive impairment, no dementia (the Cog-VACCINE study): study protocol for a randomized controlled trial. Trials 2016;17 (1):392. DOI: 10.1186/s13063016-1523-x; PMID: 27496126 Carles S Jr, Curnier D, Pathak A, et al. Effects of short-term exercise and exercise training on cognitive function among patients with cardiac disease. J Cardiopulm Rehabil Prev 2007;27 :395–9. DOI: 10.1097/01.HCR.0000300268.00140.e6; PMID: 18197075 Sofi F, Valecchi D, Bacci D, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med 2011;269 :107–17. DOI: 10.1111/j.13652796.2010.02281.x; PMID: 20831630 Selnes OA, Royall RM, Grega MA, et al. Cognitive changes 5 years after coronary artery bypass grafting: is there evidence of late decline? Arch Neurol 2001;58 :598–604. PMID: 11295990 Román GC, Salloway S, Black SE, et al. Randomized, placebocontrolled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size. Stroke 2010;41 :1213– 21. DOI: 10.1161/STROKEAHA.109.570077; PMID: 20395618 Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 2007;6 :782–92. DOI: 10.1016/S14744422(07)70195-3; PMID: 17689146

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Expert Opinion Depression in Patients with Heart Failure: Is Enough Being Done? Ama m Mb a k w e m , F r a n c i s A i n a a n d Ca s m i r A m a d i Department of Medicine, University of Lagos, Lagos, Nigeria

Abstract Depression is a major issue in heart failure (HF). Depression is present in about one in five HF patients, with about 48  % of these individuals having significant depression. There is a wide variation in reported prevalences because of differences in the cohorts studied and methodologies. There are shared pathophysiological mechanisms between HF and depression. The adverse effects of depression on the outcomes in HF include reduced quality of life, reduced healthcare use, rehospitalisation and increased mortality. Results from metaanalysis suggest a twofold increase in mortality in HF patients with compared to those without depression. Pharmacological management of depression in HF has not been shown to improve major outcomes. No demonstrable benefits over cognitive behavioural therapy and psychotherapy have been demonstrated.

Keywords Depression, heart failure, prevalence, management, outcomes Disclosure: The authors have no conflicts of interest to declare. Received: 5 October 2016 Accepted: 19 October 2016 Citation: Cardiac Failure Review 2016;2(2):110–2. DOI: 10.15420/cfr.2016:21:1 Correspondence: Amam Mbakwem, Professor of Medicine and Consultant Cardiologist, Department of Medicine, Collage of Medicine, University of Lagos, Private Mail Bag 12003, Lagos, Nigeria. E: ambakwem@hotmail.com

The prevalence of major depression in chronic heart failure (HF) is about 20–40 %, which is 4–5 % higher than in the normal population.1–3 Depression in heart failure has become a major issue as the burden of heart failure has continued to increase, and many studies have suggested poorer outcomes in HF patients reporting depression.4–8 The cost of managing HF has continued to escalate, and high rates of depression contribute to this.9–13 The use of different methods for assessment (validated questionnaires and clinical interviews) and the effects of age, gender and race have contributed to variations in the prevalence figures reported. Antidepressant drug therapy has not yielded the desired outcomes. Even the use of selective serotonin re-uptake inhibitors (SSRIs) has not shown a consistent improvement in outcomes, as demonstrated by two recent large trials.14,15

Prevalence The aggregated point prevalence of depression in HF patients is about 21 %;1 however, the figures reported in studies range from 9 to 60 %.1 The aggregated prevalence for women is higher than for men, with 32.7  % (range 11–67  %) of women being depressed compared with 26.1 % (7–63 %) of men.1 The prevalence of depression increases with New York Heart Association (NYHA) functional class, with the biggest difference seen between NYHA classes II and III (see Table 1). The heterogeneity in the reported prevalence of depression is related to various factors, such as: the method of assessing depression (questionnaire versus structured interview); conservative versus liberal cut-offs for depression diagnosis; the severity of HF, mean patient age, ethnicity and gender; and inpatients versus outpatients.

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The plethora of depression symptom inventories, including the Beck depression inventory,16 Zung self-rating depression scale,17 geriatric depression scale,18 Center for Epidemiological Studies – depression scale,19 hospital anxiety and depression scale,20 inventory to diagnose depression,21 Hamilton rating scale for depression,22 Hopkins symptom checklist,23 medical outcomes study – depression24 and multiple affect adjective checklist,25 has also contributed to the heterogeneity (see Figure 1).

Pathophysiological Implications of Depression in Cardiovascular Disease The adverse effects of depression on cardiovascular disease (CVD) are believed to be mediated by a shared pathophysiological mechanism. Natriuretic peptides in HF are altered in areas of the brain regulating blood pressure and fluid control in experimental animals.26 Drugs used in the treatment of HF may reverse these changes.27 Central natriuretic peptides have an antagonistic effect on blood pressure and fluid neurotransmitters in HF, and are associated with mental and emotional changes in HF.28,29 Depression may contribute to dysregulation of the autonomic system, with reduction in the parasympathetic and increase in the sympathetic tone and its attendant increase in heart rate, reduction in heart rate variability and lower threshold for myocardial ischaemia and adverse cardiac events in patients with CVD.30,31 The heightened sympathetic tone is associated with increased levels of cortisol,30 serotonin, renin, aldosterone, angiotensin and free radicals.3 High levels of circulating catecholamines may also induce a pro-

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Depression in HF

coagulant phase by increasing platelet activation 32,33 and inhibiting the synthesis of protective eicosanoids in response to the increased haemodynamic stress on the vascular wall.34 Reduced inhibition of macrophage activation via the cholinergic anti-inflammatory pathway contributes to the elevation of pro-inflammatory markers, such as C-reactive protein and cytokines, such as interleukin-1beta, interleukin-6 and tumour necrosis factor alpha (TNF-alpha), in depression. TNF-alpha administration in healthy subjects has been shown to reduce serotonin levels and produce depressed mood, sleep disorders and malaise.35,36 A number of other mechanisms for poorer outcomes in depressed HF patients have been proposed in the literature. It has been suggested that inflammation may be responsible for worse outcomes in depressed HF patients.37 High levels of inflammatory cytokines, such as interleukin-6 and TNF-alpha, are independent predictors of HF-related deaths and exacerbations.38–40 Despite this suggestion, however, the evidence linking outcomes in HF patients with depression to individual biomarkers is still debatable. Recently the effect of reduced blood flow to the hippocampus, which has an important role in emotion and memory, has been alluded to as a possible mechanism for depression and cognitive decline in patients with HF.41 Experimentally there is strong evidence for the modulating role of the immune system on the relationship between depression and CVD via the hypothalamic–pituitary–adrenal axis and the autonomic nervous system.42

Table 1: Prevalence of Depression in Patients with Heart Failure Based on New York Heart Association (NYHA) Functional Class NYHA functional class

N*

Depression rate

I

222

0.11

II

774

0.20

III

638

0.38

IV

155

0.42

Estimates compiled from five studies reporting depression rates specific to NYHA functional class. Adapted from Rutledge et al.1 Permission to reproduce granted by Elsevier (© 2006).

Figure 1: Prevalence of Depression in Heart Failure Patients and 95 % Confidence Intervals from 27 Studies Proportion meta-analysis plot [random effects] de Denus et al 2004 N=171

0.20 (0.14, 0.27)

Faris et al 2002 N=396

0.21 (0.17, 0.25)

Fraticelli et al 1996 N=50

0.18 (0.09, 0.31)

Freedland et al 1991 N=60

0.17 (0.08, 0.29)

Freedland et al 2003 N=682

0.20 (0.17, 0.23)

Friedman & Griffin 2001 N=170

0.31 (0.24, 0.39)

Fulop et al 2003 N=203

0.22 (0.17, 0.29)

Gottlieb et al 2004 N=155

0.17 (0.11, 0.24)

Havranek et al 1999 N=45

0.24 (0.13, 0.40)

Haworth et al 2005 N=100

0.14 (0.08, 0.22)

Jiang et al 2001 N=357

0.14 (0.11, 0.18)

Koenig 1998 N=107

0.37 (0.28, 0.47)

Kurylo et al 2004 N=27

0.44 (0.25, 0.65)

Lane et al 2001 N=146

0.32 (0.25, 0.40)

Lesperance et al 2003 N=443

0.14 (0.11, 0.18)

Murberg et al 1998 N=119

0.13 (0.07, 0.20)

Parissis et al 2004 N=35

0.43 (0.26, 0.61)

Pihl et al 2005 N=47

0.17 (0.08, 0.31)

Rumsfeld et al 2003 N=466

0.30 (0.26, 0.34)

Skotzko et al 2000 N=33

0.42 (0.25, 0.61)

Sullivan et al 2002 N=1098

0.29 (0.26, 0.32)

Sullivan et al 2004 N=142

0.10 (0.05, 0.16)

Turvey et al 2002 N=199

0.11 (0.07, 0.16)

Turvey et al 2003 N=133

0.11 (0.06, 0.18)

Vaccarino et al 2001 N=391

0.09 (0.06, 0.12)

Westlake et al 2005 N=200

0.17 (0.12, 0.23)

Yu et al 2004 N=227

0.54 (0.47, 0.61)

Despite these interrelationships between depression and CVD, no causal relationship has yet been demonstrated. Most of the studies in this area were case-controlled or cross-sectional, but they did not control for behavioural mediators such as poor treatment adherence.

The Management of Depression in Heart Failure There is still no consensus on the best way to treat HF patients with depression. Studies have shown improvement in depressive symptoms with the use of SSRIs;14,15,43,44 however the large Setraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART)14 and Morbidity, Mortality and Mood in Depressed Heart Failure Patients (MOOD-HF)15 trials failed to show any significant benefit over placebo. No clear benefits were shown between usual care (optimal HF treatment without antidepressants) and the use of SSRIs in SADHART or MOOD-HF.

0.22 (0.18, 0.26)

combined 0.0

0.2

0.4

0.6

0.8

Proportion (95 % confidence interval)

Source: Rutledge et al.1 Permission to reproduce granted by Elsevier (© 2006).

Figure 2: All-cause Mortality in Heart Failure Patients by Severity of Depression 100

Survival (%)

80

Psychotherapy has been shown to reduce the depressive symptoms in CVD but has no effect on the major outcomes of the disease.45 A small study comparing Internet-based cognitive behavioural therapy with a web-based discussion forum did not demonstrate a significant difference in the management of depression in HF. There was, however, a significant improvement in depressive symptoms of the Internet-based cognitive behavioural therapy group when compared with baseline.46

60 P<0.001

40 1=None to minimal depression 2=Mild depression 3=Moderate to severe depression

20

0

1

3

2

Years after heart failure diagnosis

Outcomes in Depressed Heart Failure Patents Studies have suggested a worse outcome in HF patients with depression across a broad range of events including mortality, healthcare use and associated clinical conditions, especially in more severely depressed patients (see Figure 2).1,47 Depression was found to be an independent risk factor for mortality in HF, and this persists independent of NYHA class.7

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Source: Adapted from Moraska et al.47 Permission to reproduce granted by Wolters Kluwer Health (© 2013).

A recent large Danish study found depression to be related to allcause mortality in patients with an ejection fraction ≤35  % but not in other types of HF.48 There was no interaction between mortality and age, sex, HF cause, NYHA class or comorbidities. Depression in

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Comorbidities HF has also been shown to be the strongest predictor of short-term declines in health status, significant worsening of HF symptoms, physical and social functions, and quality of life.8

method of diagnosing depression, self-reported depression symptoms or antidepressant use, and inability to account for confounders such as smoking and alcohol use.1,7,47

A meta-analysis of nine studies shows that the relationship between depression and mortality is dependent on the severity of depression: severe and not mild depression are associated with increased mortality.49 The increased mortality related to depression in HF persists over a long period of time.50 Depression is associated with death and readmission for HF, especially in patients with milder HF, a shorter duration of symptoms and lower blood pressures.51

Conclusion

There are a number of factors that could lead to the overestimation of the impact of depression on mortality. These include differences in the

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Rutledge T, Reis VA, Link SE. Depression in heart failure: a meta-analytic review of prevalence, intervention effects and associations with clinical outcomes. J Am Coll Cardiol 2006;48 :1527–37. DOI: 10.1016/j.jacc.2006.06.055; PMID: 17045884 Konstram V, Moser DK, De Jong MJ. Depression and anxiety in heart failure. J Card Fail 2005;11 :455–63. DOI: 10.1016/ j.cardfail.2005.03.006; PMID: 16105637 Parissis JT, Fountoulaki K, Paraskedvaidis I, et al. Depression in chronic heart failure: novel pathophysiological mechanisms and therapeutic approaches. Expert Pin Investig Drugs 2005;14:567–77. DOI: 10.1517/13543784.14.5.567; PMID: 15926864 Ponikowski P, Voors AA, Anker SD, et al.; Authors/Task Force Members. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37 :2129–200. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819 Sullivan MD, Levy WC, Crane BA, et al. Usefulness of depression to predict time to combined end point of transplant or death for outpatients with advanced heart failure. Am J Cardiol 2004;94 :1577–80. DOI: 10.1016/ j.amjcard.2004.08.046; PMID: 15589024 Jiang W, Alexander J, Christopher E, et al. Relationship of depression to increased risk of mortality and rehospitalisation in patients with congestive heart failure. Arch Int Med 2001;161 :1849–56. PMID: 11493126 Junger J, Schellberg D, Müller-Tasch T, et al. Depression increasingly predicts mortality in congestive heart failure. Eur J Heart Fail 2005;7 :261–7. DOI: 10.1016/j.ejheart.2004.05.011; PMID: 15701476 Rumsfield JS, Havranek E, Masoudi FA, et al.; Cardiovascular Outcome Research Consortium. Depressive symptoms are the strongest predictors of short-term declines in health status in patients with heart failure. J Am Coll Cardiol 2003;42 :1811–7. PMID: 14642693 Sullivan M, Simon G, Spertus J, et al. Depression-related costs in heart failure care. Arch Intern Med 2002;162 :1860–6. PMID: 12196084 Cline CMJ, Israelsson BYA, Willenheimer RB, et al. Cost effective management programme for heart failure reduces hospitalization. Heart 1998;80 :442–6. PMID: 9930041 Freedland KE, Rich MW, Skala JA, et al. Prevalence of depression in heart failure patients. Psychosom Med 2003;65 :119–28. PMID: 12554823 Mbakwem AC, Aina FO. Comparative study of depression in hospitalized and stable heart failure patients in an urban Nigerian teaching hospital. Gen Hosp Psychiatry 2008;30 :435–40. DOI: http://dx.doi.org/10.1016/ j.genhosppsych.2008.04.008 Gottlieb SS, Khatta M, Friedman E, et al. The influence of age, gender and race on the prevalence of depression in heart failure patients. J Am Coll Cardiol 2004;43 :1542–9. DOI: 10.1016/j.jacc.2003.10.064; PMID: 15120809 O’Connor CM, Jiang W, Kuchibhatlla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure. Results of the SADHART-CHF (Setraline Against Depression and Heart Disease in Chronic Heart Failure) Trial. J Am Coll Cardiol 2010;56 :692–9. DOI: 10.1016/ j.jacc.2010.03.068; PMID: 20723799 Angermann CE, Gelbrich G, Stork S, et al.; MOOD-HF Investigators. Rationale and design of a randomized, controlled, multicenter trial investigating the effects of selective serotonin re-uptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD-HF). Eur J Heart Fail 2007;9 :1212–22. DOI: 10.1016/ j.ejheart.2007.10.005; PMID: 18029292 Beck AT. Depression Inventory . Philadelphia, PA: Center for Cognitive therapy, 1978.

