CFR 2.1

Volume 2 • Issue 1 • Spring 2016

www.CFRjournal.com

Novel Imaging Techniques for Heart Failure Josep L Melero-Ferrer, Raquel López-Vilella, Herminio Morillas-Climent, Jorge Sanz-Sánchez, Ignacio J Sánchez-Lázaro, Luis Almenar-Bonet and Luis Martínez-Dolz

Should Angiotensin Receptor Neprilysin Inhibitors Replace Angiotensin-converting Enzyme Inhibitors in Heart Failure With a Reduced Ejection Fraction?

Sam Hayman and John J Atherton

Beta-blockers or Digoxin for Atrial Fibrillation and Heart Failure?

Laurent Fauchier, Guillaume Laborie, Nicolas Clementy and Dominique Babuty

Cardiac Rehabilitation in Patients With Heart Failure: New Perspectives in Exercise Training Maurizio Volterrani and Ferdinando Iellamo

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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 • reduction of post-surgical complications.11-12 1.

2.

3.

4.

5.

6.

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.

Lilleberg et al. Eur J Heart Fail. 2007; 9:75-82.

7.

8.

9.

10.

11.

12.

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.

Eriksson et al. Ann Thorac Surg 2009;87:448–54.

Harrison et al. J Cardiothorac Vasc Anesth 2013;27(6):1224-32.

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-

Simdax_AD.indd 1

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

10/05/2016 22:43

Volume 2 • Issue 1 • Spring 2016

www.CFRjournal.com

Editor-in-Chief Andrew JS Coats

William T Abraham

Adelino Leite-Moreira

Ali Ahmed

Alexander Lyon

Washington DC VA Medical Center, USA

Imperial College London, UK

Inder Anand

Theresa A McDonagh

University of Minnesota, USA

King’s College Hospital, UK

John Atherton

Kenneth McDonald

Royal Brisbane and Women’s Hospital, Australia

St Vincent’s Hospital, Ireland

Michael Böhm

Ileana L Piña

Saarland University, Germany

Montefiore Einstein Center for Heart & Vascular Care, USA

Alain Cohen Solal

Kian-Keong Poh

Paris Diderot University, France

National University Heart Center, Singapore

Henry J Dargie

A Mark Richards

Carmine De Pasquale

Giuseppe Rosano

Frank Edelmann

Martin St John Sutton

Michael B Fowler

Allan D Struthers

Michael Fu

Michal Tendera

David L Hare

Maurizio Volterrani

Michael Henein

Cheuk Man Yu

University of Porto, Portugal

The Ohio State University, USA

Western Infirmary, Glasgow

University of Otago, New Zealand

Flinders University, Australia

St George’s University of London, UK

Charité University Medicine, Germany

Hospital of the University of Pennsylvania, USA

Stanford University, USA

Ninewells Hospital & Medical School, UK University of Silesia, Poland

Sahlgrenska University Hospital, Sweden

IRCCS San Raffaele Pisana, Italy

University of Melbourne, Australia

The Chinese University of Hong Kong, Hong Kong

Heart Centre and Umea University, Sweden

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

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Design Tatiana Losinska

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Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

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

Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2016 All rights reserved

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Established: March 2015 Frequency: Bi-annual Current issue: Spring 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.

Structure and Format •

Cardiac Failure Review is a bi-annual journal comprising review

Submissions and Instructions to Authors • •

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 • •

• •

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.

On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion.

Online

The Managing Editor, following consultation with the Editor-in-Chief

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

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.

•

returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are

2

CFR_A+S_2.1.indd 2

© RADCLIFFE CARDIOLOGY 2016

10/05/2016 23:54

3 RD WORLD CONGRESS ON ACUTE HEART FAILURE 21-24 May Florence, Italy

Heart Failure: state of the art

Register Now Early fee deadline Late fee deadline

21 March 18 April

Congress Key Figures 4 4 700+ 1 700+ 2 000+ 100+ 300+ 40+

www.escardio.org/HFA

HFA_2016.indd 3

days of scientific exchange healthcare professionals from 90+ countries abstracts and clinical cases submitted m2 of exhibition scientific sessions international expert faculty members industry sessions and workshop

#heartfailure2016

10/05/2016 22:46

Content Contents

Foreword

6

Andrew JS Coats and Giuseppe Rosano

Pathophysiology

8 14

Deranged Cardiac Metabolism and the Pathogenesis of Heart Failure Gabriele Fragasso

Current Understanding of the Compensatory Actions of Cardiac Natriuretic Peptides in Cardiac Failure: A Clinical Perspective Noel S Lee and Lori B Daniels

Clinical Evaluation

20 27

Decompensated Heart Failure in Pregnancy John Anthony and Karen Sliwa

Novel Imaging Techniques for Heart Failure Josep L Melero-Ferrer, Raquel López-Vilella, Herminio Morillas-Climent, Jorge Sanz-Sánchez, Ignacio J Sánchez-Lázaro, Luis Almenar-Bonet and Luis Martínez-Dolz

Pharmacological Therapy

35 40 47

Beta-blockers or Digoxin for Atrial Fibrillation and Heart Failure?

Laurent Fauchier, Guillaume Laborie, Nicolas Clementy and Dominique Babuty

The Mechanism of Action of LCZ696 Juan Tamargo Menendez

Should Angiotensin Receptor Neprilysin Inhibitors Replace Angiotensin-converting Enzyme Inhibitors in Heart Failure With a Reduced Ejection Fraction?

Sam Hayman and John J Atherton

51

Nitrates as a Treatment of Acute Heart Failure Mohammad S Alzahri, Anita Rohra and W Frank Peacock

Acute Heart Failure

56

Shock Management for Cardio-surgical Intensive Care Unit Patient: The Silver Days Till Hauffe, Bernard Krüger, Dominique Bettex and Alain Rudiger

Rehabilitation

63

Cardiac Rehabilitation in Patients With Heart Failure: New Perspectives in Exercise Training Maurizio Volterrani and Ferdinando Iellamo

4

CFR_2.1_ToC.indd 4

CARDIAC FAILURE REVIEW

11/05/2016 17:15

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

www.radcliffecardiology.com A free-to-access community supporting best practice in cardiovascular care

Interventional

www.ICRjournal.com

The Role of Percutaneous Haemodynamic Support in High-risk Percutaneous Coronary Intervention and Cardiogenic Shock Dagmar M Ouweneel, Bimmer E Claessen, Krischan D Sjauw and José PS Henriques

Intravascular Ultrasound vs. Optical Coherence Tomography For Coronary Artery Imaging - Apples And Oranges?

Krishnaraj S Rathod, Stephen M Hamshere, Daniel A Jones, and Anthony Mathur US Cardiology Review

Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation Roberto Spina, Chris Anthony, David WM Muller and David Roy

www.AERjournal.com

Volume 4 • Issue 1 • Spring 2015

Volume 10 • Issue 1 • Spring 2016 • RELAUNCH ISSUE

www.USCjournal.com

Percutaneous Closure of Patent Foramen Ovale – Data from Randomized Clinical Trials and Meta-Analyses Volume 10 • Issue 1 • Spring 2016 • RELAUNCH ISSUE

Stefan Stortecky and Stephan Windecker

Biology of the Sinus Node and its Disease Moinuddin Choudhury, Mark R Boyett and Gwilym M Morris

Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation Philipp Bushoven, Sven Linzbach, Mate Vamos and Stefan H Hohnloser

Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation

Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors Michelle Kittleson, MD, PhD

Ischemic Complications of Pregnancy: Who is at Risk?

Sara C Martinez, MD, PhD and Sharonne N Hayes, MD

Optimizing Heart Rate and Controlling Symptoms in Atrial Fibrillation

Amir A Schricker, Junaid Zaman and Sanjiv M Narayan

Public Reporting of Cardiovascular Data: Benefits, Pitfalls, and Vision for the Future

Computer Modelling for Better Diagnosis and Therapy of Patients

by Cardiac Resynchronisation Therapy

Gregory J Dehmer, MD, MACC, MSCAI, FAHA, FACP ISSN: 1756-1477

Marieke Pluijmert, Joost Lumens, Mark Potse, Tammo Delhaas, Angelo Auricchio and Frits W Prinzen

Intravascular ultrasound

Optical coherence tomography image of normal coronary arteries

Intra-procedural fluoroscopy and the animation of valve implantation process SNS

Phase +π

Radcliffe Cardiology ICR10.1_FC+spine.indd All Pages

-2 -π

NP receptors t=939 ms

t=964 ms

t=1,029 ms

Simulated Activation Times on the Endocardia of Both Ventricles

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Radcliffe Cardiology

Natriuretic peptides

RAAS

Neurohormal systems

→

Non-invasive Mapping of Atrial Fibrillation Re-entrant and Focal Driver Domains

→ → →→ → →

Voltage Map of the Left Atrium During Atrial Fibrillation Ablation

β blockers

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Vasoconstriction Lifelong Learning for Cardiovascular Professionals Heart rate Contractility RAAS activity 26/02/2015 21:17 Vasopressin NPS

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Vasodilatation in heartNeprilysin failure Blood pressure X Sympathetic tone Inactive Vasopressin fragments Aldosterone Hypertrophy Fibrosis Natriurersis/diuresis

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ACEI, ARB, MRA Left coronary artery

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oblique projection

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ARNIs Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

Radcliffe Cardiology

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Lifelong Learning for Cardiovascular Professionals

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RC PRODUCTS AD.indd 5

LIVE FROM THE HAMMERSMITH

Pragnesh Parikh, MD and KL Venkatachalam, MD

→ → →→ →

Arrhythmia & Electrophysiology Review Volume 4 • Issue 1 • Spring 2015

ar iology Review Volume 10 • Issue 1 • Spring 2015

Volume 10 • Issue 1 • Spring 2015

C Academy C Webinars C Webinars

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10/05/2016 23:10

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 second volume of Cardiac Failure Review to our readers. In recent weeks we have attended innovative conferences that have highlighted new devices that show great promise in heart failure treatment, one in Brussels, Belgium that coincided with the tragic events there, and one in Seoul, Korea – an impressive emerging Asian superstar.

In heart failure news, the UK’s NICE committee has recommended the combination agent sacubitril–valsartan (LCZ696) for rapid uptake by the NHS. This follows US Food and Drug Administration and European Medicines Agency approval.

We also await with great anticipation the launch of the 2016 European Society of Cardiology/Heart Failure Association guidelines for the diagnosis and treatment of acute and chronic heart failure at the Heart Failure Association meeting in Florence, Italy.

This is the first update of these important guidelines since 2012 and we wait to see how pivotal studies such as the Echo-CRT (Echocardiography Guided Cardiac Resynchronization Therapy)1 and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)2 studies have altered the recommendations. It is an exciting time in heart failure globally.

In this issue we have leading experts review a crucial list of subjects relevant to the practising heart failure specialist and interested generalist alike.

Martinez-Dolz and colleagues review novel imaging techniques in heart failure. Of course, echocardiography emerges as the investigation for the majority of heart failure assessment. Its familiarity, safety, low cost and availability make it an essential tool for any cardiologist. Long gone are the days when you could manage a patient without this tool. It is a must for all patients at some stage in the clinical journey, and indeed can be used repeatedly to assess response to therapy, and to assess the likelihood of responding to certain therapies. They also review more advanced imaging options including cardiovascular magnetic resonance (CMR), nuclear imaging-positron emission tomography, single-photon emission computed tomography and computed tomography (CT). The authors update us on new techniques in echocardiography such as 3D echocardiography and myocardial contrast enhanced echocardiography3 and the more sensitive measure of systolic function that can be gained by measuring global longitudinal strain, usually assessed by speckle-tracking echocardiography.4 This appears to be gaining acceptance as a sensitive way of monitoring left ventricular systolic function in patients receiving potentially cardiotoxic anticancer chemotherapy.5 They also review the advantages of accurate left atrial imaging and assessment.6,7 In the section on CMR, we are updated of the added value of late gadolinium enhancement patterns, which provide diagnostic utility for distinguishing between ischaemic and non-ischaemic cardiomyopathy,8 and to predict viability and recovery of contractile function after revascularisation.9,10 There is also a valuable update on the growing role of multi-detector CT, as well as hybrid imaging techniques that combine the advantages of multiple modalities.

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Foreword

Tamargo Menendez reviews the most significant advance in the therapy of chronic heart failure for a decade: the demonstration that LCZ696 (the combination of the neprilysin inhibitor, sacubitril, with an angiotensin II receptor blocker, valsartan) is more affective than the angiotensin converting enzyme (ACE) inhibitor, enalapril.

The PARADIGM-HF trial showed that LCZ696 significantly reduced CV death or HF hospitalisation (20 %; p<0.001), CV death (20 %) and all-cause mortality (16 %), versus enalapril.2 This review covers the modes of action of this exciting new combination drug therapy, however reports of poor uptake suggest concern about the narrow inclusion criteria of this single trial, limiting the comparability of the PARADIGM-HF population and other chronic heart failure patients.

Hayman and Atherton take up the theme by asking whether this new agent – coined an angiotensin receptor neprilysin inhibitor (ARNI) – should routinely replace ACE inhibitors in the management of heart failure with a reduced ejection fraction (HFrEF). They review the added value of neprilysin inhibition when added to blockade of the adverse effects of angiotensin II in HFrEF. Hayman and Atherton also remind us that neprilysin is an enzyme that catalyses the degradation of a number of vasoactive compounds, including natriuretic peptides, and that natriuretic peptides have multiple actions that could have a favourable effect on heart failure disease progression, including vasodilation, natriuresis and diuresis11 – a topic taken up in more detail in the excellent review by Lee and Daniels, also in this issue. This reasoning suggests inhibition of neprilysin may add therapeutic benefit, despite the fact that the mimetic, nesiritide, had no effect on death or rehospitalisation rates in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) study.12 This may indicate there is something special about sacubitiril, or that the different heart failure syndromes – HFrEF, heart failure with preserved ejection fraction13 and acute heart failure – are simply too different to be treated in the same way. Hayman and Atherton argue that PARADIGM-HF is the only trial supporting the use of ARNI over ACEI in patients with HFrEF, but that nonetheless this was a large study primarily powered to detect a difference in cardiovascular mortality, which it convincingly showed. They hold that the most appropriate population to receive ARNI in clinical practice would match those who were studied in the PARADIGM-HF study, namely patients with symptomatic HFrEF despite appropriate doses of ACEI (or ARB) and beta-blockers. They concentrate our attention on

the exclusion criteria, ways in which the potential target population can be whittled away to a non-representative subset of HFrEF. These included hypotension, estimated glomerular filtration rate <30 ml/min/1.73 m2 of body surface area, hyperkalaemia, a history of angioedema or unacceptable side effects from ACEI or ARB and anyone intolerant to forced up-titration of either LCZ696 or enalapril to quite high doses. Therefore, they argue to restrict LCZ696 in favour ACEI or ARB therapy in patients without symptomatic hypotension or systolic blood pressures <95–100 mmHg. Fauchier and colleagues discuss the surprisingly topical issue of whether beta-blockers or digoxin should be used for atrial fibrillation in heart failure. Surprising because we thought we had answered these questions in major trials nearly two decades ago. They review the very live debates on a possible reduced efficacy of beta-blockers in HFrEF patients in atrial fibrillation following the recent impressive individual patient data meta-analysis that analysed the total body of evidence for a prognostic role of beta-blockers in this setting and concluded there was none.14 They also review recent safety concerns over digoxin use in treating HFrEF patients with atrial fibrillation. They conclude that the benefit of beta-blockers on survival may be lower in patients with HFrEF when atrial fibrillation is present and that digoxin does not improve survival, but may help to obtain satisfactory rate control in combination with a beta-blocker; and that digoxin may also be useful in the presence of hypotension or an absolute contraindication to betablocker treatment in HFrEF with background atrial fibrillation.

We also highly recommend the review on cardiac rehabilitation in chronic heart failure by one of the pioneers of this field, our expert colleague Volterrani, and Iellamo, and the review by Alzahri, Rohra and Peacock on the role of nitrates in the treatment of acute heart failure. Last, but certainly not least in importance, there are excellent reviews by Anthony and Sliwa on decompensated heart failure in pregnancy; Rudiger and colleagues on the management of what they describe as “the silver days” – intensive care management beyond the 6 hours of cardiogenic shock; and Fragasso on the role of deranged cardiac metabolism in the pathogenesis of heart failure and potential interventions to improve outcomes by targeting this mostly universal but largely ignored aspect of chronic heart failure pathophysiology.

We hope you will enjoy reading this issue as much as we enjoyed helping assemble it. n

Acknowledgements The authors are proud to be the editors of Cardiac Failure Review. We acknowledge the importance of ethical publishing and hereby state that we abide by the statement of ethical publishing in biomedical journals.15

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2.

3.

4.

5.

Ruschitzka F, Abraham WT, Singh JP, et al. Cardiacresynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395–405. DOI: 10.1056/ NEJMoa1306687; PMID: 23998714 McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. DOI: 10.1056/NEJMoa1409077 Ahmed A, Gurunathan S, Senior R. Myocardial contrast echocardiography: ready for the prime time. International Cardiovascular Forum Journal 2014;1:207–8.

DOI: 10.17987/icfj.v1i5.59 Kong LY, Yu C, Guo J, Zhu T. Comparison of left ventricular global longitudinal strain measured with real time triplane and 2-dimensional echocardiography in patients with atrial fibrillation. International Cardiovascular Forum Journal 2015;2:24–9.

DOI: 10.17987/icfj.v4i0.156 Thavendiranathan P, Poulin F, Lim K, et al. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy. J Am Coll Cardiol 2014;63:2751–68. DOI:

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10.1016/j.jacc.2014.01.073; PMID: 24703918 Mor-Avi V, Yodwut C, Jenkins C, et al. Real-time 3D echocardiographic quantification of left atrial volume: multicenter study for validation with CMR. JACC Cardiovasc Imaging 2012;5:769–77. DOI: 10.1016/j.jcmg.2012.05.011; PMID: 22897989 7. Berisha G, Bajraktari G, Ibrahimi P, et al. Impaired left atrial reservoir function in metabolic syndrome predicts symptoms in HFpEF patients. International Cardiovascular Forum Journal 2015;4:37–42. DOI: 10.17987/icfj.v4i0.171 8. Karamitsos TD, Francis JM, Myerson S, et al. The role ofcardiovascular magnetic resonance imaging in heart failure. J Am Coll Cardiol 2009;54:1407–24. DOI: 10.1016/j. jacc.2009.04.094; PMID: 19796734 9. Selvanayagam JB, Kardos A, Francis JM, et al. Value of delayed-enhancement cardiovascular magnetic resonance imaging in predicting myocardial viability after surgical revascularization. Circulation 2004;110:1535–41. PMID: 15353496 10. Talib A. Assessment of myocardial viability: a review of 6.

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current non invasive imaging techniques. International Cardiovascular Forum Journal 2014;1:113–117.

DOI: 10.17987/icfj.v1i3.34 Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphatedependent signaling functions. Endocr Rev 2006;27:47–72.

PMID: 16291870 O’Connor C, Starling R, Hernandez A, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43. DOI: 10.1056/NEJMoa1100171 Coats A, Shewan L. The management of heart failure with preserved ejection fraction (HFpEF). International Cardiovascular Forum Journal 2014;1:108–12. DOI: 10.17987/icfj.v1i3.33 Kotecha D, Holmes J, Krum H, et al. Efficacy of beta-blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014;384:2235– 43. DOI: 10.1016/S0140-6736(14)61373-8; PMID: 25193873 Shewan LG, Coats AJS, Henein M. Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015;2:2 DOI: 10.17987/icfj.v2i1.4

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Pathophysiology

LE ATION.

Deranged Cardiac Metabolism and the Pathogenesis of Heart Failure G a b r i e l e Fra g a s s o San Raffaele Hospital, Milan, Italy

Abstract Activation of the neuro-hormonal system is a pathophysiological consequence of heart failure. Neuro-hormonal activation promotes metabolic changes, such as insulin resistance, and determines an increased use of non-carbohydrate substrates for energy production.

Fasting blood ketone bodies as well as fat oxidation are increased in patients with heart failure, yielding a state of metabolic inefficiency.

The net result is additional depletion of myocardial adenosine triphosphate, phosphocreatine and creatine kinase levels with further decreased efficiency of mechanical work. In this context, manipulation of cardiac energy metabolism by modification of substrate use by the failing heart has produced positive clinical results. The results of current research support the concept that shifting the energy substrate preference away from fatty acid metabolism and towards glucose metabolism could be an effective adjunctive treatment in patients with heart failure. The additional use of drugs able to partially inhibit fatty acids oxidation in patients with heart failure may therefore yield a significant protective effect for clinical symptoms and cardiac function improvement, and simultaneously ameliorate left ventricular remodelling. Certainly, to clarify the exact therapeutic role of metabolic therapy in heart failure, a large multicentre, randomised controlled trial should be performed.

e. lare.

Keywords Adrenergic system, beta-blockers, free fatty acids inhibitors, heart failure, left ventricular function, metabolic therapy, myocardial metabolism, perhexiline, renin-angiotensin-aldosterone system, trimetazidine Disclosure: GF has received travel grants from and performed remunerated lectures for Servier.

Received: 18 December 2015 Accepted: 24 March 2016 Citation: Cardiac Failure Review, 2016;2(1):8â&#x20AC;&#x201C;13 DOI: 10.15420/cfr.2016:5:2 Correspondence: Gabriele Fragasso, Heart Failure Unit, Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milan, Italy. E: gabriele.fragasso@hsr.it

The development of heart failure is rarely dependent on primary alterations of cardiac metabolism. The majority of heart failure cases result from diseases of the cardiac muscle, most frequently ischaemic heart disease. However, whatever the cause of heart failure, the net result will be depletion of myocardial adenosine triphosphate (ATP), phosphocreatine and creatine kinase levels with decreased efficiency of mechanical work. Once heart failure has developed, the neurohormonal axis is activated with the aim to sustain haemodynamic failure. Activation of adrenergic and renin-angiotensin-aldosterone systems indirectly determine specific metabolic alterations in the cardiac and skeletal muscles. Over the last two decades, despite the adoption of drugs able to block neuro-hormonal activation in heart failure dramatically improving the overall prognosis of this deadly disease, mortality and morbidity remain a critical problem. In fact, apart from the well-known effects on chronotropism, inotropism, vascular tone and blood volume, the residual physiological effects of neuro-hormones indirectly determine a state of low metabolic efficiency in both the skeletal and cardiac muscles. The aim of this review is to analyse the metabolic derangement in the failing heart and, on this basis, speculate on possible new therapeutic targets.

Deranged Cellular Metabolism in Heart Failure Under normal conditions, the healthy heart derives most of its energy from the free fatty acid (FFA) pathway that accounts for approximately two-thirds of energy production; the other source of energy being derived from glucose oxidation and lactate.1,2 FFA and glucose metabolism inter-regulate each other, a process referred to as the

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Randle cycle.3 Increasing FFA oxidation in the heart decreases glucose oxidation, while increasing glucose oxidation inhibits FFA oxidation.

However, energy being derived from FFA oxidation is a less efficient source of energy than glucose oxidation (in terms of ATP produced per O2 molecules consumed) and determines a reduction of cardiac efficiency. In fact, the amount of ATP produced per O2 consumed is greater when glucose is oxidised compared with FFA and, therefore, FFA is a less efficient energy substrate than glucose. Elevated FFA oxidation can result in up to a 30 % decrease in cardiac efficiency.2 Progressive heart failure induces an imbalance between the requirement of cardiac tissue for oxygen and metabolic supplies and their availability, resulting in functional, metabolic and morphological alteration of the myocardium. At a cellular level, glucose uptake is decreased and conversion to lactate is increased; lactate uptake by the heart is switched to lactate production, and pyruvate is mostly transformed into lactate, thereby increasing cell acidosis. The FFA pathway is also slowed down, yet most of the produced energy comes from FFA oxidation, resulting in less ATP production. These metabolic changes lead to disruption of cell homeostasis, alterations in membrane structure and, ultimately, cell death. The following sections will attempt to clarify the mechanism at the base of these metabolic changes.

Effects of the Neuro-hormonal Activation on Metabolism of the Failing Heart Neuro-hormonal activation significantly contributes to cardiac mechanical and metabolic inefficiency of the cardiac muscle and

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whole body of patients with heart failure. This vicious circle is likely mediated by increased use of non-carbohydrate substrates for energy production,2 resulting from different mechanisms. Adrenergically mediated increased peripheral lipolysis (wasting of subcutaneous fat and skeletal muscle) results in grossly augmented FFA availability.

In fact, fasting blood ketone bodies4 as well as fat oxidation during exercise5 have been shown to be increased in patients with heart failure. Adrenergic activation may also induce insulin resistance, which is also associated with heart failure6 and may further contribute to increased circulating FFA levels by the development of ketosis and consequent impaired suppression of lipolysis. Indirect effects of augmented adrenergic tone in heart failure include increased heart rate, vasoconstriction and inotropism, which, in turn, may also indirectly contribute to a state of functional and metabolic inefficiency.

Angiotensin II is also an important regulator of cardiac energy metabolism and function.7 There are several mechanisms through which angiotensin II contributes to heart failure occurrence and persistence.

Angiotensin II damages mitochondria in the cardiomyocyte by increasing reactive oxygen species production8 and affects mitochondrial oxidative phosphorylation, including FFA oxidation.9,10 These data suggest that angiotensin II affects FFA oxidation. There is also evidence that angiotensin II regulates glucose oxidation7,11 and its inhibition may exert beneficial effects. In addition, by decreasing oxidative metabolism, angiotensin II can compromise ATP production, thus reducing its availability.12 In this context, angiotensin II antagonism represents an attractive therapeutic approach. Studies using the euglycaemic insulin clamp technique have indicated that the beneficial effect of angiotensin II is exerted on insulin sensitivity. In fact, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists have been shown to improve both left ventricular function and glucose homeostasis.13,14 Increased blood flow in skeletal muscle, accumulation of bradykinin or more efficient insulin release may be suggested as potential modes of action.

Endothelial dysfunction, a critical component in the progression of heart failure, may result from increased oxidative stress, secondary to activation of the adrenergic and the renin-angiotensin systems and to the production of inflammatory cytokines.15 In heart failure, the role of reduced bioavailability of nitric oxide (NO) is still under debate,16,17 while increased endothelin-1 (ET-1) levels are a mainstay.18 Growth factors, vasoactive substances and mechanical stress contribute to the increased ET-1 levels in patients with heart failure. Despite the known adaptative aspect of supporting contractility of the failing heart, persistent increases in cardiac ET-1 expression in the failing heart have a pathophysiological maladaptive aspect and are associated with the severity of myocardial dysfunction.19 It has been observed that trimetazidine could reduce endothelin release in patients with cardiac disease.20,21 Trimetazidine-induced reduction of intracellular acidosis in ischaemic myocardium might not only influence myocardial but also endothelial membranes.22 By decreasing endothelial damage, trimetazidine could inhibit ET-1 release that, in turn, may decrease myocardial damage. A second hypothesis is that, by just decreasing the effects of chronic myocardial ischaemia, trimetazidine could inhibit ET-1 release. Therefore, the observed decrease in ET-1 release with trimetazidine, could likely be linked to trimetazidine-induced reduction of myocardial ischaemia. Finally, keeping in mind the close relation between endothelium and insulin sensitivity, the observed effects of trimetazidine on endothelial function could also explain the beneficial action of trimetazidine on glucose metabolism.

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In the same context, the potential beneficial effect of 6 weeks of oral L-arginine supplementation on endurance exercise, an important determinant of daily-life activity in patients with chronic stable heart failure, has been assessed.23 L-Arginine is the precursor of endogenous NO, which is a potent vasodilator acting via the intracellular second-messenger cyclic guanosine monophosphate.

In healthy individuals, L-arginine induces peripheral vasodilation and inhibits platelet aggregation due to an increased NO production.

The results of this study show that arginine enhanced endurance exercise tolerance, reducing both heart rate and circulating lactate levels, suggesting that chronic arginine administration might be useful as a therapeutic adjuvant to improve the patient’s physical fitness.

In summary, in the failing heart neuro-hormonal activation determines a combination of direct and indirect haemodynamic and metabolic actions, which, despite a potential teleological purpose, will eventually lead to further deterioration of cardiac function, mainly mediated by the resulting decreased metabolic efficiency of the cardiomyocytes.

Specific therapies may attenuate these effects.

Abnormal Glucose Metabolism in Heart Failure As glucose and lactate are more efficient fuels for aerobic respiration, increasing the use of these substrates can improve the oxygen consumption efficiency of the myocardium by 16–26 %.24 In addition, skeletal muscle glucose uptake in the heart and arm is inversely related to serum FFA levels25 and increased FFA flux from adipose tissue to non-adipose tissue amplifies metabolic derangements that are characteristic of the insulin resistance syndrome.26 Further findings suggest that raised FFA levels not only impair glucose uptake in heart and skeletal muscle but also cause alterations in the metabolism of vascular endothelium, leading to premature cardiovascular disease.27

Global Energy Expenditure in Heart Failure Energy consumption at rest appears higher in patients with heart failure than in healthy subjects.28–30 It has been shown that increased rate of energy expenditure is related to increased serum FFA oxidation and that both energy expenditure and serum FFA oxidation are inversely correlated with left ventricular ejection fraction and positively correlated with growth hormone, epinephrine and norepinephrine concentrations.31 Norepinephrine increases whole-body oxygen consumption, circulating FFA concentrations, and FFA oxidation.32 These changes have been attributed to stimulation of hormone-sensitive lipase in adipose tissue, and to stimulation of oxygen consumption independent of lipolysis by norepinephrine.33 These data, together with close correlations between plasma norepinephrine concentrations, energy expenditure at rest and FFA oxidation, make increased sympathetic activity the most likely explanation for alterations in fuel homeostasis in patients with heart failure.33 Therefore, intervention strategies aimed at optimising global and cardiac metabolism could be useful for interrupting the vicious circle of reduced function at greater metabolic expenses in different cardiac conditions.

Pharmacological Implications of Impaired Myocardial Metabolism in Heart Failure Given the above-described pathophysiological background and the difficulty of standard treatment to control the total symptomatic and prognostic burden in many patients with heart failure, it seems logical to consider pharmacological manipulation of cardiac energy metabolism as an adjunctive therapeutic option. Optimisation of cardiac energy metabolism is based on promoting cardiac glucose oxidation.

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Pathophysiology Figure 1: Metabolic Vicious Circle in Heart Failure.

Lactate

Pyruvate

G6p

Glucose

Sodium DCA PDH Citric acid cycle ATP Acetyl-CoA

NADH

FFA beta-oxidation CPT-II

Perhexiline Etomoxir Oxfenicine

CPT-I

ATP-ase

e transport chain

Trimetazidine

Inner mitochondrial membrane Outer mitochondrial membrane

Fatty acid-CoA

FFAs inhibit glycolysis and glucose uptake by the heart. Plasma FFA taken up by the heart is activated and transported by CPT-I into the mitochondria to uncouple respiration with oxygen wastage. In addition, hyperadrenergic state downregulates beta-adrenergic receptors. Acetyl CoA = acetyl coenzyme A; ATP = adenosine triphosphate; CPT = carnitine palmitoyltransferase; DCA = dichloroacetate; FFA = free fatty acid; PDH = pyruvate dehydrogenase.

Stimulation of myocardial glucose oxidation can be achieved either directly with stimulation of glucose metabolism, or indirectly through inhibition of fatty acid beta-oxidation, in order to shift energy substrate utilisation away from fatty acid metabolism and towards glucose metabolism which, as explained above, is more efficient in terms of ATP production per mole of oxygen used. Therefore, metabolic therapy could play a beneficial role in terms of glucose metabolism homeostasis.

The concept that drugs able to promote the use of glucose and non-fatty substrates by the mitochondria may increase metabolic efficiency and function of the failing heart has prompted several clinical studies. Experimental studies have first shown that stimulation of pyruvate dehydrogenase activity leads to enhanced glycolysis and use of lactate by the myocardium for aerobic respiration.34 Myocardial consumption of FFA is simultaneously inhibited, with the overall effect of a change of substrate use from predominantly non-esterified FFA to glucose and lactate,35 finally resulting in improved left ventricular mechanical efficiency.36 Trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine dihydrochloride) has been shown to directly inhibit FFA oxidation by blocking 3-ketoacyl-coenzyme A thiolase (3-KAT), the last enzyme involved in beta-oxidation,37 although this issue remains controversial. 38,39 Trimetazidine affects myocardial substrate use by inhibiting oxidative phosphorylation and by shifting energy production from FFA to glucose oxidation (see Figure 1).40 Several studies have outlined the potential benefits of this agent on regional and global myocardial dysfunction.41â&#x20AC;&#x201C;49 3-KAT inhibitors could also play a beneficial role in terms of glucose metabolism homeostasis at both cardiac and skeletal muscle level. The beneficial effect of trimetazidine on left ventricular function, has been attributed to preservation of phosphocreatine (PCr) and ATP intracellular levels.50 Clinical studies using phosphorus-31 magnetic resonance spectroscopy to measure PCr:ATP ratios in human myocardium have shown that this ratio is reduced in failing human myocardium.51 The PCr:ATP ratio is a measure of myocardial energetics and its reduction may depend on imbalance of myocardial oxygen supply and demand,52 and reduction of the total creatine pool, a phenomenon known to occur in heart failure.53 In a study performed in patients with heart failure of different aetiologies receiving full

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standard medical therapy, it was observed that the trimetazidineinduced improvement of functional class and left ventricular function was associated with an improvement of PCr:ATP ratio, supporting the hypothesis that trimetazidine may preserve myocardial high-energy phosphate intracellular levels.54 These results appear particularly interesting, especially in view of previous evidence indicating the PCr:ATP ratio as a significant predictor of mortality.55 In fact, imetazidine has been shown to improve prognosis in patients with heart failure in a multicentre retrospective cohort study56 and in two meta-analyses.57,58 On this basis, its use in patients with heart failure has been advocated in a recently published position paper.59 Similarly to trimetazidine, ranolazine has also been shown to significantly improve left ventricular performance in experimental models of heart failure.60â&#x20AC;&#x201C;63 Sabbah et al. measured haemodynamics before and 40 minutes after intravenous ranolazine administration in a canine model of heart failure.60 Results in 13 experimental dogs were compared with those obtained in eight normal healthy dogs. Ranolazine significantly decreased left ventricular end-diastolic pressure and increased left ventricular ejection fraction in the absence of any effects on heart rate or blood pressure. In subsequent experiments from the same laboratory, Chandler et al. reproduced these findings and determined that the improvement in left ventricular performance was not associated with an increase in myocardial oxygen consumption (MO2) compared with an intravenous infusion of dobutamine that improved left ventricular performance to a similar extent, but was associated with a significant increase in MO2 requirements.61 Overall, these data confirm that selective inhibition of 3-KAT represents a new therapeutic window in the treatment of patients with heart failure of different aetiologies.

Combined Metabolic Action of Beta-blockers and Trimetazidine ACE inhibitors and beta-blockers remain the clinical mainstay of the treatment of heart failure. It is interesting to note that beta-blockers may yield an ancillary metabolic effect. Their principal mechanism of action is based on reduction of oxygen consumption by reduced heart rate and inotropism. However, a direct complementary metabolic effect could be exerted by beta-blockers themselves, by reducing peripheral lipolysis and determining reduction of FFA availability. There is indeed evidence that beta-blockade can reduce FFA use in favour of greater glucose use in patients with cardiac disease.64 This change in myocardial energetics could provide a potential mechanism for the decreased MO2 and improved energy efficiency seen with beta-adrenoreceptor blockade in the treatment of ischaemic heart disease and heart failure.65 The issue of whether non-selective, compared with selective betaadrenoreceptor blockers are more efficient in shifting total body substrate use from lipid to glucose oxidation66 remains controversial.67 Nevertheless, a better metabolic disposition of non-selective betablockers may contribute to improved survival rates observed with their use.68 In addition, central inhibition of sympathetic nervous activity with moxonidine has been associated with increased mortality rates in patients with chronic heart failure.69 In fact, despite a significant reduction of cathecolamine spillover and, consequently, heart rate, moxonidine has been shown to increase FFA use and increase MO2 consumption.70 This could be the reason for the failure of central sympathetic inhibition in preventing death in long-term studies in patients with chronic heart failure. It also indicates that the predominant

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mechanism of action of beta-blockers in cardiac syndromes is likely related to mechanisms of action other than simple heart rate reduction. In patients with heart failure the magnitude of heart rate reduction may therefore be a marker of improved functional response following beta-blockade administration, a consequent effect rather than a mechanism. Nonetheless, a clinical trial in which the cardiac â&#x20AC;&#x2DC;funnyâ&#x20AC;&#x2122; (If) channel inhibitor ivabradine (a pure heart rate-lowering agent) was added to beta-blockade (SHIFT [Systolic Heart Failure Treatment With the lf Inhibitor Ivabradine Trial]) clearly demonstrated that the greater the heart rate reduction the greater the reduction of hospitalisation events in patients with heart failure.71 Therefore, apart from the importance of heart rate lowering per se, a complementary synergistic metabolic action of beta-blockers and trimetazidine can be hypothesised: whereas the former reduce FFA availability, the latter decrease their cardiac use. Overall, this drug-induced metabolic shift could reduce FFA oxidation and increase the flux through pyruvate dehydrogenase with a consequent energy-sparing effect.54,72 Additional data also suggest that the metabolic effect of trimetazidine may also take place in other organs and tissues.72 In fact, apart from a reduction of whole-body energy demand, a trend for a reduction of whole-body lipid oxidation and of fasting plasma FFA concentration has also been observed.72 This general metabolic shift could reduce the overall metabolic requirements of the body, resulting in an attractive adaptation strategy in the context of coronary and myocardial insufficiencies. Interestingly, beta-blockers have also been shown to exert a direct effect on whole-body metabolism. In trained athletes, beta-adrenergic blockade abolishes the marked increase in plasma glucose levels during intense exercise as a result of enhanced peripheral glucose uptake, with no significant change in glucose production.73 These effects of adrenergic blockade on glucose kinetics could be mediated by direct effects or indirectly through changes in lipid substrates and/or counter-regulatory hormones.

Other Inhibitors of Fatty Acids Oxidation Etomoxir, perhexiline and oxfenicine are carnitine palmitoyltransferase I (CPT-I) inhibitors. CPT-I is the key enzyme for mitochondrial FFA uptake; its inhibition, therefore, reduces FFA oxidation and their inhibitory effect on pyruvate dehydrogenase. As a consequence, glucose oxidation is increased.74,75 Etomoxir, initially developed as an antidiabetic agent, has been observed to improve left ventricular performance of pressure-overloaded rat heart.76 These effects have been considered due to a selective modification of gene expression of hypertrophic cardiomyocytes.77 Etomoxir has also been shown to increase phosphatase activation, have a direct effect on peroxisome proliferator-activated receptor-alpha and upregulate the expression of various enzymes involved in beta-oxidation.77 The first clinical trial employing etomoxir in patients with heart failure showed a significant clinical and cardiac function improvement.78 In experimental animal studies, etomoxir has also been shown to improve glucose metabolism.79 However, the use of etomoxir may be limited by the observations that it may cause cardiac hypertrophy80 and oxidative stress.81 Analogous to etomoxir, perhexiline and oxfenicine, originally classified as calcium antagonists, reduce cardiac use of long-chain fatty acids by inhibiting CPT-I.82â&#x20AC;&#x201C;84 They were initially developed as antianginal agents.85,86 However, they have since been employed in patients with heart failure. In a previous study, metabolic modulation with perhexiline improved maximal oxygen consumption at the cardiopulmonary exercise test, left ventricular ejection fraction, symptoms, resting and

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peak stress myocardial function, and skeletal muscle energetics.87 More recently, and similarly to trimetazidine, perhexiline has been shown to improve cardiac energetics and symptom status with no evidence of altered cardiac substrate use, further supporting the hypothesis of energy deficiency in heart failure and further consideration of metabolic therapies in its management.88 Therefore, similarly to 3-KAT inhibitors, CPT-I inhibitors may represent a novel treatment in patients with heart failure with a good safety profile, provided that the dosage is adjusted according to plasma levels.

FFA Inhibition in Older Patients Age-related changes of mitochondria impair the human host cells homeostasis and contribute to the development of most common ageing diseases. Older subjects without overt cardiac diseases are prone to develop heart failure with preserved ejection fraction. Risk factors do not fully account for the aged heart functional loss that might be underlined by a common pathogenic denominator (i.e. cell energy alteration at mitochondrial level in organs requiring high energy). In older men without overt cardiovascular disease, the presence of prepathologic conditions (pre-hypertension, reduced insulin sensitivity, impaired myocardial contractile reserve, inadequate vasodilation due to endothelial dysfunction, reduced cardiomyocytes renewal, systemic inflammation and raised coagulation capacity) are possibly related to reduced mitochondrial function and density. Several studies have indeed shown reduced mitochondrial content and function with ageing, leading to the theory that decreased mitochondrial content and increased uncoupling with age compromises the energy state of the cell.89 Indeed, altered beta-oxidation increases the reliance on long-chain fatty acids relative to glucose with subsequent decrease of cellular metabolic efficiency at any given level of tissue activity. On this basis, in older patients with coronary artery disease, partial fatty acid oxidation inhibition by trimetazidine added to standard optimal medical therapy has been shown to improve reverse remodelling of chronically dysfunctional myocardium 90 and improve cardiac symptoms and quality of life.91 The observed improvement could be related to increased cellular energy reserve,54 which could be pivotal in a context of ageing-induced reduction of mitochondrial efficiency.

