ECR 10.1 by Radcliffe Cardiology

European Cardiology Review Volume 10 • Issue 1 • Summer 2015

Volume 10 • Issue 1 • Summer 2015

www.ECRjournal.com

Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography Iana Simova

Risk Stratification in Hypertrophic Cardiomyopathy Alexandros Klavdios Steriotis and Sanjay Sharma

Chemotherapy Related Cardiomyopathy Susan E Piper and Theresa A McDonagh

Novel Biomarkers in Heart Failure Beyond Natriuretic Peptides — The Case for Soluble ST2 Antonio J Vallejo-Vaz

ISSN: 1758-3756

Ventriculogram Diastolic and Systolic Frames

Evaluation of Coronary Flow in Right CoronaryArtery

Virtual Anatomic Rendering

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Volume 10 • Issue 1 • Summer 2015

www.ECRjournal.com

Editor-in-Chief Juan Carlos Kaski St George’s University of London, London, UK

Associate Editor

Velislav Batchvarov

Nesan Shanmugam

St George’s University of London, London, UK

Luigi Paolo Badano

Koichi Kaikita

Sven Plein

Kumamoto University, Kumamoto, Japan

University of Leeds, Leeds, UK

Velislav Batchvarov

Juan Carlos Kaski

St George’s University of London, London, UK

Piotr Ponikowski

Elijah Behr

Sverre Kjeldsen

St George’s University of London, London, UK

University Hospital, Oslo, Norway

John Beltrame

Wolfgang Koenig

University of Adelaide, Adelaide, Australia

University of Ulm, Ulm, Germany

Richard Conti

Steen Dalby Kristensen

University of Padua, Padua, Italy

University of Florida, Florida, US

Aarhus University, Aarhus, Denmark

Martin Cowie

Imperial College London, London, UK

Filippo Crea

Catholic University of the Sacred Heart, Milan, Italy

Alberto Cuocolo

University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan

Colentina University Hospital, Bucharest, Romania

Polychronis Dilaveris

Hippokration General Hospital, Athens, Greece

Kenneth Earle

St George’s University of London, London, UK

Perry Elliott

University College London, London

Albert Ferro

Patrizio Lancellotti University of Liège, Liège, Belgium

Gaetano Antonio Lanza Catholic University of the Sacred Heart, Milan, Italy

Giuseppe Mancia University of Milano-Bicocca, Milan, Italy

Antoni Martínez-Rubio University Hospital of Sabadell, Sabadell, Spain

Mario Marzilli University of Pisa, Pisa, Italy

Attilio Maseri Vita-Salute San Raffaele University, Milan, Italy

Noel Bairey Merz Cedars-Sinai Heart Institute, Los Angeles, US

Petros Nihoyannopoulos

King’s College London, London

Imperial College London, London, UK

Wroclaw Medical University, Wroclaw, Poland

Eva Prescott Bispebjerg Hospital, København, Denmark

Fausto Rigo Ospedale dell’Angelo Hospital, Venice, Italy

Giuseppe Rosano IRCCS San Raffaele, Rome, Italy

Magdi Saba St George’s University of London, London, UK

Nesan Shanmugam St George’s University of London, London, UK

Sanjay Sharma St George’s University of London, London, UK

Hiroaki Shimokawa Tohoku University, Sendai, Japan

Rosa Sicari Italian National Research Council

Iana Simova National Cardiology Hospital, Sofia, Bulgaria

Philippe Gabriel Steg Imperial College London, London, UK

Jun Takata Kochi University, Nankoku, Japan

Augusto Gallino

Argyrios Ntalianis National and Kapodistrian University of Athens, Athens, Greece

Dimitris Tousoulis

Xavier Garcia-Moll

Autònoma University, Barcelona, Spain

Camici Paolo

Konstantinos Toutouzas

Simon Gibbs

San Raffaele Hospital, Segrate, Italy

University of Athens, Athens, Greece

Imperial College London, London, UK

Zoltan Papp

Dimitrios Tziakas

Tommaso Gori

University of Debrecen, Debrecen, Hungary

Democritus University of Thrace, Xanthi, Greece

Antonio Pelliccia

Hiroshi Watanabe

Technical University of Munich, Munich, Germany

Institute of Sports Medicine of the Italian National Olympic Committee, Rome, Italy

Hamamatsu University School of Medicine, Hamamatsu, Japan

Eileen Handberg

Joep Perk

José Luis Zamorano

Linnaeus University, Kalmar, Sweden

University Complutense, Madrid, Spain

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Johannes Gutenberg University Mainz, Mainz, Germany

Martin Halle

University of Florida, Florida, US

University of Athens Medical School, Athens, Greece

Design & Production Tatiana Losinska • Digital Commercial Manager Ben Sullivan Publishing Director Liam O’Neill • Account Executive Ryan Challis • Managing Director David Ramsey Managing Editor editor@radcliffecardiogy.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com Cover image Human Heart, Cardiovascular System © Eraxion | shutterstock.com

Radcliﬀe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved © RADCLIFFE CARDIOLOGY 2015

Established: April 2005 Frequency: Bi-annual Current issue: Summer 2015

Aims and Scope

Submissions and Instructions to Authors

• European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiology medicine and practice. • European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • European Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the and invited by the Editor-in-Chief with support from the Associate Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjuction with the Editor-in-Chief formalise the working title and scope of the article. • Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. • The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details. The ‘Instructions to Authors’ information is available for download at www.ECRjournal.com.

Structure and Format • European Cardiology Review is a bi-annual journal comprising review articles, editorials, and case reports. • The structure and degree of coverage assigned to each category of the journal is determined by the Editor-in-Chief, with the support of the Associate Editors and the Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of European Cardiology Review is replicated in full online at www.ECRjournal.com

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

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

Reprints All articles included in European Cardiology Review are available as reprints (minimum order 1,000). Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Distribution and Readership European Cardiology Review is distributed bi-annually through controlled circulation to senior professionals in the field in Europe. All manuscripts published in the journal are free-to-access online at www.ECRjournal. com and www.radcliffecardiology.com

Abstracting and Indexing European Cardiology Review is abstracted, indexed and listed in Embase, Scopus, Google Scholar.

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

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

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Contents

Foreword 5 Juan Carlos Kaski Expert Opinion 6 What is Takotsubo (Stress) Cardiomyopathy?

Abhiram Prasad

9 Pulmonary Hypertension Brendan P Madden

C oronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography

Iana Simova

Cardiomyopathy and Heart Failure

C hemotherapy-related Cardiomyopathy

Susan E Piper and Theresa A McDonagh

25 Takotsubo Cardiomyopathy

Esha Sachdev, C Noel Bairey Merz and Puja K Mehta

31 Risk Stratification in Hypertrophic Cardiomyopathy

Alexandros Klavdios Steriotis and Sanjay Sharma

37 Novel Biomarkers in Heart Failure Beyond Natriuretic Peptides — The Case for Soluble ST2

Antonio J Vallejo-Vaz

42 Diuretic Therapy in Heart Failure – Current Approaches

Gavino Casu and Pierluigi Merella

Electrophysiology and Sudden Cardiac Death

48 Sudden Cardiac Death in Athletes Andrew D’Silva and Michael Papadakis

The Diagnosis and Clinical Implications of Interatrial Block

Atherosclerotic Disease Prevention

Antonio Bayés de Luna, Albert Massó-van Roessel, and Luis Alberto Escobar Robledo

60 At the Heart of Brain Disorders – Preventing Cognitive Decline and Dementia

Augusto Vicario and Gustavo H. Cerezo

64 Cholesteryl Ester Transfer Protein Inhibitors – Future Soon to be REVEALed

Christopher Huggins, Nicoletta Charolidi and Gillian W Cockerill

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Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), Honorary Consultant Cardiologist at St George’s Hospital, NHS Trust, London, UK and Director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Prof Kaski is Doctor of Science, University of London, immediate Past-President of ISCP (International Society of Cardiovascular Pharmacotherapy) and editorial board member and associate editor of numerous peer review journals. He is also fellow of the ESC (FESC), the ACC (FACC), the AHA (FAHA), the Royal College of Physicians (FRCP), and over 30 other scientific societies worldwide. Prof Kaski’s research areas include mechanisms of rapid coronary artery disease progression, inflammatory and immunological mechanisms of atherosclerosis, microvascular angina and biomarkers of cardiovascular risk. Prof Kaski has published over 400 papers in peer-review journals, over 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

his new issue of ECR features important contributions. There are three articles that deal with different aspects of non-ischemic cardiomyopathy and heart failure; two conditions

that represent major clinical and public health problems. McDonagh’s paper on chemotherapy related cardiomyopathy will be of great interest to the practicing physician, together with Casu’s review on the rational use of diuretics in heart failure patients. Discussions on a form of cardiomyopathy, “stress cardiomyopathy” otherwise known as “takotsubo syndrome”, continues to puzzle physicians on both sides of the Atlantic. This is discussed and presented by Prasad and Mehta, respectively. Madden et al provides expert opinion on the diagnosis and management of pulmonary hypertension and propose useful diagnostic algorithms. A paper on sudden cardiac death in athletes by Papadakis provides insight into possible mechanisms, early detection and risk stratification in subjects who engage in competitive sport. Similarly, Sharma analyses the variables that help risk stratifying individuals with hypertrophic cardiomyopathy and which may be of practical interest to practicing cardiologists. Expert opinion on the controversial issue as to whether there is a therapeutic role for cholesteryl ester transfer protein inhibitor agents, is provided by Cockerill and strategies for prevention of cognitive impairment and dementia are proposed by Vicario in a brief review article on this timely topic. The issue also features papers on the role of biomarkers of in heart failure risk stratification and management and the assessment of coronary blood flow reserve using Transthoracic Doppler echocardiography. Bayes de Luna et al describe the diagnostic features and clinical implications of a new syndrome proposed by the authors and involving interatrial block. In summary, this issue of ECR offers exciting material that we proudly present to our readers. n

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Expert Opinion

LE ATION.

What is Takotsubo (Stress) Cardiomyopathy? Abhiram Prasad Cardiovascular and Cell Sciences Institute, St George’s, University of London, London, UK

Abstract Takotsubo/stress cardiomyopathy (TC) or apical ballooning syndrome is an increasingly recognised entity around the world. It is an acute reversible cardiac syndrome that has a striking female predominance, with approximately 90 % of cases occurring in women, the vast majority of whom are post-menopausal. Chest pain and dysponea are the most common presenting symptoms. The symptoms and signs are similar to those in other acute cardiac conditions characterised by acute myocardial ischemia or heart failure. A characteristic feature of the syndrome is its relationship to emotional or physical stressful triggers. The process of diagnosing TC is, to a large extent, one of exclusion of other conditions that it mimics. The Mayo Clinic diagnostic criteria are the most widely used. Since acute coronary syndrome is often suspected before the diagnosis of TC is made, initial treatment is often similar to that for an acute myocardial infarction. However, after the diagnosis of TC is confirmed, treatment is supportive with monitoring and treatment of complications. The vast majority of patients with TC have good prognosis with complete resolution of systolic dysfunction.

Keywords Apical ballooning syndrome, Takotsubo cardiomyopathy, stress cardiomyopathy Disclosure: The author has no conflicts of interest to declare. Received: 1 June 2015 Accepted: 1 June 2015 Citation: European Cardiology Review, 2015;10(1):6–8 Correspondence: Abhiram Prasad, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK. E: aprasad@sgul.ac.uk

Takotsubo cardiomyopathy (TC) or syndrome was first described more than 2 decades ago by Dote and colleagues in Japan, but has since been increasingly recognised around the world.1 Takotsubo is the Japanese name for a the traditional octopus trapping pot that has a round bottom and narrow neck, resembling the appearance the left ventricle during the acute presentation (see Figure 1).2 Although, as early as the 1980s, sporadic cases from Europe had described the association between acute stress causing a transient regional wall motion abnormalities of the left ventricle,3 it was Desmet and colleagues who first reported a case series of TC in Europe.4 Twelve of 13 of their patients were women with a mean age of 62 years. A triggering factor was documented in nine cases. All patients had extensive apical akinesia and hence the term apical ballooning was used in their paper.

tract obstruction and plaque rupture with spontaneous thrombolysis. The catecholamine hypothesis is supported by the observations that: i) plasma catecholamines levels are elevated in some patients;9 ii) pheochromocytoma associated and neurogenic cardiomyopathies produce a similar transient regional wall motion abnormality of the left ventricle in the setting of high catecholamine activity; iii) an immobilisation-induced stress rat model has been shown to elevate catecholamine levels and produce reversible ventricular ballooning; and iv) in a mouse model high levels of epinephrine has been shown to be negatively inotropic. The vascular hypothesis is supported by the frequent detection of impaired coronary microcirculatory function as well as the occasional finding of multi-vessel coronary spasm.

Clinical Features Apical ballooning syndrome is an alternative name for TC that was also coined in Japan by Tsuchihashi and colleagues who published their seminal case series of 88 patients in 2001, identified from a registry of patients with coronary artery disease.5 Alternative nomenclature for TC includes stress cardiomyopathy, and the one favoured in the lay press is Broken Heart Syndrome. TC is the terminology used in a position statement from the European Society of Cardiology in which it is listed as an unclassified cardiomyopathy.6

Pathogenesis The pathogenesis of TC is not well established, and many aspects of the condition, such as the predisposition in post-menopausal women and the characteristic pattern of regional wall motion abnormality, remain unexplained.7,8 Leading hypotheses include catecholamine excess and microvascular dysfunction (see Figure 2). Less likely explanations include coronary spasm, dynamic mid-cavity or left ventricular outflow

Prasad_FINAL.indd 6

TC is an acute reversible cardiac syndrome that has a striking female predominance, with approximately 90 % of cases occurring in women, the vast majority of whom are post-menopausal. Due to their advanced age, affected patients often have cardiovascular comorbidities and approximately 10 % have incidental coronary artery disease.10 An estimate for its incidence, outside of Japan, comes from the Nationwide Inpatient Sample database in the US, which represents a random sample of all admissions from 20 % of community hospitals. In 2008, there were 6,837 patients diagnosed with TC among 33,506,402 hospitalisations, amounting to a rate of 0.02 %.11 It is estimated that the syndrome accounts for approximately 2 % of patients initially suspected of an acute coronary syndrome.12 Chest pain and dyspnoea are the most common presenting symptoms. The symptoms and signs are similar to those in other acute cardiac conditions characterised by acute myocardial ischaemia or heart

27/07/2015 21:21

What is Takotsubo (Stress) Cardiomyopathy?

failure. A characteristic feature of the syndrome is its relationship to emotional or physical stressful triggers. Emotional stressors range from a discrete event resulting in anger, frustration, grief or loss; to ongoing stressful situations such as moving to a new home, involvement in legal proceedings or challenging interpersonal relationships at home or at work. Physical stressors typically involve exacerbation of obstructive airways disease, major surgery, orthopaedic trauma, neurological catastrophes and other critical illnesses. TC closely resembles the entity previously known as neurological stunned myocardium, which is now believed to be the same condition.13 Of note, approximately onethird of cases occur without an identifiable stressor.

Figure 1: Left Ventriculogram Diastolic and Systolic Frames Showing the Classic Apical Ballooning with Hyperdynamic Basal Contraction and Akinesis of the Mid And Apical Segments

Diagnosis The process of diagnosing TC is, to a large extent, one of exclusion of other conditions that it mimics (e.g. acute coronary syndrome and myocarditis). This is based on the clinical presentation, and findings from the electrocardiogram (ECG), biomarkers and cardiac imaging: 30–50 % of cases present with ST-segment elevation and one-third with deep T-wave inversion. Deep T-wave inversion and QT prolongation may be seen at presentation or develop in the days following admission. Using contemporary troponin assays, a modest elevation in troponin is universally detected. Routine measurement of catecholamine levels has not been shown to be helpful. Catecholamines may be measured in select cases where there is no clear trigger for TC to screen for a pheochromocytoma, especially if hypertension is present. Neither the troponin profile nor the ECG is helpful in differentiating TC from and acute myocardial infarction (MI).

Figure 2: Pathophysiology of Takotsubo Cardiomyopathy

Left ventriculography, echocardiography and magnetic resonance imaging demonstrate the typical wall motion abnormalities of TC (see Figure 1). The imaging modality used depends on the clinical setting, availability and local expertise. Left ventriculography is typically performed, and is very helpful, in cases where an acute coronary syndrome is initially suspected, but angiography demonstrates normal or mildly diseased arteries. Cardiac magnetic resonance imaging is useful in excluding myocarditis and infarction, especially in cases where there is diagnostic uncertainty. Transient proximal or mid-segment occlusion of a large left anterior descending artery may produce a regional wall motion abnormality pattern that mimics TC. Thus, it is essential to carefully evaluate for regional wall motion abnormality in the distribution of all three major epicardial coronary arteries in order to distinguish the classic form of TC from a left anterior descending artery territory infarct or stunning. In these cases, the presence of true lateral wall systolic dysfunction is useful in differentiating features between TC and anterior MI. Other variant patterns of regional wall motion abnormalities of TC have been described, and while less common, tend to be pathognomonic. These include the mid-ventricular variant where apical function is preserved, or inverted/reverse TC, where the apical (and often the mid) segments are preserved with akinesis/hypokinesis of the basal regions.

abnormalities extend beyond a single epicardial vascular distribution. (Follow-up imaging is required to demonstrate that the ventricular dysfunction was transient); ii) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture (TC may occasionally occur in patients with obstructive coronary atherosclerosis); iii) new electrocardiographic abnormalities (either ST-segment elevation and/ or T-wave inversion) or modest elevation in cardiac troponin; iv) exclusion of myocarditis and pheochromocytoma.

Coronary angiography is indicated whenever TC is suspected in order to exclude obstructive multi-vessel coronary artery disease. Computed tomography (CT) angiography may be appropriate in cases where cardiac catheterisation is not safe or feasible.

Physical Stressor

Emotional Stressor Catecholamine release

Intrinsic susceptibility

Multivessel epicardial spasm

Microvascular dysfunction

Myocardial stunning and minor injury

Management Since acute coronary syndrome is often suspected before the diagnoses of TC is made, initial treatment is often similar to that for an acute MI. However, after the diagnosis of TC is confirmed, treatment is supportive with monitoring and treatment of complications, such as acute heart failure, left ventricular outflow tract obstruction, mitral regurgitation, hypotension, arrhythmias and thromboembolism. There are no randomised trial data to direct therapy. Initiation of beta-blocker therapy is recommended given the potential pathophysiological role of catecholamines, and the treatment is continued long term with the goal of preventing recurrence. However, it is worth noting that retrospective studies have shown that TC can occur in patients who are prescribed beta-blockers raising doubt over their efficacy in this condition.15 Treatment with a renin-angiotensin system antagonist should also be considered until there is spontaneous recovery of left ventricular function, which typically occurs over 4–6 weeks. If coincidental coronary artery disease is detected, secondary prevention measures should be initiated. Screening for acute or chronic emotional stress and psychiatric disorders is important and interventions may be reasonable in some cases.

The Mayo Clinic diagnostic criteria are the most widely used and require all four of the following:14 i) presence of transient regional

Prognosis

wall motion abnormality of the left (and often right) ventricular midsegments with or without apical involvement. The regional wall motion

The vast majority of patients with TC have good prognosis with complete resolution of systolic dysfunction. In-hospital mortality from early studies

EUROPEAN CARDIOLOGY REVIEW

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Expert Opinion was estimated at approximately 2 %.16 Higher in-hospital mortality of 4.2 % has recently been reported from the National Inpatient Sample database in the US.17 In a meta-analysis of 37 case series with a total of 2,120 patients from 11 countries, the in-hospital mortality rate was 4.5 %. Thirty-eight percent of deaths were directly related to TC complications, but the rest were due to underlying non-cardiac conditions.18 This highlights the fact that acute morbidity related to complications such as pulmonary oedema, cardiogenic shock and arrhythmias can be

3. 4.

Dote K, Sato H, Tateishi H, et al., [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases]. J Cardiol . 1991;21 :203–14. Sato H, Tateishi H, Dote K, et al., Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hori M, eds. Clinical aspect of myocardial injury: From ischemia to heart failure . Tokyo, Japan: Kagakuhyoronsha Publishing Co, 1990:56–64. Pavin D, Le Breton H, Daubert C, Human stress cardiomyopathy mimicking acute myocardial syndrome. Heart . 1997;78:509–11. Desmet WJ, Adriaenssens BF, Dens JA, Apical ballooning of the left ventricle: first series in white patients. Heart . 2003;89 :1027–31. Tsuchihashi K, Ueshima K, Uchida T, et al., Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol . 2001;38 :11–8. Elliott P, Andersson B, Arbustini E, et al., Classification of the cardiomyopathies: A position statement from the European

Prasad_FINAL.indd 8

significant. Among those who have complete recovery, long-term survival appears to be similar to the age- and gender-matched population.16 In another study, there was increased mortality in TC patients compared with age- and gender- matched controls in the first year after the index event, but all the deaths in this case series were non-cardiac, mostly due to cancer.15 In one of the longest follow-ups available to date of patients with TC, recurrence of the condition was observed in approximately 10 % of patients over a mean follow-up duration of 4 years.16 n

Society of Cardiology working group on myocardial and pericardial diseases. Eur Heart J . 2008;29 :270–6. 7. Bybee KA, Prasad A, Stress-related cardiomyopathy syndromes. Circulation . 2008;118 :397–409. 8. Ghadri J, Ruschitzka F, Lüscher TF, Templin C, Takotsubo cardiomyopathy: still much more to learn. Heart . 2014;100 :1804–12. 9. Wittstein IS, Thiemann DR, Lima JA, et al., Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med . 2005;352 :539–48. 10. Hoyt J, Lerman A, Lennon RJ, et al., Left anterior descending artery length and coronary atherosclerosis in apical ballooning syndrome (Takotsubo/stress induced cardiomyopathy). Int J Cardiol . 2010;145 :112–5. 11. Deshmukh A, Kumar G, Pant S, et al., Prevalence of Takotsubo cardiomyopathy in the United States. Am Heart J . 2012;164 :66–71 e1. 12. Bybee KA, Prasad A, Barsness GW, et al., Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical

ballooning syndrome. Am J Cardiol . 2004;94 :343–46. 13. Lee VH, Connolly HM, Fulgham JR, et al., Tako-tsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: an underappreciated ventricular dysfunction. J Neurosurg . 2006;105 :264–70. 14. Prasad A, Lerman A, Rihal CS, Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Herat J . 2008;155 :408–17. 15. Sharkey SW, Windenburg DC, Lesser JR, et al., Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol . 2010;55 :333–41. 16. Elesber AA, Prasad A, Lennon RJ, et al., Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol . 2007;50 :448–52. 17. Brinjikji W, El-Sayed AM, Salka S, In-hospital mortality among patients with takotsubo cardiomyopathy: a study of the National Inpatient Sample 2008 to 2009. Am Heart J . 2012;164 :215–21. 18. Singh K, Carson K, Shah R, et al., Meta-analysis of clinical correlates of acute mortality in takotsubo cardiomyopathy. Am J Cardiol . 2014;113 :1420–8.

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Expert Opinion

Pulmonary Hypertension Brendan P Madden Cardiothoracic Unit, St Georges Hospital, London, UK

Abstract Pulmonary hypertension is said to occur when the mean pulmonary arterial pressure exceeds 25 mmHg at rest or 30 mmHg during exercise. There are many causes but the term Pulmonary arterial hypertension (PAH) is used to describe a rare group of illnesses that share histopathological similarities in the small muscularised pulmonary arterioles leading to vascular remodelling (plexogenic pulmonary arteriopathy) and progressive elevation in the pulmonary vascular resistance. Left untreated, patients die as a consequence of right heart failure and the mortality approaches that of commonly encountered malignancies. There is no effective cure. Most treatment for PAH patients has focused on the endothelial cell vascular dysfunction known to occur in these disorders and indeed agents such as endothelin receptor antagonists, phosphodiesterase pathway V inhibitors and prostacyclin analogues have been shown to improve morbidity and delay rate of deterioration. More recently evidence has emerged that they may have a positive impact on survival. These agents have also been applied to treat patients with chronic thromboembolic pulmonary hypertension (CTEPH) and selected patients with CTEPH may also benefit from pulmonary thromboendarterectomy. For a small number of patients with PAH lung transplantation may be considered

Keywords Pulmonary hypertension diagnosis, clinical presentation, investigation and therapeutic strategies Disclosure: We have received 50 % funding of the salary of our pulmonary hypertension nurse from Actelion. This is an unconditional grant to develop our clinical service and engage in audit. Received: 22 June 2015 Accepted: 1 July 2015 Citation: European Cardiology Review, 2015;10(1):9–11 Correspondence: Brendan P Madden, Cardiothoracic Unit, St Georges Hospital, London SW17 0QT, UK. E: Brendan.Madden@stgeorges.nhs.uk

Pulmonary hypertension is said to occur when the mean pulmonary artery pressure exceeds 25 mmHg at rest or 30 mmHg with exercise. The term pulmonary arterial hypertension (PAH) denotes a series of apparently unrelated disorders that share the histopathological entity known as plexogenic pulmonary arteriopathy (PPA).

Pulmonary hypertension associated with chronic pulmonary thremboembolism is included in Group 4 and Group 5 and comprises miscellaneous conditions with unclear or multifactorial aetiologies such as histiocytosis, lymphangioleiomyomatosis, glycogen storage disease, Gaucher disease and post splenectomy.

There are many conditions that can lead to the development of pulmonary hypertension and these have traditionally been classified into five groups (World Conference on Pulmonary Hypertension, Venice 2003; Dana Point meeting on Pulmonary Hypertension 2008).

Pathology

Those disorders listed in Group 1 share the histopathology of PPA although why such apparently diverse disorders should do so remains unclear. Examples of Group 1 disorders include idiopathic PAH, PAH associated with genetic factors (e.g bone morphogenetic protein receptor 2 mutations), connective tissue disorders (e.g systemic lupus erythematosis), portal hypertension, HIV and anorexigens, congenital heart diseases, pulmonary veno occlusive disease and pulmonary capillary haemangiosis. Advanced pulmonary vasodilator therapy is given to patients who have pulmonary hypertension associated with these conditions. Group 2 disorders comprise left heart disorders e.g valvular disease and atrial or ventricular dysfunction while Group 3 diseases reflect pulmonary hypertension in association with lung disease or hypoxemia e.g chronic obstructive pulmonary disease (COPD), interstitial lung disease or sleep disordered breathing.

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It is possible that the lung has only a small number of responses to injury that feed into common final pathway mechanisms. Many insults can lead to the development of the acute respiratory distress syndrome (ARDS) but the pathology is similar (and not PPA) regardless of initiating injury. Similarly obliterative bronchiolitis seen as a consequence of rheumatoid arthritis or infection with respiratory syncytial virus in children is similar to that believed to be a form of chronic allograft rejection in lung transplant recipients. In PPA there is an initial period of vasoconstriction followed by migration of smooth muscle cells from the inner half of the media of muscular pulmonary arterioles into the lumen. Here they become myofibroblasts that are capable of laying down both smooth muscle and fibrous tissue. The myofibroblasts proliferate in a concentric fashion and, upon sectioning, the vessels look like a cut onion, hence the term ‘onion skin proliferation’. This leads to a progressive reduction in the radial size of the vessel, the resistance to flow increases in accordance with Poiseuilles law (where among other things flow is proportional to the fourth power of the radius, r4) vessel rupture at proximal points of weakness (e.g. at branches) occurs. Haemorrhage

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Expert Opinion ensues and primitive networks of blood vessels (a ‘plexus’, hence plexiform lesion) grow into the area. The combination of onion skin (or concentric laminar intimal) proliferation and plexiform lesions is known as PPA. It is possible that patients may have a genetic predisposition or risk factor, such as a connective tissue disease or HIV, and that this causes a vascular injury or modification in antigenic determinants. Endothelial cell dysfunction follows with derangement of the normal release of endothelial derived factors, which facilitates inflammation and promotes loss of local vaso reactivity and thrombus formation. Decreased progression and vascular remodelling can then occur. The pulmonary endocrine cells immuno reactive for calcitonin and gastrin releasing peptide may adversely influence smooth muscle cells.

Disease Progression At onset there may be few symptoms, but as the disease progresses the PVR rises and the cardiac output falls. Common symptoms include dyspnoea on exertion or at rest, chest pain (due to right ventricular angina), palpitations and pre-syncope or syncope. Ultimately the signs and symptoms of right heart failure develop and death occurs. A median survival of 2.8 years has been reported for untreated patients in New York Heart Association (NYHA) class III or IV. Sudden acute elevations in PVR can occur (known as pulmonary hypertensive crises) leading to an acute reduction in left heart filling and profound systemic hypotension and can sometimes be fatal. This can occur during general anaesthetic induction and is one of the reasons why patients with PAH need careful preoperative evaluation prior to surgical intervention.

Treatment Diagnosis Although there is increasing awareness among clinicians regarding pulmonary hypertension, much more work needs to be carried out to promote earlier and accurate diagnosis. The clinical features are often non-descript and include fatigue, malaise, chest pain, palpitations, pre-syncope or syncope or haemoptysis. Additionally, the diagnosis may not be considered in patients with co-existing cardiac or pulmonary disease and yet underlying pulmonary hypertension may be the reason for the apparent failure to respond to conventional treatment of their primary disease. Furthermore, it is essential that pulmonary hypertension is carefully assessed and optimised where appropriate if patients are required to undergo intervention (e.g surgery) or should they become pregnant. In addition to history and clinical examination the following investigations are routinely performed to assess patients with suspected pulmonary hypertension; 1. Routine haematological and biochemical parameters including autoimmune profile, HIV serology and thrombophilia screen (if pulmonary embolism is suspected) or genetic studies if familial PAH is being considered and BNP. 2. Chest X-ray. 3. Electrocardopgram (ECG). 4. 2D echocardiography. 5. Lung function tests and arterial blood gas analysis. 6. Thoracic computed tomography (CT) scan/CT pulmonary angiography or ventilation–perfusion (VQ) scan. 7. Right heart catheter. This investigation is considered gold standard for diagnosing patients with pulmonary hypertension and provides information regarding right arterial pressure, pulmonary arterial pressure, right ventricular pressure, cardiac output and mixed venous (pulmonary arterial) oxygen saturation and left atrial filling pressure (the pulmonary capillary wedge pressure). The pulmonary vascular resistance (PVR) is derived from the formula:

PVR =

mean pulmonary artery pressure – mean pulmonary capillary wedge pressure

Other tests that may be performed include exercise test, magnetic resonance imaging (MRI), overnight oximetry and, occasionally, pulmonary angiogram.

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There is concern that treating patients with pulmonary vasodilating agents whose left atrial filling pressure exceeds 15 mmHg will lead to increased venous return to the heart that in turn could lead to, or exacerbate, left heart failure. There is little evidence to justify treating patients with advanced pulmonary vasodilator therapy who have pulmonary hypertension associated with lung disease. Those with obstructive sleep apnoea should have appropriate treatment e.g with nocturnal nasal continuous positive airway pressure (CPAP) and lifestyle advice and only have consideration given to treating pulmonary hypertension should it persist after standard therapies for sleep disordered breathing having been tried. There is no effective cure for patients who develop PAH but specific targeted therapeutic agents have been shown to improve exercise capacity, WHO functional class, haemodynamic parameters and time to clinical worsening. Recently there has been a suggestion that a newer endothelin receptor antagonist (ERA) may be associated with improved survival although further studies are needed to confirm this. However, it is accepted that the prognosis for patients with PAH is improving. Approximately 10 % of patients with PAH will respond to calcium channel blockers, and such patients will usually demonstrate reversibility (a reduction in mean pulmonary artery pressure by >10 mmHg to achieve an absolute value of <40 mmHg with an unchanged or increased cardiac output) at right heart catheterisation.

mean cardiac output

The PVR can be indexed (PVRi) and the systemic vascular resistance can also be calculated and indexed (SVRi).

In general, if pulmonary hypertension occurs in association with other conditions, treatment of the primary disorder should be optimised first. Algorithms for the treatment of PAH vary around the world. Typically therapeutic agents specifically targeting pulmonary hypertension are given to those patients who are in Groups 1 and 4 and these who are in renal failure on dialysis. Advanced pulmonary vasodilation therapy is prescribed if the mean pulmonary artery pressure exceeds 25 mmHg and the mean pulmonary capillary wedge pressure is <15 mmHg. Such therapy is usually given to patients who are in World Health Organization (WHO) functional class II, III or IV.

Sildenafil and tadalalfil are phosphodiesterase 5 inhibitors and act on the nitric oxide pathway to cause vasodilation. Sildenafil may also possess anti proliferative effects on vascular smooth muscle. A newer class of agents, soluble guanylate cyclase stimulators, reduce intracellular calcium in an NO dependant and independent fashion and have been used to treat patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH).

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Pulmonary Hypertension

Endothelin levels are increased in PAH and relate to disease severity and prognosis. Different ERA can block one (A) or both of the endothelin receptors (A and B) to antagonise vasoconstriction and vascular remodelling promoted by excessive endothelin release.

a high (almost 50 %) complication rate. Bilateral lung transplantation is available for some patients with PAH but donor organ availability and the late complication of obliterative bronchiolitis remain major problems to be addressed.

The deficiency of endogenous prostacyclin can be addressed by administration of prostacyclin or its analogues by continuous intravenous (IV) infusion, by regular inhalational therapy or by subcutaneous injection. The precise role of combination therapies and the timing of their introduction into the therapeutic regime of the PAH patient is being evaluated. Other therapies under trial include lipidlowering drugs, anti-inflammatory agents, monoclonal antibodies and anti-platelet agents.