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Depression is a common finding in patients with HF and constitutes an additional burden on the management of these patients. Wide variations in reported prevalence rates are due to varied cohort characteristics and the multiplicity of instruments and methodologies used. The presence of depression, however, leads to poor outcomes, morbidity and mortality. Treatment with newer SSRIs, although effective, does not improve outcomes and is not superior to cognitive behavioural therapy and psychotherapy. There are still many knowledge gaps to fill and issues to be addressed. ■

17. Zung WWK. A self-rating depression screening scale. Arch Gen Psychiatry 1965;12 :63–70. PMID: 14221692 18. Yesavage JA, Brink TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982–1983;17 :37–49. PMID: 7183759 19. Radloff L. The CES-D Scale: a self-report depression scale research in the general population. Appl Psychol Meas 1977;1 :385–90. DOI: 10.1177/014662167700100306 20. Zigmond AS, Snath RP. The hospital anxiety and depression scale. Acta Psychatr Scand 1983;67 :361–70. PMID: 6880820 21. Zimmereman M, Coryell M, Corenthal C, et al. A self-report scale to diagnose major depressive disorder. Arch Gen Psychiatry 1986;43 ;1076–86. PMID: 3767597 22. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6 :278–46. PMID: 6080235 23. Lipman RS, Covi L, Shapiro AK. The Hopkins symptom checklist (HSCL)-factors derived from the HSCL-90. J Affect Disord 1979;1 :9–24. PMID: 162184 24. Nagel R, Lynch D, Tamburrino M. Validity of the medical outcomes study depression screener in family practice training centers and community settings. Fam Med 1998;30 :362–5. PMID: 9597535 25. Zuckerman M, Lubin B. The Multiple Affect Adjective Check List. San Diego, CA: Educational and Industrial Testing Service, 1965. 26. Hu K, Gaudron P, Bahner U, et al. Changes of atrial natriuretic peptide in brain areas of rats with chronic myocardial infarction. Am J Physiol 1996;270 :H312–6. 27. Hu K, Bahner U, Gaudron P, et al. Chronic effects of ACEinhibition (quinapril) and angiotensin-II-type receptor blockade (losartan) on atrial natriuretic peptide in brain nuclei of rats with experimental myocardial infarction. Basic Res Cardiol 2001;96 :258–66. DOI: 10.1007/s003950170056; PMID: 11403419 28. Ertl G, Hu K, Gaudron P, et al. Remodeling of the heart post myocardial infarction: focus on central ANF. Basic Res Cardiol 1997;92 :82–4. DOI: 10.1007/s003950050024 29. Hemman-Lingen C, Binder L, Klinge M, et al. High plasma levels of N-terminal pro-atrial natriuretic peptide associated with low anxiety in severe heart failure. Psychosom Med 2003;65 :517–22. PMID: 12883099 30. Hughes JW, Watkins L, Blumenthal JA, et al. Depression and anxiety symptoms are related to increased 24h-hour urinary norepinephrine excretion among healthy middleaged women. J Psychosom Res 2004;57:353–8. DOI: 10.1016/ j.jpsychores.2004.02.016; PMID: 15518669 31. Craney RM, Freeland KE, Veith RC. Depression, the autonomic nervous system and coronary heart disease. Pschosom Med 2005;67 :S29–33. DOI: 10.1097/01. psy.0000162254.61556.d5; PMID: 15953797 32. Musselman DL, Tomer A, Mnatunga AK, et al. Exaggerated platelet activity in major depression. Am J Psychiatry 1996;153 :1313–7. DOI: 10.1176/ajp.153.10.1313; PMID: 8831440 33. Bruce EC, Musselman DL. Depression alteration in platelet function and ischaemic heart disease. Psychosome Med 2005;67 :S34–6. DOI: 10.1097/01.psy.0000164227.63647.d9; PMID: 15953798 34. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999;340 :115–26. DOI: 10.1056/NEJM199901143400207; PMID: 9887164 35. Capuron L, Ravaid A, Miller AH, et al. Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferonalpha cancer therapy. Brain Behav Immun 2004;18 :205–13. DOI: 10.1016/j.bbi.2003.11.004; PMID: 15050647

36. Xiong GL, Prybol K, Boyle SH, et al.; SADHART-CHF Investigators. Inflammation markers and Major Depressive Disorder in Patients with Chronic Heart Failure: Results from the Sertraline against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) study. Psychosom Med 2015;77 :808–15. DOI: 10.1097/PSY.0000000000000216; PMID: 26186432 37. Kop WJ, Synowski SJ, Gottlieb SS. Depression in heart failure: biobehavioral mechanisms. Heart Fail Clin 2011;7 :23–38. DOI: 10.1016/j.hfc.2010.08.011; PMID: 21109205 38. Orus J, Roig E, Perez-Villa F, et al. Prognostic value of serum cytokines in patients with congestive heart failure. J Heart Lung Transplant 2000;19 :419–25. PMID: 10808148 39. Rauchhaus M, Doehner W, Francis DP, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000;102 :3060–7. PMID: 11120695 40. Pasic J, Levy WC, Sullivan MD. Cytokines in depression and heart failure. Psychosom Med 2003;65 :181–93. PMID: 12651985 41. Suzuki H, Matsumoto Y, Ota H, et al. Hippocampal blood flow abnormality associated with depressive symptoms and cognitive impairment in patients with chronic heart failure. Circ J 2016;80 :1773–80. DOI: 10.1253/circj.CJ-16-0367; PMID: 27295999 42. Kop WJ, Gottdiener JS. The role of the immune system parameters in the relationship between depression and coronary artery disease. Psychosom Med 2005;67 :S37–41. DOI: 10.1097/01.psy.0000162256.18710.4a; PMID: 15953799 43. Gottlieb SS, Kop WJ, Thomas SA, et al. A double blind placebo controlled pilot study of controlled release paroxetine on depression and quality of life in chronic heart failure. Am Heart J 2007;153 :868–73. DOI: 10.1016/j.ahj.2007.02.024; PMID: 17452166 44. Laspérance F, Frasure-Smith N, Laliberté MA, et al. An open label study of nefazodone treatment of major depression in congestive heart failure. Can J Psychiatry 2003;48 :695–701. PMID: 14674053 45. Bechman LF, Blumenthal J, Burg M, et al.; Enhancing Recovery in Coronary Heart Disease Patients Investigators (ENRICHD). Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA 2003;289 :3106–16. DOI: 10.1001/jama.289.23.3106; PMID: 12813116 46. Lundgren JG, Dahlström O, Andersson G, et al. The effect of guided web-based cognitive behavioral therapy on patients with depressive symptoms and heart failure: a pilot randomized controlled trial. J Med Internet Res 2016;18 :e194. DOI: 10.2196/jmir.5556; PMID: 27489077 47. Moraska AR, Chamberlain AM, Shah ND, et al. Depression, healthcare utilization and death in heart failure: a community study. Circ Heart Fail 2013;6 :387–94. DOI: 10.1161/ CIRCHEARTFAILURE.112.000118; PMID: 23512984 48. Adelborg K, Schimidt M, Sundboll J, et al. Mortality risk among heart failure patients with depression: A nationwide population-based cohort study. J Am Heart Assoc 2016;5 :e004137. DOI: 10.1161/JAHA.116.004137 49. Fan H, Yu W, Zhang Q, et al. Depression after heart failure and risk of cardiovascular and all-cause mortality: a meta-analysis. Prev Med 2014;63 :36–42. DOI: 10.1016/j. ypmed.2014.03.007; PMID: 24632228 50. Adams J, Kuchibhatla M, Christopher EJ, et al. Association of depression and survival in patients with chronic heart failure over 12 years. Psychosomatics 2012;53 :339–46. DOI: 10.1016/ j.psym.2011.12.002; PMID: 22281436 51. Faris R, Purcell H, Henein MY, et al. Clinical depression is common and significantly associated with reduced survival in patients with non-ischaemic cardiomyopathy. Eur J Heart Fail 2002;4 :541–51. PMID: 12167395

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Comorbidities

Expert Opinion Should We Let Sleeping Dogs Lie? Controversies of Treating Central Sleep Apnoea in HFrEF Following the SERVE-HF Study Ali Va zi r , K o s t a n t i n o s B r o n i s a n d S i m o n Pe a r s e Royal Brompton Hospital, National Heart and Lung Institute, Imperial College London, London, UK

Abstract Central sleep apnoea (CSA) is common in patients with heart failure (HF), with a prevalence of 20–45 %. It is a marker of severity of HF and is independently associated with increased morbidity and mortality rates in patients with HF. Targeting CSA with adaptive servoventilation (ASV) was postulated to improve outcomes; however, the results of the recent SERVE-HF (Treatment of Sleep-disordered Breathing by Adaptive Servo-ventilation in Heart Failure Patients) trial showed that in patients with CSA and HF with reduced ejection fraction (HFrEF), ASV, despite successfully treating CSA, was associated with increased risk of cardiovascular death compared with medical therapy. In this expert opinion we discuss the controversies of treating CSA in HFrEF following the SERVE-HF study.

Keywords Central sleep apnoea, heart failure, adaptive servo-ventilation Disclosure: AV and SP have received project grants from Boston Scientific. KB has nothing to declare. Received: 22 April 2016 Accepted: 3 August 2016 Citation: Cardiac Failure Review 2016;2(2):113–4. DOI: 10.15420/cfr.2016:8:2 Correspondence: Dr Ali Vazir, Consultant in Cardiology and Critical Care (HDU) and Honorary Clinical Senior Lecturer, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E: a.vazir@imperial.ac.uk

Central sleep apnoea (CSA) is characterised by cycles of apnoea, hypopnoea and hyperpnoea during sleep due to abnormalities in the regulation of breathing within the respiratory centre in the brainstem. CSA, defined as an apnoea–hypopnoea index (AHI) of ≥15 events/h, is common in patients with heart failure (HF), with a prevalence of 20–45 %.1, 2 Its presence is reported to be a marker of severity of HF. It is also described in some studies to be independently associated with increased morbidity and mortality rates in patients with HF.3 Improving the underlying HF has often resulted in resolution of CSA. Cardiac resynchronisation therapy,4 ventricular assist device implantation5 and cardiac transplantation6 have led to reduction of AHI to normal levels (i.e. <5 events/h). During CSA, the recurrent cycles of oxygen desaturations and autonomic arousals (elevation in sympathetic activity with rise in heart rate and blood pressure) may contribute to worsening HF, thus targeting CSA may be a potential treatment option that could slow the progression of HF and improve outcomes. Treatment modalities targeting CSA have included drugs such as theophyllines, opiates, carbonic anhydrase inhibitors, oxygen and various forms of positive pressure ventilation. To date, the most extensively studied modalities of positive pressure treatments are continuous positive airway pressure (CPAP) support and adaptive servo-ventilation (ASV). CPAP delivers constant and continuous pressure throughout both inspiration and expiration through a nasal or face mask. ASV is a form of positive pressure ventilation with variable pressure algorithm that delivers back-up breaths and high pressures during apnoea and lower pressure during

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hyperpnoea, resulting in resolution of AHI to normal levels in most cases. ASV has been shown to treat CSA more effectively than CPAP. In small studies, both CPAP and ASV have shown a fall in AHI levels coinciding with improvement in surrogate markers of HF,7–9 such as biomarkers (e.g. brain natriuretic peptide), exercise capacity, ejection fraction and symptoms. The enthusiasm generated by these small studies of CPAP and ASV for the treatment of CSA in patients with HF with reduced ejection fraction (HFrEF), led to larger outcome studies. The first outcome study, the CANPAP (Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure) trial (N=203), assessed the effectiveness of CPAP versus medical therapy on transplant-free survival in patients with HFrEF with CSA.10 The findings from this study showed that the use of CPAP, which resulted in a drop in mean AHI level from 40±16 events/h to approximately 19±16 events/h, did not improve survival rates. However, a post hoc analysis of this trial suggested that those patients who had their CSA suppressed by CPAP (to an AHI level <15 events/h) had a significantly better survival rate compared with those in whom CPAP did not suppress CSA effectively. However, the number of events in this analysis were low – five in the CPAP-suppressed versus 13 in the CPAP-unsuppressed group;11 thus interpretation of these data, as with most post hoc analyses, requires cautious interpretation. Subsequently, the SERVE-HF (Treatment of Sleep-disordered Breathing by Adaptive Servo-ventilation in Heart Failure Patients) study (N=1325) assessed the effectiveness of ASV versus optimal medical therapy

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Comorbidities on survival in patients with HFrEF with CSA.12 This trial unexpectedly demonstrated that ASV, despite effectively treating CSA (with a drop in mean AHI levels from 31.2 events/h at baseline to 6.6 events/h at 12 months), had no impact on the primary endpoint of the trial, which was a composite endpoint of time-to-event analysis of first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock) or unplanned hospitalisation for worsening HF (54.1 % in the ASV group versus 50.8 % in the medical group; hazard ratio 1.13; 95 % CI [0.97–1.31]; P=0.10). Surprisingly, ASV was associated with harm with increased all-cause mortality rate (hazard ratio 1.28; 95 % CI [1.06–1.55]; P=0.01), predominantly due to an increased risk of cardiovascular death (hazard ratio 1.34; 95 % CI [1.09–1.65]; P=0.006). The latter was driven by an increased number of sudden cardiac death events; the mechanism by which this occurred is unclear. Results for further analyses from SERVE-HF study are eagerly awaited.

Stroke volume and circulation may increase in the presence of swings in intrathoracic pressure with alternating hyper- and hypoventilation. Furthermore, the hyperventilation phase may reduce sympathetic and increase vagal activity, and the development of hypocapnia and respiratory alkalosis may aid cardiac function during hypoxaemia by improving oxygen delivery (via Bohr and Haldane effects). In addition, hyperventilation leads to a larger end-tidal volume that may act as a reservoir of oxygen-counteracting hypoxaemia in the context of pulmonary oedema. Thus correcting CSA and the loss of these protective mechanisms may in part explain the increased cardiovascular mortality rates observed in the SERVE-HF study. Another factor that should be considered as a potential mechanism of increased cardiovascular mortality rates in the SERVE-HF study is the impact of positive pressure ventilation in patients with HF who have low left ventricular (LV) filling pressures and poor LV systolic function, considering that positive pressure may reduce both the LV preload and afterload, predisposing such patients to the development of haemodynamic instability.14

The surprising results of the SERVE-HF study have caused a reassessment of the way we construe CSA, such that this adaptation may in fact be favourable in HF and perhaps treating it may not be beneficial, as was argued by Naughton in 2012.13 The cycles of apnoea and hyperventilation may in fact have several benefits. An apnoea may prevent respiratory muscle fatigue that develops with continuous tachypnoea in the context of pulmonary congestion.