The Importance of a Correct Metabolic Substrate Availability It remains questionable whether metabolic substrate availability rather than pharmacological shift from fatty acids to glucose oxidation may be appropriate in patients with long-lasting heart failure.92 In fact, the anti-lipolytic drug acipimox, which reduces substrate availability and impairs fatty acid oxidation, has been shown to worsen left ventricular function in patients with idiopathic dilated cardiomyopathy.93 In addition, when substrate availability is acutely modulated during exercise testing in patients with stable coronary artery disease and preserved left ventricular function using a high-carbohydrate meal versus a high-fat meal, a lower ischaemic threshold and greater ischaemia magnitude is observed following the high-carbohydrate meal.94 Reduced lipid uptake and disposal in the setting of heart failure may represent therefore a maladaptive response. A recent study evaluated the metabolic and functional effects of high- and low-serum FFA availability in the presence of normal fasting serum glucose and insulin concentrations.95 In patients with chronic heart failure, short-term reduction in serum FFA concentration, while serum glucose and insulin concentrations remained closed to the fasting levels, induced an impairment of left ventricular energy metabolism and left ventricular function at rest. A two-fold serum FFA increment

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Pathophysiology in the same experimental conditions did not induce any detectable change.95 Although in previous studies pharmacological manipulation of the heart substrates preferences has been shown to exert beneficial effects, these data demonstrate that direct deprivation of energy substrates is detrimental for cardiac metabolism and function.

The clinical fallout is that metabolic manipulation at the systemic level may be considered in order to optimise the treatment of these patients; we also believe that special cautions should be considered when iatrogenic and acute changes of substrates and regulatory hormones of glucose and FFA metabolism are to be performed in these extremely vulnerable patients.

Conclusion All cardiac syndromes may induce and be maintained by modifications of cardiac metabolism. Heart failure may be dependent on and promote metabolic changes in part through neurohormonal activation

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determining an increased use of non-carbohydrate substrates for energy production. This metabolic adaptation yields a state of metabolic inefficiency. The net result is depletion of myocardial ATP, phosphocreatine and creatine kinase levels with decreased efficiency of mechanical work. Different therapeutic approaches have been developed to manipulate cardiac energy metabolism. However, the most effective approach consists in modifying substrate use by the failing heart and includes several pharmacological agents. These agents have been originally adopted to increase the ischaemic threshold in patients with effort angina. However, the results of current research support the concept that shifting the energy substrate preference away from fatty acid metabolism and glucose metabolism could be an effective adjunctive treatment in patients with heart failure. Nevertheless, the exact role of metabolic therapy in heart failure is yet to be established, and a large multicentre randomised trial is necessary. n

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48. Sisakian H, Torgomyan A, Barkhudaryan A. The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy. Acta Cardiol 2007;62 :493–9. PMID: 17982971.

49. Di Napoli P, Di Giovanni P, Gaeta MA, et al. Trimetazidine and reduction in mortality and hospitalization in patients with ischemic dilated cardiomyopathy: a post hoc analysis of the Villa Pini d’Abruzzo Trimetazidine Trial. J Cardiovasc Pharmacol 2007;50 :585–9. PMID: 18030070.

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53. Nascimben L, Ingwall JS, Pauletto P, et al. The creatine kinase system in failing and nonfailing human myocardium.

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54. Fragasso G, De Cobelli F, Perseghin G, et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 2006;27 :942–8. PMID: 16510466.

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56. Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: Results from an international multicentre retrospective cohort study. Int J Cardiol 2013;163 :320–5. DOI: 10.1016/j.ijcard.2012.09.123; PMID: 23073279.

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58. Zhang L, Lu Y, Jiang H, et al. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol 2012;59 :913–22. DOI: 10.1016/j.jacc.2011.11.027; PMID: 22381427.

59. Lopatin YM, Rosano GM, Fragasso G, et al. Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol 2015;203 :909–15. DOI: 10.1016/j. ijcard.2015.11.060; PMID: 26618252.

60. Sabbah HN, Chandler MP, Mishima T, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002;8 :416–22. PMID: 12528095.

61. Chandler MP, Stanley WC, Morita H, et al. Short-term treatment with ranolazine improves mechanical efficacy in dogs with chronic heart failure. Circ Res 2002;91 :278–80.

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63. Aaker A, McCormack JG, Hirai T, Musch TI. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol 1996;28 :353–62. PMID: 8877580.

64. Wallhaus TR, Taylor M, DeGrado TR, Russell DC. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001;103 :2441–6. PMID: 11369683.

65. Spoladore R, Fragasso G, Perseghin G, et al. Beneficial effects of beta-blockers on left ventricular function and cellular energy reserve in patients with heart failure.

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66. Podbregar M, Voga G. Effect of selective and nonselective beta-blockers on resting energy production rate and total body substrate utilization in chronic heart failure. J Cardiac Fail 2002:8 :369–78. PMID: 12528088.

67. Sharma V, Dhillon P, Wambolt R, et al. Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin (STZ) diabetic rat. Am J Physiol Heart Circ Physiol 2008;294 :H1609–20. DOI: 10.1152/ajpheart.00949.2007; PMID: 18203848.

68. Poole-Wilson P, Swedberg K, Cleland J, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients

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Fragasso G, Salerno A, Lattuada G, et al. Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. Heart 2011;97 :1495–500. DOI: 10.1136/ hrt.2011.226332; PMID: 21700755.

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Lopashuck GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 1988;63:1036–43.

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Pathophysiology

LE ATION.

e. lare.

Current Understanding of the Compensatory Actions of Cardiac Natriuretic Peptides in Cardiac Failure: A Clinical Perspective Noel S Lee and Lori B Daniels Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, CA, USA

Abstract Natriuretic peptides play a crucial role in maintaining cardiovascular homeostasis. Among their properties are vasodilation, natriuresis, diuresis, and inhibition of cardiac remodeling. As heart failure progresses, however, natriuretic peptides fail to compensate. Knowledge of their processing and signaling pathways has guided the development of pharmacological therapies aimed at bolstering their effects.

The drugs that have achieved the most clinical success have also stirred the most controversy. Nesiritide, the synthetic B-type natriuretic peptide, yielded significant symptomatic relief and improved haemodynamics but its use was plagued with questions surrounding its possibly harmful impact on renal function. More recently, compounds containing inhibitors of neprilysin, the enzyme responsible for degrading natriuretic peptides, have demonstrated morbidity and mortality benefit, but have also been linked to possible negative side effects. Clearly, potentiating the actions of natriuretic peptides for the benefit of patients is not as simple as just raising their serum concentration. This article reviews the current understanding of the compensatory actions of cardiac natriuretic peptides in heart failure and how this knowledge is revolutionizing heart failure therapy.

Keywords ANP, BNP, heart failure, natriuretic peptides, neprilysin, nesiritide, LCZ696, omapatrilat Disclosure: NSL has no relevant disclosers to make. LBD has received consulting fees from Alere and diaDexus, and has received speaking fees from Critical Diagnostics and Roche Diagnostics.

Received: 17 December 2015 Accepted: 22 March 2016 Citation: Cardiac Failure Review, 2016;2(1):14–9 DOI: 10.15420/cfr.2016:4:2 Correspondence: Lori B Daniels, Division of Cardiology, Sulpizio Cardiovascular Center, University of California, San Diego, Mail Code 7411, 9444 Medical Center Drive, La Jolla, CA 92037-7411, USA. E: lbdaniels@ucsd.edu

Today, natriuretic peptides are ubiquitously utilized for the diagnosis, treatment, and prognostication of heart failure in the Emergency Department, as well as inpatient and outpatient settings alike.1–5 These endogenous hormones counteract some of the most detrimental effects of heart failure. Given their clinical and physiological importance, the fact that a manuscript describing the vasodilatory, diuretic, and natriuretic properties of atrial natriuretic peptide (ANP) – the first natriuretic peptide to be identified – was initially rejected from publication in 1980 today seems astonishing.6 The discovery propelled subsequent investigation that still continues over 30 years later. Much more detail is now known about these chemical messengers. This article reviews the current understanding of the compensatory actions of cardiac natriuretic peptides in heart failure and how this knowledge is revolutionizing heart failure therapy.

myocardium and named for its structural similarity to a natriuretic peptide found in Dendroaspis angusticeps snake venom, 11 and urodilatin, which is a component of human urine.12 Both ANP and BNP are secreted as pre-pro-polypeptides – that is, they are produced as inactive proteins attached to an N-terminal signal peptide, which is removed in the endoplasmic reticulum.

After removal of the signal peptide, proANP – a 126-amino acid peptide – is stored in cardiac atria granulae.8 Upon cellular stimulation, such as myocardial stretch, vasoconstriction by endothelin, or increased levels of angiotensin II, a serine protease called corin cleaves proANP into the 28-amino-acid active ANP. In a normal healthy heart, ANP is not found in the ventricles. Heart failure is associated with a decrease in atrial ANP and increase in ventricular myocyte ANP.13

Background Structurally related and made biologically active by a 17-amino-acid core ring and a cysteine bridge,7 the natriuretic peptides are a group of compounds that possess diverse actions in cardiovascular, renal, and endocrine homeostasis. The most recognized are ANP and B-type natriuretic peptide (BNP), which are released from both the atria and ventricles,8,9 and are the focus of this review. Other known natriuretic peptides include C-type natriuretic peptide (CNP), which is derived in the endothelium,10 Dendroaspis natriuretic peptidelike immunoreactivity (DNP-LI), which is present in the normal atrial

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The mechanism of BNP activation is similar. Its pre-pro-polypeptide contains 134-amino acids.8 Removal of the N-terminal signal peptide generates proBNP1-108, which, after cellular stimulation, is cleaved by the serine proteases furin and corin into inactive N-terminal-proBNP (NT-proBNP) and active BNP1-32.14–16 Paralleling the expression of ANP in the progression of heart failure, the expression of BNP is solely derived from the atria in normal healthy conditions, increasing in the atria in early left ventricular dysfunction, and only later rising in the ventricle in overt volume overload.9

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A Clinical Perspective on CNPs in Cardiac Failure

Active ANP and BNP bind to their receptor, natriuretic peptide receptor A (NPR-A), which is widely expressed in the body, including in the kidney, heart, lungs, brain, adrenal glands, adipose tissue, and vasculature. This binding activates guanylyl cyclase. The resulting increase in cyclic guanosine monophosphate (cGMP) mediates several protective mechanisms within the renal, vascular, and cardiac systems as discussed below. The active peptides are removed from circulation by natriuretic peptide receptor C (NPR-C) and degraded by neutral endopeptidase 24.11 (NEP), also known as neprilysin.8,17 Insulin-degrading enzyme (IDE) is also involved in natriuretic peptide cleavage.18 Figure 1 shows a simplified portrait of ANP and BNP cellular processing.

Figure 1: Basic Mechanism of ANP and BNP Cellular Processing Triggers of Release • Myocardial stretch • ↑ AG II • Vasoconstriction

Activation proANP proBNP

corin corin/furin

Degradation ANP BNP

At first, the two sides seem to function in harmony. But chronically, the continuous fight to maintain cardiac output leads to volume overload. Natriuretic peptides eventually fail to compensate, and a vicious cycle of worsening heart failure perpetuates itself.

+ inactive NT-proBNP

NPR-A ↑ cGMP

Natriuresis Diuresis

Vasodilation

Physiological Effects The neurohumoral response to heart failure is complex and incompletely understood. It involves a multitude of peptides and mediators. One can consider a simplified model composed of two opposite yet complementary forces, though. On one hand are the sympathetic nervous system, renin–angiotensin–aldosterone system, and vasopressin, which work together to preserve cardiac output via fluid retention, augmented contractility, and increased heart rate.

These effects are vasoconstricting, anti-natriuretic, anti-diuretic, and growth-promoting. On the other hand are the natriuretic peptides, which are vasodilating, natriuretic, diuretic, and anti-mitogenic, protecting against fibrosis and hypertrophy.19–25 BNP may inhibit the sympathetic nervous system directly as well.26

NEP NPR-C

Anti-hypertrophy Anti-fibrosis

RV

Inhibition of sympathetic nervous system

LV

AG II = angiotensin II; ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; LV = left ventricle; NEP = neutral endopeptidase 24.11; NPR-A = natriuretic peptide receptor A; NPR-C = natriuretic peptide receptor C; RV = right ventricle.

Therapeutic Strategies Given the beneficial effects of natriuretic peptides, four main strategies seem plausible for increasing their plasma concentrations in hopes of potentiating and prolonging their compensatory actions: 1) by activating corin and furin; 2) by administering recombinant natriuretic peptides; 3) by antagonizing NPR-C; or 4) by inhibiting NEP. Of these targets, recombinant natriuretic peptides and NEP inhibitors have been most actively developed and hold the most clinical promise.

Recombinant Natriuretic Peptides What causes the collapse of these compensatory measures? The breakdown is multifactorial. Studies suggest that in acute heart failure, the body reaches a maximum level of circulating natriuretic peptide that cannot be surpassed with greater elevations in atrial pressure.27,28 Even as higher pressures become longstanding, the body still cannot mount more natriuretic peptide, underscoring an impaired compensatory capacity during chronic volume overload.27 Research has also demonstrated reduced corin levels and predominantly altered, inactive forms of natriuretic peptide in patients with decompensated heart failure.29,30 High-molecular-weight forms of BNP, for example, have been isolated from patient samples, likely a combination of proBNP1-108 and its polymers.31–35 Further proteolyzed, degraded forms of BNP have also been quantified.36 Inability to produce and release active forms of natriuretic peptide is not the only hindrance to the body’s efforts to protect itself. In chronic severe heart failure, the end organs are also unable to respond fully to the hormone that is released into the bloodstream. Blunted natriuresis and vasodilatation have been shown in experimental heart failure.37–39 Explanations for the attenuated response to natriuretic peptides in chronic heart failure include NPR-A downregulation and desensitization to cGMP due to chronically high ANP and BNP levels. Tsutamoto et al. compared the plasma ANP and cGMP levels in patients with chronic mild to moderate heart failure with those in patients with chronic severe heart failure.40 Although plasma ANP and cGMP levels were positively correlated in the first group, no significant correlation was found in the latter group.40 Moreover, despite high concentrations of ANP in patients with chronic severe heart failure, cGMP concentrations plateaued.40

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Infusions of synthetic ANP (such as anaritide and carperitide) have been used for years in Japan to treat hospitalized patients with acute decompensated heart failure.41 Small s udies of synthetic ANP in chronic heart failure as well have demonstrated vasodilatory and diuretic benefits, in addition to enhanced renal blood flow and glomerular filtration rate.42,43 Synthetic BNP (nesiritide), however, has made bigger headlines in the US since it gained US Food and Drug Administration.

(FDA) approval in 2001.

Colucci et al. first studied the clinical use of nesiritide in hospitalized patients with acute decompensated heart failure in a two-part multi-center study: an efficacy trial and a comparative trial.44 The efficacy trial, which aimed to evaluate the drug’s short-term effects on haemodynamics, global clinical status (judged independently by both the patient and the investigator), and symptoms, included 127 patients with a pulmonary capillary wedge pressure (PCWP) of at least 18 mmHg and a cardiac index of no more than 2.7 l/min/m2. Using a double-blind placebo-controlled design, the subjects were randomised to a 6-hour infusion of either placebo or low- or high-dose nesiritide.

The low-dose group received a 0.3 µg/kg bolus followed by an infusion at 0.015 µg/kg/min. The high-dose group received a 0.6 µg/kg bolus followed by 0.030 µg/kg/min.

Results demonstrated a dose-dependent and statistically significant decrease in PCWP and increase in cardiac index in the nesiritide groups (p<0.001). Patient-reported global clinical status improvement was noted in 60 % and 67 % of patients in the low- and high-dose nesiritide groups, respectively, compared with 14 % of patients receiving placebo (p<0.001 for both comparisons). Physician-reported

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Pathophysiology global clinical status improvement was observed in 55 % and 77 % of patients in the low- and high-dose nesiritide groups, respectively, compared with 5 % of patients receiving placebo (p<0.001 for both comparisons). Similarly, patients on nesiritide reported statistically significant improvements in dyspnea and fatigue.

In the comparative trial, 305 patients were randomly assigned in a 1:1:1 ratio to ‘open label standard therapy’ (consisting of single vasoactive drug therapy, such as dobutamine, milrinone, nitroglycerin, or nitroprusside) or double-blind dosing of nesiritide (at the same dosing as the efficacy trial) for up to 7 days. Most patients in the study were treated for 1–2 days, and all groups witnessed improvement in global clinical status, dyspnea, and fatigue at 6 hours, 24 hours, and at the end of therapy. None of the results showed significant differences between nesiritide and standard therapy, though.

Dose-related hypotension was the main adverse effect in these trials.

Although predominantly asymptomatic, symptomatic hypotension occurred in 4 % of the standard-therapy group in the comparative trial, compared with 11 % and 17 % of the low- and high-dose nesiritide groups, respectively (p=0.008). The investigators argued that in clinical practice, the incidence of hypotension would be minor because the initial nesiritide dose would be low and titrated to blood pressure. Overall, the study concluded that nesiritide could achieve rapid symptomatic relief and improved haemodynamics in hospitalized patients.44 Given questions over adverse blood pressure effects, a larger bolus dose but smaller infusion dose was used in the Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC) trial.45 This multi-center prospective, randomised, double-blind trial sought to evaluate the efficacy and safety of intravenous nesiritide compared with intravenous nitroglycerin and placebo. The study involved 489 hospitalized patients with acute decompensated heart failure and New York Heart Association class IV symptoms. Nesiritide was given as a 2 µg/kg bolus followed by an infusion of 0.01 µg/kg/min for 3 hours.

At 3 hours, reduction in PCWP from baseline was significantly greater in the nesiritide group (p<0.001 compared with placebo; p=0.03 compared with nitroglycerin). Although nesiritide provided significant symptomatic relief compared with the placebo, no significant difference was found compared with nitroglycerin. Rates of hypotension were similar between nesiritide and nitroglycerin, and again, most hypotensive episodes were mild.45 Skepticism over the drug continued when a meta-analysis of randomised clinical trials later raised concern that nesiritide significantly increased the risk of renal impairment, even at the lowest dose.46 In response to the enormous controversy, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) was undertaken. The trial randomised 7,141 patients with acute, decompensated heart failure to receive standard therapy in addition to either placebo or nesiritide.47 ASCEND-HF confirmed that nesiritide had no effect on renal function.

Investigators postulated that the meta-analysis results were at least in part due to inclusion of studies that did not compare nesiritide with a placebo but with drugs like dobutamine or nitroglycerin, which could have improved renal function. Still, the earlier concerns, coupled with studies highlighting lack of significant improvement in re-hospitalisation, mortality, or symptoms, led to a drastic decrease in the use of nesiritde.48,49

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NEP Inhibition After the rise and fall of synthetic BNP, investigators have focused more on NEP inhibition. Small studies with NEP inhibitors like candoxatril and sinorphan have shown that halving NEP activity effectively doubles the ANP level.50 NEP inhibition also circumvents the unwanted physiological effects of diuretic therapy like increased renin and aldosterone.51 Some studies reported clinical benefits, although the results were limited by very short-term therapy. One of them found an association with decreased PCWP, but only 12 male patients were included, with a treatment duration of 2 days.50 Another study demonstrated improved exercise duration over 12 weeks of therapy, although the result was not statistically significant.52 Despite these promising characteristics, NEP inhibitors did not result in a significant decrease in blood pressure;53 in fact, these drugs actually increased systolic pressure in healthy subjects.54 This initially unexpected effect was later attributed to the fact that angiotensin II and endothelin I are NEP substrates as well.55,56 As such, the haemodynamic result of NEP inhibitors is not simply a vasodilatory response to increased natriuretic peptide levels but dependent on the net balance with its vasopressor effects as well.

The complex interaction between these drugs and the renin– angiotensin–aldosterone system was demonstrated in a study in which two groups of healthy subjects displayed opposite haemodynamic responses to NEP inhibition.57 Subjects were pretreated with either low or high doses of candoxatril, then administered stepwise infusions of angiotensin II. Angiotensin II concentrations were augmented in both groups, particularly with higher doses of candoxatril. Whereas the lower dose of candoxatril was associated with about a 10 mmHg increase in systolic and diastolic blood pressures, the higher dose was not.57 Possible explanations were that the modest negative sodium balance that resulted in the high-dose group reduced the pressor response to angiotensin II, and that higher doses of candoxatril enhanced ANP enough to offset the angiotensin II pressor action as well. These results suggested that in high renin states, NEP inhibitors could exacerbate hypertension; but in low renin states, these drugs could potentiate vasodilation.

Combination Therapy To combat the blood pressure effect, ‘vasopeptidase inhibitors’ like omapatrilat – containing a combination of an angiotensin-convertingenzyme (ACE) inhibitor and a NEP inhibitor – were developed. But, despite its theoretical promise, omapatrilat had disappointing results.

In the Omapatrilat versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE), the study drug proved non-inferior to enalapril in decreasing mortality and rates of heart failure hospitalisation requiring intravenous therapy among 5,770 patients, but more patients treated with omapatrilat experienced angioedema (0.8 % versus 0.5 % with enalapril)58, likely because bradykinin is also a substrate of NEP.59 More specifically, bradykinin degradation is dependent on ACE, aminopeptidase P, dipetidyl peptidase IV, and NEP.60 Many ACE inhibitors are known to inhibit aminopeptidase P as well.61 In the face of a NEP inhibitor/ACE inhibitor combination drug, bradykinin clearance relies heavily on dipetidyl peptidase IV, whereas an ACE inhibitor alone produces less blockade of these metabolic pathways (as does a combination NEP inhibitor/angiotensin receptor blocker).

The Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) study employed lower doses of omapatrilat in 25,302 patients with hypertension (not heart failure) and again confirmed significantly more cases of angioedema (2.2 versus 0.7 %; p<0.005).62 Given the

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Table 1: Summary of Neutral Endopeptidase 24.11 Inhibition Studies Study name

OVERTURE58

Author

Packer

Year

2002

N

5,770

et al.

Main inclusion

Trial drug

Comparison Mean

criteria

and dose

drug and dose

duration

CHF (NYHA II–IV) or

Omapatrilat

Enalapril

14.5 months

EF ≤30 % with heart

40 mg once

10 mg twice

decreasing mortality and rates

failure hospitalisation

daily

daily

of heart failure hospitalisation • Increased risk of angioedema

mean EF 23.5 % Kostis

2004

25,302

et al.

• Non-inferior to enalapril in

requiring intravenous therapy

within the past year,

OCTAVE62

Key findings

treatment

Untreated or

Omapatrilat

Enalapril

uncontrolled

10 mg once

5 mg once

hypertension

daily, titrated

daily, titrated

to maximum

to maximum

80 mg once

40 mg once

daily

daily

24 weeks

• Reduced systolic blood pressure by 3.6 mmHg more than enalapril • Fewer adjunctive antihypertensive medications needed • Increased rate of angioedema, including two patients with airway compromise

PARADIGM-HF59 McMurray 2014

8,442

et al.

Enalapril

CHF (NYHA Class II–IV) LCZ696 and EF ≤40 % (later

(sacubitril/

• Reduction in composite endpoint of death from cardiovascular causes

10 mg twice

or hospitalisation for heart failure

daily

changed to EF ≤35 %); 160 mg mean 30 %

27 months

• Symptomatic hypotension more

valsartan)

common with LCZ696

200 mg twice

• LCZ696 not associated with

daily

increased risk of angioedema PARAMOUNT64

Solomon

2012

et al.

301

CHF (NYHA Class II–IV), LCZ696 200 mg Valsartan EF ≥45 % (mean 58 %), twice daily

160 mg twice

and NT-proBNP

daily

36 weeks

• Lower NT-proBNP with LCZ696 • Similar rates of hypotension and renal impairment

>400 pg/ml PARAGON65

Novartis

Currently

CHF (NYHA II–IV),

LCZ696 100 mg Valsartan

recruiting

EF ≥45%

twice daily

<57 months

• Primary outcome: composite

80 mg twice

endpoint of cardiovascular death and

daily

total heart failure hospitalisations

CHF = congestive heart failure; EF = ejection fraction; NYHA = New York Heart Association

lack of benefit in heart failure compared with standard therapy, and significant safety concerns, the drug never gained FDA approval.

Researchers returned to the drawing boards, formulating a plan to combat the unwanted angioedema of omapatrilat while still considering the lessons learned from prior manipulations of the natriuretic peptide system. The result was LCZ696: a combination of the angiotensin II receptor blocker valsartan and NEP inhibitor sacubitril. So far, the drug has achieved very promising results.

The Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGMHF) study was stopped early due to the unequivocal benefit found with LCZ696 after a median follow-up of 27 months.59,63 This double-blind study of 8,442 patients with symptomatic chronic systolic heart failure with reduced ejection fraction of ≤40 % (the protocol was later adjusted to ≤35 %, and the mean was 30 %) compared twice daily dosing of LCZ696 with enalapril, showing reduction in the composite endpoint of death from cardiovascular causes or hospitalisation for heart failure (hazard ratio 0.80; 95 % CI [0.73–0.87]; p<0.001), as well as a reduction in all-cause mortality (hazard ratio 0.84; 95 % CI [0.76–0.93]; p<0.001).59 Symptomatic hypotension was more common with LCZ696 than with enalapril but did not lead to increased discontinuation of therapy.

Two welcomed results with respect to the previous nesiritide and omapatrilat controversies were: 1) increases in serum creatinine and related discontinuation of therapy were more common with enalapril;

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and 2) as expected, LCZ696 was not associated with an increased risk of angioedema59 (since this drug leaves both ACE and aminopeptidase P to clear bradykinin). Criticisms of PARADIGM-HF include that although LCZ696 employs the maximum dose of valsartan, the study compared the drug with half the maximum dose of enalapril.

With these promising findings, investigators sought to determine whether substantial morbidity and mortality benefit extended to heart failure patients with preserved ejection fraction. The first step was the Prospective Comparison of angiotensin receptor-neprilysin inhibitor with angiotensin receptor blocker on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) study, a phase-2, randomised, double-blind trial to examine the efficacy and safety of LCZ696 in this population. Patients were randomised to 200 mg of LCZ696 twice daily or 160 mg valsartan twice daily for 36 weeks. Chosen for its association with adverse outcomes in heart failure patients, the primary endpoint examined change in NT-proBNP. Results demonstrated a greater reduction in NT-proBNP in the LCZ696 group (p=0.01), and similar rates of hypotension and renal impairment compared with valsartan alone.64 The Prospective comparison of Angiotensin Receptorneprilysin inhibitor with Angiotensin receptor blocker Global Outcomes in heart failure with preserved ejection fraction (PARAGON) trial is a phase-3 study aiming to build on this data and support the morbidity and mortality benefit seen in PARADIGM-HF for heart failure patients with preserved ejection fraction.65 The NEP inhibition studies are summarized in Table 1.

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Pathophysiology Effect of NEP Inhibition on Clinical use of Natriuretic Peptide Levels Current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) heart failure practice guidelines give measurement of BNP or NT-proBNP a Class I recommendation for both diagnosing and establishing prognosis in heart failure, and a Class II recommendation for guiding therapy.66 With the FDA approval of LCZ696 (sacubitril/valsartan), important questions arise as to how this drug and other neprilysin inhibitors will affect the clinical interpretation of natriuretic peptide levels for each of these indications. In the PARADIGMHF trial, LCZ696 was associated with a significant increase in BNP and urinary cGMP levels at 4 weeks and 8 months compared with enalapril (p<0.0001).67 In contrast, NT-proBNP and troponin T levels were lower in patients receiving LCZ696 than in those receiving enalapril (p<0.0001).

A similar effect on NT-proBNP levels was seen in PARAMOUNT.64 The PARADIGM-HF authors suggest that among patients receiving LCZ696, increased levels of BNP may be related to the mechanism of the drug (since inhibiting neprilysin augments BNP concentration), whereas decreased levels of NT-proBNP (which is not a substrate for neprilysin) may be indicative of the cardiac effects of the drug in reducing wall stress and myocyte injury.67 If this hypothesis is correct, NT-proBNP may be a more appropriate marker choice for monitoring heart failure patients on neprilysin inhibitors, though this theory has not yet been proven. If true, ANP, CNP, and their respective N-terminal peptides could also be considered as monitoring biomarkers, as neprilysin has higher affinity for these peptides;68 assays for NT-proBNP and BNP, however, are currently in wider clinical use.

An alternate explanation is possible. Analyses of blood samples from heart failure patients reveal that proBNP and NT-proBNP undergo

1.

Maisel A, Mueller C, Nowak R, et al. Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55 :2062–76. doi: 10.1016/j. jacc.2010.02.025; PMID: 20447528 2. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106 :416– 22. doi: 10.1161/01.CIR.0000025242.79963.4C; PMID: 12135939 3. Daniels LB. Natriuretic peptides and assessment of cardiovascular disease risk in asymptomatic persons. Curr Cardiovasc Risk Rep 2010;4 :120–7. doi: 10.1007/s12170-0100078-8; PMID: 20672100 4. Daniels LB, Clopton P, Jiang K, et al. Prognosis of stage A or B heart failure patients with elevated B-type natriuretic peptide levels. J Card Fail 2010;16 :93–8. doi: 10.1016/j. cardfail.2009.10.020; PMID: 20142019 5. Betti I, Castelli G, Barchielli A, et al. The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF study.

J Card Fail 2009;15 :377–84. doi: 10.1016/j.cardfail.2008.12.002; PMID: 19477397 6. de Bold AJ, Borenstein HB, Veress AT, et al. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Reprinted from Life Sci 1981;28:89–94. J Am Soc Nephrol 2001;12: 403–9; discussion 403–8, 408–9. PMID: 11158233 7. Misono KS, Fukumi H, Grammer RT, et al. Rat atrial natriuretic factor: complete amino acid sequence and disulfide linkage essential for biological activity. Biochem Biophys Res Commun 1984;119 :524–9. doi: 6538787; PMID: 6538787 8. Boomsma F, van den Meiracker AH. Plasma A- and B-type natriuretic peptides: physiology, methodology and clinical use. Cardiovasc Res 2001;51 :442–9. doi: 10.1016/S00086363(01)00195-X; PMID: 11476734 9. Luchner A, Stevens TL, Borgeson DD, et al. Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure. Am J Physiol 1998;274 :H1684–9.

PMID: 9612380 10. Izumiya Y, Araki S, Usuku H, et al. Chronic C-type natriuretic peptide infusion attenuates angiotensin II-induced myocardial

18

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11.

12.

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18.

19.

20.

post-translational modifications including glycosylation at several sites.69 Most assays for NT-proBNP rely on antibodies directed against epitopes that can undergo glycosylation.69,70 Glycosylation, however, interferes with antibody binding.69 Neprilysin inhibitors may cause assays to underrepresent the actual concentration of NT-proBNP by increasing glycosylation of NT-proBNP.71 How these neprilysin inhibitor-induced changes in natriuretic peptide measurements will affect the accuracy and implications of assay results has not been studied yet. At the very least, cutpoints will likely need to be recalibrated for use in patients on these drugs, particularly if BNP is being measured. Regardless, more studies are needed to help guide the optimal use of BNP and/or NT-proBNP measurements in patients taking neprilysin inhibitors.

Conclusion Great steps have been made in harnessesing the understanding of natriuretic peptide processing and signaling for heart failure therapy. The resulting drugs have aimed to reinforce the ability of natriuretic peptides to compensate for the ill-effects of the sympathetic nervous system and renin–angiotensin–aldosterone system in chronic heart failure. Despite the latest success in NEP inhibitor combination therapies, controversy surrounding these drugs has not waned, including a theoretical concern of reduced amyloid beta degradation and consequent increased longterm risk of Alzheimer’s dementia.72 Clinicians still must weigh the intended benefits with the potential unwanted side effects of these therapies. The long-term efficacy and risks of these drugs are still unknown, as are the optimal ways to utilise natriuretic peptide assays in patients on these drugs, and their economic impacts, though much of these uncertainties will be sorted out with time. So far, this story is one of success, but its ending remains unwritten as we await further data to guide our targeted titration of agents in the natriuretic peptide system to the benefit of our patients. n

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treatment of bradykinin-mediated angioedema: outcomes from an angioedema expert consensus meeting. Int Arch Allergy Immunol 2014;165 :119–27. doi: 10.1159/000368404; PMID: 25401373 Hooper NM, Hryszko J, Oppong SY, et al. Inhibition by converting enzyme inhibitors of pig kidney aminopeptidase P. Hypertension 1992;19 :281–5. doi: 10.1161/01.HYP.19.3.281; PMID: 1312513 Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17 :103–11. doi: 10.1016/j. amjhyper.2003.09.014; PMID: 14751650 McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15 :1062–73. doi: 10.1093/eurjhf/hft052; PMID: 23563576 Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380 :1387–95. doi: 10.1016/ S0140-6736(12)61227-6; PMID: 22932717 Novartis Pharmaceuticals. Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2003– [cited 2015 Dec 05]. Available from: https://www.clinicaltrials.gov/ct2/ show/NCT01920711 NLM Identifier: NCT01920711.

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62 :e147–239. doi: 10.1016/j. jacc.2013.05.019; PMID: 23747642 Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131 :54–61. doi: 10.1161/ CIRCULATIONAHA.114.013748; PMID: 25403646 Langenickel TH, Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today: Therapeutic Strategies 2012;9 :e131–9. doi: 10.1016/j.ddstr.2013.11.002 Mair J. Clinical significance of pro-B-type natriuretic peptide glycosylation and processing. Clin Chem 2009;55 :394–7. doi: 10.1373/clinchem.2008.119271; PMID: 19147726 Seferian KR, Tamm NN, Semenov AG, et al.

Immunodetection of glycosylated NT-proBNP circulating in human blood. Clin Chem 2008;54 :866–73. doi: 10.1373/ clinchem.2007.100040; PMID: 18339697 Jaffe AS, Apple FS, Mebazaa A, et al. Unraveling N-terminal pro-B-type natriuretic peptide: another piece to a very complex puzzle in heart failure patients. Clin Chem 2015;61 :1016–8. doi: 10.1373/clinchem.2015.243626; PMID: 26078443 Li Y, Wang J, Zhang S, et al. Neprilysin gene transfer: A promising therapeutic approach for Alzheimer’s disease.

J Neurosci Res 2015;93 :1325–9. doi: 10.1002/jnr.23564; PMID: 26096375

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Clinical Evaluation

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Decompensated Heart Failure in Pregnancy John Anthony 1 and Karen Sliwa 2,3 1. Division of Obstetrics and Gynaecology Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; 2. Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; 3.

Soweto Cardiovascular Research Group University of the Witwatersrand, South Africa

Abstract Heart disease is a common cause of morbidity and mortality during pregnancy. Symptoms and signs of heart failure in a pregnant woman are an indication for urgent assessment to establish a diagnosis and appropriate management. This is best accomplished through a multidisciplinary approach in which both cardiologists and obstetricians need to participate in order to provide expert counselling and care in pursuit of safe motherhood. Congenital heart disease, although common, once corrected is an unusual source of complications, which are more likely to develop as a consequence of ventricular failure, pulmonary hypertension and aortic arch disease. Rheumatic valvular heart disease is a challenge because of the need for anticoagulation during pregnancy and the risk of sepsis associated with childbirth. This review outlines a contemporary approach to heart failure presenting during pregnancy.

Keywords Pulmonary oedema, heart failure, pregnancy, maternal mortality, cardiomyopathy Disclosure: The authors have no conflicts of interest to declare.

Received: 14 August 2015 Accepted: 21 October 2015 Citation: Cardiac Failure Review, 2015;1(2):20–6 DOI: 10.15420/cfr.2015:24:2 Correspondence: Karen Sliwa, Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town, Private Bag X3 7925 Observatory, Cape Town, South Africa. E: Karen.Sliwa-Hahnle@uct.ac.za

‘Heart failure’ is a term that may be loosely or precisely defined. The development of pulmonary oedema does not necessarily indicate a cardiac cause and of the cardiac causes for pulmonary oedema, not all can be attributed to left ventricular failure.1 The majority of women developing symptoms and signs of heart failure during pregnancy have no known pre-existing cardiomyopathy. This article describes the cardiac causes of pulmonary oedema presenting in pregnancy with reference to other differential diagnoses.

Significance of Heart Failure as a Cause for Mortality and Morbidity Cardiac disease complicating pregnancy is categorised as an ‘indirect’ cause of maternal mortality, meaning that it is unrelated to any complication of the pregnancy itself.2 Medical and surgical disorders that cause indirect maternal deaths are a diverse group of diseases that include various medical, surgical and infective causes of maternal illness.

Globally, indirect causes of maternal mortality account for a quarter of the deaths reported by industrialised countries with even higher rates in southern Asia and sub-Saharan Africa: 29.3 and 28.6 %, respectively.3 Accurate epidemiological data have been reported in a few countries that have pursued statutory notification of all maternal deaths. In the UK, the rates of maternal mortality have been recorded in single digit figures per 100,000 live-births.4 By contrast, South African data (also accumulated by means of statutory, confidential enquiry) reflect rates of 179 per 100,000 live-births.5 The South African data are dominated

by HIV-related mortality, accounting for 40 % of all deaths. However, medical and surgical disorders, representing the bulk of the remaining indirect causes of death account for 8.8 % of mortality, rendering this

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the fourth most-common cause of mortality, ranking only behind HIV, haemorrhagic deaths and deaths due to hypertension.2 Significantly, the category of ‘medical and surgical’ disorders contains a preponderance of cardiac deaths, which are the single most-common entity in this group accounting for 36.5 % of mortality with ventricular failure responsible for just over half these deaths.

The data from the UK identify indirect deaths attributable to cardiac disease as a cause for 20 % of the reported mortality, being the single commonest cause of indirect death and the commonest overall cause for maternal death.6 In this series, nearly a quarter of the cardiac deaths were diagnosed to be due to cardiomyopathy. The preponderance of deaths due to ventricular failure is further underlined by deaths that occurred outside the window in which postpartum cases are usually reported. ‘Late’ deaths due to peripartum cardiomyopathy often remain unreported and the true estimate of mortality related to ventricular failure during pregnancy may be underestimated by up to 50 %. The data from the UK are diagnostically specific, allowing characterisation of different kinds of ventricular failure into those due to peripartum cardiomyopathy, dilated cardiomyopathy of various kinds and right ventricular arrhythmogenic cardiomyopathy.

Genetic and social variations do exist within individual communities giving rise to disparities in the incidence of ventricular failure due to peripartum cardiomyopathy seen in multicultural societies. Hence, in the US, large disparities are seen with 1 : 1,421 in African Americans developing ventricular failure in pregnancy compared with an incidence of 1 : 2,675 Asians, 1 : 4,075 in Caucasians and 1 : 9,861 in people of Hispanic origin.7

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Although the relative prevalence of cardiac disease varies between different countries, it remains a common cause of maternal death in both developing countries and industrialised societies with ventricular failure being the single most- common mechanism of death.

Cardiovascular Physiology During Pregnancy The physiological demands of pregnancy are partly met through changes in cardiovascular physiology, which has to accommodate the extra metabolic demands presented by the foetus and other organ systems required to perform an augmented physiological role. Hence, the increase in uterine size and activity together with the blood flow into the choriodecidual space are a significant component of the extra cardiovascular work during pregnancy accounting for 12 % of the total cardiac output in a term pregnancy.8 The kidneys and the skin, in particular, have augmented perfusion to disperse heat and allow the retention of sodium and water during pregnancy. The increased blood volume secondary to hyperaldosteronism allows an increase in cardiac output mediated by increased stroke volume and heart rate; the cardiac output rises in the first trimester peaking towards the end of the second trimester at between 3.5 and 6 litres per minute (which is 30–50 % higher than non-pregnant values).9,10 The increased cardiac output is discharged into a dilated peripheral systemic circulation that shows a falling systemic vascular resistance from the first trimester onwards. The extent of the adaptation is such that the arteriovenous oxygen difference falls during early pregnancy and rises towards pre-pregnancy levels by the end of the pregnancy. Both left and right ventricles show evidence of increased mass, volume and enddiastolic volume during pregnancy. These changes reflect the increase in cardiac output and intravascular blood volume and reverse after delivery.11 These adaptations are summarised in Figure 1 below.

Aetiology and Pathophysiology of Heart Failure in Pregnancy Cardiovascular disease complicating pregnancy may be considered in groups including those attributable to increased vascular resistance, diseases of the aortic root, heart disease itself due to either obstruction, ventricular failure or congenital abnormalities of the heart and proximal vasculature. Three pregnancy-specific causes of heart failure are identifiable (pre-eclampsia, peripartum cardiomyopathy and amniotic fluid embolism) together with all the non-pregnancyrelated causes of heart failure that may become co-morbid diseases complicating pregnancy.

Increased Vascular Resistance

Figure 1: Summary of Physiological Changes Occurring During Pregnancy

Plasma volume by 40 %

Systematic vascular resistance

Physiological anaemia

Cardiac output by 30–50 %

Cardiac output during delivery/ postpartum

Transient LV dilatation

Hypercoagulable state

Weeks to months for CO and SVR to normalise

CO = cardiac output; LV = left ventricle; SVR = systemic vascular resistance.

Hypertensive Cardiomyopathy Chronic hypertension complicating pregnancy in the absence of superimposed pre-eclampsia is not clearly associated with adverse maternal outcome16,17 Chronic hypertension prior to pregnancy is, however, increasing in frequency due to the worldwide obesity epidemic and is prevalent in 3 % of all US pregnant women.18 Chronic hypertension leads to increased frequency of preeclampsia (17–25 % versus 3–5 % in the general population), as well as placental abruption, foetal growth restriction and preterm birth.18 Hypertensive CMO may lead to diastolic dysfunction; together with the increase in pregnancy preload, this may predispose some patients to mild pulmonary oedema, usually at the time that plasma volume expansion reaches peak values at 32 to 34 weeks’ gestation.19,20

Pulmonary Hypertension and Right Heart Failure The symptoms suggestive of pulmonary hypertension are those exertional dyspnoea with everyday activities. Weakness and recurrent syncope are also common. These symptoms may be followed by signs consistent with right heart failure (increased jugularis venous pressure [JVP], loud second heart sound/P2, hepatomegaly and peripheral oedema with clear lung fields). The causes of pulmonary hypertension are grouped into primary (idiopathic) and secondary causes and have been classified in a consensus statement.21 The secondary causes are divided into pre- and post-capillary pulmonary hypertension. These are typically due to lung parenchymal disease or the various cardiac causes of increased left-sided filling pressures. Pregnant women with primary pulmonary hypertension are at particular risk of acute right-sided heart failure after delivery and may have a sudden death. The mechanism of acute deterioration has not been elucidated.22

Pre-eclampsia Pre-eclampsia commonly results in pulmonary oedema that, together with cerebrovascular haemorrhage, has been identified as the dominant cause of hypertensive maternal mortality by a South African confidential enquiry.2 Pregnancy and pre-eclampsia are usually associated with a hyperdynamic circulation and enhanced left ventricular contractility.12 In the case of pre-eclampsia, increased systemic vascular resistance may increase the filling pressures in the left atrium and, together with intravenous fluid administration, will increase the likelihood of developing pulmonary oedema. The direct cardiac contribution to the development of pulmonary oedema is usually due to diastolic dysfunction.13 The left ventricle tolerates an intravenous fluid load poorly showing a rapid rise in left-sided filling pressures without any similar observable changes in the right heart.14,15 Occasionally mildly impaired systolic function will be identified in severe pre-eclampsia, although this is usually transitory.