Conclusion

Atrial septostomy is available for a small number of patients with class IV disease in an attempt to offload the failing right ventricle as a bridge to transplantation. There is encouraging experience with pulmonary thromboendarterectomy for selected patients with CTEPH. However, this is a major operation with

Further Reading 1. Madden B (editor), Treatment of Pulmonary Hypertension – Current Cardiovascular Therapy , Cham, Switzerland: Springer International Publishing, 2015. 2. Bacon JL, Peerbhoy MS, Wong E, et al., Current diagnostic investigations in pulmonary hypertension. Curr Respir Med Rev. 2013;9:79–100. 3. Madden BP, Pulmonary hypertension and pregnancy. Int J Obstet Anesth . 2009;18 :156–64. 4. Ranu H, Smith K, Nimako K, et al., A retrospective review to evaluate the safety of right heart catheterisation via the internal jugular vein in the

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PAH is a progressive and lethal disease whose initial symptoms are non-specific. Improved awareness is required to enable patients with PAH to be diagnosed earlier and to have their disease carefully characterised and receive appropriate therapeutic intervention as soon as possible. Patients with PAH should be managed in a centre with specialist clinicians and nurses who are trained in the assessment and management of these challenging patients (often in conjunction with a local hospital) and who are available to offer advice and support when complications arise, should patients become pregnant or should surgical intervention be necessary. It is hoped that an improved understanding of the pathophysiological mechanisms involved in PAH will lead to the development of more effective treatments. n

assessment of pulmonary hypertension. Clin Cardiol . 2010;33 :303–6. Madden BP, Sheth A, Ho T, Kanagasabay R, A potential role for sildenafil in the management of perioperative pulmonary hypertension and right ventricular dysfunction following cardiac surgery. Br J Anaesth . 2004;93 :155–6. Galiè N, Hoeper MM, Humbert M, et al., Guidelines for the diagnosis and treatment of pulmonary hypertension. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society

(ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J . 2009;30 :2493– 537. Humbert M, Lau EMT, Montani D, et al., Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation . 2014;130 :2189–208. Ghofrani HA, Galiè N, Grimminger F, et al., Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med . 2013;369:330–40. Pulmonary hypertension in UK clinical practice: an update. Br J Cardiol . 2015;22(Suppl. 1):S2–S15.

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Expert Opinion

Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography Iana Simova National Cardiology Hospital, Sofia, Bulgaria

Abstract Coronary flow velocity reserve (CFVR) reflects global coronary atherosclerotic burden, endothelial function and state of the microvasculature. It could be measured using transthoracic Doppler echocardiography in a non-invasive, feasible, reliable and reproducible fashion, following a standardised protocol with different vasodilatory stimuli. CFVR measurement is a recommended complement to vasodilator stress echocardiography. It could serve as a diagnostic tool for coronary microvascular dysfunction and in the setting of epicardial coronary artery stenoses could help in identification and assessment of functional significance of coronary lesions and follow-up of patients after coronary interventions. CFVR has also a prognostic significance in different clinical situations.

Keywords Coronary flow velocity reserve, echocardiography, non-invasive Disclosure: The author has no conflicts of interest to declare. Received: 5 May 2015 Accepted: 23 June 2015 Citation: European Cardiology Review, 2015;10(1):12–8 Correspondence: Iana Simova, Department of Noninvasive Cardiovascular Imaging and Functional Diagnostics, National Cardiology Hospital, 65 Koniovitsa Str, Sofia 1309, Bulgaria. E: ianasimova@gmail.com

Coronary flow velocity reserve (CFVR) represents the ratio between maximal (stimulated) coronary blood flow, induced by using a coronary vasodilator, and baseline (resting) blood flow (see Figure 1). As a ratio it is a dimensionless variable. It could be measured with different tools – some of them, such as intracoronary Doppler flow wire and coronary sinus thermodilution, are invasive methods and therefore associated with certain risks, radiation exposure, increased cost and ethical considerations.1 Other methods, such as cardiac magnetic resonance imaging and cardiac nuclear imaging, are non-invasive and useful for clinical research, but with limited clinical application because they are complex, time-consuming, with limited availability and expensive.2,3 Transthoracic Doppler echocardiography (TDE) as a tool to measure CFVR has the advantages of being non-invasive, widely available, easily performed at bedside, without radiation exposure, inexpensive and not so time-consuming (mean time to complete a CFVR test is around 15 minutes; when it is combined with a cold-pressor test – see below, the duration is prolonged by 5 more minutes). However, CFVR assessment has a steep learning curve and operator experience is important. This review focuses on the technical details for CFVR assessment and major clinical applications.

Technical Details All three coronary arteries could be visualised with TDE and CFVR could be assessed. The left anterior descending (LAD) coronary artery has been the most commonly interrogated, followed by the posterior descending artery (PDA). Technical feasibility to investigate LAD is high with more than 90 % in experienced hands4–6 and reaches nearly 100 % with the use of intravenous contrast agents.7 The feasibility

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of CFVR assessment in PDA is lower – in the range between 54 and 86 %.4,5,8 Left circumflex coronary artery (LCx) is most challenging of the three due to the particular anatomy of the artery and the poor resolution of the lateral wall.2 Interobserver and intraobserver variability of CFVR measurements have been assessed in various studies and both are in the range of 5 %.9,10 Intra-individual variability has also been shown to be low.10

Settings The appropriate setting of the echo scanner is an important prerequisite for CFVR assessment. LAD is visualised either with a high-frequency transducer (4–8 MHz) or with transthoracic low-frequency probe (3.5–5 MHz) with a second harmonic capability.2,11 PDA is situated more deeply in the chest and a low frequency transducer is needed to assess coronary flow.11,12 Color Doppler pulse repetition frequency should be 15–25 cm/s, wall filters set high and pulse Doppler filters should be low. Pulse wave Doppler sample volume should be 3–4 mm.2

Proximal or Distal to a Stenosis? The best way to assess the functional significance of a stenosis is to evaluate the coronary flow in the distal tract of the artery according to the lesion. Proximal to the stenosis, CFVR could be normal because there are usually side branches between the sampling site and the stenosis with preserved perfusion in adjacent territories. At the site of the stenosis, the flow accelerates to compensate for lumen loss.2,14 Considering the fact that CFVR is measured most commonly in the distal LAD and PDA, while the majority of relevant stenoses are located in the proximal to middle part of LAD and in the proximal right

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Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography

Figure 1: CFVR Assessment During Dipyridamole Stress Echocardiography. Coronary Flow Velocity is Measured at Baseline and at Peak Hyperaemia (Sixth Minute of Dipyridamole Infusion)

Figure 2: Evaluation of Coronary Flow in the Distal Part of LAD from Modified Apical View

Typical diastolic flow is seen with pulsed wave Doppler.

CFVR (coronary flow velocity reserve) in this case is 3.1.

coronary artery (RCA) before the crux cordis, CFVR usually provides post-stenotic values.3

Echocardiographic Views All three LAD segments (proximal, mid and distal) are visible with the new technical applications in TDE. CFVR is usually assessed in the distal and sometimes middle LAD segment. Distal LAD segment is evaluated from an apical view, somewhere between the classic twoand three-chamber view where the anterior interventricular groove runs, and near left-ventricular apex (see Figure 2). The mid-to-distal LAD segment is visualised in a modified left parasternal view with the patient in the left lateral decubitus position and the transducer moved lower and more lateral in order to visualise the anterior interventricular groove.15 PDA is assessed from a modified apical two-chamber view showing the posterior interventricular groove and adjacent to the ostium of the coronary sinus (see Figure 3).12 The distal LCx is searched at the basal and mid-portion of left ventricular lateral wall in an apical fourchamber view.13 When the appropriate position is achieved, the respective artery is searched for using color Doppler flow mapping and predominantly diastolic signal. Blood flow velocity is measured using pulsed wave Doppler echocardiography. Angle correction is not necessary since

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CFVR is a ratio between baseline and hyperaemic flow velocity and is not affected by the absolute value of flow velocity. Nevertheless, angle should be kept as low as possible (below 40Â°).2,15

Systole or Diastole? Coronary flow is biphasic with diastolic predominance. The blood supply to cardiac myocytes is largely diastolic due to the typical function of heart muscle â&#x20AC;&#x201C; contracting in systole with generation of high intramural pressure, which impedes perfusion. Due to the translational motion of coronary arteries during the cardiac cycle it is sometimes difficult to obtain a complete Doppler signal throughout the cardiac cycle. This is not a problem, since only the diastolic flow is usually needed to assess baseline and hyperaemic coronary flow and calculate CFVR.2 Coronary flow velocities can be measured online or offline. Maximal flow velocity (averaging three cardiac cycles) at baseline and during hyperaemia is considered, although mean flow velocity could be used as well without influencing the final CFVR value, which represents the ratio between baseline and hyperaemic velocities. It should be emphasised that during administration of a vasodilating agent the probe must be kept in the same position and machine settings must not be changed compared with baseline.

Vasodilators The most commonly used vasodilators are dipyridamole and adenosine. A comparison between modes of application, and advantages and disadvantages of both methods is presented in Table 1.

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Expert Opinion Table 1: Comparison between Dipyridamole and Adenosine as Vasodilators for CFVR Assessment Dose

Dipyridamole Adenosine 0.84 mg/kg/minute for 6 minutes 140 mcg/kg/minute for 2–3 minutes

Half-life

11 hours

10 seconds

Onset of action

After 4–6 minutes infusion

Immediate

Duration of action

30 minutes

30 seconds

Diameter of coronary arteries

Increased

Not changed

Combination with LV contractility and

Yes

Antidote

Aminophylline

Not necessary

Side effects

Hypotension, flushing, headache,

AV conduction delay (including complete AV block),

hyperventilation, antidote-resistant ischaemia

flushing, chest discomfort, throat, neck or jaw discomfort,

WMS analysis during stress

abdominal pain, lightheadness, nausea, headache

Contraindications

Asthma with ongoing wheezing

Active bronchospasm

Second- or third-degree AV block without

Second- or third-degree AV block without pacemaker or sick

pacemaker or sick sinus syndrome

sinus syndrome

Systolic blood pressure <90 mmHg

Acute coronary syndrome

Recent use of dipyridamole containing medications or

Recent use of dipyridamole containing

methylxanthines (e.g. caffeine)

medications or methylxanthines (e.g. caffeine)

Hypersensitivity

Main advantage

Prolonged action allows assessment of CFVR and

wall motion abnormalities during single examination

CFVR = coronary flow velocity reserve; LV = left ventricular; WMS = wall motion score.

Table 2: Comparison Between Non-invasive CFVR and Invasive FFR/CFR Radiation exposure

Non-invasive CFVR Yes

Invasive FFR/CFR No

Invasiveness

Yes

Hospitalisation required

Yes

Feasibility

Imperfect: LAD

Perfect

(≈95 %) > RCA

(≈70 %) > RCx

Cut-off value

May be different

Fixed cut-off value

in different

but presence of

clinical settings

grey zone

Dependence on

Yes

Cost

Low

High

Suitable for follow-up

Yes

Suitable for assessment

Yes

Figure 3: Evaluation of Coronary Flow in Right Coronary Artery (Proximal Part Of Posterior Descending Artery) from Modified Apical Two-chamber View

human factors and skills Special equipment required

of pharmacological efficacy LAD = left anterior descending; RCA = right coronary artery; RCx = ramus circumflexus.

CFVR could also be assessed during dobutamine stress echocardiography. However, it is not widely used since dobutamine increases coronary flow via different mechanisms compared with dipyridamole and adenosine.11 Both exercise and dobutamine are submaximal stimuli for coronary flow reserve (CFR) and technically more demanding for imaging of CFVR compared with dipyridamole and adenosine.3

Non-invasive or Invasive CFVR A comparison between non-invasive (with transthoracic echocardiography) CFVR and invasive (during cardiac catheterisation and coronary angiography) FFR/CFR assessment is presented in Table 2.

Learning Curve CFVR assessment is an advanced echo tool requiring time and devotion. A detailed anatomical and technical knowledge is required

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Position of the sample volume (left); Doppler coronary flow signal (right).

in order to begin training. A period of supervision by a physician with considerable skills and experience in CFVR measurement is highly recommended. As with other techniques implicating technical skills, there is a learning curve and feasibility of CFVR measurement increases gradually in time.

Cold Pressor Test It should be noted that both adenosine and dipyridamole induce a hyperaemic stimulus that relaxes vascular smooth muscle cells in coronary arteries in a fashion only partially dependent on endothelial function. The cold pressor test (CPT) is a well-validated, sympathetic

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Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography

Figure 4: Cold Pressor Test-derived Coronary Flow Velocity is Measured In Left Anterior Descending at Baseline (0.20 M/S) and at First Minute (0.20 M/S), Second Minute (0.20 M/S) and Fourth Minute (0.37 M/S) after Placing Patient’s Hand in Ice Water Slurry

CFVR (coronary flow velocity reserve) in this case is 1.85.

stimulus able to induce hyperaemic vasodilation that depends totally on the endothelial release of nitric oxide (NO).16,17 CPT is performed according to a standardised protocol,18 by placing the subject’s hand and distal part of the forearm in ice-water slurry for 3 minutes. CPT-derived CFVR is measured as the ratio between coronary diastolic peak flow velocities at rest and during maximal hyperaemia (see Figure 4).

Pitfalls There are several possible ways to make mistakes during CFVR assessment. Errors occur more often at the beginning of the learning curve and diminish significantly as operators gain experience. Common pitfalls include loss of flow signal during investigation, mapping different coronary artery tracts during the same study, misinterpretation of coronary arteries (e.g. diagonal or intermediate branches for LAD, or recurrent distal part of LAD for PDA) or misinterpretation of wall noise or epicardial space due to mild pericardial effusion and investigating right ventricular flow. It should be noted that CFVR as a stand-alone technique can not distinguish between microvascular and macrovascular disease – the reason for a decrease in coronary reserve could be either epicardial coronary artery stenosis, or microvascular dysfunction, or both.

Normal Values If a normal value for CFVR should be defined, then the cut-off value of 2 must be accepted, because it has been demonstrated in various

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studies that CVFR <2 detects epicardial coronary artery stenosis and predicts myocardial ischaemia in the underlying territory.7,19,20 The sensitivity and specificity for the cut-off value of <2 CFVR to detect significant LAD stenosis are both more than 90 %. In the setting of normal epicardial coronary arteries CFVR assesses coronary microcirculatory function and in this setting ‘normal’ CFVR values vary significantly according to the studied population, 21–23 presence and extent of atherosclerostic risk factors,24,25 concomitant therapy,21,26 etc. Ageing also affects CFVR – baseline flow velocity increases with age, while maximal hyperaemic flow does not change and therefore CFVR value decreases with advancing age.27 Therefore in a clinical setting and in a study population a more useful way to interpret CFVR values is to compare CVFR before and after an event or therapeutic intervention, or to a control group, instead of using pre-defined cut-off values.

Clinical Application Given the physiological basis of CFVR measurement the method has two major areas of application: evaluation of epicardial coronary artery stenosis and assessing microvascular myocardial function in the absence of epicardial stenosis (see Figure 5). CFVR could be useful as a diagnostic and prognostic tool in different clinical situations, such as the diagnosis of functionally significant coronary stenosis, evaluation of patients with intermediate coronary stenosis, follow-up after percutaneous coronary intervention

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Expert Opinion Figure 5: Schematic Drawing of CFVR Main Clinical Applications Suspected epicardial coronary stenosis Coronary macrovascular disease

Functional assessment of intermediate stenosis Suspected restenosis

Hypertension

Diabetes

CFVR

Coronary microvascular disease

Cardiomyopathies

Aortic stenosis

Evaluating the effect of pharmacological interventions Coronary artery disease

Prognosis

Cardiomyopathies

Cardiac transplantation CFVR = coronary flow velocity reserve.

(PCI), coupling left ventricular function with perfusion during stress echocardiography, evaluation of coronary microcirculation in the setting of hypertension, diabetes and other conditions, assessment of the effectiveness of certain therapeutic intervention and risk stratification in patients with dilated cardiomyopathy, after heart transplantation and other diseases. Focusing the attention on patients with suspected or proved coronary artery disease, a practical guide to the application of CFVR is as follows:3 1. Before coronary angiography a. Suspected epicardial coronary stenosis (CFVR combined with wall motion score). b. Suspected microvascular abnormalities (CFVR in LAD). 2. After coronary angiography a. Abnormal coronary angiogram – functional assessment of intermediate stenosis (CFVR combined with wall motion score). b. Normal coronary angiogram – confirmation or exclusion of microvascular dysfunction (CFVR in LAD). 3. Follow-up after initial coronary angiogram a. Follow-up of functional significance of intermediate stenosis (CFVR combined with wall motion score). b. Patients with suspected restenosis (CFVR combined with wall motion score). c. Verification of beneficial effect of pharmacological interventions (CFVR in LAD).

Coronary Artery Stenosis Evaluation of patients with coronary stenosis in the range of 50–70 % is challenging. CFVR is a useful tool to assess the functional significance of the stenosis. When CFVR is <2 revascularisation could be safely deferred given the high negative predictive value of CFVR to detect ischaemia.20,28 The diagnostic accuracy of CFVR (adenosine) in three major coronary arteries for detecting ischaemia has been compared with FFR in a

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prospective study in 172 vessels of 140 patients with at least one ≥50 % stenosis in a major epicardial artery. A CFVR cut-off of 2.2 demonstrated high sensitivity and specificity to predict FFR ≤0.75.29

Percutaneous Coronary Interventions Immediately after a PCI CFVR could be measured invasively with intracoronary Doppler. Surprisingly, however, these early (immediate) measurements have shown a high rate of impaired CFVR even in the absence of any residual angiographic stenosis.3 This could be explained by microvascular stunning due to microembolisation, thrombogenicity (thrombin release) and vasoconstriction (endothelin release), or to temporary reactive hyperaemia, which masks normal reserve. Therefore, invasive immediate-after-PCI CFVR measurement is not a reliable baseline reference value, which could serve for followup of patients and monitoring for restenosis. It is better to measure CFVR at least several days after PCI and here comes the role of the non-invasive, repeatable, inexpensive and accessible transthoracic Doppler echocardiography. CFVR value <2 in LAD after PCI predicts the presence of restenosis with high sensitivity (from 78 to 89 %) and specificity (from 90 to 93 %).30–32 Using a cut-off CFVR value of 2 is useful in the setting of intermediate coronary stenosis or after PCI but a more sensitive way to follow-up the progression of an intermediate lesion or to detect restenosis is to evaluate the evolution of CFVR over time and to compare current values with a reference value established for the individual patient.2 The introduction of drug-eluting stents (DES) in the field of interventional cardiology has significantly reduced the rate of restenosis after PCI. DES, however, are associated with delayed healing, which could lead to vasodilator dysfunction and late stent thrombosis. It is of interest therefore to dispose of a reliable, repeatable, non-invasive and inexpensive method to monitor vasodilator function in this setting. In a recent small study in 24 patients with acute coronary syndrome and PCI with DES in LAD, 3 months after the index procedure CFVR measured with transthoracic Doppler echocardiography and with invasive thermodilution method showed good agreement, suggesting that the non-invasive CFVR measurement is a feasible and reliable method for assessment of vasodilator dysfunction after DES implantation33.

Microcirculatory Dysfunction More than 20 % of patients referred for coronary angiography because of chest pain have no angiographic evidence of coronary artery stenosis. According to a recent study, however, more than 75 % of these patients have occult coronary abnormalities, mostly endothelial dysfunction and microvascular impairment.34 Microvascular dysfunction could develop before the occurrence of atherosclerotic epicardial artery involvement and it could also coexist with angiographically significant coronary artery disease. Coronary microvasculature cannot be visualised directly and CFVR represents a useful tool to assess microcirculatory function. Many risk factors and clinical conditions have been proved to be associated with microcirculatory impairment. Patients with type 2 diabetes, for example, have reduced CFVR compared with healthy controls, and diabetics with CFVR ≤2 have worse prognosis compared with those with CFVR >2, despite the fact that both groups have preserved left ventricular ejection fraction, normal wall motion score analysis during dipyridamole stress test and absence of angiographically significant coronary stenoses.35

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Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography

In patients with chronic kidney disease in the absence of obstructive coronary artery disease, the presence of microvascular dysfunction, defined as CFVR <2, was associated with worse cardiovascular outcomes, independent of traditional cardiovascular risk factors.36

Stress Echocardiography According to the European Association of Cardiovascular Imaging Expert consensus statement for performing stress echocardiography from 2008 wall motion analysis should be combined with perfusion assessment (CFVR) in order to provide dual imaging vasodilator stress echocardiography.37 Wall motion abnormalities are more specific for inducible ischaemia while perfusion changes are more sensitive and may occur in the absence of ischaemia. CFVR and wall motion analysis offer complementary information during stress echo, combining flow and function together. Wall motion abnormality is more efficient to include coronary artery disease, while a normal CFVR is more efficient to exclude it (CFVR has higher negative predictive value). In a study of 1,660 patients with chest pain and no wall motion abnormalities at rest and during dipyridamole stress echocardiography, decreased CFVR on LAD was associated with significantly increased 4-year event rate both in women and men.38 Although some authors have reported successful application of three-vessel CFVR assessment during vasodilator stress test,28 dual imaging vasodilator stress echocardiography at present utilises LADonly CFVR evaluation. A three-coronary approach would probably be more fruitful but it remains too technically challenging. Moreover, microvascular dysfunction, which is the mainstay of perfusion abnormalities detected with LAD CFVR measurement during stress echocardiography, is a global phenomenon and could be adequately assessed with Doppler interrogation of the distal LAD segment.

Athletes’ Heart CFVR could be used to differentiate between physiological left ventricular hypertrophy (typical for endurance athletes) and pathological hypertrophy in the setting of hypertrophic cardiomyopathy (CMP) and hypertensive heart disease. In a group of 29 male endurance athletes CFVR has been found to be supranormal (mean value 5.9) and significantly higher compared with healthy controls despite the presence of left ventricular hypertrophy in the former group.39

Aortic Stenosis Aortic stenosis induces a pressure overload of the left ventricle, leading eventually to concentric left ventricular remodelling and hypertrophy, and increase in left ventricular mass. In order to provide an adequate blood supply to an increased muscle mass at rest coronary arteries dilate. This baseline vasodilation leads in turn to a reduced capacity to increase coronary flow during exercise (or after pharmacological challenge with adenosine or dipyridamole) and therefore to a reduction in CFVR. Decreased CFVR in patients with haemodynamically significant aortic stenosis in the absence of epicardial coronary artery stenosis has been repeatedly demonstrated and also the prognostic value of CFVR has been shown in this population. In the SummariZation of long-tErm prognostic siGnificance of coronary flow rEserve in special Disorders (SZEGED) study 49 aortic stenosis patients were followed-up for nearly 9 years after baseline CFVR assessment. Univariate and multivariate regression analysis showed that CFVR was an independent predictor

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of cardiovascular morbidity and mortality. The authors found that CFVR cut-off value of 2.13 had the highest accuracy in predicting cardiovascular outcome.40 In a larger study of 127 asymptomatic patients with moderate and severe aortic stenosis with preserved ejection fraction and without obstructive epicardial coronary disease followed-up for nearly 3 years, CFVR was shown to bear an independent prognostic significance of total mortality. A CFVR cut-off value of 1.85 had the highest accuracy in predicting death.41 After aortic valve replacement, CFVR increases together with a decrease in left ventricular mass. This has been demonstrated in a study with 39 aortic stenosis patients evaluated before and 6 months after aortic valve replacement: CFVR increased from 1.76±0.5 to 2.61±0.7, which paralleled a decrease in left ventricular mass index from 154±21 to 134±21g/m2.42

Cardiomyopathy In patients with hypertrophic CMP CFVR is markedly lower compared with healthy controls. Abnormal CFVR values were more common in symptomatic compared with asymptomatic subjects and in those with left ventricular outflow tract obstruction. Impaired CFVR was a strong and independent predictor of outcome in hypertrophic CMP patients.43 In 132 patients with idiopathic dilated CMP with angiographically normal coronary arteries and left ventricular ejection fraction <40 % CFVR values were abnormal (<2) in nearly two-thirds of the participants and were associated with a worse prognosis during 2-year follow-up.44

Prognostic Value Recently, low CFVR values have been shown to have prognostic significance in different clinical situations. In octogenarians (369 subjects) a reduced CFVR in LAD in the setting of a stress echo negative for wall motion abnormalities helps to risk stratify the subset at higher risk of mortality and major adverse cardiac events (MACE). The best CFVR cut-off predicting untoward cardiac events in this population was 1.93.45 In nearly 400 patients with angiographically normal coronary arteries, normal wall motion during stress and chest pain (microvascular angina), those with CFVR value >2 showed significantly better outcome during almost 5-year follow-up compared with the group with impaired CFVR.46 In more than 300 subjects with known or suspected coronary artery disease but with negative stress echocardiography (by wall motion criteria), CFVR ≤1.92 with dipyridamole is an independent predictor of worse prognosis.47 The 3-year event-free survival is 68 % versus 98 % in groups with reduced and preserved CFVR, respectively. In the setting of intermediate coronary stenosis (50–70 %) a CFVR value >2 predicts good prognosis during a mean follow-up of 15 months.48 Reduced CFVR (<2 with dipyridamole) is an independent predictor of unfavourable outcome in patients with non-ischaemic dilated cardiomyopathy during 22 months of follow-up.23 After heart transplantation CFVR <2.6, using adenosine, is the main independent predictor of MACE for a period of almost 2 years49. In the largest study so far on CFVR assessment – 4,313 patients with known or suspected coronary artery disease – 4-year mortality was markedly higher in subjects with CFVR ≤2 than in those with CFR >2,

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Expert Opinion both considering the group with ischaemia and the group without ischaemia at stress echocardiography. CFVR was also an independent predictor of mortality along with inducible ischaemia during stress echocardiography, resting wall motion score, left bundle branch block, age, male gender and diabetes mellitus.50

Clinical Utilisation Considering the multiple areas of clinical application of CFVR measurement, the reasonable question arises why CFVR has not become a routine diagnostic test and a standard part of noninvasive echocardiographic assessment in patients suspected of or at increased risk of epicardial or microvascular coronary artery disease? A meaningful explanation for the lack of more widespread utilisation of CFVR measurement is that this method requires considerable anatomical and technological knowledge. A specific setting of the echo scanner is a prerequisite in order to be able to assess coronary

10.

11.

12.

13.

14. 15.

16.

17.

18.

L’Abbate A, Sambuceti G, Haunsø S, Schneider-Eicke J, et al., Methods for evaluating coronary microvasculature in humans. Eur Heart J 1999;20 :1300–13. Meimoun P, Tribouilloy C, Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. Eur J Echocardiogr 2008;9 :449–57. Dimitrow PP, Transthoracic Doppler echocardiography – noninvasive diagnostic window for coronary flow reserve assessment. Cardiovascular Ultrasound 2003;1 :4. Rigo F, Murer B, Ossena G, et al., Transthoracic echocardiographic imaging of coronary arteries: tips, traps, and pitfalls. Cardiovascular Ultrasound 2008;6 :7. Rigo F, Coronary flow reserve in stress-echo lab. From pathophysiologic toy to diagnostic tool. Cardiovasc Ultrasound 2005;3 :8. Nohtomi Y, Takeuchi M, Nagasawa K, et al., Simultaneous assessment of wall motion and coronary flow velocity in the left anterior descending coronary artery during dipyridamole stress echocardiography. J Am Soc Echocardiogr 2003;16 :457–63. Caiati C, Montaldo C, Zedda N, et al., New non-invasive method for coronary flow reserve assessment: contrastenhanced transthoracic second harmonic echo Doppler. Circulation 1999;99 :771–8. Watanabe H, Hozumi T, Hirata K, et al., Noninvasive coronary flow velocity reserve measurement in the posterior descending coronary artery for detecting coronary stenosis in the right coronary artery using contrast-enhanced transthoracic Doppler echocardiography. Echocardiography 2004;21 :225–33. Takeuchi M, Miyazaki C, Yoshitani H, et al., Which is the best method in detecting significant left anterior descending coronary artery stenosis during contrast-enhanced dobutamine stress echocardiography: coronary flow velocity reserve or wall-motion assessment? J Am Soc Echocardiogr 2002;16 :614–21. Meimoun P, Malaquin D, Sayah S, et al., The coronary flow reserve is transiently impaired in tako-tsubo cardiomyopathy: a prospective study using serial transthoracic Doppler echocardiography. J Am Soc Echocardiograph 2008;21 :72–7. Meimoun P, Sayah S, Tcheuffa JC, et al., Transthoracic coronary flow velocity reserve assessment: comparison between adenosine and dobutamine. J Am Soc Echocardiogr 2006;19 :1220–8. Takeuchi M, Ogawa K, Wake R, et al., Measurement of coronary flow velocity reserve in the posterior descending coronary artery by contrast-enhanced transthoracic Doppler echocardiography. J Am Soc Echocardiogr 2004;17 :21–7. Murata E, Hozumi T, Matsumura Y, et al., Coronary flow velocity reserve measurement in three major coronary arteries using transthoracic Doppler echocardiography. Echocardiography 2006;23 :279–86. Voci P, Pizzuto F, Romeo F, Coronary flow: a new asset for the echo lab? Eur Heart J 2004;25 :1867–79. Galderisi M, Cicala S, Caso P, et al., Coronary flow reserve and myocardial diastolic dysfunction in arterial hypertension. Am J Cardiol 2002;90 :860–4. Zeiher AM, Drexler H, Wollschlaeger H, et al., Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium. J Am Coll Cardiol 1989;14 :1181–1190. Egashira K, Inou T, Hirooka Y, et al., Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993;328 :1659–64. Wirch JL, Wolfe LA, Weissgerber TL, et al., Cold pressor test protocol to evaluate cardiac autonomic function. Appl Physiol

Simova_FINAL.indd 18

flow. Also, there is a learning curve and initially a lot of time has to be dedicated to technical aspects and to acquiring necessary skills.