In light of the unexpected results of the SERVE-HF study, the optimal treatment of CSA remains controversial. Whether CSA should be interpreted merely as a marker of severity of HF or as a target for treatment remains unknown. Further adequately powered studies are required to determine whether ventilatory or non-ventilatory therapies (e.g. phrenic nerve stimulation, acetozlamide) are beneficial before we can conclude that we should let sleeping dogs lie. ■

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Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97 :2154–9. PMID: 9626176. Vazir A, Hastings PC, Dayer M, et al. A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction. Eur J Heart Fail 2007;9 :243–50. DOI: 10.1016/ j.ejheart.2006.08.001; PMID: 17030014. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007;49 :2028–34. DOI: 10.1016/ j.jacc.2007.01.084; PMID: 17512359 Sinha AM, Skobel EC, Breithardt OA, et al. Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure. J Am Coll Cardiol 2004;44 :68–71. DOI: 10.1016/ j.jacc.2004.03.040; PMID: 15234409 Vazir A, Hastings PC, Morrell MJ, et al. Resolution of central sleep apnoea following implantation of a left ventricular

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assist device. Int J Cardiol 2010;138 :317–9. DOI: 10.1016/ j.ijcard.2008.06.072; PMID: 18752859 6. Mansfield DR, Solin P, Roebuck T, et al. The effect of successful heart transplant treatment of heart failure on central sleep apnea. Chest 2003;124 :1675–81. PMID: 14605034. 7. Pepperell JC, Maskell NA, Jones DR, et al. A randomized controlled trial of adaptive ventilation for CheyneStokes breathing in heart failure. Am J Respir Crit Care Med 2003;168 :1109–14. DOI: 10.1164/rccm.200212-1476OC; PMID: 12928310. 8. Sin DD, Logan AG, Fitzgerald FS, et al. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102 :61–6. PMID: 10880416. 9. Tkacova R, Liu PP, Naughton MT, Bradley TD. Effect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J Am Coll Cardiol 1997;30 :739–45. PMID: 9283534. 10. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure.

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N Engl J Med 2005;353 :2025–33. DOI: 10.1056/NEJMoa051001; PMID: 16282177. Arzt M, Floras JS, Logan AG, et al. 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 (CANPAP). Circulation 2007;115 :3173–80. DOI: 10.1161/ CIRCULATIONAHA.106.683482; PMID: 17562959. 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. Naughton MT. Cheyne-Stokes respiration: friend or foe? Thorax 2012;67 :357–60. DOI: 10.1136/thoraxjnl-2011-200927; PMID: 22318163. Spießhöfer J, Fox H, Lehmann R, et al. Heterogenous haemodynamic effects of adaptive servoventilation therapy in sleeping patients with heart failure and Cheyne–Stokes respiration compared to healthy volunteers. Heart Vessels 2015;31 :1117–30. DOI: 10.1007/s00380-015-0717-6; PMID: 26296413.

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Imaging

The Role of Cardiovascular Magnetic Resonance Imaging in Heart Failure Ma rk A P et e r z a n , 1 ,2 O l i v e r J Ri d e r 2 a n d L i s a J A n d e r s o n 1 1. Cardiology Clinical Academic Group, St George’s Hospital, London, UK; 2. University of Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, Oxford, UK

Abstract Cardiovascular imaging is key for the assessment of patients with heart failure. Today, cardiovascular magnetic resonance imaging plays an established role in the assessment of patients with suspected and confirmed heart failure syndromes, in particular identifying aetiology. Its role in informing prognosis and guiding decisions around therapy are evolving. Key strengths include its accuracy; reproducibility; unrestricted field of view; lack of radiation; multiple abilities to characterise myocardial tissue, thrombus and scar; as well as unparalleled assessment of left and right ventricular volumes. T2* has an established role in the assessment and follow-up of iron overload cardiomyopathy and a role for T1 in specific therapies for cardiac amyloid and Anderson–Fabry disease is emerging.

Keywords Cardiovascular magnetic resonance, heart failure, late gadolinium enhancement, delayed enhancement, T1 mapping, T2*, myocarditis, cardiomyopathy, cardio-oncology, prognosis Disclosure: The authors have no conflicts of interest to declare. Received: 19 January 2016 Accepted: 24 June 2016 Citation: Cardiac Failure Review, 2016;2(2):115–22. DOI: 10.15420/cfr.2016:2:2 Correspondence: Lisa J Anderson, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK. E: lisa.anderson@stgeorges.nhs.uk

Heart failure (HF) can be defined haemodynamically as any abnormality of cardiac structure or function resulting in a failure to deliver oxygen at a rate adequate for tissue requirements, despite normal filling pressures – or only at the expense of increased filling pressures.1 Around half of patients with HF have reduced left ventricle ejection fraction (LVEF; EF 40 %) at rest (HF-REF).2 Diagnosis of suspected HF starts with medical history, physical examination, 12-lead electrocardiogram, chest X-ray and natriuretic peptide measurement. Transthoracic echocardiography is the first-line imaging modality.3–5 Cardiovascular magnetic resonance (CMR) imaging plays an important complementary role in evaluating the underlying aetiology (or aetiologies) of the suspected HF, informing prognosis and guiding decision making, particularly where echocardiographic windows are inadequate or findings are inconclusive. CMR is not part of the assessment process in acute HF owing to reduced monitoring capability, patient intolerance of lying flat and reduced image quality (arrhythmias and reduced ability to breath hold). For the diagnosis of the ambulatory patient with suspected HF, CMR receives a class IC recommendation in the European Society of Cardiology (ESC) HF Guidelines.1 CMR is frequently used in the management of HF patients: the European CMR registry reported that the most common indications for CMR include risk stratification in suspected ischaemia, assessment of viability and assessment of suspected myocarditis and cardiomyopathy.6 The image signal in MR arises from hydrogen nuclei, which are aligned to the field of the scanner and then ‘excited’ by radiofrequency wave pulses. Energy is released as the excited nuclei or spins relax back to equilibrium magnetisation. Decay of the longitudinal and transverse components of magnetisation are exponential processes named T1

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and T2 relaxation, respectively. Whereas T2 relaxation takes into account dephasing due to random proton–proton interaction, T2* relaxation is a faster process, as it also takes into account dephasing accelerated by local inhomogeneities in the global magnetic field. Datasets in patients with HF typically start with T1-weighted blackblood spin-echo sequences for anatomy, gradient-echo (bright-blood steady-state-free precession) cine sequences in three long-axis and three short-axis planes to acquire chamber volumes, and contrast-enhanced inversion-recovery gradient-echo sequences with appropriate nulling of normal myocardium to look for late gadolinium enhancement (LGE). Further tissue characterisation sequences are acquired selectively to answer specific questions. The advantages of CMR over other non-invasive imaging modalities are accuracy, reproducibility,7,8 unrestricted field of view, lack of ionizing radiation, and the ability to characterize myocardial tissue. CMR is the gold standard modality for the assessment of LV volumes and EF,9,10 LV thrombus (see Figure 1),11–13 left atrium (LA) volumes14 and the right ventricle (RV).15 CMR tissue characterisation techniques may include inversion recovery images acquired either early (for thrombus imaging) or late (for scar imaging) after contrast administration, diffuse fibrosis assessment with T1 mapping and extracellular volume (ECV) measurement,16–18 iron concentration using T2* and non-contrast ‘native’ T1 measurements, oedema evaluation using T2-weighted images, fatty infiltration with fat saturation sequences or T1-weighting, perfusion imaging with first-pass T1-weighted images and metabolism assessment using MR spectroscopy (MRS).19 Its limitations are its availability, cost, the exclusion of patients with non-MR-compatible devices,20 cerebrovascular clips or metallic objects in the eye, and the inability to scan patients who are too breathless to lie flat or who have claustrophobia. In patients with HF, electrocardiographic gating may

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Imaging Figure 1: LV Thrombi Identified on Early Gadolinium-enhanced Images

Left: multiple thrombi in short-axis mid ventricle view; right: apical thrombus with transmural apical enhancement in a three-chamber view.

Figure 2: Extensive Anterior and Anteroseptal Subendocardial LGE Distribution Typical of Anteroseptal Ischaemic Injury

LGE

late gadolinium enhancement.

Figure 3: Inferior and Inferoseptal Subendocardial Inducible Perfusion Deficit on Vasodilator-stress First-pass Gadolinium Contrast Images

be challenging in those with AF, high ectopic burden or broad QRS width. Furthermore, linear gadolinium chelates are contraindicated in individuals with estimated creatinine clearances 30ml/min, and renal dysfunction is relatively common in HF. Newer macrocyclic chelates have a better safety profile, but should still be used with caution in patients with advanced renal dysfunction.21

Ischaemic Cardiomyopathy In patients presenting with de novo acute HF and no clinical or electrocardiographic suggestion of ischaemic aetiology, LGECMR is sensitive and specific for the presence of underlying significant coronary artery disease (CAD).22,23 Identifying ischaemic cardiomyopathy (ICM) as the aetiology of HF implies a worse prognosis than non-ICM.24 Patients with single-vessel disease ( 75 % luminal stenosis) not involving the proximal left anterior descending (LAD) or left main arteries and with no history of MI or prior revascularisation have a prognosis similar to patients with non-ischaemic HF. 25 However, the absence of angina and significant stenoses on coronary angiography does not exclude CAD as the cause of HF, as infarction may follow coronary spasm or embolism, or be followed by coronary recanalisation.26 Around 15 % of patients with unobstructed coronaries are found to have LGE in distributions typical of prior infarction and would be misclassified as having dilated cardiomyopathy (DCM) were LGE-CMR imaging not performed.27,28 Patterns typical of prior infarction

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show subendocardial or transmural enhancement respecting one or more coronary territories, reflecting the ‘wavefront phenomenon’ of ischaemic injury (see Figure 2).29 For the detection of suspected stable CAD in patients with intermediate (15–85 %) pre-test probability of disease and preserved and reduced LVEF, vasodilator stress CMR for first-pass perfusion and dobutamine stress CMR for inducible wall-motion abnormalities (WMA) are well established, feasible and safe (see Figure 3).30–33 Quantitating deformation with strain-encoded CMR improves the accuracy of high-dose dobutamine stress CMR over visual assessment of WMA on cine imaging.34,35 Threedimensional stress perfusion techniques acquire datasets covering the whole heart rather than three short-axis slices, allowing quantitation of ischaemic burden with good agreement with stress perfusion singlephoton emission computed tomography (SPECT).36,37 High-resolution stress perfusion CMR is feasible in patients with HF.38 In hearts with resting LVEF 40 % and established left-main, leftmain-equivalent or significant proximal LAD and multivessel disease (with fractional flow reserve 0.80), coronary revascularisation is indicated for the relief of angina and for ‘prognosis’ (ESC/European Association for Cardio-Thoracic Surgery class IA recommendation).39 CMR strategies for estimating the likelihood of improvement include assessing the response to low-dose dobutamine, extent of LGE transmurality, and myocardial thickness.40 CMR myocardial feature tracking reduces inter-observer variability compared with visual analysis of the response to low-dose dobutamine.41 Contractile reserve correlates inversely with infarct transmurality, but cannot be straightforwardly predicted in segments with infarction of intermediate transmural extent.42 Greater transmurality of infarction as assessed by LGE-CMR has been shown to correlate inversely with the likelihood of segmental and global functional recovery post revascularisation.43–45 LGE transmurality is often used as a surrogate for viability, the attraction being that no stress or metabolic imaging step is required, and in a meta-analysis of prospective trials was shown to carry the highest sensitivity and negative predictive value for recovery.46 Multiple earlier reports and a meta-analysis showed that the presence of viability in patients with ICM, as assessed by thallium nuclear perfusion SPECT, 18-F fluorodeoxyglucose positon emission tomography or dobutamine echocardiography, predicted improved survival after revascularisation.47–50 However, the viability substudy of the Surgical Treatment for Ischemic Heart Failure (STICH) trial did not find an association between viability and outcomes on multivariate analysis.51,52 However, this study was criticised for the following reasons: the protocol was amended to make viability testing optional and at the investigators’ choice performed by either SPECT or dobutamine echocardiography, the definition of viability was not prospectively validated and did not require segments to be hypocontractile at rest, and post-revascularisation regional and global changes in LV function were not reported.53 Further trials investigating the predictive value of CMR viability are warranted. A meta-analysis of studies of subjects with known or suspected CAD showed that the presence and extent of LGE predict future major adverse cardiovascular events (MACE) and mortality;54 however, many of these studies did not recruit subjects with HF. In a large cohort with mostly preserved EF, LGE and WMA inducible upon dobutamine stress were independent predictors of MACE; conversely, absence of inducible WMA predicted excellent prognosis over the following

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3 years.55,56 However, in one study in which patients with LVEF 55 % and regional WMA at rest were recruited, dobutamine-induced increases in wall-motion score index provided additive predictive power for MACE beyond resting LVEF when resting LVEF was 40 %.57 In studies of patients with ICM and reduced EF, greater extents of scar volume as a proportion of total myocardial volume independently predicted MACE, 58,59 and larger peri-infarct ‘intermediate zones’ independently predicted mortality60,61 and inducibility of monomorphic ventricular tachycardia.62 In the setting of recent acute MI, CMR correlates of higher risk include LVEF, infarct and peri-infarct zone sizes, the presence of microvascular obstruction (MVO) (see Figure 4), reduced RVEF,63 and lower degrees of myocardial salvage, assessed as the difference between the area at risk on T2 weighting and the final infarct size.64 CMRdetected MVO, defined as a lack of gadolinium retention (dark region) in the core of a segment surrounded by tissue showing gadolinium enhancement, is an independent predictor of MACE65,66 and adverse LV remodelling.67 Greater extents of late MVO (assessed 15 minutes after gadolinium administration), rather than early MVO (1 minute after), independently predict MACE after primary percutaneous coronary intervention for ST-segment elevation MI.68 Hypointense infarct cores on T2 weighting, a marker of intramyocardial haemorrhage (IMH), are associated with larger infarcts and greater extents of late MVO, and predict MACE and adverse LV remodelling independent of the presence of MVO.69 IMH, alternatively detected by a hypointense infarct core with T2* 20 ms, also independently predicts MACE and adverse LV remodelling.70

Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is a clinical diagnosis based on dilation and systolic dysfunction of the left or both ventricles that is unexplained by abnormal loading conditions or CAD.71 CMR studies have shown that increased native T1, LA volumes and RV dysfunction, but not greater degrees of trabeculation, are independent predictors of survival and HF outcomes in patients with DCM.72–75 If present in DCM, LGE is typically found in a mid-wall distribution (see Figure 5). 27,76 Co-existent endocardial LGE may indicate concurrent ischaemic contribution to HF aetiology. Mid-wall LGE was found in 10–28  %28,27 of patients with DCM in adult case series, but may be less common in children.77 In adults, the presence of LGE in non-ischaemic DCM independently predicts an increased risk of MACE, including hospitalisation for decompensated HF, sudden and non-sudden cardiac death, ventricular arrhythmia78,79 and allcause mortality.80 Mid-wall LGE distribution confers a higher risk of inducible ventricular tachycardia.81 Larger extents of mid-wall LGE independently predict lower likelihoods of LV reverse remodelling in patients with recent-onset DCM.82 Cardiac energy metabolism is deranged in patients with HF, and MRS is the most powerful method for its non-invasive assessment in vivo.83 Its clinical use has been limited owing to its low temporal and spatial resolution, but this is arguably less important in diffuse myocardial processes such as DCM. In DCM, myocardial phosphocreatine:adenosine triphosphate ratios are reduced and lower ratios independently predict mortality. 84 Forward creatine kinase shuttle flux is reduced in non-ischaemic cardiomyopathy and this also independently predicts mortality.85,86 The hypothesis that altered energetics play a causal role in HF remains controversial

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Figure 4: Microvascular Obstruction at the Core of a Recent Anteroseptal Infarct

Microvascular obstruction is identified at the core of a recent anteroseptal infarct. There is surrounding subendocardial anteroseptal, inferoseptal and anterior LGE. LGE late gadolinium enhancement.