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Diseases Affecting the Aortic Root This can be broadly classified into medial disorders with a risk of dissection such as Marfan’s syndrome, inflammatory diseases of the aorta, usually Takayasu’s arteritis and atherosclerotic disease.

Marfan’s and Takaysu’s syndromes are the two common aortic arch diseases that may present during pregnancy. The presenting features of Takayasu’s disease are predominantly hypertension, although some patients may present with heart failure.23 Arterial dissection and acute aortic regurgitation are more likely acute presentations of Marfan’s syndrome during pregnancy, especially in those with a dilated aortic root.24

Cardiac Disease – Ventricular Failure Cardiomyopathy is generally the commonest cause of mortality developing during or after pregnancy.25,26

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Clinical Evaluation Peripartum Cardiomyopathy This is a well-characterised disease developing in previously well women who develop left ventricular systolic dysfunction with an ejection fraction of less than 45 % during the last month of pregnancy or within 6 months of delivery.27 The European Society of Cardiology definition is less specific, stating that it is an idiopathic cardiomyopathy presenting with left ventricular failure towards the end of pregnancy or in the months following pregnancy for which no other cause can be found. Typically, but not inevitably, this is a dilated cardiomyopathy that develops in the absence of any identifiable cause of heart failure, including genetic cardiomyopathies. The pathophysiology is incompletely understood but a 16 kDa cathepsin cleavage product of prolactin has been identified as a possible mechanism based upon the induction of myocyte apoptosis.27,28 Other identified mechanisms include inflammatory changes that induce oxidative stress and the development of autoimmunity to proteins of cardiac origin.29 The latter mechanism may be the result of cardiac injury rather than a causative mechanism. Other investigators have pointed out the association between peripartum cardiomyopathy, preeclampsia and multiple pregnancy, which are all linked to an imbalance in angiogenic and antiangiogenic factors raising the possibility that this mechanism may also be one of the pathways leading to the development of cardiomyopathy.30

Hereditary Cardiomyopathies Hereditary cardiomyopathies are grouped into hypertrophic (HOCM), dilated (DCMO) and right ventricular arrhythmogenic cardiomyopathy (RVCMO), broadly representing genetic mutations in the cardiac sarcomere, the myocyte and desmosomes, respectively.31 Of these conditions, the hypertrophic form of the disease is well tolerated in pregnancy providing there are no pre-pregnancy symptoms related to HOCM.32,33 The diagnosis of HOCM is phenotypic, based upon the increase in left ventricular wall diameter that cannot be accounted for by co-existing hypertension or valvular disease. Dilated cardiomyopathy is more usually due to conditions other than genetic disease, which account for about one-third of such cases. There are no specific data detailing the pregnancy outcomes in women with genetic DCMO. In general, the outcome of pregnancies complicated by the presence of a DCMO is predicted by the severity of pre-pregnancy symptoms. Right ventricular arrhythmogenic CMO is associated with a risk of sudden cardiac death, which is not altered by the occurrence of pregnancy.34

Drug-induced CMO The drugs associated with induced CMO consist of a long list of which certain agents are more notable than others. In particular, alcohol, cocaine, amphetamines, methamphetamine, catecholamines, ephedrine, zidovudine, chloroquine, cyclophosphamide and certain antimitotic drugs. While the use and abuse of these agents may take place during pregnancy they are rarely identified as a cause of acute heart failure

Autoimmune and Infective CMO Myocarditis on the basis of viral infection or autoimmunity commonly leads to dilated cardiomyopathy with chronic heart failure. Acute damage caused by viral infection may be followed by the exposure of sequestered intracellular antigens that perpetuate immune damage via both the innate and adaptive immune systems.35

poorly understood but the release of large amounts of amniotic fluid and fetal squames into the maternal circulation triggers acute pulmonary hypertension followed by left ventricular failure requiring inotropic support for a protracted period of time. Arrhythmias are also common.

Ischaemic Heart Disease This is a rare complication of pregnancy that usually presents with symptoms of ischaemia rather than heart failure. It is estimated to affect one in 10,000 pregnancies. The major risk to the mother is that of mortality secondary to acute myocardial infarction during pregnancy; however, the recent literature suggests that acute coronary syndromes are unusual and the mortality risk may not be as high as previously suspected.25 Apart from the usually identified dyslipidaemia giving rise to coronary artery disease, anomalous origins of the coronary arteries, coronary artery dissection, severe aortic stenosis and hypertrophic cardiomyopathy may all present with ischaemic symptoms and signs.

Deaths due to coronary artery disease are unusual in European countries and have not been recorded in African maternal mortality reviews either.

Cardiac Disease – Valvular Lesions Post-rheumatic valvular heart disease may lead to pulmonary oedema during pregnancy for a number of reasons. The haemodynamic consequences of pregnancy alone may precipitate pulmonary oedema on the basis of an increasingly hyperdynamic circulation and increased plasma volume. The increased plasma volume peaks at 34 weeks’ gestation with an acute rise immediately after delivery of the baby and placenta. The increased pulse rate of pregnancy, further aggravated by the pain of labour, means that left ventricular filling times diminish increasing the risk of heart failure in women with stenosed mitral valve disease.

In general, regurgitant lesions, such as mitral and aortic valve regurgitation, are better tolerated in pregnancy compared with stenotic lesions.37 Limited data exist on mixed valve lesions or multiple lesions affecting several valves due to rheumatic heart disease. In addition, arrhythmias and various co-morbidities such as anaemia, hypertension and thyroid disease all contribute to a greater risk of pulmonary oedema in patients with valve disease. In the European registry, valvular heart disease were commonly diagnosed for the first time during pregnancy and led to a greater risk of maternal mortality than heart disease caused by congenital defects.25 Heart failure, arrhythmias and obstetric haemorrhage were all noted to be complications of valvular disease.

Cardiac Disease – Congenital Abnormalities of the Heart and Proximal Vasculature Uncorrected congenital heart disease complicating pregnancy is a rare event. Generally operated congenital heart disease women have uncomplicated pregnancies providing their pre-pregnancy effort tolerance is good.38 Of the uncorrected lesions, Marfan syndrome with a dilated aortic root and Eisenmenger syndrome carry the greatest risk of mortality due to dissection or heart failure. Congenitally stenosed valves, cyanotic disease in the absence of pulmonary hypertension, a systemic right ventricle or Fontan circulation carry a moderate risk of heart failure whereas the septal defects and repaired co-arctation are regarded as low-risk lesions.39

Amniotic Fluid Embolism Amniotic fluid embolism is a complication of labour with an acute onset of a syndrome characterised by cardiovascular collapse, pulmonary oedema, seizure activity and a bleeding diathesis.36 The mechanisms are

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Clinical Presentation The clinical presentation of acute heart failure in pregnancy may be divided into clinical signs of left, right or bi-ventricular heart failure.

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Dyspnoea is the most common phenotypic expression of all kinds of acute heart failure. There are many causes for dyspnoea and a diagnosis cannot be made without a thorough examination and investigation.

Causes and Nature of Dyspnoea Dyspnoea and tiredness are often terms used interchangeably by pregnant women. True shortness of breath may be experienced in a normal pregnancy as a consequence of increased respiratory drive mediated by the effects of progesterone.40 Physiological over-breathing is a pregnancy adaptation accelerating the excretion of carbon dioxide allowing the foetus a greater gradient down which to offload carbon dioxide and to maintain acid-base homeostasis. Dyspnoea aggravated by exertion together with other symptoms suggestive of cardiac failure, such as orthopnoea, paroxysmal nocturnal dyspnoea, blackouts and palpitations, clearly indicates the need for further assessment. Fett has suggested that women could monitor their own symptoms, which would allow earlier recognition of dyspnoea in those at risk of heart failure, and has even suggested a scoring system to facilitate this process.41

Clinical Signs Pregnancy may mimic some signs of heart disease.42 A bounding full pulse and mildly elevated jugular venous pressure is a consequence of increased plasma volume and a hyperdynamic circulation. Worsening peripheral oedema is also a physiological consequence whereby extravascular fluid is allowed to accumulate towards the time of delivery when haemorrhage following childbirth may necessitate physiological transfusion of fluid stored in the tissues into a depleted intravascular compartment. Palmar erythema is commonly observed in the absence of liver disease and reflects increased skin perfusion. The heart rate is mildly elevated with arrhythmias including sinus arrhythmia occurring more commonly.43 Examination of the praecordium may show an apex beat displaced to the sixth intercostal space beyond the mid-clavicular line. Systolic flow murmurs are commonly heard at the left sternal edge, caused by increased flow through the aortic and pulmonary valves.44 A mammary souffle may also be heard from increased flow through the internal thoracic vessels. A third heart sound can also be heard in a normal pregnancy.

When assessing a pregnant woman with a history suggestive of heart failure, the findings that should prompt further investigation if they include any evidence of cyanosis or clubbing, a resting tachycardia, any arrhythmia, a collapsing pulse, hypertension or hypotension, any tachypnoea or other clinical signs of respiratory distress, a pulsatile and elevated JVP, any cardiac murmur that is heard in diastole, any cardiac murmur that is pansystolic or radiates beyond the left sternal edge, any loud murmur with an associated thrill or any clinical signs of pulmonary oedema.

Assigning Severity of Risk Traditionally, the New York Heart Association Classification has been used to grade degrees of exertional dyspnoea.45 Although still in use, epidemiological data have been combined with the presence or absence of symptoms into a modified World Health Organization (WHO) classification aimed at defining the risk of adverse outcomes (morbidity and mortality) in pregnant women.39,46 Class I cardiac disease is not associated with any risk and includes uncomplicated mild pulmonary stenosis, patent ductus arteriosus and mitral valve prolapse together with repaired septal defects and isolated supra ventricular and ventricular ectopic beats. Class II diseases include all other arrhythmias, repaired tetralogy of Fallot and operated septal defects that are all associated with a small increase in risk. WHO category II–II disease in which there is a significantly increased risk of adverse outcomes, include all forms of cardiomyopathy, prosthetic heart valves, Marfan syndrome with a graduated risk according to the extent of aortic dilatation, cyanotic heart disease, fontan circulation and a systemic right ventricle. WHO IV, where the risk of adverse outcome is high enough to consider pregnancy contraindicated, includes pulmonary hypertension, severe symptomatic aortic or mitral stenosis, previous peripartum cardiomyopathy with residual ventricular impairment, severe left ventricular failure (ejection fraction less than 30 %) and aortic disease (either coarctation or Marfan’s syndrome with dilated aortic root of more than 45 mm).

The WHO classification underscores the importance of expert counselling and joint care shared between cardiologists and obstetricians for all women with WHO class III and IV disease.26 Combined assessment clinics are commonly centralised in large teaching hospitals in both industrialised and developing countries with successful outcomes documented when treating women with WHO stage III and IV disease.

Differential Diagnosis Heart failure in pregnancy needs to be differentiated from other causes of respiratory distress.

Non-cardiogenic pulmonary oedema must be distinguished from cardiovascular causes of pulmonary oedema. Adult respiratory distress syndrome is an uncommon complication of pregnancy and usually the sequel to pre-existing lung pathology, such as infection.47 A diagnosis of non-cardiogenic pulmonary oedema cannot be made before thorough investigation of the cardiovascular system to eliminate any cardiac contribution to the development of pulmonary oedema.

Chest X-ray and electocardiogram (ECG) are needed in all circumstances. The pregnancy physiological changes may result in increased pulmonary vascular markings and the enlarging uterus may displace the diaphragm upwards, mitralising the cardiac shadow. The ECG may show ST segment abnormalities suggestive of ischaemia as well as supraventricular arrhythmias in a normal pregnancy.42

Pulmonary parenchymal disease arising from infection as well as interstitial lung disease may present during pregnancy. Although the clinical and radiological signs may help to distinguish one cause of respiratory distress from another, the clinical differential diagnosis of infection compared with pulmonary oedema may sometimes be difficult to resolve. Pulmonary thromboembolism is often also considered in the differential diagnosis of acute respiratory distress during pregnancy.

Pregnancy is a pro-coagulant condition and thromboembolism is a common cause of both acute morbidity and mortality; the clinical diagnostic criteria for thromboembolism are poorly predictive of the condition and consequently special investigation is mandatory when thromboembolism is part of the differential diagnosis.48

Echocardiography in pregnancy has the same utility as it does in nonpregnant women and ought to be routinely utilised in anyone with symptoms suggestive of cardiac disease.

Metabolic disorders can also lead to tachypnoea with various causes of acidosis in question. Diabetic ketoacidosis is seen commonly whereas lactic acidosis may result from the adverse effects of certain drugs.

Investigations

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Clinical Evaluation Sub-diaphragmatic pathology associated with any pain may cause rapid shallow respiration, which may be mistaken for respiratory distress. Pre-eclampsia complicated by ischaemic liver necrosis (the syndrome of Haemolysis, Elevated Liver enzmes and Low Platelets otherwise known as the HELLP syndrome) is one such common cause for this presentation.49 Addressing the differential diagnosis requires a comprehensive history and clinical examination followed by relevant investigations with the most-common differential being between infection, pulmonary oedema and thromboembolism.

Management Principles Drug therapy The pharmacological management of pregnant women with cardiac lesions including the management of heart failure and the possible effect of the medication on the foetus has recently been summarised in a dedicated book.50

Diuretics Diuretics are the first line of treatment for most pregnant women with heart failure.51 The increased preload associated with pregnancy is part of the mechanism by which a hyperdynamic circulation develops.

Women with normal ventricular function respond to increased preload with increased output. That may not happen when the left ventricular contractility is abnormal. Reducing preload will diminish left-sided filling pressures as well as pulmonary capillary pressures allowing the resorption of pulmonary interstitial fluid. There is a theoretical concern that using treatment that partially reverses or limits the physiological changes of pregnancy may adversely affect the pregnancy outcome by limiting the necessary increase in uterine and, therefore, placental perfusion. However, the foetuses of women with cardiac disease are prone to develop restricted growth and discerning the effects of treatment from those of the disease (low cardiac output due to ventricular failure) is difficult outside the context of controlled studies.

There is no evidence that diuretics are an independent risk factor for foetal growth restriction and the use of diuretics in circumstances where the mother becomes symptomatic on the basis of increased preload complicating left ventricular dysfunction justifies the use of diuretic therapy as first-line treatment.

Whereas diuretic therapy may be useful when ventricular dysfunction is the cause of pulmonary oedema, in other circumstances the use of diuretics may be less beneficial. Pre-eclampsia when presenting as acute severe disease, does so with elevated vascular resistance and often some degree of left ventricular diastolic dysfunction.14 In this setting, afterload reduction using parenteral vasodilators is a preferable treatment because falling vascular resistance allows an increase in left ventricular stroke volume and cardiac output with a secondary decrease in left-sided filling pressures.52 Diuretic therapy, by contrast, may deplete an already contracted intravascular volume with no reduction in systemic vascular resistance. The diversity of underlying mechanisms giving rise to pulmonary oedema makes clinical discrimination and rational therapy very difficult when all causes have a common phenotype, namely pulmonary oedema. Only patients with access to invasive haemodynamic monitoring or ready access to echocardiography are likely to be managed consequentially based upon a recognised haemodynamic subset.53,54

women admitted to intensive care. This is especially so in women who have hypertension due to pre-eclampsia complicated by both left ventricular systolic failure and simultaneous renal failure. Increasing venous capacitance under these circumstances may be beneficial.

The heterogeneity of pathophysiological mechanisms related to the development of pulmonary oedema may also confound epidemiological investigations that use the phenotype alone to recruit patients into randomised studies.

Angiotensin Converting Enzyme Inhibitors This class of drugs includes the angiotensin receptor blockers and converting enzyme inhibitors.55 The drugs intercept the reninangiotensin-aldosterone axis leading to natriuresis, reduced intravascular volume and vasodilation. Whereas these drugs are standard forms of treatment in non-pregnant individuals with heart failure, pregnancy is a state of physiological hypereninism in which the use of these drugs are relatively contraindicated.42 Apart from the effects of the renin-angiotensin-aldosterone axis in regulating central haemodynamics, the mechanism may also be important in controlling specific perfusion of certain organs, notably the uterus and the kidney.56 Babies delivered by mothers treated with angiotensin converting enzyme (ACE) inhibitors during pregnancy are at increased risk of neonatal renal failure and for this reason the drugs are viewed as being contraindicated.57 The breastfeeding mother can safely take ACE inhibitors with sufficient data available to establish the safety of this practice.

Beta-blockers Beta-adrenergic receptor blockade slows the heart rate and allows greater filling during diastole. The use of beta-blockers in patients with systolic dysfunction and an ejection fraction <40Â % has been associated with improved symptoms and survival.58 During pregnancy, data pertaining to the use of beta-blockers in women with hypertension has shown an association between the use of beta-blockers and intrauterine growth restriction and increased perinatal mortality.59 This does not constitute a contraindication to the use of beta blockade during pregnancy when the motherâ&#x20AC;&#x2122;s life is at risk and where both the underlying maternal disease and the treatment can cause adverse perinatal outcome. Epidemiological data identifying risks associated with the use of beta blockade are all confounded by an inability to discriminate between the perinatal effects of the disease and the effects of the treatment.

Spironolactone This is a potassium-sparing aldosterone antagonist that is a mild diuretic.

The effects of spironolactone are synergistic with those of other diuretics and co-treatment with spironolactone results in a significantly reduced risk of mortality among those who have heart failure.60 In pregnancy, the anti-androgen effects of spironolactone, together with some evidence of teratogenesis in the rat-model, has meant that the drug should not be used during pregnancy. In the puerperium, the treatment of the mother should proceed according to the needs of the adult. The use of spironolactone in these circumstances results in less <1Â % of the drug passing from mother to child in the breastmilk.

Bromocriptine Nitroglycerine as a combined arterial and venous vasodilator may have a role to play especially in the management of acutely ill pregnant

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The suppression of lactation and prolactin secretion may be important in specific circumstances. Where the diagnosis of peripartum

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cardiomyopathy has been made, research suggests that one of the mechanisms causing this condition may be the presence of a 16 kDa cathepsin-cleavage product of prolactin with apoptotic effects on the myocardium.28 In these circumstances, given the poor prognosis of peripartum cardiomyopathy, the use of bromocriptine to suppress lactation is a reasonable treatment, based on limited data, although consensus is still lacking for this intervention.

A multicentre randomised study is in progress to examine the effects of bromocriptine on left ventricular function in women who present with peripartum cardiomyopathy.61

Managing Arrhythmias Sudden cardiac death accounts for up to 50Â % of the deaths associated due to heart failure. The most common arrhythmia encountered is atrial fibrillation, which may be treated with beta-blockers and (if necessary) digoxin. Ventricular arrhythmias causing sustained ventricular tachyarrhythmia may be diagnosed more accurately when implantable devices are used for continuous monitoring. The management of these patients may include the use of amiodarone and implantable cardioverter defibrillators.62

Inotropic Support and Assist Devices Inotropic support may be a necessary treatment in acutely ill women with severely impaired ventricular function. Persistent hypotension due to refractory heart failure may benefit from temporary inotropic support while reversing the pregnancy preload and treating underlying hypertensive disease. There is no randomised data characterising the management of pregnant women needing this intervention and the treatment will always be based upon the clinical assessment of women needing intensive care. Assist devices are a potential adjunct in the management of intractable heart failure where they may bridge the gap between the initial presentation of the patient and access to cardiac transplantation services. Again, there is limited evidence.62

Treating Reversible Factors

The obstetric management of a woman with decompensated heart failure in pregnancy depends upon an assessment of the degree to which the pregnancy physiology is contributing to the development of heart failure and the risks of continuing with the pregnancy.

These factors are a matter of professional judgement, which take into account the specific risks to the mother, the consequence of preterm birth for the baby and the opinion of the mother and her partner in reaching a decision about continuation or termination of the pregnancy. Most cardiac causes for pulmonary oedema would be subject to a trial of treatment with medical therapy before considering ending the pregnancy. Pulmonary oedema developing in pre-eclamptic mothers is always an indication for ending the pregnancy because of the high fatality rate and clear epidemiological association between the onset of pulmonary oedema and the risk of maternal mortality.

The Mode of Delivering the Foetus The option of operative delivery or vaginal birth needs to be considered. The haemodynamic consequences of labour are a further increase in left ventricular workload, a pain-mediated increase in catecholamines and an acute increase in intravascular blood volume at the point of delivery, offset to some extent by blood loss at the time of delivery. The second stage of labour is a time during which the mother may need to valsalva, the cardiovascular effects of which may be limited by means of assisted vaginal delivery using either forceps or a vacuum extractor.

The process of induced labour is unpredictable both in terms of the time that may elapse between the decision to end the pregnancy and eventual delivery and will always include the possibility that emergency caesarean section will be necessary. Caesarean delivery itself, either elective or emergency surgery, is associated with the risks of anaesthesia, haemorrhage and post-operative complications.

Factors that may aggravate heart failure increasing the heart rate include anaemia, overt or occult infection and hyperthyroidism. These factors should be considered and managed, each on their own merits.

Hyperthyroidism in relationship to pregnancy may be a particularly under diagnosed condition in the puerperium.63 In the first year after delivery, postpartum thyroiditis may affect up to 5Â % of women. This is often subclinical and undiagnosed.

The decision to allow either vaginal delivery or to perform an elective caesarean delivery is peculiar to the individual case with multiple factors to be considered including the parity of the mother, any other obstetric co-morbidities and the severity of the cardiac lesion.

There is no justification for routine caesarean delivery in women with heart failure during pregnancy although many will be delivered by this means. Individualised recommendations are available from sources such as the European Society of Cardiology Guidelines on the management of cardiovascular disease during pregnancy.39

Of the infections, urinary infection is a frequent cause of sepsis during pregnancy and together with the risk of genital tract sepsis after delivery, needs to be recognised and treated in good time.

The Puerperium and Long-term Management

Supportive Measures The critical care measures taken in women with decompensated heart failure during pregnancy are all standard measures that include the maintenance and monitoring of oxygenation. Pharmacological intervention is detailed in the preceding section and immediate management is usually followed by the necessary investigations to establish the diagnosis.

During pregnancy, the hospitalised pregnant woman with heart failure is in need of thromboprophylaxis, which should be given in the form of subcutaneous low molecular weight heparin as a daily dose; which should be given in a prophylactic dose, typically 40 mg of enoxaparin.64

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Attention in the immediate puerperium should be directed to avoiding fluid overload. The delivery of the placenta leads to uterine contraction and expulsion of blood from this vascular organ into the systemic circulation. Women with severe stenosed valves and those with failing ventricles may benefit from intravenous diuretic therapy at the time of delivery. The oxytocic drugs used to facilitate active management of the third stage of labour may have vasoactive properties that should be considered prior to administration; hence bolus dose oxytocin leads to vasodilatation and reflex tachycardia while any preparation containing ergometrine will have a vasoconstrictor effect on the peripheral circulation.65 In general, low-dose oxytocin is advocated and ergometrine-containing preparations avoided. Attention also needs to be paid to the prevention of infection using prophylactic antibiotics. Recent evidence suggests that prophylactic antibiotics are necessary to limit the risk of endocarditis.66

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Clinical Evaluation The matters of identifying and treating aggravating factors has already been addressed and the question of breastfeeding also requires attention in women with peripartum cardiomyopathy.

Conclusion Pregnancy represents a window of opportunity during which women present primarily for pregnancy care while offering an opportunity to optimise the management of known medical co-morbidities, and during which time newly diagnosed disease may be first discovered. Pregnancy

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Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54 :S43–S54.

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pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 1998;31 :1650–7.

Sharma BK, Jain S, Vasishta K. Outcome of pregnancy in Takayasu arteritis. Int J Cardiol 2000;75 :S159–S162.

Milewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients with Marfan syndrome. Circulation 2005;111:e150–e157.

Roos-Hesselink JW, Ruys TP, Stein JI, et al. Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology. Eur Heart J 2013;34 :657–65.

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Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;368 :687–93.

Ansari AA, Fett JD, Carraway RE, et al. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol 2002;23 :301–24.

Patten IS, Rana S, Shahul S, et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 2012;485 :333–8.

WatkinsH, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med 2011;364 :1643–56.

Autore C, Conte MR, Piccininno M, et al. Risk associated with pregnancy in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40 :1864–9.

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Systematic review of pregnancy in women with inherited cardiomyopathies. Eur J Heart Fail 2011;13 :584–94.

Basso C, Corrado D, Marcus FI, et al. Arrhythmogenic right ventricular cardiomyopathy. Lancet 2009;373:1289–300.

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Autoimmunological features in inflammatory cardiomyopathy.

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Sliwa K, Johnson MR, Zilla P, Roos-Hesselink JW. Management of valvular disease in pregnancy: a global perspective. Eur Heart J 2015;36 :1078–89.

Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. Eur Heart J 2005;26 :2325–33.

European Society of Gynecology (ESG), Association for European Paediatric Cardiology (AEPC), German Society for Gender Medicine (DGesGM), et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy.

Eur Heart J 2011;32 :3147–97.

Jensen D, Webb KA, O’Donnell DE. Chemical and mechanical adaptations of the respiratory system at rest and during exercise in human pregnancy. Appl Physiol Nutr Metab 2007;32 :1239–50.

Fett JD, Validation of a self-test for early diagnosis of heart failure in peripartum cardiomyopathy. Crit Pathw Cardiol 2011;10 :44–5.

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Shotan A, Ostrzega E, Mehra A, et al. Incidence of arrhythmias in normal pregnancy and relation to palpitations, dizziness, and syncope. Am J Cardiol 1997;79 :1061–4.

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46. Thorne S, Nelson-Piercy C, MacGregor A, et al. Pregnancy and contraception in heart disease and pulmonary arterial hypertension. J Fam Plann Reprod Health Care 2006;32 :75.

47. Catanzarite VA, Willms D, Adult respiratory distress syndrome in pregnancy: report of three cases and review of the literature. Obstet Gynecol Surv 1997;52 :381–92.

48. Soubra SH, Guntupalli KK. Critical illness in pregnancy: an overview. Crit Care Med 2005;33 :S248–S255.

49. Anthony, J., R. Johanson, and J. Dommisse, Critical care management of severe pre-eclampsia. Fetal Matern Med Rev 1994;6 :219–29.

50. Sliwa K, Anthony J. Cardiac Drugs in Pregnancy . London, UK: Springer, 2014.

51. ter Maaten JM, Dunning AM, Valente MA, et al. Diuretic response in acute heart failure—an analysis from ASCENDHF. Am Heart J 2015;170 :313–21.

52. Belfort M, Akovic K, Anthony J, et al. The effect of acute volume expansion and vasodilatation with verapamil on uterine and umbilical artery Doppler indices in severe preeclampsia. J Clin Ultrasound 1994;22 :317–25.

53. Clark SL, Greenspoon JS, Aldahl D, Phelan JP. Severe preeclampsia with persistent oliguria: management of hemodynamic subsets. Am J Obstet Gynecol 1986;154 :490–4.

54. Gilbert WM, Towner DR, Field NT, Anthony J. The safety and utility of pulmonary artery catheterization in severe preeclampsia and eclampsia. Am J Obstet Gynecol 2000;182 :1397–403.

55. Lüscher TF, An update on heart failure and peripheral arterial disease. Eur Heart J 2015;36 :885–7.

56. Irani RA, Xia Y. The functional role of the renin–angiotensin system in pregnancy and preeclampsia. Placenta 2008;29 :763–71.

57. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. The American Journal of Medicine 1994;96 :451–6.

58. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334 :1349–55.

59. Swan L, Lupton M, Anthony J, et al. Controversies in pregnancy and congenital heart disease. Congenit Heart Dis 2006;1 :27–34.

60. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341 :709–17.

61. Haghikia A, Podewski E, Berliner D, et al. Rationale and design of a randomized, controlled multicentre clinical trial to evaluate the effect of bromocriptine on left ventricular function in women with peripartum cardiomyopathy, Clin Res Cardiol 2015;1–7.

62. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur J Heart Fail 2008;10 :933–89.

63. Learoyd DL, Fung HY, McGregor AM. Postpartum thyroid dysfunction. Thyroid 1992;2 :73–80.

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Clinical Evaluation

Novel Imaging Techniques for Heart Failure Josep L Melero-Ferrer, Raquel López-Vilella, Herminio Morillas-Climent, Jorge Sanz-Sánchez, Ignacio J Sánchez-Lázaro, Luis Almenar-Bonet and Luis Martínez-Dolz Advanced Heart Failure and Heart Transplantation Unit, Cardiology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain

Abstract Imaging techniques play a main role in heart failure (HF) diagnosis, assessment of aetiology and treatment guidance. Echocardiography is the method of choice for its availability, cost and it provides most of the information required for the management and follow up of HF patients. Other non-invasive cardiac imaging modalities, such as cardiovascular magnetic resonance (CMR), nuclear imaging-positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and computed tomography (CT) could provide additional aetiological, prognostic and therapeutic information, especially in selected populations. This article reviews current indications and possible future applications of imaging modalities to improve the management of HF patients.

e. lare.

Keywords Heart failure, imaging, ecocardiography, computed tomography, cardiac magnetic resonance, nuclear imaging Disclosure: The authors have no conflicts of interest to declare.

Received: 9 December 2015 Accepted: 21 January 2016 Citation: Cardiac Failure Review, 2016;2(1):27–34 DOI: 10.15420/cfr.2015:29:2 Correspondence: Josep L Melero, Advanced Heart Failure and Heart Transplantation Unit, Cardiology Department, Hospital Universitari i Politècnic La Fe, Avenida Abril Martorell 106, 46026 Valencia, Spain. E: josep.melero@gmail.com

Heart failure (HF) is an epidemic with an increasing prevalence and an absolute mortality rate of approximately 50 % within 5 years of diagnosis. Imaging plays a main role in HF diagnosis, assessment of aetiology and treatment guidance. This article reviews current HF applications for all the available non-invasive imaging modalities: echocardiography, cardiovascular magnetic resonance (CMR), nuclear imaging-positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and computed tomography (CT). Echocardiography, with its recent developments, such as 3D echo, is the main imaging test used in the evaluation of HF patients, given its availability and reliability in assessing cardiac structure and function. CMR allows the characterisation of myocardial tissue, in addition to providing information on the structure and cardiac function, so it is a great help in the determination of HF aetiology and may predict patient outcomes. Nuclear imaging can detect ischaemia and viability and can obtain additional prognostic data. Cardiac CT is a reliable method for the detection of coronary artery disease (CAD), and recent advances have in turn provided information about function and myocardial perfusion. In general, available imaging methods yield reliable measures of cardiac performance in HF, and recent advances allow detection of subclinical disease. In the following pages, current indications and possible future applications of each one of the above mentioned modalities are developed with further detail.

Echocardiography Although echocardiography is a relatively ‘ancient’ technique, its versatility makes it unique in the provision of volumes, function, haemodynamics or valvular regurgitation. In addition, because of its availability, safety and low cost, echocardiography is the first and most widely used test for the diagnosis, selection of appropriate treatment and prognosis of HF.1 Echocardiography is also the most used imaging

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method in the reassessment of HF patients. It remains unclear when to repeat echocardiographic exams, but it is deemed appropriate at least in patients with worsening symptoms.

Systolic Function Global left ventricular (LV) function is of paramount importance regarding therapeutic decisions. Visual estimation of ejection fraction (EF), the Teichholz and Simpson methods, have been widely validated.2,3 However, in 2D imaging, because of its operator-dependent nature, repeated testing has a high probability of producing variable volume and EF results.

The apparition of 3D fully sampled matrix transthoracic echocardiography has enabled easier acquisition of images,4 simplifying its routinary application. There have been many studies comparing 2D and 3D echocardiography (2DE and 3DE) and a ‘reference’ standard (generally CMR). A recent meta-analysis of all 3DE studies evaluating LV volumes and EF demonstrated that 3DE generally underestimated volumes, but not as significantly as 2DE. There was also less variability than 2D compared with CMR.5 Nonetheless, 3DE echocardiography may be challenging and not practical in patients with low image quality (e.g. critical patients), in whom 2DE measures are more realiable. 3DE is also a less standardised techique than 2DE, and because of this reason most laboratories use the more universally applicable 2DE measurements in clinical practice. Only recently, large analyses of LV parameters using 3DE in large cohorts of healthy individuals have been published to establish race, age and gender-specific reference ranges to facilitate the standardisation of this technique.6 The most commonly used strain-based measure of LV global systolic function is global longitudinal strain (GLS), which is usually assessed by

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Clinical Evaluation Figure 1: Novel Techniques in Echocardiography Applied on Heart Failure Patients A

B

(A) 3D echo displaying endocardial surface rendering of the left ventricle. (B) Bulls-eye plot of regional strain of a patient with ischaemic cardiomyopathy. Scar (septal wall) and ischaemic (anteroseptal and inferior walls) tissues show lower global longitudinal strain (GLS) values than healthy tissue (lateral wall)

Figure 2: Example of Left Ventricular Dyssynchrony Analysis from Mid-ventricular Short-axis Views in a Patient With Left Bundle Branch Block A

Strain is of special interest in two clinical scenarios. Studies in patients with chemotherapy demonstrate that early alterations of myocardial deformation precede significant change in EF. A 10 % to 15 % early reduction in GLS during therapy is the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or HF.9 Moreover, 2D speckle-tracking imaging could be useful in differentiating cardiac amyloidosis from other causes of LV hypertrophy by showing reduced basal strain and regional variations in LS from base to apex and a relative ‘apical sparing’ (average apical LS/[average basal LS + midLS]) pattern. GLS also provided incremental prognostic value over N-terminal of the prohormone brain natriuretic peptide (NT-proBNP), cardiac troponin and other clinical variables.10,11 In addition, although currently at an experimental level, strain imaging may help to detect subclinical cardiac dysfunction, e.g. in patients with diabetes.

Diastolic Function Comprehensive diastolic assessment by tissue Doppler imaging, transmitral flow velocities and deceleration time, pulmonary venous Doppler, left atrial (LA) size and pulmonary artery pressures is mandatory in the evaluation of suspected HF. Nonetheless, the concordance between observers in this setting is limited.12 LA volume has a stronger association with outcomes compared with anteroposterior diameter. 3DE is more accurate than 2D assessment and provides fewer underestimated values in connection with CMR.13

B

C

In some patients, LV diastolic pressures are normal at rest but become abnormal under exercise. The typical echocardiographic parameters acquired during exercise or immediately thereafter are the E/e’ ratio and peak tricuspid regurgitant velocity.14 These parameters have a high specificity (96 %) but a relatively low sensitivity (76 %). An increase in the E/e´ ratio under physical exercise indicates a concomitant increase in LV end-diastolic pressures and a worse prognosis.15,16 Strain rate during the isovolumetric relaxation time (IVRsr) or early diastolic strain rate (e´sr), derived from global longitudinal speckletracking strain, were recently proposed to estimate LV filling pressures, although both parameters are still experimental.17

Right Ventricular Function Pulmonary artery systolic pressure and TAPSE represent the minimum dataset of RV parameters in HF patients.18 Other common techniques used are DTI derived s´ wave velocity, fractional area change and Tei index (which also evaluates diastolic function).

Dyssynchrony is shown as time difference (white arrow) between time-to-peak speckle-tracking radial strain in anterior septum (red curve) and posterior wall peak speckle-tracking strain (purple curve). (A) In baseline conditions, this patient exhibited significant left ventricular (LV) dyssynchrony (QRS width 175 ms). Furthermore, there was a delayed mechanical activation of the posterior wall compared with the anteroseptum (AS-P delay 134 ms). (B) With conventional biventricular pacing configuration, a decrease in the value of LV dyssynchrony was showed (AP-S delay 80 ms). (C) With multi-point pacing configuration, a higher decrease in LV dyssynchrony was shown (AS-P delay 34 ms) by earlier mechanical activation of the posterior wall that is synchronised to the timing of mechanical activation of the anteroseptal wall.

speckle-tracking echocardiography and describes the relative length change of the LV myocardium between end-diastole and end-systole.

The preponderance of currently available data is for midwall GLS, and, although there is a wide heterogeneity in the published literature, a peak GLS in the range of 20 % can be expected in a healthy person.7,8 It is essential to know the pitfalls and limitations of this method, specially the critical importance of optimised echocardiographic recordings and avoidance of apical foreshortening (which may significantly change the value of the obtained measurements).

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One emergent technique is RV 3D EF, which does not require geometric assumptions. Real-time 3D techniques have been shown to accurately provide objective measurement of RV volumes19 and are especially attractive after cardiac surgery, when conventional indices of longitudinal RV function are generally reduced.20 Strain, particularly speckle tracking technique of the free wall, is a promising technique. Although less validated than in the LV, pooled data suggest that global longitudinal RV free wall strain lower than -20 % is likely abnormal. This parameter has prognostic value in advanced chronic HF.21,22

Aetiology of Heart Failure Echocardiography is inferior compared with other imaging methods (e.g. CMR) in determining the aetiology of HF. However, stress

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Novel Imaging Techniques for Heart Failure

echocardiography can rule out ischaemia (with experimental techniques such as the use of microbubbles in development),23 and is of special interest because of its dynamic nature, in doubtful cases of hypertrophic cardiomyopathy or mitral regurgitation.24,25 Moreover, 3D echocardiography can help to elucidate the exact mechanism of some underlying valvulopathies, e.g. mitral valve prolapse.

Figure 3: Examples of Late Gadolinium Enhancement Patterns (Arrows) A

B

Selection and Optimisation of Therapies Echocardiography has been exhaustively evaluated in cardiac resynchronisation therapy (CRT), and some signs, e.g. septal flash, seem to indicate higher likelihood of success. Although dyssynchrony failed to improve patient selection beyond electrocardiogram (ECG) criteria,26 newer methods such as speckle tracking and 3D echocardiography are under investigation. By contrast, radial strain demonstrated its value in guiding the placement of the LV lead and subsequently improving the response to CRT in the small trials Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) and A Prospective Randomized Controlled Study of EchocardiographicGuided Lead Placement For Cardiac Resynchronization Therapy (STARTER).27 Nowadays, no accepted echo criteria for CRT implantation exist, and it is still an experimental field.

Echocardiography also has a main role in the selection and follow-up of patients with LV assist devices, with routine exams recommended to optimise the performance of these devices.28

Dyssynchrony is shown as time difference (white arrow) between time-to-peak speckle-tracking radial strain in anterior septum (red curve) and posterior wall peak speckle-tracking strain (purple curve). (A) In baseline conditions, this patient exhibited significant left ventricular (LV) dyssynchrony (QRS width 175 ms). Furthermore, there was a delayed mechanical activation of the posterior wall compared with the anteroseptum (AS-P delay 134 ms). (B) With conventional biventricular pacing configuration, a decrease in the value of LV dyssynchrony was showed (AP-S delay 80 ms). (C) With multi-point pacing configuration, a higher decrease in LV dyssynchrony was shown (AS-P delay 34 ms) by earlier mechanical activation of the posterior wall that is synchronised to the timing of mechanical activation of the anteroseptal wall.

Figure 4: Iodine-123-metaiodobenzylguanidine Imaging in Heart Failure A

H/M=1.9

B

H/M=1.2

Cardiovascular Magnetic Resonance The high spatial and temporal resolution of CMR makes it suitable for use in the assessment of right (RV) and LV, providing a comprehensive study that includes anatomical evaluation, functional data and great information about myocardial perfusion and viability.29 During a CMR examination, the patient is brought into a highstrength static magnetic field that aligns the spins of the hydrogen atoms. These atoms are then excited intermittently by pulses of radiofrequency waves (MR sequences) and the signal emitted from the body in return is detected, determining two distinct MR relaxation parameters, longitudinal relaxation time (T1) and transverse relaxation time (T2). A CMR sequence consists of a series of radiofrequency pulses, magnetic gradient field switches and timed data acquisitions.

To prevent artifacts from cardiac motion, most CMR images are generated with fast sequences gated to the R-wave of the ECG. Respiratory motion, another source of artifacts, is usually eliminated by acquiring CMR images in end-expiratory breath-hold.

Late gadolinium enhancement (LGE) patterns have been shown to provide diagnostic utility for distinguishing between ischaemic cardiomyopathy (ICM) and non-ischaemic cardiomyopathy (NICM),30 but gadoliniumbased contrast agents (GBCA) have been recently linked with a rare multisystemic fibrosing disorder known as nephrogenic systemic fibrosis.

The patients at risk of developing this disease are those with severe renal insufficiency (glomerular filtration rate <30 ml/min/1.73 m2), there is no specific treatment and symptoms may appear from several days to few years after the exposition. Therefore, in high-risk patients, GBCA should be avoided unless the diagnostic information is essential and not available from non-contrast enhanced CMR or other imaging modalities

Ischaemia Assessment CMR, and in particular the LGE and T2-weighted (‘edema’) imaging, is useful to determine whether a LV dysfunction has an ischaemic aetiology.31,32

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Uptake reduction with the progression of the severity of the disease. (A) Patient with heart failure (HF) in functional class II. (B). Patient with HF in functional class IV. H/M = heart to mediastinal ratio.

Figure 5: Contrast-enhanced Multidetector Computed Tomography Image A

B

(A) Coronary computed tomography (CT) showing significant stenosis on circumflex artery.

(B). Thoracic CT with helical acquisition after administration of intravenous iodinated contrast.

Reconstructions of 2 mm, filter mediastinum and lung. Severe dilation of left cavities (left ventricle basal diameter of 76 mm, left atrium area of 34 cm2). Right cavities not dilated. Cardiac resynchronisation therapy device, distal end of electrodes in right ventricle apex, right atrial appendage and left marginal vein.

A recent study on the diagnostic utility of CMR found 100 % sensitivity and 96 % specificity for the identification of the cardiomyopathy aetiology,33 reducing requirements of invasive angiography. However, total

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Clinical Evaluation absence of LGE does not completely rule out ischaemic cardiomyopathy in the rare setting of global myocardial hibernation.