Conclusions Transthoracic Doppler echocardiography is a reliable way to study CFVR with the advantage of being non-invasive, available and inexpensive. It is used to measure flow reserve in both stenosed and normal epicardial coronary arteries (every one of the three major coronary arteries can be evaluated although most of the experience is with CFVR measurement in LAD). In the presence of coronary artery stenosis CFVR is useful to detect a significant stenosis, to assess the functional significance of intermediate stenosis and to monitor for restenosis during follow-up after coronary revascularisation. In patients with anatomically normal epicardial coronary arteries impaired CFVR is a marker of microvascular dysfunction in different clinical settings. n

Nutr Metab 2006;31 :235–43. 19. Matsumara Y, Hozumi T, Watanabe H, et al., Cut-off value of coronary flow velocity reserve by transthoracic Doppler echocardiography for diagnosis of significant left anterior descending artery stenosis in patients with coronary risk factors. Am J Cardiol 2003;92 :1389–93. 20. Meimoun P, Benali T, Sayah S, et al., Evaluation of left anterior descending coronary artery stenosis of intermediate severity using transthoracic coronary flow reserve and dobutamine stress echocardiography. J Am Soc Echocardiogr 2005;12 :1233–40. 21. Galderisi M, Cicala S, D’Errico A, et al., Nebivolol improves coronary flow reserve in hypertensive patients without coronary heart disease. J Hypertens 2004;22 :2201–8. 22. Neishi Y, Akasaka T, Tsukjii M, et al., Reduced coronary flow reserve in patients with congestive heart failure assessed by transthoracic Doppler echocardiography. J Am Soc Echocardiogr 2005;18 :15–9. 23. Rigo F, Gherardi S, Galderisi M, et al., The prognostic impact of coronary flow-reserve assessed by Doppler echocardiography in non-ischaemic dilated cardiomyopathy. Eur Heart J 2006;27 :1319–23. 24. Erdogan D, Yildirim I, Ciftci O, et al., Effects of normal blood pressure, prehypertension, and hypertension on coronary microvascular function. Circulation 2007;115 :593–9. 25. Galderisi M, de Simone G, Cicala S, et al., Coronary flow reserve in hypertensive patients with hypercholesterolemia and without coronary heart disease. Am J Hypertens 2007;20 :177–83. 26. Kawata T, Daimon M, Hasegawa R, et al., Effect on coronary flow velocity reserve in patients with type 2 diabetes mellitus: comparison between angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor antagonist. Am Heart J 2006;151 :798.e9–15. 27. Galderisi M, Rigo F, Gherardi S, et al., The impact of aging and atherosclerotic risk factors on transthoracic coronary flow reserve in subjects with normal coronary angiography. Cardiovasc Ultrasound 2012;10 :20. 28. Okayama H, Sumimoto T, Hiasa G, et al., Assessment of intermediate stenosis in the left anterior descending coronary artery with contrast-enhanced transthoracic Doppler echocardiography. Coron Artery Dis 2003;14 :247–54. 29. Wada T, Hirata K, Shiono Y, et al., Coronary flow velocity reserve in three major coronary arteries by transthoracic echocardiography for the functional assessment of coronary artery disease: a comparison with fractional flow reserve. Eur Heart J Cardiovasc Imaging 2014;15:399–408. 30. Lethen H, Tries HP, Brechtken J, et al., Comparison of transthoracic Doppler echocardiography to intracoronary Doppler guidewire measurements for assessment of coronary flow reserve in the left anterior descending artery for detection of restenosis after coronary angioplasty. Am J Cardiol 2003;91 :412–7. 31. Ruscazio M, Montisci R, Colonna P, et al., Detection of coronary restenosis after coronary angioplasty by contrast-enhanced transthoracic echocardiographic Doppler and of coronary flow velocity reserve. J Am Coll Cardiol 2002;40 :896–903. 32. Pizzuto F, Voci P, Mariano E, et al., Assessment of flow velocity reserve by transthoracic Doppler echocardiography and venous adenosine infusion before and after left anterior descending coronary artery stenting. J Am Coll Cardiol 2001;38 :155–62. 33. Varho V, Karjalainen PP, Ylitalo A, et al., Transthoracic echocardiography for non-invasive assessment of coronary vasodilator function after DES implantation. Eur Heart J Cardiovasc Imaging 2014;15 :1029–34 34. Lee B-K, Lim H-S, Fearon WF, et al., Invasive Evaluation of Patients With Angina in the Absence of Obstructive Coronary

Artery Disease. Circulation 2015;131 :1054–60. 35. Cortigiani L, Rigo F, Gherardi S, et al., Prognostic meaning of coronary microvascular disease in type 2 diabetes mellitus: a transthoracic Doppler echocardiographic study. J Am Soc Echocardiogr . 2014;27 :742–8. 36. Nakanishi K, Fukuda S, Shimada K, et al., Prognostic value of coronary flow reserve on long-term cardiovascular outcomes in patients with chronic kidney disease. Am J Cardiol 2013;112 :928–32. 37. Sicari R, Nihoyannopoulos P, Evangelista A, et al., Stress echocardiography expert consensus statement. European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur Heart J 2008;9 :415–37. 38. Cortigiani L, Rigo F, Gherardi S, et al., Prognostic effect of coronary flow reserve in women versus men with chest pain syndrome and normal dipyridamole stress echocardiography. Am J Cardiol 2010;106 :1703–8. 39. Hildick-Smith DJ, Johnson PJ, Wisbey CR, et al., Coronary flow reserve is supranormal in endurance athletes: an adenosine transthoracic echocardiographic study. Heart 2000;84:383–9. 40. Nemes A, Balázs E, Csanády M, et al., Long-term prognostic role of coronary flow velocity reserve in patients with aortic valve stenosis – insights from the SZEGED Study. Clin Physiol Funct Imaging 2009;29 :447–52. 41. Banovic M, Vujisic-Tesic B, Brkovic V, et al., Prognostic value of coronary flow reserve in asymptomatic moderate or severe aortic stenosis with preserved ejection fraction and nonobstructed coronary arteries. Echocardiography 2014;31 :428–33. 42. Hildick-Smith D, Shapiro LM, Coronary flow reserve improves after aortic valve replacement for aortic stenosis: an adenosine transthoracic echocardiography study. J Am Coll Cardiol . 2000;36 :1889–96. 43. Cortigiani L, Rigo F, Gherardi S. et al., Prognostic implications of coronary flow reserve on left anterior descending coronary artery in hypertrophic cardiomyopathy. Am J Cardiol 2008;102 :1718–23. 44. Rigo F, Gherardi S, Galderisi M, et al., The independent prognostic value of contractile and coronary flow reserve determined by dipyridamole stress echocardiography in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 2007;99 :1154–8. 45. Cortigiani L, Rigo F, Gherardi S, et al., Prognostic value of Doppler echocardiographic-derived coronary flow velocity reserve of left anterior descending artery in octogenarians with stress echocardiography negative for wall motion criteria. Eur Heart J Cardiovasc Imaging 2015;16 :653–60. 46. Sicari R, Rigo F, Cortigiani L, et al., Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries. Am J Cardiol 2009;103 :626–31. 47. Rigo F, Cortigiani L, Pasanisi E, et al., The additional prognostic value of coronary flow reserve on left anterior descending artery in patients with negative stress echo by wall motion criteria: a transthoracic vasodilator stress echocardiography study. Am Heart J 2006;151 :124–30. 48. Meimoun P, Tcheuffa JC, Louzoun V, et al., Prognosis value of transthoracic coronary flow reserve in patients with proximal LAD stenosis of intermediate severity. Eur J Echocardiogr 2006;7 (Suppl. 1):pS184 (abstract 1074). 49. Tona F, Caforio AL, Montisci R, et al., Coronary flow velocity pattern and coronary flow reserve by contrast-enhanced transthoracic echocardiography predict long-term outcome in heart transplantation. Circulation 2006;114 (Suppl. 1):I49–55. 50. Cortigiani L, Rigo F, Gherardi S, et al., Coronary Flow Reserve During Dipyridamole Stress Echocardiography Predicts Mortality. JACC Cardiovasc Imaging 2012;5 :1079–85.

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Cardiomyopathy and Heart Failure

LE ATION.

Chemotherapy-related Cardiomyopathy Susan E Piper and Theresa A McDonagh King’s College London, The James Black Centre, London, UK; Kings College Hospital NHS Foundation Trust, London, UK

Abstract Advances in chemotherapeutic agents have resulted in significantly improved cancer survival rates. Cardiac toxicity, however, has emerged as a leading cause of morbidity, both during and years after treatment. One of the most common manifestations of cardiotoxicity is that of heart failure and left ventricular systolic dysfunction. In this review, current opinions and guidelines in this field are discussed, with particular focus on the most common culprits, the anthracyclines, and the monoclonal antibody, trastuzumab.

Keywords Heart failure, chemotherapy, anthracyclines, monoclonal antibodies, trastuzumab Disclosure: The authors have no conflicts of interest to declare. No funding was received for the preparation of this manuscript. Acknowledgements: Susan E Piper has received chairperson and speaker fees from Servier Laboratories. Theresa A McDonagh has received honoraria for lectures and advisory boards for Merck, Novartis and Vifor. Susan E Piper and Theresa A McDonagh have received an unrestricted educational grant from Novartis for a research project. Received: 21 May 2015 Accepted: 23 July 2015 Citation: European Cardiology Review, 2015;10(1):19–24 Correspondence: Susan E Piper, Department of Cardiology, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. E: susanpiper@kcl.ac.uk

Support: The research was supported by the National Institute for Health Research (NIHR) Clinical Research Facility at Guy’s & St Thomas’ NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Over the past 20 years, research and development in the field of oncology has produced significant changes and progress in cancer care. With the implementation of more aggressive cancer screening programmes, improvements in diagnostic testing and more effective treatment options, cancer death rates are gradually declining while cancer survivorship is steadily rising.1–3 Such statistics, however, have not been achieved without consequence, and are often offset by long-term adverse effects. While conventional chemotherapy has been known for decades to induce detrimental effects on the heart and peripheral vasculature, the use of novel agents are also increasingly being shown to have harmful off-target consequences to cardiac function. Thus, concurrent with advances in cancer therapies, so there has been a significant increase in cardiovascular side effects.4 One of the most common manifestations of cardiotoxicity associated with exposure to anticancer therapies is the development of left ventricular systolic dysfunction (LVSD) and overt heart failure (HF). As a result, the need for specialist cardiology input is becoming increasingly recognised as an important resource in the management of both longterm survivors and those undergoing active treatment. The aim of this paper is to review current opinions on the diagnosis, pathophysiology, management and prevention of chemotherapy-related cardiomyopathy, with specific focus on the commonest, and most studied culprits: the anthracyclines and monoclonal antibodies.

practice and trials remain lacking. Such definitions range from the development of HF symptoms, to the development of overt LV dysfunction and a reduction in ejection fraction (EF) on cardiac imaging (see Table 1). Indeed, the incidence of HF or LVSD in chemotherapy trials has been shown to range from 5 to 65 % depending on the criteria used.5,6 Moreover, it is widely accepted that chemotherapyinduced LVSD is often sub-clinical in the early stages, with overt changes in LVEF occurring after only a significant level of damage has occurred. Nevertheless, currently, a change in LVEF remains the basis for all definitions of cardiotoxicity issued by scientific societies in both Europe and the US.7,8

Anthracyclines Anthracyclines are widely used to treat a variety of haematological, soft-tissue and solid malignancies. Cardiac toxicity has been recognised as a complication of treatment since the 1970s,15,16 with presentations ranging from subclinical ventricular dysfunction to severe cardiomyopathy and overt HF. Classically, cardiac dysfunction is related to anthracycline therapy in an exponentially dose-dependent manner. The early incidence of HF and LVSD ranges from 1 to 16 %, with increasing incidence as time post treatment progresses.17–19 Consequently, childhood cancer survivors have a high risk of experiencing symptomatic cardiac events at an early age, and this risk remains high for at least 30 years, when almost one in eight will experience severe heart disease.2

Pathophysiology of Anthracycline-related Cardiomyopathy

Definition of Chemotherapy-induced Cardiomyopathy Despite the increasing recognition of chemotherapy-induced cardiomyopathy, consensus on international definitions in both clinical

Mcdonagh_FINAL.indd 19

The cardiotoxic effects of the anthracyclines are not completely understood. Several mechanisms have been proposed, with the most widely accepted theory being the formation of anthracycline–iron

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Cardiomyopathy and Heart Failure Table 1: Comparison of Different Definitions of Cardiotoxicity in Several Large Randomised Controlled Trials Study

Chemotherapy

Definition

Agent Schwartz 19879 Doxorubicin

Absolute 10 % drop in LVEF or a decrease to below 50 % in patients with baseline LVEF >50 %, or an absolute 10 % drop in LVEF or a drop below 30 % in patients with baseline LVEF <50 %

Slamon 2001

O’Brien 200411

Trastuzumab

NYHA classification

Anthracycline

Decline in LVEF of 20 points  to >50 % or at least 10 points to <50 % or clinical CHF

Tan-Chiu

Trastuzumab

Decline LVEF by 10% to <55 %

(NSABP-31) 200512 Romond

200513

Doxorubicin and

Decline of LVEF >16 % or <LLN

cyclophosphamide followed by trastuzumab Ryberg

200814

Anthracycline

Decline of LVEF <45% or 15 points from baseline

CHF = congestive heart failure; LLN = lower limit of normal; NSABP = National Adjuvant Breast and Bowel Project; NYHA = New York Heart Association.

complexes and stimulation of free-radical formation.2,20–23 In support of this is the finding that iron-chelating compounds inhibit this toxic effect.24 Despite this being the preferred theory, it is by no means the only mechanism by which the anthracyclines are thought to cause myocardial damage. More recently, Zhang et al.25 have demonstrated that, in mouse studies, deletion of the enzyme Top2b (encoding topoisomerase-IIβ) in cardiac myocytes was protective against the doxorubicin-induced DNA double-strand breaks and transcription changes that are responsible for defective mitochondrial biogenesis and the formation of reactive oxygen species. Furthermore, this deletion protected against the development of doxorubicin-induced HF, suggesting that doxorubicin-induced cardiotoxicity may be mediated by topoisomerase-IIβ in mammalian cardiomyocytes. Other proposed cardiotoxic actions of anthracyclines include: decreased adenosine triphosphate production; formation of toxic metabolites; inhibition of nucleic acid and protein synthesis; release of vasoactive amines; impairment of mitochondrial membrane binding, assembly and creatine kinase activity; induction of apoptosis; disturbances in intracellular calcium homeostasis; induction of nitric oxide synthetase; increased cytochrome C release from mitochondria; and increases in immune functions.14,26,27

Risk Factors for Anthracycline Related Cardiomyopathy Perhaps the most predictive measure of the development of anthracycline-related cardiotoxicity is the total cumulative dose.28,29 In a review of three prospective trials assessing the effect of doxorubicin, Swain et al. demonstrated an incidence of HF of 3 % at a cumulative dose of 400 mg/m2, increasing to 7 % and 18 % at cumulative doses of 550 mg/m2 and 700 mg/m2, respectively.28 Combined with other treatment-related risk factors, such as additional cardiotoxic chemotherapeutic agents and radiotherapy, the incidence of HF is substantially increased.10

Mcdonagh_FINAL.indd 20

Several patient-related factors have also been identified as markers of risk in the anthracycline-treated population. These range from genetic predisposition (female sex, Trisomy 21, African-American ancestry,28,30–32 and carriers of the haemochromatosis C282Y HFE gene mutation33), to recognised pre-existing cardiac risk factors such as extremes of age, prior ischaemic heart disease, valvular heart disease and, in particular, hypertension.34

Prevention of Anthracycline-related Cardiomyopathy A number of strategies and agents have been examined for potential use in preventing HF or LVSD related to anthracycline therapy, with varying levels of success.26,35–61 Such strategies include attempts to reduce peak plasma concentrations, prevention of iron-dependent free-radical formation52 and the use of evidence-based HF medications.

Limitation of Peak Plasma Concentrations Several strategies have been examined to limit peak plasma concentrations, including the use of liposomal anthracycline preparations, novel synthetic anthracyclines and infusion versus bolus administration. Despite promising results in terms of maintained anti-cancer therapy,35–37 many strategies to limit peak plasma concentrations have either been limited by side effects44 or have not been associated with significant reductions in long-term risk of cardiomyopathy.45,46,50,51,62,63 Most promising results have been with the use of liposomal preparations, with rates of cardiotoxicity being significantly lower compared with conventional preparations.36,37,64

Iron Binding Dexrazoxane binds intracellular iron and prevents iron-dependent free-radical formation.52 Although initial results led to the approval of its use to prevent long-term cardiotoxicity in patients receiving doxorubicin or epirubicin,53,54 subsequent clinical trials reported cases of secondary leukaemia in children and adults.55,56

Angiotensin Converting Enzyme Inhibitors, Beta-Blockers and Mineralocorticoid Receptor Antagonists Angiotensin converting enzyme inhibitors (ACE-I) and beta (ß)-blocker therapy have both been shown to have protective effects against chemotherapy-induced HF or LVSD in both animal models and in adult patients with early toxicity.57–59 More recently, the results of the preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies (OVERCOME) trial60 have demonstrated that, compared with those in the treatment arm, those in the control group had a significantly higher reduction in LVEF, incidence of death or HF at six-months follow-up (p=0.02). Less evidence exists for the use of mineralocorticoid receptor antagonists (MRAs). In one recently published small randomised controlled trial, Akpek et al.61 demonstrated preservation of LV systolic and diastolic function in the group treated with spironolactone prior to the initiation of chemotherapy at 6-months follow-up. Further studies are needed to corroborate these findings.

Trastuzumab (Herceptin ® ) Trastuzumab is a monoclonal antibody used in the treatment of HER2+ breast cancer. It exerts its actions by blocking the HER2 epidermal growth factor receptor, which is overexpressed in approximately 15–20 % of breast tumours and associated with more aggressive disease.65,66 Following phase III trials demonstrating significant improvements in both overall survival and risk of relapse, it was approved for clinical use in 1998.67

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Chemotherapy-related Cardiomyopathy

Introduction of trastuzumab into routine clinical practice, however, led to the unexpected finding of ‘off-target’ effects on the cardiovascular system. In one landmark trial, Slamon et al. demonstrated incidence rates of cardiac dysfunction of 27 % and New York Heart Association (NYHA) class III/IV symptoms of 16 % when trastuzumab was used in combination with both anthracyclines and cyclophosphamide.10

Table 2: Reported Incidences of Cardiotoxicity in Other Chemotherapeutic Agents Other Chemotherapy Agents Alkylating Agents Cyclophosphamide

Appear to have dose-dependent effects on

and Ifosfamide

cardiac myocytes. With doses ≥150 mg/kg, cyclophosphamide has been associated with HF

Pathophysiology of Trastuzumab-related Cardiomyopathy

in 7–28 % of patients. Ifosfamide has been

The pathogenesis of trastuzumab cardiotoxicity is not completely understood, but appears to be related to blockage of HER2 receptor signals in cardiac myocytes – signalling that appears essential for cardiac myocyte repair.68

associated with HF in 17 % of patients treated with doses ≥12.5 g/m2.4,5 Microtubule Agents Paclitaxel and docetaxal Both paclitaxel and docetaxel are widely used in the treatment of multiple malignancies, with relatively low incidences of HF, estimated at 1.68 %.79

When given concurrently with anthracyclines, it has been proposed that the administration of anthracyclines results in initial oxidative damage to cardiac myocytes, resulting in those cells sustaining sufficient damage undergoing apoptosis or necrosis. The remaining injured myocytes undergo repair processes but remain temporarily vulnerable – the so-called ‘vulnerable window hypothesis’.69 In the presence of trastuzumab, inhibition of the normally upregulated HER2 results in loss of the usual repair mechanisms, driving the myocytes to further apoptosis and necrosis. In support of this theory are the findings of later studies examining the use of sequential anthracyclines and trastuzumab therapy. In these trials, initiation of a 3-week interval between treatments resulted in a reduction in the incidence of NYHA class III/IV HF to 3.8 %.12 With a longer 90-day interval, this reduced to just 0.6 %, with systolic dysfunction occurring in only 7 % compared with the 27 % reported by Slamon et al.10

Proteosome Inhibitors Bortezomib. Used to treat multiple myeloma and mantle cell (Velcade®)

estimated at 2–5 %.80 Small Molecule Tyrosine Kinase Inhibitors Lapatinib Experience to date in a relatively small studied population suggests relatively low rates of symptomatic cardiac failure. In patients treated with prior anthracyclines, trastuzumab, or neither, the incidence of cardiac events was 2.2 %, 1.7 % and 1.5 %, respectively.81 Sunitinib

Risk Factors for Trastuzumab-related Cardiomyopathy Apart from the well-recognised and documented risk in the setting of concurrent anthracycline therapy, risk factors for the development of trastuzumab-induced HF or LVSD are less well defined. In part, this is due to the exclusion of both older patients and those with ‘traditional’ risk factors for cardiac disease from clinical trials. Several retrospective cohort analyses have attempted to address this matter.68,71,72 Results suggest those with borderline lower limit of normal LVEF, history of heart disease or prior treatment with anti-hypertensive medication and those of advanced age have the highest risk of cardiotoxicity.

Initial reports of its use in renal cell carcinoma suggest a 10 % incidence of asymptomatic drop in LVEF to >10 % of lower limit of normal, with full

In most instances, HF or LVSD related to trastuzumab is a sub-acute phenomenon, with the majority of cases being observed during treatment. It does, however, appear to be reversible after drug withdrawal and does not appear to be dose dependent.4

lymphoma, incidence of HF and HF events has been

recovery when treatment was completed82. Monoclonal Antibody-based Tyrosine Kinase Inhibitors Bevacizumab

Incidence of HF ranges from 1.7 % to 3 %.4

HF = heart failure; LVEF = left ventricular ejection fraction.

but did demonstrate reduced incidence of cardiac events.74 Results from the Synergism or Long Duration (SOLD),75 Short-HER76 and PERSEPHONE77 trials are awaited to validate these findings. No large randomised controlled trials have yet to report on the use of prognostically indicated HF medications to prevent HF or LVSD by trastuzumab. The Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research (MANTICORE) trial is due to address this issue by evaluating the efficacy of perindopril or bisoprolol for the prevention of LV remodelling in women with early breast cancer scheduled for chemotherapy and 1 year of trastuzumab.78

Other Chemotherapy Agents Prevention of Trastuzumab-related Cardiomyopathy Few strategies have been adequately evaluated to determine their usefulness in preventing trastuzumab-induced HF or LVSD. Aside from delaying therapy until after treatment with anthracyclines is complete, possible strategies could include minimising trastuzumab treatment duration or the use of evidence-based HF medication. Optimum duration for trastuzumab therapy remains unknown. Results from the Herceptin Adjuvant (HERA) trial comparing treatment over 12 and 24 months demonstrated no additional survival advantage with extended therapy, but did demonstrate continued risk of HF or LVSD.73 The Protocol of Herceptin Adjuvant with Reduced Exposure (PHARE) trial compared six versus 12 months of trastuzumab and failed to show non-inferiority of the shorter treatment administration

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Several other chemotherapy agents have also been associated with the development of heart failure (see Table 2).4,11,79–82

Monitoring Cardiotoxicity of Chemotherapy Cardiac Imaging Monitoring cardiac function for early disease is recommended for all cancer survivors exposed to cardiotoxic therapies.8,83 As a result of the different timings of presentation and potential for reversibility, algorithms proposed by the European Society of Medical Oncology (ESMO) for monitoring patients exposed to anthracycline or trastuzumab have been developed to reflect these differences. Most notably, guidelines for trastuzumab incorporate advice on continuation or discontinuation of therapy and allow for the presence of potentially reversible changes (see Figure 1).

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Cardiomyopathy and Heart Failure Figure 1: Algorithm for Continuation and Discontinuation of Trastuzumab Based on LVEF Assessments 8

Figure 3: ESC Guidelines for the Management of LVSD 100 Diuretics to relieve symptoms/signs of congestion +

LVEF assessment

ACE inhibitor (or ARB if not tolerated) LVEF ≥50 %

LVEF <50 %

LVEF 40–50 %

LVEF <40 %

Still NYHA class II–IV?

Start treatment

LVEF 10 % point below baseline

Hold treatment Repeat LVEF in 3 weeks

ADD a beta-blocker

Yes

LVEF Higher 10 % below baseline

ADD a MR antagonist Still NYHA class II–IV?

Hold treatment Repeat LVEF in 3 weeks

Continue treatment

LVEF <40 %

LVEF >45 % or LVEF 40–50 %

STOP treatment

RESUME treatment

Yes

LVEF ≤35 %? Yes

Sinus rhythm and HR ≥70 beats/minute?

LVEF = left ventricular ejection fraction.

Figure 2: Algorithm for the Management of Cardiotoxicity in Patients Treated with Anthracyclines 8 Baseline cardiological evaluation, ECHO

ADD ivabradine

Still NYHA class II-IV and LVEF ≤35 %?

Anthracycline-CT Tnl evaluation at each cycle

Yes

Yes Tnl not evaluated during CT

No QRS duration ≥ 120 ms

ECHO at end CT Tnl POS

Yes

Tnl NEG LVD

ECHO at 3 months

Enalapril for 1 year

No LVD ECHO end CT, 3, 6, 9 months

ACEI + BB

ECHO at 6 months No LVD ECHO at 9 months

ECHO 12 months

ECHO every 6 months for 5 years

ECHO every year

Clinical follow-up

No LVD

No LVD ECHO at 12 months No LVD

Consider CRT-P/CRT-D

Consider ICD

Still NYHA class II–IV? Yes

No further specific treatment Continue in disease-management programme

Consider digoxin and/or H-ISDN if end stage, consider LVAD and/or transplantation

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CRT-D = cardiac resynchronisation therapy defibrillator; CRT-P = cardiac resynchronisation therapy pacemaker; HF = heart failure; H-ISDN = hydralazine and isosorbide dinitrate; ICD = implantable cardioverter defibrillator; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic dysfunction; MR = mineralocorticoid receptor; NYHA = New York Heart Association.

ECHO every year ACEI = angiotensin converting enzyme inhibitor; CT = chemotherapy; ECHO = echocardiogram; LVD = left ventricular dysfunction; NEG = negative; Tnl = troponin; NEG = negative; POS = positive.

In recognition of the limitations of LVEF in detecting sub-clinical cardiotoxicity, several studies have examined the use of more sophisticated techniques, such as tissue velocity and strain imaging by echocardiography, and delayed contrast enhancement by cardiac magnetic resonance imaging (CMRI). A recent meta-analysis of the use of myocardial strain imaging by echocardiography showed that, in late survivors of cancer, measures of global radial and circumferential strain are consistently abnormal, even in the context of normal LVEF.84 Their clinical value in predicting subsequent LVSD or HF, however, has yet to be fully explored, however, speckle tracking echocardiography (STE) and assessment of peak systolic global longitudinal strain (GLS) appears to be the most promising measure, with a 10–15 % early reduction in GLS by STE during therapy being predictive of cardiotoxicity. Several studies have examined the use of CMRI and delayed contrast enhancement in the setting of chemotherapy-induced cardiotoxicity.

Mcdonagh_FINAL.indd 22

While no specific changes have been identified in the anthracycline population, trastuzumab has been associated with mid-wall delayed enhancement of the lateral wall.85,86 Such findings have, however, only been reported in a small number of patients and further work is ongoing.

Biomarkers Over the last two decades, data examining the use of biomarkers has demonstrated their measurement to be a more sensitive and specific tool for early identification; assessment and monitoring of chemotherapy-induced cardiac injury.69,87–89 Several studies have reported on the use of cardiac troponins during anthracycline treatment and subsequent development of LV dysfunction.88,90–92 As a result, the latest guidance from ESMO has advocated the use of troponin in routine monitoring of patients undergoing anthracycline chemotherapy (see Figure 2). 8 The use of troponins to identify patients at risk of trastuzumab-induced HF or LVSD is less well defined, but has been shown to identify those at risk of developing LVSD and, among them, those less likely to recover.69,93

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A number of studies have looked at the use of the B-type natriuretic peptides, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide (BNP and NTproBNP), in predicting LVSD in both anthracyclineand trastuzumab-induced cardiotoxicity, with mixed results. 94–99 Consequently, current routine use of the natriuretic peptides for monitoring cardiotoxic effects of chemotherapy remains controversial.

Treatment of Chemotherapy-induced Left Ventricular Systolic Dysfunction To date, no guidelines regarding the treatment of LVSD have been independently validated in the oncology setting. It is widely accepted, however, that once LVSD has ensued, treatment with evidence-based medications as per national and international guidelines should be instigated (see Figure 3).8,100,101

therapy including ACE-I and ß-blockers, with the remainder recovering without treatment. Of particular interest, 25 of those recovering after medical therapy were subsequently re-challenged with trastuzumab, with only three experiencing recurrence of LVSD. These results require confirmation in larger, randomised controlled trials but do indicate that monitoring may be a viable option for some patients with trastuzumabinduced cardiotoxicity and re-challenge may be ‘safe’. Moreover, several studies have demonstrated that LVSD related to trastuzumab therapy appears to be reversible, with resolution of cardiac function in approximately 80 % of cases seen in the majority of trials.73 As a result of these findings, guidelines from ESMO suggest that the introduction of prognostically indicated HF medication may not be required unless the LVEF is <40 %.8

Conclusion Of the evidence that does exist in the oncology setting, most has been based on treatment of anthracycline-related LVSD. In a study of 201 adult patients, Cardinale et al. demonstrated that LV dysfunction was potentially reversible but crucially depended on the time to treatment with ACE-I and ß-blockers, supporting the need for serial monitoring.102 In contrast to LVSD secondary to anthracyclines, LVSD induced by trastuzumab is less well studied, but the initial data are promising. In a small study by Ewer, et al.,103 38 patients with a diagnosis of trastuzumab-induced LVSD all patients demonstrated recovery of LV function. Thirty-two of these were temporally associated with medical

1. 2.

10.

11.

12.

13.

14.

Yusuf SW, Cipolla C, Durand JB, Lenihan DJ, Cancer and cardiovascular disease. Cardiol Res Pract 2011;2011:943748. Jones RL, Ewer MS, Cardiac and cardiovascular toxicity of nonanthracycline anticancer drugs. Expert Rev Anticancer Ther 2006;6 :1249–69. Maddams J, Utley M, Moller H, Projections of cancer prevalence in the United Kingdom, 2010–2040. Br J Cancer 2012;107 :1195–202. Yeh ET, Bickford CL, Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53 :2231–47. Pai VB, Nahata MC, Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000;22 :263–302. Cardinale D, Colombo A, Cipolla CM, Prevention and treatment of cardiomyopathy and heart failure in patients receiving cancer chemotherapy. Curr Treat Options Cardiovasc Med 2008;10 :486–95. Eschenhagen T, Force T, Ewer MS, et al., Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2011;13 :1–10. Curigliano G, Cardinale D, Suter T, et al., Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 (Suppl. 7):vii155–66. Schwartz RG, McKenzie WB, Alexander J, et al., Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987;82 :1109–18. Slamon DJ, Leyland-Jones B, Shak S, et al., Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344 :783–92. O’Brien ME, Wigler N, Inbar M, et al., Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15 :440–9. Tan-Chiu E, Yothers G, Romond E, et al., Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23 :7811–9. Romond EH, Perez EA, Bryant J, et al., Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353 :1673–84. Ryberg M, Nielsen D, Cortese G, et al., New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst 2008;100 :1058–67.

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Chemotherapy-related cardiotoxicity in the form of HF or LVSD is a serious ‘off-target’ side effect of several important chemotherapeutic agents. At present monitoring of cardiac function and intervention in the presence of deterioration is the mainstay of management, but it is widely acknowledged that earlier detection and intervention is required to improve longer-term prognosis. Advanced imaging techniques and the use of cardiac specific biomarkers may herald significant changes in our management of this condition. It is inevitable, however, that with continued advances in the field of oncology, the incidence of ‘off-target’ cardiac side effects will likely increase. Cross-specialty collaboration will undoubtedly be the key to ensuring the best care for cancer patients. n

15. Lenaz L, Page JA, Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 1976;3 :111–20. 16. Von Hoff DD, Rozencweig M, Layard M, et al., Daunomycininduced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 1977;62 :200–8. 17. Gilladoga AC, Manuel C, Tan CT, et al., The cardiotoxicity of adriamycin and daunomycin in children. Cancer 1976;37 (Suppl. 2), 1070–8. 18. Praga C, Beretta G, Vigo PL, et al., Adriamycin cardiotoxicity: a survey of 1273 patients. Cancer Treat Rep 1979;63 ():827–34. 19. Bjorkhem G, Garwicz S, Echocardiographic assessment of left ventricular function during the injection of adriamycin. Acta Paediatr Scand 1977;66 :595–600. 20. Gewirtz DA, A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 1999;57 :727–41. 21. Horenstein MS, Vander Heide RS, L’Ecuyer TJ, Molecular basis of anthracycline-induced cardiotoxicity and its prevention. Mol Genet Metab 2000;71 (1–2), 436–44. 22. Hershko C, Link G, Tzahor M, Pinson A, The role of iron and iron chelators in anthracycline cardiotoxicity. Leuk Lymphoma 1993;11 (3–4), 207–14. 23. Link G, Tirosh R, Pinson A, Hershko C, Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction. J Lab Clin Med 127 (3), 272–278 (1996). 24. Hershko C, Pinson A, Link G: Prevention of anthracycline cardiotoxicity by iron chelation. Acta haematologica 1996;95 :87–92. 25. Zhang S, Liu X, Bawa-Khalfe T, et al., Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18 :1639–42. 26. Wouters KA, Kremer LC, Miller TL, et al., Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 2005;131 :561–78. 27. Kalyanaraman B, Joseph J, Kalivendi S, et al., Doxorubicininduced apoptosis: implications in cardiotoxicity. Mol Cell Biochem 2002 May–Jun;234–235(1–2):119–24. 28. Swain SM, Whaley FS, Ewer MS, Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003;97 :2869–79. 29. Von Hoff DD, Layard MW, Basa P, et al., Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91 :710–7. 30. Lipshultz SE, Colan SD, Gelber RD, et al., Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324 :808–15. 31. Krischer JP, Epstein S, Cuthbertson DD, et al., Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 1997;15 :1544–52.

32. Adams MJ, Lipshultz SE, Pathophysiology of anthracyclineand radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer 2005;44 :600–606. 33. Lipshultz SE, Lipsitz SR, Kutok JL, et al., Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 2013;119 (19), 3555–62. 34. Barry E, Alvarez JA, Scully RE, et al., Anthracyclineinduced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother 2007;8 :1039–1058. 35. Alberts DS, Muggia FM, Carmichael J, et al., Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials. Semin Oncol 2004;31 (6 Suppl. 13), 53–90. 36. Batist G, Harris L, Azarnia N, et al., Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs 2006;17:587–95. 37. Safra T, Cardiac safety of liposomal anthracyclines. Oncologist 2003;8 (Suppl. 2)17–24. 38. Conklin KA, Coenzyme q10 for prevention of anthracyclineinduced cardiotoxicity. Integr Cancer Ther 2005;4 (),110–30. 39. Emanuelov AK, Shainberg A, Chepurko Y, et al., Adenosine A3 receptor-mediated cardioprotection against doxorubicininduced mitochondrial damage. Biochem Pharmacol 2010;79 :180–7. 40. Fu P, Arcasoy MO, Erythropoietin protects cardiac myocytes against anthracycline-induced apoptosis. Biochem Biophys Res Commun 2007;354 :372–8. 41. Gebbia N, Flandina C, Leto G, et al., The role of histamine in doxorubicin and teniposide-induced cardiotoxicity in dog and mouse. Tumori 1987;73 :279–87. 42. Van Dalen EC, Caron HN, Dickinson HO, Kremer LC, Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2011;Cd003917. 43. Williams CJ, Doxorubicin cardiotoxicity: role of digoxin in prevention. BMJ 1978;1 :176. 44. Rivankar S, An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther 2014;10 :853–8. 45. Lahtinen R, Kuikka J, Nousiainen T, et al., Cardiotoxicity of epirubicin and doxorubicin: a double-blind randomized study. Eur J Haematol 1991;46 :301–5. 46. Robert J, Rigal-Huguet F, Hurteloup P, Comparative pharmacokinetic study of idarubicin and daunorubicin in leukemia patients. Hematol Oncol 1992;10 (),111–6. 47. Casper ES, Gaynor JJ, Hajdu SI, et al., A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 1991;68 :1221–9.