Figure 5: Extensive Mid-wall LGE Distribution Seen on Shortaxis Imaging in a Patient with DCM

DCM

dilated cardiomyopathy; LGE

late gadolinium enhancement.

and the modulation of substrate use as a therapeutic target remains under investigation.87

Takotsubo Syndrome Takotsubo syndrome is an acute and usually reversible HF syndrome whose presentation mimics an acute coronary syndrome (ACS).88,89 Recently proposed diagnostic criteria include transient and reversible regional WMA of the LV or RV frequently preceded by a stressful trigger, circumferential involvement of ventricular segments beyond a single coronary territory, the absence of culprit coronary events and viral myocarditis, new and reversible electrocardiographic changes, significant increases in natriuretic peptide levels, and troponin level increases that are modest for the degree of dysfunction.90 CMR detects ‘typical’ apical ballooning and ‘atypical’ variants (e.g. biventricular, midventricular, basal and focal ballooning).91–93 Oedema is detected on T2-weighted CMR in both takotsubo and myocarditis. However, LGE is usually absent acutely in takotsubo,94,95 unlike in MI (subendocardial) and acute myocarditis (non-ischaemic distribution). Where available, CMR is recommended within 7 days of presentation in suspected takotsubo syndrome to aid diagnosis and detect LV thrombus, and to confirm myocardial recovery on follow-up.96

Myocarditis Myocarditis is an inflammation of myocardial tissue of infectious, immune or toxic aetiology that presents as an ACS, new-onset or worsening HF or life-threatening arrhythmia in the absence of CAD or known causes of HF. It may resolve spontaneously, recur or become chronic, and may predate the development of DCM. Strictly speaking, myocarditis is diagnosed when endomyocardial biopsy (EMB) findings meet certain histological, immunohistochemical and immunological criteria.97,98 In life-threatening presentations, urgent EMB has a class 1B

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Imaging Figure 6: Multi-parametric Assessment of Normal Heart, Cardiac Amyloidosis and Acute Myocarditis

Top row: normal appearances on LGE (left), T2 STIR imaging (middle), and native T1 mapping (right). Middle row: cardiac amyloidosis on LGE imaging (left, middle) demonstrates abnormal blood-pool appearance with ‘zebra-stripe’ enhancement of and difficulty nulling the myocardium; there is heterogeneous diffuse increase in myocardial T1 on native T1 mapping (right). Bottom row: acute myocarditis demonstrates subepicardial lateral-wall enhancement on LGE imaging (left), diffusely increased signal relative to skeletal muscle on T2 STIR imaging (middle), and increased lateral wall T1 on native T1 mapping (right). LGE late gadolinium enhancement; STIR short T1 inversion recovery.

Figure 7: T2* imaging of Two Patients with Thalassaemia

These recommendations require two of the following three criteria for diagnosis: T2-weighted images showing increased global or regional myocardial signal intensity relative to skeletal muscle (indicating myocardial oedema), early gadolinium-enhanced T1-weighted images showing increased global myocardial signal intensity relative to skeletal muscle (indicating myocardial hyperaemia/capillary leak) and 1 focal lesion on LGE with non-ischaemic distribution (indicating necrosis/fibrosis). The most common LGE distribution is focal and patchy and involves the subepicardial lateral wall.104,105 The sensitivity of the 2009 CMR criteria is greatest for patients with infarct-like, rather than HF, presentations.106 Where conventional techniques do not detect abnormalities or where gadolinium is contraindicated, native (non-contrast) T1 mapping (see Figure 6) can detect oedema in non-ischaemic distributions and thus improve diagnostic confidence when imaging is performed at a median of 3 days from presentation.107,108 Native T1 values raised 5 standard deviations above the mean of the normal range independently identified acute myocarditis and were more raised in acute compared with convalescent stages of the process.109 Conversely, in another study of patients with recent-onset HF and clinically suspected myocarditis, T2 mapping revealed higher median global myocardial T2 values in those with biopsy-proven active myocarditis, while there were no significant differences in native or post-contrast global myocardial T1.110 The prognostic value of CMR findings in myocarditis requires further investigation. The presence of LGE on CMR within 5 days of presentation was an independent predictor of all-cause and cardiac mortality in patients with biopsy-proven viral myocarditis,111 and in an LGE-positive cohort, initial LVEF, but not LGE extent, predicted outcome.112

Iron Overload Cardiomyopathy

Left: shows iron loading of the heart sparing the liver; right: shows iron loading of the liver sparing the heart. LV left ventricle; RV right ventricle.

indication, as only EMB can distinguish aetiologies (e.g. viral from nonviral, lymphocytic from giant-cell). However, as EMB may be limited by sampling error or complicated by tamponade, it is not recommended for all patients.99 CMR is the primary non-invasive imaging modality for the assessment of suspected myocarditis in clinically stable patients – it supports the diagnosis by identifying abnormalities of cardiac structure, function and tissue characteristics; excludes ischaemic patterns of injury; and acts as a gatekeeper to EMB.100,101

In patients with HF and suspected cardiac iron overload, and especially in those with transfusion-dependent beta-thalassaemia major, CMR with T2* at 1.5 T field strength should be performed at the earliest opportunity to expedite definitive diagnosis and treatment, and advice from a centre of expertise should be sought.113 T2* is a magnetic relaxation property of any tissue and is inversely related to intracellular iron stores. Myocardial T2* 20 ms is a reproducible, specific marker of significant cardiac iron content, which does not correlate with liver iron or serum ferritin concentrations (see Figure 7).114 Myocardial T2* and iron concentration in the septum are excellent predictors of mean total cardiac iron concentration in explanted hearts.115 T2* declines before LVEF, and is the best predictor of future HF and ventricular arrhythmias, with T2* 10 ms indicating high risk and 10–20 ms indicating intermediate risk.116 If iron chelation therapy is started early, declines in LVEF are preventable and reversible; T2* imaging has had a major impact on survival in patients with thalassaemia.117

Cardiac Amyloidosis The accuracy of CMR diagnosis of myocarditis is variably reported, and depends on the combination of techniques used, the time point in the inflammatory process at which images are taken, the severity of the inflammation in the group studied and whether EMB is the comparison standard. Combining tissue characterisation techniques improves diagnostic performance.102 The recommended clinical diagnostic algorithm for suspected myocarditis98 includes the CMR criteria proposed in the 2009 Journal of the American College of Cardiology White Paper for CMR assessment of myocarditis.103

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Amyloidosis results from extracellular deposition of abnormal insoluble fibrils derived from a misfolded, normally soluble protein.118 The three most common types of amyloidosis affecting the heart include systemic amyloid light-chain (AL) amyloidosis, where the fibrils derive from monoclonal immunoglobulin light chains in the setting of B-cell dyscrasias, hereditary systemic (variant) TTR amyloidosis, where the fibrils derive from variant transthyretin, and senile systemic (wild-type) ATTR amyloidosis. The V122I variant is the most common mutation and is found in 3–4 % of African Americans, carriers of which have

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an increased risk of HF compared with non-carriers over long-term follow-up.119 ATTR amyloidosis is an underdiagnosed cause of HF. Biopsy remains the gold standard for diagnosis.120 Given the short median survival in cardiac AL amyloidosis ( 5 months), CMR is indicated in patients with HF and suspected cardiac amyloidosis to expedite diagnosis and treatment with chemotherapy. CMR findings in cardiac amyloidosis reflect interstitial expansion with high myocardial gadolinium uptake, and typically reveal global subendocardial or transmural LGE, shortening of subendocardial T1, rapid blood pool wash-out and suboptimal myocardial nulling (see Figure 8).121–124 Compared with AL, ATTR involvement is characterised by greater LV mass and LGE extent, greater likelihood of transmural and RV LGE, and longer survival.125 Elevated T1 on native T1 mapping (see Figure 6) has high accuracy for cardiac involvement in AL amyloidosis126 and together with raised ECV predicts mortality.127 Raised native T1 also has high accuracy in ATTR cardiac amyloidosis as compared with HCM, ATTR mutation carriers and normal controls, and may represent an early disease marker.128 The value of native T1 as a marker of disease burden during therapy is under investigation in international trials of TTR-specific therapies.

Figure 8: LGE in Cardiac Amyloidosis

Left: widespread transmural distribution in ATTR. Right: global subendocardial distribution in AL with transmurality at the base of the LV. AL amyloid light chain; ATTR transthyretin amyloidosis; LGE late gadolinium enhancement; LV left ventricle.

Figure 9: Basal Inferolateral LGE Distribution Seen in a Patient with Anderson–Fabry Disease

Anderson–Fabry Disease Anderson–Fabry disease (AFD) is an X-linked recessive disorder caused by reduced or absent activity of the enzyme alpha-galactosidase A, resulting in lysosomal glycosphingolipid accumulation in several organs. LV hypertrophy (LVH), fibrosis, HF (initially with preserved EF) and sudden arrhythmic death may occur.129,130 In the presence of renal replacement therapy, cardiac involvement drives mortality. Early enzyme replacement therapy can cause regression of LVH.131 In patients with AFD, LGE may be detected particularly affecting the basal inferolateral wall in the absence of CAD (see Figure 9).132,133 Native myocardial T1 is reduced in AFD,134,135 differentiating this condition from HCM, oedema and amyloidosis, where T1 is increased. CMR can identify AFD in unexplained LVH and offers the potential for early detection. In one study, native T1 was lowered in patients with genotype-positive, LVH-negative AFD, although correlation with lipid burden on biopsy was not performed.136 Current guidelines advocate the CMR measures of LV wall thickness, mass index and LGE to guide enzyme replacement therapy in patients with AFD.137

Heart Failure with Preserved Ejection Fraction The diagnosis of HF with preserved EF (HF-PEF) requires the following criteria: resting LVEF 50 %; a non-dilated LV (indexed volume <97/ml/m2); and sufficient biomarker, imaging and/or invasive evidence of diastolic dysfunction.138 Although outcomes are similar in patients with HF-PEF and HF-REF,139 no drug therapies have been shown to improve survival in HF-PEF to date.140,141 While 2D-echocardiography has superior temporal resolution for assessment of LV filling, CMR may contribute superior assessment of LVEF, LV mass and LA volumes, in addition to correlates of pulmonary hypertension (e.g. pulmonary artery:aorta ratio142 and RV function143). The use of correlations between diastolic dysfunction and diffuse myocardial fibrosis144 and between post-contrast T1 and outcome145 is under investigation and CMR indices of diastolic function are not yet routinely measured.146–148

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LGE

late gadolinium enhancement.

Cardio-oncology Detection and management of the cardiotoxic effects of anticancer treatments is of growing importance.149,150 Treatments implicated in causing LV dysfunction include anthracyclines, cyclophosphamide, docetaxel, bortezomib, trastuzumab, bevacizumab and sunitinib.151,152 Most children with cancer will become long-term survivors and be more likely to develop HF than their siblings.153 Early detection and prompt treatment of anthracycline-related cardiotoxicity can prevent LV dysfunction and promote LV recovery.154–156 The Trastuzumab Trials Cardiac Review and Evaluation Committee defined treatment-related cardiac dysfunction as a symptomatic fall in LVEF by 5 % to 55 %, or an asymptomatic fall in LVEF by 10 % to 55 %.157 Current criteria for discontinuing trastuzumab depend on detection of LVEF 40–49 % and 10 % below baseline or LVEF 40 %.158 Compared with radionuclide cardiac blood pool imaging and echocardiography, the ‘standard’ imaging modality for serial LVEF assessment – CMR – offers a radiation-free, more accurate modality for detecting LVEF 50 %.159 Expert consensus guidelines recommend CMR in particular when ventricular function nears thresholds for chemotherapy discontinuation or when there is significant regurgitant valve disease.160 LGE is an insensitive marker with poor prognostic utility in cancer survivors.161 The use of ECV, LA volume, oedema, and deformation imaging to detect cardiotoxicity before declines in LVEF is under investigation.162–166 In a series of childhood cancer survivors who previously received 200 mg/m2 anthracycline and had normal indices of global systolic function by standard CMR parameters, CMR tagging techniques detected significant falls in global and segmental LV peak longitudinal and circumferential strain and detected more widespread regional falls in strain than did speckletracking by echocardiography.167

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Imaging Other Cardiomyopathies HF is an uncommon first presentation for HCM, arrhythmogenic RV cardiomyopathy, and cardiac sarcoidosis, and the role of CMR in the assessment of these conditions has been reviewed extensively elsewhere. 26,168–171

Conclusion CMR has established and evolving roles in the assessment of patients with HF, particularly the confirmation of underlying aetiology. The

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extent of involvement detected on CMR carries prognostic information in patients with ICM, DCM, iron overload, cardiac amyloidosis and AFD. The identification of diffuse interstitial fibrosis in many of the cardiomyopathies is increasing knowledge about the mechanisms of the disease processes involved. The role of T2* in assessment of response to therapy in iron overload is established and a potential role for T1 in specific therapies for cardiac amyloidosis and AFD is emerging. The use of T1, T2 and T2* mapping sequences is increasing for myocardial tissue assessment in the cardiomyopathies. ■

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CIRCULATIONAHA.108.794529; PMID: 19153271. 132. Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Eur Heart J 2003;24 :2151–5. PMID: 14643276. 133. Moon JC, Sheppard M, Reed E, et al. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson 2006;8 :479–82. PMID: 16755835. 134. Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 2013;6 :392–8. DOI: 10.1161/ CIRCIMAGING.112.000070; PMID: 23564562. 135. Thompson RB, Chow K, Khan A, et al. T1 mapping with cardiovascular mri is highly sensitive for Fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imaging 2013;6 :637–45. DOI: 10.1161/CIRCIMAGING.113.000482; PMID: 23922004. 136. Pica S, Sado DM, Maestrini V, et al. Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2014;16 :99. DOI: 10.1186/s12968-014-0099-4; PMID: 25475749. 137. West, M., et al. Canadian Fabry disease treatment guidelines . Ottawa: The Garrod Association, 2012. 138. Paulus WJ, Tschöpe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28 :2539–50. DOI: 10.1093/eurheartj/ehm037; PMID: 17428822. 139. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355 :260–9. DOI: 10.1056/NEJMoa051530; PMID: 16855266. 140. Garg N, Senthilkumar A, Nusair MB, et al. Heart failure with a normal left ventricular ejection fraction: epidemiology, pathophysiology, diagnosis and management. Am J Med Sci 2013;346 :129–36. DOI: 10.1097/MAJ.0b013e31828c586e; PMID: 23503335. 141. Shah SJ. Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter. J Am Coll Cardiol 2013;62 :1339–42. DOI: 10.1016/j. jacc.2013.07.010; PMID: 23916923. 142. Karakus G, Kammerlander AA, Aschauer S, et al. Pulmonary artery to aorta ratio for the detection of pulmonary hypertension: cardiovascular magnetic resonance and invasive hemodynamics in heart failure with preserved ejection fraction. J Cardiovasc Magn Reson 2015;17 :79. DOI: 10.1186/s12968-015-0184-3; PMID: 26318496. 143. Goliasch G, Zotter-Tufaro C, Aschauer S, et al. Outcome in heart failure with preserved ejection fraction: the role of myocardial structure and right ventricular performance. PLoS One 2015;10 :e0134479. DOI: 10.1371/journal.pone.0134479; PMID: 26225557. 144. Su M-Y, Lin LY, Tseng YH, et al. CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF. JACC Cardiovasc Imaging 2014;7 :991–7. DOI: 10.1016/j.jcmg.2014.04.022; PMID: 25240451. 145. Mascherbauer J, Marzluf BA, Tufaro C, et al. Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging 2013;6 :1056–65. DOI: 10.1161/ CIRCIMAGING.113.000633; PMID: 24036385. 146. Götte MJ, Germans T, Rüssel IK, et al. Myocardial strain and torsion quantified by cardiovascular magnetic resonance tissue tagging: studies in normal and impaired left ventricular function. J Am Coll Cardiol 2006;48 :2002–11. DOI: 10.1016/j. jacc.2006.07.048; PMID: 17112990. 147. Schuster A, Stahnke VC, Unterberg-Buchwald C, et al. Cardiovascular magnetic resonance feature-tracking assessment of myocardial mechanics: Intervendor agreement and considerations regarding reproducibility. Clin Radiol 2015;70 :989–98. DOI: 10.1016/j.crad.2015.05.006; PMID: 26139384. 148. Andre F, Steen H, Matheis P, et al. Age- and genderrelated normal left ventricular deformation assessed by cardiovascular magnetic resonance feature tracking. J Cardiovasc Magn Reson 2015;17 :25. DOI: 10.1186/s12968-0150123-3; PMID: 25890093. 149. Eschenhagen T, Force T, Ewer MS, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2011;13 :1–10. DOI: 10.1093/eurjhf/ hfq213; PMID: 21169385. 150. Yoon GJ, Telli ML, Kao DP, et al. Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies: are clinicians responding optimally? J Am Coll Cardiol 2010;56 :1644–50. DOI: 10.1016/j.jacc.2010.07.023; PMID: 21050974. 151. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53 :2231–47.