This technique is based in T1 mapping of pixel-based quantifications of gadolinium retention.50

The typical LGE in ICM should always involve the subendocardium (subendocardial or transmural) and be located in a region that is consistent with the perfusion territory of an epicardial coronary artery.34 Between 10 % and 26 % of NICM patients without features of infarction show patchy or longitudinal striae of midwall hyperenhancement unrelated to a particular coronary artery territory, this distinct pattern of LGE corresponds to focal fibrosis.35

Cardiovascular Magnetic Resonance in Other Cardiomyopathies

Stress perfusion CMR accurately identifies significant CAD, with higher accuracy than SPECT perfusion imaging.36 In HF patients, CMR has shown an excellent safety profile when assessing ischaemia or viability.37

Viability Assessment Multiple studies have confirmed the ability of LGE-CMR to predict recovery of contractile function after revascularisation.38,39 Despite the contradictory findings of the Surgical Treatment for Ischemic Heart Failure (STICH) viability trial,40 a more recent study has shown that the identification of viable but dysfunctional myocardium using LGE-CMR in HF patients is associated with worse outcomes when managed medically rather than undergo surgical revascularisation.41 Scars taking up >75 % of wall thickness indicate that the likelihood for functional recovery is low, but scars <25 % have a positive predictive accuracy of functional improvement.42 The predictive value of segments with an intermediate (25 % to 75 %) transmural extent of scarring is lower. In these situations, a low-dose dobutamine study to assess the contractile reserve may be helpful.

A considerable number of patients (5–50 %) show lack of restoration of blood flow at myocardial level despite a successful procedure.

This is called no-reflow and is due to microvascular obstruction.43 It is related to more severe myocardial damage, increases with the duration of ischaemia time and is independently associated with lack of functional recovery, adverse ventricular remodelling and worse patient outcome. 44,45 It typically presents on LGE imaging as a subendocardially located hypointense area within the enhanced myocardium.

Therapy Guidance The scar extent and the spatial distribution of LGE have been proposed as predictors of response in HF patients referred for CRT.46,47 Those patients with transmural necrosis in either the septal or inferolateral walls experience an absence of improvement in LV volumes at 6 months. Performance of LGE-CMR prior to CRT implantation can help to guide the procedure; therefore, the lead can be delivered to viable tissue targets, improving event-free survival.48 In the same way, LGE-CMR can also predict arrhythmia risk. Among patients with ICM or NICM, those having appropriate ICD therapy or who had survived sudden cardiac death (SCD) showed higher scar extent on LGE imaging.49

Diffuse Fibrosis Assessment One of the most promising future applications of CMR is the ability to identify diffuse myocardial collagen content. This approach could be useful to detect subclinical disease in at-risk populations, such as hypertensive or diabetic patients, infiltrative myocardial diseases, etc.

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Acute myocarditis may present as new-onset HF and its diagnosis could be challenging. The T2-weighted images show hyperintense subepicardial and midwall areas of myocardial oedema.51 LGE is typically seen more pronounced in the subepicardial areas in inferolateral segments. Finally, hyperaemia and capillary leak (visualised on CMR images acquired early after gadolinium injection) have shown to be the best predictor in patients with chronic myocarditis.52 Regarding hyperthrophic cardiomyopathy, LGE extent is an independent predictor of adverse outcome.53,54 In cardiac amyloidosis, LGE characteristically involves the subendocardium in a circumferential pattern, showing sometimes a patchier transmural pattern.55

Nuclear Imaging Nowadays, the main clinical application for radionuclide imaging in HF is myocardial perfusion imaging for the assessment of ischaemia and/or viability.56 The evaluation of sympathetic innervation by SPECT or PET has regained interest in the last years due to the apparition of new articles regarding its prognostic and predictive value.

Myocardial Blood Flow and Viability Testing One of the first steps when studying a patient with HF is the identification of the underlying aetiology. Moreover, those patients with ICM and viable myocardium could benefit from revascularisation procedures, as some dysfunctional myocardium may not be irreversibly damaged. Nuclear imaging could be useful in this setting.

SPECT imaging with thallium-201 (201Tl) or technetium 99m (99mTc) has shown remarkable diagnostic capabilities to evaluate for the presence of infarction, ischaemia and/or viability.56 Prior studies suggest excellent negative predictive values but poor positive negative values.57 Reversible perfusion defects indicate ischaemia and fixed defects indicate scarring tissue. In general, ICM shows more extensive, diffuse and severe perfusion defects than NICM, but a noteworthy degree of overlap exists. Gated SPECT improves accuracy and provides information on LV volumes, LVEF and motion abnormalities.58 Summed scores can be derived from this technique. Higher summed stress scores were found in patients with ICM.58 SPECT perfusion defects also predict mortality in patients with ICM.59,60 PET imaging can also be used for this purpose. This technique determines an absolute quantification of myocardial blood flow and coronary flow reserve (CFR), as well as providing higher temporal and spatial resolution. For this reason, PET has better diagnostic performance than SPECT to detect ICM.61 In addition, PET myocardial perfusion reserve has shown61 to be a stronger predictor of unfavourable outcomes in ICM. Likewise, in NICM, CFR abnormalities can be detected due to microvasculature disease62 and have been associated with increased risk of death.63 Radionuclide techniques are of use also to evaluate the presence of viable myocardium in patients with ICM. SPECT has been widely utilised in this scope, demonstrating high sensitivity to detect viability.64,65 Nevertheless, the gold standard for myocardium viability assessing is 18-fludeoxyglucose (18F-FDG) PET. Metabolic

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Table 1: Main Indications and Applications for Each one of the Available Imaging Modalities in the Assessment of Heart Failure Patients 2D ECO

3DE

LV/RV volumes

RU

AI

LV systolic function

RU

AI

LV diastolic function

RU (GS)

RV function

RU

Ischaemia

Strain

Cardiovascular Magnetic Nuclear

Tomography

AI (GS)

AI

AI

AI (GS)

AI

AI

AI

AI (GS)

RU

AI

AI (GS)

AI (GS)

Viability

RU

AI

AI (GS)

AI (GS)

Cardiomyopathies and other heart

RU

AI

AI (GS)

AI

Computed

Resonance

AI

failure aetiologies Risk assessment (arrhythmia) Therapy guidance (cardiac resynchronisation therapy) Follow-up

RU

Green: best performance of the technique for this indication; yellow: the technique could provide useful information for this indication; red: no/little use for this indication. AI = provides additional information to that obtained with 2D echocardiogram; GS = gold standard; RU = routinely used for this indication. LV = left ventricular; RV = right ventricular.

PET imaging yields the highest accuracy (>90 % sensitivity) for predicting functional recovery66 after revascularisation. Data obtained from the PET and Recovery Following Revascularization-2 (PARR-2) study67 showed a threshold of 7 % of hibernating myocardium above which a patient could benefit from revascularisation. Although there is considerable evidence in the literature68 proving improved survival with revascularisation in patients with viable myocardium, surprisingly, the STICH study40 failed to find a correlation between demonstrations of myocardial viability and benefit from revascularisation.

occurrence.75 Moreover, studies consistently show that the H/R can reflect response to HF therapies, such as β-blockers76 or LVADs,77 as increases in H/R correlate with other clinical or analytical parameters.

Regional uptake assessment on SPECT adds relevant clinical information.

Areas with autonomic tracer defect, but preserved perfusion tracer uptake (autonomic-perfusion mismatch), are more prone to develop lethal arrhythmias due to denervation supersensitivity.78 The extent or severity of autonomic defects predicted VT inducibility79 and occurrence of an ICD discharge or SCD.80

Sympathetic Activity Hyperactivity of the autonomic nervous system (ANS) plays a major role in the pathophysiology of HF, causing myocardial β-adrenoceptor down-regulation. Viable myocardium with reduced innervation may be hyperresponsive to catecholamines, leading to the development of ventricular tachycardia (VT). There are SPECT/PET tracers that are analogues of the sympathetic neurotransmitters.69 As they are uptaken and stored in the presynaptic nerve endings, the visualisation of sympathetic innervation is warranted. SPECT imaging with iodine123-metaiodobenzylguanidine (123I-MIBG) is the most often used.

123I-MIBG studies comprise both planar and SPECT imaging in two phases: early (10–20 minutes after tracer administration) and late (3–4 hours after). Image analysis includes the heart mediastinal ratio (H/M) for the quantification of global uptake, the washout rate (WR) to reflect catecholamine turnover and sympathetic activity and regional uptake on SPECT imaging. In HF patients, cardiac innervation is reduced, thus 123I-MIBG uptake is globally reduced.

H/M has emerged as one of the most powerful independent predictors of adverse cardiovascular events. 70,71 The AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) trial,72 a prospective multicentre study involving 961 patients, showed that a H/M <1.6 doubled the risk of HF progression, VT or cardiac death. More recently, a Japanese meta-analysis including 1,322 patients73 proved that patients with H/M <1.68 or WR >43 % showed lower survival over a mean follow-up of 6.5 years. Other studies have evaluated 123I-MIBG imaging for the prediction of VT and SCD. In one of them, H/M resulted as an independent predictor for appropriate ICD therapy;74 while in the other one WR correlated with higher SCD

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PET tracers such as 11C-hydroxyephedrine (11-CHED) improve the signal–noise ratio allowing better quantification.81 The recent Prediction of Arrhythmic Events with Positron Emission Tomography (PAREPET) study82 has proved that the extent of uptake defects correlated with the occurrence of SCD or ICD discharge.

Despite the increasing evidence, currently the assessment of cardiac innervation is not recommended as a routine test in the evaluation of HF patients. More studies are needed to define the subgroup of patients that could benefit most of this imaging technique.

Molecular Imaging Molecular imaging techniques are emerging tools providing insight into disease manifestation before structural and physiological abnormalities become evident, although to date it has mainly been used for research purposes. A key factor in HF patients is myocardial remodelling. A multitude of cellular pathways implied in remodelling processes can be targeted: extracellular matrix degradation, angiogenesis, collagen deposition, etc.83,84 Most tracers are still under development and have been only tested in animal models. Imaging myocardial activity of renin–angiotensin system seems to be a promising tool to monitor disease progression and medical therapy effectiveness in HF patients.85

Computed Tomography Latest generation of multidetector CT (MDCT) allows obtaining high-quality images using a smaller amount of iodinated contrast.86 In patients with HF, the increasing use of ICD-CRT devices, limits the

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Clinical Evaluation possibilities of performing a CMR. In this group of patients, MDCT emerges as a valid alternative to assess LV volumes and function.

In cardiac transplantation, CT may obviate the need for routine invasive angiography to assess coronary allograft vasculopathy.107,108

Coronary Artery Disease

Limitations and Contraindications of Computed Tomography

Evaluation of coronary calcium is a reliable test to discriminate ICM from NICM.87 Coronary MDCT in patients with HF has a high negative predictive value to confirm in a non-invasive way the absence of CAD,88–94 especially in new-onset HF patients. Taking into account the significance of CAD in HF patients, MDCT may be one of the most important non-invasive tests to perform in these patients. However, coronary MDCT provides anatomic but not physiological data on coronary disease, so no information about perfusion abnormalities can be extracted from it.

Due to the different attenuation characteristics of infarcted versus normal myocardium, measuring the infarct size is possible with MDCT. Those measurements have accurately correlated with those obtained on nuclear scanning and CMR.95–98

Cardiac Structure and Function Several studies have shown excellent correlation between cardiac MDCT and other imaging modalities regarding diverse LV measurements: LVEF and global function, regional wall motion, wall thickness, chamber diameter, chamber volumes, stroke volume and cardiac output,99–103 and provides adequate visualisation of RV wall thickness and function.104,105 It can also obtain useful images to differentiate between some anatomic aetiologies of HF (for example, dilated versus hypertrophic cardiomyopathy). However, CMR is considered the gold standard for ventricular assessment and echocardiography is the most commonly used clinical test for this purpose.

Other Uses MDCT can provide an accurate anatomic description of the pericardium (pericardial thickening, calcification, fatty infiltration and effusion), information of the anatomy of cardiac valves and assessment of ventricular contraction dyssynchrony, especially in those being assessed for CRT implantation.106

1.

2.

3.

4.

5.

6.

7.

8.

Kirkpatrick JN, Vannan MA, Narula J, et al. Echocardiography in heart failure: applications, utility, and new horizons. J Am Coll Cardiol 2007;50 :381–96. PMID: 17662389 Foster E, Cahalan MK. The search for intelligent quantitation in echocardiography: “eyeball,” “trackball” and beyond. J Am Coll Cardiol 1993;22 :848–50. PMID: 8354822 Lang R, Badano L, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16 :233–71. doi: 10.1093/ehjci/jev014 PMID: 25712077 Morbach C, Lin B, Sugeng L., et al. Clinical application of three-dimensional echocardiography. Prog Cardiovasc Dis 2014;57 :19–31. doi: 10.1016/j.pcad.2014.05.005 PMID: 25081399 Dorosz JL, Lezotte DC, Weitzenkamp DA, et al. Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis. J Am Coll Cardiol 2012;59 :1799–808. doi: 10.1016/j.jacc.2012.01.037 PMID: 22575319 Muraru D, Badano LP, Peluso D, et al. Comprehensive analysis of LV geometry and function by three-dimensional echocardiography in healthy adults. J Am Soc Echocardiogr 2013;26 :618–28. doi: 10.1016/j.echo.2013.03.014 PMID: 23611056 Dalen H, Thorstensen A, Aase SA, et al. Segmental and global longitudinal strain and strain rate based on echocardiography of 1266 healthy individuals: the HUNT study in Norway. Eur J Echocardiogr 2010;11 :176–83. doi: 10.1093/ejechocard/jep194 PMID: 19946115 Kocabay G, Muraru D, Peluso D, et al. Normal left ventricular mechanics by two-dimensional speckle tracking echocardiography. Rev Esp Cardiol 2014;67 :651–8. doi: 10.1016/j.rec.2013.12.009 PMID: 25037544

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9.

10.

11.

12.

13.

14.

15.

16.

The two major risks with the procedure include contrast administration and radiation exposure. Cardiac CT cannot be performed in patients with contraindications to injection of iodinated contrast. Other relative contraindications include moderate to severe renal insufficiency and previous allergies to contrast. As for radiation, the effective radiation dose with 64-slice MDCT angiography is estimated to be approximately 11 to 22 mSv.

Hybrid Devices Computed Tomography Nuclear Image Dual-image techniques offer the opportunity to use a single device for different purposes, such as determining perfusion, function and metabolism: adenosine stress CT myocardial perfusion imaging could detect haemodynamic significance of coronary stenosis detected by CT angiography.109,110 Diverse combinations of hybrid imaging of myocardial perfusion (CT + SPECT, CT + PET and CT + CMR) are gaining increasing interest because they provide both anatomic and functional information, improving the overall performance of the diagnostic test.

Conclusion There are several imaging modalities available for the evaluation of HF patients, each one with its highlights and pitfalls. Echocardiography continues to be the method of choice for its availability, cost and usefulness, it provides most of the information required for the management and follow up of HF patients and it has been enhanced with the development of 3DE and strain. Other non-invasive cardiac imaging modalities could provide additional aetiological, prognostic and therapeutic information, being helpful in making treatment decisions, especially in some subsets of patients (ischaemic heart disease, cardiomyopathies …) (see Table 1). An appropriate utilisation of imaging procedures should improve management and clinical outcomes in HF patients. n

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69. Langer O, Halldin C. PET and SPET tracers for mapping the cardiac nervous system. Eur J Nucl Med Mol Imaging 2002;29 :416–34. PMID: 12002720 70. Agostini D, Verberne HJ, Burchert W, et al. I-123-mIBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: Insights from a retrospective European multicenter study. Eur J Nucl Med Mol Imaging 2008;35 :535–46. PMID: 18043919 71. Manrique A, Bernard M, Hitzel A, et al. Prognostic value of sympathetic innervation and cardiac asynchrony in dilated cardiomyopathy. Eur J Nucl Med Mol Imaging 2008;35 :2074–81. doi: 10.1007/s00259-008-0889-8 PMID: 18682936 72. Jacobson AF, Senior R, Cerqueira MD, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol 2010;55 :2212–21. doi: 10.1016/j. jacc.2010.01.014 PMID: 20188504 73. Nakata T, Nakajima K, Yamashina S, et al. A pooled analysis of multicenter cohort studies of I-123-mIBG cardiac sympathetic innerva- tion imaging for assessment of longterm prognosis in chronic heart failure. J Am Coll Cardiol Imaging 2013;6 :772–84. doi: 10.1016/j.jcmg.2013.02.007 PMID: 23845574 74. Nagahara D, Nakata T, Hashimoto A, et al. Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function.

J Nucl Med 2008;49 :225–33. doi: 10.2967/jnumed.107.042564 PMID: 18199625 75. Kioka H, Yamada T,Mine T, et al. Prediction of sudden death in patients with mild-to-moderate chronic heart failure by using cardiac iodine-123 metaiodobenzylguanidine imaging. Heart 2007;93 :1213–8. PMID: 17344327 76. Treglia G, Stefanelli I, Giordano BA. Clinical usefulness of myocardial innervation imaging using Iodine-123meta-iodobenzylguanidine scintigraphy in evaluating the effectiveness of pharmacological treatments in patients with heart failure: An overview. Eur Rev Med Pharmacol Sci 2013;17 :56–8.

77. George RS, Birks EJ, Cheetham A, et al. The effect of longterm left ventricular assist device support on myocardial sympathetic activity in patients with non-ischaemic dilated cardiomyopathy. Eur J Heart Fail 2013;15 :1035–43. doi: 10.1093/ eurjhf/hft059 PMID: 23610136 78. Simões MV, Barthel P, Matsunari I, et al. Presence of sympathetically denervated but viable myocardium and its electrophysiologic correlates after early revascularised, acute myocardial infarction. Eur Heart J 2004;25 :551–7. PMID: 15120051 79. Bax JJ, Kraft O, Buxton AE, et al. 123I-mIBG Scintigraphy to predict inducibility of ventricular arrhythmias on cardiac electrophysiology testing: A prospective multicenter pilot study. Circ Cardiovasc Imaging 2008;1 :131–40. doi: 10.1161/ CIRCIMAGING.108.782433 PMID: 19808530 80. Boogers MJ, Borleffs CJ, Henneman MM, et al. Cardiac sympathetic denervation assessed with 123-Iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol 2010;55 :2769–77. doi: 10.1016/j. jacc.2009.12.066 PMID: 20538172 81. Luisi AJ Jr, Suzuki G, Dekemp R, et al. Regional 11C-Hydroxyephedrine retention in hibernating myocardium: Chronic inhomogeneity of sympathetic innervation in the absence of infarction. J Nucl Med 2005;46 :1368–74. PMID: 16085596 82. Fallavollita JA, Canty JM. Dysinnervated but viable myocardium in ischemic heartdisease, J Nucl Cardiol 2010;17 :1107–15. doi: 10.1007/s12350-010-9292-5 PMID: 20857351 PMCID: PMC3026632 83. Chen IY, Wu JC. Cardiovascular molecular imaging: focus on clinical translation. Circulation 2011;123 :425–43. doi: 10.1161/ CIRCULATIONAHA.109.916338 PMID: 21282520 [PubMed indexed for MEDLINE] PMCID: PMC3073678 84. Kramer CM, Sinusas AJ, Sosnovik DE, et al. Multimodality imaging of myocardial injury and remodeling. J Nucl Med 2010;51 :107S–121S. doi: 10.2967/jnumed.109.068221 PMID: 20395347 [PubMed - indexed for MEDLINE] PMCID: PMC3078824 85. Fukushima K, Bravo PE, Higuchi T, et al. Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors. J Am Coll Cardiol 2012;60 :2527–34. doi: 10.1016/j.jacc.2012.09.023 PMID: 23158533 [PubMed - indexed for MEDLINE] PMCID: PMC3522758 86. Butler J. The emerging role of multi-detector computed tomography in heart failure. J Card Fail 2007;13 :215–26. PMID: 17448420 87. Shemesh J, Tenenbaum A, Fisman EZ, et al. Coronary calcium as a reliable tool for differentiating ischemic from nonischemic cardiomyopathy. Am J Cardiol 1996;77 :191–4.

PMID: 8546091 88. Andreini D, Pontone G, Pepi M, et al. Diagnostic accuracy of multidetector computed tomography coronary angiography in patients with dilated cardiomyopathy. J Am Coll Cardiol 2007;49 :2044–50. PMID: 17512361 89. Cornily JC, Gilard M, Le Gal G, et al. Accuracy of 16-detector multislice spiral computed tomography in the initial evaluation of dilated cardiomyopathy. Eur J Radiol 2007;61 :84–

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91. D’Ascenzo F, Cerrato E, Biondi–Zoccai G, et al. Coronary computed tomographic angiography for detection of coronary artery disease in patients presenting to the emergency department with chest pain: a meta-analysis of randomized clinical trials. Eur Heart J Cardiovasc Imaging 2013;14 :782–9. doi: 10.1093/ehjci/jes287 PMID: 23221314 92. Hulten E, Pickett C, Bittencourt MS, et al. Meta-analysis of coronary CT angiography in the emergency department.

Eur Heart J Cardiovasc Imaging 2013;14 :607. doi: 10.1093/ehjci/ jet027 PMID: 23460725 93. Gebhard C, Fiechter M, Fuchs TA, et al. Coronary artery stents: influence of adaptive statistical iterative reconstruction on image quality using 64-HDCT. Eur Heart J Cardiovasc Imaging 2013;14 :969–77. doi: 10.1093/ehjci/jet013 PMID: 23428650 PMID: 23360870 94. Rubinshtein R, Gaspar T, Lewis BS, et al. Long-term prognosis and outcome in patients with a chest pain syndrome and myocardial bridging: a 64-slice coronary computed tomography angiography study. Eur Heart J Cardiovasc Imaging 2013;14 :579–85. doi: 10.1093/ehjci/jet010 95. Baks T, Cademartiri F, Moelker AD, et al. Multislice computed tomography and magnetic resonance imaging for the assessment of reperfused acute myocardial infarction. J Am Coll Cardiol 2006;48:144e52. PMID: 16814660 96. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial

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dysfunction. N Engl J Med 2000;343 :1445e53. PMID: 11078769 97. Mendoza DD, Joshi SB, Weissman G, et al. Viability imaging by cardiac computed tomography. J Cardiovasc Comput Tomogr 2010;4 :83–91. doi: 10.1016/j.jcct.2010.01.019 PMID: 20430338 98. Le Polain de Waroux JB, Pouleur AC, Goffinet C, et al.

Combined coronary and late-enhanced multidetectorcomputed tomography for delineation of the etiology of left ventricular dysfunction: comparison with coronary angiography and contrast-enhanced cardiac magnetic resonance imaging. Eur Heart J 2008;29 :2544–51. doi: 10.1093/ eurheartj/ehn381 PMID: 18762553 99. Juergens KU, Grude M, Maintz D, et al. Multi-detector row CT of left ventricular function with dedicated analysis software versus MR imaging: initial experience. Radiology 2004;230 :403e10. PMID: 14668428 100. Mahnken AH, Koos R, Katoh M, et al. Sixteen-slice spiral CT versus MR imaging for the assessment of left ventricular function in acute myocardial infarction. EurRadiol 2005;15 :714e20. PMID: 14668428 101. Dewey M, Muller M, Teige F, Hamm B. Evaluation of a semiautomatic software tool for left ventricular function analysis with 16-slice computed tomography. EurRadiol 2006;16 :25e31. PMID: 15965660 102. Heuschmid M, Rothfuss JK, Schroeder S, et al. Assessment of left ventricular function using 16-slice multidetectorrow computed tomography: comparison with MRI and echocardiography. EurRadiol 2006;16 :551e9. PMID: 16215736 103. Butler J, Shapiro MD, Jassal DS, et al. Comparison of multidetector computed tomography and two-dimensional transthoracic echocardiography for left ventricular assessment in patients with heart failure. Am J Cardiol 2007;99 :247–9.

104. Dogan H, Kroft LJ, Bax JJ, et al. MDCT assessment of right ventricular systolic function. Am J Roentgenol 2006;186 :S366e70. PMID: 16714610 105. Kim TH, Ryu YH, Hur J, et al. Evaluation of right ventricular volume and mass using retrospective ECG-gated cardiac MDCT: comparison with first-pass radionuclide angiography.

EurRadiol 2005;5 :1987e93. PMID: 15776241 106. Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39 :194e201. PMID: 11788207 107. Taylor DO, Edwards LB, Boucek MM, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant reportd2004. J Heart Lung Transplant 2004;23 :796e803.

PMID: 15285065 108. Sigurdsson G, Carrascosa P, Yamani MH, et al. Detection of transplant coronary artery disease using multidetector computed tomography with adaptative multisegment reconstruction. J Am Coll Cardiol 2006;48 :772–8. PMID: 16904548 109. Rossi A, Uitterdijk A, Dijkshoorn M, et al. Quantification of myocardial blood flow by adenosine-stress CT perfusion imaging in pigs during various degrees of stenosis correlates well with coronary artery blood flow and fractional flow reserve. Eur Heart J Cardiovasc Imaging 2013;14 :331–8. doi: 10.1093/ehjci/jes150 PMID: 22843541 110. Schaap J, Kauling RM, Boekholdt SM, et al. Incremental diagnostic accuracy of hybrid SPECT/CT coronary angiography in a population with an intermediate to high pre-test likelihood of coronary artery disease. Eur Heart J Cardiovasc Imaging 2013;14 :642–9. doi: 10.1093/ehjci/jes303 PMID: 23291392

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Pharmacological Therapy

LE ATION.

e. lare.

Beta-blockers or Digoxin for Atrial Fibrillation and Heart Failure?

La urent Fa uc hier, Guillau m e L a b o r i e, N i c o l a s Cl e m e n t y a n d D o m i n i q u e B a b u t y Department of Cardiology, Trousseau University Hospital and Faculty of Medicine, University François Rabelais, Tours, France

Abstract In patients with atrial fibrillation (AF) and heart failure (HF) with or without systolic dysfunction, either rhythm control or rate control is an acceptable primary therapeutic option. If a rate control strategy is chosen, treatment with a beta-blocker is almost always required to achieve rate control. Adequate ventricular rate control is usually a resting rate of less than 100 beats per minute, but lower resting rates may be appropriate. Non-dihydropyridine calcium channel blockers are often contraindicated when AF is associated with HF with systolic dysfunction. There have been recent debates on a possible reduced efficacy of beta-blockers as well as safety issues with digoxin when treating HF patients with AF. The benefit of beta-blockers on survival may be lower in patients with HF with reduced ejection fraction when AF is present. Digoxin does not improve survival but may help to obtain satisfactory rate control in combination with a beta-blocker.

Digoxin may be useful in the presence of hypotension or an absolute contraindication to beta-blocker treatment.

Keywords Atrial fibrillation, beta-blocker, digoxin, heart failure Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: Sophie Rushton-Smith (Medlink Healthcare Communications Ltd) provided editorial assistance with editing the final version and was funded by the authors.

Received: 5 December 2015 Accepted: 21 January 2016 Citation: Cardiac Failure Review, 2016;2(1):35–9 DOI: 10.15420/cfr.2015:28:2 Correspondence: Laurent Fauchier, Service de Cardiologie et Laboratoire d’Electrophysiologie Cardiaque, Centre Hospitalier Universitaire Trousseau, 37044 Tours, France. E: lfau@med.univ-tours.fr

Atrial fibrillation (AF) and heart failure (HF) with or without systolic dysfunction are common cardiac conditions that frequently coexist and share multiple risk factors. HF is a risk factor for AF and AF is a risk factor for HF. Recent studies have focused on the prognostic nature of AF and HF with systolic dysfunction and the questionable use of digoxin and beta-blocker therapy when these conditions coexist. The predominant questions today are whether catheter ablation and rhythm control offer benefit in high-risk patients with AF and HF with or without systolic dysfunction with respect to a reduction in risk of mortality or other ‘hard endpoints’, and whether more conservative management with drugs for rate control is still an acceptable strategy for many patients. Large randomised multicentre studies are currently ongoing to address these important questions.1,2 Only beta-blockers have been shown to improve the prognosis of patients with HF and left ventricular systolic dysfunction, a substantial minority of whom had AF as their baseline rhythm.3–5 Whether digoxin significantly affects prognosis and mortality in AF associated with HF is poorly known.6 Furthermore, digoxin does not improve survival of patients with HF who are in sinus rhythm,7 and long-term therapy with digoxin has been suggested to be a risk factor for death in patients with AF without HF.8 Among patients with both AF and HF with systolic dysfunction, only a few trials have specifically investigated the use of adding a beta-blocker to digoxin or the opposite.9,10 In these studies, no comparison was made between beta-blockers alone versus digoxin alone, or the combination. This article reviews the effects of betablockers, digoxin and their combination in patients with AF and HF.

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Rate Control in Atrial Fibrillation With Heart Failure Rate control is a major part of therapy for all patients with AF. Betablockers, non-dihydropyridine calcium channel blockers (diltiazem, verapamil) and digitalis are the primary drugs used for ventricular rate control during AF.11–13 Calcium channel blockers should be avoided in patients with HF. In these patients, regardless of systolic dysfunction, both digoxin and beta-blockers reduce the ventricular rate and both may improve symptoms.

The primary goals of rate control are to improve symptoms and prevent deterioration of cardiac function associated with excessively rapid ventricular rates during AF. In addition, the aims of therapy for rate control are to improve exercise tolerance and quality of life (QoL) and to prevent hospitalisation. In the past, adequate heart rate control had been empirically defined as <80 beats per minute (bpm) at rest.

However, the Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II (RACE II) study showed that, compared with strict rate control, lenient rate control was not inferior in terms of preventing major clinical events.14,15 In patients with HF and reduced ejection fraction (EF) from the Swedish Heart Failure Registry, a higher heart rate (HR) was associated with increased mortality in sinus rhythm (SR), but in AF, this was true only for HR >100 bpm.16 The evidence to support the benefit of HR reduction in improving quality of life and symptoms also remains limited. A study by Jaber et al. analysed the influence of HR (measured by the 6-minute walk test [6MWT] and 24-hour Holter monitoring) on QoL in 89 patients with chronic AF.17 Jaber et al. found a significant

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Pharmacological Therapy difference in QoL as measured by physical and mental summary scores in patients with maximal HR ≤110 bpm compared with HR >110 bpm (6MWT), and in the physical summary score in patients with average HR ≤ 80 bpm compared with HR >80 bpm (Holter monitor).17 Today, it is recommended that treatment for rate control of persistent or permanent AF should aim for a resting HR of <100 bpm.12,18 In all cases, the HR target may need modification based on the patient’s symptoms and preferences.

Beta-blockers Beta-blockers are currently a cornerstone in the treatment of patients with HF and reduced EF. The results of pivotal trials have shown a reduction of about one-third in the relative risk of all-cause death with the use of these drugs.3,4,19 Based on the highest level of evidence, beta-blockers are strongly recommended in clinical European and US guidelines for the management of HF and reduced EF.20,21 These guidelines state that beta-blockers are indicated in all patients, except those with atrioventricular block, bradycardia and asthma, and recommend use of beta-blockers in patients with HF regardless of baseline rhythm.

In AF, beta-blockers are preferred as a rate-control agent in patients after myocardial infarction and in patients with congestive heart failure.12,22 They may be avoided in patients with chronic pulmonary disease and at risk of bronchoconstriction.23,24 Of note, carvedilol is a less-potent beta-adrenergic blocking agent compared with metoprolol and is less effective than metoprolol for rate control of AF.25 Recent findings have suggested that the effect of beta-blockers on outcome in HF patients with reduced systolic left ventricular ejection fraction (LVEF) who have AF is less than in those who have SR.26 However, an individual-patient data meta-analysis has shown that beta-blockers reduce mortality risk in patients with HF and reduced LVEF who are in SR but not in those who are in AF.27 Similar results applied also to cardiovascular death or first hospitalisation for HF.27 More specifically, treatment effect, judged by reduction in all-cause mortality, seemed to be less in 3066 patients with AF (hazard ratio 0.97, 95 % CI [0.83–1.14]) than in the 13,946 patients not in AF (hazard ratio 0.73, 95 % CI [0.67–0.80]). The results of this analysis suggest that beta-blockers are unlikely to be harmful for AF patients with HF and reduced EF, but the prognostic benefits of beta-blockers have consequently been questioned for patients with HF and AF. A significant concern is that we have no clear explanation for these recent findings. Clinical experience makes them surprising and counterintuitive although it is possible that our impressions are wrong in evaluating absolute and relative competing risks for the many events in these patients. A rapid ventricular rate in patients with AF is commonly suspected in worsening HF with or without systolic dysfunction (even precipitating hospital admission), whereas control of the ventricular rate in patients with AF seems to improve HF. Betablockers are still an effective means of controlling the ventricular rate in patients with AF. In a recent nationwide AF cohort in Taiwan, the adjusted risk of mortality was lower for patients receiving rate-control treatment with beta-blockers.28 In patients with reduced EF from the Swedish Heart Failure Registry, beta-blocker use was associated with reduced mortality both in SR and in AF.16 It is thus unclear why betablockers would not prevent worsening HF and cardiovascular events in patients with AF. Examination of treatment effect in subgroups is commonly considered with caution, because different baseline characteristics and small numbers of events in subgroups might lead to unreliable conclusions. Additional issues should be addressed,

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such as the possibility of a drug interaction between digoxin and beta-blocker treatment, unmeasured confounding such as a conduction system disease, expected benefit in patients with previous myocardial infarction, more common use of cardiac resynchronisation therapy and defibrillators nowadays and whether patients with milder symptoms might respond differently to those with more advanced disease. Because most AF patients with HF have a high risk of cardiovascular events, the g eneral view of many clinicians is that the clinical benefit of beta-blockers remains likely, and practice should not change until these questions undergo further evaluation.29

Digoxin Digoxin and other related cardiac glycosides have been used for more than 200 years for the treatment of HF, and for almost 100 years for heart rate regulation in AF.30 Since the Digitalis Investigation Group (DIG) study,7 which demonstrated that whilst digoxin reduced HF hospitalisation there was no significant overall effect on mortality, the place of digoxin in treating HF with systolic dysfunction has steadily declined.31–34 There remain significant knowledge gaps about how digitalis works and how it should be used in the modern treatment of AF. Studies on digoxin use in patients with AF and the risk of all-cause and cardiovascular mortality have reported rather conflicting results.

Whilst digoxin aids HR control in AF, this drug may suffer from a narrow therapeutic index and a potential to contribute to life-threatening ventricular tachyarrhythmias and severe bradyarrhythmias.35 Digoxin and cardiac glycosides function by inhibiting the membranebound Na+/K+ ATPase, thereby impeding the transport of sodium from the intracellular to the extracellular space. The resulting loss of the transmembrane sodium gradient decreases the activity of Na+/Ca2+ homeostasis and the increasing intracellular Ca2+ concentrations that are thought to lead to the positive inotropic effect of digitalis.36 In non-cardiac tissue, digoxin acts as a neurohormonal modulator by increasing parasympathetic tone and decreasing activation of the sympathetic nervous system and renin–angiotensin–aldosterone system. Furthermore, in addition to its direct sympatholytic effects at low doses, digoxin indirectly decreases sympathetic outflow by improving carotid sinus baroreceptor sensitivity. Finally, digoxin slows firing at the sinoatrial node and prolongs conduction at the atrioventricular node but has limited electrophysiological effects on the remainder of the conduction system.37 Clinically, digoxin may help to control HR in patients with AF without a deleterious decrease in blood pressure. However, digoxin may be less effective, or inadequate, for controlling the ventricular rate during exercise or when sympathetic tone is increased.38,39 Based on US guidelines,40 digoxin as a rate control drug is no longer a class 1 indication and is a first-line recommended treatment for management of HR in AF in patients with HF, hypotension or, possibly, in patients who are predominantly sedentary (obviating the need for rate control during activity). As a consequence, digoxin is commonly used by elderly people with a higher risk profile, who are thus expected to have a less favourable prognosis. The Stockholm Cohort of Atrial Fibrillation (SCAF) study showed that digoxin is mainly given to an elderly and frailer subset of patients with AF.41 When these and other differences in patient characteristics were accounted for, digoxin use appeared to be neutral for long-term mortality in patients with AF. Some recent observational or post-hoc analyses found an increased mortality among digoxin-treated patients. The Registry of Information

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Beta-blockers, digoxin and atrial fibrillation

and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA) examined 1-year outcomes in patients on digoxin with AF, congestive HF with reduced or preserved EF, or both, by comparing them with a matched group of patients who were not receiving digoxin.8 Overall mortality was significantly higher in the 4426 digoxin-treated patients with AF and no history of HF compared with 16 587 controls at discharge (hazard ratio 1.42, 95 % CI [1.28–1.56]). No such difference was seen in patients with HF. Although this study included a large number of patients, it was performed in an intensive care setting, which makes it difficult to translate the results into other clinical settings.

A substudy from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial reported that in patients with AF, digoxin was associated with increased all-cause mortality after controlling for comorbidities and propensity scores, regardless of the presence or absence of underlying HF.42 In this study, digoxin was used as a time-dependent covariate in a Cox proportional hazard model. Patients changed from being in the ‘on-digoxin’ group to the ‘not on-digoxin’ group if their medication use changed during the study, and their associated time at risk for death contributed to each respective group. However, another study from AFFIRM, by Gheorghiade et al., which employed a propensity-matched analysis, did not reveal a difference in all-cause mortality. 43 Digoxin use was there assessed at a fixed time point only, at the time of randomisation. Another post-hoc analysis from the AFFIRM study44 even suggested that digoxin may play a beneficial role in patients with AF and significant left ventricular dysfunction as part of a rate control strategy, adding questions to the general confusion with recent very conflicting reports.34, 46–48 A plausible explanation of digoxin-associated higher mortality in the post-hoc analysis from the AFFIRM study by Whitbeck et al. is the use of digoxin as a time-dependent treatment variable. The effect of a time-dependent treatment on survival may only be valid in situations where the changes in treatment over time are random and are not related to health deteriorations.49,50 Another major limitation in the article by Whitbeck et al. is that age was not used as a covariate to generate the propensity score. Digoxin is mainly given to elderly people, with older age obviously being associated with an increased mortality. Medication interaction may also play a role in these patients. In the Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) trial, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death.52 In 1269 consecutive patients with both AF (permanent or nonpermanent) and HF (preserved or reduced LVEF), we found, after thorough adjustment on baseline characteristics, that treatment with beta-blocker alone or with beta-blocker plus digoxin was associated with a similar decrease in the risk of death. Digoxin alone was associated with a similar (and not worse) survival to that of patients without any rate control treatment.52 More generally, it was found in a recent meta-analysis of observational and controlled trial data that digoxin was associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types.53 Digoxin has minimal pro-arrhythmic effects when dosed to achieve the therapeutic serum drug concentration (SDC). By contrast, at a supratherapeutic SDC or therapeutic SDC with concomitant hypokalaemia, atrioventricular block and escape rhythms are electrocardiographic manifestations of toxicity. Overall, the relationship between digoxin effect and/or toxicity and drug concentrations is

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poorly defined, and measuring concentrations to assess drug effect (as opposed to true toxicity) has unclear benefit. However, the results from a post-hoc study conducted by Rathore et al. suggest that the effectiveness of digoxin in the DIG trial varied according to patients’ serum drug concentrations.35 An SDC of 0.5–0.8 ng/ml would likely constitute the optimal therapeutic range for digoxin, and another study from AFFIRM found that 2 ng/ml or higher may be harmful. Moreover, although digoxin improves the overall neurohormonal profile in severe HF at low doses, it has been suggested that further dose increases within the therapeutic range have no added neurohormonal benefit and may in fact have a sympathetic action.54 These findings may suggest that the serum concentration of digoxin could be a determinant of clinical events.55–57 In the AFFIRM trial, an SDC ≥1.0 ng/ ml was encouraged and higher doses of digoxin were used to meet the stringent rate control requirement (resting HR of <80 bpm and exercise heart rate <110 bpm), which might not be the case in everyday clinical practice.

Perspectives for Future Investigation To date, there is no clear information on the benefit of beta-blocker and/or digoxin treatment in subgroups of patients with HF and AF (whether permanent or non-permanent), with HF and decreased or preserved systolic HF, or with the ischaemic or non-ischaemic aetiology associated with the disease. Most current knowledge about digoxin use in AF comes from observational cohorts and not from randomised trials.7 By contrast, only limited observational data are available from everyday clinical practice regarding the events and possible benefits associated with beta-blocker use in patients with AF and HF.52 From an ethical perspective, it might be difficult today to carry out a large randomised trial with digoxin for rate control, as there are other adequate treatments. Several studies have performed propensity score analysis in order to increase the comparability of patient characteristics between digoxin-treated and untreated patients.

Even with sophisticated statistical techniques, it may be challenging to fully adjust for disease severity and the indication for treatment as assessed by the provider. Thus, the association between digoxin and/ or beta-blocker use and mortality may still be wrongly estimated. This is due to unknown or unmeasured potential residual confounders, particularly those related to severity of HF, symptoms, haemodynamic status and general side-effects, all of which should be better characterised in future adjusted observational studies. Reporting non-randomised, ‘real-world’ registry data from large cohorts of consecutive patients recruited with AF may be relevant in that these data are complementary to the data possibly reported in randomised clinical trials, which are unlikely to be reinitiated. Observational studies may be of value because they shed light on the use of competing treatment options in current practice and because they include patients at high risk who are frequently not represented in clinical trials.

Another limitation in many studies is that information about patients’ exposure to digoxin and beta-blockers is most often fragmentary.

Medication changes during follow-up are not recorded in many observational studies. Similarly, the compliance with digoxin or betablocker therapy, and whether it relates to clinical events, should be better characterised in future analyses. Finally, HR is difficult to fully describe in any analysis with AF patients and presents a field of investigation. This may help to establish whether the best target for an optimal rate control strategy is HR during AF episodes,

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Pharmacological Therapy or alternatively HR in SR for patients with non-permanent AF, whether it is mean HR or maximum HR, or possibly HR above a given limit for a given duration, both of which need to be determined.