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Cardiomyopathy and Heart Failure 48. Hortobagyi GN, Frye D, Buzdar AU, et al., Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 1989;63 :37–45. 49. Shapira J, Gotfried M, Lishner M, Ravid M: Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer 1990;65 :870–3. 50. Lipshultz SE, Giantris AL, Lipsitz SR, et al., Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol 2002;20 :1677–82. 51. Lipshultz SE, Miller TL, Lipsitz SR, et al., Continuous versus bolus infusion of doxorubicin in children with ALL: Long-term cardiac outcomes. Pediatrics 2012;130 :1003–11. 52. Cvetkovic RS, Scott LJ, Dexrazoxane: a review of its use for cardioprotection during anthracycline chemotherapy. Drugs 2005;65 :1005–24. 53. Testore F, Milanese S, Ceste M, et al., Cardioprotective effect of dexrazoxane in patients with breast cancer treated with anthracyclines in adjuvant setting: a 10-year single institution experience. Am J Cardiovasc Drugs 2008;8 :257–63. 54. Venturini M, Michelotti A, Del Mastro L, et al., Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 1996;14 :3112–20. 55. Research CFDEA: Drug Safety and Availability – FDA Statement on Dexrazoxane. Available at: http://www.fda.gov/ Drugs/DrugSafety/ucm263729.htm (accessed 8 July 2015). 56. Tebbi CK, London WB, Friedman D, et al., Dexrazoxaneassociated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 2007;25 :493–500. 57. Cardinale D, Colombo A, Sandri MT, et al., Prevention of high-dose chemotherapy-induced cardiotoxicity in highrisk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114 :2474–2481. 58. Spallarossa P, Garibaldi S, Altieri P, et al., Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol 2004;37 :837–46. 59. Kalay N, Basar E, Ozdogru I, et al., Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48 :2258–62. 60. Bosch X, Rovira M, Sitges M, et al., Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61 :2355–62. 61. Akpek M, Ozdogru I, Sahin O, et al., Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail 2015;17 :81–9. 62. Anderlini P, Benjamin RS, Wong FC, et al., Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol 1995;13 :2827–34. 63. Creutzig U, Ritter J, Zimmermann M, et al., Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 2001;15 :348–54. 64. Harris L, Batist G, Belt R, et al., Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 2002;94 :25–36. 65. Pegram M, Slamon D, Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. Semin Oncol 2000;27 (5 Suppl. 9), 13–19. 66. Baselga J, Albanell J: Mechanism of action of anti-HER2 monoclonal antibodies. Ann Oncol ESMO 2001;12(Suppl. 1), S35–41. 67. Research CFDEA: Therapeutic Biologic Applications (BLA) Trastuzumab Product Approval Information – Licensing Action 9/25/98, 1998. 68. Crone SA, Zhao YY, Fan L, et al., ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002;8 :459–65.

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69. Morris PG, Chen C, Steingart R, et al., Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res 2011;17 :3490–9. 70. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al., Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353 :1659–72. 71. Gunaldi M, Duman BB, Afsar CU, et al., Risk factors for developing cardiotoxicity of trastuzumab in breast cancer patients: An observational single-centre study. J Oncol Pharm Pract 2015 [Epub ahead of print]. 72. Naumann D, Rusius V, Margiotta C, et al., Factors predicting trastuzumab-related cardiotoxicity in a real-world population of women with HER2+ breast cancer. Anticancer Res 2013;33 :1717–20. 73. De Azambuja E, Procter MJ, Van Veldhuisen DJ, et al., Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J Clin Oncol 2014;32 :2159–65. 74. Pivot X, Romieu G, Debled M, et al., 6 months versus 12 months of adjuvant trastuzumab for patients with HER2positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncology 2013;14 :741–8. 75. Clinicaltrials.Gov: The Synergism Or Long Duration (SOLD) Study. Available at: https://clinicaltrials.gov/ct2/show/ NCT00593697 (accessed 8 July 2015). 76. Guarneri V, Frassoldati A, Bruzzi P, et al., Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer 2008;8 :453–6. 77. Clinicaltrials.Gov: Trastuzumab in Treating Women With HER2Positive Early Breast Cancer. Available at: https://clinicaltrials. gov/ct2/show/NCT00712140 (accessed 8 July 2015). 78. Pituskin E, Haykowsky M, Mackey JR, et al., Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101--Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI. BMC Cancer 2011;11 :318. 79. Marty M, Cognetti F, Maraninchi D, et al., Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23 :4265–74. 80. Richardson PG, Sonneveld P, Schuster MW, et al., Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352 :2487–98. 81. Perez EA, Koehler M, Byrne J, et al., Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clinic proceedings 2008;83 :679–86. 82. Schmidinger M, Zielinski CC, Vogl UM, et al., Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008;26 :5204–12. 83. Lipshultz SE, Adams MJ, Colan SD, et al., Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 2013;128 :1927–95. 84. Thavendiranathan P, Poulin F, Lim KD, et al., Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014;63(25 Pt A):2751–68. 85. Fallah-Rad N, Lytwyn M, Fang T, et al., Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy. J Cardiovasc Magn Reson 2008;10 :5. 86. Fallah-Rad N, Walker JR, Wassef A, et al., The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting

early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 2011;57 :2263–70. 87. Tian S, Hirshfield KM, Jabbour SK, et al., Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol 2014;4 :277. 88. Cardinale D, Sandri MT, Colombo A, et al., Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109 :2749–54. 89. Dolci A, Dominici R, Cardinale D, et al., Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. Am J Clin Pathol 2008;130 :688–95. 90. Herman EH, Zhang J, Lipshultz SE, et al., Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 1999;17 :2237–43. 91. Morandi P, Ruffini PA, Benvenuto GM, et al., Serum cardiac troponin I levels and ECG/Echo monitoring in breast cancer patients undergoing high-dose (7 g/m(2)) cyclophosphamide. Bone Marrow Transplant 2001;28 :277–82. 92. Specchia G, Buquicchio C, Pansini N, et al., Monitoring of cardiac function on the basis of serum troponin I levels in patients with acute leukemia treated with anthracyclines. J Lab Clin Med 2005;145 :212–20. 93. Cardinale D, Colombo A, Torrisi R, et al., Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28 :3910–6. 94. Aggarwal S, Pettersen MD, Bhambhani K, et al., B-type natriuretic peptide as a marker for cardiac dysfunction in anthracycline-treated children. Pediatr Blood Cancer 2007;49 :812–6. 95. Lipshultz SE, Miller TL, Scully RE, et al., Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 2012;30 :1042–9. 96. Sandri MT, Salvatici M, Cardinale D, et al., N-terminal proB-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction? Clin Chem 2005;51 :1405–10. 97. Suzuki T, Hayashi D, Yamazaki T, et al., Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J 1998;136 :362–3. 98. Sawaya H, Sebag IA, Plana JC, et al., Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 2012;5 :596–603. 99. Daugaard G, Lassen U, Bie P, et al., Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction. Eur J Heart Fail 2005;7 :87–93. 100. 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. 101. 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;128 :1810–52. 102. Cardinale D, Colombo A, Lamantia G, et al., Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55 :213–20. 103. Ewer MS, Vooletich MT, Durand JB, et al., Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23 :7820–6.

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LE ATION.

Takotsubo Cardiomyopathy Esha Sachdev, C Noel Bairey Merz and Puja K Mehta Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California, US

Abstract Takotsubo cardiomyopathy (TTC) is an acute, stress-induced cardiomyopathy with an increased prevalence in post-menopausal women. The syndrome is most frequently precipitated by an acute emotional or physical stressor and mimics acute myocardial infarction with symptoms, electrocardiogram (ECG) changes and cardiac troponin elevation that are indistinguishable from those caused by plaque rupture or coronary thrombosis. Diagnosis of TTC is made when coronary angiography reveals no obstructive coronary artery disease and the left ventricle demonstrates apical ballooning and basal hypercontractility. Other ventricular patterns have also been described. An abnormal myocardial response to the catecholamine surge from an emotional or a physical stressor is implicated in the pathophysiology, but the reasons for the high prevalence of TTC presentations in post-menopausal women are unknown. Several mechanisms including multi-vessel coronary vasospasm, endothelial and coronary microvascular dysfunction and direct catecholamine toxicity have been proposed. No specific guidelines for treatment of TTC have been established, but treatment is based on the American Heart Association/ American College of Cardiology guidelines for acute coronary syndrome/acute myocardial infarction and heart failure guidelines. In this review article, we discuss the characteristic clinical presentation of TTC and the commonly proposed mechanisms.

Keywords Mental stress, women heart disease, catecholamine Disclosure: Esha Sachdev, MD, C Noel Bairey Merz, MD, and Puja K Mehta, MD, have no conflicts of interest to declare. Received: 26 October 2014 Accepted: 10 May 2015 Citation: European Cardiology Review, 2015;10(1):25–30 Correspondence: Puja K Mehta, Director, Non-Invasive Vascular Function Research Lab 127 S San Vicente Blvd, AHSP 3212, Los Angeles, CA 90048, US. E: Puja.mehta@cshs.org

Support: This work was supported by contracts from the National Heart, Lung and Blood Institutes nos N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, US, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, CA, US, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, US, and QMED, Inc., Laurence Harbor, NJ, US, the Edythe L Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women’s Health Research (SWHR), Washington, DC, US, The Linda Joy Pollin Women’s Heart Health Program and the Erika Glazer Women’s Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California, US.

Takotsubo cardiomyopathy (TTC) has gained more recognition since its first description in 1990 by Satoh et al.1,2 The word takotsubo refers to the Japanese octopus trapping pot with a large round base and narrow neck, which is the characteristic shape of the left ventricle (LV) in this syndrome, although other morphologies have since been described.3 TTC is known by many names including stress cardiomyopathy, broken heart syndrome, apical ballooning syndrome and ampulla cardiomyopathy. It is a reversible form of cardiomyopathy that presents clinically as an acute myocardial infarction (MI) triggered by an emotionally or physically stressful event. An abnormal response to a catecholamine surge leads to TTC and a stressor can be identified in a majority of cases. TTC occurs at a significantly higher frequency in post-menopausal women with 80–85 % of all cases presenting in women. Less than 3 % of cases occur in those less than 50 years of age.4 The exact incidence of TTC is unknown since it is likely under-diagnosed. The annual rate is between 7,000–14,000 cases per year in the US and it is estimated that 1–2 % of acute coronary syndrome (ACS) diagnosed in the US is actually TTC.4,5 The Nationwide Inpatient Sample (NIS) database in

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2008 found that 0.02 % of all hospitalisations in the US were attributed to TTC.5 This study also found that hyperlipidaemia, active smoking, alcohol abuse, anxiety and stress were associated with TTC.5 One study found significantly lower cardiovascular risk factors in TTC patients compared with population-matched MI patients.6 On the contrary, the recently published systematic review of TTC patients, known as the COmorbidity freqUency iN Takotsubo Syndrome (COUNTS) study, reported a high prevalence of cardiovascular risk factors in TTC patients compared with the general population.7,8 Out of the 1,109 patients in this study, on average 17 % were obese, 54 % had hypertension, 32 % hyperlipidaemia, 17 % were people with diabetes and 22 % were smokers.7 Common comorbidities reported in TTC patients include malignancy, neurological disorders including stroke, pulmonary diseases, chronic kidney disease, thyroid disease and psychological disorders.7 Unlike the study by El-Sayed et al., the COUNTS study reports a poor association between TTC and drug abuse, chronic liver disease and sepsis.6,7 Interestingly, TTC cases occurred at a higher rate in July in contrast to acute MIs, which peak in occurrence in winter months.5 The exact reasons for this potential seasonal variation in TTC are unknown.

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Cardiomyopathy and Heart Failure Table 1: Mayo Clinic Criteria to Diagnose TTC 9 1. Transient hypokinesis, akinesis or dyskinesis of the left ventricular mid segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present 2. Absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture 3. New electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin

and 11 % had no evidence of any stressor.10 In the COUNTS study, 39 % patients experienced a preceding emotional trigger and 34 % patients a physical stressor.7 Emotional stressors range from public speaking, work conflicts/job concerns, anger, to hearing bad news such as death of a family member or a pet. Physical stressors include medical illness such as undergoing surgery or chemotherapy, a fall or drug use. Even though a clear precipitating stressor could not be identified in some TTC patients, the lack of a stressor does not exclude the possibility of diagnosing TTC.

4. Absence of pheochromocytoma or myocarditis TTC = Takotsubo cardiomyopathy.

Figure 1: Reported Stressors Preceding Onset of Takotsubo Cardiomyopathy

Physical stressor: exercise, car accident, mechanical fall

Non-cardiac surgery/medical procedure: cholecystectomy, dental procedure, intubation

Natural disaster: earthquake, hurricane

Emotional triggers:

Panic attack/ fear: claustrophobia, public speaking

Onset of disease: flu, atrial fibrillation, seizure, subarachnoid haemorrhage

death of loved one, divorce,financial loss, violent argument, diagnosis of serious medical condition

Mechanisms of Catecholamine Toxicity

Takotsubo cardiomyopathy

Figure 2: Mechanisms Implicated in TTC

Catecholamine Surge Direct myocyte injury Abnormal free fatty acid metabolism and glucose uptake

Coronary vasospasm or multi-vessel spasm

Coronary microvascular/ endothelial dysfunction

Cardiac neuronal dysfunction/ sympathetic hyperactivity

Takotsubo Cardiomyopathy

TTC = Takotsubo cardiomyopathy.

The Mayo Clinic proposed criteria in 2004 for diagnosing TTC (see Table 1).9 They suggested that all four criteria should be present in order to diagnose TTC. In 2006 the American Heart Association (AHA) classified TTC as a primary acquired cardiomyopathy.

Precipitating Factors In most cases, TTC presents shortly after the individual experiences a major emotional or physical stressor (see Figure 1). A prospective study of 136 patients presenting with TTC found that 47 % of the patients experience an emotional stressor, 42 % a physical stressor

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Certain drugs are shown to be precipitating factors in TTC. Out of 58 patients with case reports of drug-induced TTC, 45 were due to medications that cause direct or indirect stimulation of the sympathetic nervous system (SNS).11 These included agents such as dobutamine, epinephrine, norepinephrine, ephedrine, ergonovine, atropine, nortriptyline and oxymetazoline.11 Levothyroxine has been linked to TTC, and although it does not act on the SNS, the cardiac effects of levothyroxine mimic those caused by catecholamines. Pazopanib is a vascular endothelial growth factor receptor antagonist that inhibits nitric oxide production, and increases sensitivity to catecholamines.11 Agents with no clear link to catecholamine activity including dypyridamole, potassium chloride, lumiracoxib, 5-fluoruracil and combretastatin have also been implicated in TTC.11

It is evident that an abnormal response to a catecholamine surge leads to the development of TTC, but the mechanisms by which it does so have not been clearly established (see Figure 2). Introducing rats to a stressful situation such as immobilisation induces the typical apical ballooning pattern of TTC.12 It has been shown that pre-treatment with a beta-blocker, alpha-blocker or a combination of the two prevented the occurrence of TTC in immobilised rats.12 Furthermore, giving rats an alpha or beta agonist actually induced TTC.13 Plasma catecholamine levels in patients that have undergone a major emotional or physical stressor with subsequent TTC are found to be at supraphysiological levels 1–2 days after the initial stressor and half the peak values after 1 week.14 These levels are twice as high as are observed in patients with Killip class III MI.14 There is evidence of increased sympathetic activity in patients with TTC as confirmed by 123I-meta-iodobenzylguanidine (123I-mIBG) single-photon emission computed tomography (SPECT) imaging.15 Additionally, the plasma levels of catecholamine precursors and neuronal as well as extraneuronal breakdown products are elevated, implicating increased catecholamine synthesis as well as neuronal and extraneuronal metabolism.14 Epicardial coronary artery spasm causing ischaemia has also been implicated in TTC. The elevation of catecholamine levels stimulates the α1 receptors on the coronary vasculature leading to coronary vasoconstriction with resultant ischaemia. This is supported by ST elevations being a common finding in TTC despite the absence of obstructive coronary artery disease. However, the ST elevations in TTC are more diffuse and do not typically follow a distinct epicardial distribution. Thus, it is proposed that multi-vessel coronary vasospasm may be responsible for the development of TTC. Tsuchihashi et al. demonstrated that 21 % (n=48) of patients have inducible vasospasm with use of acetylcholine.16 Another systematic review showed 27.6 % of subjects have provoked coronary vasospasm in response to acetylcholine or ergovine.17 Thus, while an important contributor towards the development of TTC, multi-vessel epicardial coronary spasm does not explain the majority of TTC cases.

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Alternatively, coronary microvascular and endothelial dysfunction is another hypothesised mechanism of TTC. One of the major arguments for this mechanism is that electrocardiogram (ECG) changes are diffuse and not suggestive of a single coronary artery territory and on cardiac catheterisation the majority of patients do not have obstructive coronary artery disease. Additionally, the peak troponin level and the extent of ECG changes in patients with TTC are shown to correlate to the severity of endothelial dysfunction.18 These patients are found to have a reduced coronary blood flow during the acute TTC event that remains impaired after the resolution of TTC left ventricular dysfunction, suggesting that coronary microvascular dysfunction is present at baseline in patients with TTC.19,20 Moreover, female patients with a history of TTC have evidence of impaired microvascular dilation in response to acetylcholine as well as a significantly lower increase in peak coronary blood flow compared with age-matched women with normal microvascular responses.20 The reactive hyperaemia peripheral arterial tonometry (PAT) is a reflection of changes in peripheral endothelial function and correlates with coronary endothelial function. TTC patients compared with post-MI and post-menopausal control women demonstrate more adverse mental stress PAT scores compared with the other groups, consistent with a persistently abnormal physiological response in TTC patients.21 Excessive vasoconstriction and impaired endothelium dependent vasodilation is suggested to cause this abnormal response to mental stress testing.20 It has previously been proposed that left ventricular outflow tract (LVOT) obstruction leads to TTC. The theory is that catecholamine release causes LOVT obstruction thus increasing the mechanical stress on the cardiac apex and subsequently leads to myocardial stunning.22 A recent study reveals that dobutamine causes mid-ventricular outflow gradients in both patients with and without a history of TTC.22 This means that there are no differences in patients with or without a TTC history that would predispose them to develop TTC. It is not likely that LVOT obstruction is the sole cause of TTC given that the incidence of LVOT obstruction in TTC is about 20–25 %.23 A fourth proposed mechanism is that the elevated catecholamine levels may cause direct myocyte injury. In previous studies it is shown that norepinephrine causes an increase in cyclic adenosine monophosphate (cAMP)-mediated intracellular calcium overload that is responsible for myocyte toxicity.24 Furthermore, catecholamines can be a source of oxygen-derived free radicals that then interfere with intracellular calcium transporters, leading to excess calcium influx and subsequent myocyte damage.14,25 One way in which increased intracellular calcium may cause cell injury is through the high-energy phosphate deficiency that results from excessive activation of the calcium dependent ATPase, therefore leading to impaired mitochondrial function.24 Histologically, myocytes have been shown to have contraction band necrosis and mononuclear inflammation, both characteristic signs of catecholamine toxicity that differ from ischaemic-induced necrosis.25 Contraction band necrosis and mononuclear inflammation are also seen in other catecholamine-excess states, such as subarachnoid haemorrhage and pheochromocytoma.25 It has been hypothesised that the fibrosis seen in TTC does not reach a critical value due to the concomitant release of anti-fibrotic factors by norepinephrine, and is the reason that TTC is reversible.25

β1-adrenoreceptors that are coupled to Gs proteins, subsequently increasing cAMP to activate protein kinase A and therefore cause increased contractile response via release of calcium. Epinephrine has the same effect but with a higher affinity for the β2-adrenoreceptors, which also leads to a positive inotropic response. At supraphysiological epinephrine levels, the β2-adrenoreceptors couple to Gi protein instead of the Gs protein therefore leading to a negative inotropic effect on the heart.2 Additionally, although there are more sympathetic nerve endings in the basal myocardium, there is a higher concentration of β-adrenoreceptors at the apex thus explaining the typical apical ballooning pattern due to apical akinesis.26 Once the epinephrine levels return to normal, the β2-adrenoreceptors are once again coupled to the Gs protein.2 The switch to Gi protein may have a protective role in the myocardium. High levels of β1-adrenoreceptor-mediated Gs activation can stimulate apoptotic pathways therefore switching to Gi protein via β2-adrenoreceptors inhibits apoptosis from occurring.27 Additionally, as previously mentioned, intracellular calcium overload by the Gs receptor can be cardiotoxic, so the switch to the Gi pathway may be cardioprotective. Neurogenic stunned myocardium is another mechanism proposed to cause TTC. The fact that an emotional stressor causes TTC suggests that the brain plays a role in inducing cardiac injury. Patients with subarachnoid haemorrhage are found to have elevated catecholamine levels. These patients, particularly females, demonstrate similar findings as those in TTC such as diffuse ST elevation without obstructive coronary artery disease on cardiac catheterisation, significantly reduced wall motion of the apex, and histological changes consistent with those of catecholamine excess, such as contraction band necrosis.28,29 In subarachnoid haemorrhage, ischaemia of the hypothalamus releases excess amounts of norepinephrine and subsequently leads to myocyte stunning.28 A more recent study with three patients shows direct evidence that brain activation is implicated in TTC by measuring cerebral blood flow via SPECT.30 Cerebral blood flow was increased in the hippocampus, brainstem and basal ganglia and decreased in the pre-frontal cortex during the acute phase of TTC in all three subjects.30 This pattern of brain activation is is found in acute stress and with sympathetic activation.30 In a recent study by Vaccaro et al., TTC patients are found to have increased SNS activity at baseline and a decreased baroreceptor response compared with congestive heart failure (CHF) patient controls.31 CHF patients have elevated SNS activity, thus this study demonstrated that TTC patients have even higher sympathetic activity. Moreover, TTC patients also had decreased baroreceptor inhibition of the SNS. In this study, SNS activity was directly measured by assessing muscle sympathetic nerve activity (MSNA).31 The study only determined an association between increased SNS and decreased baroreceptor response but did not determine causality. Also, by looking at the musculature, the study focused on the SNS activation of the peripheral vasculature but not the heart itself. However, it does suggest that autonomic dysfunction could play a role in TTC. This can further be supported by the fact that many patients with haemorrhage or ischaemic stroke have high occurrence of TTC, and may serve as an alternative explanation for neurogenic stunning.

Clinical Presentation Another theory of acute-myocardial stunning via alterations in cell signalling is proposed as a further cause of the direct effect of catecholamines on the heart. Normally, norepinephrine binds to the

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The clinical presentation of TTC is indistinguishable from acute MI in terms of symptoms, elevation of cardiac enzymes and ECG changes. The most common symptoms upon presentation are anginal chest

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Cardiomyopathy and Heart Failure pain and dyspnea. Syncope can also be a presenting symptom but is less frequently observed. Patients can less commonly present with arrhythmias, sudden cardiac death, asystole or cardiogenic shock. There are many ECG patterns described in TTC, most prominently ST elevations and/or diffuse T wave inversions, and prolongation of the QTc interval.3,4,17 The ST elevations occur primarily in the precordial leads therefore mimicking an acute anterior MI.4 The ST elevations typically resolve after 2–3 days and rarely will patients develop pathological Q waves. Similarly, the T wave inversions are also transient and resolve within 3–4 months. Other less-frequent ECG findings include ST depressions, new-onset bundle branch block, high-degree atrioventricular (AV) block, or simply a normal ECG.3 Additionally, troponin is often elevated, which further makes TTC difficult to distinguish from ACS. Multiple studies have noted that the extent of troponin T elevation is less than that of STEMI and inexplicably low for the wall motion abnormalities seen with TTC.4 Furthermore, the magnitude of troponin elevation does not correlate with the ECG pattern, clinical features, LV contraction pattern or patient outcomes.10

Imaging For the typical presentation of TTC, imaging of the LV shows apical and mid-wall hypokinesis with a hypercontractile basal myocardium.2,3 Atypical patterns of LV wall motion abnormalities exist in TTC and are increasingly recognised, which include isolated basal ballooning, mid-ventricular ballooning with basal and apical sparing and biventricular ballooning.3 The most common atypical form is the ‘inverted Takotsubo’ pattern that consists of basal ventricular akinesis with normal apical function.2,3,17 Cardiac magnetic resonance imaging (CMR) has been gaining popularity as a diagnostic modality for TTC. In a large prospective study consisting of 256 TTC patients, 81 % were found to have myocardial oedema correlating to areas of wall motion abnormalities.3 Myocardial oedema in TTC is global, and the amount of myocardial oedema in a particular area predicted the extent of wall motion abnormality.32 Although decreased, myocardial oedema was still present after 3-month follow-up. The extent of myocardial oedema correlated with that of peak N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, a marker of inflammation and NT-proBNP values also remained elevated for 3 months.32 This suggests inflammation as a cause of the oedema, and that the inflammatory response persists even after recovery of systolic function.32 Late gadolinium enhancement (LGE), indicative of myocardial scarring, is present in 9 % of TTC patients. Eitel et al. have created the following diagnostic criteria for diagnosing TTC via CMR: severe left ventricular dysfunction in a non-coronary distribution pattern, myocardial oedema collocated with the regional wall motion abnormalities, absence of high signal areas in LGE images and increased early myocardial gadolinium uptake.3

Treatment There are no specific guidelines for the treatment of LV dysfunction in TTC. Physicians generally follow the AHA/American College of Cardiology (ACC) treatment guidelines for ACS/non-ST segment elevation myocardial infarction (NSTEM/STEMI), as the syndrome’s presentation mimics ACS.33,34 Although only found in 20 % of patients, left heart failure is the most common complication of TTC.4 Angiotensin-converting-enzyme (ACE) inhibitors and diuretics are used for LV dysfunction and treatment of acute heart failure as needed.35 Patients are also started on an alpha and beta-blocker given the catecholamine surge in TTC. However, some authors do not

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recommend beta-blockers due to the concern of unopposed alpha stimulation in the setting of catecholamine excess.36 In the setting of cardiogenic shock, a differentiation should be made between pump failure and LVOT obstruction. If LVOT obstruction is present, then preload and afterload optimisation with the use of betablockers is recommended. Propranolol was shown to significantly increase left ventricular ejection fraction (LVEF) in patients with LVOT obstruction, but not in those without it.23 Beta-blockers will reduce the ventricular gradient and therefore reduce hypotension and increase LVEF. If dobutamine is given in the setting of LVOT obstruction, it will worsen the ventricular gradient and subsequently exacerbate hypotension.23 In cases of cardiogenic shock from primary pump failure, inotropic therapy did not show any benefit due to stimulation of the beta-2 and alpha adrenergic receptors, which can further exacerbate TTC.37 As a result, there should be early consideration of the possibility of intra-aortic balloon pump use. In some case reports, the use of levosimendan, a non-catecholamine inotrope, is shown to be beneficial in treating patients with cardiogenic shock due to pump failure.38,39 However, no large-scale studies have been carried out to date to prove efficacy. Given apical hypokinesis in TTC, echocardiography and often cardiac MRI are needed to evaluate for LV thrombus. Anticoagulation is considered in the initial stages where there is severe LV dysfunction, and especially if thrombus is identified in the LV apex.4 Anticoagulation should be used with caution due to the increased risk of LV rupture with apical ballooning.36 There are no current guidelines on the duration of therapy with anticoagulation. Patients with recurrent episodes can be continued on beta-blocker therapy in addition to stress management.

Natural History and Prognosis While TTC has a good prognosis, it is by no means a benign disease. In the majority of cases, the LV wall motion abnormalities resolve in days to weeks. Systolic function can take longer to normalise and on average resolves over 4–10 weeks.4,10,40 One study that followed patients with TTC demonstrates that the rate of recurrence is 2.9 % per year within the first 4 years, and 1.3 % per year subsequently.40 In-hospital mortality from TTC in the acute phase is generally around 1 % though it can be as high as 9 %.4,10,41,42 Independent predictors for mortality in TTC include the presence of certain comorbid conditions and male gender.41 A study by Brinjikji et al. using the NIS from 2008 to 2009 demonstrated that in-hospital mortality was significantly higher in males than in females: 8.4 versus 3.6 % respectively.41 Males also had a higher incidence of developing life-threatening complications including cardiogenic shock and cardiac arrest as well as dying from these complications, whereas females were more likely to develop acute CHF. However, out of the patients who experienced in-hospital mortality, over 80 % consisted of those with concomitant critical illnesses, such as sepsis, acute renal failure, stroke and respiratiory insufficiency.41 Since men had more underlying critical illnesses than women, this could explain their higher mortality rate and higher rates of developing and dying from acute complications.41 Furthermore, significantly more males present initially with cardiogenic shock or out-of-hospital cardiac arrest.43 Cardiogenic shock occurs in 4–20 % of patients with TTC,41,44 as a result of ventricular failure or LVOT obstruction. If LVOT obstruction is responsible for cardiogenic shock, it is usually accompanied by

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systolic anterior motion (SAM) of the mitral valve. Mortality from cardiogenic shock with TTC is reported to be as high as 16 % in some cases.41 Ventricular arrhythmias occur in 4–9 % of TTC patients in the acute phase. Of those that develop ventricular fibrillation or cardiac arrest, mortality is reported to range from 1 % to as high as 27 %.41 Interestingly, causes of long-term mortality differ in patients with a history of TTC compared with patients with ACS: a majority of TTC patients die of non-cardiac causes in the long term. Sharkey et al. reported that during an average follow-up period of 1.3 years, 17 out of the 133 TTC survivors died, with none being from a cardiac cause.10 In another study by Song et al., with a mean follow up of 42 months, mortality from non-cardiac causes was significantly higher than that from cardiac causes: 21 versus 2 %, respectively.42 Non-cardiac diseases, such as malignancy and stroke, were found to be an independent risk factor for long-term mortality.42 This is different from ACS patients in whom long-term mortality is usually from cardiac causes.45 Increasing evidence for an association between malignancy and TTC exists. One study shows TTC patients to have a significantly higher incidence of any malignancy compared with population-matched MI and orthopaedic patients.6 Another study demonstrated that 18 % of TTC patients versus 3 % of MI patients have a history of malignancy at the time of the event.45 Subsequently, seven patients in the TTC group versus zero patients in the MI group went on to develop cancer at the follow-up time of about 1.6 years.45 Additionally, in the COUNTS study, 10 % of patients have a malignancy.7 The association of malignancy with TTC brings up the possibility that TTC may be a manifestation of a paraneoplastic syndrome,7,43,45 which may imply that TTC is neither as benign as previously believed, nor does it have as favourable a long-term prognosis.

Why Predominantly Women? TTC affects a disproportionately greater number of post-menopausal women compared with pre-menopausal women and age-matched men.5 There are several mechanisms proposed to explain this sex difference. It has been reported that catecholamine stress induces upregulation of immediate early genes (IEGs), certain proto-oncogenes and heat shock proteins that are not shown to be activated during reperfusion after an ischaemic episode.13 Oestrogen minimises the catecholamine-induced upregulation of IEGs, genes that are transiently activated to rapidly adapt to a stressor. 13 Supplementation with oestradiol decreased the stress-induced upregulation of IEGs in rat models. Oestradiol-supplemented ovariectomised rats did not show any significant reduction in LV contraction whereas ovariectomised rats without supplementation with oestradiol showed a significant reduction in LV contraction.46 Therefore, oestrogen counteracts the cardiac effects of the SNS by decreasing the production of IEGs.8

Satoh H, Tateishi H, Uchida T, et al., Takotsubo type cardiomyopathy due to multivessel spasm. In: Kodama K, Haze K, Hon M, eds, Clinical aspect of myocardial injury: from ischemia to heart failure , Tokyo: Kagakuhyouronsya, 1990;56–64. Lyon AR, Rees PS, Prasad S, et al., Stress (takotsubo) cardiomyopathy–a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med . 2008;5 :22–9. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al., Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA . 2011;306 :277–86. Prasad A, Lerman A, Rihal CS, Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): A mimic of acute myocardial infarction. Am Heart J . 2008;155 :408–17. Deshmukh A, Kumar G, Pant S, et al., Prevalence of takotsubo cardiomyopathy in the United States. Am Heart J .

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Oestrogen has also been implicated in maintaining appropriate glucose uptake for cardiac energy. A recent report indicates that the female heart depends on glucose as its energy source more than the male heart.47 The female heart most efficiently utilises glucose between ages 51–70 and after age 70, glucose uptake is reduced.47 The relative lack of oestrogen as women age, therefore, may potentiate this attenuated glucose uptake thus predisposing postmenopausal females to TTC. Males are not predisposed to TTC despite their relative lack of oestrogen because they are not as dependent on glucose as their preferential cardiac energy substrate.47 Oestrogen may also play a role in enhancing the β-adrenoreceptor sensitivity and in promoting vasodilation. Post-menopausal women have a decreased β-adrenoreceptor responsiveness to catecholamine stimulation than younger females.48 However, their α-adrenoreceptor vasoconstriction response to catecholamines remains the same.48 As a result, there is more α-adrenoreceptor stimulation in relation to β-adrenoreceptor responsiveness thus leading to more vasoconstriction, which in the setting of endothelial dysfunction may trigger TTC. Additionally, oestrogen indirectly increases the production of nitric oxide thus promoting vasodilation.8 This nitric oxide-induced vasodilation helps minimise the effect of catehcholamines, especially in the microvasculature.8 Stollberger et al.49 discuss two opposing speculations related to the sex difference in TTC: 1) males are better protected biologically against stress and 2) males are biologically less resistant than females against stress. Historically, men were exposed to more physical stressors than women and therefore may be better protected biologically than women.49 Additionally, males have a higher density of adrenergic receptors compared with women and can thus protect themselves from catecholamine excess better than females.5 On the other hand, males have a higher rate of sudden cardiac death and therefore possibly die more frequently from the acute LV dysfunction and thus die before they are diagnosed with TTC.49

Conclusion TTC is an acute, reversible form of catecholamine stress-induced cardiomyopathy that mimics acute MI, and predominates in postmenopausal women. It presents with signs and symptoms of ischaemia and acute left ventricular dysfunction with regional wall motion abnormalities in the setting of no obstructive coronary artery disease. An emotional or physical stressor usually precedes TTC. The syndrome has a good prognosis although a few percentage of patients experience recurrent events. Mechanisms implicated in TTC include multi-vessel coronary spasm, endothelial and coronary microvascular dysfunction and direct catecholamine toxicity. Clinicians should be aware of this syndrome and studies that investigate mechanistic pathways of TTC may help with development of preventive and management strategies. n

2012;164 :66–71 e61 El-Sayed AM, Brinjikji W, Salka S, Demographic and co-morbid predictors of stress (takotsubo) cardiomyopathy. Am J Cardiol . 2012;110 :1368–72. 7. Pelliccia F, Parodi G, Greco C, et al., Comorbidities frequency in takotsubo syndrome: An international collaborative systematic review including 1109 patients. Am J Med . 2015;128:654.e11–9. 8. Pelliccia F, Greco C, Vitale C, et al., Takotsubo syndrome (stress cardiomyopathy): An intriguing clinical condition in search of its identity. Am J Med . 2014;127 :699–704. 9. Madhavan M, Prasad A. Proposed Mayo clinic criteria for the diagnosis of tako-tsubo cardiomyopathy and long-term prognosis. Herz . 2010;35 :240–3. 10. Sharkey SW, Windenburg DC, Lesser JR, et al., Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol . 2010;55 :333–41. 6.