DOI: 10.1016/j.jacc.2009.02.050; PMID: 19520246. 152. Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J 2013;34 :1102–11. DOI: 10.1093/ eurheartj/ehs181; PMID: 22789916. 153. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006;355 :1572–82. DOI: 10.1056/NEJMsa060185; PMID: 17035650. 154. Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000;36 :517–22. PMID: 10933366. 155. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy–induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114 :2474–81. DOI: 10.1161/ CIRCULATIONAHA.106.635144; PMID: 17101852. 156. Cardinale D, Colombo A, Lamantia G, et al. Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55 :213–20. DOI: 10.1016/j.jacc.2009.03.095; PMID: 20117401. 157. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20 :1215–21. PMID: 11870163. 158. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 (suppl 7):vii155–66. DOI: 10.1093/annonc/mds293; PMID: 22997448. 159. Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 2012;30 :2876–84. DOI: 10.1200/JCO.2011.40.3584; PMID: 22802310. 160. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27 :911–39. DOI: 10.1016/j.echo.2014.07.012; PMID: 25172399. 161. Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging 2013;6 :1080–91. DOI: 10.1161/ CIRCIMAGING.113.000899; PMID: 24254478. 162. Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol 2013;111 :717–22. DOI: 10.1016/j. amjcard.2012.11.022; PMID: 23228924. 163. Tham EB, Haykowsky MJ, Chow K, et al. Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling. J Cardiovasc Magn Reson 2013;15 :48. DOI: 10.1186/1532-429X-15-48; PMID: 23758789. 164. de Ville de Goyet M, Brichard B, Robert A, et al. Prospective cardiac MRI for the analysis of biventricular function in children undergoing cancer treatments. Pediatr Blood Cancer 2015;62 :867–74. DOI: 10.1002/pbc.25381; PMID: 25597617. 165. Jordan JH, D’Agostino RB Jr, Hamilton CA, et al. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance. Circ Cardiovasc Imaging 2014;7 :872–9. DOI: 10.1161/ CIRCIMAGING.114.002217; PMID: 25273568. 166. Fallah-Rad N, Walker JR, Wassef A, et al. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 2011;57 :2263–70. DOI: 10.1016/j.jacc.2010.11.063; PMID: 21616287. 167. Toro-Salazar OH, Gillan E, O’Loughlin MT, et al. Occult cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy. Circ Cardiovasc Imaging 2013;6 :873–80. DOI: 10.1161/CIRCIMAGING.113.000798; PMID: 24097420. 168. Karamitsos TD, Neubauer S. Cardiovascular magnetic resonance in heart failure. Curr Cardiol Rep 2011;13 :210–9. DOI: 10.1007/s11886-011-0177-2; PMID: 21360113. 169. Kim YJ, Kim RJ. The role of cardiac MR in new-onset heart failure. Curr Cardiol Rep 2011;13 :185–93. DOI: 10.1007/s11886011-0179-0; PMID: 21399925. 170. Swoboda PP, Plein S. Established and emerging cardiovascular magnetic resonance techniques for prognostication and guiding therapy in heart failure. Expert Rev Cardiovasc Ther 2014;12 :45–55. DOI: 10.1586/ 14779072.2014.870035; PMID: 24345093. 171. te Riele AS, Tandri H, Bluemke DA. Arrhythmogenic right ventricular cardiomyopathy (ARVC): cardiovascular magnetic resonance update. J Cardiovasc Magn Reson 2014;16 :50. DOI: 10.1186/s12968-014-0050-8; PMID: 25191878.

CARDIAC FAILURE REVIEW

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Therapeutics

The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelines Iv a n Milink ov ic´, 1 Gius e p p e R o s a n o, 2 ,3 Yu r i L o p a t i n 4 a n d P e t a r M S e f e r o v i c´1 1

2

3

Department of Cardiology, Clinical Centre of Serbia, Belgrade, Serbia; IRCCS San Raffaele, Rome, Italy; Cardiovascular and Cell Sciences Institute, 4

St George’s University of London, London, UK; Volgograd Medical University, Cardiology Centre, Volgograd, Russia

Abstract The prevalence of heart failure (HF) is increasing, representing a major cause of death and disability, and a growing financial burden on healthcare systems. Despite the use of effective treatments with both drugs and devices, mortality remains high. There is therefore a need for new and effective therapeutic agents. Ivabradine is a specific sinus node inhibiting agent that was approved in 2005 by the European Medicines Agency, alone or in combination with a beta-blocker. Trimetazidine is a cytoprotective, anti-ischaemic agent established in the treatment of angina pectoris. In the 2012 European Society of Cardiology (ESC) guidelines for diagnosis and treatment of HF, ivabradine was recommended in symptomatic HF patients who are in sinus rhythm with left ventricular ejection fraction ≤35 % and heart rate higher than 70 beats per minute, despite optimal medical therapy, including maximally tolerated dose of beta-blocker. The role of trimetazidine in this setting was not mentioned. In the 2016 ESC guidelines, recommendations for ivabradine are unchanged but trimetazidine is included for the treatment of angina pectoris with HF. This article discusses the need for new therapeutic options in HF and reviews clinical evidence in support of these two therapeutic options.

Keywords Ivabradine, trimetazidine, heart failure, ESC guidelines Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the authors. Received: 20 June 2016 Accepted: 23 June 2016 Citation: Cardiac Failure Review, 2016;2(2):123–9. DOI: 10.15420/cfr.2016:13:1 Correspondence: Petar M Seferovic´, Department of Cardiology, Clinical Centre of Serbia, 26 Visegradska, 11000 Belgrade, Serbia. E: seferovic@med.bg.ac.rs

Chronic heart failure (HF), a complex and heterogeneous clinical syndrome, is a major cause of morbidity and mortality worldwide, and represents a major challenge to health care systems. The prevalence of HF and the number of hospitalisations is rising, even more in the ageing population.1 The direct costs of HF management reached 1–2 % of total health care expenditure and approximately two-thirds are attributable to hospitalisations. In 2012, in 197 countries, covering 99 % of the world’s population, the overall cost of HF management was estimated at US$108 billion per annum, and is predicted to rise.2 HF is caused by structural and/or functional cardiac abnormality, mainly by following aetiologies: coronary artery disease, arterial hypertension, valvular heart disease, inflammatory heart disease and/or primary cardiomyopathy. The typical symptoms are breathlessness, ankle swelling and fatigue, and may be accompanied by signs such as elevated jugular venous pressure, pulmonary crackles and peripheral oedema.3 Based on assessment of left ventricular ejection fraction (LVEF) HF is classified as HF with reduced LVEF (HFrEF; EF <40  %) and HF with preserved LVEF (HFpEF; EF >50 %). If LVEF is in the range of 40–49 % (‘grey area’), it is defined as HF with mid-ranged LVEF (HFmrEF).4 Around 60 % of total HF patients has HFrEF, which is associated with high reninangiotensin-aldosterone and sympathetic nervous systems activation. Most recent therapeutic improvements in these patients are due to the use of pharmacological agents that modulate these neuro-hormonal axes, angiotensin-converting enzyme inhibitors (ACEI), angiotensin

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receptor blockers (ARB), beta-blockers and mineralocorticoid receptor antagonists (MRAs). The beneficial effects of these treatments include the reduction of HF mortality by approximately one-third in a period of two decades. Despite this success, HF mortality rates remain high: the 5-year survival is worse than in many cancers.5,6 The 2016 European Society of Cardiology (ESC) HF guidelines recommend ACEI and beta-blockers as first-line therapy in symptomatic patients with HFrEF.4 However, both registries and clinical reports underline that the treatment of HF patients is suboptimal much more than expected, and that the heart rate is increased despite beta-blocker therapy.7–12 The registry of 12,440 patients demonstrated heterogeneity in treatment strategies, due to the drug side effects and contraindications.7 A European registry13 reported that only 17 % of patients were receiving the optimal combination and recommended dose of diuretic, ACEI and beta-blockers. Results from a French registry on 50,000 HF patients14 also confirmed suboptimal treatment of HF, demonstrating that after the first month following hospitalisation for worsening HF, only 47 % received an ACEI, 54 % a beta-blocker, and 17 % MRAs. The I Brazilian Registry of Heart Failure (BREATHE)15, conducted in 57 hospitals in Brazil, revealed that 69 % of HF patients were receiving an ACEI or ARB, 60 % a beta-blocker, and 49 % MRAs. However, only 17 % were receiving all three drugs together. Therefore, a need to identify a novel pathways and strategies for HF treatment is obvious and clinically justified. This article reviews the clinical evidence and guidelines recommendations for the use of two novel therapies in HF: ivabradine and trimetazidine.

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Therapeutics Table 1: Clinical Studies Investigating Ivabradine in Heart Failure Study CARVIVA HF19

Design Randomised open-blinded endpoint study.

Efficacy Outcomes HR reduction in all three groups, more with

Safety/Tolerability Maximal dose of ivabradine, better tolerated

Groups: carvedilol ≤25 mg twice daily

combination therapy. Improvement in

than carvedilol combination therapy; (p<0.01).

(n=38),ivabradine ≤7.5 mg twice daily (n=41)

6-MWT MVO2 in ivabradine and

and carvedilol/ivabradine ≤12.5/7.5 mg

combination groups (both p<0.01).

twice daily (n=42). Follow-up 3 months.

Improvement of peak VO2 and VAT in ivabradine (p<0.01) and combination group (p<0.03). Improved QoL scores in ivabradine (p<0.01) and combination groups (p<0.02).

SHIFT27

Double-blind placebo-controlled study,

24 % patients in the ivabradine group

Fewer serious adverse events in ivabradine

(n=6,558; 3,268 on ivabradine ≤ 7.5 mg

and 29 % of those taking placebo had

group (3,388 events; p=0.025). Symptomatic

twice daily). Median follow-up 22.9

a primary endpoint event (cardiovascular

bradycardia in 150 (5 %) on ivabradine, 32 (1 %)

(IQR 18–28) months.

death or hospitalisation for worsening

on placebo (p<0.0001). Visual side-effects

HF; (HR 0.82; 95 % CI [0.75–0.90];

(phosphenes) in 89 (3 %) on ivabradine and

(p<0.0001). Events driven mainly by

17 (1 %) on placebo (p<0.0001).

hospital admissions for worsening heart failure (21 % placebo versus 16 % ivabradine; HR; 95 % CI [0.74, 0.66–0.83]; p<0.0001) and deaths due to heart failure 5 % versus 3 %; (HR 0.74 95 % CI [0.58–0.94] p=0.014). INTENSIFY37

Prospective, open-label multicentre

Heart rate reduction to 67±8.9 bpm. Decrease

study, (n=1,956). Follow-up 4 months.

in signs of decompensation by 5.4 %. Symptom improvement, maintaining normal activities of patients with BNP levels >400 pg/mL to 26.7 %. Shift to lower NYHA classification (24.0 % in NYHA I and 60.5 % in NYHA II). Improvement of EQ5D to 0.79±0.21.

BPM = beats per minute; EQ5D = European quality of life – 5 dimensions; HR = hazard ratio; IQR = interquartile range; QoL = quality of life; MVO2 = mixed venous oxygen saturation; NYHA = New Yourk Heart Association; peak VO2 = maximum rate of oxygen consumption; QoL = quality of life; VAT = ventilatory anaerobic threshold; 6-MWT = 6-minute walk test.

Use of Ivabradine in Heart Failure The mechanism of ivabradine’s beneficial effect is based on heart rate reduction at rest and/or exercise, which prolongs diastolic perfusion time, improves coronary blood flow, and increases exercise capacity. In contrast to beta-blockers, ivabradine causes increase in stroke volume, which may have beneficial cardiac effects. In both preclinical and clinical studies, ivabradine exerted an anti-remodelling effect, improving left ventricle (LV) structures and functions.16 In patients with HF, ivabradine not only reduces heart rate but also improves heart rate variability. No significant bradycardia, ventricular arrhythmias or supraventricular arrhythmias were reported.17 The efficacy and safety of ivabradine in HF has been established by two pivotal clinical trials and an open-label study (see Table 1). The effect of the drug can be assessed regarding four clinical aspects: functional improvement and symptoms relief, amelioration of the uality of life (QoL), effects on rehospitalisation and mortality and safety profile in HF.