Some ongoing randomised clinical trials may help to answer these questions in AF patients with HF, such as the Randomized Ablationbased Atrial Fibrillation Rhythm Control Versus Rate Control Trial in Patients With Heart Failure and High Burden Atrial Fibrillation (RAFT-AF) trial, which will test the hypothesis that restoration of SR is superior to rate control in patients with AF and HF with either impaired or preserved LV function. More generally with respect to perspective for future investigations, the serious limitations of observational cohort studies in improving or understanding the benefit versus the risk of digoxin or beta-blockers in AF patients with HF advocate for smaller, but blinded and randomised studies to assess their potential benefits on wellbeing, exercise tolerance and QoL, which are the primary reason to administer drugs in this setting.

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Am Heart J 2012;164 :292–302. doi: 10.1016/j.ahj.2012.05.017; PMID: 22980294.

Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334 :1349–55. PMID: 8614419.

CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.

Lancet Lond Engl 1999;353 :9–13. PMID: 10023943.

Joglar JA, Acusta AP, Shusterman NH, et al. Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program.

Am Heart J 2001;142 :498–501. PMID: 11526364.

Neuberger H-R, Mewis C, van Veldhuisen DJ, et al.

Management of atrial fibrillation in patients with heart failure.

Eur Heart J 2007;28 :2568–77. PMID: 17855740.

Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure.

N Engl J Med 1997;336 :525–33. PMID: 9036306.

Hallberg P, Lindbäck J, Lindahl B, et al. Digoxin and mortality in atrial fibrillation: a prospective cohort study. Eur J Clin Pharmacol 2007;63 :959–71. PMID: 17684738.

Cristodorescu R, Roşu D, Deutsch G, et al. The heart rate slowing effect of pindolol in patients with digitalis resistant atrial fibrillation and heart failure. Médecine Interne 1986;24 :207–15. PMID: 3775215.

Khand AU, Rankin AC, Martin W, et al. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol 2003;42 :1944–51. PMID: 14662257.

Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31 :2369–429. doi: 10.1093/ eurheartj/ehq278; PMID: 20802247.

Gillis AM, Verma A, Talajic M, et al. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: rate and rhythm management. Can J Cardiol 2011;27 :47–59. doi: 10.1016/j. cjca.2010.11.001; PMID: 21329862.

January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–76. PMID: 24685669 Van Gelder IC, Groenveld HF, Crijns HJGM, et al. Lenient versus strict rate control in patients with atrial fibrillation.

N Engl J Med 2010;362 :1363–73. doi: 10.1056/NEJMoa1001337; PMID: 20231232.

Groenveld HF, Tijssen JGP, Crijns HJGM, et al. Rate control efficacy in permanent atrial fibrillation: successful and failed strict rate control against a background of lenient rate control: data from RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation). J Am Coll Cardiol 2013;61 :741–8. doi: 10.1016/j.jacc.2012.11.038; PMID: 23410544.

Li S-J, Sartipy U, Lund LH, et al. Prognostic significance of resting heart rate and use of β-blockers in atrial fibrillation and sinus rhythm in patients with heart failure and reduced ejection fraction: findings from the Swedish Heart Failure Registry. Circ Heart Fail 2015;8 :871–9. doi: 10.1161/ CIRCHEARTFAILURE.115.002285; PMID: 26243796.

Jaber J, Cirenza C, Jaber J, et al. Influence of heart rate on quality of life in patients with chronic atrial fibrillation.

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Conclusion Based on values and preferences, rate control therapy most often includes a beta-blocker, but should be individualised on the basis of the type and severity of underlying structural heart disease, the activity level of the patient and other individual considerations.

Digoxin is mainly given to elderly AF patients with HF and impaired LV function. Consequently, its use is associated with increased crude rates of mortality in observational analysis.58 Once differences in patient characteristics have been accounted for, it is unclear whether digoxin has a clear independent association with increased mortality. Although these results are from moderate-quality evidence only, one may suggest that digoxin should not be used as the initial therapy for active patients. Rather, it should be reserved for rate control in AF patients who are sedentary or who have left ventricular systolic dysfunction, particularly when beta-blockers do not achieve sufficient rate control and when they are poorly tolerated or contraindicated. n

Clin Cardiol 2010;33 :E28–32. doi: 10.1002/clc.20528; PMID: 20162738.

18. Camm AJ, Lip GY, De Caterina R, et al. ESC Committee for Practice Guidelines-CPG; 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14:1385– 413. Epub 2012 Aug 24. PMID: 22923145.

19. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet Lond Engl 1999;353 :2001–7. PMID: 10376614.

20. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33 :1787–847. doi: 10.1093/eurheartj/ehs104; PMID: 22611136.

21. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62 :e147–239. doi: 10.1016/j.jacc.2013.05.019; PMID: 23747642.

22. Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group.

Circulation 1991;83:52–60. PMID: 1984898.

23. Boriani G, Biffi M, Diemberger I, et al. Rate control in atrial fibrillation: choice of treatment and assessment of efficacy.

Drugs 2003;63 :1489–509. PMID: 12834366.

24. Dorian P, Connors SP. Pharmacological and nonpharmacological methods for rate control. Can J Cardiol 2005;21 Suppl B:26B–30B. PMID: 16239984.

25. Vittorio TJ, Zolty R, Kasper ME,et al. Differential effects of carvedilol and metoprolol succinate on plasma norepinephrine release and peak exercise heart rate in subjects with chronic heart failure. J Cardiovasc Pharmacol Ther 2008;13:51–7. doi: 10.1177/1074248407312629; PMID: 18287590.

26. Rienstra M, Damman K, Mulder BA, et al. Beta-blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail 2013;1:21–8. doi: 10.1016/j. jchf.2012.09.002; PMID: 24621795.

27. Kotecha D, Holmes J, Krum H, et al. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet Lond Engl 2014;384 :2235–43. doi: 10.1016/S0140-6736(14)61373-8; PMID: 25193873.

28. Chao T-F, Liu C-J, Tuan T-C, et al. Rate-control treatment and mortality in atrial fibrillation. Circulation . 2015;132 :1604–12. doi: 10.1161/CIRCULATIONAHA.114.013709; PMID: 26384160.

29. McMurray JJV, van Veldhuisen DJ. β blockers, atrial fibrillation, and heart failure. Lancet Lond Engl 2014;384 :2181–3. doi: 10.1016/S0140-6736(14)62340-0; PMID: 25625384.

30. Withering W. An account of the foxglove and some of its medical uses, with practical remarks on dropsy, and other diseases. Class Cardiol 1941;231–52.

31. Freeman JV, Yang J, Sung SH, et al. Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure. Circ Cardiovasc Qual Outcomes 2013;6 :525–33. doi: 10.1161/CIRCOUTCOMES.111.000079; PMID: 24021697.

32. Georgiopoulou VV, Kalogeropoulos AP, Giamouzis G, et al.

Digoxin therapy does not improve outcomes in patients with advanced heart failure on contemporary medical therapy.

Circ Heart Fail 2009;2 :90–7. doi: 10.1161/ CIRCHEARTFAILURE.108.807032; PMID: 19808323.

33. Butler J, Anand IS, Kuskowski MA, et al. Digoxin use and heart failure outcomes: results from the Valsartan Heart Failure Trial (Val-HeFT). Congest Heart Fail Greenwich Conn 2010;16 :191–5. doi: 10.1111/j.1751-7133.2010.00161.x; PMID: 20887614.

34. Ahmed A, Bourge RC, Fonarow GC, et al. Digoxin use and lower 30-day all-cause readmission for Medicare beneficiaries hospitalized for heart failure. Am J Med 2014;127 :61–70. doi: 10.1016/j.amjmed.2013.08.027; PMID: 24257326; PMCID: PMC3929967.

35. Rathore SS, Curtis JP, Wang Y, et al. ASsociation of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289 :871–8. PMID: 12588271.

36. Akera T, Baskin SI, Tobin T,et al. Cardiac glycosides: temporal relationship between the inotropic action and binding to and dissociation from Na+-K+-activated ATPase in vitro. Recent Adv Stud Cardiac Struct Metab 1974;4 :149–54. PMID: 4283208.

37. Wasserstrom JA, Aistrup GL. Digitalis: new actions for an old drug. Am J Physiol Heart Circ Physiol 2005;289 :H1781–93.

PMID: 16219807.

38. Farshi R, Kistner D, Sarma JS, et al. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens.

J Am Coll Cardiol 1999;33 :304–10. PMID: 9973007.

39. Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis 2002;44 :251–66. PMID: 12007081.

40. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/ AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61 :1935–44. doi: 10.1016/j.jacc.2013.02.001; PMID: 23558044.

41. Friberg L, Hammar N, Rosenqvist M. Digoxin in atrial fibrillation: report from the Stockholm Cohort study of Atrial Fibrillation (SCAF). Heart Br Card Soc . 2010;96 :275–80. doi: 10.1136/hrt.2009.175786; PMID: 19710030.

42. Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortality among patients taking digoxin-analysis from the AFFIRM study. Eur Heart J 2013;34 :1481–8. doi: 10.1093/eurheartj/ ehs348; PMID: 23186806.

43. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial. Eur Heart J 2013;34 :1489–97. doi: 10.1093/eurheartj/eht120; PMID: 23592708.

44. Patel NJ, Hoosien M, Deshmukh A, et al. Digoxin significantly improves all-cause mortality in atrial fibrillation patients with severely reduced left ventricular systolic function. Int J Cardiol 2013;169 :e84–6. PMID: 24377111.

45. Allen LA, Fonarow GC, Simon DN, et al. digoxin use and subsequent outcomes among patients in a contemporary atrial fibrillation cohort. J Am Coll Cardiol 2015;65 :2691–8. doi: 10.1016/j.jacc.2015.04.045; PMID: 26112191; PMCID: PMC4483195.

46. Dardas TF, Levy WC. Digoxin: in the cross hairs again. J Am Coll Cardiol 2015;65 :2699–701. doi: 10.1016/j.jacc.2015.04.044; PMID: 26112192.

47. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet Lond Engl 2015;385 :2363–70. doi: 10.1016/S01406736(14)61836-5; PMID: 25749644.

48. Khan SS, Gheorghiade M. Digoxin use in atrial fibrillation: a critical reappraisal. Lancet Lond Engl . 2015;385 :2330–2. doi:

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Beta-blockers, digoxin and atrial fibrillation

10.1016/S0140-6736(14)62301-1; PMID: 25749645.

49. Murphy SA. When “digoxin use” is not the same as “digoxin use”: lessons from the AFFIRM trial. Eur Heart J 2013;34 :1465–7. doi: 10.1093/eurheartj/eht087; PMID: 23592709.

50. Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model. Annu Rev Public Health 1999;20 :145–57. PMID: 1035285.

51. Hohnloser SH, Halperin JL, Camm AJ, et al. Interaction between digoxin and dronedarone in the PALLAS trial.

Circ Arrhythm Electrophysiol 2014;7 :1019–25. doi: 10.1161/ CIRCEP.114.002046; PMID: 25378467.

52. Fauchier L, Grimard C, Pierre B, et al. Comparison of beta blocker and digoxin alone and in combination for management of patients with atrial fibrillation and heart

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failure. Am J Cardiol 2009;103 :248–54. doi: 10.1016/j. amjcard.2008.09.064; PMID: 19121446.

53. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ 2015;351 :h4451. doi: 10.1136/bmj.h4451; PMID: 26321114; PMCID: PMC4553205.

54. Gheorghiade M, Hall VB, Jacobsen G, et al. Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Circulation 1995;92 :1801–7. PMID: 7671364.

55. Ahmed A, Pitt B, Rahimtoola SH, et al. Effects of digoxin at low serum concentrations on mortality and hospitalization in

heart failure: a propensity-matched study of the DIG trial.

Int J Cardiol 2008;123 :138–46. PMID: 17382417; PMCID: PMC2474767.

56. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial.

Eur Heart J 2006;27 :178–86. PMID: 16339157; PMCID: PMC2685167.

57. Ahmed A, Waagstein F. Low-dose digoxin and reduction in mortality and morbidity in heart failure. Int J Cardiol 2009;136 :91–2. PMID: 20640177; PMCID: PMC2904633.

58. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J 2015;36 :1831–8. doi: 10.1093/eurheartj/ ehv143; PMID: 25939649.

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Pharmacological Therapy

The Mechanism of Action of LCZ696 Juan Tamargo Menendez Department of Pharmacology, School of Medicine, University Complutense, Madrid, Spain

Abstract Heart failure (HF) represents a growing financial burden on healthcare systems and despite therapeutic advances, mortality remains high. Current treatments focus on blocking neurohormonal pathways, such as the renin-angiotensin aldosterone system (RAAS). Recent research has focused on the natriuretic peptide system, which confers beneficial effects in HF, whereas activation of the RAAS and of the sympathetic nervous system has detrimental effects. LCZ696 (sacubutril/valsartan), a first-in-class angiotensin II AT1 receptor neprilysin inhibitor, has a unique mode of action that targets both pathways. Clinical studies to date indicate that LCZ696 is effective and safe in mild to moderate arterial hypertension and in HF patients with preserved ejection fraction, and has been shown to be superior to enalapril in patients with moderate to severe HF due to reduced left ventricular ejection fraction.

Keywords Angiotensin receptor, neprilysin inhibitor heart failure, natriuretic peptides, LCZ696, neprilysin, renin-angiotensin-aldosterone system Disclosure: The author has no conlicts of interest to declare.

Acknowledgement(s): This work was supported by grants from the Instituto de Salud Carlos III (PI11/01030 and Red de Investigación Cardiovascular-RIC, RD12/0042/0011) and Fundación BBVA. Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the author, funded by Novartis Pharma AG. Received: 27 January 2016 Accepted: 3 February 2016 Citation: Cardiac Failure Review, 2016;2(1):40–6 DOI: 10.15420/cfr.2016:1:1 Correspondence: Juan Tamargo Menendez, Department of Pharmacology, School of Medicine, University Complutense, 28040 Madrid, Spain. E: jtamargo@med.ucm.es

Chronic heart failure (HF) is a complex and progressive clinical syndrome resulting from any abnormality of cardiac structure or function. The American College of Cardiology Foundation/American Heart Association guideline defines HF as ‘a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood’.1 The European Society of Cardiology definition is ‘an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolising tissues, despite normal filling pressures (or only at the expense of increased filling pressures).2 HF prevalence and the number of HF-related hospitalisations are increasing, and the prognosis remains poor, with a 5-year mortality worse than many cancers.3,4 There has been significant progress in HF therapy, but mostly in HF with reduced ejection fraction (HFrEF), while for patients with preserved ejection fraction (HFpEF), no therapy has improved clinical outcomes.2,5 Despite such advances, however, morbidity and mortality of HFrEF still remains high. It is evident, therefore, that substantial unmet needs exist in HF therapy. This article aims to review the mechanism of action and clinical development of sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor that has recently received regulatory approval in the US and Europe.

The Role of the Renin-Angiotensin-Aldosterone System in Heart Failure Neurohumoral activation, in particular, of the renin-angiotensinaldosterone system (RAAS) and the sympathetic nervous system, plays a major role in the development and progression of HF.1,2 The RAAS is an essential component in the regulation of cardiovascular homeostasis that exerts its actions through the hormones angiotensin

40

Tamargo_FINAL.indd 40

II and aldosterone. The RAAS regulates vascular tone and blood pressure (BP) by means of vasoconstriction and renal sodium and water retention.6 Abnormalities in cardiac function in HF activate the RAAS and sympathetic nervous system in order to maintain perfusion of vital organs.7 However, prolonged activation of these systems increases systemic vascular resistance and causes sodium and water retention, myocardial hypertrophy, fibrosis and apoptosis, which accelerates the progression of HF and promotes end-organ damage.6,8–10 The blockade of beta-adrenergic receptors leads to symptomatic improvement and reduced morbidity and mortality in patients with HFrEF.9–13 In addition, the central role of the RAAS system in HF has led to the therapeutic use of RAAS inhibitors,2,8 including angiotensin-converting enzyme (ACE) inhibitors,14 angiotensin receptor blockers (ARBs) in patients who cannot tolerate ACE inhibitors15 and mineralocorticoid receptor antagonists in the treatment of chronic HF.16,17 ARBs competitively inhibit the binding of angiotensin II to its AT1 receptors located on blood vessels and other tissues, and improve symptoms, haemodynamics and outcomes in chronic HF.1,2 These beneficial effects are attributed to the inhibition of the deleterious effects of AT1 receptor stimulation, i.e., vasoconstriction, Na+ and water retention, aldosterone and vasopressin release, stimulation of sympathetic tone, inflammation, fibrosis and cell growth (see Figure 1).

However, ACE inhibitors, ARBs, aldosterone receptor antagonists and combinations of drugs in these classes are limited in their ability to fully inhibit the activity of the RAAS.6,18 Furthermore, ACE inhibitors and ARBs induce a reactive rise in plasma renin activity that may eventually surpass their RAAS-inhibitory effect, and plasma aldosterone levels remain elevated in a subset of patients despite therapy, a phenomenon

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LCZ696

known as aldosterone escape or aldosterone breakthrough.19 In addition, ARBs do not enhance bradykinin-mediated vasodilation and are considered less effective than ACE inhibitors.2 For the past 25 years, an add-on therapy approach to chronic HF has been used, beginning with diuretics, then adding ACE inhibitors (or ARBs) and beta blockers, followed by mineralocorticoid receptor antagonists.13,20,21 Ivabradine, which reduces heart rate, is also approved as an add-on therapy in HF.22 Nevertheless, morbidity and mortality remain high and there is, therefore, a need for new therapeutic targets in HF.

Figure 1: The Role of the Natriuretic Peptides in Heart Failure Heart failure

Natriuretic peptides system

Sacubitril (AHU377)

ANP, BNP, CNP Inactive products

A growing body of evidence suggests that hypertension and HF may be consequences of a dysregulated NP system and that patients with HF and hypertension may have a deficiency of biologically active NPs.28,29 NPR-C clears NP from the circulation through receptormediated internalisation and degradation. Urodilatin, a renally synthesised isoform of ANP, stimulates NPR-A located in the glomeruli and collecting ducts and promote Na+ excretion.30

Clinical Development of Vasopeptidase Inhibitors Augmentation of NPs by direct administration of these peptides is difficult because oral delivery is ineffective and parenteral delivery problematic. While nesiritide has been shown to produce a modest improvement in dyspnoea, it does not favourably affect clinical outcomes, decongestion or renal function33–35 and safety concerns have been raised.36,37 Blockade of NP breakdown by neprilysin inhibitors has, therefore, been investigated.38 Oral neprilysin inhibitors, such as candoxatril, produced clinical benefit in patients with chronic HF.39,40 However, candoxatril has no effect on, or increases, systolic BP (SBP) in

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Tamargo_FINAL.indd 41

Ang I

LBQ657

Adrenomedullin Bradykinin Angiotensin II Substance P Endothelin-1 β amiloid peptide

Vasoconstriction ↓Blood pressure ↓Sympathetic tone ↓Aldosterone levels ↓Hypertrophy/fibroses ↓Inflammation Diuresis/natriuresis

VALSARTAN

AT1R Vasoconstriction ↑Blood pressure ↑Sympathetic tone ↑Aldosterone levels ↑Hypertrophy/fibroses ↑Inflammation ↓Cardiac output Na+/water retention Endothelial dysfunction

The natriuretic peptide (NP) system comprises three homologous peptides: atrial (ANP), brain (BNP) and C-type (CNP), and two biologically active receptors. ANP and BNP bind to the natriuretic receptor-A (NPR-A) and CNP specifically binds to the NPR-B. NPR-A and NRP-B are coupled to particulate forms of guanylyl cyclase (GC-A and GC-B) and catalyse the synthesis of cyclic guanosine (cGMP), which modulates the activity of cGMP-dependent protein kinase G (PKG) to exert its multiple cardiac, vascular and renal actions. The NP-cGMP-PKG signalling pathway is terminated by phosphodiesterases (PDEs) that hydrolyse cGMP to guanosine monophosphate (GMP). NPs are removed from the circulation and inactived by the clearance receptor (NPR-C) and degraded by several peptidases, including neprilysin (neutral endopeptidase) (NEP). In addition, the NPR-C mediates non-cGMP regulated biological actions. DAG: = diacilglicerol; GTP = guanosine triphosphate; IP3 = inositol 1,4,5-trifosfato; LTCC = L-type calcium channel; PLC = phospholypase C; RAAS = renin-angiotensinaldosterone system; UROD = urodilatin.

Figure 2: Mechanism of Action of LCZ696 on Natriuretic Peptides NEP 24.11 ANP BNP UROD

LTCC

Ca2+

Degradation ANP, BNP CNP, UROD

CNP

NPR-A

NPR-B AC

P

ATP GC GC

GTP

Another key component of the NP system is neprilysin (neutral endopeptidase 24.11), which catalyses the degradation of ANP, BNP and CNP as well as the degradation of bradykinin, adrenomedullin, endothelin-1, substance P and angiotensin II (see Figure 1).31 Neprilysin is a potentially useful therapeutic target in HF.6,28 Inhibition of neprilysin increases the levels of NP, causing vasodilation and a reduction in extracellular fluid volume. Neprilysin does not hydrolyse N-terminal prohormone of brain NP (NT-proBNP), therefore the latter is a useful cardiac biomarker to assess therapeutic effect and prognosis in patients treated with neprilysin inhibitors.32

Neprilysin

Angiotensinogen

Ang II

Role of Natriuretic Peptides in Heart Failure While the activation of the RAAS and sympathetic nervous system is detrimental in HF, other counter-regulatory pathways are activated in HF, including the natriuretic peptide (NP) system (see Figure 2).

The NP system consists of atrial (ANP),23 B-type (BNP)24 and C-type (CNP) NPs; these hormones regulate BP and fluid homeostasis.25–27 ANP is synthesised and secreted in atria, BNP is secreted from the ventricles in response to mechanical stretch and increased intracardiac volume/ pressure and CNP mostly originates from endothelial and renal cells and is secreted in response to endothelium-dependent agonists and pro-inflammatory cytokines.25,26,28 NPs activate three transmembrane receptors: natriuretic peptide receptor (NPR)-A, NPR-B and NPR-C.27 The binding of NPs to type A (NPR-A) and type B (NPR-B) receptors activates guanylate cyclase, increasing levels of the second messenger cyclic guanosine monophosphate (cGMP) and its effector molecule protein kinase G. This induces natriuresis, diuresis, vasodilation and inhibition of the RAAS system and the sympathetic nervous system, as well as antifibrotic, antiproliferative and antithrombotic effects (see Figure 2).25,26,28

Renin angiotensin system

LCZ696

GC GC

cGMP PKG

NPR-C

α1

β γ

AC cAMP GTP

Inactive products

PLC

DAG +IP3 non-cGMP mediated effects

PDE

Arteriolar and venous vasodilation, natriuresis, inhibition of the RAAS and sympathetic tone, inhibition of platelet aggregation, antifibrotic, antihypertrophic, anit-inflammatory and lusitropic effects.

ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; CNP = C-type natriuretic peptide; cGMP = cyclic guanosine monophospate; DAG = diacilglicerol; GC = guanylyl cyclase-A; GMP = guanosine monophosphate; GTP = guanosine triphosphate; IP3 = inositol 1,4,5-trifosfato; LTCC = L-type calcium channel; NEP = neprilysin (neutral endopeptidase); NPR = natriuretic peptide receptor; PDE = phosphodiesterase; PKG = protein kinase G; PLC = phospholypase C; RAAS = renin-angiotensin-aldosterone system; UROD = urodilatin.

normotensives, an effect prevented by enalapril, and does not reduce BP in hypertensive subjects, probably because its vasodilatory effect may be offset by an increased activity of the RAAS and sympathetic nervous system and/or by downregulation of NP receptors.41,42 In addition, since neprilysin acts on numerous physiological targets, the effect of candoxatril was broader than anticipated.41 Neprilysin inhibition results in activation of the RAAS, therefore, in order to be clinically beneficial, neprilysin inhibition requires concomitant inhibition of the RAAS.43 Vasopeptidase inhibitors are dual inhibitors of ACE and neprilysin and, therefore, emerged as a new therapeutic

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Pharmacological Therapy Table 1: Summary of Clinical Trials of LCZ696 Authors/Trial

Clinical Setting

Name

Trial

Treatment

Primary Endpoint

Primary Outcomes

Description

PARADIGM-HF57

TITRATION60

HFrEF: class II–IV, LVEF

LCZ696 (200 mg twice

Composite of CV death or HF

LCZ696 significantly reduced CV

≤40 % (changed to ≤35 %), R, DB, PG, ACS

Phase III

daily) or enalapril

hospitalisation

or hospitalisation (20 %; p<0.001),

plasma BNP ≥150 pg/ml

n=8,442

(10 mg twice daily)

(N-terminal pro-BNP

Follow-up 27

≥600 pg/ml)

months

HFrEF (NYHA class II–IV,

Phase I

LCZ696: from 50 to

Proportion of patients

Treatment was successful in

LVEF ≤35 %, on beta

R, DB, PA

200 mg twice daily in a

experiencing pre-specified

78 % and 84 % of patients in the

blockers)

n=498

3-week (condensed)

adverse events* and laboratory

condensed and conservative

versus 6-week

outcomes including SBP <95

regimens, respectively. The

(conservative) regimen

mmHg and a doubling of serum

target dose was achieved and

creatinine from baseline

maintained for 12 weeks in 76 %

CV death (20 %) and all-cause mortality (16 %) versus enalapril

of patients PARAMOUNT61

PARAGON-HF

63

HFpEF (LVEF ≥45 %,

Phase II

LCZ696 (200 mg twice daily) Change in NT-proBNP from

At 12 weeks, NT-proBNP was

NT-proBNP >400 pg/ml)

DB, R, PG

versus valsartan (160 mg

significantly reduced in the

n=301

twice daily) for 36 weeks

HFpEF (NYHA class II–IV,

Phase III

LCZ696 (50, 100 and 200

LVEF >45 %)

R, DB, ACS

mg) versus valsartan (40, 80 death and total (first and

n=4,300

and 160 mg) for up to

baseline to 12 weeks

LCZ696 group versus valsartan Composite endpoint of CV

Ongoing

recurrent) HF hospitalisations

57 months UK HARP-III

Proteinuric CKD (eGFR

Phase III

LCZ696 (200, 400 mg once

Difference in change in

R

daily) versus irbesartan

measured eGFR from baseline

n=360

(150, 300 mg once daily)

to 6 months

Mild–moderate

Phase III

LCZ696 (100, 200, 400 mg

Mean difference across the

Significant reduction of SBP/

hypertension

R, DB, PC, ACS

once daily); valsartan

three single-dose pairwise

DBP with LCZ696 200 mg and

n=1,215

(80, 160, 320 mg once

comparisons of LCZ696 versus

400 mg versus valsartan 160

daily); AHU377 (200 mg

valsartan in mean sitting DBP

and 320 mg Significant reduction

once daily) versus placebo

at 8 weeks

in ambulatory BP with LCZ696

(ISRCTN11958993)73 ≥20 <45 ml/min/1.73m2; or eGFR ≥45 <60 ml/

Ongoing

min/1.73m2 and urine ACR ≥20 mg/mmol) Ruilope et al

64

versus valsartan Kario et al

65

Mild–moderate

Phase III

LCZ696 (100, 200 or 400 mg Mean difference across the

Significant reductions in SBP/

hypertension (Asian

R, DB, PC

once daily) versus placebo

3 single-dose pairwise

DBP, and pulse pressure with

population)

n=362

for 8 weeks

comparisons of LCZ696 versus

LCZ696 versus placebo

placebo in DBP *Symptomatic hypotension, hyperkalaemia, renal dysfunction, angioedema. ACR = albumin:creatinine ratio; ACS = active-controlled study; BP = blood pressure; CI = confidence interval; CKD = chronic kidney disease; CV = cardiovascular; DB = double-blind; eGFR = estimated glomerular filtration rate; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HR = hazard ratio; LA = left atria; LV = left ventricle; LVEF = left ventricular ejection fraction; N-terminal pro-BNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association; PC = placebo-controlled; PA = parallel assignment; PG = parallel group; R = randomised; SBP/DBP = systolic/diastolic blood pressure.

option in HF and hypertension, but their pharmacological profile is complex.44 Omapatrilat was more effective than either lisinopril or amlodipine in reducing BP,44 but in patients with chronic HF it was not more effective than enalapril in reducing the combined risk of death or hospitalisation for HF requiring intravenous treatment.45 However, omapatrilat was discontinued due to the risk of angioedema, possibly due to excessive inhibition of bradykinin degradation (presumably via neprilysin, ACE and aminopeptidase P).46,47

Mechanism of Action of LCZ696 Following the disappointing outcomes of combined ACE/neprilysin inhibition, the combination of neprilysin and an ARB was investigated.

ARBs have a lesser effect on bradykinin48 and have been associated with lower risk of angioedema compared with ACE inhibitors, not significantly different from placebo.49,50 Therefore, RAAS blockade at the AT1 receptor appears to be a preferable strategy to ACE inhibition.51 LCZ696 (Entresto™, Novartis) is a first-in-class angiotensin II receptorneprilysin inhibitor (ARNI) whose multimodal mode of action involves neprilysin inhibition and AT1 receptor blockade. LCZ696 is composed

42

Tamargo_FINAL.indd 42

of two molecular moieties (in a 1:1 molar ratio) in a single crystalline complex comprising valsartan (an ARB) and sacubitril (AHU377).52 After ingestion, LCZ696 undergoes rapid dissociation into valsartan and sacubitril, a prodrug that is subsequently de-ethylated by esterases to LBQ657, a neprilysisn inhibitor.

In healthy volunteers, LCZ696 causes dose-dependent increases in ANP, plasma and urinary cGMP, renin concentration and activity and angiotensin II levels, as a result of neprilysin inhibition and AT1 receptor blockade (see Figure 1).52 After LCZ696 administration, levels of cGMP significantly increased at 4 and 12 hours and returned to baseline levels at 24 hours; all RAAS biomarkers reached a maximum after 4 hours and remained elevated at 24 hours.52 Thus, the pharmacodynamic effects of valsartan and LBQ657 are similar. In HF patients, levels of urinary cGMP, plasma BNP and renin concentration and activity were higher during treatment with LCZ696 than with enalapril, while circulating levels of markers of myocardial wall stress (N-terminal pro-BNP) and myocardial injury (troponin T) were lower during treatment with LCZ696 than with enalapril.53,54 After 21 days of LCZ696 administration (100 mg titrated to

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Nevertheless, the precise mechanism by which LCZ696 reduces cardiovascular mortality in HF patients is uncertain.56 The observed benefit is likely to be related to the incremental benefits of neprilysin inhibition, which may counteract the detrimental effects of RAAS and sympathetic nervous system activation. Other possible mechanisms might include: a haemodynamic improvement related to NP-mediated reduction in ventricular wall stress; an improvement in ventricular function; modification of the basis for fatal ventricular arrhythmias via decreased myocardial fibrosis and hypertrophy, attenuation of ventricular remodelling or direct anti-arrhythmic properties; sympatholytic or vagotonic effects of hormones potentiated by neprilysin inhibition; and anti-atherosclerotic or anti-thrombotic effects of enhanced NP expression leading to an improvement in regional myocardial perfusion.56 Further understanding of the mechanisms of action of LCZ696 would provide a deeper insight into the pathophysiology of HF and should be a priority in the future.

Pharmacokinetic Properties of LCZ696 Valsartan and LBQ657 have similar pharmacokinetic profiles, with rapid absorption, reaching maximum plasma concentrations within 1.5–4.5 hours, and a half-life of 8.9–16.6 and 9.9–11.1 hours, respectively, indicating that both agents exhibit comparable pharmacokinetic properties and that LCZ696 was suitable for once- or twice-daily dosing.52 Sacubitril (AHU377) reaches peak plasma levels within 0.5–1.1 hours and presents a half-life of 1.1–3.6 hours owing to its rapid conversion into the active metabolite LBQ657, which explains the rapid onset of activity of LCZ696. LCZ696 achieves 90 % inhibition of neprilysin.52 Importantly, LCZ696 does not inhibit aminopeptidase A, unlike omapatrilat, thus minimising the risk of angiodema.52 In healthy volunteers, LCZ696 400 mg and valsartan 320 mg provide similar exposure to valsartan.

Clinical Development of LCZ696 Heart Failure The main clinical trials investigating the efficacy and safety of LCZ696 are summarised in Table 1. The pivotal clinical trial in the development of LCZ696 was the Prospective comparison of ARNI with ACEI to Determine Impact on. Global Mortality and morbidity in Heart Failure (PARADIGM-HF) study, which recruited patients (n=8,442) with chronic HF (New York Heart Association [NYHA] class II–IV) and reduced left ventricular ejection fraction (LVEF; ≤40 % to ≤35 %).57 The trial began with a single-blind run-in period to test drug tolerability.

Patients received enalapril 10 mg twice daily for 2 weeks, then 100 mg LCZ696 twice daily for 1–2 weeks and then 200 mg twice daily for 2–4 weeks. Two brief (one day) washout periods were also included to minimise the potential risk of angioedema due to overlapping ACE and neprilysin inhibition. During the run-in period, 12 % of patients withdrew due to an adverse event. Following the run-in period, patients underwent double-blind 1:1 randomisation to LCZ696 200 mg twice daily or enalapril 10 mg twice daily. Exclusion criteria included symptomatic hypotension (SBP <100 mmHg) (at screening or 95 mmHg at randomisation), an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at screening or at randomisation or a decrease in the eGFR >25 % (which was amended to 35 %) between screening and randomisation, a serum K+ level >5.2 mmol/L at screening (or >5.4 mmol/L at randomisation) or a history of angioedema or unacceptable side effects during ACE inhibitor or ARB therapy.

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Figure 3: Kaplan-Meier Curve for Primary Study Endpoint of PARADIGM-HF (Composite of Death from Cardiovascular Causes or First Hospitalisation for Heart Failure) Primary endpoint 1.0

Cumulative probability

200 mg daily) a significant lowering of plasma NT-proBNP, aldosterone and endothelin-1 levels was observed.55

Hazard ratio, 0.80 (95 % confidence interval, 0.73–0.87) p<0.001

0.6 0.5 0.4

Enalapril

0.3

LCZ696

0.2 0.1 0.0

0

Number at risk LCZ696 4,187 Enalapril 4,212

180

3,922 3,883

720 900 360 540 Days since randomisation 3,663 3,579

3,018 2,922

2,257 2,123

1,544 1,488

1,080

1,260

896 853

249 236

The natriuretic peptide (NP) system comprises three homologous peptides: atrial (ANP), brain (BNP) and C-type (CNP), and two biologically active receptors. ANP and BNP bind to the natriuretic receptor-A (NPR-A) and CNP specifically binds to the NPR-B. NPR-A and NRP-B are coupled to particulate forms of guanylyl cyclase (GC-A and GC-B) and catalyse the synthesis of cyclic guanosine (cGMP), which modulates the activity of cGMP-dependent protein kinase G (PKG) to exert its multiple cardiac, vascular and renal actions. The NP-cGMPPKG signalling pathway is terminated by phosphodiesterases (PDEs) that hydrolyse cGMP to guanosine monophosphate (GMP). NPs are removed from the circulation and inactived by the clearance receptor (NPR-C) and degraded by several peptidases, including neprilysin (neutral endopeptidase) (NEP). In addition, the NPR-C mediates non-cGMP regulated biological actions.

DAG: = diacilglicerol; GTP = guanosine triphosphate; IP3 = inositol 1,4,5-trifosfato; LTCC = L-type calcium channel; PLC = phospholypase C; RAAS = renin-angiotensin-aldosterone system; UROD = urodilatin. From McMurray et al., Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371(11): 993–1004. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

The trial was terminated early after a median follow up of 27 months due to evidence of an overwhelming benefit with LCZ696. The primary endpoint, a composite of death from cardiovascular causes or hospitalisation for HF, occurred in 21.8 % of the LCZ696 group and 26.5 % of the enalapril group (hazard ratio [HR] in the LCZ696 group, 0.80; 95 % confidence interval [CI], 0.73–0.87; p<0.001) (see Figure 3). During the trial, the numbers of patients who would need to have been treated to prevent one primary event and one cardiovascular death were 21 and 32, respectively. Death from any cause was reported in 17 % of patients receiving LCZ696 and 19.8 % receiving enalapril (HR 0.84; 95 % CI 0.76–0.93; p<0.001); of these 13.3 % and 16.5 %, respectively, died from cardiovascular causes (HR 0.80; 95 % CI 0.71–0.89; p<0.001).57 Using actuarial estimates from the PARADIGM-HF trial, and assuming that the protective effects of LCZ696 are sustained during long-term use, it has been estimated that treatment with LCZ696 could result in 1 to 2 years of increased life expectancy in patients with HF.58 LCZ696 also reduced the risk of hospitalisation for HF by 21 % compared with enalapril (p<0.001) and decreased HF symptoms (p=0.001).57 Interestingly, these benefits were also observed in 2,907 patients with diabetes. In a sub-analysis of PARADIGM-HF, the benefit of LCZ696 compared with enalapril was consistent, regardless of glycaemia status.59 In addition, two recent analyses have focused on the effect of LCZ696 on the risk of clinical deterioration. A subanalysis of PARADIGM-HF focused on pre-specified measures of non-fatal clinical deterioration.53 Compared with enalapril, fewer patients in the LCZ696 group required treatment intensification for HF (520 versus 604; HR 0.84; 95 % CI 0.74–0.94; p=0.003) or an emergency department visit for worsening HF (HR 0.66; 95 % CI 0.52–0.85; p=0.001). Patients receiving LCZ696 had 23 % fewer hospitalisations for worsening HF (851 versus 1,079; 95 % CI 0.67–0.85; p<0.001) and 18 % fewer stays in intensive care

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Pharmacological Therapy (768 versus 879; p=0.005), and were 31 % less likely to receive intravenous positive inotropic agents (p<0.001) and 22 % less likely to have cardiac transplantation or implantation of a cardiac device for HF (p=0.07). The reduction in hospitalisation was noted within the first 30 days after randomisation. Worsening symptoms were consistently more commonly reported in the enalapril group.53 Another analysis focused on the mode of death in the PARADIGMHF trial. The majority of deaths were cardiovascular (80.9 %), and treatment with LCZ696 significantly reduced the risk of cardiovascular death (HR 0.80; 95 % CI 0.72–0.89; p<0.001). This reduced risk was primarily due to a reduction in both sudden cardiac death (HR 0.80; 95 % CI 0.68–0.94; p=0.008) and death due to worsening HF (HR 0.79; 95 % CI 0.64–0.98; p=0.034). The treatment effect on sudden cardiac death was not affected by the presence or absence of an implantable cardioverter-defibrillator.56 Of note, LCZ696 reduced cardiovascular death to a similar extent as its reduction of HF hospitalisation, while the results of many pivotal studies of RAAS in HF found a more pronounced reduction in hospitalisations for worsening HF than cardiovascular death.56 The Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients (TITRATION) study demonstrated the safety and efficacy of up-titrating LCZ696 from 50 mg twice daily to a target dose of 200 mg twice daily in a 3- (condensed) versus 6-week (conservative) regimen in patients with HFrEF (EF ≤35 %) on beta-blockers. The study enrolled a broader range of patients than PARADIGM-HF, including inpatients and patients naïve to ACE inhibitors or ARBs.60 The study involved an open-label run-in period in which LCZ696 was tested for tolerability and safety at a 50 mg twice daily for 5 days. Patients were then randomised to up-titration of LCZ696 to 200 mg during the next 3 (condensed) or 6 weeks (conservative) regimen. Primary endpoints included the proportion of patients experiencing pre-specified adverse events (symptomatic hypotension, hyperkalaemia, renal dysfunction, angioedema) and outcomes including SBP <95 mmHg and a doubling of serum creatinine from baseline. In the primary endpoint of tolerability, there were no differences between groups. Treatment was successful in 78 % and 84 % of patients in the condensed and conservative regimens, respectively (p=0.07). The target dose was achieved and maintained for 12 weeks in 76 % of patients. The study also suggested that patients on ACE inhibitors or ARBs should probably be moved less quickly to up-titration of LCZ696.

There is a lack of effective treatments for patients with HFpEF, therefore LCZ696 was evaluated in this treatment setting. Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fraction (PARAMOUNT) was a phase II study in patients with NYHA class II–III HF and LVEF ≥45 %. Participants (n=301) were randomised to LCZ696 (titrated to 200 mg twice daily) or valsartan (titrated to 160 mg twice daily). The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress.61 At 12 weeks, NT-proBNP was significantly reduced in the LCZ696 group compared with the valsartan group (from 783 pg/ml to 605 pg/ml in the LCZ696 group versus from 862 pg/ml to 835 pg/ml in the valsartan group; ratio LCZ696:valsartan, 0.77; 95 % CI 0.64–0.92; p=0.005). In addition, after 36 weeks more patients in the LCZ696 group showed improvements in NYHA functional class and reduced left atrial size compared with valsartan, consistent with reverse left atrial remodelling. LCZ696 was well tolerated with adverse effects similar to those of valsartan. A recently reported analysis from this study investigated the effects of LCZ696 on renal function in patients with

44

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HFpEF. Treatment with LCZ696 for 36 weeks resulted in lower serum creatinine, higher eGFR and an increase in urinary albumin to creatinine ratio compared with valsartan.62 Although the PARAMOUNT study was not powered to detect clinical outcomes, it was a hypothesis-generating trial that provided the basis for the ongoing phase III Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure (PARAGON-HF) trial, which aims to enrol 4,300 patients.

Enrolment criteria are symptomatic HFpEF, NYHA class II–IV, LVEF ≥45 % requiring treatment with diuretics for HF ≥30 days prior to study entry, structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram, a HF hospitalisation within 9 months prior to study entry and/or an elevated NT-proBNP.63 The primary endpoint is a composite of cardiovascular death and total HF hospitalisations. The treatment arm with the lower rate of events will be deemed to have the most successful response.