11. Amariles P, A comprehensive literature search: Drugs as possible triggers of takotsubo cardiomyopathy. Curr Clin Pharmacol . 2011;6 :1–11. 12. Ueyama T, Kasamatsu K, Hano T, et al., Emotional stress induces transient left ventricular hypocontraction in the rat via activation of cardiac adrenoceptors: A possible animal model of ‘tako-tsubo’ cardiomyopathy. Circ J. 2002;66 :712–3. 13. Ueyama T, Emotional stress-induced tako-tsubo cardiomyopathy: Animal model and molecular mechanism. Ann N Y Acad Sci . 2004;1018 :437–44. 14. Wittstein IS, Thiemann DR, Lima JA, et al., Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med . 2005;352 :539–48. 15. Akashi YJ, Nakazawa K, Sakakibara M, et al., 123i-mibg myocardial scintigraphy in patients with “takotsubo” cardiomyopathy. J Nucl Med . 2004;45 :1121–7. 16. Tsuchihashi K, Ueshima K, Uchida T, et al., Transient left

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17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol . 2001;38 :11–8. Pilgrim TM, Wyss TR, Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: A systematic review. Int J Cardiol . 2008;124 :283–92. Elesber A, Lerman A, Bybee KA, et al., Myocardial perfusion in apical ballooning syndrome correlate of myocardial injury. Am Heart J . 2006;152 :469 e469–13. Kurisu S, Inoue I, Kawagoe T, et al., Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction. J Am Coll Cardiol . 2003;41 :743–8. Patel SM, Lerman A, Lennon RJ, Prasad A, Impaired coronary microvascular reactivity in women with apical ballooning syndrome (takotsubo/stress cardiomyopathy). Eur Heart J Acute Cardiovasc Care . 2013;2 :147–52. Martin EA, Prasad A, Rihal CS, et al., Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome. J Am Coll Cardiol . 2010;56 :1840–6. Looi JL, Gabriel R, Khan A, et al., Left ventricular morphology and response to beta-adrenergic stimulation in apical ballooning syndrome. Eur Heart J Cardiovasc Imaging . 2012;13 :510–6. Yoshioka T, Hashimoto A, Tsuchihashi K, et al., Clinical implications of midventricular obstruction and intravenous propranolol use in transient left ventricular apical ballooning (tako-tsubo cardiomyopathy). Am Heart J. 2008;155 :526 e521–7. Mann DL, Kent RL, Parsons B, Cooper GT, Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation . 1992;85 :790–804. Nef HM, Mollmann H, Kostin S, et al., Tako-tsubo cardiomyopathy: Intraindividual structural analysis in the acute phase and after functional recovery. Eur Heart J . 2007;28 :2456–64. Kawano H, Okada R, Yano K, Histological study on the distribution of autonomic nerves in the human heart. Heart Vessels . 2003;18 :32–9. Chesley A, Lundberg MS, Asai T, et al., The beta(2)adrenergic receptor delivers an antiapoptotic signal to

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cardiac myocytes through g(i)-dependent coupling to phosphatidylinositol 3’-kinase. Circ Res . 2000;87 :1172–9. 28. Kono T, Morita H, Kuroiwa T, et al., Left ventricular wall motion abnormalities in patients with subarachnoid hemorrhage: Neurogenic stunned myocardium. J Am Coll Cardiol . 1994;24 :636–40. 29. Lee VH, Oh JK, Mulvagh SL, Wijdicks EF, Mechanisms in neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care . 2006;5 :243–9. 30. Suzuki H, Matsumoto Y, Kaneta T, et al., Evidence for brain activation in patients with takotsubo cardiomyopathy. Circ J . 2014;78 :256–8. 31. Vaccaro A, Despas F, Delmas C, et al., Direct evidences for sympathetic hyperactivity and baroreflex impairment in tako tsubo cardiopathy. PloS One . 2014;9 :e93278. 32. Neil C, Nguyen TH, Kucia A, et al., Slowly resolving global myocardial inflammation/oedema in tako-tsubo cardiomyopathy: Evidence from t2-weighted cardiac MRI. Heart . 2012;98 :1278–84. 33. Hurst RT, Prasad A, Askew JW, 3rd, et al., Takotsubo cardiomyopathy: A unique cardiomyopathy with variable ventricular morphology. JACC Cardiovasc Imaging. 2010;3:641–9. 34. Antman EM, Anbe DT, Armstrong PW, et al., ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol . 2004;44 :E1–E211. 35. Hunt SA, Abraham WT, Chin MH, et al., 2009 focused update incorporated into the ACC/AHA 2005 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. J Am Coll Cardiol . 2009;53 :e1–e90. 36. Akashi YJ, Goldstein DS, Barbaro G, Ueyama T, Takotsubo cardiomyopathy: A new form of acute, reversible heart failure. Circulation . 2008;118 :2754–62. 37. Fujiwara S, Takeishi Y, Isoyama S, et al., Responsiveness to dobutamine stimulation in patients with left ventricular

apical ballooning syndrome. Am J Cardiol . 2007;100 :1600–3. 38. Antonini M, Stazi GV, Cirasa MT, et al., Efficacy of levosimendan in takotsubo-related cardiogenic shock. Acta Anaesthesiol Scand . 2010;54 :119–20. 39. Padayachee L, Levosimendan: The inotrope of choice in cardiogenic shock secondary to takotsubo cardiomyopathy? Heart Lung Circ . 2007;16 (Suppl. 3):S65–70. 40. Elesber AA, Prasad A, Lennon RJ, et al., Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol . 2007;50 :448–52. 41. Brinjikji W, El-Sayed AM, Salka S, In-hospital mortality among patients with takotsubo cardiomyopathy: A study of the national inpatient sample 2008 to 2009. Am Heart J . 2012;164 :215–21. 42. Song BG, Hahn JY, Cho SJ, et al., Clinical characteristics, ballooning pattern, and long-term prognosis of transient left ventricular ballooning syndrome. Heart Lung . 2010;39 :188–95. 43. Schneider B, Athanasiadis A, Sechtem U, Gender-related differences in takotsubo cardiomyopathy. Heart Fail Clin . 2013;9 :137–46, vii. 44. Madhavan M, Rihal CS, Lerman A, Prasad A, Acute heart failure in apical ballooning syndrome (takotsubo/stress cardiomyopathy): Clinical correlates and Mayo clinic risk score. J Am Coll Cardiol . 2011;57 :1400–1. 45. Burgdorf C, Kurowski V, Bonnemeier H, et al., Long-term prognosis of the transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): Focus on malignancies. Eur J Heart Fail. 2008;10 :1015–9. 46. Ueyama T, Hano T, Kasamatsu K, et al., Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of tako-tsubo (ampulla) cardiomyopathy. J Cardiovasc Pharmacol . 2003;42 (Suppl. 1):S117–9. 47. Kakinuma Y, Okada S, Nogami M, Kumon Y., The human female heart incorporates glucose more efficiently than the male heart. Int J Cardiol . 2013;168 :2518–21. 48. Hart EC, Charkoudian N, Wallin BG, et al., Sex and ageing differences in resting arterial pressure regulation: The role of the beta-adrenergic receptors. J Physiol . 2011;589 :5285–97. 49. Stollberger C, Finsterer J, Why does takotsubo (“broken heart syndrome”) affect more females than males? Int J Cardiol . 2011;147 :175–6.

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Cardiomyopathy and Heart Failure

LE ATION.

Risk Stratification in Hypertrophic Cardiomyopathy Alexandros Klavdios Steriotis and Sanjay Sharma CRY Centre for Inherited Cardiovascular Conditions & Sports Cardiology, St George’s University of London, London, UK

Abstract Hypertrophic cardiomyopathy (HCM) is a hereditary primary myocardial disease that is most commonly due to mutations within genes encoding sarcomeric contractile proteins and is characterised by left ventricular hypertrophy in the absence of a cardiac or systemic cause. Although the overall prognosis is relatively good with an annual mortality rate <1 %, the propensity to potentially fatal ventricular arrhythmias is the most feared complication. The identification of patients at risk of arrhythmogenic sudden cardiac death (SCD) is an essential component in disease management. Aborted SCD and malignant ventricular arrhythmias are the most powerful risk factors for SCD and ICD implantation is recommended in such circumstances. The selection of patients who may benefit from ICD therapy for primary prevention purposes is more challenging. The heterogeneous nature of the disease and the variation in trigger factors provides an adequate explanation for the low predictive accuracy of most conventional risk factors in isolation. A new risk model for risk stratification proposed by the European Society of Cardiology HCM outcome group shows promise but requires validation in different cohorts. The ICD is the only effective therapy in preventing SCD for the disease with a relatively low adverse event rate, but most deaths occur in relatively young patients. However, it is also difficult to ignore the complications with the ICD, therefore, the strive to perfect risk stratification in HCM should continue to ensure that only the most high-risk patients receive an ICD.

Keywords Hypertrophic cardiomyopathy, risk stratification, sudden cardiac death Disclosure: The authors have no conflicts of interest to declare. Received: 22 May 2015 Accepted: 19 June 2015 Citation: European Cardiology Review, 2015;10(1):31–6 Correspondence: Sanjay Sharma, St George’s University of London, Cranmer Terrace, London, SW17 0RE, UK. E: sasharma@sgul.ac.uk

Hypertrophic cardiomyopathy (HCM) is a hereditary primary myocardial disease that is most commonly caused by mutations within genes encoding sarcomeric contractile proteins and is characterised by left ventricular hypertrophy in the absence of a cardiac or systemic cause.1,2 The condition is inherited as an autosomal dominant trait and has a prevalence of one in 500.3,4 Marked genetic heterogeneity, diverse clinical phenotypes and a highly variable natural history are well recognised.4–6 Although the overall prognosis is relatively good with an annual mortality rate <1 %, the propensity to potentially fatal ventricular arrhythmias is the most feared complication particularly because the peak incidence of sudden cardiac death (SCD) is during adolescence and early adulthood.6–9 The association with SCD is most frequently highlighted when a young, previously asymptomatic athlete falls victim and HCM is considered the commonest cause of SCD in young athletes worldwide.10–12 The arrhythmogenic substrate comprises left ventricular hypertrophy, myocyte disarray and interstitial fibrosis.13–17 Triggers for arrhythmias may include myocardial ischaemia, excessive sympathetic stimulation, left ventricular outflow tract obstruction (LVOTO) and paroxysmal atrial fibrillation (AF).18–20 The identification of patients at risk of arrhythmogenic SCD is an essential component in disease management given that the implantable cardioverter defibrillator (ICD) is the most effective therapy in preventing SCD.21–25 However, the low risk of adverse events in most patients coupled with the complex and unpredictable relationship between the arrhythmic substrate and triggers for arrhythmias means that risk stratification for arrhythmogenic SCD is a challenging aspect

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of the disease. A low threshold to implant an ICD into most patients with HCM is not cost-effective and is hampered by the high prevalence of inappropriate shocks and other complications relating to the implantation of the ICD.23–26 Aborted SCD and malignant ventricular arrhythmias are the most powerful risk factors for SCD.27–30 Patients who survive an episode of ventricular tachycardia (VT) or ventricular fibrillation (VF) remain at high risk of recurrent arrhythmogenic events, having an estimated risk of 10.6 % per annum and both the American College of Cardiology Foundation/ American Heart Association (ACCF/AHA) and American College of Cardiology/European Society of Cardiology (ACC/ESC) management guidelines for HCM recommend ICD implantation in such patients.27–30

Conventional Risk Factors for SCD in HCM The selection of patients who may benefit from ICD therapy for primary prevention purposes is more challenging. Several potential risk factors for SCD have been reported, however conventionally regarded major risk factors include unexplained syncope, family history of sudden cardiac death (FHSCD), severe left ventricular hypertrophy (LVH), non-sustained VT (NSVT) on the Holter-monitoring or during exercise and an abnormal blood pressure response to exercise (ABPRE) (see Table 1).19,28–32 Consistent with the clinical diversity of the disease, all of these risk factors have a relatively low positive predictive accuracy in the range of 20 %.29 Conversely, each factor has an excellent negative predictive accuracy therefore a patient who does not exhibit any of these risk factors is suitably deemed low risk.29,31 Nevertheless, up to

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Cardiomyopathy and Heart Failure Table 1: Major SCD Risk Factors and Modifiers Used in the Current Guidelines and Putative Risk Factors Described in the Literature, but not Included in the Current Guidelines Major SCD Risk Factors

References

(2003 ACC/ESC and 2011 ACCF/AHA Guidelines) Family history of sudden cardiac death

37, 41, 54

Unexplained syncope

37, 38, 42, 43, 54

Severe left ventricular hypertrophy

33, 36, 44, 45, 52, 54

Non-sustained ventricular tachycardia

33, 37, 47, 48, 54

Abnormal blood pressure response to exercise

33, 35, 50, 51, 54

Potential SCD Risk Modifiers (2011 ACCF/AHA Guidelines) Left ventricular outflow tract obstruction 32, 51–54

of HCM-related SCD experience appropriate electrical discharges comparable to other patient subsets with high-risk markers.41

Unexplained Syncope Determination of the possible cause of unwitnessed syncope is challenging in HCM because there are multiple potential causes that include vasovagal syncope, arrhythmogenic syncope, abnormal vascular responses or transient severe mechanical LVOTO.28 However, the clinical perception is that syncope is the only premonitory cardiac symptom that is associated with SCD.28,42,43 Patients with syncopal events that occur in close temporal proximity (6 months) to the initial evaluation, show a substantially higher risk of SCD than patients without syncope.38 Older patients with remote syncopal events do not show an increased risk.38

Late Gadolinium enhancement on CMR Imaging

60, 62, 63, 70,

Genetic Mutations

76–83

Severe Left Ventricular Hypertrophy

Left ventricular apical aneurysm

End-stage phase of HCM (EF <50 %)

85, 86

The severity and extent of LVH is associated with increased risk of SCD.30 Several studies have shown that a maximum wall thickness of ≥30 mm is associated with greatest risk of SCD.44–46 The ACCF/AHA guidelines state that the presence of extreme LVH alone is reasonable to recommend ICD29 (see Figure 1); however, extreme LVH is relative rare and the maximum wall thickness of a single segment may not adequately represent the true burden of hypertrophy.19 According to the 2003 ESC guidelines, the degree of maximum left ventricle (LV) wall thickness should be considered in the context of a multifactorial approach to risk stratification, rather than as an isolated risk factor.28,36 An exception may be the development of severe LVH at a young age (<18 years).36

Additional SCD Risk Factors (2014 ESC Guidelines)* Increased left atrial diameter 9, 38 Young age at the evaluation

9, 36–39

Putative SCD Risk Factors Paced ventricular electrogram fractionation

QRS fragmentation on the ECG

87, 88

Exercise-induced NSVT/VF

Severe obstructive coronary disease

Microvascular ischaemia

94–96

Midventricular obstruction

89, 90

Non-sustained Ventricular Tachycardia

Atrial fibrillation

28, 92

The presence of repetitive ventricular arrhythmias, at rest or effortinduced is frequently used as a marker of increased electrical instability of the myocardium in clinical practice.37,47 NSVT (defined as ≥3 consecutive beats with a heart rate of ≥120 bpm) is detected in approximately 20 % of HCM patients and is associated with a substantial increase in SCD risk in young patients aged ≤30 years old.37 A relationship between the frequency, duration and rate of NSVT episodes has not yet been clearly demonstrated.37 In clinical practice isolated brief runs of NSVT on random Holter-monitoring rarely trigger decisions for prophylactic ICD, whereas frequent and/or prolonged (>10 beats) bursts of NSVT identified over serial monitoring periods, intuitively carry greater weight as a risk factor.48 In one study of 104 HCM patients with an ICD the presence of NSVT was the most predictive risk factor for appropriate ICD discharge in the 78 patients of the primary prevention group.24

*The 2014 European Society of Cardiology (ESC) guidelines considered as sudden cardiac death (SCD) risk factors: left atrial diameter, age, family history of SCD, unexplained syncope, left ventricular outflow tract obstruction (LVOTO), severe left ventricular hypertrophy and non-sustained ventricular tachycardia (NSVT) and excluded the abnormal blood pressure response to exercise. ACC = American College of Cardiology; ACC = American College of Cardiology Foundation; AHA = American Heart Association; CMR = cardiovascular magnetic resonance; ECG = electrocardiogram; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; VF = ventricular fibrillation.

3 % of arrhythmogenic SCDs occur in patients who do not exhibit any of these risk factors.33,34 The significance of these risk factors is governed by age.32–39 In young patients, syncope, severe LVH and NSVT are particularly associated with an increased risk of SCD.30,35–39 In older patients who have survived more than 60 years, the risk of arrhythmogenic SCD is low despite the presence of the five conventional risk factors above.39

Abnormal Blood Pressure Response to Exercise Invasive electrophysiological studies, such as programmed ventricular stimulation, have a poorer predictive accuracy than some of the risk factors mentioned above and is not indicated for risk stratification.30 Paced ventricular electrogram fractionation analysis has been reported to reveal a positive predictive accuracy in the range of 38 %.40 However, the invasive nature of the procedure in combination with the dynamic nature of the risk profile of SCD in HCM patients means that periodical assessment is impractical.

Approximately one-third of patients with HCM, have an ABPRE (defined as either the failure to increase by at least 20 mmHg or a drop of at least 20 mmHg during effort), which can be due to central and peripheral mechanisms.28,29,49 An ABPRE rarely represents the sole indication for a prophylactic ICD implant in clinical practice and is usually considered in association with other risk factors (see Figure 1).29,35 The 2014 ESC guidelines did not consider the ABPRE as a risk factor since it has not been independently associated with SCD in any multivariate survival analysis (see Figure 2).29,30,50,51

Family History of SCD A FHSCD from HCM in first-degree relatives of an affected patient or the presence of one or more premature SCD in the family has always been considered to represent an important risk factor because it is recognised that SCD events often cluster in families.29 Patients receiving an ICD for primary prevention based on a family history

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Potential SCD Modifiers in HCM according to 2011 ACCF/AHA guidelines Left Ventricular Outflow Tract Obstruction at Rest Dynamic LVOTO is reported in approximately 25 % of patients during resting conditions.52,53 A study on 917 patients, including almost one-

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Risk Stratification in Hypertrophic Cardiomyopathy

Figure 1: Flow Chart of the 2011 ACCF/AHA Model for ICD Implantation for Primary Prevention

Single risk factor: FHSCD (first degree relative) or LVWT ≥30 mm or recent unexplained syncope

Yes

ICD is reasonable to recommend

ICD is not recommended

Figure 2: Flow Chart of 2014 ESC Model for ICD Implantation for Primary Prevention

HCM RISK-SCD variables: • Age • FHSCD • Unexplained syncope • LVOTO • Maximum LVWT • Left atrial diameter • NSVT

No HCM RISK-SCD score

Risk factor: NSVT or ABPRE

Yes

Are other risk factors or potential SCD risk modifiers present? • LVOTO • LGE on CMR • LV apical aneurysm • Genetic mutations

Yes

ICD can be useful

Role of ICD is uncertain

ABPRE = abnormal blood pressure response to exercise; CMR = cardiovascular magnetic resonance; FHSCD = family history of sudden cardiac death (SCD); ICD = implantable cardioverter defibrillator; LGE = late Gadolinium enhancement; LVOTO = left ventricular outflow tract obstruction; LVWT = left ventricular wall thickness; NSVT = non-sustained ventricular tachycardia.

third with LVOTO, demonstrated an association between LVOTO and increased risk of SCD and appropriate ICD discharges over a 61-month median follow-up period.54 The risk of SCD was related to the severity of LVOTO and the presence of other recognised risk factors for SCD. Multivariable analysis demonstrated that LVOTO was an independent predictor of SCD/ICD discharge, with a 2.4-fold increase in the risk of SCD/ICD discharge.54 The role of provocable LVOTO with exercise is unclear and current guidelines do not recommend exercise-induced LVOTO in the risk stratification.30,55

Late Gadolinium Enhancement on CMR Study The past decade has witnessed a burgeoning in the number of articles relating to the role of cardiovascular magnetic resonance (CMR) in HCM.56–76 In one study of 265 patients the quantification of LV mass correlated weakly with maximal wall thickness and was 100 % sensitive in predicting HCM-related mortality, but had a specificity of just 39 %.56 However, most of the interest in CMR is focused on the late enhancement after Gadolinium.57–72 Late Gadolinium enhancement (LGE) probably constitutes areas of myocardial replacement fibrosis and is detected in up to 60–70 % of HCM patients.57–63 As with all other aspects of the disease there is considerable heterogeneity in the extent and pattern of LGE.57–63 Fibrotic remodelling occurs early in disease pathogenesis of HCM but it may also be a secondary phenomenon related to microvascular ischaemia.13–17,64–66 Fibrous tissue represents a principal substrate for re-entrant ventricular arrhythmias and contributes to increased ventricular stiffness.59 A few studies have reported that the presence of LGE is significantly associated with heart failure death and all-cause mortality and is an independent predictor of adverse outcome and disease progression.59–62 In one study of 217 HCM patients the presence of fibrosis was associated with a 3.4-fold risk of major adverse events and the risk was proportional to the extent of

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Low risk 5-year risk <4 %

Intermediate risk 5-year risk ≥4 to <6 %

High risk 5-year risk ≥6 %

ICD generally not indicated

ICD may be considered

ICD should be considered

ABPRE = abnormal blood pressure response to exercise; CMR = cardiovascular magnetic resonance; FHSCD = family history of sudden cardiac death (SCD); ICD = implantable cardioverter defibrillator; LGE = late Gadolinium enhancement; LV = left ventricle; LVOTO = left ventricular outflow tract obstruction; LVWT = left ventricular wall thickness; NSVT = non-sustained ventricular tachycardia.

LGE.59 Another study of 177 HCM patients showed that the presence of LGE may identify patients with increased susceptibility to ventricular tachyarrhythmias on the ambulatory Holter-monitoring (including a sevenfold increase in the risk of NSVT) and even small areas of LGE may be sufficient to promote arrhythmias.68 The significance of LGE in predicting arrhythmogenic SCD remains controversial. A recent metanalysis of four studies evaluating 1,053 patients, over an average follow-up of 3.1 years, concluded that LGE shows a trend towards significance for predicting SCD, but failed to shown a significant independent association.60 The high prevalence of LGE in HCM patients means that it would be impractical to consider it as a risk factor for SCD in isolation although extensive LGE has been shown to be associated with progressive ventricular dilatation and heart failure.58,59,69 Recently, two studies have provided conflicting results regarding the value of the extensive LGE in risk stratification for SCD.63,70 One study included 711 HCM patients, with a median follow-up of 3.5 years and 66 % of patients had LGE.63 The extent of LGE was found to be a strong univariable predictor of SCD, which was not maintained after adjustment for LV ejection fraction.63 The other study included 1,293 HCM patients, with a median follow-up of 3.3 years and presence of LGE in 42 % of patients. SCD events occurred in 37 patients (3 %), including 17 (1.3 %) with appropriate ICD discharge, which was considered equivalent to SCD.70 The extent of LGE was associated with an increased risk of SCD events and in particular LGE ≥15 % of the LV mass demonstrated a twofold increase in SCD event rate in those patients who would otherwise considered be at low risk. The authors concluded that extensive LGE provided additional information for assessing SCD event risk, particularly in HCM patients otherwise judged to be at low risk.70 The major criticism of this study was that even if the statistical analysis appeared to support this statement, the raw data did not.71 In the 20 patients that died suddenly or experienced aborted SCD only one revealed extensive LGE, while in the 17 patients experiencing an appropriate ICD shock, 13 patients had recognised conventional risk factors and

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Cardiomyopathy and Heart Failure from the rest only three had extensive LGE.70 In conclusion, the extent of LGE on CMR has some utility in predicting cardiovascular mortality, but the current data are contradictory and not conclusive in order to support the use of LGE in predicting the risk of arrhythmogenic SCD.30,71 Newer CMR techniques (as T1-mapping) may improve the characterisation of myocardial substrate of the arrhythmias.72–75

Additional Role of Genetics Most sarcomere mutations capable of causing HCM are novel and limited to individual families; therefore, genetic screening is of limited value in risk stratification in most cases.4,5,29,30,76,77 The presence of multiple mutations or specific mutations encoding troponin T and lysosomalassociated membrane protein-2 (LAMP-2) may be indicative of a high risk of fatal events.78–83

Specific Cases Left Ventricular Aneurysm Left ventricular apical aneurysm with regional scarring is considered as a potential risk factor for primary prevention and has recently been reported in a high-risk subset of HCM patients.84 Left ventricular apical aneurysm is rare (approximately in 2 % of HCM patients) and is best characterised by CMR imaging. In one study of 28 patients, almost half of the patients with left ventricular apical aneurysm experienced adverse disease complications (event rate 10.5 %/year), including SCD, appropriate ICD discharges, non-fatal thromboembolic stroke and progressive heart failure and death.84

respectively.22,23 A recent meta-analysis of 16 HCM cohorts reported inappropriate ICD interventions and complication of 4.8 %/year and 3.4 %/year, respectively.25

HCM Risk-SCD Model of the 2014 ESC Guidelines A fundamental problem with the aforementioned risk stratification procedure is the assumption that the significance of all of the risk factors remains static throughout life. Furthermore, important parameters such as LVH or LVOTO, which are contiguous variables, are treated as binary factors (present or absent). The ESC HCM outcome investigators have recently recommended a 5-year risk calculator derived from a model involving a large retrospective longitudinal multicentre experience from 3,675 patients.9,30 Eight clinical parameters were included as pre-specified predictors that were independently associated with SCD in at least one published study of multivariate survival analysis. Of the eight parameters, seven were associated with SCD or an appropriate ICD shock at the 15 % significance level and these were: age, FHSCD, maximal LV wall thickness, left atrial diameter, maximal LVOTO, NSVT and unexplained syncope (see Figure 2). The incorporation of these parameters into the model equation is used to estimate the 5-year risk of SCD for any particular patient. The cut-off level of ≥6 % SCD risk in 5 years is recommended for considering an ICD implant for primary prevention. Individuals with a risk score of <4 % are considered as low risk, whereas those with a risk score of 4–6 % of SCD characterise an intermediate-risk group where ICD may be considered (see Figure 2).

End-stage Phase of HCM End-stage phase of HCM affects 3–8% of individuals and is characterised by progressive thinning of the myocardium with cavity enlargement and impaired systolic function.85,86 The complication is a result of extensive and transmural fibrosis and has a high incidence of SCD with an annual mortality rate exceeding 10 %.85,86 In such patients, prophylactic ICD implantation is a generally accepted clinical practice.29,85,86

2003 ACC/ESC Guidelines versus 2011 ACCF/AHA Guidelines The main disagreement between the US and Europe guidleines is historically based on the number of risk factors required before consideration of an implantation of an ICD for primary prevention.28,29 Given the low positive predictive value of each of the conventional risk factors, the European approach has been to implant an ICD only in the presence of >1 risk factor.28 By contrast, the US approach recommends ICD implantation patients with FHSCD from HCM in a first-degree relative, LV wall thickness ≥30 mm or recent unexplained syncope as isolated risk factors whereas those patients with NSVT or an ABPRE require another risk factor or risk modifier (such as LVOTO, LGE on CMR imaging, LV apical aneurysm or a high-risk genetic mutation)29 (see Figure 1). This difference in approach is partially due to the conflicting results between American and European studies regarding the risk stratification.22,33 Previous American studies have reported that an important proportion of discharges occur in patients implanted with a prophylactic ICD with just one risk factor.22 The European concern is that if ICDs were inserted in all patients with one risk factor the incidence of device complications would surpass the potential benefits.33,34 Although there is no doubt about the value of an ICD in preventing SCD with appropriate discharge rates ranging from 2–3.6 %/year for primary prevention cases and 4.3–10.6 %/ year for secondary prevention cases, the inappropriate shock rate and implant complications range from 16–27 % and 12–18 %,

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The results of this study indicate that the use of this model is superior to prior conventional methods for detecting high-risk individuals previously considered at low or intermediate risk. The model also scores highly for correctly identifying individuals at high risk of SCD.30 The new 2014 ESC risk stratification model is limited to some extent in that it was not validated in paediatric patients (<16 years), in patients with syndromic LVH or in a large population of non-Caucasian individuals. Furthermore the effect of latent LVOTO or the effect of LVOTO reduction by alcohol ablation or myectomy was not tested and very few patients had extreme LVH ≥35 mm.30

Other Potential Risk Factors and Arbitrators not Included in the Current Guidelines A number of electrical, structural and functional markers that can be assessed using simple investigations have been proposed for risk stratification. The fragmentation of the QRS on the ECG has been postulated to predict ventricular arrhythmic events.87,88 A study in 167 patients with a mean follow-up of 6.3 years, fragmentation of the QRS was a strong independent predictor for major arrhythmic events including SCD.87 There are reports that HCM associated with midventricular obstruction (with pressure gradient ≥30 mmHg) may be an independent predictor of adverse outcomes, especially the combined endpoint of SCD and potentially lethal arrhythmic events.89,90 Conversely, apical HCM has been associated with a benign prognosis.91 Myocardial ischaemia that may be caused by small vessel disease or concomitant severe epicardial coronary artery disease has also been considered as possible risk factor.28,92,93 In one study of 433 HCM patients, 27 % had severe epicardial CAD and this was a significant predictor

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for cardiac death and SCD.92 Assessment of coronary microvascular dysfunction is challenging and stress perfusion CMR imaging could have a future role in risk stratification.94–96 Exercise capacity has also been proposed to help risk stratification in different studies.97–99 It has been demonstrated that peak VO2 is associated with an increased risk of major events during short-term follow-up.99 In conclusion, there have been significant advances in the risk stratification of HCM since the disease was first described over 5 decades ago. The heterogeneous nature of the disease and the

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19. 20. 21.