Functional Improvement and Symptoms Relief The evidence supporting functional improvement in patients with HFrEF is convincing. Treatment with ivabradine 7.5 mg twice daily resulted in improvement of functional parameters and exercise capacity. In addition, it was correlated with a significant increase in LVEF and a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP). The selection of the patients represented not only difficult treatment challenges but also the real-daily clinical practice pattern. It should be noted that use of ivabradine significantly improves the exercise capacity, gas exchange, functional HF class, QoL and neurohormonal modulation in patients with ischaemic HF.18 Furthermore, the CARVedilol, IVAbradine or their combination on

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exercise capacity in patients with Heart Failure (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.19 If a patient is treated concomitantly with betablocker and ivabradine, the smaller doses and briefer titration period can be noticed. The addition of ivabradine to carvedilol in 69 patients in sinus rhythm, ischaemic HF (NYHA class II–III) and HR ≥70  beats per minute (bpm) revealed a shorter beta-blocker up-titration period, higher final beta-blocker dose as well as greater heart rate reduction and better exercise capacity.20

Amelioration of the Quality of Life Improvement in symptoms and maintaining normal activities are important treatment goals for patients with chronic disabling diseases like HF. In the first weeks of ivabradine treatment, dyspnea at rest, exercise capacity and fatigue were improved. In a sub-analysis of the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) in 1944 patients, health-related quality of life, as recorded by the disease-specific Kansas City Cardiomyopathy Questionnaire, was found to be inversely associated with clinical events.21 Treatment with ivabradine was associated with improvements in QoL scores and better outcomes. That was due to the improvement in exercise capacity and symptoms. The reported effect on quality of life with ivabradine and carvedilol is most likely related to the improved exercise capacity and reduction of the beta-blocker–related fatigue.19,22

Effects on Rehospitalisation and Mortality Although there is a short-term improvement after each admission for acute HF, patients generally leave the hospital with a further

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Role of Ivabradine and Trimetazidine

Every HF hospitalisation is a strong predictor for mortality,26 reinforcing the preventive interventions known to reduce HF hospitalisation and death. The majority of HF hospitalised patients will not see a cardiologist during the 3 months following discharge and therefore it is essential to adjust therapy, including ivabradine, before discharge. The SHIFT trial randomised 6,558 HF patients to ivabradine or placebo.27 A total of 90 % were receiving a beta-blocker, 92 % an ACEI or ARB, and 60 % MRA. In comparison with the standard clinical practice, the SHIFT patients were more adequately treated than in most countries.12,13 A reduction of 18 % in the primary composite endpoint (cardiovascular death or hospitalisation for worsening HF), as well as a 26 % reduction in hospitalisations for worsening HF and a 26 % reduction in pump-failure death were reported in the ivabradine group (see Figure 1).27 The magnitude of heart rate reduction caused by beta-blocker and ivabradine, rather than background beta-blocker dose, primarily determines subsequent effect on outcomes.28 The beneficial effects of ivabradine in SHIFT population was confirmed in all subgroups including patients with diabetes, arterial hypertension, concomitant treatment with MRAs or beta-blocker treatment and chronic obstructive pulmonary disease.29–33 Furthermore, the effect of heart rate reduction with ivabradine is maintained regardless of presence and number of co-morbidities. There was no interaction between one or more co-morbidities and the effect of treatment with ivabradine on outcomes in chronic HF.34 Age does not limit the appropriate use of ivabradine in patients with chronic HF and systolic dysfunction. The safety and efficacy of ivabradine are comparable across all age groups.35 Although heart rate is not clearly elucidated previously, the reduction in heart rate by ivabradine had no negative effect on renal function (2-year follow-up). The beneficial cardiovascular effects and safety of ivabradine were similar in patients with and without renal dysfunction.36

Figure 1: Patients From the SHIFT Trial Reaching the Composite Primary Endpoint (Cardiovascular Death or Hospitalisation For Worsening Heart Failure) in Placebo and Ivabradine Groups 40

Primary composite endpoint (% patients)

decrease in cardiac function.23 This can directly and negatively influence renal function via a decrease in cardiac output, high venous pressure or vasodilatation. After an episode of acute HF, approximately 25 % require readmission within 30 days,24 and 50 % within 6 months.25 HF hospitalisations also significantly duce the QoL of patients with HF, most of whom are older adults.

Placebo (937 events) Ivabradine (793 events) HR 0.82; 95 % CI [0.75–0.90]; p<0.0001

30

20

10

0

0

6

12

18

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30

27

CI = confidence interval; HR = hazard ratio. Source: Swedberg et al. Reproduced with permission from Elsevier © 2010.

Table 2: Summary of Clinical Studies Investigating Trimetazidine in Heart Failure Study Di Napoli et al.48

Design Open versus conventional

Efficacy Outcomes Mean LVEF improvement

therapy, (n=61). Follow-up

11 % (p<0.001). Improvement

18 months

in NYHA class, end-systolic

Open versus conventional

Mean LVEF improvement 7 %

therapy, (n=55). Follow-up

(p=0.002). Improvement in

13 ± 3 months

NYHA class and end-systolic

Double-blind placebo-

Mean LVEF improvement

and end-diastolic volumes Fragasso et al.49

volume Brottier et al.50

controlled (n=20). Follow-up 9.3 % (p<0.018). Improvement Fragasso et al.51

6 months

in dyspnoea

Double-blind, placebo-

Mean LVEF improvement

controlled crossover

8.5 % (p<0.001). Improvement

(n=16). Follow-up 6 months in left ventricular end-systolic and end-diastolic diameters and volumes Rosano et al.52

Double-blind placebo-

Mean LVEF improvement

controlled (n=32).

5.4 % (p<0.05). Improvement

Follow-up 6 months

in end-diastolic diameters,

Safety Profile in Heart Failure Ivabradine is well tolerated in HF patients. The prospective, openlabel multicentre PractIcal daily EffectiveNess and TolEraNce of Procoralan® in chronic SystolIc heart Failure in GermanY (INTENSIFY) study analysed the effectiveness and tolerability of ivabradine in daily practice over a 4-month period. In addition to improvements in New York Heart Association (NYHA) functional class and reduction in heart rate, the study revealed an association between ivabradine and improvement in QoL. Effects were more pronounced in patients with higher NYHA classes.37 In the SHIFT trial there was a lower incidence of serious adverse events with ivabradine than with placebo.27 In total, 21 % of patients on ivabradine discontinued treatment, versus 19 % of patients on placebo. Bradycardia was more frequent with ivabradine than with placebo (11 % versus 2 %, respectively). In addition, visual luminous phenomena (phosphenes) were reported in 3 % of patients in the ivabradine group.27 Additional safety evidence for ivabradine comes from the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction

24

Time (months)

wall motion score index and E/A wave ratio Vitale et al.53

Double-blind placebo-

Mean LVEF improvement

controlled (n=47).

7.4 % (p<0.0001). Improvement

Follow-up 6 months

in LV end-systolic and enddiastolic diameters and volumes, wall motion score index, NYHA class and QoL

Sisakian et al.54

Open versus conventional

Mean LVEF improvement

therapy, (n=82). Follow-up

3.5 % (p=0.05) Improvement

3 months

in tolerance to physical activity on 6-minute walking test

Fragasso et al.59

Double-blind,

Mean LVEF improvement

placebo-controlled

5 % (p=0.003). Improvement

Crossover (n=12).

in cardiac PCr:ATP ratio,

Follow-up 3 months

NYHA class and metabolic equivalent system

LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; QoL = quality of life.

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Therapeutics Figure 2: Effect of Trimetazidine and Conventional Therapy Alone on Quality of Life 90

p<0.04

85 80 75 70 65 60 55 50 Trimetazidine

Conventional therapy

Quality of life (0–100 %) at baseline (blue bars) and at follow-up (purple bars). Overall quality 49 of life was evaluated on a visual analog scale (range 0 to 100). Source: Fragasso et al. Reproduced with permission from Elsevier © 2006.

Table 3: A Summary of Meta-analysis of Clinical Studies Investigating Trimetazidine in Heart Failure Study

N

Efficacy Outcomes

Gao et al.64

17/955

NYHA class −0.41 (p<0.01) Exercise duration +30.26 seconds (p<0.006) LVEF +7.37 % in ischaemic HF (p<0.01) LVEF +8.72 % in non-ischaemic HF (p<0.01) All-cause mortality (RR 0.29; 95 % CI [0.17–0.49]; p<0.00001)

Trimetazidine in Heart Failure Trimetazidine offers metabolic modulation as a different treatment option in HF. Several drugs that affect cellular metabolism have been investigated over the last decades.39–41 Their mechanism of action is believed to involve inhibition of oxidation of free fatty acids in ischaemic myocytes. Since glucose metabolism requires less oxygen per mole of adenosine triphosphate generated, it is preferable to fatty acid oxidation when oxygen availability is limited in underperfused myocardium.42,43 Due to the lack of large-scale clinical trials, this clinical concept is not widely accepted and, as a result, the this drug received regulatory approval only for treatment of angina pectoris.44–47 Several small randomised clinical trials (RCTs) confirmed the efficacy of trimetazidine in patients with HF. Benefical effects include improving NYHA functional class, exercise tolerance, QoL, LVEF and cardiac volumes (see Table 2).48–54 Among the first reports was the study of Brottier et al. who analysed clinical results with long-term treatment with trimetazidine on top of conventional therapy.50 After follow up of 6 months, improvement of LVEF by 9.3 % and the HF symptoms was demonstrated. In an open label study on 55 patients with HF (add-on trimetazidine versus conventional therapy), trimetazidine improved NYHA functional class significantly in comparison to the conventional therapy. Treatment with trimetazidine significantly decreased LV end-systolic volume and increased LVEF, and significantly improved QoL (see Figure 2).51 In patients with ischaemic cardiomyopathy, the trimetazidine treatment was associated not only to functional improvement and reduction in hospitalisations and mortality, but also with a significant positive effect on ventricular remodeling.48,49,55–58

Cardiovascular events andvhospitalisation (RR 0.42; 95 % CI [0.30–0.58]; p<0.00001) Zhang et al.65 16/884

NYHA class −0.57 (p<0.0003) Exercise duration +63.75 seconds (p<0.00001) LVEF +6.46 % (p<0.00001) LVEDV −17.60 ml (p=0.10) LVEDD −6.05 mm (p<0.00001) LVESV −20.60 ml (p=0.02) LVESD −6.67 mm (p<0.00001) BNP −203.40 pg/ml (p<0.0002) All-cause mortality (RR 0.47; 95 % CI [0.12–1.78]; p=0.27) Hospitalisation for cardiac causes (RR 0.43; 95 % CI [0.21–0.91]; p=0.03)

Grajek, et al.66 3/326

All-cause mortality (RR=0.28; 95 % CI [0.16–0.49];

Zhou, et al.67 19/994

NYHA class −0.55 (p<0.001)

p<0.0001) Exercise duration +18.58 seconds (p=0.153) LVEF +7.3 % (p<0.001) LVEDV −11.24 ml (p<0.01) LVESV −17.01 ml (p<0.01) BNP −157.1 pg/ml (p<0.001) All-cause mortality (RR 0.47; 95 % CI [0.12–1.78]; p=0.27) Hospitalisation for cardiac causes (RR 0.43; 95 % CI [0.21–0.91]; p=0.03) CI = confidence interval; LVEF = left ventricular ejection fraction; LVEDD = left ventricular enddiastolic dimension; LVEDV = left ventricular end-diastolic volume; LVESD = left ventricular end-systolic dimensions; LVESV = left ventricular end-systolic volume; NYHA = New York Heart Association; RR = risk ratio.

(BEAUTIFUL) trial in coronary heart disease and an LVEF less than 40 %. In this study 22.5 % patients in the ivabradine group had serious adverse events compared with 22.8 % in the placebo group. However there was a higher incidence of bradycardia (including asymptomatic bradycardia) in the ivabradine group than in the placebo group (21 % versus 2 %).38

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In several subsequent studies, the similar finding was confirmed, based on both global and regional LV systolic function improvement, as well as the enhancement of LV diastolic function.48–50,59 Furthermore, the improvement of LV remodelling processes and the reduction of the plasma inflammatory response, natriuretic peptides, cardiac troponin levels and a recovery of the endothelium-dependent relaxation of conduit arteries was shown.48,49,56,59 These results were obtained in HF patients with ischaemic aetiology while no effects of trimetazidine in patients with HF of nonischaemic aetiology was revealed.49,60–62 Regarding co-morbidities, in pilot study of 20 patients with HF and diabetes, it was suggested that trimetazidine may be particularly beneficial in this patient group.63 The potential mechanism may include the compensation for reduced glucose uptake utilisation of myocardial cells resulting from the altered insulin levels.52 Several meta-analyses of small studies assessing the therapeutic effect of trimetazidine in HF have been published (see Table 3). Metaanalysis of 17 trials involving 955 HF patients (between 1966 and May 2010) concluded that trimetazidine therapy significantly reduces LV end-systolic volume, improves NYHA functional class and exercise duration, as well as decreasing all-cause mortality, cardiovascular events and hospitalisation (see Figure 3).64 Furthermore, metaanalysis of 16 RCTs involving 884 patients with chronic HF, highlighted that trimetazidine as add-on therapy may decrease hospitalisation for cardiac causes, improve clinical symptoms and cardiac function and simultaneously ameliorate LV remodelling.65 Another metaanalysis involving 326 patients from three RCTs reviewed the effect of adding trimetazidine to pharmacological HF therapy on all-cause mortality, concluding the beneficial effect on all-cause mortality and event-free survival.66 In a meta-analysis of 19 RCTs involving 994 HF patients on treatment with trimetazidine or placebo, trimetazidine

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therapy was associated with several positive effects. These include improvement in LVEF, NYHA functional class, significant decrease in LV end-systolic volume, LV end-diastolic volume, hospitalisation for cardiac causes, B-type natriuretic peptide and C-reactive protein. However, there were no significant differences in exercise duration and all-cause mortality between patients treated with trimetazidine and placebo.67

Figure 3: Data from a Meta-analysis Comparing Clinical Outcomes of Patients with Heart Failure Receiving Trimetazidine or Placebo for (A) All-cause Mortality and (B) Cumulative Events

Adverse effects associated with trimetazidine have been minor and mostly gastrointestinal. However, retrospective studies have found an association between long-term use of trimetazidine and Parkinson syndrome, gait disturbances and tremor.68,69 In the majority of cases, withdrawal of the drug leads to rapid resolution of these symptoms.70 Further clinical trial data is required to determine the long-term safety of trimetazidine.71

Recommendations for the Use of Ivabradine and Trimetazidine According to the 2016 ESC Guidelines for Diagnosis and Treatment of Heart Failure

Risk ratio M-H, Random, 95 % CI

A

0.01

0.1

1

10

100

Favours placebo

Favours trimetazidine

Risk ratio M-H, Random, 95 % CI

B

The role of ivabradine for treatment of HF was again stressed in 2016 ESC guidelines. Ivabradine is recommended in symptomatic HF patients who are in sinus rhythm with LVEF ≤35 % and heart rate higher than 70 bpm, despite treatment with optimal or maximal tolerated dose of beta-blocker. Those patients should also be on ACEI (or ARB) and MRA. This treatment was proven to reduce the risk of HF hospitalisation and cardiovascular death4 (class IIa, level of evidence B). In addition, for the patients who are unable to tolerate or have contra-indications for a beta-blocker, ivabradine is indicated with the class IIa, level of evidence C.4

0.01

0.1

1

10

Favours trimetazidine

100

Favours placebo 64

Ivabradine is also recommended for the treatment of stable angina pectoris with symptomatic (NYHA Class II-IV) HFrEF, in combination with an anti-angina drug, with the exception of ranolazine and nicorandil (because of unknown safety), class IIa, level of evidence B).4 Ivabradine is not recommended in patients with atrial fibrillation in HF.4 The 2012 guidelines did not include trimetazidine in HF treatment. The 2016 guidelines indicate 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.4 This recommendation is based on the body of evidence suggesting that trimetazidine may improve NYHA functional capacity, exercise duration and LV function in patients with HFrEF. There is no recommendation for trimetazidine in the setting of HF alone.

Summary and Clinical Implications The treatment goals in patients with HF are to relieve heart failurerelated symptoms, prevent hospital admission and improve survival. Most recent therapeutic improvements are due to the use of pharmacological agents that modulate neuro-hormonal axes, ACEI, ARB, beta-blockers and MRAs. The impact of lowering heart rate on heart failure outcomes is well established and beta-blockers are recommended as first-line therapy in patients with HFrEF. Ivabradine offers further heart rate reduction and clinical and prognostic benefits in the patients on maximally tolerated dose of beta-blockers (or those intolerant to beta-blockers).

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CI = confidence interval. Source: Gao et al. Reproduced with permission from BMJ Publishing Group Ltd © 2011.