Arterial Hypertension LCZ696 has also shown efficacy in clinical studies of hypertension. In a multinational study with sites in 18 countries, patients (n=1,328) with mild-to-moderate hypertension were randomised to 8 weeks’ treatment with LCZ696 (100, 200 or 400 mg daily), valsartan (80, 160 or 320 mg daily), sacubitril (200 mg daily) or placebo.64 The reduction in mean resting SBP and diastolic BP (DBP) was significantly greater for 200 mg LCZ696 versus 160 mg valsartan (-11/-6.1 versus -5.7/-3.2 mmHg; p<0.001) and for 400 mg LCZ696 versus 320 mg valsartan (-12.5/-6.9 versus -6.4/4.1 mmHg; p<0.005).64 Response rates were also significantly higher in patients on 200 mg LCZ696 versus 160 mg valsartan (91/163, 56 %; p=0.0095), and on 400 mg LCZ696 versus 320 mg valsartan (103/163, 63 %; p=0.026). No differences were found between 100 mg LCZ696 and 80 mg valsartan. In a multicentre study carried out in Japan, China, South Korea, Taiwan and Thailand, patients aged ≥18 years (n=389) with hypertension were randomised to LCZ696 (100, 200 or 400 mg once daily once daily) or placebo (n=92) for 8 weeks. Reductions in SBP, DBP (p<0.0001) and pulse pressure (p<0.001) were significantly greater with all doses of LCZ696 than with placebo. The reductions are greater than those observed in white European populations, as this Asian population has a higher salt intake and increased salt sensitivity. There were also significant reductions in 24-hour, daytime and nighttime ambulatory SBP, DBP and pulse pressure for all doses of LCZ696 compared with placebo (p<0.0001).65 Although the mechanism is uncertain, this effect can be related to its vascular effects and/or to reduced effective circulating volume. In the PARAMOUNT trial the reduction from baseline in mean SBP/DBP was -9.3/-4.9 mmHg with LCZ699 (200 mg twice daily) and -2.9/-2.1 mmHg with valsartan (160 mg twice daily).61 In the PARADIGMHF trial where 71 % of patients had hypertension, LCZ696 therapy resulted in a significant reduction in SBP compared with enalapril (mean difference -2.7 mmHg; p<0.001) over a period of 3 years. The role of the reduction in SBP on the decreased rate of death and HF hospitalisation observed in this trial is uncertain.

Safety Profile of LCZ696 In clinical studies of hypertension, LCZ696 was well-tolerated and no cases of angioedema or deaths were reported. The most common adverse events were headache and pruritus,64 nasopharyngitis and upper respiratory tract infection.64,65 Hypotension or syncope occurred in five patients (one each in the placebo, 400 mg LCZ696 and 200 mg AHU377 groups; two in the 200 mg LCZ696 group).64 Adverse events

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resulting in treatment discontinuation occurred in 1–2 % of patients on LCZ696, with the highest occurrence in the AHU377 and placebo groups.64 However, patients with diabetes and renal disease (eGFR >30 ml/min/1.73 m2) were excluded from these trials.

In the PARADIGM-HF study, 12 % of patients did not complete the run-in period because of adverse events, most frequently cough, hyperkalaemia, renal dysfunction or hypotension. Across the study period, LCZ696 was discontinued in 746 patients (17.8 %) and enalapril in 833 patients (19.8 %). During the double-blind phase, the LCZ696 group had higher rates of hypotension (p<0.001) and non-serious angioedema (p=0.31), but significantly lower rates of serum creatinine ≥2.5 mg/dl, serum potassium ≥6 mmol/L and cough than the enalapril group, and a lower overall incidence of adverse events. Fewer patients in the LCZ696 group than in the enalapril group stopped drug medication because of an adverse event (10.7 % versus 12.3 %; p=0.03) or renal impairment (0.7 % versus 1.4 %; p=0.002).57 In the PARAMOUNT trial the number of patients with hypotension, renal dysfunction or hyperkalemia did not differ between groups.61 However, questions remain regarding the safety of LCZ696. Although it is better tolerated than valsartan in clinical studies, it showed a higher incidence of hypotension, an important consideration in elderly patients, although this rarely resulted in discontinuation of treatment, and the number of discontinuations due to hypotension were balanced across both groups. In addition, the question of angioedema in daily clinical practice remains unanswered. Angioedema is more common in patients of African origin,66,67 but these were under-represented in the PARADIGM-HF (5 %). There is also a need for studies in ACE inhibitornaïve patients, where benefits were less pronounced in PARADIGM-HF, although it should be noted that all patients had an enalapril run-in phase so were not truly naïve.

A recent review paper discussing preclinical models and human genetic analyses suggested that neprilysin inhibitors may lead to an accumulation of amyloid beta-peptide in the brain and may thus accelerate Alzheimer’s disease progression in at-risk patients.68 This is a hypothetical concern and not based on any human studies: a Chinese study found no association between two NEP gene polymorphisms and Alzheimer’s disease in elderly people.69 Furthermore, a 2-week LCZ696 administration in human healthy volunteers did not modify Abeta1−40 and Abeta1−42 levels in the cerebrospinal fluid70 and no cognition-related adverse events related to treatment have been reported in any of the randomised clinical trials to date, probably because multiple (20) proteins are involved in the clearance of amyloid beta-peptides. There is therefore no conclusive evidence for an association between NEP and Alzheimer’s disease in humans. Cognition-related adverse effects were observed in the PARADIGM-HF trial, as expected in a study population including elderly patients, but the incidence was balanced in both treatment arms.71 Serial cognition testing will be performed in PARAGON-HF.63 In addition, a dedicated study investigating cognition and PET imaging is planned.

1.

2.

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62 :e147–239. DOI: 10.1016/j.jacc.2013.05.019; PMID: 23747642 McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33 :1787–847. DOI: 10.1093/

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3.

4.

5.

Although clinical trials to date have demonstrated the tolerability of LCZ696, it can be argued that the similar rates of adverse events among LCZ696 and standard therapy may have been the result of patient selection bias. Thus, data from on-going clinical trails and clinical practice are needed to evaluate its long-term efficacy.

Clinical use of LCZ696 LCZ696 has been approved by the European Medicines Agency72 and US Food and Drug Administration73 to reduce the risk of cardiovascular death and hospitalisation in adult patients with symptomatic chronic HFrEF. It is usually administered in conjunction with other HF therapies, in place of an ACE inhibitor or an ARB. If switching from an ACE inhibitor, a washout period of 36 hours is important. The recommended starting dose is 49/51 mg (sacubitril/valsartan) twice daily. This may be increased after 2–4 weeks to the target maintenance dose of 97/103 mg (sacubitril/ valsartan) twice daily as tolerated by the patient. The starting dose should be reduced to 24/26 mg (sacubitril/valsartan) twice daily for patients not currently taking an ACE inhibitor or an ARB, or previously taking a low dose of these agents, i.e. patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) and patients with moderate hepatic impairment (Child-Pugh B).

Conclusion While drugs targeting the RAAS represent the cornerstone of HF treatment, there is a need for novel therapeutic approaches. LCZ696 is an effective and safe alternative to ACE inhibitors and may change future first-line approaches to HF therapy because of its significant improvement in survival and reduced rates of rehospitalisation.

Additionally, LCZ696 has been found more effective than valsartan in hypertensive patients, although comparative studies with other antihypertensive drugs are needed and its effects on cardiovascular outcomes are unknown. Ongoing clinical trials will define its future role in the treatment of HF and other cardiovascular diseases, where ACE inhibitors or ARBs are currently first-line therapies.

For LCZ696 to displace ACE inhibitors and ARBs in daily clinical practice, more information on real-life use of LCZ696 is required, including safety and efficacy in patient groups not included in PARADIGM-HF, i.e. patients with acute decompensated HF and more advanced symptoms (NYHA IV only represented 0.8 % of the study population); elderly and black patients; patients with resistant hypertension, nephropathy and proteinuric renal disease; patients receiving high doses (≥10 mg twice daily); or treated with ARBs. There is some preliminary evidence of LCZ696 in hypertensive patients with diabetes; furthermore, the benefit of LCZ696 in the PARADIGM-HF trial was reported in 2,907 patients with diabetes. It will also be important to determine which patients will benefit most, for example ACE inhibitor/ARB naïve patients, who are commonly encountered in the clinic. For the first time in 30 years, physicians must make a careful therapeutic decision: instead of adding to a drug regimen, they have the option to replace ACE inhibitors or ARBs with LCZ696. This decision should be made with the knowledge that the agent provides proven benefits in terms of reduced mortality and fewer re-hospitalisations. n

eurheartj/ehs104; PMID: 22611136 Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131 :e29–322. DOI: 10.1161/ CIR.0000000000000152; PMID: 25520374 Stewart S, MacIntyre K, Hole DJ, et al. More “malignant” than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail 2001;3 :315–22. PMID: 11378002 Senni M, Gavazzi A, Oliva F, et al. In-hospital and 1-year

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CIRCHEARTFAILURE.112.000289; PMID: 23694773 Schrier RW, Abdallah JG, Weinberger HH, et al. Therapy of heart failure. Kidney Int 2000;57 :1418–25. PMID: 10760077 Brewster UC, Setaro JF, Perazella MA. The renin-angiotensinaldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 2003;326 :15–24. PMID: 12861121 Lopez-Sendon J, Swedberg K, McMurray J, et al. Expert consensus document on beta-adrenergic receptor blockers.

Eur Heart J 2004;25 :1341–62. PMID: 15288162 McMurray J, Cohen-Solal A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, betablockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice. Eur J Heart Fail 2005;7 :710–21. PMID: 16087129 CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.

Lancet 1999;353 :9–13. PMID: 10023943 Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344 :1651–8. PMID: 11386263 MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353 :2001–7. PMID: 10376614 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325 :293–302. PMID: 2057034 Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362 :759–66. PMID: 13678868 Nappi JM, Sieg A. Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure. Vasc Health Risk Manag 2011;7 :353–63. DOI: 10.2147/VHRM.S13779; PMID: 21731887 Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364 :11–21. DOI: 10.1056/NEJMoa1009492; PMID: 21073363 Nobakht N, Kamgar M, Rastogi A, et al. Limitations of angiotensin inhibition. Nat Rev Nephrol 2011;7 :356–9. DOI: 10.1038/nrneph.2011.29; PMID: 21502972 Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007;3 :486– 92. PMID: 17717561 Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure, J Am Coll Cardiol 2004;44 :1825–30. PMID: 15519014 McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362 :767–71. PMID: 13678869 Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376 :875–85. DOI: 10.1016/S0140-6736(10)61198-1; PMID: 20801500 de Bold AJ, Borenstein HB, Veress AT, et al. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981;28:89–94. PMID: 7219045 Sudoh T, Kangawa K, Minamino N, et al. A new natriuretic peptide in porcine brain. Nature 1988;332 :78–81. PMID: 2964562 Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphatedependent signaling functions. Endocr Rev 2006;27 :47–72.

PMID: 16291870 Boerrigter G, Burnett JC Jr. Recent advances in natriuretic peptides in congestive heart failure. Expert Opin Investig Drugs 2004;13 :643–52. PMID: 15174950 Zois NE, Bartels ED, Hunter I, et al. Natriuretic peptides in cardiometabolic regulation and disease. Nat Rev Cardiol 2014;11 :403–12. DOI: 10.1038/nrcardio.2014.64; PMID: 24820868 Mangiafico S, Costello-Boerrigter LC, Andersen IA, et al.

Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

Eur Heart J 2013;34 :886–93c. DOI: 10.1093/eurheartj/ehs262; PMID: 22942338 Macheret F, Heublein D, Costello-Boerrigter LC, et al. Human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and BNP. J Am Coll Cardiol 2012;60 :1558–65. DOI: 10.1016/j.jacc.2012.05.049; PMID: 23058313; PMCID: PMC4041520 Forssmann W, Meyer M, Forssmann K. The renal urodilatin system: clinical implications. Cardiovasc Res 2001;51 :450–62.

PMID: 11476735 Ferro CJ, Spratt JC, Haynes WG, et al. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation 1998;97 :2323–30. PMID: 9639376 Martinez-Rumayor A, Richards AM, Burnett JC, et al. Biology

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of the natriuretic peptides. Am J Cardiol 2008;101 :3–8. DOI: 10.1016/j.amjcard.2007.11.012; PMID: 18243856 33. Marcus LS, Hart D, Packer M, et al. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial. Circulation 1996;94 :3184–9. PMID: 8989127 34. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure.

N Engl J Med 2011;365 :32–43. DOI: 10.1056/NEJMoa1100171; PMID: 21732835 35. Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation 2004;110 :1620–5.

PMID: 15337695 36. Sackner-Bernstein JD, Kowalski M, Fox M, et al. Shortterm risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293 :1900–5. PMID: 15840865 37. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111 :1487–91. PMID: 15781736 38. Chen HH, Burnett JC Jr. Therapeutic potential for existing and novel forms of natriuretic peptides. Heart Fail Clin 2006;2 :365– 73. PMID: 17386905 39. Northridge DB, Newby DE, Rooney E, et al. Comparison of the short-term effects of candoxatril, an orally active neutral endopeptidase inhibitor, and frusemide in the treatment of patients with chronic heart failure. Am Heart J 1999;138 :1149– 57. PMID: 10577447 40. Westheim AS, Bostrøm P, Christensen CC, et al. Hemodynamic and neuroendocrine effects for candoxatril and frusemide in mild stable chronic heart failure. J Am Coll Cardiol 1999;34 :1794–801. PMID: 10577572 41. Ando S, Rahman MA, Butler GC, et al. Comparison of candoxatril and atrial natriuretic factor in healthy men.

Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension 1995;26 :1160–6. DOI: 10.1161/01.HYP.26.6.1160 42. Corti R, Burnett JC Jr, Rouleau JL, et al. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation 2001;104 :1856–62. DOI: 10.1161/ hc4001.097191 43. Margulies KB, Perrella MA, McKinley LJ, et al. Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure. J Clin Invest 1991;88 :1636–42. PMID: 1658047; PMCID: PMC295690 44. Nathisuwan S, Talbert RL. A review of vasopeptidase inhibitors: a new modality in the treatment of hypertension and chronic heart failure. Pharmacotherapy 2002;22 :27–42.

PMID: 11794428 45. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106 :920–6. PMID: 12186794 46. Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema, Hypertension 2008;51 :141–7. PMID: 18025295 [PubMed - indexed for MEDLINE] PMCID: PMC2749928 47. Messerli FH, Nussberger J, Vasopeptidase inhibition and angio–oedema, Lancet 2000;356 :608–9. PMID: 10968427 48. Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation 2005 ;111:315–20.

PMID: 15655136 49. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359 :995–1003.

PMID: 11937178 50. Makani H, Messerli FH, Romero J, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol 2012;110 :383–91. DOI: 10.1016/j.amjcard.2012.03.034; PMID: 22521308 51. Toh S, Reichman ME, Houstoun M, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med 2012;172:1582–9. DOI: 10.1001/2013.jamainternmed.34; PMID: 23147456 52. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010;50 :401–14. DOI: 10.1177/0091270009343932; PMID: 19934029 53. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131 :54–61. DOI: 10.1161/ CIRCULATIONAHA.114.013748; PMID: 25403646 54. Kobalava Z, Averkov O, Meray I, et al. Natriuretic peptide

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Kobalava ZhD, Pavlikova EP, Averkov OA, et al. [First experience of clinical application of LCZ696 – an AT1angiotensin receptors and neprilysin inhibitor – in patients with chronic heart failure and reduced ejection fraction].

Kardiologiia 2015;55 :14–25.

Desai AS, McMurray JJ, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36 :1990–7. DOI: 10.1093/eurheartj/ehv186; PMID: 26022006 McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371 :993–1004. DOI: 10.1056/NEJMoa1409077; PMID: 25176015 Claggett B, Packer M, McMurray JJ, et al. Estimating the long-term treatment benefits of sacubitril-valsartan. N Engl J Med 2015;373 :2289–90. DOI: 10.1056/NEJMc1509753; PMID: 26630151 Kristensen SL, Preiss D, Jhund PS, et al. Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights from prospective comparison of ARNI With ACEI to determine impact on global mortality and morbidity in heart failure trial. Circ Heart Fail 2016;9 :pii: e002560. DOI: 10.1161/ CIRCHEARTFAILURE.115.002560; PMID: 26754626; PMCID: PMC4718182 Senni M, Reyes A, Majercak I, et al. Results of the TITRATION study: A 12-week, multicentre, randomized, double-blind, safety evaluation of a 3- versus 6-week up-titration regimen of LCZ696 in patients with HFrEF. Presented at Heart Failure 2015, Seville, Spain, 23–26 May 2015. Presentation 44.

Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380 :1387–95. DOI: 10.1016/S01406736(12)61227-6; PMID: 22932717 Voors AA, Gori M, Liu LC, et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2015;17 :510–7. DOI: 10.1002/ejhf.232; PMID: 25657064 NCT01920711, Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF). Available at: https://clinicaltrials.gov/ct2/show/NCT01920711 (3 November 2015).

Ruilope LM, Dukat A, Böhm M, et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebocontrolled, active comparator study. Lancet 2010;375 :1255–66.

DOI: 10.1016/S0140-6736(09)61966-8; PMID: 20236700 Kario K, Sun N, Chiang FT, et al. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, doubleblind, placebo-controlled study. Hypertension 2014;63 :698–705.

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PMID: 8689816 Gibbs CR, Lip GY, Beevers DG. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol 1999;48 :861–5. PMID: 10594491 Vodovar N, Paquet C, Mebazaa A, et al. Neprilysin, cardiovascular, and Alzheimer’s diseases: the therapeutic split? Eur Heart J 2015;36 :902–5. DOI: 10.1093/eurheartj/ ehv015; PMID: 25636748 Fu Y, Li AF, Shi JJ, et al. Lack of association of neprilysin gene polymorphisms with Alzheimer’s disease in a southern Chinese community. Int Psychogeriatr 2009;21 :354–8. DOI: 10.1017/S1041610208008338; PMID: 19250583 Langenickel TH, Tsubouchi C, Ayalasomayajula S, et al.

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Pharmacological Therapy

LE ATION.

e. lare.

Should Angiotensin Receptor Neprilysin Inhibitors Replace Angiotensin-converting Enzyme Inhibitors in Heart Failure With a Reduced Ejection Fraction?

Sam Hayman 1 and John J Atherton 1,2 1. Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia; 2. University of Queensland, Brisbane, Queensland, Australia

Abstract Angiotensin-converting enzyme inhibitors (ACEIs) have been the cornerstone of treatment of heart failure with reduced ejection fraction (HFrEF) for over two decades. Inhibition of neprilyisin augments vasoactive substances including natriuretic peptides, which may have multiple advantageous effects in chronic HF. Early studies of neprilyisin inhibition led to drug discontinuation due to lack of efficacy or safety concerns. Sacubitril/valsartan is a first-in-class combined angiotensin receptor/neprilysin inhibitor (ARNI). The PARADIGM-HF study demonstrated robust superiority of ARNI compared with enalapril in patients with chronic symptomatic HFrEF, raising the question of whether ACEI should still have a role in the management of HFrEF.

Keywords Angiotensin-converting enzyme inhibitor, angiotensin receptor/neprilysin inhibitor, heart failure Disclosure: SH has no relevant conflicts of interest to declare. JJA has received honoraria, consultancy fees and sponsorship to attend conferences from Novartis.

Received: 6 January 2016 Accepted: 11 March 2016 Citation: Cardiac Failure Review, 2016;2(1):47–50 DOI: 10.15420/cfr.2016:2:2 Correspondence: John J Atherton, Director of Cardiology, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, Brisbane, Queensland 4006, Australia.

E: john.atherton@health.qld.gov.au

Heart failure (HF) is associated with significant morbidity and mortality and confers a major economic burden.1 Large randomised controlled trials (RCTs) have demonstrated that inhibition of the renin–angiotensin– aldosterone and sympathetic nervous systems improve outcomes in patients with HF and a reduced left ventricular ejection fraction (HFrEF) (see Figure 1),2–9 with clinical guidelines recommending angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and mineralocorticoid receptor antagonists in all patients with symptomatic HFrEF unless contraindicated.10–12 However, despite the considerable therapeutic gains made in the field of HFrEF, outcomes remain poor especially in patients with persisting left ventricular systolic dysfunction.

Evidence for Angiotensin-converting Enzyme Inhibitors in Heart Failure The ACEIs was the first class of drug shown to improve survival rates and reduce HF hospitalisation rates in patients with mild, moderate or severely symptomatic HF.2,3 A meta-analysis of RCTs evaluating ACEI in patients with HF reported substantial reductions in total mortality rates (hazard ratio [HR] 0.77; 95 % CI [0.67–0.88]; P<0.001), with consistent benefits across multiple subgroups.4 More recent studies demonstrated that angiotensin receptor blockers (ARBs) also improve outcomes, with clear benefits in patients unable to tolerate ACEIs.13–15 On the basis of these studies, ACEI are given the highest level of evidence in HF clinical guidelines,11,12 with recent registries and real-world studies reporting prescription rates >90 % for ACEI/ARB therapy in eligible patients with HF.16,17

Rationale for Neprilysin Inhibition in Heart Failure Neprilysin is an enzyme that catalyses the degradation of a number of vasoactive compounds, including natriuretic peptides. Natriuretic peptides

© RADCLIFFE CARDIOLOGY 2016

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have multiple actions that could have a favourable effect on HF disease progression including vasodilation, natriuresis and diuresis;18 thus the promotion of natriuretic peptides through exogenous administration or inhibition of neprilysin are attractive therapeutic options. Intravenous nesiritide, a synthetic B-type natriuretic peptide (BNP), was shown to reduce the rates of dyspnoea and pulmonary capillary wedge pressure compared with placebo in the Vasodilation in the Management of Acute Congestive HF (VMAC) study; however, there was no difference in symptom improvement compared with nitroglycerin.19 Furthermore, nesiritide had no effect on death or rehospitalisation rates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study, and is therefore not recommended for routine use.20 The first orally available neprilysin inhibitor, candoxatril, although displaying a dose-dependent increase in atrial natriuretic peptide levels accompanied by natriuresis and haemodynamic benefits in the setting of HF in short-term studies,21,22 was associated with increases in levels of angiotensin II and endothelin, which likely offsets the favourable haemodynamic effects in the absence of renin–angiotensin system inhibition.23,24 Another neprilysin inhibitor, ecadotril, failed to show benefit in a dose-ranging study with a trend towards increased mortality rates.25 The combination ACE–neprilysin inhibitor, omapatrilat, was compared with enalapril in 5,770 patients with HFrEF in the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) study. There was no reduction in the primary endpoint of death or HF hospitalisation, although the secondary endpoint of cardiovascular death or hospitalisation was significantly reduced, as was the primary endpoint in a post-hoc analysis using the Studies of Left Ventricular Dysfunction-

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Pharmacological Therapy Figure 1: Estimated RRR † in Mortality Conferred by Bestpractice Pharmacological Therapy ‡ in HFrEF Patients Extrapolated From RCT Data is 60–70 %

Mortality rate†

18

NYHA 3–4

NYHA 2–3 60

-23%

-31%

50

14

-34%

10

40

-24%

30

6

-30%

20

-38%

10

2

0

SOLVDTreatment

Placebo

MERITHF

EMPHASIS

CONSENSUS

RALES

COPERNICUS

Active treatment‡

†RRR at 12 months used in the SOLVD-Treatment, MERIT-HF, CONSENSUS and COPERNICUS trials; RRR at median follow-up used in the EMPHASIS-HF and RALES trials; ‡angiotensinconverting enzyme inhibitors + beta-blockers + mineralocorticoid receptor antagonists. HFrEF = heart failure with reduced left ventricular ejection fraction; NYHA = New York Heart Association Functional Classification; RCT = randomised controlled trial; RRR = relative risk reduction.

Treatment (SOLVD-T) study definition for hospitalisation.26 A higher rate of angioedema, especially in the setting of hypertension (including rare reports of severe cases) led to withdrawal of the drug.27 The increased rate of angioedema was theoretically attributed to inhibition of ACE, neprilysin and aminopeptidase-P, which are all involved in bradykinin breakdown, given that increased levels of plasma bradykinin has been documented during acute angioedema episodes.28 LCZ696 is a first in the angiotensin receptor–neprilysin inhibitor (ARNI) class that combines the effects of angiotensin receptor blockade with valsartan and neprilysin inhibition with sacubitril. This was designed to have a reduced risk of angioedema compared with omapatrilat, because it does not inhibit ACE or aminopeptidase-P. The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study was stopped early by the data and safety monitoring committee because of overwhelming benefit of LCZ696 compared with enalapril in 8,442 patients with HFrEF.29 There was a highly significant reduction in the primary endpoint of cardiovascular death or HF hospitalisation (HR 0.80; 95 % CI [0.71–0.87]; P<0.001), driven by significant reductions in both cardiovascular death and HF hospitalisation rates. The secondary endpoint, all-cause mortality, was also reduced, accompanied by beneficial effects on quality of life. LCZ696 was well tolerated with fewer patients randomised to receive LCZ696 stopping treatment because of an adverse event compared with the enalapril group.29

Applying the Evidence for Angiotensin Receptor–neprilysin Inhibitors to Clinical Practice When determining whether the results of a clinical trial can be applied to clinical practice, one should consider the population studied, the intervention, the comparator and the outcome measures (referred to as the PICO approach – see Table 1). In the PARADIGM-HF study patients with chronic HFrEF with a left ventricular ejection fraction (LVEF) ≤40 % (later lowered to ≤35 %) were evaluated. Patients had to be symptomatic with an elevated BNP level (or N-terminal proBNP [NTproBNP]) ≥150 (≥600) pg/ml, or ≥100 (≥400) pg/ml if they had been hospitalised for HFrEF within the previous 12 months. They were required to be on a stable dose of an ACEI or an ARB (equivalent to ≥10 mg enalapril daily), and a beta-blocker for at least 4 weeks.

Mineralocorticoid receptor antagonists were encouraged.29 The trial design included a single-blind, run-in phase to ensure that patients could tolerate the recommended target doses for both treatment arms.

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The patients were generally well treated with high levels of evidencebased pharmacological therapies including beta-blockers (93 %) and mineralocorticoid receptor antagonists (60 %).

The intervention evaluated in the PARADIGM-HF study was dual blockade of the renin–angiotensin system and neprilysin.29 This study was not designed to test whether the benefit of LCZ696 was dose related, nor whether the relative effect on these neurohormonal systems varied at different doses. In other words, we cannot assume that superiority over an ACEI (presumably related to the additional effect of neprilysin inhibition) will be maintained at low doses of LCZ696. It is therefore important that when clinicians prescribe LCZ696, they aim for the target dose tested in the PARADIGM-HF study.

An ACEI was chosen as the comparator in the PARADIGM-HF study, given its robust evidence for safety and clinical effectiveness in HFrEF, and that ACEIs are recommended as first-line therapy in all major HF clinical guidelines.11,12 Enalapril was specifically chosen because it has been shown to reduce mortality rates in patients with chronic HFrEF; and the target dose of 10 mg twice daily was the same as that in the SOLVD-T study.3,29 Indeed, the mean daily dose achieved in the PARADIGM-HF study was 18.9 mg, which was higher compared with that in previous HF studies.2,3 The outcome measures chosen in PARADIGM-HF study were robust and clinically relevant, including beneficial effects on symptoms, quality of life, rates of hospitalisation and other health resource utilisation, and mortality rates.29,30 Furthermore, there were no subgroups where the point estimate HR was >1.0. The only pre-specified subgroup with a nominally significant interaction for the primary endpoint (unadjusted for multiple comparisons) was New York Heart Association class; however, there was no significant interaction effect for cardiovascular death. The benefits were observed on top of background therapy with 93 % of patients receiving beta-blockers at the time of randomisation. Although only 55 % of patients were receiving a mineralocorticoid receptor antagonist at the time of randomisation, significant reductions in the primary endpoint and cardiovascular death were observed in patients with or without prior mineralocorticoid receptor antagonist therapy.29 Furthermore, significant reductions in sudden death rates were observed in both patients with and without an implantable defibrillator device.31 Only 7 % of patients had a cardiac resynchronisation therapy device at the time of randomisation; however, the benefits of LCZ696 and cardiac resynchronisation therapy should be maintained in patients who meet the inclusion criteria for these treatments, including a persistent moderate to severe reduction in LVEF.

Limitations of the Evidence for Angiotensin Receptor–neprilysin Inhibitors in Heart Failure The PARADIGM-HF study is the only one supporting the use of ARNI over ACEI in patients with HFrEF. It is nonetheless a large study that was primarily powered to detect a difference in cardiovascular mortality rates. Indeed, the P value achieved for the primary endpoint was equivalent to at least four trials with a P value <0.05.32 On this basis, it would appear unethical to conduct a similar study to confirm the PARADIGM-HF findings.

The most appropriate population to receive ARNI in clinical practice would match those who were studied in the PARADIGM-HF study, namely patients with symptomatic HFrEF despite appropriate doses of ACEI (or ARB) and beta-blockers. Although a clinical trial investigator

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ARNI or ACEI to treat HFrEF?

Table 1: PICO Criteria Applied to the PARADIGM-HF Study 29 PICO criteria Population

PARADIGM-HF Chronic symptomatic HFrEF (LVEF ≤35–40 %) despite ACEI/ARB and

Real-world implementation Consider inclusion criteria

beta-blocker for at least 4 weeks with elevated BNP/NTproBNP

Consider exclusion criteria (especially hypotension) Consider broader application (e.g. treatment-naïve HFrEF)

Intervention

LCZ696 (TD 200 mg twice daily)

Aim for TD

Comparator

Enalapril (TD 10 mg twice daily)

Consistent with current best practice

Outcome

20% RRR CV death

Robust and clinically relevant outcomes

21% RRR HF hospitalisation

Consistent benefit across subgroups

Avoid co-prescription with ACEI

Symptom/quality-of-life benefits ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin Inhibitor; BNP = B-type natriuretic peptide; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced left ventricular ejection fraction; LVEF = left ventricular ejection fraction; NTproBNP = N-terminal pro B-type natriuretic peptide; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PICO = population, intervention, comparator, outcome; RRR = relative risk reduction; TD = target dose.

may argue that the inclusion criteria for a clinical trial should be applied in clinical practice, one should also consider whether this allows clinicians to identify those patients most likely to benefit. For example, the patients enrolled in the PARADIGM-HF study had elevated BNP/NTproBNP levels; however, there was no significant interaction effect for the primary endpoint according to baseline BNP/NTproBNP levels. Therefore, this would not meet the diagnostic test requirements for a co-dependent technology to determine treatment eligibility.

Closer attention should be applied to the exclusion criteria in the PARADIGM-HF study.29 These included hypotension, estimated glomerular filtration rate below 30 ml/min/1.73 m2 of body surface area, hyperkalaemia, and a history of angioedema or unacceptable side effects to ACEI or ARB. Given that fewer patients in the LCZ696 group experienced a serum creatinine level of ≥221 µmol/l or a serum potassium level of >6.0 mmol/l, it would appear that the same restrictions for renal impairment and hyperkalaemia should be applied to ARNI and ACEI. However, hypotension was more common with LCZ696, although this did not lead to more treatment withdrawals. Nonetheless, hypotension may limit uptitration of other disease-modifying therapies including betablockers, and the relative efficacy of low doses of LCZ696 compared with ACEI is unknown. Therefore, it would seem appropriate to avoid LCZ696 and favour ACEI or ARB therapy (at least initially) in patients with symptomatic hypotension or systolic blood pressure <95–100 mmHg. As with most studies that have demonstrated the safety and clinical efficacy of treatments in HF, the patients in the PARADIGM-HF study were on average a decade younger with fewer co-morbidities compared with those enrolled in clinical registries.33 Although there was no significant interaction between treatment efficacy and age, systolic blood pressure, or the presence or absence of diabetes mellitus or chronic kidney disease for the patients enrolled in PARADIGM-HF study,29 clinicians will need to balance the safety and efficacy of LCZ696 in the broader HFrEF population.

Patients with a new diagnosis of HFrEF were not evaluated in the PARADIGM-HF study.29 Such treatment-naïve patients would be more likely to experience side effects, and the relative efficacy of ARNI may be reduced, given that a proportion of HFrEF patients clinically improve

1.

2.

Roger V. Epidemiology of Heart Failure. Circ Res 2013;113 :646– 59. DOI: 10.1161/CIRCRESAHA.113.300268; PMID: 23989710.

Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial

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with substantial reverse remodelling on current best-practice therapy.

One approach could be to start standard therapy (including an ACEI, beta-blocker and mineralocorticoid receptor antagonist) in all patients with a new diagnosis of HFrEF, and to switch the ACEI to LCZ696 in those patients with persistent HFrEF after ≥4 weeks. This may involve repeating the assessment of LVEF, which is currently common practice after 3–6 months in patients with a new diagnosis of HFrEF. However, such an approach would further complicate the medication uptitration process and needs to be tempered with the recently reported early benefits experienced in the LCZ696 group in the PARADIGM-HF study, including a significantly lower rate of HF hospitalisation by 30 days.30 An alternative and reasonable approach would be to prescribe an ARNI in all patients with HFrEF (including those with a new diagnosis) provided there are no contraindications such as previous angioedema or significant hypotension; however, this will be guided by local regulatory and reimbursement processes.

This review has not considered cost effectiveness or total healthcare costs, which will be of interest to payers and jurisdictions that provide reimbursement for pharmaceuticals. Finally, implementing ARNI into clinical practice will need to be accompanied by broad education of multiple healthcare professionals including primary care physicians, pharmacists, HF nurses, cardiologists and geriatricians. This will be particularly important to ensure appropriate prescribing to avoid leakage to patients unlikely to benefit and avoid inadvertent co-prescription of ARNI and ACEI, given that ACEI have been recommended as first-line HFrEF treatment for over two decades.

Conclusion The superiority of ARNI compared with ACEI in chronic HFrEF has been conclusively demonstrated in the PARADIGM-HF study. Although clinical practice will be guided by local regulatory approvals, there is little reason to think that this would not be applicable to the broader HFrEF population, including treatment-naïve patients. However, this should not be at the expense of other disease-modifying therapies, such as betablockers. Finally, given the well-established role of ACEI for over two decades, implementation of ARNI will need to be accompanied by broad education of healthcare professionals involved in HF management. n

Study Group. N Engl J Med 1987;316 :1429–35. PMID: 2883575.

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.

The SOLVD Investigators. N Engl J Med 1991;325 :293–302.

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Garg R, Yusuf S. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. J Am Med Assoc 1995;273 :1450–6.

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spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341 :709–17. PMID: 10471456.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353 :2001–7.

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The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. PMID: 10023943.

Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344 :1651–8. PMID: 11386263.

Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364 :11–21. DOI: 10.1056/NEJMoa1009492; PMID: 21073363.

Krum H, Jelinek MV, Stewart S, et al. 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med J Aust 2011;194 :405–9. PMID: 21495941.

McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14 :803–69. DOI: 10.1093/eurjhf/hfs105; PMID: 22828712.

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62 :e147–239. DOI: 10.1016/j.jacc.2013.05.019; PMID: 23747642.

Pitt B, Poole-Wilson P, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial - the Losartan Heart Failure Survival Study (ELITEII). Lancet 2000;355 :1582– 87. PMID: 10821361.

Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345 :1667–75. PMID: 11759645.

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candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362 :772–6.

PMID: 13678870.

Maggioni AP, Anker SD, Dahlstrom U, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines?

Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15 :1173–84. DOI: 10.1093/eurjhf/hft134; PMID: 23978433.

Bohm M, Tschope C, Wirtz J, et al. Treatment of heart failure in real-world clinical practice: Findings from the REFLECTHF registry in patients with NYHA class II symptoms and a reduced ejection fraction. Clin Cardiol 2015;38 :200–7. DOI: 10.1002/clc.22375; PMID: 25733185.

Potter L, Abbey-Hosch S, Dickey D. Natriuretic peptides, their receptors, and cyclic guanosine monophosphatedependent signaling functions. Endoc Rev 2006;27 :47–72.

PMID: 16291870.

Publication Committee for the VMAC Investigators (Vasodilation in the management of Acute CHF).

Intravenous nesiritide vs nitroglycerin for the treatment of decompensated congestive heart failure: a randomized control trial. JAMA 2002;287:1531–40. PMID: 11911755.

O’Connor C, Starling R, Hernandez A, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365 :32–43. DOI: 10.1056/ NEJMoa1100171; PMID: 21732835.

Northridge DB, Newby DE, Rooney E, et al. Comparison of the short-term effects of candoxatril, an orally active neutral endopeptidase inhibitor, and frusemide in the treatment of patients with chronic heart failure. Am Heart J 1999;138 :1149– 57. PMID: 10577447.

Westheim AS, Bostrom P, Christensen CC, et al.

Hemodynamic and neuroendocrine effects for candoxatril and frusemide in mild stable chronic heart failure. J Am Coll Cardiol 1999;34 :1794–801. PMID: 10577572.

Ando S, Rahman MA, Butler GC, et al. Comparison of candoxatril and atrial natriuretic factor in healthy men.

Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension 1995;26 :1160–6.

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24. McDowell G, Nicholls D. The endopeptidase inhibitor, candoxatril, and its therapeutic potential in the treatment of chronic heart failure in man. Expert Opin Invest Drugs 1999;8 :79–84. PMID: 15992061.

25. Cleland J, Swedberg K, on behalf of The International Ecadotril Multi-centre Dose-ranging Study Investigators. Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. Lancet 1998;351 :1657–8. PMID: 9620738.

26. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106 :920–6. PMID: 12186794.

27. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17 :103–11. PMID: 14751650.

28. Fryer RM, Segreti J, Banfor PN, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol 2008;153 :947–55. PMID: 18084312.

29. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371 :993–1004. DOI: 10.1056/NEJMoa1409077; PMID: 25176015.

30. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131 :54–61. DOI: 10.1161/ CIRCULATIONAHA.114.013748; PMID: 25403646.

31. Desai AS, McMurray JJV, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients.

Eur Heart J 2015;36 :1990–7. DOI: 10.1093/eurheartj/ehv186; PMID: 26022006.

32. McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Fail 2015;17:242–7. DOI: 10.1002/ejhf.250; PMID: 25756942.

33. Newton PJ, Davidson PM, Reid CM, et al. Acute heart failure admissions in New South Wales and the Australian Capital Territory: the NSW heart fasilure snapshot study. Med J Aust 2016;204 :113e1–8. PMID: 26866550.

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Nitrates as a Treatment of Acute Heart Failure Moha mma d S A l z a h r i , 1,2 A n i t a R o h ra 1 a n d W Fra n k Pe a c o c k 1 1. Baylor College of Medicine, Houston, TX, USA; 2. King Saud University, Riyadh, Saudi Arabia

Abstract The purpose of this article is to review the clinical efficacy and safety of nitrates in acute heart failure (AHF) by examining various trials on nitrates in AHF. Management of AHF can be challenging due to the lack of objective clinical evidence guiding optimal management.

There have been many articles suggesting that, despite a benefit, nitrates are underused in clinical practice. Nitrates, when appropriately dosed, have a favourable effect on symptoms, blood pressure, intubation rates, mortality and other parameters.

Keywords Nitrates, nitroglycerine, nitrite, isosorbide dinitrate, nesiritide, nitric oxide, acute heart failure, congestive heart failure, inotropes, pulmonary congestion, pulmonary oedema, vasodilatation Disclosure: WFP has received research grants from Abbott, Alere, Banyan, Cardiorentis, Janssen, Portola, Pfizer, Roche, The Medicine’s Company and ZS Pharma; acted as a consultant for Alere, Cardiorentis, Ischemia Care, Janssen, Phillips, Portola, Prevencio, The Medicine’s Company and ZS Pharma; and has ownership interests in Comprehensive Research Associates LLC and Emergencies in Medicine LLC. MSA and AR have no relevant disclosures.

Received: 4 January 2016 Accepted: 7 April 2016 Citation: Cardiac Failure Review, 2016;2(1):51–5. DOI: 10.15420/cfr.2016:3:3 Correspondence: W Frank Peacock, Ben Taub General Hospital, Emergency Medicine, 1504 Taub Loop, Houston, TX 77030, USA. E: frankpeacock@gmail.com

Acute heart failure (AHF) presents symptoms primarily the result of pulmonary congestion due to elevated left ventricular (LV) filling pressures with or without reduced ejection fraction (EF). Common precipitating pathology includes coronary artery disease (CAD), hypertension and valvular heart diseases, in addition to other noncardiac conditions, such as diabetes, anaemia and kidney dysfunction.1,2 Additionally, AHF poses major medical and socioeconomic burdens.

It represents the most common discharge diagnosis in patients over 65 years of age in the US, and an AHF patient that requires hospitalisation has a 90-day mortality approaching 10 %.3,4 The cornerstone of AHF treatment is diuretics and vasodilators, such as nitrates. Due to a lack of randomised controlled trials, the use of nitrates for management of AHF is not universally adopted.

While organic nitrates are among the oldest treatments for chronic stable angina, they are underutilised in AHF. Organic nitrates are available as sublingual tablets, capsules, sprays, patches, ointments or intravenous (IV) solutions, all of which are potent vasodilators.

Because of the challenges in AHF research, a data imbalance between acute and chronic HF treatment exists as more studies have been performed in the latter. Thus, the current level of evidence for the use of nitrates in AHF is only rated as 1C, i.e., ‘expert opinion’.5,6 The purpose of this article is to review the clinical efficacy and safety data of nitrates in AHF.

How Nitrate Works Mechanism of Action Nitrate-induced vasodilatation starts at cellular level by the activation of the enzyme soluble guanylyl cyclase on nitrate-derived nitric oxide (NO), leading to increased bioavailability of cyclic guanosine-3′,-5′monophosphate (cGMP) and activation of cGMP-dependent protein kinases. Downstream vasodilation resulting from these processes

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requires reduction of intracellular calcium levels by decreasing calcium exit from the cytoplasmic reticulum and reducing its influx from the extracellular space. The decrease in intracellular calcium leads to venous and arterial vasodilation.7,8 More recent studies suggest epigenetic regulation of nitrate-induced smooth muscle relaxation where nitroglycerin may increase histone acetylase activity, and N-lysine acetylation of contractile proteins that may then influence nitroglycerin-dependent vascular responses.9,10 Applied to the patient with congestive HF, vasodilatation induces a substantial reduction in biventricular filling pressure. Moreover, it reduces systemic and pulmonary vascular resistance and systemic arterial blood pressure (BP),11 all of which lead to modest increases in cardiac stroke volume and cardiac output.12 Overall, the two most commonly used IV NO sources used clinically in the setting of AHF is the organic nitrate donor nitroglycerin, and the inorganic nitrate source sodium nitroprusside (SNP). Nitroglycerin potently dilates large arteries (including coronary arteries) but has less effect on smaller arterioles, while SNP is a predominant arteriolar dilator. That makes SNP is effective in recompensating patients with AHF.13 Other important clinical differences between organic and inorganic nitrates are summarised in Table 1.14

Do Nitrates Have any Effect on Acute Heart Failure?