Elliott P, Andersson B, Arbustini E, et al., Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases, Eur Heart J , 2008;29 :270–6. Maron BJ, Towbin JA, Thiene G, et al., American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention, Circulation , 2006;113 :1807–16. Maron BJ, Gardin JM, Flack JM, et al., Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults, Circulation ,1995;92 :785–9. Ackerman MJ, Priori SG, Willems S, et al., HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies, Europace , 2011;13 :1077–109. Charron P, Arad M, Arbustini E, et al., Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, Eur Heart J , 2010;31 :2715–26. Cecchi F, Olivotto I, Montereggi A, Santoro G, et al., Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population, J Am Coll Cardiol , 1995;26 :1529–36. Maron BJ, Olivotto I, Spirito P, et al., Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population, Circulation , 2000;102 :858–64. Elliott PM, Gimeno JR, Thaman R, et al., Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy, Heart , 2006;92 :785–91. O’Mahony C, Jichi F, Pavlou M, et al., Hypertrophic Cardiomyopathy Outcomes Investigators. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD), Eur Heart J , 2014;35 :2010–20. Maron BJ, Shirani J, Poliac LC, et al., Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles, JAMA , 1996;276 :199–204. Corrado D, Basso C, Schiavon M, et al., Screening for hypertrophic cardiomyopathy in young athletes, N Engl J Med , 1998;339 :364–9. de Noronha SV, Sharma S, Papadakis M, et al., Aetiology of sudden cardiac death in athletes in the United Kingdom: a pathological study, Heart , 2009;95 :1409–14. Shirani J, Pick R, Roberts WC, et al., Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death, J Am Coll Cardiol , 2000;35 :36–44. Varnava AM, Elliott PM, Sharma S, et al., Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease, Heart , 2000;84 :476–82. Varnava AM, Elliott PM, Mahon N, et al., Relation between myocyte disarray and outcome in hypertrophic cardiomyopathy, Am J Cardiol , 2001;88 :275–9. Maron BJ, Wolfson JK, Epstein SE, et al., Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy, J Am Coll Cardiol , 1986;8 :545–57. Basso C, Thiene G, Corrado D, et al., Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia, Hum Pathol , 2000;31 :988–98. Cha YM, Gersh BJ, Maron BJ, et al., Electrophysiologic manifestations of ventricular tachyarrhythmias provoking appropriate defibrillator interventions in high-risk patients with hypertrophic cardiomyopathy, J Cardiovasc Electrophysiol , 2007;18 :483–7. O’Mahony C, Elliott PM. Prevention of sudden cardiac death in hypertrophic cardiomyopathy, Heart , 2014;100 :254–60. Sen-Chowdhry S, McKenna WJ, Sudden death from genetic and acquired cardiomyopathies, Circulation , 2012;125 :1563–76. Maron BJ, Shen WK, Link MS, et al., Efficacy of implantable

EUROPEAN CARDIOLOGY REVIEW

Sharma_FINAL.indd 35

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

variation in trigger factors provides an adequate explanation for the low predictive accuracy of most conventional risk factors in isolation. A new risk model for risk stratification proposed by the ESC HCM outcome group shows promise but requires validation in different cohorts. The ICD is the only effective therapy in preventing SCD for the disease with a relatively low adverse event rate, but most deaths occur in relatively young patients. However, it is also difficult to ignore the complications with the ICD, therefore, the strife to perfect risk stratification in HCM should continue to ensure that only the most high-risk patients receive an ICD. n

cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy, N Engl J Med , 2000;342 :365–73. Maron BJ, Spirito P, Shen WK, et al., Implantable cardioverterdefibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy, JAMA , 2007;298 :405–12. O’Mahony C, Lambiase PD, Quarta G, et al., The longterm survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic cardiomyopathy, Heart , 2012;98 :116–25. Syska P, Przybylski A, Chojnowska L, et al., Implantable cardioverter-defibrillator in patients with hypertrophic cardiomyopathy: efficacy and complications of the therapy in long-term follow-up, J Cardiovasc Electrophysiol , 2010;21 :883–9. Schinkel AF, Vriesendorp PA, Sijbrands EJ, et al., Outcome and complications after implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: systematic review and meta-analysis, Circ Heart Fail , 2012;5 :552–9. Lin G, Nishimura RA, Gersh BJ, et al., Device complications and inappropriate implantable cardioverter defibrillator shocks in patients with hypertrophic cardiomyopathy, Heart , 2009;95 :709–14. Elliott PM, Sharma S, Varnava A, et al., Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy, J Am Coll Cardiol , 1999;33 :1596–601. Maron BJ, McKenna WJ, Danielson GK, et al., American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents; European Society of Cardiology Committee for Practice Guidelines. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines, Eur Heart J , 2003;24 :1965–91. Gersh BJ, Maron BJ, Bonow RO, et al., 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Circulation , 2011;124 :e783–831. Elliott PM, Anastasakis A, Borger MA et al., 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC), Eur Heart J , 2014;35 :2733–79. O’Mahony C, Elliott P, McKenna, Sudden cardiac death in hypertrophic cardiomyopathy, Circ Arrhythm Electrophysiol , 2013;6 :443–51. Christiaans I, van Engelen K, van Langen IM, et al., Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers, Europace , 2010;12 :313–21. Elliott PM, Poloniecki J, Dickie S, et al., Sudden death in hypertrophic cardiomyopathy: identification of high risk patients, J Am Coll Cardiol , 2000;36 :2212–8 O’Mahony C, Tome-Esteban M, Lambiase PD, et al., A validation study of the 2003 American College of Cardiology/ European Society of Cardiology and 2011 American College of Cardiology Foundation/American Heart Association risk stratification and treatment algorithms for sudden cardiac death in patients with hypertrophic cardiomyopathy, Heart , 2013;99 :534–41. Olivotto I, Maron BJ, Montereggi A, et al., Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol , 1999;33 :2044. Olivotto I, Gistri R, Petrone P, et al., Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy, J Am Coll Cardiol , 2003;41 :315–21. Monserrat L, Elliott PM, Gimeno JR, et al., Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients, J Am Coll Cardiol , 2003;42 :873–9. Spirito P, Autore C, Rapezzi C, et al., Syncope and risk of sudden death in hypertrophic cardiomyopathy, Circulation , 2009;119 :1703–10. Maron BJ, Rowin EJ, Casey SA, et al., Risk stratification and outcome of patients with hypertrophic cardiomyopathy ≥60

years of age, Circulation , 2013;127 :585–93. 40. Saumarez RC, Pytkowski M, Sterlinski M, et al., Paced ventricular electrogram fractionation predicts sudden cardiac death in hypertrophic cardiomyopathy, Eur Heart J , 2008;29 :1653–61. 41. Bos JM, Maron BJ, Ackerman MJ, et al., Role of family history of sudden death in risk stratification and prevention of sudden death with implantable defibrillators in hypertrophic cardiomyopathy, Am J Cardiol , 2010;106 :1481–6. 42. Takagi E, Yamakado T, Nakano T, Prognosis of completely asymptomatic adult patients with hypertrophic cardiomyopathy, J Am Coll Cardiol , 1999;33 :206–11. 43. Kofflard MJ, Ten Cate FJ, van der Lee C, et al., Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration, J Am Coll Cardiol , 2003;41 :987–93. 44. Spirito P, Bellone P, Harris KM, et al., Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy, N Engl J Med , 2000;342 :1778–85. 45. Elliott PM, Gimeno Blanes JR, Mahon NG, et al., Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy, Lancet , 2001;357 :420–4. 46. Maron BJ, Spirito P, Ackerman MJ, et al., Prevention of sudden cardiac death with implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy, J Am Coll Cardio l, 2013;61 :1527–35. 47. Gimeno JR, Tomé-Esteban M, Lofiego C, et al., Exerciseinduced ventricular arrhythmias and risk of sudden cardiac death in patients with hypertrophic cardiomyopathy, Eur Heart J , 2009;30 :2599–605. 48. Spirito P, Rapezzi C, Autore C, et al., Prognosis of asymptomatic patients with hypertrophic cardiomyopathy and nonsustained ventricular tachycardia, Circulation , 1994;90 :2743–7. 49. Ciampi Q, Betocchi S, Lombardi R, et al., Hemodynamic determinants of exercise-induced abnormal blood pressure response in hypertrophic cardiomyopathy, J Am Coll Cardiol , 2002;40 :278–84. 50. Sadoul N, Prasad K, Elliott PM, et al., Prospective prognostic assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy, Circulation , 1997;96 :2987–91. 51. Maki S, Ikeda H, Muro A, et al., Predictors of sudden cardiac death in hypertrophic cardiomyopathy, Am J Cardiol , 1998;82 :774–8. 52. Autore C, Bernabò P, Barillà CS, et al., The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms, J Am Coll Cardiol , 2005;45 :1076–80. 53. Maron MS, Olivotto I, Betocchi S, et al., Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy, N Engl J Med , 2003;348 :295–303. 54. Elliott PM, Gimeno JR, Tomé MT, et al., Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy, Eur Heart J , 2006;27 :1933–41. 55. Maron MS, Olivotto I, Zenovich AG, et al., Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction, Circulation , 2006;114 :2232–9. 56. Olivotto I, Maron MS, Autore C, et al., Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy, J Am Coll Cardiol , 2008;52 :559–66. 57. Moon JC, Reed E, Sheppard MN, et al., The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy, J Am Coll Cardiol , 2004;43 :2260–4. 58. Moon JC, McKenna WJ, McCrohon JA, et al., Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance, J Am Coll Cardiol , 2003;41 :1561–7. 59. O’Hanlon R, Grasso A, Roughton M, et al., Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy, J Am Coll Cardiol , 2010;56 :867–74. 60. Green JJ, Berger JS, Kramer CM, et al., Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy, JACC Cardiovasc Imaging , 2012;5 :370–7. 61. Lyons KS, Dixon LJ, Johnston N, et al., Late gadolinium

29/07/2015 22:06

Cardiomyopathy and Heart Failure

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

enhancement is common in patients with hypertrophic cardiomyopathy and no clinical risk factors for sudden cardiac death: A single center experience, Cardiol J , 2014;21 :29–32. Bruder O, Wagner A, Jensen CJ, et al., Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy, J Am Coll Cardiol , 2010;56 :875–87. Ismail TF, Jabbour A, Gulati A, et al., Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy, Heart , 2014;100 :1851–8. Ho CY, Abbasi SA, Neilan TG, et al., T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy, Circ Cardiovasc Imaging , 2013;6 :415–22. Ho CY, López B, Coelho-Filho OR, et al., Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy, N Engl J Med , 2010;363 :552–63. Kwon DH, Smedira NG, Rodriguez ER, et al., Cardiac magnetic resonance detection of myocardial scarring in hypertrophic cardiomyopathy: correlation with histopathology and prevalence of ventricular tachycardia, J Am Coll Cardiol , 2009;54 :242–9. Kwon DH, Setser RM, Popović ZB, et al., Association of myocardial fibrosis, electrocardiography and ventricular tachyarrhythmia in hypertrophic cardiomyopathy: a delayed contrast enhanced MRI study, Int J Cardiovasc Imaging , 2008;24 :617–25. Adabag AS, Maron BJ, Appelbaum E, et al., Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance, J Am Coll Cardiol , 2008;51 :1369–74. Olivotto I, Maron BJ, Appelbaum E, et al., Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy, Am J Cardiol , 2010;106 :261–7. Chan RH, Maron BJ, Olivotto I, et al., Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy, Circulation , 2014;130 :484–95. McKenna WJ, Nagueh SF, Cardiac magnetic resonance imaging and sudden death risk in patients with hypertrophic cardiomyopathy, Circulation , 2014;130 :455–7. Dass S, Suttie JJ, Piechnik SK, et al., Myocardial tissue characterization using magnetic resonance noncontrast t1 mapping in hypertrophic and dilated cardiomyopathy, Circ Cardiovasc Imaging , 2012;5 :726–33. McGill LA, Ismail TF, Nielles-Vallespin S, et al., Reproducibility

Sharma_FINAL.indd 36

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

of in-vivo diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy, J Cardiovasc Magn Reson , 2012;14 :86. Wong TC, Cardiovascular Magnetic Resonance Imaging of Myocardial Interstitial Expansion in Hypertrophic Cardiomyopathy, Curr Cardiovasc Imaging Rep , 2014;7 :9267. Ellims AH, Iles LM, Ling LH, et al., A comprehensive evaluation of myocardial fibrosis in hypertrophic cardiomyopathy with cardiac magnetic resonance imaging: linking genotype with fibrotic phenotype, Eur Heart J Cardiovasc Imaging , 2014;15 :1108–16. Arad M, Monserrat L, Haron-Khun S, et al., Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic, Isr Med Assoc J , 2014;16 :707–13. Calore C, De Bortoli M, Romualdi C, et al., A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life, J Med Genet , 2015;52 :338–47. Gimeno JR, Monserrat L, Pérez-Sánchez I, et al., Hypertrophic cardiomyopathy. A study of the troponin-T gene in 127 Spanish families, Rev Esp Cardiol , 2009;62 :1473–7. Revera M, Van der Merwe L, Heradien M, et al., Long-term follow-up of R403WMYH7 and R92WTNNT2 HCM families: mutations determine left ventricular dimensions but not wall thickness during disease progression, Cardiovasc J Afr , 2007;18 :146–53. Maron BJ, Roberts WC, Arad M, et al., Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy, JAMA , 2009;301 :1253–9. Maron BJ, Maron MS, Semsarian C, Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors, Heart Rhythm , 2012;9 :57–63. Ingles J, Doolan A, Chiu C, et al., Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling, J Med Genet , 2005;42 :e59. Wang J, Wang Y, Zou Y, et al., Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy, Eur J Heart Fail , 2014;16 :950–7. Maron MS, Finley JJ, Bos JM, et al., Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy, Circulation , 2008;118 :1541–9. Harris KM, Spirito P, Maron MS, et al., Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy, Circulation , 2006;114 :216–25. Kawarai H, Kajimoto K, Minami Y, et al., Risk of sudden death in end-stage hypertrophic cardiomyopathy, J Card Fail , 2011;17 :459–64.

87. Femenía F, Arce M, Van Grieken J, et al., Fragmented QRS in Hypertrophic Obstructive Cardiomyopathy (FHOCM) Study Investigators. Fragmented QRS as a predictor of arrhythmic events in patients with hypertrophic obstructive cardiomyopathy, J Interv Card Electrophysiol , 2013;38 :159–65. 88. Kang KW, Janardhan AH, Jung KT, et al., Fragmented QRS as a candidate marker for high-risk assessment in hypertrophic cardiomyopathy, Heart Rhythm , 2014;11 :1433–40. 89. Minami Y, Kajimoto K, Terajima Y, et al., Clinical implications of midventricular obstruction in patients with hypertrophic cardiomyopathy, J Am Coll Cardiol , 2011;57 :2346–55. 90. Efthimiadis GK, Pagourelias ED, Parcharidou D, et al., Clinical characteristics and natural history of hypertrophic cardiomyopathy with midventricular obstruction, Circ J , 2013;77 :2366–74. 91. Eriksson MJ, Sonnenberg B, Woo A, et al., Long-term outcome in patients with apical hypertrophic cardiomyopathy, J Am Coll Cardiol , 2002;39 :638–45. 92. Sorajja P, Ommen SR, Nishimura RA, et al., Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease, Circulation , 2003;108 :2342–8. 93. Maron MS, Olivotto I, Maron BJ, et al., The case for myocardial ischemia in hypertrophic cardiomyopathy, J Am Coll Cardiol , 2009;54 :866–75. 94. Petersen SE, Jerosch-Herold M, Hudsmith LE, et al., Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging, Circulation , 2007;115 :2418–25. 95. Gyllenhammar T, Fernlund E, Jablonowski R, et al., Young patients with hypertrophic cardiomyopathy, but not subjects at risk, show decreased myocardial perfusion reserve quantified with CMR, Eur Heart J Cardiovasc Imaging , 2014;15 :1350–7. 96. Huang L, Han R, Ai T, Sun Z, et al., Assessment of coronary microvascular dysfunction in hypertrophic cardiomyopathy: first-pass myocardial perfusion cardiovascular magnetic resonance imaging at 1.5 T, Clin Radiol , 2013;68 :676–82. 97. Peteiro J, Bouzas-Mosquera A, Fernandez X, et al., Prognostic value of exercise echocardiography in patients with hypertrophic cardiomyopathy, J Am Soc Echocardiogr , 2012;25 :182–9. 98. Desai MY, Bhonsale A, Patel P, et al., Exercise echocardiography in asymptomatic HCM: exercise capacity, and not LV outflow tract gradient predicts long-term outcomes, JACC Cardiovasc Imaging , 2014;7 :26–36. 99. Finocchiaro G, Haddad F, Knowles JW, et al., Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment, JACC Heart Fail , 2015;3 :408–18.

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Cardiomyopathy and Heart Failure

Novel Biomarkers in Heart Failure Beyond Natriuretic Peptides — The Case for Soluble ST2 A n t o n i o J Va l l e j o - Va z Cardiovascular Sciences, Cardiovascular and Cell Sciences Research Institute, St George’s University of London, London, UK

Abstract Despite more effective management of heart failure over the past few decades, its burden as a chronic disease has grown and is expected to continue to rise, representing a major health problem for years to come. Having reliable tools for early diagnosis and risk stratification can help managing the condition more efficiently. In this context, the interest for biomarkers has increased considerably in the last years following the useful clinical role of B-type natriuretic peptides. These biomarkers have been extensively studied and have become established diagnostic and prognostic biomarkers in heart failure. Despite their usefulness, limitations still remain a problem in clinical practice and the search for new biomarkers has therefore continued. Amongst the most promising newer biomarkers, soluble ST2 deserves further consideration. The present review will focus on the role of this new biomarker in the context of heart failure.

Keywords Heart failure, biomarkers, soluble ST2, interleukin-33 Disclosure: The author has no conflicts of interest to declare. Received: 5 November 2014 Accepted: 26 January 2015 Citation: European Cardiology Review, 2015;10(1):37–41 Correspondence: Antonio J Vallejo-Vaz, Cardiovascular Sciences Department, Cardiovascular and Cell Sciences Research Institute, St George’s University of London, Cranmer Terrace, SW17 0RE, London, UK. E: avallejo@sgul.ac.uk

Heart Failure – A Major Global Health Problem Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in developed countries and its burden is progressively increasing.1–4 Coronary artery disease (CAD) and other conditions, such as hypertensive heart disease or diabetes mellitus, are rated among the foremost reasons for morbi-mortality worldwide.1–4 In this context, heart failure (HF) has emerged as an extremely important condition that appears to be reaching epidemic proportions. The reported prevalence and incidence of HF varies depending on the studies considered, the definitions used, subjects included in studies and quality of data recorded.5,6 An overall prevalence of 1–2 % has generally been reported in western countries,5–7 and this is considerably higher in the elderly i.e. >10 %.6,8 From the Framingham Heart Study it has been estimated that in the general population the lifetime risk of developing HF at the age of 40 is as high as 20–21 %,9 and these figures were reported by the Chicago Heart Association Detection Project in Industry (CHA) and the Cardiovascular Health Study (CHS)10 to be even higher (20 % to 42 % at age 45, depending on gender and race). Progressively better and more-effective management of HF in the last decades has improved patient survival but its incidence has remained stable;5,7 hence the burden imposed by HF, as a chronic disease, on both health systems and the individual, has increased, affecting mainly the elderly.5–7 Despite a reduction in hospitalisation and mortality rates in the past years, these remain high.5–7,11 Indeed, age- and sex-standardised hospitalisation rates of 468 and 1,359 per 100,000 people for primary and secondary HF, respectively, have been reported in the US in 2009.11 Moreover, in the population-based Rotterdam Study, survival rates after incident HF in subjects ≥55 years old were 86 %, 63 %, 51 % and 35 % at 30 days and 1, 2 and 5 years of follow-up, respectively.8 These data underscore the importance of HF as a

Vallejo_FINAL.indd 37

major global health problem and the need for having reliable and accurate tools that facilitate decisions regarding its prevention, management and outcomes. In this context, the interest in identifying novel biomarkers that can aid diagnosis, risk stratification, prognosis and treatment strategies, has grown considerably in recent years.

Biomarkers in Heart Failure HF is primarily diagnosed in the presence of symptoms and signs that, in many cases, are non-specific.7,12 Symptoms of HF result from an impairment in the normal heart function as a consequence of structural or functional disorders affecting ventricular filling and/or blood ejection.7,12 Recently, biomarkers such as brain natriuretic peptide (BNP) or amino-terminal pro-brain natriuretic peptide (NT-proBNP) have emerged, which appear to represent an important tool for diagnosis, risk stratification and prognosis.7,12 A biomarker has been defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.13 Although this definition is wide and can include any measured parameter, the term ‘biomarker’ is more commonly used in relation to biological substances that are detected in body fluids. Figure 1 summarises the characteristics that make a biomarker useful in clinical practice in the context of CVD and HF.14–18

Natriuretic Peptides Based on the results of studies such as the Breathing Not Properly Multinational Study,19 ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE),20,21 Rapid Emergency Department Heart failure Outpatient Trial (REDHOT),22 Valsartan Heart Failure Trial (Val-HeFT),23 Groenning et al.24 or the International Collaborative of NT-proBNP Study,25

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Cardiomyopathy and Heart Failure Figure 1: Summary of the Proposed Characteristics for a Biomarker to be Useful in Clinical Practice in the Context of Cardiovascular Disease and Heart Failure • Should reflect important underlying pathophysiological mechanisms playing a role at any stage of the disease; concentrations should be proportionate to HF stage and specific for the condition • Should be carefully evaluated and validated in clinical trials via rigorous statistical analysis in a wide range of subjects, including communitybased population studies; should show a consistent association with the condition and patient outcomes • Should have acceptable sensitivity, specificity and predictive values (for diagnosis) and appropriate risk ratios, and discrimination and calibration indexes (for prognosis) • Analytical procedures should be validated and standardised, and measurements be accurate and reproducible, with low analytical imprecision, and having a defined biological variation and validated decision cut-off limits • Should be stable, easy and simple to measure, widely accessible and cost-effective • Should provide new valuable information, over and above that provided by currently used tools Biomarkers can help clinicians to assess different aspects of the condition i.e. assisting in early-detection (i.e. subclinical stage), confirming or rejecting the diagnosis, risk stratification, severity and risk of progression, prognosis, guiding therapy, and monitoring the course of the disease and the response to treatment.14–18

Table 1: Biomarker Classification Based on their Known Pathophysiological Role in Heart Failure*15,16,34,35

practice, some limitations must still be acknowledged. For instance, the optimal cut-off points are still not well-established and different thresholds have been proposed;18,27,31–33 additionally, there is a range of values (a ‘grey zone’) where they are less helpful in decision-making;27,31,32 furthermore, while low NP concentrations make the diagnosis of HF unlikely (high negative predictive value), increased levels can be also a consequence of several cardiac and non-cardiac conditions.7,12,27 Levels of NP can also be affected by factors such as age, obesity, anaemia and renal function.12 In addition, NP are released as a result of myocyte stress caused by pressure or volume overload;16,34,35 therefore, they may not completely reflect other mechanisms within the complex pathophysiology of HF (e.g. renin–angiotensin–aldosteron system; autonomic nervous sytem). Finally, more evidence is needed in relation to the use of NP to guide therapy. This aspect has been approached in different trials comparing a strategy based on BNP or NT-proBNP-guided therapy versus the usual or standard care;36 however, many of these studies were small, lacked power to assess major end-points and their results were not always consistent.12,30,36 More recently, several meta-analyses have suggested that NP-guided therapy strategies could be associated with a reduction in all-cause mortality and HF-related hospitalisations in CHF;30,36–42 this is of interest, but the findings seemed to be influenced by age as it was mainly observed in individuals aged <70–75 years.30,36,39–42 Better understanding of the role of NPs in clinical practice and their contribution to the diagnosis and management of HF in recent years16,18 has stimulated research into newer biomarkers. As an example, Table 1 shows a classification of established and novel biomarkers.15,16,34,35 A multi-marker strategy, covering different and complementary aspects of HF in an integrated algorithm, has been proposed and may improve both diagnostic and prognostic assessment strategies.43–45 The incorporation of newer biomarkers may however potentially increase the complexity of the assessment and costs, a matter that will need to be explored in due course.

Pathophysiological Pathway Myocyte stress

Examples of Biomarkers

natriuretic peptide; MR-proADM; soluble ST2

Myocyte injury

Troponins I and T; creatine kinase MB fraction;

myosin light-chain kinase I; heart-type fatty-acid-

binding protein; pentraxin 3; heat shock proteins

Inflammation

C-reactive protein; TNF-α and TNF-soluble

Soluble ST2 – An Emerging Biomarker

receptors; cytokines (e.g. IL-1, IL-6, IL-18);

adiponectin; soluble ST2; pentraxin 3;

osteoprotegerin; procalcitonin

Oxidative stress

Oxidised low-density lipoprotein; myeloperoxidase;

urinary biopyrrins; isoprostanes; plasma

The interleukin-1 receptor-like 1 (IL1RL1) protein, commonly referred to as ST2 (growth stimulation expressed gene 2), has emerged as a promising novel biomarker for AHF and CHF46–49 and other related conditions, such as CAD50,51 and hypertension.52 While soluble ST2 (sST2) lacks disease specificity, which may limit its role in the diagnosis of HF,53 it may have a role regarding prognosis assessment in HF. The recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines on HF management state that ST2 can provide additive value regarding risk stratification, particularly in patients with acutely decompensated HF (Class IIb, level of evidence A) and those with CHF (Class IIb, level of evidence B).12 sST2 was first described in 1989 by Klemenz et al.54,55 and Tominaga.56 It was independently identified and subsequently designated as T1,54,55 ST,2,56,57 delayed early response gene 4 (DER-4)58 and Fit-1 (the homologue of mouse ST2/ T1 protein).59 The expression of the IL1RL1 gene generates three different messenger RNA (mRNA) isoforms by alternative 3’ splicing: a membrane-bound (ST2L), a secreted (sST2) and a variant (ST2V) protein.57,59–63 ST2L is a transmembrane receptor expressed in the cell surface, having an intracellular domain, a single transmembrane domain and an extracellular domain formed by three immunoglobulin (Ig)-like repeats.57,59,61,64 Like the rest of the members of the IL-1 receptor/toll-like receptor (IL-1R/TLR) superfamily, it has a cytosolic toll/IL-1 receptor (TIR) domain responsible for signalling after receptor activation;64–66 and as part of the type I IL-1 receptor (IL-1RI)-like subfamily, it has extracellular Ig-like domains responsible for ligand binding.64 The sST2 form can be measured in circulating blood and consists of the extracellular domain

BNP; N-terminal pro-BNP; N-terminal pro-atrial

malondialdehyde Neurohormones

Norepinephrine; renin; angiotensin II; aldosterone;

vasopressin/copeptin; endothelin; chromogranins;

adrenomedullin and MR-proADM

Extracellular matrix

MMPs; tissue inhibitors of MMP; collagen

remodelling

propeptides (propeptide procollagen type I,

procollagen type III); galectin-3; soluble ST2; growth

differentiation factor 15

Cardio-renal syndrome Serum creatinine; urinary albumin-to-creatinine

ratio; cystatin-C; neutrophil gelatinase-associated

lipocalin; β-trace protein Others Haemoglobin; serum albumin; red blood cell distribution width; vascular adhesion molecules *Inflammation, oxidative stress, extracellular-matrix remodelling, neurohormones, myocyte stress and injury, cardio-renal syndrome and other metabolic, vascular or extracardiac processes. BNP = brain natriuretic peptide; IL = interleukin; MMP = matrix metalloproteinases; MR-proADM = TNF = tumour necrosis factor.

among others, international guidelines on both acute and chronic HF (AHF/CHF) describe a role for BNP and NT-proBNP in the diagnosis and prognostic assessment of HF.7,12,15,26–29 Additionally, increasing evidence is emerging about a possible role for natriuretic peptides (NP) to guide therapy.12,30 However, despite their usefulness and increasing use in clinical

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only, lacking the transmembrane and intracellular ones; it is considered to act as a decoy receptor, competitively binding IL-33, hence preventing its effect through the ST2L receptor.57,59,61,67–70 The third ST2 form (ST2V) is the result of an inserted nucleotide sequence in the middle of ST2 DNA, leading to the absence of the third Ig-like domain;62 it seemed to have a different expression pattern from sST2 and ST2L,63 and the importance and physiological role of this variant remain unknown.

ST2 and Functional Ligands — Interleukin-33 and IL-33/ST2 Signalling Despite that ST2 was first described in 1989, it was not until 2005 when the IL-33 was identified as its functional ligand.71 Secreted IL-33 mediates its effects in target cells by binding ST2L,66,71,72 as part of the IL-33 receptor (IL-33R) complex; this is a heterodimeric receptor constituted by the ST2L transmembrane protein, which is the ligand-binding subunit, and by the so-called IL-1 receptor accessory protein (IL-1RAcP), which seems to be necessary for the IL-33-mediated signal transduction and its effects in vivo.66,72,73 Once IL-33 binds the IL-33R complex, signalling is induced through the TIR domain, leading to the recruitment of different proteins (e.g. myeloid differentiation primary-response protein 88 [MyD88], IL-1R-associated kinases [IRAK], tumour necrosis factor [TNF] receptorassociated factor 6 [TRAF-6]) and subsequent activation of different signalling pathways (e.g., transcription nuclear factor-κB [NF-κB] pathway, mitogen-activated protein kinases [MAPK] pathway, PI3K/Akt), which ultimately leads to the production and secretion of different inflammatory factors, chemokines and cytokines.67,70,71,73–81 IL-33 is widely expressed in many tissues, including the heart,71,74 and in many cells, including, among others, endothelial and smooth muscle cells, cardiomyocytes, fibroblasts or macrophages.71,74,78,82 A dual role for IL-33 has been described, both as a cytokine released from the cells (cytokine-like, therefore binding ST2L in target cells), and as an intracellular nuclear factor (nuclear factor-like).74,75,79,83 In fact, IL-33 was first described as a nuclear factor with a DNA-binding domain present in endothelial cells.84 A nuclear location of IL-33 has later further confirmed, although the pathophysiological role of IL-33 as a nuclear factor is not well-known;78,82,85–88 different studies have suggested that IL-33 could play a role as a danger endogenous signal, which would be released as an active full-length protein to alert cells of immune system during damage or infection, whereas in case of apoptosis IL-33 would be cleaved and inactivated by caspases, preventing an inflammatory response in case of programmed cell death.74,75,78,79,82,83,89–93 This would be supported by the wide expression of IL-33 in cell types in normal human tissues,71,74,78,79,82,88,89 suggested to be constitutively expressed in the nucleus of several cell types, including human endothelial cells, fibroblasts, cardiomyocytes and coronary artery smooth muscle cells.78,82,88

Soluble ST2 in the Cardiovascular System The expression of ST2 in the cardiovascular system was first described by Weinberg et al. in 2002, when the authors observed that serum levels of ST2 and levels of mRNA ST2 in left ventricular (LV) tissue were significantly increased in rat cardiomyocytes subjected to mechanical strain and in an in vivo model of experimental myocardial infarction (MI) in mice by ligation of a coronary artery compared with controls not subjected to these procedures.94 These experimental results were also supported in humans after studying 69 patients with acute MI randomly selected from the Healing and Early Afterload Reducing Therapy (HEART) study: serum ST2 levels at day 1 were significantly higher compared with those at days 14 and 90, and correlation studies suggested that ST2 might be related with the extent of myocardial injury or biomechanical

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load after MI.94 Later studies have confirmed and expanded these initial findings, demonstrating a cardioprotective effect of IL-33 through ST2 signalling, in both in vitro and in vivo models.67,68,71,76,78,80,86,95 For instance, treatment with IL-33 was found to reduce the infarct volume and fibrosis in rats 15 days after ischaemia-reperfusion injury, as well as to improve echocardiographic and invasive haemodynamic parameters, suggesting that the beneficial structural changes produced by IL-33 may also lead to a better cardiac contractile function.68 Sanada et al. confirmed a role of IL-33/ST2 signalling in controlling cardiomyocyte hypertrophy and cardiac fibrosis in vitro (rat neonatal cardiomyocytes and cardiac fibroblasts subjected to biomechanical strain) and in vivo (pressure overload induced by transverse aortic constriction [TAC]);67 additionally, administration of sST2 decreased the antihypertrophic effect of IL-33 in a dose-dependent manner, and blocking the ST2L receptor with an anti-ST2L monoclonal antibody also eliminated the effects of IL-33, unlike controls.67 These results have been further confirmed in vivo in ST2-null mice, lacking both ST2L and sST2 (ST2-/-) subjected to TAC;67,68 compared with wild-type mice, ST2-null mice showed increased cardiac fibrosis and hypertrophy, macrophage infiltration, impaired echocardiographic parameters (including impaired systolic function or increased left ventricle dilation), increased gene expression of NP or increased mortality; by treating with IL-33, these findings were reduced and survival improved in wild-type mice but not in ST2-/-.67,68 Different mechanisms, such as inhibition of cardiomyocyte apoptosis and increased expression of anti-apoptotic proteins, reduced mast cell density in infarct areas, promotion of a shift towards a Th2 response in lymphocytes, involvement of cardiac stem cells influencing processes as regeneration, differentiation or repairing after injury (autocrine or paracrine signalling), inhibition of cardiac fibroblasts migration or activation of different cytokines expression, among others, have been suggested to be involved in the beneficial effects of the IL-33/ST2 pathway.68,76,78,95 Altogether, data from both in vitro and in vivo models suggest a cardioprotective effect of IL-33 through ST2 signalling: IL-33, mechanically or by injury (ischaemia) induced in both, cardiac fibroblast and cardiomyocytes, and acting as a ligand for the ST2L receptor, would play a favourable cardioprotective role against hypertrophic-, fibrotic- and inflammatory-related signals following mechanical overload or injury; sST2 would act as a decoy receptor that binding IL-33 in blood prevents its action through the ST2L receptor. An atheroprotective role of IL-33 through ST2L signalling, counteracted by sST2, has also been described,69,70,81,96,97 including a reduction in the atherosclerotic lesion size,69 lower macrophage foam cell accumulation in the plaques97 or promotion of angiogenesis.81 A modulatory role of IL-33/ ST2L in the inflammation of atherosclerosis has been proposed to explain these effects, such as promoting a Th1-to-Th2 switch response (Th2mediated immunity),69 increased levels of oxidised-low-density lipoprotein (LDL) antibodies,69 regulation of adhesion molecules70 or an increased activity of T-reg cells.96

Soluble ST2 and Prognosis in Chronic and Acute Heart Failure Soon after its relation to the CV system was described, sST2 was suggested to be associated with prognosis in CHF; in 161 patients with severe CHF (New York Heart Association (NYHA) III-IV, LV ejection fraction [LVEF] <30 %) from the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) study, Weinberg et al. found sST2 changes from baseline to 2 weeks to be significantly associated with mortality or heart transplantation, independent of BNP or proANP;98 in

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Cardiomyopathy and Heart Failure this first study, however, baseline sST2 was not significantly associated with events, unlike BNP.98 Later studies with larger cohorts and longer follow-up, including analyses from the Penn HF Study, CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure) or Val-HeFT studies, among others, have supported higher baseline sST2 to be a predictor of adverse outcomes, such as all-cause, CV or HF death, sudden cardiac death or hospitalisation.46,47,99–102 In these prognostic studies, sST2 levels have been found to be higher in subjects with more advanced disease, such as increased NYHA class, higher NTproBNP or worse renal function;46,101 some studies also suggest its levels to be higher in males,46,99,101 though the effect of gender as well as other factors such as the ethnicity or HF aetiology are not well established. However, the prognostic value of sST2 in CHF seems not to be significantly influenced by renal function.103 The role of sST2 compared with NP remains more controversial. In many of the studies, sST2 was reported to be a significant predictor of adverse events in multivariable adjusted models including NP and it improved risk stratification;46,100–102,104 however, in the CORONA study this relationship was no longer significant after including NTproBNP (together with C-reactive protein) in the models (except for the secondary outcomes of HF death or CV or HF hospitalisation).47 In analyses from Val-HeFT, when NTproBNP was included in the models, sST2 did not add significant prognostic information.99 And in HF-ACTION, sST2 did not improve significantly reclassification of risk in models already containing NTproBNP.101 Most of the prognostic studies in CHF have been focused mainly in patients with systolic HF, with low LVEF (mean/median around 30 %), so its value in HF with preserved LVEF is uncertain; finally, many of them are post hoc analysis or sub-studies from previous larger trials not specifically designed to assess sST2. Apart from CHF, sST2 has been reported to be consistently associated with prognosis in AHF as well as in patients attending the emergency department (ED) with dyspnoea. In a large cohort of over 1,000 subjects presenting with dyspnoea at ED, Socrates et al. found higher sST2 to be predictive of mortality at 1 year even when including NP in multivariable adjusted models (in both all participants with dyspnoea and in those with AHF as the cause for such symptoms).48 This association with mortality was consistently confirmed in other studies;49,105–107 also with

5. 6. 7.