Due to its unique mechanism of action, ivabradine is now considered a well-established drug in the treatment of chronic HF. Heart rate reduction caused by ivabradine prolongs diastolic perfusion time and increases coronary blood flow and exercise capacity. The clinical effects of ivabradine in HF can be summarised as effects on rehospitalisation QoL. The clinical indications for ivabradine include all patients with symptomatic HFrEF in sinus rhythm with LVEF ≤35 % who remain with heart rate above 70 bpm, despite optimal medical therapy including maximally tolerated dose of beta-blockers. In addition, ivabradine is also recommended for the treatment of symptomatic HFrEF and stable angina pectoris, in combination with an anti-anginal drug for patients intolerant to beta-blockers. Ivabradine has a good tolerability and safety profile. Trimetazidine acts directly at cardiac cell level by inhibition of oxidation of free fatty acids in ischaemic myocardium, offering metabolic modulation, as a different treatment option. Potential beneficial effects are the improvement of NYHA functional class, exercise tolerance, QoL, LVEF and cardiac volumes. In clinical practice, 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. Adverse effects associated with trimetazidine have been minor and mostly gastrointestinal, although the association between the long-term treatment with trimetazidine and Parkinson’s disease, gait disturbances and tremor need to be further investigated. ■

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Therapeutics

Complementary and Synergic Role of Combined Beta-blockers and Ivabradine in Patients with Chronic Heart Failure and Depressed Systolic Function: A New Therapeutic Option? Ma uriz i o V o l t e r r a n i 1 a n d F e r d i n a n d o I e l l a m o 1 ,2 1. Department of Cardiac Rehabilitation, IRCCS San Raffaele, Rome, Italy; 2. Department of Clinical Sciences and Translational Medicine, University Tor Vergata, Rome, Italy

Abstract While substantial advances have been made in the treatment of chronic heart failure (CHF) in the past decade, the prevalence of CHF is increasing. CHF represents a growing financial burden on healthcare systems and, despite therapeutic advances, mortality remains high. There is a need for new therapeutic targets and treatment strategies. Beta-blockers remain the drugs of choice for reducing heart rate (HR) in CHF with reduced ejection fraction (EF), but evidence suggests that their use is suboptimal; a substantial proportion of patients with heart failure do not tolerate the doses of beta-blockers used in the large clinical trials and more than half of patients have inadequately controlled HR. For these patients, clinical evidence supports the addition of ivabradine to beta-blocker therapy. Ivabradine reduces HR via a different mechanism to beta-blockers and has been recommended in European Society of Cardiology guidelines to reduce the risk of CHF hospitalisation and cardiovascular death in symptomatic patients with EF ≤35  % who are in sinus rhythm and have a resting HR ≥70 beats per minute despite treatment with an evidence-based therapy. In addition to HR-lowering, ivabradine exerts other effects on the myocardium that are synergic and complementary to beta-blockers, and may be beneficial in CHF syndrome. In this review we summarise current findings on ivabradine therapy in CHF and advance the hypothesis, with related rationale, for combining ivabradine and beta-blocker therapy from the early stages of CHF in patients with reduced EF as an alternative strategy to up-titration of beta-blockers to an optimal dose.

Keywords Ivabradine, beta-blockers, chronic heart failure Disclosure: The authors have no relevant conflicts of interest to declare. Acknowledgements: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the authors. Received: 20 June 2016 Accepted: 23 June 2016 Citation: Cardiac Failure Review 2016;2(2)130–6. DOI: 10.15420/cfr.2016:12:1 Correspondence: Maurizio Volterrani, Dipartimento di Cardiologia Riabilitativa, IRCCS San Raffaele Pisana, via della Pisana 235, 00163 Rome, Italy. E: maurizio.volterrani@sanraffaele.it

Chronic heart failure (CHF) is a progressive disorder characterised by elevated cardiac filling pressures, reduced cardiac output and decreased oxygen delivery to the tissues.1 Activation of the sympathetic nervous system (SNS), along with activation of the renin–angiotensin–aldosterone system (RAAS), plays a fundamental role in the pathophysiology of CHF syndrome.2–5 Early in the course of heart failure (HF) development, the neuro-endocrine system is activated and maintains haemodynamic stability and cardiac output, but over time these compensating mechanisms lead to deterioration of cardiovascular function through several pathways.6 Thus, inhibition of SNS by beta-blockers and RAAS by angiotensin converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists has become the current standard pharmacological treatment for CHF. Despite the widespread use of these drugs, CHF patients still remain at high risk of death and worsening HF, possibly because of suboptimal drug therapy management. There is growing clinical evidence that more than half of patients with CHF who are on beta-blockers have inadequately controlled heart rate (HR)7–11 and a substantial proportion of patients do not tolerate the target doses of beta-blockers used in the large clinical trials.8

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Moreover, further up-titration of beta-blockers is not achievable in many patients.12 This is of concern since elevated HR is associated with an increased incidence of cardiovascular events in patients with CHF.13–16 High resting HR has been found to be a predictor for clinical outcomes17 and total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease18 and in the general population, as well as in CHF patients.19 There is therefore a need for further strategies to reduce HR in CHF patients. Within this framework, clinical data support the addition of ivabradine to betablocker therapy. This brief review aims to summarise clinical evidence supporting the combined use of beta-blockers and ivabradine in patients suffering from systolic CHF.

SNS Activation and Beta-blocker Therapy in CHF The left ventricle ‘remodelling’ process, resulting in a progressive enlargement of the left ventricle and decline in contractility – one measure of which is a reduced ejection fraction (EF) – characterises CHF with systolic dysfunction.20,21 Continued SNS activation over time results in myocardial injury and in systemic effects that are detrimental for the blood vessels, kidneys and muscles. Together with RAAS activation,

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Combined Beta-blocker and Ivabradine Therapy

Table 1: Clinical Studies Investigating the Combination of Beta-blockers and Ivabradine Study Name

Description

Efficacy Outcomes

Safety/Tolerability

CARVedilol, IVAbradine or

HF patients, three groups:

Heart rate reduced in all three groups,

Maximal dose of study treatment was more

their Combination on Exercise

carvedilol <25 mg twice

but to a greater extent by the

frequently tolerated in patients receiving

Capacity in Patients with

daily (n=38); ivabradine

combination. Six-minute walk test

ivabradine (36/41) than in those receiving

Heart Failure (CARVIVA HF)37

<7.5 mg twice daily (n=41);

myocardial venous oxygen consumption

carvedilol (18/38) or combination therapy

and carvedilol/ivabradine

results significantly improved in the

(32/42; p<0.01 ivabradine versus carvedilol).

<12.5/7.5 mg twice

ivabradine and combination groups

daily (n=42).

(both p<0.01), as did peak venous oxygen and ventilatory anaerobic threshold (p<0.01 for ivabradine and p<0.03 for combination versus carvedilol). No changes in those with carvedilol. Ivabradine and combination groups had better quality of life (p<0.01 versus baseline for ivabradine and p<0.02 for combination) versus no change with carvedilol.

MorBidity-mortality EvAlUaTion

Phase III coronary artery

Ivabradine did not affect the primary

Serious adverse events were similar: 22.5 %

of the If Inhibitor Ivabradine in

disease and left ventricular

composite endpoint (HR 1.00; 95 %

patients in the ivabradine group verus 22.8 %

Patients with Coronary Artery

ejection fraction <40 %

CI [0.91–1.1]; p=0.94). In a subgroup

of controls (p=0.70).

Disease and Left Ventricular

(n=10,917): 5,479 patients

of patients with a heart rate of ≥70 bpm,

Dysfunction (BEAUTIFUL)39

received 5 mg ivabradine,

ivabradine did not affect the primary

(increased to target dose of

composite outcome (HR 0.91; 95 %

7.5 mg twice a day), and

CI [0.81–1.04]; p=0.17), cardiovascular

5,438 received matched placebo

death or admission to hospital for

in addition to appropriate

new-onset or worsening HF. It did

cardiovascular medication;

reduce hospitalisation for fatal and

87 % of patients were taking

non-fatal MI (HR 0.64; 95 % CI [0.49–0.84];

beta-blockers. Median follow-

p=0.001) and coronary revascularisation

up 19 months.

(HR 0.70; 95 % CI [0.52–0.93]; p=0.016).

Systolic Heart Failure

Phase III HF (n=6,558) 90 %

Primary endpoint event (composite of

Serious adverse events: 3,388 ivabradine

Treatment with the If

taking beta-blockers, randomised

cardiovascular death or hospital

patients versus 3847 placebo patients

inhibitor Ivabradine Trial

to ivabradine (n=3,268) <7.5 mg

admission for worsening HF (HR 0.82;

(p=0.025). Symptomatic bradycardia: 150 (5 %)

(SHIFT)40

twice daily or placebo (n=3,290).

95 % CI [0.75–0.90]; p<0.0001): 24 %

ivabradine patients versus 32 (1 %) placebo

Data available for 3,241 patients

ivabradine versus 29 % placebo group.

patients (p<0.0001).

in the ivabradine group and

Events driven mainly by hospital

Visual side-effects (phosphenes): 89 (3 %)

3,264 patients allocated to

admissions for worsening HF (21 %

ivabradine patients versus 17 (1 %) placebo

placebo. Median follow-up

placebo versus 16 % ivabradine; HR

patients (p<0.0001)

22.9 months (interquartile

0.74; 95 % CI [0.66–0.83]; p<0.0001)

range: 18–28 months).

and deaths due to HF (3 % ivabradine versus 5 % placebo; HR 0.74; 95% CI [0.58–0.94]; p=0.014).

PractIcal Daily EffectiveNess

HF (n=1,956) prospective, open-

After 4 months of treatment with

and TolEraNce of Procoralan®

label multicentre study. Initial

ivabradine, HR was reduced to 67±8.9 bpm;

in Chronic SystolIc Heart Failure

mean European quality of life-5

patients presenting with signs of

in GermanY (INTENSIFY)48

dimensions (EQ-5D) index score:

decompensation decreased to 5.4 %;

0.64±0.28.

brain natriuretic peptide levels >400 pg/mL dropped to 26.7 %; NYHA classification shifted towards lower grading (24.0 % and 60.5 % in NYHA I and II, respectively). EQ-5D index improved to 0.79±0.21.

Bagryi et al.56

Systolic HF (n=69) prospective,

Patients receiving ivabradine had lower

open-label, single-centre study,

resting heart rate at 5 months (61.6±3.1

5-month follow-up.

versus 70.2±4.4 bpm; p<0.05). Adding

Treatment tolerability was satisfactory.

ivabradine to carvedilol was associated with increases in 6-minute walk test and ejection fraction (all p<0.05). Patients receiving ivabradine and carvedilol had lower heart rates and better exercise capacity than those on carvedilol alone. Effect of early treatment with

Systolic HF (n=71): beta-blockers +

Heart rate 28 days (64.3±7.5 versus

ivabradine combined with

ivabradine (33) versus beta-

70.3±9.3 bpm; p=0.01) and 4 months

administration of ivabradine (asymptomatic

beta-blockers versus beta-

blockers alone (38), starting

(60.6±7.5 versus 67.8±8 bpm; p=0.004)

bradycardia <60 bpm in seven patients in the

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No severe side effects attributable to early

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Therapeutics Table 1: Cont. Study Name

Description

blockers alone in patients

24 hours after hospital admission after discharge were significantly lower

Efficacy Outcomes

ivabradine + beta-blocker group versus six

hospitalized with heart failure

for acute HF; 4-month follow-up.

patients in the beta-blocker alone group).

in the combination therapy group.

and reduced left ventricular

Ejection fraction, brain natriuretic peptide

ejection fraction (ETHIC-AHF)57

levels and severity of symptoms significantly

Safety/Tolerability

improved in the combination therapy group. No differences were found in morbidity and mortality. bmp = beats per minute; HF = heart failure; HR = hazard ratio; NYHA = New York Heart Association.

Figure 1: Mechanism of Action of Ivabradine

Ivabradine selectively inhibits the If current the sinus node

Sinus node The pacemaker of the heart

Na+

Na+ Ivabradine

f-channel K+

K+

ΔHR

0 mv

Heart rate reduction

−40 mv −70 mv Ivabradine reduces the slow diastolic depolarisation phase Source: http://www.shift-study.com/ivrabradine/mode-of-action/ Reproduced with the permission of Servier © 2016.

this creates a pathophysiological cycle responsible for worsening CHF syndrome and death.20,21 The altered haemodynamic homeostasis of CHF patients is associated with an increased HR, which carries a negative prognosis;22–24 whereas the beneficial effect of beta-blockers has been linked to their HR-lowering effect.14–25 However, as previously mentioned, beta-blockers are often underused in clinical practice, are seldom prescribed at the doses proven to reduce events,26–29 and their up-titration in response to persistently elevated HR can be associated with an increased risk of adverse reactions.12 A non beta-blockade approach to HR reduction has recently become available30,31 following discovery of the If current that modulates the slope of spontaneous diastolic depolarisation of the sino-atrial node: namely, ivabradine.

Use of Ivabradine in Heart Failure Ivabradine (Procolaran®, Servier) selectively and specifically inhibits the If current in the sino-atrial node, reducing HR without affecting the autonomic nervous system (see Figure 1).32–34 The effectiveness of ivabradine in CHF has been tested in the Systolic Heart Failure Treatment with the If inhibitor Ivabradine Trial (SHIFT)35 in which 6,558 patients with CHF on stable background therapy, including beta-blockers, and a HR ≥70 beats per minute (bpm) with sinus rhythm were randomised to ivabradine (up to 7.5 mg twice daily) or placebo. At the median follow-up of 22.9 months, the results indicated improved clinical outcomes: 18 % reduction in the primary composite endpoint of cardiovascular death

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or hospitalisation for worsening HF, 26 % reduction in hospitalisation for worsening HF and 26 % reduction in pump failure death in the ivabradine group. Since the majority of patients in SHIFT were taking beta-blockers, it was hypothesised that the combination of beta-blockers plus ivabradine rather than the dose of beta-blocker was relevant to these findings. A subanalysis of SHIFT appeared to confirm this hypothesis, by showing that the combination of drugs rather than the dose of beta-blockers was important in improving the primary endpoints of cardiovascular death and hospitalisation.36 A further study concluded that the combination of beta-blockers plus ivabradine resulted in improved outcomes regardless of the individual beta-blocker prescribed.37 A number of clinical studies have evaluated the use of ivabradine in combination with beta-blockers (Table 1). The first large randomised controlled study of ivabradine was the MorBidity-mortality EvAlUaTion of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial38 in which patients (n=10,917) with stable coronary artery disease and an EF <40 % were randomised to ivabradine 7.5 mg twice daily or placebo. Most patients (87 %) were receiving beta-blockers in addition to the study drug. After a median of 19 months, no significant difference was found between ivabradine and placebo in terms of the primary composite endpoints (cardiovascular death, hospitalisation for myocardial infarction and worsening HF). However, ivabradine reduced hospitalisation for myocardial infarction and coronary revascularisation in patients with a HR >70 bpm by 36 % (p=0.001), suggesting that the lowering of raised HR may be associated with improved outcomes. Importantly, the study also showed that the combination of a beta-blocker and ivabradine was well tolerated. In SHIFT,35 patients with symptomatic CHF had a higher baseline HR and a greater HR reduction due to ivabradine than in the BEAUTIFUL trial. In this study, patients (n=6,558) with CHF on stable background therapy were randomised to ivabradine (up to 7.5 mg twice daily) or placebo. At the median follow-up of 22.9 months, data were available for 3,241 patients in the ivabradine group and 3,264 patients in the placebo group. Use of ivabradine was associated with an 18 % reduction in the primary composite endpoint of cardiovascular death or hospitalisation for worsening HF: 24 % of patients in the ivabradine group and 29 % of those taking placebo had a primary endpoint event (hazard ratio (HR) 0.82; 95  % CI [0.75–0.90]; p<0.0001; Figure 2). The effects were driven mainly by hospital admissions for worsening HF (21  % placebo versus 16 % ivabradine; HR 0.74, 95% CI [0.66–0.83]; p<0.0001) and deaths due to HF (5 % versus 3 %; HR 0.74; 95 % CI [0.58–0.94]; p=0.014). The risk of cardiovascular outcomes increased with HR, and every 5-bpm increase in baseline HR was associated with a 16 % increase in the risk of primary outcome in the placebo arm.35 This is in agreement with a meta-analysis by McAlister et al. indicating that, in CHF patients, a reduction of 5 bpm