Several studies have suggested that nitrates are ineffective in AHF. The Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC) study was a randomized, controlled AHF trial comparing nesiritide (the recombinant B-type natriuretic peptide) in 204 patients receiving either nitroglycerin (n=143) or placebo (n=142). While this study demonstrated that nitrates are not extremely effective in

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Pharmacological Therapy Table 1: Differences Between the two Main Nitrate Classes Variables Clinical studies in heart failure

Nitroglycerin +

Nitroprusside –

Tolerance

++

–

Effect on coronary blood flow

↑↑

↓

Myocardial ischaemia

↓

↑

Effect on neurohormones

+/-

↑

improving haemodynamics or AHF symptoms, the major criticism is that they tested low, but commonly used, IV nitroglycerin doses, i.e.

30–60 μg/minute.15 In fact, Corstiaan et al., suggested that the 13 μg/ minute median dose of nitroglycerin used in VMAC was too low to improve global haemodynamic parameters. This was demonstrated by the absolute lack of any benefit on haemodynamic parameters between the nitroglycerin-treated patients and those in the placebo arm.16 Similarly, Beltrame et al. in a study evaluating ventilatory parameters in 69 AHF patients, compared 2.5 to 10 mcg/minute of nitroglycerin to morphine and furosemide and found no differences.17 These studies suggest that there is no acute clinical benefit from lowdose nitroglycerin in AHF. In 2015, Turner et al. published a 634 patient systematic review to evaluate the effect, safety and tolerability of IV nitrates in AHF. After searching the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, they found only four randomised controlled trials that met the inclusion criteria of comparing nitrates (isosorbide dinitrate and nitroglycerin) with alternative interventions (furosemide and morphine, furosemide alone, hydralazine, prenalterol, IV nesiritide and placebo) in the management of AHF with a primary outcome of rapidity of symptom relief. The authors stated that there was no difference between nitrate therapy and alternative interventions in regard to symptom relief and haemodynamic variables. However, they also concluded that nitrates were associated with a lower incidence of adverse effects after 3 hours versus placebo, suggesting that the dose may have been inadequate. Ultimately, this systematic review could not draw a firm recommendation or a conclusion as to the optimal therapy given the limitations of such a small number of adequately powered studies.18

Are High-dose Nitrates Effective?

Investigators have addressed the dose-response relationship for the use of nitroglycerin in AHF. In a recent review, Corstiaan et al, proposed the more aggressive use of nitrates and a more conservative use of inotropes in AHF patients with normal or high BP. The dose of nitrates they reported as associated with favorable effects was at least 33 μg/ minute or higher.16 The above conclusions are supported by a number of smaller sized interventions. In a pilot study, Breidthardt et al., randomised 128 AHF patients to standard therapy with or without high-dose sublingual and transdermal nitrates. The median nitrate dose during the first 48 hours in the high-dose group was 82.4 mg versus 20 mg in the standard therapy group, and the primary endpoint was cardiac recovery, as quantified by B-type natriuretic peptide (BNP) levels, in the first 48 hours. Although mean BNP levels decreased in all patients, the decrease was larger in the high-dose nitrate cohort, with most of the decrease in BNP already apparent within 12 hours (decreased by an average of 29±4.9 versus 15±5.4 % in the high- and low-dose groups, respectively; P<0.0001). They concluded that adding a high-dose nitrate strategy to standard therapy accelerates cardiac recovery and was a

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notably safe strategy. Although this study randomised a small number of patients, its baseline characteristics, treatment and in-hospital mortality rates were similar to those reported by large registries.19 Similarly, in an open label, non-randomised trial, Levy et al. studied the effect of high-dose nitroglycerin in severely hypertensive decompensated HF patients. Nitroglycerin dosing consisted of 2,000 mcg every 3 minutes, to a maximum of 20,000 mcg. They foundthigher doses were more effective at decreasing intubation (13.8 versus 26.7 %) and intensive care unit (ICU) admissions (37.9 versus 80.0 %) compared with non-high-dose nitroglycerin. In the high-dose group, a rapid and profound decrease in BP occurred, but without an associated increase in adverse events.20 Finally, an ICU study of 40 severe AHF patients showed benefit from higher-dose nitrates. Patients were randomised to receive either low-dose IV furosemide (40 mg) and high-dose IV isosorbide dinitrate (3,000 mcg) every 5 minutes, or 1 mg/hour of isosorbide dinitrite (ISDN) that was increased every 10 minutes by 1 mg/hour with and high-dose IV furosemide bolus 80 mg repeated every 15 minutes.

They reported high-dose nitrate patients had fewer intubations (20 versus 80 %; P<0.0004), higher oxygenation at 1 hour (96 versus 89 %; P<0.017) and a lower rate of the combined endpoint of death, MI and endotracheal intubation (25 versus 85 %; P<0.0003).21 The studies reviewed in the two sections above suggest that while low-dose nitroglycerin may offer minimal clinically detectable benefit in AHF, higher dose nitroglycerin may provide significant advantages over standard therapy. Also of import is that the rates of adverse events in hypertensive AHF patients receiving high-dose nitrates appear to be low.

Do Nitrates Improve Mortality and Endotracheal Intubation Rates?

Like Sharon et al.,21 Cotter et al. evaluated high-dose nitrates in 110 AHF patients. They randomised patients into two groups: (1) high-dose ISDN (3 mg bolus every 5 minutes) and low-dose furosemide (40 mg IV bolus single dose); (2) low-dose ISDN (1 mg/hour ISDN, increased every 10 minutes by 1 mg/hour) and high-dose IV furosemide (80 mg IV bolus every 15 minutes). They reported that only 20 % of the highdose nitrate cohort required mechanical ventilation versus 80 % in the low-dose group (P<0.001). In addition, the high-dose ISDN group had a more rapid increase in arterial oxygen saturation.22 Other studies have demonstrated potentially beneficial mortality effects with nitrates as well. The Acute Decompensated Heart Failure National Registry (ADHERE) reported, in a propensity scorematched data analysis of hospitalised AHF patients, that those treated with inotropes (dobutamine, dopamine or milrinone) suffered higher mortality than those treated with vasodilators. The authors suggested a benefit of vasodilator therapy on reducing in hospital mortality.23 Using the ADHERE Registry, Peacock et al. demonstrated that early vasoactive initiation is associated with improved outcomes in patients hospitalised for AHF. They examined the relationship between vasoactive time and inpatient mortality within 48 hours of hospitalisation. Vasoactive agents were used early (defined as <6 hours) in 22,788 (63.8 %) patients and late in 12,912 (36.2 %). Median vasoactive time was 1.7 and 14.7 hours in the early and late groups, respectively. In-hospital mortality was significantly lower in the early group (odds ratio, 0.87; 95 % CI [0.79–0.96]; P=0.006), and the adjusted

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odds of death increased 6.8 % for every 6 hours of treatment delay (95 % CI [4.2–9.6]; P<0.0001).24 Finally, Aziz et al. evaluated outcomes in 430 AHF patients receiving diuretics alone (furosemide mean dose is 59 mg), nitroglycerin plus diuretics (nitroglycerin range doses are 5–15 mcg/minute; furosemide mean dose is 75 mg), or neither. They reported 24-month mortality was lower with nitroglycerin plus diuretics (13 %), than either diuretics alone (18 %) or neither (21 %; P=0.002). Of note, all treatments were initiated in the emergency department.25

Potential Mechanism for the Beneficial Effects of Nitrates The exact mechanism for clinical improvement with nitrates is not clearly defined; however, a number of investigators have proposed potential mechanisms. Corstiaan et al., was the first study demonstrating that the nitroglycerin increases the number of patent capillaries in patients with AHF. In this investigation nitroglycerin was given as an IV infusion at a fixed dose of 33 mcg/minute. Using sidestream dark field imaging, sublingual microvascular perfusion was evaluated. They concluded that impaired microcirculation can be improved by the use of a lower dose IV nitroglycerin infusion.16 Another potential mechanism for improved outcomes with nitrates in AHD is the hypothesis that nitrates may improve myocardial stress.

This is reflected in a number of natriuretic peptide studies that have reported decreased BNP levels after initiation of nitrate therapy.19,26 Further, Chow et al. randomised 89 AHF patients to either nesiritide or nitroglycerin. They reported significant reductions in N-terminal proBNP and BNP levels with similar clinical and haemodynamic improvements.27 In this study, both treatments did not have statistically significant effects on morbidity or mortality in this high-risk group of patients.

Finally, vasodilators in general – and nitrates in particular – may provide improved short-term clinical outcomes due to their ability to provide rapid haemodynamic benefits. This is due to their vasodilatory effect that may induce a substantial reduction in right and LV filling pressures, decrease systemic and pulmonary vascular resistance, as well as lower systolic BP (SBP). Ultimately this leads to a downward shift of the ventricular pressure and volume relationship, such that the same volume has lower filling pressures, and myocardial efficiency improves.

Current Practice and Recommendations When not to use Nitrates The current American Heart Association guidelines recommend the use of a vasodilator, e.g., nitrates, in addition to diuretics in patients who do not respond to diuretics alone, and in those with evidence of severe fluid overload in the absence of systemic arterial hypotension (class of recommendation IIa, level of evidence C).6,28 Alternatively, the European Society of Cardiology (ESC) recommends the use of nitrates as a continuous infusion in patients with SBP >110 mmHg, and to be used with caution in patients with SBP between 90 and 110 mmHg (class of recommendation I, level of evidence B).29 While nitrates have been used in AHF for many years, the lack of well-powered studies to support their use has lead to large practice variations. In fact, data from the EuroHeart Failure survey showed that in some regions of Europe nitrates are given to 70 % of patients presenting with AHF versus as little as 6 % in other regions.30 Similar findings were reported from the US ADHERE registry.23 Similarly, the

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Heart Failure Association of the ESC, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine published a recommendation on pre-hospital and early hospital management of AHF. They recommended that when SBP is normal to high (>110 mmHg), IV vasodilator therapy might be given for symptomatic relief as an initial therapy. Alternatively, sublingual nitrates may be considered.31 The Canadian Cardiovascular Society Heart Failure updated their management guidelines for AHF in 2012 as the following: We recommend the following intravenous vasodilators, titrated to SBP >100 mmHg, for relief of dyspnea in haemodynamically stable patients (SBP >100 mmHg): 1. Nitroglycerin (strong recommendation, moderate-quality evidence); 2. Nesiritide (weak recommendation, high-quality evidence); 3. Nitroprusside (weak recommendation, low-quality evidence).32 Like all vasodilators, nitrates are contraindicated in the setting of hypotension, as well as in LV outflow tract obstruction, and in AHF mimics (e.g., chronic obstructive pulmonary disease) where vasodilation is unlikely to provide a benefit. Furthermore, nitrates may result in excessive hypotension if there is concurrent vascular obstruction as occurs in pulmonary embolus. They should be used with caution in patients whom are preload dependent, and never in patients who are on phosphodiesterase inhibitors (i.e., sildenafil, tadalafil, vardenfil, etc.).

Challenges to Current Guidelines Treatment algorithms suggested by recent ESC guidelines recommend the administration of diuretics to all patients with congestion and the addition of vasodilators (e.g., IV nitrates) if SBP is >110 mmHg. Despite this, the range of patients receiving concurrent vasodilator therapy is large. In a retrospective, observational study from the ESC-HF LongTerm Registry, 211 cardiology centres from 21 ESC member countries enrolled 12,440 patients (40.5 % with AHF) between 2011 and 2013.

They found only 6.8 % of patients with a SBP >110 mmHg received vasodilators. Overall, treatment with IV nitrates is not adherent to guideline recommendations, and the authors suggest the variation in clinical practice may be the result of a lack of large randomised controlled trial evidence.33 The lack of quality research to support guidelines has been discussed by others: Cotter et al., in 2014, stated “despite a generation of clinical research we continue to treat patients with AHF with iv therapies during the first days of admission based on little or no evidence.

Recent attempts to improve our knowledge base by examining the effects of such therapies in small, underpowered studies only add to this lack of certainty by reporting mostly equivalent results within wide confidence intervals. Hence, our clinical practice continues to be uninformed and we may very well be under treating patients by denying them effective therapies simply because we do not know they if are effective or administering therapies that cause harm because we do not know they do cause harm.”34 Conversely, it is important to mention Wakai et al., in a Cochrane review, could not contradict the current recommendation as their review could offer no evidence to alter the current standard use.35

Side Effects and Tolerance Physicians have a long-term familiarity with nitrates as they have been used in ischaemic heart disease for years, with well-described side

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Pharmacological Therapy effects. This is less so in AHF; however, the existing data suggests a relatively large safety margin. The VMAC study reported headache (in 20 %) and symptomatic hypotension in 5 % as the most common adverse events during the first 24 hours after start of nitroglycerin therapy.15 Apart from these potential adverse events, a major drawback of nitrate therapy is resistance and tolerance. HF patients may be uniquely resistant to nitrates, thus explaining the need for larger than standard doses. To evaluate this possibility, a group of investigators studied femoral artery blood flow velocity differences after nitroglycerin in normal versus HF subjects. They reported attenuated vasodilatory response to IV nitroglycerin in AHF patients that was independent of prior nitrate use, suggesting that an underlying nitrate resistance may affect dosing requirements in AHF patients.36 Beyond baseline resistance, a rapid decrease in initially effective doses, known as tolerance, may occur with nitrates.

The physiology of nitrate tolerance is still unclear. Various hypotheses include that it may be due to activation of neurohormoal systems (i.e., pseudo tolerance) versus a true vascular tolerance, the activation of vasoconstrictive mechanisms in blood vessels, impaired nitroglycerin biotransformation, increased vascular superoxide production, desensitisation of soluble guanylate cyclase or impaired endogenous NO production.37 Which is the dominate cause requires additional investigations. In a recent review of many small studies, Munzel et al. stated that nitrate tolerance is a complex phenomenon caused by abnormalities in the biotransformation and signal transduction of nitrates and by activation of counterregulatory mechanisms.38 However, while tolerance may be a challenge when treating chronic decompensated HF, the fact that it is not seen for several hours makes nitrates suitable for AHF. Strategies suggested to overcome nitrate tolerance are to increase the dosage, or adding hydralazine concurrently (75 mg four times per day).39 The favourable interaction between hydralazine and nitrates has been demonstrated in the Veterans Heart Failure Trial (V-HeFT) and in the African-American Heart Failure Trial (A-HeFT). This study showed beneficial effects on LV function and exercise capacity; most

1.

2.

3.

4.

5.

6.

7.

Cleland JG, Swedberg K, Follath F, Komajda M. The Euro Heart Failure Survey Programme: a survey on the quality of care among patients with heart failure in Europe, part 1: patient characteristics and diagnosis. Eur Heart J 2003;24:442–63.

PMID: 12633546.

Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011].

Cochrane Collaboration 2011.

Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209–16. PMID: 15846257 Fonarow GC, Abraham WT, Albert N, Gattis W. Impact of evidence-based heart failure therapy use at hospital discharge on treatment rates during follow-up: a report from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol 2005;45:345A. DOI: 10.1161/ CIRCHEARTFAILURE.107.748376 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293–302.

PMID: 2057034 Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154–e235.

DOI: 10.1161/CIRCULATIONAHA.105.167586.

Ignarro LJ, Lippton H, Edwards JC, et al. Mechanism of

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8.

9.

10.

11.

12.

13.

14.

15.

16.

importantly it has been shown to improve survival in large studies in patients with severe heart failure. Although prevention of tolerance is only one of the possible mechanisms to explain the benefit of this combination.40,41 Other strategies to overcome nitrates tolerance is allowing nitrate-free interval. This strategy is more applicable in managing chronic heart failure.42

Potential Future Vasodilator for Acute Heart Failure: Nitrite It is well documented that patients receiving IV organic nitrate develop haemodynamic tolerance in as little as 4 hours. Nitrite (NaNO2) does not suffer this limitation and thus may have a future therapeutic role. Physiologically, in healthy subjects, NaNO2 selectively dilates pulmonary capacitance vessels and results in a modest reduction in systemic arterial pressure. However, clinical outcomes in AHF with NaNO2 are less clearly defined.

Ormerod et al., reported the first in-human HF efficacy/safety study of short-term NaNO2 infusion. In 25 patients with severe chronic HF, 5 minutes of IV NaNO2 resulted in a 29 % and 40 % decrease in pulmonary vascular resistance and right atrial pressure, respectively, but only a 4 mmHg decrease in mean arterial pressure. They concluded that NaNO2 has an attractive profile during short-term IV infusion, may have favorable effect in decompensated HF and warrants further evaluation with longer infusion regimens.43

Conclusion A case for the early use of high-dose nitrates in AHF can be made based on the current literature. This is supported by the knowledge of their mechanism of action given the unique combination of microvascular and haemodynamic effects. Consistent with guideline recommendations, in the absence of systemic hypotension, nitrates appear to be a safe and effective. Initial data suggest that when highdose nitrates are used, they are associated with improved symptoms and reduced mortality in AHF patients. Future research is needed to support future clinical adoption. n

vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates.

J Pharmacol Exp Ther 1981;218:739–49. PMID: 6115052 De Luca L, Fonarow GC, Adams KF Jr, et al. Acute heart failure syndromes: clinical scenarios and pathophysiologic targets for therapy. Heart Fail Rev 2007;12:97–104. PMID: 17487581 Schlossmann J, Feil R, Hofmann F. Insights into cGMP signalling derived from cGMP kinase knockout mice.

Front Biosci 2005;10:1279–89. PMID: 15769624 Chen Z, Zhang J, Stamler JS. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci USA 2002;99:8306–11. PMID: 12048254 Colussi C, Scopece A, Vitale S, et al. P300/CBP associated factor regulates nitroglycerin-dependent arterial relaxation

by N(epsilon)- lysine acetylation of contractile proteins.

Arterioscler Thromb Vasc Biol 2012;32:2435–43. DOI: 10.1161/ ATVBAHA.112.254011; PMID: 22859492 Münzel T, Steven S, Daiber A. Organic nitrates: Update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascul Pharmacol 2014;63:105–13.

DOI: 10.1016/j.vph.2014.09.002; PMID: 25446162 Sellke F, Tomanek R, Harrison D. L-cysteine selectively potentiates nitroglycerin-induced dilation of small coronary microvessels. J Pharmacol Exp Ther 1991;258:365–9. PMID: 1906539 Vizzardi E, Bonadei I, Rovetta R, D’Aloia A. When should we use nitrates in congestive heart failure? Cardiovasc Ther 2013;31:27–31. DOI: 10.1111/j.1755-5922.2012.00311.x; PMID: 22953723 Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). IV nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531–40. PMID: 11911755 den Uil CA, Brugts JJ. Impact of IV nitroglycerin in the management of acute decompensated heart failure.

Curr Heart Fail Rep 2015;12:87–93. DOI: 10.1007/s11897-0140230-8; PMID: 25301529 17. Beltrame JF, Zeitz CJ, Unger SA, et al. Nitrate therapy is an alternative to furosemide/ morphine therapy in the management of acute cardiogenic pulmonary edema.

J Card Fail 1998;4:271–9. PMID: 9924848 18. Turner J, Kirschner J. Do IV nitrates improve dyspnea in acute heart failure syndromes more than alternative pharmacologic interventions? Ann Emerg Med 2015;66:27–9. DOI: 10.1016/j. annemergmed.2014.08.041 19. Breidthardt T, Noveanu M, Potocki M, Reichlin T. Impact of a high-dose nitrate strategy on cardiac stress in acute heart failure: a pilot study. J Intern Med 2010;267:322–30. DOI: 10.1111/j.1365-2796.2009.02146.x; PMID: 19694900 20. Levy P, Compton S, Welch R, Delgado G. Treatment of severe decompensated heart failure with high-dose IV nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med 2007;50:144-52. PMID: 17509731 21. Sharon A, Shpirer I, Kaluski E, et al. High-dose iv isosorbidedinitrate is safer andbetter than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema.

J Am Coll Cardiol 2000;36:832–7. PMID: 10987607 22. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary edema. Lancet 1998;351:389–93.

PMID: 9482291 23. Costanzo MR, Johannes RS, Pine M, et al. The safety of IV diuretics alone versus diuretics plus parenteral vasoactive therapies in hospitalized patients with acutely decompensated heart failure: a propensity score and instrumental variable analysis using the Acutely Decompensated Heart Failure National Registry (ADHERE) database. Am Heart J 2007;154:262–77. PMID: 17643575 24. Peacock WF, Emerman C, Costanzo MR, et al. Early vasoactive drugs improve heart failure outcomes. Congest Heart Fail 2009;15:256–64. DOI: 10.1111/j.1751-7133.2009.00112.x;

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PMID: 19925503 25. Aziz EF, Kukin M, Javed F, et al. Effect of adding nitroglycerin to early diuretic therapy on the morbidity and mortality of patients with chronic kidney disease presenting with acute decompensated heart failure. Hosp Pract 1995;39:126–32.

DOI: 10.3810/hp.2011.02.382; PMID: 21441767 26. Nelson GI, Silke B, Ahuja RC, et al. Haemodynamic advantages of isosorbide dinitrate over furosemide in acute heart failure following myocardial infarction. Lancet 1983;1:730–3. PMID: 6132082 27. Chow SL, O’Barr SA, Peng J, et al. Modulation of novel cardiorenal and inflammatory biomarkers by IV nitroglycerin and nesiritide in acute decompensated heart failure. Circ Heart Fail 2011;4:450–5. DOI: 10.1161/ CIRCHEARTFAILURE.110.958066; PMID: 21576282 28. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2013;62:e147–e239. DOI: 10.1161/ CIR.0b013e31829e8807; PMID: 23741057 29. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the diagnosis and management of heart failure in adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:1977–2016. DOI: 10.1161/CIRCULATIONAHA.109.192064; PMID: 19324967 30. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart

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failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69. DOI: 10.1093/eurjhf/hfs105; PMID: 22828712 Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail 2015;17:544–58. DOI: 10.1002/ejhf.289 McKelvie RS, Moe GW, Ezekowitz JA, et al. The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. Can J Cardiol 2013;29:168–81. DOI: 10.1016/j.cjca.2012.10.007; PMID: 23201056 Maggioni AP, Anker SD, Dahlstrom U, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines?

Evidence from 12 440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173–84.

DOI: 10.1093/eurjhf/hft134; PMID: 23978433 Cotter G, Davison B. IV therapies in acute heart failure–lack of effect or lack of well powered studies? Eur J Heart Fail 2014;16:355–7. PMID: 24578198 Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev 2013;CD005151.

DOI: 10.1002/14651858.CD005151.pub2; PMID: 23922186 Dupuis J, Lalonde G, Lemieux R, et al. Tolerance to IV NTG in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack

of prevention with N-acetylcysteine. J Am Coll Cardiol 1990;16:923–31. PMID: 1976661 37. Gori T, Mak SS, Kelly S, Parker JD. Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans. J Am Coll Cardiol 2001;38:1096–101.

PMID: 11583888 38. Munzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance.

Circulation 2011;123:2132–44. DOI: 10.1161/ CIRCULATIONAHA.110.981407; PMID: 21576678 39. Gogia H, Mehra A, Parikh S, et al. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine. J Am Coll Cardiol 1995;26:1575–80. DOI: 10.1161/ CIRCULATIONAHA.110.981407; PMID: 21576678 40. Cohn JN, Tam SW, Anand IS, et al. Isosorbide dinitrate and hydralazine in a fixed-dose combination produces further regression of left ventricular remodeling in a welltreated black population with heart failure: results from A-HeFT. J Card Fail 2007;13:331–9. PMID: 17602978 41. Gogia H, Mehra A, Parikh S, et al. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure. J Am Coll Cardiol 1995;26:1575–80. PMID: 7594088 42. Packer M, Lee WH, Kessler PD, et al. Prevention and reversal of nitrate tolerance in patients with congestive heart failure.

N Engl J Med 1987;317:799–804. PMID: 3114637 43. Ormerod JO, Arif S, Mukadam M, Evans JD. Short-term IV sodium nitrite infusion improves cardiac and pulmonary hemodynamics in heart failure patients. Circ Heart Fail 2015;8:565–71. DOI: 10.1161/CIRCHEARTFAILURE.114.001716; PMID: 25838311

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LE ATION.

e. lare.

Shock Management for Cardio-surgical Intensive Care Unit Patient: The Silver Days T ill Ha uffe, Bern a r d K r ü g e r, D o m i n i q u e B e t t e x a n d A l a i n Ru d i g e r Cardiosurgical Intensive Care Unit, Institute of Anaesthesiology, University Hospital Zurich, Switzerland

Abstract Shock in cardio-surgical intensive care unit (ICU) patients requires prompt identification of the underlying condition and timely therapeutic interventions. Management during the first 6 hours, also referred to as “the golden hours”, is of paramount importance to reverse the shock state and improve the patient’s outcome. The authors have previously described a state-of-the-art diagnostic work-up and discussed how to optimise preload, vascular tone, contractility, heart rate and oxygen delivery during this phase. Ideally, shock can be reversed during this initial period. However, some patients might have developed multiple organ dysfunction, which persists beyond the first 6 hours despite the early haemodynamic treatment goals having been accomplished. This period, also referred to as “the silver days”, is the focus of this review. The authors discuss how to reduce vasopressor load and how to minimise adrenergic stress by using alternative inotropes, extracorporeal life-support and short acting beta-blockers. The review incorporates data on fluid weaning, safe ventilation, daily interruption of sedation, delirium management and early rehabilitation. It includes practical recommendations in areas where the evidence is scarce or controversial. Although the focus is on cardio-surgery ICU patients, most of the considerations apply to critical ill patients in general.

Keywords Shock, cardiac surgery, levosimendan, esmolol, extracorporeal life support (ECLS), acute kidney injury, nutrition, fluid overload Disclosure: The authors have no conflicts of interest to declare.

Received: 11 November 2015 Accepted: 24 March 2016 Citation: Cardiac Failure Review, 2016;2(1):56–62 DOI: 10.15420/cfr.2015:27:2 Correspondence: PD Dr med A Rudiger, Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. E: alain.rudiger@usz.ch

Shock in cardio-surgical intensive care unit (ICU) patients is a serious condition associated with a high morbidity and mortality.1,2 Prompt identification of the underlying condition and timely therapeutic interventions are key to reverse the shock state and to improve the patients’ outcome. Hence, the management during the first 6 hours is of paramount importance. This time period is also referred to as “the golden hours”. Ideally, a correct diagnosis is established allowing specific treatments. The authors have previously described a state-ofthe-art diagnostic work-up and discussed how to optimise preload, vascular tone, contractility, heart rate and oxygen delivery during this phase.3 Ideally, shock can be reversed during this initial period, however some patients might have developed multiple organ dysfunction that persists beyond the first 6 hours despite the early haemodynamic treatment goals been accomplished.4 This period, also referred to as “the silver days”, is the focus of this review. The authors discuss the management of organ dysfunction in critically ill patients after cardiac surgery. The following recommendations (summarised in Table 1) are not exclusive, rather they highlight some important considerations to be made while treating these patients after the initial resuscitation phase.

Methods For this narrative review, a search of the PubMed database and a review of bibliographies from selected articles were performed to identify original data relating to this topic. Key words used for the search were, among others, “haemodynamic management” “vasopressors”, “levosimendan”, inotropes”, inotropic therapy”, “nutrition”, “sedation”, “ventilation”, “weaning from mechanical ventilation”, “delirium” and

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“procalcitonin”. National and international guidelines were reviewed and integrated, e.g. the “Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure” of the European Society of Cardiology (ESC)5 and the “Consensus on circulatory shock and haemodynamic monitoring“ from the Task force of the Society of Intensive Care Medicine (ESICM).6 Articles were scrutinised regarding their study design, population evaluated, interventions, outcomes and limitations. Finally, personal recommendations were included and highlighted as such to give a comprehensive overview on this topic.

Optimise Haemodynamics Reduce Vasopressor Load The optimal mean arterial blood pressure (MAP) under vasopressor therapy is still under investigation. For patients with septic shock, no benefit was found after increasing the MAP by use of vasopressors above 65–70 mmHg.7 Moreover, higher vasopressor loads were associated with higher mortality.8 However Asfar et al. showed that targeting a MAP of 80–85 mmHg in patients with chronic arterial hypertension reduced the incidence of renal replacement therapy.7 Therefore, the authors follow the recommendations of the 2014 consensus report of the ESICM6 and target an individualised blood pressure rather than fixed MAP-goals after the first phase of lifesaving measures. In patients that remain anuric despite a MAP of 70 mmHg, the blood pressure target is reduced. In patients with critical vascular stenosis or right heart failure, the MAP is not reduced

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Table 1: Summary of Recommendations During Shock Management for Cardio-surgical Intensive Care Unit Patient (The Silver Days) Diagnosis

• Re-evaluate the diagnosis and treat the underlying disease.

Haemodynamic

• Consider a reduction of the MAP goal.

management

• Consider levosimendan in patients with impaired cardiac contractility.

• Consider extracorporeal life support as bridge to recovery, bridge to transplant or bridge to destination in prolonged states of shock and patients with increased risk of hypoperfusion.

• Treat non-compensatory tachycardia with esmolol, aim for a heart rate between 80 to 95 BPM.

Renal replacement therapy

• CVVHD in patients with fluid overload not responding to diuretics, metabolic acidosis (pH <7.2) or potassium levels >6.0 mmol/l.

Lung-protective ventilation

• Select tidal volume of 6 ml/kg ideal body weight.

• Limit plateau pressure to < 30 mbar.

• Consider deleterious heart lung-interactions with high PEEP.

Nutrition

• Start enteral nutrition with 5 kcal/kg when shock resolves.

• Increase daily caloric intake to 25 kcal/kg ideal body within 4 days.

• Consider parenteral nutrition from day four if caloric intake is <60 % of target and increase supplementation stepwise to 80 % of target.

Control blood glucose

• Target 4.5–8.5 mmol/l with continuous insulin infusion.

Sedation/delirium

• Use light sedation, define RASS target.

• Prefer short acting sedatives.

• Interrupt sedation daily if long-acting sedatives are used.

• Identify and treat delirium.

Reassess antibiotic

• Switch to more specific treatment.

treatment

• Consider termination of an empirical antibiotic therapy, if no organism is identified and shock has resolved.

BPM = beats per minute; CVVHD = continuous veno-venous haemodyalisis; MAP = mean arterial pressure; PEEP = positive end-exspiratory pressure; RASS = Richmond Agitation–Sedation Scale

<65 mmHg. In all others, MAP targets are continuously reduced and sometimes tolerated as low as 50 mmHg in order to reduce the amount of vasopressors necessary.

without a bolus, if systolic blood pressure is >100 mmHg with low dose vasopressors (noradrenaline <0.1 mcg/kg/min). Experimental and clinical studies also suggest an improvement of cardiac function with levosimendan in patients with septic shock.17,24

Consider Alternative Inotropes Beta-adrenergic drugs have been associated with considerable risks including adverse effects on metabolism, bacterial growth and alterations of the innate immune response.9–13 Also, the amount and duration of catecholamines is independently associated with adverse cardiac events such as tachyarrhythmia and prolonged elevated heart rate.14 Hence, efforts are necessary to limit the use of these drugs as much as possible.

One alternative is the inodilator levosimendan. It increases the troponin C affinity for Ca2+, which results in strengthening of the myocardial contraction without increasing oxygen demand.15 Also, it has vasodilatorproperties via activation of ATP-dependent potassium channels.16 The use of Levosimendan in cardiogenic shock is controversial because patients with cardiogenic shock have been excluded in safety studies as levosimendan causes vasodilation.17 It is recommended by the 2013 ESC guidelines on heart failure in cardiogenic shock and second line treatment for low output heart failure if the effect of beta blockage is thought to be the reason for hypoperfusion.5 The Levosimendan Infusion versus Dobutamine (LIDO) study showed a survival benefit of levosimendan after 6 months.16,18 The Survival Of Patients With Acute Heart Failure In Need Of Intravenous Inotropic Support (SURVIVE) study found an advantage in patients with decompensated chronic heart failure previously treated with beta blockers.17,19,20 Another study showed the combination of levosimendan and dobutamine to be more effective compared to dobutamine alone.21 In cardiac surgery, levosimendan has shown to produce a dose dependent effect on stroke volume, also when given preoperatively in patient at risk, and to shorten length of ICU stay.22 It is the only inotrope which might decrease the mortality after cardiac surgery.23 The authors use levosimendan for persisting heart failure after shock resolution, weaning failure from inotropic therapy, or weaning from extracorporeal life support (ECLS) with a dose of 0.1–0.2 mcg/kg/min

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Evaluate Mechanical Support In situations with increasing inotrope requirements or inadequate oxygen delivery despite high doses of inotropes, mechanic circulatory support must be evaluated.25 ECLS with an extracorporeal membrane oxygenator can be established quickly in experienced hands and offers an opportunity for temporary haemodynamic support.26 This might give time for decision-making (bridge to decision) or for the ventricle to recover (bridge to recovery). The ESC guidelines give IIb and IIa recommendations for short-term mechanical support as a bridge to decision and bridge to recovery, respectively.5 In patients with multiple organ dysfunctions mortality rates may be excessively high, prohibiting the use of ECLS in this particular patient population.27 Recently, the concept of awake ECLS has been introduced.28 The benefits of having patients on ECLS without mechanical ventilation include the possibility to assess the patients’ cognitive functions. It also allows interaction with the patient and the possibility to inquire his will, particularly in view of future therapeutic options (ventricular assist device, transplantation).

As positive pressure ventilation and sedation can be avoided, patients awake on ECLS have a better haemodynamic stability.

In selected patients with persisting cardiogenic shock under optimised pharmacologic therapy and/or weaning failure from ECLS, commercially available left- or biventricular assist devices (LVAD or BVAD) will provide sufficient organ perfusion for everyday life. These devices may be used in end-stage heart failure patients before heart transplantation (bridge to transplantation).26 Mechanical support will allow early rehabilitation leading to improved nutritional state, muscle strength and physical performance status. According to the ESC heart-failure guidelines, LVADs are a IIa indication for long-term use when transplantation is not possible (bridge to destination).5

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Acute Heart Failure Table 2: Advantages and Risks of Extracorporeal Life Support ECLS Device

Advantages

Problems, Risks

Comments, Recommendations

References

Intra-aortic balloon

• Left ventricular afterload-

• Limb ischaemia

• No benefit on 30-day mortality in

25,33,127

pump

reduction

• Infections

patients with myocardial infarction

• 20 % decrease in wall tension

• Bleeding

complicated by cardiogenic shock

• Increase in coronary blood flow

• Thrombo-embolic

• No general recommendation for

(collateral flow)

complications

use in cardiogenic shock

Extracorporeal

• Emergency biventricular support

• Peripheral cannulation: retrograde

• 75 % survival rate for acute

membrane

• Temporary bridge

flow, competing with normal

myocarditis

oxygenation

• Peripheral or central canulation

blood flow

• Overall survival to discharge: 58 %

26, 28, 29

• Difficult weaning • Bleeding • Thromboembolism • Limb ischaemia • Infections Ventricular assist

• Decompression of the left/right

• Anticoagulation required

• Selected patients with end-stage

device

ventricle

• Intra-cardiac shunts or aortic

heart failure despite optimal

(left- or

• Optimising organ-perfusion

insufficiency prevent sufficient

pharmacological treatment and

bi-ventricular)

• Bridge to transplantation

decompression

who are otherwise suitable

• Bridge to destination (one year

• Right heart failure by increase

for heart transplantation

survival 86 %)

in RV volume, loss of septal

• Patients not suitable for heart

contribution to RV output, increase

transplantation, but expected to

myocardial work; RV function must

survive >1 year with good functional

be assessed beforehand

status (Class IIa; Level B)

25,26,32

• Drive line/cannula infection • Bleeding • Thromboembolism • Haemolysis • Arrhythmias • Timing RV = right ventricular

Increased cardiac output by a LVAD may enlarge right ventricular (RV) volume load and cause RV-failure. Therefore, RV function must be assessed before considering the implantation of a LVAD.25 Surely the decision should be made in a multidisciplinary approach by experts due to the invasive nature of these devices. Complications may be related to the mandatory use of anticoagulation (bleeding, thromboembolism), mechanical shear stress on cellular blood components (haemolysis) and long-term infections of the implanted materials (drive line, cannulas, device).25,26,29–33 A summary of the advantages and risks of ECLS is provided in Table 2.

Control Heart Rate Adrenergic stress might induce inflammation and contribute to the pathogenesis of organ dysfunction.12,34 Hence, the use of beta-adrenergic drugs must be limited to a minimum. Taking this concept to the next level, the theoretical benefits of beta-blockers during critical illness have been discussed.35 Recently, Morelli et al. tested the effects of esmolol in septic patients.36 He included high-risk patients, who required noradrenaline and had a heart rate ≥95 beats per minute (BPM) despite 24 hours of haemodynamic optimisation (MAP ≥65 mmHg, pulmonary artery occlusion pressure ≥ 12 mmHg, SvO2 ≥65 %). Esmolol was started at a dose of 0.5 mg/min and increased by 0.5–1.0 mg/min increments at 20-minute intervals to an upper dose limit of 30 mg/min. The goal was a heart rate reduction to a rate between 80 to 94 BPM. If mixed venous oxygen saturation (SmvO2) decreased below 65 % and/or arterial lactate concentrations increased despite appropriate oxygenation (SaO2 ≥95 %) and a haemoglobin concentration ≥8 g/dl, levosimendan

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was administered at a dose of 0.05–0.2 mcg/kg/min for 24 hours.

In their cohort study from 2013, the authors showed improvements in stroke volume, a decrease in norepinephrine requirement and a reduction of mortality.36 If these results are confirmed in future multicentre trials, this concept might revolutionise current practice in sepsis management. Potentially, this new concept might be usefully expanded to other critical ill patients with non-compensatory tachycardia.

A reduction in heart rate will allow a better ventricular filling in patients with diastolic myocardial dysfunction, resulting in an increase in stroke volume. The same is true for patients with supraventricular arrhythmias and atrial fibrillation (AF) with a high ventricular response rate.37 Additionally, a reduction in heart rate will reduce myocardial oxygen expenditure, hence inducing cardio-protection. However, some patients will have a high heart rate in order to compensate for a low stroke volume and/or an insufficient oxygen delivery. In these patients, prolonged heart rate reduction will result in haemodynamic collapse and eventually death. Hence, short-acting drugs should be used in patients in which it is unclear whether tachycardia is compensatory or not. In such situations, the authors use esmolol, a selective beta1blocker with a short half-life of 9 minutes, as an intravenous bolus (10–20 mg-wise up to 1 mg/kg), followed by a continuous infusion of 0.05 mg/kg/min. The infusion rate can be increased every 30 minutes if needed. Of note, the negative inotropic effects of esmolol must be balanced against the potential benefits, and close haemodynamic monitoring including echocardiography is mandatory in unstable patients treated with beta-blockers.

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Start Fluid Weaning Fluid resuscitation is one of the corner stones of shock therapy to restore tissue perfusion.38 However, it was demonstrated that a liberal fluid regime increased mortality and morbidity in a diverse group of patients.39 Targeting a central venous pressure (CVP) between 8–12 mmHg seemed to impair the microcirculation, was a risk factor for acute kidney injury (AKI) and increased mortality.39 The underlying mechanism seems to be a consecutive reduction in renal blood flow and glomerular filtration rate by a high venous pressure.39,40 Of note, there is no good correlation between CVP and fluid responsiveness41–43 and therefore other preload variables should be used.44

• Strict hand disinfection, • oral hygiene with application of chlorhexidin, • elevation of upper body >30° (if possible from a haemodynamic point of view), • defined weaning and sedation protocols, • continous subglottical suction, • cuffpressure-control, • daily reevaluation of gastric ulcer prophylaxis, • Routine change of ventilator circuits and filters.

Manage Acute Renal Dysfunction Understand Renal Dysfunction

Since fluid overload leads to increased morbidity in acute respiratory distress syndrome,45 pancreatitis46 and sepsis,47 the authors recommend a conservative fluid regime with fluids being administered preferably after assessing responsiveness.6 As soon as the patient has stabilised and noradrenaline requirements are below 10 mcg/min, fluid weaning is started. In haemodynamic stabile patients with AKI, protocolled renal replacement therapy (RRT) allows large negative fluid balances.48 Net fluid removal usually causes improvements in lung function, therefore leading to a reduction in ventilation days. Reduction of oedema in the bowel and the extremities will facilitate nutrition and mobilisation of the patient.

Ventilate Safely The authors use also the concept of lung-protective ventilation derived from acute respiratory distress syndrome (ARDS) patients for ICU patients with normal lungs. A tidal volume of ≤6 ml/kg should be chosen with plateau pressure of <30 mbar. Positive end-expiratory pressures (PEEP) are increased with increasing oxygen requirements.

However, high PEEP levels increase RV afterload and might cause RV dysfunction.49 These heart-lung interactions might reduce RV stroke volume and consequently cardiac output, thereby decreasing oxygen delivery to the periphery. In case of further aggravation of hypoxaemia under increased PEEP, a persisting foramen ovale should be excluded.

Hypercarbia causes pulmonary vasoconstriction and increases RV afterload, thus normoventilation should be targeted if possible in patients with pulmonary artery hypertension and/or RV dysfunction.

Another risk of invasive ventilation is ventilator associated pneumonia (VAP), which was defined by the following criteria during a time frame of 48 hours after intubation:50,51 • • • • •

new or progressive pulmonary infiltrates; fever; leucocytosis; purulent secretion; reduction of the PaO2:FiO2 ratio by ≥ 15 %.