World Health Organization, The top 10 causes of death, Fact sheet No. 310, Updated May 2014. Available at: www.who. int/mediacentre/factsheets/fs310/en (accessed 12 February 2015). Perk J, De Backer G, Gohlke H, et al., European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The fifth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts), Eur Heart J , 2012;33 :1635–701. Roger VL, Go AS, Lloyd-Jones DM, et al., Heart disease and stroke statistics–2012 update: A report from the american heart association, Circulation , 2012;125 :e2–e220. Fuster V, Kelly BB, Epidemiology of cardiovascular disease. In: Fuster V, Kelly BB, eds, Institute of Medicine (US) committee on preventing the global epidemic of cardiovascular disease: Meeting the challenges in developing countries , Washington DC: National Academies Press (US), 2010. Roger VL, Epidemiology of heart failure, Circ Res, 2013;113 :646–59. Mosterd A, Hoes AW, Clinical epidemiology of heart failure, Heart , 2007;93 :1137–46. 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 Heart J , 2012;33 :1787–847. Bleumink GS, Knetsch AM, Sturkenboom MC, et al., Quantifying the heart failure epidemic: Prevalence, incidence rate, lifetime risk and prognosis of heart failure, the

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10.

11.

12.

13.

14. 15.

16. 17.

18.

in-hospital mortality;108 and in the PRIDE study the predictive value remained significant at a longer follow-up of 4 years.109 In these reports, the baseline levels of sST2 have been repeatedly found to be higher in those patients with AHF as the cause of dyspnoea and among decedents during the follow-up than in survivors.48,49,106,108 Likewise, results suggest that its levels are lower in HF with preserve LVEF compared with systolic HF,48,107 though it remained an independent predictor of mortality in both situations.107 Changes in the decompensated status of patients following management and therapy of AHF could have its reflection in the levels of biomarkers. In this respect, serial measurements of sST2 from presentation to a variable time (e.g. first 48 hours,108 admission to discharge110 or baseline to 2 weeks111) have been reported. In these studies, a failure of sST2 levels to decrease from baseline (a certain percentage reduction, again variable depending on the study) has been associated with subsequent mortality108,110 or cardiac events111 in the following months. These observed dynamic changes of sST2 according to the clinical status and response to HF management may suggest a potential role of this biomarker for monitoring the course of the disease and response to therapy,53,111 though this aspect needs to be specifically studied and confirmed.

Summary and Conclusions In the HF context, some biomarkers constitute a valuable tool that can help physicians address more efficiently the management of the different stages of the disease, from early detection and diagnosis to risk prediction and also guiding therapy. While many biomarkers have been studied over the last years, only a few of them have been accepted for use in clinical practice. Nowadays, B-type-related NP are probably the most established biomarkers in clinical practice for both AHF and CHF diagnosis and management. Specific recommendations about their use have been released in international guidelines. However, limitations of these biomarkers for the management of HF do exist and therefore the search for newer biomarkers continues unabated. Some of the novel emerging biomarkers may provide useful additional information over and above that of currently used markers. This may be the case for sST2, for which increasing evidence points toward its utility as a prognostic marker in AHF and CHF. However, more work and studies specifically designed to assess its value in HF are required before ST2 can be incorporated to everyday clinical practice. n

Rotterdam study, Eur Heart J , 2004;25 :1614–9. Lloyd-Jones DM, Larson MG, Leip EP, et al., Lifetime risk for developing congestive heart failure: The Framingham Heart Study, Circulation , 2002;106 :3068–72. Huffman MD, Berry JD, Ning H, et al., Lifetime risk for heart failure among white and black americans: cardiovascular lifetime risk pooling project, J Am Col Cardiol , 2013;61 :1510–7. Blecker S, Paul M, Taksler G, et al., Heart failure-associated hospitalizations in the United States, J Am Col Cardiol , 2013;61 :1259–67. 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;128 :e240–327. Biomarkers Definitions Working Group, Biomarkers and surrogate endpoints: preferred definitions and conceptual framework, Clin Pharmacol Ther , 2001;69 :89–95. Morrow DA, de Lemos JA, Benchmarks for the assessment of novel cardiovascular biomarkers, Circulation , 2007;115 :949–52. Tang WH, Francis GS, Morrow DA, et al., National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines: clinical utilization of cardiac biomarker testing in heart failure, Circulation , 2007;116 :e99–109. van Kimmenade RR, Januzzi JL Jr, Emerging biomarkers in heart failure, Clin Chem , 2012;58 :127–38. Hlatky MA, Greenland P, Arnett DK, et al., Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association, Circulation , 2009;119 :2408–16. Ahmad T, Fiuzat M, Pencina MJ, et al., Charting a roadmap for heart failure biomarker studies, JACC Heart Fail, 2014;2 :477–88.

19. Maisel AS, Krishnaswamy P, Nowak RM, et al., Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure, N Engl J Med , 2002;347 :161–7. 20. Januzzi JL Jr, Sakhuja R, O’Donoghue M, et al., Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department, Arch Int Med , 2006;166 :315–20. 21. Januzzi JL Jr, Camargo CA, Anwaruddin S, et al., The N-terminal pro-BNP investigation of dyspnea in the emergency department (PRIDE) study, Am J Cardiol , 2005;95 :948–54. 22. Maisel A, Hollander JE, Guss D, et al., Primary results of the rapid emergency department heart failure outpatient trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath, J Am Col Cardiol , 2004;44 :1328–33. 23. Anand IS, Fisher LD, Chiang YT, et al., Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the valsartan heart failure trial (Val-HeFT), Circulation , 2003;107 :1278–83. 24. Groenning BA, Raymond I, Hildebrandt PR, et al., Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population, Heart , 2004;90 :297–303. 25. Januzzi JL, van Kimmenade R, Lainchbury J, et al., NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: The international collaborative of NT-proBNP study, Eur Heart J , 2006;27 :330–7.

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26. JCS Joint Working Group, Guidelines for treatment of acute heart failure (JCS 2011), Circ J , 2013;77 :2157–201. 27. Arnold JM, Howlett JG, Dorian P, et al., Canadian cardiovascular society consensus conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or acute decompensation, and use of biomarkers, Can J Cardiol , 2007;23 :21–45. 28. Al-Mohammad A, Mant J, Laramee P, Swain S, Diagnosis and management of adults with chronic heart failure: summary of updated NICE guidance, BMJ , 2010;341 :c4130. 29. 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. 30. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al., Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis, Eur Heart J , 2014;35 :1559–67. 31. Choudhary R, Iqbal N, Khusro F, et al., Heart failure biomarkers, J Cardiovasc Transl Res , 2013;6 :471–4. 32. Scali MC, Simioniuc A, Dini FL, Marzilli M, The potential value of integrated natriuretic peptide and echo-guided heart failure management, Cardiovasc Ultrasound , 2014;12 :27. 33. Araujo JP, Azevedo A, Lourenco P, et al., Intraindividual variation of amino-terminal pro-B-type natriuretic peptide levels in patients with stable heart failure, Am J Cardiol , 2006;98 :1248–50. 34. Braunwald E, Biomarkers in heart failure, N Engl J Med , 2008;358 :2148–59. 35. Ahmad T, Fiuzat M, Felker GM, O’Connor C, Novel biomarkers in chronic heart failure, Nat Rev Cardiol , 2012;9 :347–59. 36. Xin W, Lin Z, Mi S, Does B-type natriuretic peptide-guided therapy improve outcomes in patients with chronic heart failure? A systematic review and meta-analysis of randomized controlled trials, Heart Fail Rev , 2015;20 :69–80. 37. Balion C, McKelvie R, Don-Wauchope AC, et al., B-type natriuretic peptide-guided therapy: a systematic review, Heart Fail Rev , 2014;19 :553–64. 38. De Vecchis R, Esposito C, Di Biase G, et al., B-type natriuretic peptide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a systematic review with meta-analysis, J Cardiovasc Med (Hagerstown) , 2014;15 :122–34. 39. Savarese G, Trimarco B, Dellegrottaglie S, et al., Natriuretic peptide-guided therapy in chronic heart failure: a metaanalysis of 2,686 patients in 12 randomized trials, PLoS One , 2013;8 :e58287. 40. Li P, Luo Y, Chen YM, B-type natriuretic peptide-guided chronic heart failure therapy: a meta-analysis of 11 randomised controlled trials, Heart Lung Circ , 2013;22 :852–60. 41. Porapakkham P, Zimmet H, Billah B, Krum H, B-type natriuretic peptide-guided heart failure therapy: a metaanalysis, Arch Int Med , 2010;170 :507–14. 42. Felker GM, Hasselblad V, Hernandez AF, O’Connor CM, Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials, Am Heart J , 2009;158 :422–30. 43. Bahrmann P, Bahrmann A, Hofner B, et al., Multiple biomarker strategy for improved diagnosis of acute heart failure in older patients presenting to the emergency department, Eur Heart J Acute Cardiovasc Care , 2014 [Epub ahead of print]. 44. Bjurman C, Jensen J, Petzold M, et al., Assessment of a multimarker strategy for prediction of mortality in older heart failure patients: a cohort study, BMJ Open , 2013;3 :e002254. 45. Ky B, French B, Levy WC, et al., Multiple biomarkers for risk prediction in chronic heart failure, Circ Heart Fail , 2012;5 :183–90. 46. Ky B, French B, McCloskey K, et al., High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure, Circ Heart Fail, 2011;4 :180–7. 47. Broch K, Ueland T, Nymo SH, et al., Soluble ST2 is associated with adverse outcome in patients with heart failure of ischaemic aetiology, Eur J Heart Fail , 2012;14 :268–77. 48. Socrates T, deFilippi C, Reichlin T, et al., Interleukin family member ST2 and mortality in acute dyspnoea, J Intern Med , 2010;268 :493–500. 49. Januzzi JL Jr, Peacock WF, Maisel AS, et al., Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (pro-brain natriuretic peptide investigation of dyspnea in the emergency department) study, J Am Col Cardiol, 2007;50 :607–13. 50. Kohli P, Bonaca MP, Kakkar R, et al., Role of ST2 in non-STelevation acute coronary syndrome in the MERLIN-TIMI 36 trial, Clin Chem , 2012;58 :257–66. 51. Sabatine MS, Morrow DA, Higgins LJ, et al., Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction, Circulation , 2008;117 :1936–44. 52. Ho JE, Larson MG, Ghorbani A, et al., Soluble ST2 predicts elevated SBP in the community, J Hypertens , 2013;31 :1431–6. 53. Dieplinger B, Mueller T, Soluble ST2 in heart failure, Clin Chim Acta , 2014; in press. 54. Klemenz R, Hoffmann S, Werenskiold AK, Serum- and

EUROPEAN CARDIOLOGY REVIEW

Vallejo_FINAL.indd 41

55.

56.

57.

58.

59.

60.

61. 62.

63.

64. 65. 66.

67.

68.

69. 70.

71.

72.

73.

74.

75.

76. 77.

78.

79. 80.

81.

82.

83.

oncoprotein-mediated induction of a gene with sequence similarity to the gene encoding carcinoembryonic antigen, Proc Nat Acad Sci U S A, 1989;86 :5708–12. Werenskiold AK, Hoffmann S, Klemenz R, Induction of a mitogen-responsive gene after expression of the Ha-ras oncogene in NIH 3T3 fibroblasts, Mol Cell Biol , 1989;9 :5207–14. Tominaga S, A putative protein of a growth specific cdna from balb/c-3t3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor, FEBS Letters , 1989;258 :301–4. Yanagisawa K, Takagi T, Tsukamoto T, et al., Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin 1 receptor type 1, FEBS Letters , 1993;318 :83–7. Lanahan A, Williams JB, Sanders LK, Nathans D, Growth factor-induced delayed early response genes, Mol Cell Biology , 1992;12 :3919–29. Bergers G, Reikerstorfer A, Braselmann S, et al., Alternative promoter usage of the fos-responsive gene fit-1 generates mRNA isoforms coding for either secreted or membranebound proteins related to the IL-1 receptor, EMBO J , 1994;13 :1176–88. Tominaga S, Yokota T, Yanagisawa K, et al., Nucleotide sequence of a complementary DNA for human ST2, Biochim Biophys Acta , 1992;1171 :215–8. Li H, Tago K, Io K, et al., The cloning and nucleotide sequence of human ST2L cDNA, Genomics , 2000;67 :284–90. Tominaga S, Kuroiwa K, Tago K, et al., Presence and expression of a novel variant form of ST2 gene product in human leukemic cell line ut-7/gm, Biochem Biophys Res Commun , 1999;264 :14–8. Tago K, Noda T, Hayakawa M, et al., Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V, Biochem Biophys Res Commun , 2001;285 :1377–83. O’Neill LA, The interleukin-1 receptor/toll-like receptor superfamily: 10 years of progress, Immunol Rev, 2008;226:10–18. Arend WP, Palmer G, Gabay C, IL-1, IL-18, and ILl-33 families of cytokines, Immunol Rev , 2008;223 :20–38. Chackerian AA, Oldham ER, Murphy EE, et al., IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex, J Immunol, 2007;179 :2551–5. Sanada S, Hakuno D, Higgins LJ, et al., IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system, J Clin Invest , 2007;117 :1538–49. Seki K, Sanada S, Kudinova AY, et al., Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling, Circ Heart Fail , 2009;2 :684–91. Miller AM, Xu D, Asquith DL, et al., IL-33 reduces the development of atherosclerosis, J Exp Med , 2008;205 :339–46. Demyanets S, Konya V, Kastl SP, et al., Interleukin-33 induces expression of adhesion molecules and inflammatory activation in human endothelial cells and in human atherosclerotic plaques, Arterioscler Thromb Vasc Biol, 2011;31 :2080–9. Schmitz J, Owyang A, Oldham E, et al., IL-33, an interleukin-1like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, Immunity, 2005;23 :479–90. Palmer G, Lipsky BP, Smithgall MD, et al., The IL-1 receptor accessory protein (acp) is required for IL-33 signaling and soluble acp enhances the ability of soluble ST2 to inhibit IL-33, Cytokine , 2008;42 :358–64. Ali S, Huber M, Kollewe C, et al., IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells, Proc Natl Acad Sci U S A , 2007;104 :18660–5. Liew FY, Pitman NI, McInnes IB, Disease-associated functions of IL-33: The new kid in the IL-1 family, Nat Rev Immunol , 2010;10 :103–10. Miller AM, Liew FY, The IL-33/ST2 pathway – a new therapeutic target in cardiovascular disease, Pharmacol Ther , 2011;131 :179–86. Zhu J, Carver W, Effects of interleukin-33 on cardiac fibroblast gene expression and activity, Cytokine , 2012;58 :368–79. Funakoshi-Tago M, Tago K, Hayakawa M, et al., TRAF6 is a critical signal transducer in IL-33 signaling pathway, Cell Signal , 2008;20 :1679–86. Demyanets S, Kaun C, Pentz R, et al., Components of the interleukin-33/ST2 system are differentially expressed and regulated in human cardiac cells and in cells of the cardiac vasculature, J Mol Cel Cardiol , 2013;60 :16–26. Miller AM, Role of IL-33 in inflammation and disease, J Inflamm (Lond), 2011;8:22. Yndestad A, Marshall AK, Hodgkinson JD, et al., Modulation of interleukin signalling and gene expression in cardiac myocytes by endothelin-1, Int J Biochem Cell Biol, 2010;42 :263–72. Choi YS, Choi HJ, Min JK, et al., Interleukin-33 induces angiogenesis and vascular permeability through ST2/ TRAF6-mediated endothelial nitric oxide production, Blood, 2009;114:3117–26. Moussion C, Ortega N, Girard JP, The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: A novel ‘alarmin’?, PloS One, 2008;3:e3331. Haraldsen G, Balogh J, Pollheimer J, et al., Interleukin-33 cytokine of dual function or novel alarmin?, Trends Immunol ,

2009;30 :227–33. 84. Baekkevold ES, Roussigne M, Yamanaka T, et al., Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules, Am J Pathol , 2003;163 :69–79. 85. Carriere V, Roussel L, Ortega N, et al., IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo , Proc Natl Acad Sci U S A , 2007;104 :282–7. 86. Kakkar R, Hei H, Dobner S, Lee RT, Interleukin 33 as a mechanically responsive cytokine secreted by living cells, J Biol Chem , 2012;287 :6941–8. 87. Roussel L, Erard M, Cayrol C, Girard JP, Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2a-H2b acidic pocket, EMBO Rep, 2008;9 :1006–12. 88. Kuchler AM, Pollheimer J, Balogh J, et al., Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation, Am J Pathol , 2008;173 :1229–42. 89. Lefrancais E, Cayrol C, Mechanisms of IL-33 processing and secretion: Differences and similarities between IL-1 family members, Eur Cytokine Netw , 2012;23 :120–7. 90. Luthi AU, Cullen SP, McNeela EA, et al., Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases, Immunity , 2009;31 :84–98. 91. Cayrol C, Girard JP, The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1, Proc Natl Acad Sci U S A , 2009;106 :9021–6. 92. Ali S, Nguyen DQ, Falk W, Martin MU, Caspase 3 inactivates biologically active full length interleukin-33 as a classical cytokine but does not prohibit nuclear translocation, Biochem Biophys Res Commun , 2010;391 :1512–6. 93. Lamkanfi M, Dixit VM, IL-33 raises alarm, Immunity , 2009;31 :5–7. 94. Weinberg EO, Shimpo M, De Keulenaer GW, et al., Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction, Circulation , 2002;106 :2961–6. 95. Stastna M, Chimenti I, Marban E, Van Eyk JE, Identification and functionality of proteomes secreted by rat cardiac stem cells and neonatal cardiomyocytes, Proteomics , 2010;10 :245–53. 96. Wasserman A, Ben-Shoshan J, Entin-Meer M, et al., Interleukin-33 augments Treg cell levels: A flaw mechanism in atherosclerosis, Isr Med Assoc J , 2012;14 :620–3. 97. McLaren JE, Michael DR, Salter RC, et al., IL-33 reduces macrophage foam cell formation, J Immunol , 2010;185 :1222–9. 98. Weinberg EO, Shimpo M, Hurwitz S, et al., Identification of serum soluble ST2 receptor as a novel heart failure biomarker, Circulation , 2003;107 :721–6. 99. Anand IS, Rector TS, Kuskowski M, et al., Prognostic value of soluble ST2 in the valsartan heart failure trial, Circ Heart Fail , 2014;7 :418–26. 100. Gaggin HK, Szymonifka J, Bhardwaj A, et al., Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure, JACC Heart Fail , 2014;2 :65–72. 101. Felker GM, Fiuzat M, Thompson V, et al., Soluble ST2 in ambulatory patients with heart failure: association with functional capacity and long-term outcomes, Circ Heart Fail , 2013;6 :1172–9. 102. Lupon J, de Antonio M, Galan A, et al., Combined use of the novel biomarkers high-sensitivity troponin T and ST2 for heart failure risk stratification vs conventional assessment, Mayo Clin Proc , 2013;88 :234–43. 103. Bayes-Genis A, Zamora E, de Antonio M, et al., Soluble ST2 serum concentration and renal function in heart failure, J Card Fail , 2013;19 :768–75. 104. Pascual-Figal DA, Ordonez-Llanos J, Tornel PL, et al., Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction, J Am Col Cardiol , 2009;54 :2174–9. 105. Mueller T, Dieplinger B, Gegenhuber A, et al., Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failure, Clin Chem , 2008;54 :752–6. 106. Dieplinger B, Gegenhuber A, Kaar G, et al., Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department, Clin Biochem , 2010;43 :714–9. 107. Manzano-Fernandez S, Mueller T, Pascual-Figal D, et al., Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction, Am J Cardiol , 2011;107 :259–67. 108. Breidthardt T, Balmelli C, Twerenbold R, et al., Heart failure therapy-induced early ST2 changes may offer long-term therapy guidance, J Card Fail , 2013;19 :821–8. 109. Januzzi JL Jr, Rehman S, Mueller T, et al., Importance of biomarkers for long-term mortality prediction in acutely dyspneic patients, Clin Chem , 2010;56 :1814–21. 110. Boisot S, Beede J, Isakson S, et al., Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure, J Cardiac Fail , 2008;14 :732–8. 111. Bayes-Genis A, Pascual-Figal D, Januzzi JL, et al., Soluble ST2 monitoring provides additional risk stratification for outpatients with decompensated heart failure, Rev Esp Cardiol (Engl Ed) , 2010;63:1171–8.

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Cardiomyopathy and Heart Failure

LE ATION.

Diuretic Therapy in Heart Failure – Current Approaches G a v i n o Ca s u a n d Pi e r l u i g i M e r e l l a San Francesco Nuoro Hospital, Nuoro, Italy

Abstract The use of diuretics is common in patients with heart failure (HF), to relieve the congestive symptoms of HF. Although they are widely used, there are limited data on their ability to modulate HF-related morbidity and mortality. Diuretic efficacy may be limited by adverse neurohormonal activation and by ‘congestion-like’ symptoms. Diuretics are an extremely useful and varied class of agent for the management of hypervolaemic states. This review summarises the basic features of diuretics, including their mechanism of action, indications and adverse effects in heart failure.

Keywords Heart failure, diuretic therapy, diuretic resistance, loop diuretics, thiazide diuretics, potassium-sparing diuretics Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors want to thank Dr Paola Berne for helpful discussions during the writing of this paper. Received: 5 May 2015 Accepted: 5 July 2015 Citation: European Cardiology Review, 2015;10(1):42–7 Correspondence: Gavino Casu, Cardiology Department, San Francesco Nuoro Hospital, Via Mannironi 1, 08100 Nuoro, Italy. E: gavicasu@tin.it

Heart failure (HF) is a syndrome defined by the 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),1 secondary to an abnormality of the cardiac structure or function. HF is the most common cause of hospitalisation in patients over the age of 65.2 The main manifestations of the syndrome are symptoms resulting from vascular congestion, such as shortness of breath, abdominal distension, oedema formation and symptoms resulting from low systemic perfusion. HF syndrome is of relevant economic importance and in the ADHERE study signs and symptoms of congestion were the most frequent cause of hospital admission.1 Congestion often develops gradually before admission and many patients may have elevated left ventricular (LV) filling pressures even when congestion (dyspnoea, jugular venous distension or oedema)3 is absent. Diuretic therapy, and especially loop diuretic therapy, are the usual way of managing congestion, especially in volumeoverloaded patients.4 The most commonly used diuretics in HF are loop diuretics, thiazides and potassium-sparing diuretics. This review focuses on the classes of diuretics, their role in cases of HF with volume overload and current approaches when treating this complex subset of patients.

Class of Diuretics Loop Diuretics Loop diuretics, reversibly, inhibit the Na+⁄2Cl-⁄K+ co-transporter of the thick ascending loop of Henle where one-third of filtered sodium is reabsorbed. This causes decreased sodium and chloride reabsorption and increased diuresis.5 Loop diuretics also enhance the synthesis of prostaglandins, which cause renal and venous dilatation. This explains some of the cardiac

Casu_Final.indd 42

effects, such as reduction in pulmonary wedge pressure.6 However, it is important to recognise that the diuretic actions of loop diuretics may be decreased by the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), possibly because this inhibits renal prostaglandin synthesis. Loop diuretics include furosemide, bumetanide, torsemide and ethacrynic acid. While the bioavailability of oral furosemide ranges from 40 to 80 %, the bioavailability of torasemide and bumetanide exceeds 80 %; so these two molecules may be more effective in treating patients suffering from HF.7 A well-known consequence of loop diuretic therapy is depletion of other electrolytes, such as potassium, magnesium, calcium and chloride (see Table 1).

Thiazide Diuretics and Metolazone Benzothiazide diuretics inhibit the sodium–chloride transporter at the distal portion of the ascending limb and the first part of the distal tubule. They prevent maximal dilution of urine, thus increasing free water clearance and excretion of sodium and chloride through the renal tubular epithelium. The increased delivery of sodium to the collecting ducts enhances the exchange of sodium with potassium and, as a result, potassium depletion. They are less effective in patients with reduced glomerular filtration, because they exert their diuretic effects from the luminal side of the nephron. Although they are less potent than loop diuretics, they may work in synergy with them when a sequential segmental nephron blockade is achieved. Thiazides also decrease peripheral vascular resistance by a mechanism which is, at present, not well understood, resulting in a decrease of blood pressure.8

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Diuretic Therapy in Heart Failure – Current Approaches

Table 1: Summary of Diuretic Drugs used in Heart Failure

Drug

Site of Action

Duration

Common Starting Dosage

of Action Loop diuretics

Maximum

Common Side Effects

Dosage

Inhibition of Na-K-CI

Hypokalaemia, hypomagnesaemia,

co-transporter in the thick

hyperuricaemia, hypocalcaemia,

ascending loop of Henle

hyponatraemia, otoxicity

Furosemide

20 to 40 mg once or twice

600 mg

Bumetanide

4 to 6 h

0.5 to 1.0 mg once or twice

10 mg

Torasemide

12 to 16 h

10 to 20 mg once

200 mg

Ethacrynic acid

25–50 mg once or twice

200 mg

Thiazide-like

Inhibition of Na-Cl

Hypokalaemia, hypomagnesaemia,

diuretics

transporter at distal

hypercalcaemia, hyponatraemia,

nephron

hyperuricaemia

Chlorothiazide

6 to 12 h

250 to 500 mg

Once or twice

Chlorthalidone

24 to 72 h

12.5 to 25 mg once

100 mg

Indapamide

36 h

2.5 mg once

20 mg

Potassium-sparing Inhibition of mineralcarticoid diuretics

1,000 mg

Hyperkalaemia

receptor or its effectors at distal nephron

Amiloride

24 h

5 mg once

20 mg

Triamterene

7 to 9 h

50 to 75 mg twice

200 mg

Spironolactone

1 to 3 h

12.5 to 25.0 mg once

50 mg

Metolazone is not a thiazide but acts in a similar way. Metolazone is more potent than hydrochlorothiazide and retains its effectiveness even when there is severe glomerular filtration rate (GFR) reduction.

Potassium-sparing Diuretics The potassium-sparing diuretics used for treating HF are the aldosterone receptor antagonists spironolactone and eplerenone. They act at the cortical collecting duct, in particular by reducing the absorption of sodium and water and increasing the excretion of hydrogen ions and potassium, and their action is mediated by the antagonism of the actions of mineral corticoids. Only 3 % of filtered sodium is reabsorbed at the collecting duct, so this class of drugs does not have an appreciable diuretic effect. However they are often used in association with other more effective diuretics to correct or prevent potassium deficiency. They are also significantly efficacious in reducing the deleterious effects of aldosterone on the cardiovascular system. Spironolactone is a non-selective aldosterone receptor antagonist, and thus endocrine-related adverse effects (such as gynecomastia) are relatively common when it is used. Eplerone has greater selectivity on the mineral corticoid receptor, and has fewer side effects.9

Diuretics in Chronic Heart Failure Diuretics are used to achieve and maintain euvolaemia (the patient’s ‘dry weight’) with the lowest possible dose. This means that the dose must be adjusted, particularly after restoration of the dry body weight, to avoid the risk of dehydration, which leads to hypotension and renal dysfunction.10 It is important that treatment with diuretics is always coupled with neuro-hormonal system blocking, in order to slow down the progress of the disease. In general, due to their greater effectiveness, loop diuretics, such as furosemide, are the mainstay of diuretic therapy in HF. Indeed loop diuretics produce more intense and shorter diuresis than thiazides, which results in more gentle and prolonged diuresis. They are,

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Gynecomastia

however, less effective in patients with reduced kidney function.10 As a general rule, doses of loop diuretics should be as low as possible, in order to maintain a euvolaemic state. Restricting the amount of sodium and water, daily weight monitoring and avoidance of NSAIDs are critical in preventing salt and water retention. The commonly used loop diuretics only act for a short time, so common therapy schemes require twice-daily administration, in order to avoid post-diuretic rebound sodium retention. Furosemide is by far the most common oral loop diuretic, but patients with resistance to oral furosemide therapy may benefit from trials with second-generation oral loop diuretics (bumetanide and torasemide). These may be more efficacious, due to their increased oral bioavailability and potency. The longer half-life of torasemide may limit the previously described rebound phenomenon.11 In the prospective TORasemide In Chronic heart failure (TORIC) study, the use of torasemide was associated with lower mortality than furosemide in patients with HF. Furthermore, torasemide has been reported to attenuate LV remodelling in patients with congestive HF (CHF) to a greater extent than furosemide.12 Torasemide has also been reported to attenuate LV remodelling in patients with HF to a greater extent than furosemide.13 Although international guidelines do not define which diuretic should be preferred, there is not enough strong evidence to recommend torasemide and bumetanide over furosemide in HF. Careful monitoring and supplementation of electrolytes, particularly potassium and magnesium, are a crucial aspect of loop diuretic therapy. Randomised clinical trials have shown that potassium-sparing diuretics are able to reduce both hospitalisations and mortality in patients with chronic HF, although they are less useful than loop diuretics in cases of acute decompensate HF.14 Aldosterone levels are elevated in patients with acute decompensated heart failure (ADHF) despite the

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Cardiomyopathy and Heart Failure Figure 1: Schematic of a Dose‐response Curve of Loop Diuretics in Heart Failure Patients Compared with Controls

Fractional exceretion of sodium

Normal Diminished maximal responsiveness

Heart failure

Higher doses required to achieve same diuretic effect

Diuretic concentration In heart failure patients, higher doses are required to achieve a given diuretic effect and the maximal effect is blunted. Adapted, with permission, from Ellison21 and reprinted, with permission, from Felker Reproduced with permission from Felker.22

use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta-blockers. In this setting, aldosterone elevation may contribute to cardiorenal dysfunction, increasing the risk of death and ventricular arrhythmias.15,16 Studies have shown benefits using aldosterone antagonists in HF using non-diuretic doses of mineralcorticoid receptor antagonists. The objective was to completely inhibit the angiotensin–aldosteron axis. In the Emphasis-HF study, a double-blinded trial enrolling patients with chronic HF and low ejection fraction (EF), the aldosterone antagonist eplerenone compared with placebo showed a significant reduction in deaths from all causes, hospitalisation for HF and of the primary outcome (cardiovascular death or hospitalisation for HF).17 For these reasons, their use is strongly recommended in patients with HF. Their greater usefulness, as has already been mentioned, is not their diuretic properties, but their ability to antagonise the many harmful effects of hyperaldosteronism on the cardiovascular system. There are few studies in the literature describing the usefulness of high diuretic doses of aldosterone antagonists in ADHF in order to overcome congestion. In a exploratory study in ADHF patients, high doses of mineralcorticoid receptor antagonists (in more detail, about 100 mg spironolactone) were safe and were also associated with an earlier resolution of the congestive signs and with a more pronounced N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) reduction.18 Potassium-sparing diuretics have the disadvantage that their use results in a greater incidence of hyperkalaemia. However, when combined with loop diuretics, as happens frequently in clinical practice, this side effect is greatly reduced.

prevalence of diuretic resistance in the HF population is unknown due to the heterogeneity of the populations studied, the frequent comorbidity, the different treatment regimens, as well as to the different definitions used in various clinical trials. In a retrospective analysis of 1,153 patients with advanced HF, 402 patients had diuretic resistance (defined in this study as requirement of furosemide >80 mg or bumetanide >2 mg daily).20 Diuretic resistance was independently associated with total mortality, sudden death and pump failure death. Loop diuretics are ‘threshold drugs’. HF shifts the dose-response curve for loop diuretics downward and to the right. Thus a higher starting dose of loop diuretics is needed in order to achieve the same level of sodium excretion.21 The shift of the dose–response curve in HF implicates insufficient dosing as a common cause of a lack of diuretic response (see Figure 1).21,22 The magnitude of natriuresis following a defined dose of diuretics declines over time, even in normal subjects. This is the so-called ‘braking phenomenon’ and it is the result of both haemodynamic changes at the glomerulus as well as adaptive changes in the distal nephron. In a seminal study on rats by Kaissling, furosemide treatment was associated with cell hypertrophy at the distal convoluted tubule, the connecting tubule and the cortical collecting duct.23 These structural changes after furosemide treatment suggest an increase in active transcellular transport capacity of this segment.24 A partial explanation of these anatomical modifications may be the increased stimulation mediated by the renin-angiotensin and sympathetic nervous systems.23 An abrupt increase in diuretic resistance in HF patients may be due to concomitant NSAID use or to an excessive intake of sodium. This may result in renal function deteriorating and development of cardiorenal syndrome.25 A response reduction to diuretic therapy is a common problem in patients with HF and while many studies have tried to give an exact clinical definition of diuretic resistance, others have tried to find a solution to the clinical problems that this causes. Probably the single most used and reproducible marker of cardiovascular congestion is body weight. As a result, HF guidelines advocate daily body weight monitoring in order to detect the pre-symptomatic phase in patients at risk to develop acute decompensated HF.10 An interesting attempt to create a quantitative index of response to diuretic therapy was undertaken by Valente el al.26 This index was obtained by comparing the administered dose of diuretic with the reduction of body weight and was intended to measure its effectiveness. It showed a significant correlation with relevant clinical variables and also highlighted a correlation with adverse events. In another study, Testani et al. tested a metrical index of diuretic efficiency, which was defined as the net fluid lost per milligram of loop diuretic, thus demonstrating that low diuretic efficiency during decongestive therapy portends poorer long-term outcomes in patients hospitalised with decompensated HF.27

Diuretic Resistance

Once correctable variables and blockage of the neuroendocrine system have been excluded, a possible way of overcoming diuretic resistance is to use infusion therapy to avoid the limitations of oral bioavailability. For patients refractory to escalating doses of intravenous diuretics, options include use of continuous infusion rather than intermittent boluses. This strategy was tested in the DOSE study,28 but no significant difference was noted between the two treatment groups.