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Since the majority of patients in SHIFT (90 %) were taking beta-blockers, researchers hypothesised that the combination of beta-blockers plus ivabradine was important. A substudy of SHIFT to assess the impact of background beta-blocker dose on response to ivabradine found that the combination rather than the dose was important, and that the primary endpoint and HF hospitalisations were significantly reduced by ivabradine in all subgroups with <50  % of target beta-blocker dose, including patients not taking beta-blockers (p=0.012).36 A further study concluded that the combination of beta-blockers plus ivabradine resulted in improved outcomes regardless of the individual betablocker prescribed.37

Pathophysiological Mechanisms Underlying the Combined Use of Beta-blockers and Ivabradine The rationale for combining beta-blockers and ivabradine is that their actions at heart level are synergic and not limited to sinus node rate; whereas beta-blockers have several other target points that are beneficial in CHF syndrome. The randomised CARVedilol, IVAbradine or their Combination on Exercise Capacity in Patients with Heart Failure (CARVIVA-HF) study40 found that ivabradine alone or in combination with carvedilol was more effective than carvedilol alone in improving exercise tolerance and quality of life (QoL) in CHF patients. A subanalysis of SHIFT41 also found that HR reduction with ivabradine was associated with improved QoL. This finding was consolidated by data from the prospective, open-label multicentre PractIcal Daily EffectiveNess and TolEraNce of Procoralan® in Chronic SystolIc Heart Failure in GermanY (INTENSIFY) study.42 The beneficial effects of beta-blockers may only in part be related to HR reduction; their protective action against the deleterious effects of excessive sympathetic activity on the heart and other organs and their humoral mechanisms may significantly contribute to the benefits of this class of drugs. Similarly, it has been suggested that HR-independent mechanisms could contribute to the additional beneficial effects associated with ivabradine treatment.43

Haemodynamic Mechanisms HR reduction can increase the duration of diastole44,45 and therefore improve myocardial perfusion. Beta-blockers reduce HR and prolong diastolic duration, but they also impair isovolumic ventricular relaxation, offsetting part of this benefit in terms of the diastolic pressure–time integral.46 Beta-blockers also increase alpha-adrenergic coronary vasoconstriction. Ivabradine protects isovolumic ventricular relaxation and does not offset the benefit in terms of coronary blood flow46 because ivabradine does not increase alpha-adrenergic coronary vasoconstriction, as is typically seen with beta-blockers.47 This explains why, for the same level of HR reduction, the increase in diastolic time and the perfusion duration and volume are greater with ivabradine than with beta-blockers.4 Treatment with beta-blockers plus ivabradine therefore improves myocardial perfusion by these mechanisms, both at rest and during exercise.45

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Figure 2: Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) Primary Composite Endpoint of Death or Hospitalisation for Worsening Heart Failure 36 40 Cumulative frequency (%)

with beta-blocker treatment was associated with an 18  % reduction in the risk of death.39 An analysis of the SHIFT data found that in the ivabradine group there was a direct association between HR achieved at 28 days and subsequent cardiac outcomes. Patients receiving treatment who reached a target HR below 60 bpm at 28 days had the lowest event rate compared with patients with higher HRs (event rate 17.4  %; 95  % CI [15.3–19.6]), suggesting that resting HR is a powerful predictor of outcomes in CHF.13

HR (95 % CI), 0.82 (0.75–0.90) P<0.0001

Placebo −18 %

30 Ivabradine

20 10 0

0

6

12

18

24

30

Time (months) CI = confidence interval; HR = hazard ratio. Source: Swedberg et al.36 Reproduced with the permission of Elsevier © 2010.

In addition to this, ivabradine administration has been shown to significantly increase stroke volume in patients with severe CHF.48 The increase in stroke volume caused by ivabradine is of clinical relevance as beta-blockers reduce stroke volume during initiation, the first months of treatment and up-titration. This effect of beta-blockade could be compensated for by prescribing ivabradine with lower initial doses of beta-blockers. Ivabradine also reduces left ventricular (LV) end-diastolic pressure, unlike beta-blockers, with this effect being still present when ivabradine is co-prescribed with a beta-blocker, resulting in increased stroke volume and maintenance of cardiac output.48,49

Left Ventricular Structure and Function In addition to the haemodynamic mechanisms reported above, ivabradine slows the progressive modification of LV structure in the 2–3 months after the initiation of therapy, which contributes to the improvement in cardiac function.49–51 Ivabradine increases vascular compliance, thus reducing LV load, and this effect is related to beneficial outcomes in ivabradine-treated patients. Like beta-blockers, treatment with ivabradine significantly lowers RAAS activation compared with placebo. Lower RAAS activation results in improved renal and vascular pressures, and in a decrease in cardiac wall stress, thereby preventing worsening cardiac fibrosis and cardiac remodelling. Cardiac remodelling plays a crucial role in the pathophysiology of CHF and also affects the prognosis of this patient population.52 Ivabradine has been reported to induce reverse remodelling in patients with New York Heart Association Functional class II and IV HF, including modifications of LV structure (i.e. decreased in LV end-systolic and end-diastolic volumes), that have been observed after just 3 months of therapy,50,51 being accompanied by a 2.7  % increase in LVEF. A reduction in cardiac collagen53,54 and fibrosis have been also reported in animal models of HF. Another SHIFT substudy found that ivabradine reverses cardiac remodelling in patients with CHF and LV systolic dysfunction, and this effect was independent of beta-blocker use.51 Taken together, these results support the role of ivabradine in protecting LV structure and function.34

Safety Issues Associated with Combined Ivabradine and Beta-blocker Therapy Studies to date indicate that ivabradine is well tolerated in combination with beta-blockers. In the SHIFT35 there was a lower incidence of serious adverse events in the ivabradine versus placebo group.

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Therapeutics Table 2: European Society of Cardiology Practical Guidance on the Use of Ivabradine in Patients with Heart Failure with Reduced Ejection Fraction 58 WHY? To reduce the risk of HF hospitalization and cardiovascular death.

IN WHOM AND WHEN? Indications: 1. Patients with stable symptomatic HF (NYHA CIass II–IV) and an LVEF ≤35 % in sinus rhythm and resting heart rate ≥70 bpm despite guidelines-recommended treatment. 2. Start in patients with stable symptomatic HF (NYHA Class II–IV) who are already treated with maximal tolerated evidence-based doses of an ACE-I (or an ARB), a beta-blocker and an MRA. Contra-indications: 1. Unstable cardiovascular conditions (acute coronary syndrome, stroke/TIA, severe hypotension). 2. Severe liver dysfunction or renal dysfunction (no evidence on safety or pharmacokinetics for creatinine clearance <15 mL/min). 3. Pregnancy or breastfeeding. 4. Known allergic reaction/other adverse reaction (drug-specific). Cautions/seek specialist advice: 1. Severe (NYHA CIass IV) HF. 2. Current or recent (<4 weeks) exacerbation of HF (e.g. hospital admission with worsening HF). 3. Resting heart rate <50 bpm during treatment. 4. Moderate liver dysfunction. 5. Chronic retinal diseases, including retinitis pigmentosa. 6. Drug interactions: ° To look out for (due to a potential risk of bradycardia and induction of long QT as a result of bradycardia): • Verapamil, diltiazem (both should be discontinued). • Beta-blocker. • Digoxin. • Amiodarone. ° To look out for (drugs being strong inhibitors of isoenzyme CYP3A4 cytochrome P450): • Antifungal azoles (such as ketoconazole, itraconazole). • Macrolide antibiotics (such as clarithromycin, erythromycin). • HIV protease inhibitors (nelfinavir, ritonavir). • Nefazodone. WHAT DOSE? Ivabradine: starting dose 5 mg b.i.d., target dose 7.5 mg b.i.d. WHERE? • In the community in stable patients in NYHA Class II–III. • Patients in NYHA Class IV or those with a recent HF exacerbation should be referred for specialist advice. • Other exceptions–see ‘Cautions/seek specialist advice’. HOW TO USE? • Start with a low dose (5 mg b.i.d.). In patients over 75 years oId, a lower starting dose of 2.5 mg b.i.d. can be used. • Daily dose may be increased to 7.5 mg b.i.d., decreased to 2.5 mg b.i.d. or stopped depending on the patient’s resting heart rate. Double the dose not more frequently than at 2-week intervals (slower up-titration may be needed in some patients). Aim for target dose (see above) or, failing that, the highest tolerated dose based on resting heart rate. If the resting heart rate is between 50 and 60 bpm, the current dose should be maintained. • Monitor heart rate, blood pressure, and clinical status. • When to stop up-titration, reduce dose, stop treatment – see PROBLEM SOLVING. • A specialist HF nurse may assist with education of the patient, monitoring resting heart rate, follow-up (in person or by telephone), and dose up-titration. PROBLEM SOLVING • Treatment must be reduced or stopped if the resting heart rate decreases persistently below 50 bpm or if symptoms of bradycardia occur ° Review need for other heart rate-slowing drugs or drugs interfering with ivabradine liver metabolism. ° Arrange electrocardiogram to exclude other than sinus bradycardia rhythm disturbances. ° Consider screening for secondary causes of bradyarrhythmias (e.g. thyroid dysfunction). • If a patient develops persistent/continuous AF during the therapy with ivabradine, the drug should be stopped. • Visual phenomena are usually transient, and disappear during the first few months of ivabradine treatment and are not associated with serious retinal dysfunction. However, if they result in the patient’s discomfort, the discontinuation of ivabradine should be considered. • In case of lactose or galactose intolerance (component of the ivabradine tablet), if symptoms occur, there may be a need to stop the drug. ADVICE TO PATIENT • Explain expected benefits (see WHY?) ° Treatment is given to prevent worsening of HF leading to hospital admission and to reduce the risk cardiovascular death. • In order to detect a potential bradycardia, patients should be encouraged to measure and record his/her pulse on a regular basis. • Advise patient to report side effects to the physician or HF nurse. Side effects due to symptomatic bradycardia: breathlessness, fatigue, syncope, dizziness; other side effects: luminous visual phenomena. ACE = angiotensin-converting enzyme; AF = atrial fibrillation; ARB = angiotensin receptor blocker; b.i.d. = twice daily; bpm = beats per minute; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HIV = human immunodeficiency virus; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; TIA = transient ischemic attack. Source: Reproduced from Ponikowski et al.58 with the permission of Oxford University Press (UK) © 2016 European Society of Cardiology, www.escardio.org

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In total, 21  % of patients on ivabradine discontinued treatment compared to 19  % of patients on placebo (p=0.017). Bradycardia was more frequent with ivabradine than with placebo (5  % versus 1 %, p<0.0001 respectively). Visual luminous phenomena (phosphenes) were reported in 3  % of patients in the ivabradine group.35 Adverse events were not influenced by beta-blocker dosage.37 In the BEAUTIFUL trial38 no additional safety concerns were identified in patients taking beta-blockers plus ivabradine. The incidence of serious adverse events in the ivabradine and placebo groups was similar (22.5 % versus 22.8 %; p=0.70). There was, however, a higher incidence of bradycardia (including asymptomatic bradycardia) in the ivabradine group than in the placebo group (13 % versus 2 %).

Current Ivabradine Use Currently, ivabradine can be given early in hospitalisation, and can be initiated at the same time as beta-blockers.55,56 It is recommended that treatment commence with the administration of 5 mg ivabradine twice daily. After 2 weeks, the resting HR should be checked. If it exceeds 60 bpm, the dose should be raised to 7.5 mg twice daily. At a resting HR of 50–60 bpm, the dose can be maintained at 5 mg twice daily, and if HR is below 50 bpm it should be reduced to 2.5 mg twice daily.6 HR should be regularly checked throughout treatment and the dose adjusted accordingly. If HR remains below 50 bpm despite dose reduction, treatment must be discontinued. In patients aged 75 years or more, a lower starting dose should be considered (2.5 mg twice daily, i.e. half a 5 mg tablet twice daily) before up-titration if necessary. Importantly, no dose adjustment is needed in patients with hepatic or renal impairment.57 Practical guidance on the use of ivabradine in CHF is provided in an addendum to the 2016 European Society of Cardiology (ESC) Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure (see Table 2).58

Discussion Current ESC guidelines59 on CHF recommend the use of ivabradine in symptomatic patients with LVEF ≤35 % who are in sinus rhythm and

1.

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Schrier RW, Abdallah JG, Weinberger HH, Abraham WT. Therapy of heart failure. Kidney Int 2000;57:1418–25. PMID: 10760077 Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin–angiotensin–aldosterone system to clinical state in congestive heart failure. Circulation 1981;63:645–51. PMID: 7006851 Kalidindi SR, Tang WH, Francis GS. Drug insight: aldosteronereceptor antagonists in heart failure – the journey continues. Nat Clin Pract Cardiovasc Med 2007;4:368–78. PMID: 17589427 Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation 2001;103:72–7. PMID: 11136688 Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849–65. PMID: 1828192 Zannad F, Gattis Stough W, Rossignol P, et al. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J 2012;33:2782–95. DOI: 10.1093/eurheartj/ ehs257; PMID: 22942339 Franke J, Wolter JS, Meme L, et al. Optimization of pharmacotherapy in chronic heart failure: is heart rate adequately addressed? Clin Res Cardiol 2013;102:23–31. DOI: 10.1007/s00392-012-0489-2. Russell SJ, Oliver M, Edmunds L, et al. Optimized betablocker therapy in heart failure: is there space for additional heart rate control? Br J Cardiol 2012;19:21–3. DOI: 10.5837/ bjc.2012.001 Maggioni AP, Anker SD, Dahlstrom U, et al. Heart Failure Association of the ESC. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry,

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have a resting heart rate ≥70 bpm despite treatment with an evidencebased dose of beta-blocker (or maximum tolerated dose below that or those who are unable to tolerate or have contraindications to a beta-blocker), angiotensin converting enzyme inhibitor, angiotensin receptor blocker and mineralocorticoid receptor antagonist. The US Food and Drug Administration has recommended similar indications for ivabradine.60 It should be recalled that in SHIFT only around a quarter of patients achieved the recommended ESC target dose, and around half achieved at least 50 % of the target dose.35 This reflects current clinical practice.35,61 SHIFT has provided evidence for additional HR lowering with ivabradine for patients in sinus rhythm who are receiving betablockers. Ivabradine is easier to use than beta-blockers and is better tolerated. The benefit provided by ivabradine was similar in the small subgroup of SHIFT that did not receive a beta-blocker to that observed in the overall population,36 raising the possibility that combining ivabradine with suboptimal doses of beta-blockers may be a better strategy than uptitrating beta-blockers to an optimal dose. One study found that the use of beta-blockers and resting HR were independent predictors of prognosis but beta-blocker dose was not.62 Thus, it may be hypothesised that achieving a HR within the target range may be a more appropriate therapeutic goal than optimising beta-blocker dose in patients with CHF. In SHIFT, patients with the lowest risk reached a HR <60 bpm; therefore it might be reasonable, at present, to recommend this target in daily practice. There is, however, no direct evidence for this. Further trials are clearly needed before first-line use of ivabradine is recommended in patients other than those for whom beta-blockers are contraindicated.

Conclusion In this review we have reported consistent data suggesting it is possible to safety extend the use of ivabradine plus beta-blocker therapy in patients with CHF, even in less advanced stages of the disease. This combined therapy could favour lower beta-blocker doses, facilitate up-titration for the achievement of target HR, and avoid the possible dose-dependent adverse events related to their use. ■

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