In the American Thoracic Society definition from 2005, VAP is defined as pneumonia occuring 48–72 hours after intubation.52 However, diagnosis of VAP remains difficult as criteria are nonspecific and symptoms overlap as in conditions like sepsis, ARDS or atelectasis.50 Radiographic signs are neither specific nor sensitive. In a study comparing chest X-ray findings in autopsy proven pneumonia, no sign had a diagnostic efficiency greater than 68 % and positive air bronchogramms predicted 65 % of pneumonias.53 Thus, a diagnosis of VAP is made by a combination of clinical signs, radiographic findings and, importantly, microbiological cultures.54,55

Acute kidney injury (AKI) has a high incidence in patients after cardiac surgery varying between 1 and 30 %.57–61 The acute kidney injury network (AKIN) and risk, injury, failure, loss (RIFLE) criteria of AKI are accurate and early predictive of mortality with creatinine levels being the most useful marker.57,59,62,63 The pathophysiology is complex and involves pre-, intra- and post-operative risk factors.57,64 Most vulnerable is the patient with pre-existing renal dysfunction prior to surgery.57,59 Nephrotoxins such as contrast agents and antibiotics, impaired cardiac output and poor renal perfusion, inflammation caused by surgical trauma, cardio-pulmonary-bypass and sepsis are further factors contributing to AKI.59,65 No preventive pharmacological therapy has been proven to be effective although studies indicate a possible benefit of statins pre-operatively.57,66–68 If possible, cardiac surgery should be performed ≥24 hours after coronary angiography to reduce the risk of AKI.69 Patients who need renal replacement therapy have a 27 fold increased mortalitiy.70

Start Renal Replacement Therapy The ideal time point of RRT-initiation remains unclear since the benefits of RRT must outweigh the risks of RRT61,71–74 In their cardiosurgical ICU the authors start RRT with continuous veno-venous haemodialysis (CVVHD), if the patient has metabolic acidosis (pH <7.2), increasing potassium levels (>6.0 mmol/l), complications of azotaemia (blood urea >20 mmol/l) such as encephalopathy or fluid overload not responding to diuretics.

The current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a dose of 20–25 ml/kg/hour of effluent flow in patients with AKI emphasising the need to individualise the patients dose by assessing volume status, acid-base status and electrolyte disturbances.62 Anticoagulation is required to prevent membrane clotting and dysfunction. Regional anticoagulation with citrate has the advantage over heparin75 to reduce the bleeding risk in post-operative patients after cardiac surgery, as heparin anticoagulation can be complicated by platelet- and red blood cell-consumption.75 However, impaired cellular aerobic metabolism (Krebs cycle) puts the patients at risk for insufficient citrate metabolism and citrate accumulation. In order to avoid this risk, the authors accept post-filter levels of calcium [ionised] as high as 0.5 mmol/l and limit the amount of citrate used (blood flow as low as 100 ml/minute, citrate concentration fix 3 mmol/l).

The calcium quotient (total calcium [albumin corrected] divided by calcium [ionised] is measured daily. A value of ≥2.5 points to citrate accumulation and should prompt either a reduction of citrate load or a switch to alternative anticoagulation strategies.

Interrupt Sedation Daily To reduce the incidence of VAP our hospital implemented the following bundle:56

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After cardiac surgery most patients arrive in the ICU sedated and with some neuromuscular blockade. After resolving of neuromuscular

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Acute Heart Failure blockade sedation should keep the patient pain-free but interactive, calm but lucid and cooperative.76 Over-sedation was associated with prolonged mechanical ventilation and ICU-stay, while light sedation was associated with reduced length of ICU and hospital stay, less post-traumatic stress disorders and improved survival rates.76–78

The authors start nutrition with 5 kcal/kg/day after shock resolution (normalised lactate levels, decreasing noradrenaline requirements) and increase stepwise to 25 kcal/kg/day over the next days. In patients without a contraindication for enteral nutrition, an early initiation of parenteral nutritision caused longer ICU stays and higher incidence of ICU aquired infections and higher health care costs.107

In order to minimise sedation, the authors use short-acting sedative agents such as propofol or dexmedetomidine (if tolerated from a haemodynamic point of view). A non-benzodiazepine approach in critically ill patients led to a shorter duration of mechanical ventilation, a reduced length of ICU stay79 and a lower mortality80 compared to the use of benzodiazepines. The benefits of dexmedetomidine include the better sleep architecture,81 a lower risk of delirium and a shorter length of stay after cardiac surgery.82 When long-active sedatives such as midazolam must be used due to haemodynamic instability, daily interruption of sedation is mandatory, as this has been shown to reduce days on the ventilator, ICU length of stay and even mortality.78,83

Other complications such as poor glycaemic control were described with parenteral nutrition.108,109 Uncertainty exists in patients with contrandications for enteral feeding: a meta-analysis of older studies (between 1981 and 1994) showed an association with higher infection rates in patients with parenteral nutrition,110 whereas a newer study showed a shorter duration of mechanical ventilation (without effect on 60-day mortality) if patients received parenteral nutrition within 24 hours of ICU admission.111

Detect and Treat Delirium There is extensive evidence that delirium prolongs ICU stay84 and increases morbidity and mortality85–88 after cardiac surgery. Also a longer duration of delirium is associated with worse global cognition after discharge.89 Risk factors for delirium after cardiac surgery include age, preexisting cognitive impairment and cerebrovascular disease, benzodiazepine use and immobilsation.90 A review also pointed out that blood transfusion, mechanical ventilation and even use of intraaortic balloon pump91 are associated with increased risk of delirium.

The confusion assessment method for the ICU (CAM-ICU)92,93 and the intensive care delirium screening checklist (ICDSC)94 are tools for the diagnosis of delirium in critically ill patients with reported pooled sensitivities and specificities of 80 % and 75 % for the ICDSC and 76 % and 96 % for the CAM-ICU.95 Scarce data exist for the treatment of delirium.88 Cooperative patients with a hypoactive form of delirium and/or hallucinations are treated with haloperidol, preferably orally and with low doses. In the authors’ institution, agitated and noncooperative patients are treated primarily with enteral pipamperon, a mild neuroleptic agent with sedative properties. The drug is usually given in the afternoon and evening (e.g. 4pm, 6pm and 8pm) to treat agitation and to induce sleep. Intravenous dexmedetomidine is added in severely agitated patients.

Recently, a study showed benefits of parenteral nutrition was started on day four if enteral intake was <60 % of the targeted calories.112 Therefore, the authors start parenteral nutrition between days four and eight if shock has resolved and enteral calory intake is <60 % of the targeted calories. As with enteral nutrition, parenteral nutrition is gradually established over days, up to 80 % of the target calory intake.

Stress Ulcer Prophylaxis Following international guidelines, the authors recommend stress ulcer prophylaxis with proton pump inhibitors (e.g. entral or intravenous pantoprazole 40 mg once daily) in patients with risk factor of gastro-intestinal bleeding (coagulopathy or anticoagulation, prolonged mechanical ventilation >48 hours, hypotension, steroid therapy).113 Meta analysis showed significantly less upper gastrointestinal bleeding with prophylaxis (in the absence of any mortality benefit).114–116 It is worth noting that stress ulcer prophylaxis is a grade 2C recommendation in the 2013 surviving sepsis campaign.113 Since there is an increased risk of pneumonia with increased stomach pH in ambulant patients,117 there might be a greater incidence of VAP with use of stress ulcer prophylaxis. Clostridium difficile infections have also be associated with the use of prophylaxis.118 Taking these considerations into account, the use of stress ulcer prophylaxis should be limited to patients at risk of bleeding, until enteral nutrition is fully established.

Blood Glucose Control

Prolonged critical illness results in loss of lean body mass and muscle weakness.96,97 Catecholamines induce myocyte apoptosis, and muscle weakness is potentially related to excessive sympathetic tone.12,98 Physiotherapy in the ICU is safe99 and can be started in cardiac surgery patients considering safety issues which are related to devices, sheaths or sternotomy.100 Early mobilisation and physiotherapy improves functional outcome and probably reduces length of ICU stay.101–103 Even in patients with ECLS, early physiotherapy and mobilisation is possible and safe.104,105

Hyperglycaemia is common in patients with shock due to the physiological stress reaction. Excessive glucose plasma levels have been associated with adverse outcome.119,120 However, pharmacological glucose control bears the risk of hypoglycaemia.121 A large, international randomised trial showed that a liberal glucose management (targeting glucose levels <10 mmol/l) resulted in a lower mortality than targeting a glucose level of 4.5–6 mmol/l.122 As numerous arterial blood gas analyses including glucose measurements are performed, the authors have a low rate of accidental hypoglycemic episodes. In their ICU, the authors have agreed on blood glucose targets between 4.5–8.5 mmol/l using continuous insulin infusions.

Feeding and Support Metabolism

Use DVT Prophylaxis

Enteral Versus Parenteral Nutrition

As critical ill patients are at risk for deep vein thrombosis (DVT),113,123 prophylaxis is warranted. The decision when to start and how to provide DVT prophylaxis may be difficult as the bleeding risk is high after cardiac surgery. In a prospective multicentre trial independent predictors for major bleeding in patients receiving heparin thrombosis prophylaxis were described, including renal replacement therapy, low platelet count and antiplatelet agents during the past 7 days.124

Rehabilitate Early

Early enteral nutrition is recommended to preserve gastro-intestinal integrity and prevent bacterial translocation. 106 On the other hand, enteral nutrition bears the risk of vomiting and aspiration, gastrointestinal obstruction and bowel ischaemia. This is particularly true during prolonged shock, when blood is redistributed from the gut to vital organs such as the brain and the heart.

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The authors usually start DVT prophylaxis with a continuous infusion of 10,000 IE/24h of unfractionated heparin 6 hours after surgery.

In patients with an indication for therapeutic anticoagulation, the heparin dose is increased by 2,000 to 5,000 IE every 6 hours until the anti-Xa activity is between 0.3 and 0.7 IE/ml.

Infection Control During the early phase of shock, broad-spectrum intravenous antibiotics are used if sepsis is suspected and after samples for microbiology have been taken. Importantly, antibiotic therapy has to be adapted according to the microbiology results, or even stopped if the patient improves and no pathogen is identified.113 The use of procalcitonin (PCT) as a marker to guide duration of antibiotic therapy reduces length and cost of antibiotic therapy.125 However, PCT levels usually increase after cardiac surgery even without infections.126 PCT should therefore not be used as a sole marker of infection to guide antibiotic therapy in patients after cardiac surgery.

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Conclusion Shock in cardio-surgical patients is a life-threatening disorder.

Multiple organ failure can occur despite early diagnosis and prompt therapeutic interventions. The period beyond the first 6 hours of shock onset, also referred to as the silver days, is the focus of the current review. The authors discuss haemodynamic management, ventilation strategies, renal replacement therapy, sedation and nutrition in affected patients. Over the years, allegedly life-saving treatments were shown to have rather harmful effects in critically ill patients, particularly if prolonged use or high dosages are applied. Potentially harmful interventions include haemodynamic optimisation to supranormal targets, excessive fluid administration, over-feeding and oversedation. Hence, treatments of patients during the silver days must focus on reducing harm and avoiding complications related to critical care.4,127 This concept includes avoidance of fluid overload, reduction of excessive catecholamines, safe ventilation and daily interruption of sedation. Although the authors focus on cardio-surgery ICU patients, most of the considerations apply to critical-ill patients in general. n

DOI: 10.14740/jocmr1702w; PMID: 24578748; PMCID: PMC3935527 18. Follath F, Cleland J, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002;360:196–202.

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DOI: 10.1016/j.athoracsur.2012.09.012; PMID: 23201106 70. Chertow GM, Levy EM, Hammermeister KE, et al. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343–8. PMID: 9576407 71. Gaffney AM, Sladen RN. Acute kidney injury in cardiac surgery. Curr Opin Anaesthesiol 2015;28:50–59. DOI: 10.1097/ ACO.0000000000000154; PMID: 25486486 72. Liu Y, Davari-Farid S, Arora P, et al. Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury after cardiac surgery: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth 2014;28:557–63. DOI: 10.1053/j.jvca.2013.12.030; PMID: 24731742 73. Karvellas CJ, Farhat MR, Sajjad I, et al. A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Crit Care 2011;15:R72. DOI: 10.1186/cc10061; PMID: 21352532; PMCID: PMC3222005 74. Wang X, Jie Yuan W. Timing of initiation of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Ren Fail 2012;34:396–402.

DOI: 10.3109/0886022X.2011.647371; PMID: 22260302 75. Bonassin Tempesta F, Rudiger A, Previsdomini M, et al. Platelet consumption and filter clotting using two different membrane sizes during continuous venovenous haemodiafiltration in the intensive care unit. Crit Care Res Pract 2014;2014:203637. DOI: 10.1155/2014/203637; PMID: 24868460; PMCID: PMC4020532 76. Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med 2014;370:444–54. DOI: 10.1056/ NEJMra1208705; PMID: 24476433 77. Gradwohl-Matis I, Mehta S, Dünser MW. What’s new in sedation strategies? Intensive Care Med 2015;102:1696–9.

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DOI: 10.1097/CCM.0b013e3182a16898; PMID: 23989093 80. Lonardo NW, Mone MC, Nirula R, et al. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med 2014;189:1383–94. DOI: 10.1164/rccm.201312-2291OC; PMID: 24720509 81. Jakob SM. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation.

JAMA 2012;307:1151. DOI: 10.1001/jama.2012.304; PMID: 22436955 82. Lin YY, He B, Chen J, et al. Can dexmedetomidine be a safe and efficacious sedative agent in post-cardiac surgery patients? a meta-analysis. Crit Care 2012;16:R169. DOI: 10.1186/cc11646; PMID: 23016926; PMCID: PMC3682268 83. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial. Lancet (London, England) 2008;371:126–34.

DOI: 10.1016/S0140-6736(08)60105-1; PMID: 18191684 84. Norkiene I, Ringaitiene D, Misiuriene I, et al. Incidence and precipitating factors of delirium after coronary artery bypass grafting. Scand Cardiovasc J 2007;41:180–5. PMID: 17487768 85. Clarke SP, McRae ME, Del Signore S, et al. Delirium in older cardiac surgery patients. J Gerontol Nurs 2010;58:7250–7.

PMID: 21544963 86. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. N Engl J Med 2012;367:30–39. DOI: 10.1056/NEJMoa1112923; PMID: 22762316; PMCID: PMC3433229 87. Rudolph JL, Inouye SK, Jones RN, et al. Delirium: an independent predictor of functional decline after cardiac surgery. J Am Geriatr Soc 2010;58:643–9. DOI: 10.1111/j.15325415.2010.02762.x; PMID: 20345866; PMCID: PMC2856754 88. Jackson P, Khan A. Delirium in critically Ill Patients. Crit Care Clin 2015;31:589–603. DOI: 10.1016/j.ccc.2015.03.011; PMID: 26118922 89. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369:1306–16. DOI: 10.1056/NEJMoa1301372; PMID: 24088092; PMCID: PMC3922401 90. McPherson JA, Wagner CE, Boehm LM, et al. Delirium in the cardiovascular ICU: exploring modifiable risk factors. Crit Care Med 2013;41:405–13. DOI: 10.1097/CCM.0b013e31826ab49b; PMID: 23263581; PMCID: PMC3557701 91. Katznelson R, Djaiani GN, Borger MA, et al. Preoperative use of statins is associated with reduced early delirium rates after cardiac surgery. Anesthesiology 2009;110:67–73. DOI: 10.1097/ALN.0b013e318190b4d9; PMID: 19104172 92. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703–10. PMID: 11730446 93. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (CAM-ICU). Crit Care Med 2001;29:1370–9. PMID: 11445689 94. Bergeron N, Dubois MJ, Dumont M, et al. Intensive care delirium screening checklist: evaluation of a new screening tool. Intensive Care Med 2001;27:859–64. PMID: 11430542 95. Neto AS, Nassar AP, Cardoso SO, et al. Delirium screening in critically ill patients: a systematic review and metaanalysis. Crit Care Med 2012;40:1946–51. DOI: 10.1097/ CCM.0b013e31824e16c9; PMID: 22610196 96. Vanhorebeek I, Van den Berghe G. The neuroendocrine response to critical illness is a dynamic process. Crit Care Clin 2006;22:1–15. PMID: 16399016 97. Batt J, dos Santos CC, Cameron JI, et al. Intensive care unit– acquired weakness. Am J Respir Crit Care Med 2013;187:238–46.

DOI: 10.1164/rccm.201205-0954SO; PMID: 23204256 98. Ng Y, Goldspink DF, Burniston JG, et al. Characterisation of isoprenaline myotoxicity on slow-twitch skeletal versus cardiac muscle. Int J Cardiol 2002;86:299–309. PMID: 12419570 99. Parker A, Sricharoenchai T, Needham DM. Early rehabilitation in the intensive care unit: preventing physical and mental health impairments. Curr Phys Med Rehabil Rep 2013;1:307–14.

PMID: 24436844; PMCID: PMC3889146 100. Hodgson CL, Stiller K, Needham DM, et al. Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults.

Crit Care 2014;18:658. DOI: 10.1186/s13054-014-0658-y; PMID: 25475522; PMCID: PMC4301888 101. Stiller K. Physiotherapy in intensive care: an updated systematic review. Chest 2013;144:825–47. DOI: 10.1378/ chest.12-2930; PMID: 23722822 102. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874–82. DOI: 10.1016/S0140-

6736(09)60658-9; PMID: 19446324 103. Morris PE, Goad A, Thompson C, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med 2008;36:2238–43. DOI: 10.1097/ CCM.0b013e318180b90e; PMID: 18596631 104. Freeman R, Maley K. Mobilization of intensive care cardiac surgery patients on mechanical circulatory support. Crit Care Nurs Q 2013;36:73–88. DOI: 10.1097/CNQ.0b013e31827532c3; PMID: 23221444 105. Ko Y, Cho YH, Park YH, et al. Feasibility and safety of early physical therapy and active mobilization for patients on extracorporeal membrane oxygenation. ASAIO J 2015:564–8.

DOI: 10.1097/MAT.0000000000000239; PMID: 25914950 106. Kreymann KG, Berger MM, Deutz NEP, et al. ESPEN Guidelines on enteral nutrition: Intensive care. Clin Nutr 2006;25:210–23. PMID: 16697087 107. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506–17. DOI: 10.1056/NEJMoa1102662; PMID: 21714640 108. Mongardon N, Singer M. The evolutionary role of nutrition and metabolic support in critical illness. Crit Care Clin 2010;26:443–50. DOI: 10.1016/j.ccc.2010.04.001; PMID: 20643298 109. Malone AM. Permissive underfeeding: its appropriateness in patients with obesity, patients on parenteral nutrition, and non-obese patients receiving enteral nutrition. Curr Gastroenterol Rep 2007;9:317–22. PMID: 17883981 110. Braunschweig CL, Levy P, Sheean PM, et al. Enteral compared with parenteral nutrition: a meta-analysis.

Am J Clin Nutr 2001;74:534–42. PMID: 11566654 111. Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013;309:2130–8. DOI: 10.1001/ jama.2013.5124; PMID: 23689848 112. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial.

Lancet 2013;381:385–93. DOI: 10.1016/S0140-6736(12)61351-8; PMID: 23218813 113. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637. DOI: 10.1097/CCM.0b013e31827e83af; PMID: 23353941 114. Kahn JM, Doctor JN, Rubenfeld GD. Stress ulcer prophylaxis in mechanically ventilated patients: integrating evidence and judgment using a decision analysis. Intensive Care Med 2006;32:1151–8. PMID: 16788804 115. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses.

JAMA 275:308–14. PMID: 8544272 116. Marik PE, Vasu T, Hirani A, et al. Stress ulcer prophylaxis in the new millennium: a systematic review and metaanalysis. Crit Care Med 2010;38:2222–8. DOI: 10.1097/ CCM.0b013e3181f17adf; PMID: 20711074 117. Laheij RJF, Sturkenboom MCJM, Hassing R-J, et al. Risk of community-acquired pneumonia and use of gastric acidsuppressive drugs. JAMA 2004;292:1955–60. PMID: 15507580 118. Plummer MP, Blaser AR, Deane AM. Stress ulceration: prevalence, pathology and association with adverse outcomes. Crit Care 2014;18:213. DOI: 10.1186/cc13780; PMID: 25029573; PMCID: PMC4056012 119. Furnary AP, Wu Y. Clinical effects of hyperglycemia in the cardiac surgery population: the portland diabetic project.

Endocr Pract 12 Suppl 3:22–6. PMID: 16905513 120. Desai SP, Henry LL, Holmes SD, et al. Strict versus liberal target range for perioperative glucose in patients undergoing coronary artery bypass grafting: a prospective randomized controlled trial. J Thorac Cardiovasc Surg 2012;143:318–25.

DOI: 10.1016/j.jtcvs.2011.10.070; PMID: 22137804 121. Gandhi GY. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery.

Ann Intern Med 2007;146:233. PMID: 17310047 122. Finfer S, Chittock DR, Su SY-S, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283–97. DOI: 10.1056/NEJMoa0810625; PMID: 19318384 123. Cade JF. High risk of the critically ill for venous thromboembolism.

Crit Care Med 1982;10:448–50. PMID: 7044682 124. Lauzier F, Arnold DM, Rabbat C, et al. Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis. Intensive Care Med 2013;39:2135–43.

DOI: 10.1007/s00134-013-3044-3; PMID: 23942857 125. Heyland DK, Johnson AP, Reynolds SC, et al. Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Crit Care Med 2011;39:1792–9. DOI: 10.1097/CCM.0b013e31821201a5; PMID: 21358400 126. Sponholz C, Sakr Y, Reinhart K, et al. Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature. Crit Care 2006;10:R145. PMID: 17038199; PMCID: PMC1751067 127. Singer M, Glynne P. Treating Critical Illness: The importance of first doing no harm. PLoS Med 2005;2:e167. PMID: 15971943; PMCID: PMC1160576

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Rehabilitation

LE ATION.

e. lare.

Cardiac Rehabilitation in Patients With Heart Failure: New Perspectives in Exercise Training Ma uriz i o Vo l t e r ra n i 1 a n d Fe r d i n a n d o I e l l a m o 1,2 1. Research Institute San Raffaele Pisana, Rome, Italy; 2. University of Rome Tor Vergata, Rome, Italy.

Abstract Exercise training is recommended to patients with chronic heart failure (CHF) and reduced ejection fraction at a class 1 evidence level.

Currently the ‘dose’ of exercise (dose being both volume and intensity) still remains uncertain and the best form of aerobic exercise training has not been defined. Guidelines commonly use heart rate (HR) as a target factor for both moderate continuous and interval training exercises.

However, exercise training guided by HR can be limited in CHF patients due to chronotropic incompetence and beta-blocker treatment. In our study, we systematically addressed the above issues by applying a training method that takes into account both the volume and intensity of exercise on an individual basis. This method is referred to as individual TRaining IMPulses (TRIMPi). In this review, we summarise a series of investigations that used TRIMPi and different exercise forms to quantify the optimum training load in CHF patients. This review also highlights the way TRIMPi and the individual exercise dose affects cardiorespiratory, metabolic and autonomic cardiac adaptations.

Keywords Chronic heart failure, cardiac rehabilitation, individual exercise training, exercise modalities, cardiovascular system, autonomic nervous system Disclosure: The authors have no conflicts of interest to declare.

Received: 25 November 2015 Accepted: 27 December 2015 Citation: Cardiac Failure Review, 2016;2(1):63–8 DOI: 10.15420/cfr.2015:26:1 Correspondence: Maurizio Volterrani, IRCCS San Raffaele Pisana, Cardiologia Riabilitativa, Via della Pisana, 235 00163, Roma, Italy. E: maurizio.volterrani@sanraffaele.it

The US Public Health Service defines cardiac rehabilitation services as “comprehensive, long term programs involving medical evaluation, prescribed exercise, cardiac risk factor modification, education and counselling. These programs are designed to limit the physiological and psychological effect of cardiac illness, reduce the risk of sudden death or re-infarction, control cardiac symptoms, stabilise or reverse the atherosclerotic process and enhance the psychological and vocational status of the individual patient.”1 Exercise training is a core component of comprehensive rehabilitation programmes. It is currently recommended in combination with pharmacological therapy to patients with chronic heart failure (CHF) with reduced ejection fraction (EF) at a class 1 evidence level.2,3 The benefits of exercise-based cardiac rehabilitation for clinically relevant health outcomes (e.g., functional capacity, exercise tolerance and quality of life) have been widely recognised in CHF patients.4 There has also been a positive effect on heart failure (HF)-related hospitalisation and mortality.5–7 The optimum “dose” (volume and intensity) of exercise is still being questioned as well as the correct amount that should be prescribed to improve health outcomes.

Defining the optimal dose of exercise to maximise health outcomes is now considered a priority.8–10 Current guidelines for exercise prescription are commonly based on heart rate (HR): either a percentage of peak heart rate (HRmax) or heart rate reserve (HRR; the difference between resting HR and HRmax), as determined in a symptom-limited exercise test.11 Target intensity generally ranges between 70 and 80 % of HRmax, for at least 30 min on >5 days/week. Exercise training guided by HRmax or

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HRR can be limited in CHF patients due to chronotropic incompetence and beta-blocker treatment. It is important to recognise that contributionsdocumented for each patient group may not fully apply to each member, despite all patients being exposed to the same volume and intensity of physical activity adjusted for their own tolerance level. For example, a group of CHF patients exercising at 40–70 % HRR may be working at individually different relative intensities. For this reason, intensities based solely on a percentage of HRR or HRmax are likely to impose variable cardiovascular and metabolic demands in CHF patients.12,13 In addition to the dose, the best format of aerobic exercise training has not been defined. Training programmes in CHF patients have been based predominantly on continuous, moderate and vigorous aerobic exercise.11,13 However, a study by Wisloff et al. reported a greater benefit in terms of functional capacity with interval training as opposed to moderate continuous aerobic exercise training programmes in patients with CHF.14 The interval training included alternations of 3–4-minute periods of exercise at 90–95 % HRmax with exercise at moderate intensity (60–70 % HRmax). Since the study

by Wisloff et al., interval training has gained popularity.

In the past few years, our group has systematically addressed the above issues by applying a training method that takes into account the dose of exercise (both the volume and intensity) on an individual basis. This method has been referred to as individual TRaining IMPulses (TRIMPi)15 and represents an individualisation of the TRIMP method originally proposed by Bannister et al.16 The original TRIMP considers the ∆HR (HRexercise-HRrest/HRmaximal-HRrest) as the main exercise

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Rehabilitation Figure 1: Blood Lactate Concentration Plotted Against the Fractional Elevation In Heart Rate Taken From a Single Patient 8 y = 1.15.4c Blood lactate (mmol-l-1)

1.754x

4

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Fractional elevation (∆HR) The exponential line provides calculation of the weighting factor (y). Reproduced with permission from Iellamo et al.25

variable. The duration of any specific training session is multiplied by the average ∆HR achieved during that session. The ∆HR is weighted by a multiplying factor (y) in a way that reflects the intensity of effort.

This avoids providing a disproportionate conclusion to long-duration activity at low ∆HR levels compared with intense but short-duration activity. The y factor is based on the exponential rise of blood lactate levels and the fractional elevation of exercise above resting HR. It is computed using two constants in the equation that are considered equal for all subjects.15 The use of the same multiplying factor y can potentially overlook the individual physiological demands of each training session. We introduced an individual weighting factor (yi) that is calculated for each patient with the best fitting method using exponential models (see Figure 1). Thus, as exercise intensity increases, as indicated by the HR response, the weighting factor yi increases exponentially. As a result, during each training session a unique TRIMP can be calculated at any time from the area under the curve represented by the pseudo-integral of all ∆HR data points.15 We used the TRIMPi method to quantify the training load and its effect on the physiological systems in CHF patients with reduced EF in a series of investigations that are the focus of this review.

ACT and AIT modes, provided that the training stimulus is equated by an individually tailored dose of exercise.

It should be outlined that, until recently, the relationship between training and functional capacity has been investigated independently from exercise mode without regard for individual training dose. Indeed, aerobic training prescriptions based on VO2max (maximum oxygen uptake) or HRmax percentages may result in different physiological responses, even in patients with similar baseline aerobic capacity.

These differences in exercise responses might be the consequence of differences in individual internal training load. Scharhag-Rosenberger et al. recently reported a broad inter-subject variability in lactate response in individuals with similar aerobic capacity while exercising at the same percentage of VO2max.23 Hence, prescription of endurance training should not be solely based upon percentages of VO2max or HRmax (or HRR) when a comparable metabolic load is intended.

In this context, there is a general consensus that exercise training should be individually tailored to each patient’s clinical and functional status.8–10 In addition, exercise training programmed at given percentages of pre-training VO2max or HRmax is based only on preintervention criteria that are not updated during the training process to account for the increments in aerobic fitness documented at the end of the training intervention, as it is with the TRIMPi method.

The TRIMPi approach allows a close monitoring of the internal load experienced by patients with the progression of training and enables accurate weekly training load adjustments within both continuous and interval training modes.

AIT has gained popularity9,10,18 since the Wisloff et al. report of a greater improvement in aerobic capacity with AIT than ACT in a small group of patients with CHF.14 Differences in the method of quantification of the training stimulus and prescription might be the main cause of this discrepancy. In the study by Wisloff et al.,14 in which the intended difference in the training stimulus between AIT and ACT was only the intensity of exercise (i.e. maintenance of the same level of energy expenditure in the two groups), the training load was actually greater in the AIT than in the ACT group, as we demonstrated.17 Furthermore, the training programme was not updated during the training process.

Cardiorespiratory and Metabolic Adaptations To define the best dose and modality of exercise on health parameters, we investigated the effects of both aerobic continuous training (ACT) and aerobic interval training (AIT) on haemodynamic, cardiorespiratory and metabolic adaptations in patients with CHF under optimal therapy (including beta-blockers). We did this using a randomised design.17 The TRIMPi method was employed to provide equivalent doses of exercise in both ACT and AIT. In this study, the increase in functional capacity and ventilatory efficiency to exercise training did not differ between continuous and interval training modes. Resting central haemodynamics were not significantly affected by either ACT and AIT, as indicated by the lack of changes in stroke volume, cardiac output, ejection fraction and left ventricular diastolic diameter in both patient groups. This finding is in line with most studies, indicating that the beneficial effects of exercise training on functional capacity and ventilatory efficiency in patients with CHF would be mainly due to peripheral mechanisms and adaptations,18–21 although not invariably.21,22 The effect of ACT and AIT on metabolic parameters also did not differ significantly. It thus appears that adaptations to exercise training do not differ between

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Our finding of a similar increase in functional capacity with both ACT and AIT coincides with the multicentre Study on Aerobic INTerval EXercise training in CAD patients (SAINTEX-CAD) performed in patients with coronary artery disease with preserved left ventricular function. The patients were exercising with progressive optimisation of HR training zones during the programmed ACT.24 If the target HR zones were not changed, this could have resulted in low intensities of ACT than AIT and, perhaps, smaller improvements in VO2max after intervention.24 Thus, it appears that in patients with post-infarction CHF, functional capacity, ventilatory efficiency and metabolic adaptations to exercise training do not differ between continuous and interval training modes, provided that the training stimulus is matched.

Autonomic Nervous System Adaptations In addition to reduced exercise tolerance and functional capacity, patients with CHF also exhibit an increased susceptibility to lifethreatening arrhythmias and sudden death. Alterations in the autonomic control of the heart, characterised by a relative sympathetic predominance and a decreased vagal modulation, play a major role in the occurrence of arrhythmic events.4,25 Depressed

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Cardiac Rehabilitation in Patients with Heart Failure

Figure 2: Doseâ&#x20AC;&#x201C;response Relationship Between Weekly TRIMPi and Autonomic Cardiovascular Parameters During Aerobic Continuous Training (left panels) and Aerobic Interval Training (right panels) R-R interval (ms) 1240

R-R interval (ms) 1150

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BRS = baroreflex sensitivity; HRV = heart rate variability; TRIMPi = individual TRaining IMPulses. *P<0.05 versus pre-training baseline values. Reproduced with permission from Iellamo et al.25

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Rehabilitation Figure 3: Changes in the Distance Walked at the 6-minute Walking Test during the 12-week Training Period 600 *

Metres

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Interestingly, the above findings resemble those observed in marathon runners15 and otherwise healthy individuals of different ages and

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vigorous physical activity might pose a risk for arrhythmic events in high-risk populations like CHF patients. Previous studies in cardiac patients included only before and after training ANS assessments, which prevented the appreciation of the non-linear dose–response relationship between training load and ANS responses.

Baseline

Three weeks

Six weeks

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Open bars, aerobic continuous training; hatched bars, aerobic interval training. *P<0.05 versus pre-training baseline values. Reproduced with permission from Iellamo et al.25

heart rate variability (HRV) and baroreflex sensitivity (BRS) are two clinical indices of vagal control of the sinoatrial node that are linked to a greater risk of ventricular fibrillation,26,27 they also represent a dominant feature of the CHF syndrome, which parallels deterioration of CHF status28 and carries a negative prognosis.28–30 Exercise training has been reported to improve HRV and BRS in patients with CHF31–33 and may ameliorate the increasing cardiovascular risk linked with autonomic derangement of patients with CHF.27,33 However, the optimal dose of exercise required to achieve improvement in neural cardiovascular regulation has not yet been defined. Not one study addressed whether a dose–response relationship exists between training load and improvements in autonomic nervous system (ANS) parameters and their relationship with performance in patients with CHF. Our group used the TRIMPi method to address the issue of dose– response relationship of BRS and HRV to individually tailored exercise training in patients with CHF.24 We observed that BRS, HRV (standard deviation of mean R-R interval) and R-R interval as well, were significantly and very highly correlated with the dose of exercise, with a second-order regression model (r2 ranged from 0.75 to 0.96; P<0.001), resembling a bell-shaped curve in the ACT and an asymptotic-shaped curve in the AIT groups, respectively, without differences between exercise training modalities (see Figure 2). In the same study, a progressive increase in the distance walked in the 6-minute walking test (6MWT) was observed with the increase in TRIMPi, which was significant after nine weeks of training, without significant differences between ACT and AIT from the baseline throughout the study. A small, not significant, increase in the 6MWT was observed between the ninth and twelfth weeks of training with both protocols (see Figure 3).

These findings indicate that in patients with CHF under beta-blockers therapy, HRV and BRS adaptations to exercise training are dose related in a non-linear fashion on an individual basis and that higher doses of exercise training do not necessarily lead to greater improvement in HRV and BRS. Thus, a moderate dose of exercise, approximately 55–60 % of HRR for 40 to ~45 minutes four times a week, is sufficient to achieve substantial improvements in HRV and BRS. This dose maximises effects in patients with CHF; no further substantial improvements are made by employing more vigorous physical activity.

This dose is sufficient to increase cardiac vagal activity, as reflected by HRV and BRS, and protect against life-threatening arrhythmias. More

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physical fitness levels who have undergone similar, although not individualised, training methods34,35 and experienced a decrease in HRV and BRS at the highest training loads. In line with these findings, Iellamo et al. reported a decrease in vagal cardiac modulation with a shift toward a sympathetic predominance with strenuous exercise in comparison with moderate training loads in world-class endurance athletes.36 From all the above studies, it appears that despite a prominent plasticity of cardiac autonomic regulation, there is a point on the dose–response curve above which an enhanced vagal modulation of HR ceases to occur with the increase in training load. Therefore, a higher exercise dose may not provide any added protective benefit by these mechanisms in patients with CHF. There is a minor increase in functional capacity with increase in TRIMPi from moderate to higher values (see Figure 3). However, the potential benefit of increasing exercise performance by increasing training load from moderate to high doses should be weighed against the lack of improvement, even a decrease, in cardiac vagal modulation. This is coupled with the inherent, possible increase in the risk of adverse events in a high risk population, such as patients with CHF.

Subjective-based Exercise Training Prescription It is well established that to be effective over time, exercise training should be a lifelong commitment. This would imply the need of a continuous adaptation of exercise prescription, in terms of volume and intensity, especially in ageing individuals. The exercise training methods described above are usually prescribed in clinical rehabilitation centres, where patients are admitted as in- or outpatients for a limited period of time. The issue thus exists on how prescribing long-term exercise training, taking into account the need of practising regular physical activity outside medically supervised settings and physiological ageing processes, with the attendant changes in individual physical capacity over time.

The session-rate of perceived exertion (RPE) method might potentially be used by cardiac patients for long-term, self-selected physical activity management. The session-RPE is a simple method to quantify internal training load proposed by Foster et al.37 By this method, internal training load is quantified by multiplying the perceived effort of the whole training session (using the Borg category ratio scale; the CR10 scale) by its duration.38 This product represents in a single number the magnitude of internal training load, in arbitrary units (AU), and has been used and validated in athletes of different sport disciplines.39–41 The perceived exertion method that uses RPE as a marker of training intensity within the TRIMP concept37 has a physiological basis as it has been shown to be related to both HR and blood lactate markers of exercise intensity during continuous and interval running.42 Borg’s CR10 is considered a global indicator of exercise intensity including psychological and physiological factors (oxygen uptake, HR, ventilation, beta endorphin, circulating glucose concentration and glycogen depletion).43 It can be considered an accurate indicator of global internal training load. Subjects are asked to provide a

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Cardiac Rehabilitation in Patients with Heart Failure

R–R interval, HRV and BRS increased significantly with a rise in training load with both session-RPE training protocols. These were linked with a high weekly session-RPE score, with a second-order regression model resembling a bell-shaped curve in the ACT and an asymptotic-shaped curve in the AIT groups respectively. This was previously reported with the TRIMPi method.25 These findings strongly suggest that a simple method of training prescription/monitoring (i.e. the session-RPE) provides superimposable outcomes, in terms of functional capacity and autonomic adaptations, as those provided by an objective, HR-based method (i.e. the TRIMPi), in patients with CHF. The consistency of results during different exercise modalities (i.e. ACT and AIT) suggests that the session-RPE method may be useful for long-term prescription of varying exercise-based rehabilitation programmes in cardiac patients. From a practical point of view, to reach weekly effective training load (e.g. around 400 AU), an exercise training programme would need to comprise 4 days/week training with a session duration of 40–50 min at RPE score from 3–5 on the Borg 10-point scale.44 Session-RPE should not be viewed as a substitute for the current guidelines that use HR, VO2max or TRIMP methodologies for exercise prescription. Rather, session-RPE would add a further tool in the armamentarium of exercise prescription methods, particularly apt to long-term, out-of-hospital, physical activity of cardiac patients, with a large benefit also in terms of costeffectiveness in comparison with HR-based training methodologies, especially in the elderly.

Preliminary findings45 suggest that the session-RPE may be used for long-term, post-hospital, physical activity management to improve and maintain functional capacity on the basis of a subjective, yet validated, tool. If confirmed in a larger number of patients, this information might have a huge impact on long-term exercise training prescription outside medically supervised settings.

Could Findings From TRIMPi Studies Translate Into Positive Outcomes for Patients With CHF? A recent editorial by Eijsvogels and Thompson stressed the relevance of the optimal dose of physical activity to prescribe in clinical practice.46

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160

Session-RPE score (AU)

To assess the feasibility and reliability of the session-RPE method in patients with CHF, we compared functional capacity and ANS adaptations to session-RPE and TRIMPi methods, for both ACT and AIT in the same patients.44 The TRIMPi and session-RPE-based training loads were calculated from 672 training sessions and individual correlations were determined from 42 training sessions. Significant correlations were found between TRIMPi and the individual session-RPE, for both ACT and AIT, with r values ranging from 0.63 to 0.81; (P<0.05). Additionally, significant correlations between TRIMPi and session-RPE were observed when both ACT and AIT patients groups were pooled together (r=0.72; P<0.01) (see Figure 4). A progressive increase in the distance walked was observed with the increase in session-RPE score from the baseline throughout the study, as observed with the TRIMPi method.17,40 There is a significant linear relationship between session-RPE score and the distance walked at the 6MWT (r=0.85; P<0.01); (see Figure 5).

Figure 4: The Relationship Between Session-RPE Training Load and the TRIMPi Method

120

80 10

50

90

TRIMPi (AU) AU = arbitrary units; RPE = rate of perceived exertion; TRIMPi = individual TRaining IMPulses.

Reproduced with permission from Iellamo et al.25

Figure 5: Relationship Between the sum of the Weekly Session-RPE Training Load Scores and the Distance Walked at the 6-Minute Walking Test 600

Distance (metres)

global rating of the effort for the entire training session, rather than the perceived effort of the most recent exercise intensity, using whatever cues they feel to be appropriate. To facilitate a global effort assessment, subjects report their global RPE within 30 minutes after completion of each training session.

540

480

0

1500

3000

Weekly session-RPE (AU) Circles, ACT group; squares, AIT group. ACT = aerobic continuous training; AIT = aerobic interval training; AU = arbitrary units; RPE = rate of perceived exertion. Reproduced with permission from Iellamo et al.44

Some studies suggested that higher doses of exercise are not of greater benefit than moderate doses for reducing mortality47,48 and that a U- or J-shaped curve better reflects the association between physical activity dose and health. The findings ensuing from TRIMPi studies are in line, from a pathophysiological perspective, with these large longitudinal studies, in that they showed a non-linear dose–response curve between exercise training load and ANS cardiac regulation, with no improvement in HRV and BRS, and even a worsening of these risk markers at the higher doses of exercise, without any substantial benefit on functional capacity by a more vigorous physical activity.

Clearly, our studies cannot provide answers on long-term clinical outcomes but, nonetheless, they could furnish some clues to this aim.

Conclusion This review focused on the need for tailoring exercise training programmes to individuals, taking into consideration not only energy expenditure but the internal training load. Exercise prescription should

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Rehabilitation not be solely based on VO2max or HR-derived parameters when a comparable metabolic load is intended, particularly in patients with CHF, although these have proven fundamental and highly useful in exercise training. The TRIMPi and the session-RPE methods described in this review represent a step forward in the characterisation of aerobic training tailored to the clinical and functional status of each individual within cardiac rehabilitation programmes. RPE-based training might be an extra stimulus to encourage a life-long, physically active lifestyle.

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In CHF patients, the potential benefit of increasing exercise performance by increasing training load from moderate to higher doses of exercise should be weighed against the lack of an improvement in cardiac vagal modulation and the possible increase in the risk of adverse events. Further study is needed to determine the dose and mode of exercise training most effective in terms of musculoskeletal and cardiovascular complications and clinical outcomes in CHF patients. n

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