Diuretic resistance is a common problem in HF patients. Removal of excessive fluid is usually achieved by a combination of salt restriction and loop diuretics, but in some cases congestion persists despite adequate diuretic therapy. This has been termed diuretic resistance. The

Another approach is to administer two classes of diuretics together, a loop diuretic combined with a thiazide-like diuretic, thus performing a sequential nephron blockade.29 Various mechanisms explain the success of

After overcoming the acute phase of HF, in selected subgroups it will be possible to make an attempt to withdraw diuretics. A history of hypertension, baseline furosemide dose of >40 mg/day, and a low LVEF (<27 %) were independent predictors of diuretic restarting.19

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Diuretic Therapy in Heart Failure – Current Approaches

Figure 2: Mechanism of Diuretic Resistance Cardiac failure Loop diuretic administration Inhibition of macula densa

Negative sodium balance Renin-angiotensin-aldosterone system

Natriuretic dose of mineralocorticold antagonist

Secondary hyperaldosteronism

↓ Distal sodium delivery

Hypertrophy of distal nephron Increased expression of NaCl transporter Natriuretic dose of mineralocorticold antagonist

Thiazide diuretic

Mineralocorticold receptor antagonist Loop diuretic resistance

Reproduced with permission from Schrier et al.30

this combination strategy: the longer half-life of thiazide diuretics helps to counteract the rebound post-diuretic effect (see Figure 2).30 Thiazide-type diuretics inhibit sodium reabsorption in the distal nephron and primarily benefit patients who have distal nephron hypertrophy and hyperfunction due to chronic treatment with loop diuretics. Indeed, inhibiting NaCl transport along the distal tubule counteracts the reabsorption due to hyper-functioning cells in the distal tubule. In addition, they markedly increase the fractional sodium excretion, which is needed to achieve a neutral or negative sodium balance if the GFR is depressed.31

alterations in glomerular haemodynamics due to neurohormonal and

Numerous thiazide-like diuretics have been evaluated in combination with loop diuretics with similar results overall and there is no clear evidence that any single thiazide-like diuretic is superior to another, suggesting a class effect. It has been suggested that metolazone is superior to other thiazide-like diuretics in patients with advanced kidney disease, but other thiazide-like diuretics also increased the response to loop diuretics, even in patients with advanced renal failure. More recently, a small, retrospective, single-centre cohort study compared two of the most commonly used thiazide-like diuretics (oral metolazone and intravenous chlorothiazide) as add-on therapy to loop diuretics and no statistically significant differences in efficacy or safety were found.32 In some European countries, metolazone and chlorothiazide are not available and the most commonly used thiazide-like diuretics for ADHF are hydrochlorothiazide and chlorthalidone. Chorthalidone’s half-life (48–72 hours) is longer than that of hydrochlorothiazide (6–12 hours), which might increase risk of adverse events in patients hospitalised for ADHF. Moreover, head-tohead studies comparing these for treating hypertension described an increased risk of hyponatraemia with chorthalidone.33

Diuretic Therapy in Acute Decompensated Heart Failure

For these reasons, hydrochlorothiazide or metalazone could be the diuretic of choice for treating ADHF. The main problem when using sequential nephron blockage is the excessive depletion of water and electrolytes. Chronic thiazide diuretics use is a predictor of worsening renal function in chronic HF and this is of concern, given the adverse prognosis associated with worsening renal function in these patients. Impaired renal function with diuretic therapy can result from direct

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intrarenal feedback mechanisms or from overt volume depletion. To address these common concerns we need to await results of ongoing clinical trials (between these, the ‘Safety and efficacy of the combination of loop with thiazide type diuretics in patients with decompensated HF’, will compare the strategy of sequential block through add-on hydrochlorothiazide versus therapy with loop diuretics alone). As a result of the above considerations, nowadays it is not easy to apply sequential nephron blockage to outpatient settings.34

Fluid overload is a major pathophysiological mechanism underlying both acute decompensation episodes of HF and the progress of the syndrome. Loop diuretics remain a cornerstone in the pharmacological treatment of ADHF and are administered in about 90 % of patients hospitalised for HF.1 These drugs are routinely used as initial therapy in ADHF due to their ability to greatly improve the symptoms. Conversely, because of their lower natriuretic effect, thiazide diuretics are used infrequently and are limited to cases where there is diuretic resistance. The same is true for potassium-sparing diuretics, which are only used in cases of refractory oedema or concomitant hypokalaemia. One of the major concerns of clinicians is the effect of excessive diuretic therapy on the intra-arterial volume and, consequently, on the possible deleterious effects on renal function. Several studies have, indeed, demonstrated that there is a correlation between doses of diuretics and the worsening of the prognosis in patients with acute decompensated HF.35 However, no definite causal relationship has been established between diuretic therapy, its dosage, and cardiovascular mortality. It is, indeed, virtually impossible to distinguish between the multiple confounding factors, because sicker patients present often with greater congestion and therefore receive higher doses of diuretics. The pathophysiological basis of many of these concerns is that these drugs, which cause intravascular volume depletion, could increase the hyperactivation of the neuroendocrine system with resulting detrimental consequences.36,37

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Cardiomyopathy and Heart Failure Nowadays, despite many studies in ADHF on diuretic therapy, the only certainty is that such therapies can relieve the patient’s symptoms and reduce vascular congestion. It remains unclear what the preferred loop diuretic should be, what should be the appropriate combination, what is the optimal dosage and what should be the clinical goal. Current guidelines from the American College of Cardiology and the American Heart Association suggest that ‘Diuretics should be administered at doses sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume.’38

New Approaches Although in the majority of patients congestion symptoms are controlled by loop diuretic therapy, in a minority of cases other adjunctive therapies are needed. This is because of the progression of the disease or the worsening of the renal function. Other solutions have been tested in addition to the aforementioned combination therapy (sequential nephron blockade). Some trials demonstrated the positive effects of incorporating hypertonic saline solution (HSS) with standard loop diuretic therapy.39 In a large study of 1,771 patients, the SMAC-HF study, in-hospital HSS administration, combined with moderate sodium restriction, reduces hospitalisation time and increased diuresis. However, a long-term follow-up found that moderate salt restriction was associated with a better prognosis than a low sodium diet.40 The potential benefits of this therapy are the faster recovery of intra-arterial volume. This reduces the neuro-endocrine stimulation and improves glomerular perfusion, thus counteracting the common mechanisms that underlie fluid overload in various clinical scenarios.36 Regardless, this was an unblinded study and use of HSS is not recommended in current guidelines. Larger prospective and blinded studies need to be undertaken before this approach can be recommended for clinical use. HF with concomitant severe hyponatraemia is of particular clinical relevance, due to its particular prognostic and therapeutic implications.41 Such patients may benefit from treatment with arginin vasopressin antagonist (vaptans). This class of drugs can be useful in several cases of resistance to diuretics because of their specific action mechanisms.42 Despite this and other anecdotal reports, after the results of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial (Everest), tolvaptan is today approved by the US Food and Drug Administration only for the treatment of clinically significant hypervolaemic and euvolaemic hyponatraemia (serum sodium less than 125 meq/lL). This includes patients with HF and the syndrome of inappropriate antidiuretic hormone secretion. Indeed in the EVEREST trial, an international, multicentre, randomised, double-blind, placebo-controlled trial in a population of hospitalised chronic HF patients, there was no difference in the global clinical status of the two groups, although the tolvaptan group had significantly decreased dyspnoea on day 1, and decreased weight and oedema after 7 days. It is noteworthy that patients in the tolvaptan group had significantly decreased loop diuretic use compared with the placebo group. Despite these initial results, the long-term primary outcome trial showed no significant difference in overall mortality.43 In the future It would be interesting to design a specific clinical trial on use of vaptans in patients who developed diuretic resistance. Another option to be used in most complex patients is the use of diuretics in association with ultrafiltration (UF) therapy. UF moves

Casu_Final.indd 46

water and small to medium weight solutes across a semi-permeable membrane to reduce volume overload. The first interesting, but controversial, data comes from the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated HF (UNLOAD) trial. In this study treatment with UF resulted in significantly fewer hospital readmissions due to HF during a 90-day follow-up.44 Unfortunately, the study was harshly criticised because of the low doses of diuretics used and the consequent reduced clinical reproducibility. In the recent Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), a study designed to compare the effect of UF with that of stepped pharmacological therapy on renal function and weight loss in patients with HF who have worsening renal function and persistent congestion, UF patients in the UF group had a significantly greater increase in serum creatinine and more adverse events, including bleeding and vascular complications, as well as progressive renal dysfunction. Moreover, there was no significant difference in the outcome, including mortality and rehospitalisation, at 60 days.45 However the latest American guidelines suggest that UF may be considered for use after all diuretic strategies have failed.38 Further studies will be needed to assess what should be the exact role of UF in the management of patients with ADHF.

Conclusions HF remains the most common cause of hospitalisation in patients over the age of 65 and the main symptoms are vascular congestion. Fluid overload is a major pathophysiological mechanism underlying both acute decompensation in HF and the progression of the syndrome. Although there has been a lot of controversy on the possible negative effects of diuretic therapy, due to the reduced intra-arterial volume with neuro-endocrine hyperactivation, no definite causal relationship has been established between diuretic therapy, its dosage and cardiovascular mortality. Although there are three main classes of diuretics (loop diuretics, thiazide diuretics with metolazone and potassium-sparing diuretics), loop diuretics are most commonly used, because they have the most potent natriuretic action. Conversely, despite having a weak diuretic effect, potassium sparing diuretics have been shown to be significantly efficacious in improving the long-term prognosis in symptomatic HF patients. Nowadays, the primary role of thiazide-like diuretics in CHF is to attempt to overcome diuretic resistance, thus performing a sequential nephron blockade when administered in association with loop diuretics. Despite various attempts, due to the many confounding factors and the extreme heterogeneity of studied population, randomised trials failed to find any significant differences on optimal dosages and modality of administration of loop diuretics in acute HF. More data will be needed before using arginine vasopressin antagonist clinically, since the results of randomised trials failed to show the expected benefits. The same is true for UF – until stronger clinical data are available, its use will be limited to selected cases in accordance with current guidelines. Research of new physiology-based approaches designed to offset the primary determinants of water retention could improve the management of patients affected by CHF. Until then, diuretic therapy will remain the cornerstone in CHF. n

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Diuretic Therapy in Heart Failure – Current Approaches

5. 6. 7.

8. 9.

10.

11.

12.

13.

14.

15.

Adams KF Jr, Fonarow GC, Emerman CL, et al. 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. Hunt SA, Abraham WT, Chin MH, 2009 focused update incorporated into the ACC/AHA 2005 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. J Am Coll Cardiol . 2009;53 :e1–e90. Gheorghiade M, Filippatos G, De Luca L, Burnett J, Congestion in acute heart failure syndromes: an essential target of evaluation and treatment. Am J Med . 2006;119 :S3–S10. Goldsmith SR, Brandimarte F, Gheorghiade M, Congestion as a therapeutic target in acute heart failure syndromes. Prog Cardiovasc Dis . 2010;52 :383–92. Brater DC, Diuretic therapy. N Engl J Med . 1998;339:387–95. Raftery EB, Haemodynamic effects of diuretics in heart failure. Br Heart J . 1994;72 (Suppl.):S44–S47. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med . 2001;111 :513–20. Roush GC, Kaur R, Ernst ME, Diuretics: a review and update. J Cardiovasc Pharmacol Ther . 2014;19 :5–13. Struthers A, Krum H, Williams GH, A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clinical Cardiology . 2008;31 :153–8. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J , 2012;33 :1787–847. Masuyama T, Tsujino T, Origasa H, et al. Superiority of longacting to short-acting loop diuretics in the treatment of congestive heart failure. Circ J . 2012;76 :833–42. Cosin J, Diez J. TORIC Investigators. Torasemide in chronic heart failure: results of the TORIC study. Eur J Heart Fail . 2002;4 :507–13. Lopez B, Querejeta R, Gonzalez A, et al. Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure. J Am Coll Cardiol . 2004;43 :2028–35. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med . 2003;348 :1309–21. Aronson D, Burger AJ. Neurohormonal prediction of mortality

EUROPEAN CARDIOLOGY REVIEW

Casu_Final.indd 47

16.

17.

18.

19.

20.

21. 22. 23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

following admission for decompensated heart failure. Am J Cardiol . 2003;91 :245–8. Schmidt BM, Sammer U, Fleischmann I, et al. Rapid nongenomic effects of aldosterone on the renal vasculature in humans. Hypertension . 2006;47 :650–5. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. New Engl J Med . 2011,364 :11–21. Ferreira JP, Santos M, Almeida S, et al. Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure. Eur J Intern Med . 2014;25 :67–72. Grinstead WC, Francis MJ, Marks GF, et al. Discontinuation of chronic diuretic therapy in stable congestive heart failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy. Am J Cardiol . 1994;73 :881–6. Neuberg GW, Miller AB, O’Connor CM, et al. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J, 2002;144 :31–8. Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology . 2001;96 (3–4):132–43. Felker MG. Diuretic management in heart failure. Congest Heart Fail . 2010;16 (Suppl. 1):S68–S72. Kaissling B, Stanton BA. Adaptation of distal tubule and collecting duct to increased sodium delivery. I. Ultrastructure. Am J Physiol . 1988;255 (6 Pt 2):F1256–68. Kaissling B, Bachmann S, Kriz W. Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment. Am J Physiol . 1985;248 (3 Pt 2):F374–81. Stevenson LW, Nohria A, Mielniczuk L. Torrent or torment from the tubule? Challenge of the cardiorenal connections. J Am Coll Card . 2005;45 :2004–7. Valente MA, Voors AA, Damman K, et al. Diuretic response in acute heart failure: clinical characteristics and prognostic significance. Eur Heart J . 2014;35 :1284–93. Testani JM, Brisco MA, Turner JM, et al. Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail . 2014;7 :261–70. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med . 2011;364 :797–805. Knauf H, Mutschler E. Sequential nephron blockade breaks resistance to diuretics in edematous states. J Cardiovasc Pharmacol . 1997;3 :367–72. Schrier RW. Role of Diminished Renal Function in Cardiovascular Mortality. Marker or Pathogenetic Factor? J Am Coll Cardiol . 2006;47 :1–8. Verbrugge FH, Grieten L, Mullens W. Management of the cardiorenal syndrome in decompensated heart failure. Cardiorenal Med . 2014;4 :176–88. Moranville MP, Choi S, Hogg J, et al. Comparison of metolazone versus chlorothiazide in acute decompensated

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

heart failure with diuretic resistance. Cardiovasc Ther . 2015;33 :42–9. Dhalla IA, Gomes T, Yao Z, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study. Ann Intern Med . 2013;158 :447–55. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol . 2010;56 :1527–34. Hasselblad V, Stough WG, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE Trial. Eur J Heart Fail . 2007;9 :1064–9. Schrier RW. Body fluid volume regulation in health and disease: A unifying hypothesis. Ann Intern Med . 1990;113 :155–9. Bayliss J, Norell M, Canepaanson R, et al. Untreated heartfailure – clinical and neuroendocrine effects of introducing diuretics. Br Heart J . 1987;57 :17–22. 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. Paterna S, Di Pasquale P, Parrinello G, et al. Effects of highdose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure. Eur J Heart Fail. 2000;2 ;305–13. Paterna S, Fasullo S, Parrinello G, et al. Short-term effects of hypertonic saline solution in acute heart failure and longterm effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association Class III (Class C) (SMAC-HF study). Am J Med Sci . 2011;342 :27–37. Verbrugge FH, Steels P, Grieten L, et al. Hyponatremia in Acute Decompensated Heart Failure. J Am Coll Cardiol . 2015;65 :480–92. Jermyn R, Rajper N, Estrada C, et al. Triple Diuretics and Aquaretic Strategy for Acute Decompensated Heart Failure due to Volume Overload. Case Rep Cardiol. 2013;2013:750794. Konstam M, Gheorghiade M, Burnett J, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA . 2007;297 :1319–31. Costanzo MR, Saltzberg MT, Jessup M, et al. Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) Investigators Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: Results from UNLOAD. J Card Fail. 2010;16:277–84. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated HF with CRS. N Engl J Med. 2012;367:2296–304.

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Electrophysiology and Sudden Cardiac Death

LE ATION.

Sudden Cardiac Death in Athletes Andrew D’Silva and Michael Papadakis St George’s University of London, St George’s University Hospital Foundation NHS Trust, London, UK

Abstract Physical activity confers substantial health benefits to healthy individuals and patients alike. Occasionally, however, exercise may act as a trigger for arrhythmic death in athletes who harbor an occult pathological substrate. The majority of sudden cardiac deaths (SCDs) in young athletes (≤35 years old) are secondary to inherited cardiac diseases, while ischaemic heart disease predominates in older athletes. In the absence of compulsory national or international registries of SCD in athletes, it is difficult to define the exact scale of the problem. In addition, the lack of post-mortem evaluation by pathologists with expertise in cardiac adaptation to exercise and inherited cardiac diseases casts doubt to the reliability of the reported causes. The proposed preventative strategies focus primarily on preventing deaths by cardiovascular evaluation of athletes and the use of automated external defibrillators in athletic venues. Cardiovascular screening of first-degree relatives, though often neglected, has the potential to avert further tragedies given the inherited nature of most conditions predisposing to SCD in the young. This article provides an overview of the epidemiology and causes of SCD in athletes and explores potential prevention strategies.

Keywords Sudden cardiac death, athlete, pre-participation screening, cardiomyopathy, ion channelopathy, coronary artery disease, risk assessment Disclosure: Andrew D’Silva and Michael Papadakis have received research grants and work in close collaboration with the charitable organisation Cardiac Risk in the Young (CRY), which supports cardiac screening of all young individuals. Received: 13 June 2015 Accepted: 9 July 2015 Citation: European Cardiology Review, 2015;10(1):48–53 Correspondence: Michael Papadakis, Department of Cardiovascular and cell sciences, St George’s University of London, Cranmer Terrace, London, SW17 ORE. E: michael.papadakis@sgul.ac.uk

The evidence supporting the beneficial effects of physical activity on health is compelling. Regular exercise reduces cardiovascular mortality by 35 % and all-cause mortality by 33 %1 and confers an average of 7 years greater longevity.2 Most professional athletes, however, undertake doses of exercise that far exceed those recommended by the current evidence, which has been adopted by national and international health authorities. This is of relevance, as recently published data suggest that, similar to most pharmacological interventions, exercise has an optimal dose above which there is little additional benefit or there may even be harm.3,4 Occasionally athletes die suddenly and these highly publicised, tragic instances generate considerable attention from the community at large, given the widely held perception that these individuals are the epitome of fitness and health. In the majority of cases, exercise acts as the trigger of the fatal arrhythmic event rather than being the primary cause. The majority of sudden cardiac deaths (SCDs) in athletes are secondary to quiescent cardiac disease that can potentially be detected during life, galvanising discussions relating to primary and secondary prevention of similar catastrophes. Primary prevention involves the identification of those at risk of sudden cardiac arrest (SCA), through population screening or targeted screening of high-risk individuals with symptoms or family history suggestive of cardiac disease. Implementation of lifestyle interventions and appropriate clinical care can prevent SCA. Secondary prevention relates to improving the probability of survival when an SCA occurs, through the implementation of an effective emergency response plan, with high-quality cardiopulmonary resuscitation (CPR) and prompt use of automated external cardiac defibrillators (AEDs) at its core.

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Incidence of Sudden Cardiac Death in Athletes The scale of the problem of SCD in athletes is difficult to define, as calculating the precise number of cases (numerator) and defining the exact reference population (denominator) is challenging in the absence of compulsory national or international registries. Studies have arrived at vastly different estimates varying from 1 per 300,000 per year5 to 1 per 23,000 per year.6 Differences in methodology and selection biases are largely responsible for this variation with available sources for case identification ranging from registries, sporting organisations, parent organisations, media reports or a combination of these. In addition, the estimate of 1 per 23,000 per year included both cases of SCD and survivors of sudden cardiac arrest (SCA),6 which is a more reasonable strategy as both SCD and SCA should be targeted by potential preventative strategies. One large prospective study by Corrado et al. systematically assessed the incidence of SCD in young athletes.7 The study is unique as it prospectively studied a well-defined population of athletes and non-athletes in the Veneto region of Italy for 25 years. In contrast to all other studies, owing to the highly organised referral network, all deaths in young (aged 12–35 years) individuals considered to be of cardiac cause were referred for post-mortem evaluation to a single centre and underwent detailed cardiac histopathological evaluation by a small number of expert cardiac pathologists. Moreover, the unique pre-participation screening programme (PPS), which is enforced by law in Italy, ensures that athletes participating in formal competition are subjected to annual medical reviews. Based on the results of this study the incidence of SCD in young athletes was estimated at 1 per

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Sudden Cardiac Death in Athletes

Figure 1: Comparison of Causes of Sudden Cardiac Death Italy 2% 2%

US Registry 3%

By comparison, it is more difficult to investigate SCD rates in recreational and veteran athletes, as the reporting of these deaths is less consistent and in many cases unlikely to be witnessed. As a result, there are relatively fewer studies evaluating the incidence of SCD in older athletes. A comprehensive, prospective 5-year study of sports-related SCD in the French general population revealed that the overwhelming majority of sports-related SCD occurred among those aged ≥35 years and was greatest in the fifth decade of life. In this study, the overall burden of sports-related SCD was 4.6 deaths per million population per year, with only 6 % occurring in young competitive athletes.11 In a more recent study by the same group the incidence of sports-related SCA increased to 21.7 per million population per year when focusing on middle-aged individuals (aged 35–65 years).12

19 %

US Military

13 %

Possible HCM/LVH ARVC Dilated CM Coronary artery abnormality SADS

NCAA

1% 1% 1%

IHD

27 %

Aortic dissection

Other

Possible HCM/LVH/SCT Channelopathy

8% 14 %

5% 30 %

Myocarditis

12 %

31 %

ARVC = arrhythmogenic cardiomyopathy; CM = cardiomyopathy; HCM = hypertrophic cardiomyopathy; IHD = ischaemic heart disease; LVH = left ventricular hypertrophy; NCAA = National Collegiate Athletic Association; SADS = sudden arrhythmic death syndrome; SCT = sickle cell trait. Reproduced with permission from Harmon et al.13 with data taken from Corrado et al.7

Figure 2: Yield of Genetic Cardiovascular Conditions from Familial Evaluation Following Sudden Arrhythmic Death Syndrome % 100 90

Papadakis_FINAL.indd 49

8% 4%

HCM

13 %

Causes of Sudden Cardiac Death in Young Athletes

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10 % 17 %

In comparison, the results of the registry in the Veneto region of Italy place ARVC as the most common cause of SCD (23 %), followed by atherosclerotic CAD (19 %).7 Anomalous origin of the coronary arteries accounted for 13 % of SCDs, with mitral valve prolapse contributing 12 %, myocarditis 10 % and conduction system disease 8 % (see Figure 1).7 Although the Italian registry is smaller in scale compared with the US registry, the accuracy of diagnoses by specialist cardiac pathologists give additional credibility to the results. Variations between the findings in each registry may be explained in part by the differences in the population, differences in methodology relating to data collection and interpretation of autopsy findings and the fact that systematic PPS of athletes in Italy may have prevented SCDs due to HCM through the disqualification of affected athletes.

Aetiology of SCD in Athletes The causes of SCD in athletes are divided based on the age of the athlete; the age of 35 years is used as the cut-off point. In athletes ≤35 years of age, inherited or potentially inherited cardiac diseases account for most SCDs. There is, however, disparity across different registries as to the most common cause of SCD.1 In the US registry from the Minneapolis Heart Institute Foundation, hypertrophic cardiomyopathy (HCM) was the most common cause of death, accounting for 36 % of SCDs in this population. Coronary artery anomalies of abnormal origin were next in frequency at 17 % and arrhythmogenic right ventricular cardiomyopathy (ARVC) was responsible for only 4 % of deaths. Other causes of SCD such as myocarditis, ion channelopathies, coronary artery disease (CAD), dilated cardiomyopathy, mitral valve prolapse, aortic stenosis and aortic rupture each accounted for ≤6 % of SCDs (see Figure 1).14

35 %

23 %

27 %

A consistent finding across all studies is that male athletes carry a higher risk of SCD than female athletes. The reasons for this are poorly understood. Although higher male participation rates in the most popular sports may partly account for this, gender-specific influences in disease expression are likely to contribute, as similar trends are observed in the general population.9 Black athletes also appear to suffer a disproportionately higher incidence of SCD. The National Collegiate Athletic Association in the US reported a three-fold higher risk in African-American athletes compared with Caucasian athletes (1 per 17,000 versus 1 per 58,000), with the highest incidence of SCD in male African-American athletes at 1 per 13,000 per year.10

3% 3% 3%

24,000 per year prior to the initiation of the PPS,8 which is similar to that estimated by Drezner et al. in high school student athletes in the US.6

United Kingdom 12 % None Unspecified/other HCM DCM ARVC CPVT BrS LQTS

60 50 40 30 20 10 0 Behr et al, 2008 (n=57)

Van der Werf et al, 2010 (n=140)

12 %

25 % 29 %

10 %

HCM

SADS

Possible HCM/LVH

Myocarditis

ARVC

Other

Coronary artery abnormality

Right: Pie chart showing the causes of sudden cardiac death in 89 sports deaths in young athletes referred to a tertiary cardiac centre in the UK over a duration of12 years. Left: Bar chart showing the yield of genetic cardiovascular conditions from familial evaluation series following sudden unexplained death and/or SADS. ARVC = arrhythmogenic right ventricular cardiomyopathy; BrS = Brugada syndrome; CPVT = catecholaminergic polymorphic ventricular tachycardia; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LQTS = long QT syndrome; LVH = left ventricular hypertrophy; MI = myocardial infarction; SADS = sudden arrhythmic death syndrome. Data taken from de Noronha et al.,15 Behr et al.17 and Van der Werf et al.45

Contemporary Studies of Causes of SuddenCardiac Death in Athletes Contemporary studies have further added to the diversity of SCD causes in athletes and highlighted the complexity of the subject. Post-mortem examination of 89 young athletes in the UK suffering SCD revealed a normal heart as the most common finding, implicated in almost a third (29 %) of deaths.15 Other novel entities included idiopathic left ventricular hypertrophy (LVH) and idiopathic fibrosis accounting for 25 % and 7 % of SCDs, respectively. Established cardiomyopathies such as HCM and

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Electrophysiology and Sudden Cardiac Death ARVC accounted for 22 % of cases, while coronary artery pathology was present in 8 % of deaths (see Figure 2).15 Although the high prevalence of autopsy-negative SCDs in the UK study may be in part attributed to significant referral bias, further studies have reported similar results. Of the 45 SCDs in US college athletes, a structurally normal heart was the most common finding at post-mortem accounting for 31 % of cases, while idiopathic LVH was present in 8 %.13 Similarly, a 25-year review of deaths in young military recruits in the US, identified autopsy-negative sudden unexplained death in 30 % of cases (see Figure 1).16 Recognition of a normal heart on autopsy, also referred as sudden arrhythmic death syndrome (SADS), is of paramount importance given its association with inherited ion channelopathies.17 Studies on familial evaluation after a SADS death have demonstrated evidence of an ion channelopathy or cardiomyopathy in up to 50 % of families (see Figure 2).17 In addition, the significance of idiopathic LVH and idiopathic fibrosis remains uncertain and postulated theories include being innocent bystanders, pathological variants of physiological LVH in genetically predisposed individuals or part of the HCM spectrum.18 In athletes with normal hearts or autopsy findings of uncertain significance the contribution of severe metabolic or electrolyte disturbances and heatstroke must also be taken into consideration as potential causes of sudden death. One study examining life-threatening and fatal events occurring during endurance races in Israel over a 6-year period found that heatstroke was responsible for the majority of events.19

Causes of Sudden Cardiac Death in Older Athletes The predominant cause of SCD in athletes aged >35 years is atherosclerotic coronary artery disease (CAD), identified in more than 80 % of cases.20 Acute exercise can lead to transient activation of the coagulation system, which promotes a pro-thrombotic environment.21 Additional metabolic and haemodynamic changes during exercise may contribute to stress-related plaque rupture observed in sportsrelated victims of SCD.22 On post-mortem examination, coronary atheroma with significant luminal obstruction (>75 %) may be present,23,24 with associated features indicative of acute or chronic myocardial infarction. However, plaque rupture, thrombosis, acute infarction and fibrosis are not prerequisites for the cause of death to be attributable to CAD. In such cases, the presumed mode of SCD is sudden ventricular arrhythmia due to myocardial perfusion-demand mismatch and resultant ischaemia.25

Prevention and Management of SCD in Athletes The steady trickle of SCD in athletes galvanises discussions relating to potential prevention measures in order to avert such tragedies. Proposed strategies include targeted evaluation of high-risk individuals, pre-participation cardiac evaluation of all athletes to identify quiescent conditions predisposing to exercise-related SCD, comprehensive evaluation of both the victim of SCD or SCA and most importantly of the family relatives who may harbor the same condition, and emergency response planning to ensure prompt resuscitation of cardiac arrests.

Primary Prevention Strategies Targeted Evaluation of High-risk Individuals Athletes with symptoms suggestive of cardiac disease or a family history of potentially inherited conditions or SCD should receive comprehensive evaluation. Of particular concern are new-onset exertional symptoms such as chest pain, shortness of breath, presyncope and syncope. This strategy in isolation is of limited value

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as the majority of victims of SCD are asymptomatic and SCD/SCA is commonly the first presentation.15,26

Pre-participation Cardiac Evaluation of Young Athletes Pre-participation cardiac screening using the 12-lead ECG remains a controversial issue. Data from the Italian national screening programme in young athletes reported a 90 % reduction in SCD.8 In contrast, Israel’s introduction of mandatory PPS did not appear to alter the incidence of SCD in athletes.27 However, a possible explanation for the discrepancy is the difference in data collection methods between the two studies. The Israeli study collected mortality data from Israel’s two main newspapers and estimated the number of athletes in the population (denominator) for the earlier years of the study period.27 By comparison, the Italian study had well-defined population data and a robust national reporting system of SCD cases.8 Additional concerns centre on the inability of screening to identify a considerable proportion of conditions predisposing athletes to SCD, the false-positive ECGs, feasibility and cost-effectiveness. The Italian PPS programme is mandatory for all young competitive athletes aged 12–35 years. The first tier of evaluation involves history (including family history), physical examination and 12-lead ECG. If no abnormalities are detected, the athlete is eligible for competition. Those with positive findings suggestive of possible cardiac disease are investigated further based on local protocols and the condition suspected. If this second tier of targeted evaluation reveals no evidence of cardiovascular disease, the athlete is eligible for competition. Where a cardiovascular disease is diagnosed, the athlete is managed according to established protocols (see Figure 3A).28 The ECG is likely to raise suspicion of quiescent cardiac disease in the majority of individuals with cardiomyopathies and is the primary diagnostic tool for ion-channelopathies and ventricular pre-excitation. However, up to 10 % of patients with HCM,29 20 % with ARVC30 and 25 % with long-QT syndrome31 may exhibit a normal ECG. In addition, the resting ECG will not detect the vast majority of individuals with coronary artery anomalies. The false-positive ECG rate using the European Society of Cardiology (ESC) criteria has been reported to be as high as 40 % in certain athletic cohorts, which raises concerns relating to the burden of unnecessary investigations or erroneous disqualification. Recent studies in large cohorts of young athletic individuals have resulted in refinement of the ECG criteria considered to denote an abnormal result, with a considerable improvement of the ECG specificity.32,33 Further research is necessary, particularly in athletes of non-Caucasian ethnicity, as the false positive ECG rate in athletes of African-Caribbean descent remains over 15 % and limited data exist on other ethnicities.34 Widespread adoption of PPS is also hindered by the lack of expertise and facilities. With the exception of Italy, where a mandatory, National screening programme has been in place since 1980, in most other countries screening of athletes is fragmented and dependent on the availability of local expertise and individual sporting organisation mandates. Finally, studies on the cost-effectiveness of PPS are fairly limited and most rely on theoretical projection models and arbitrary assumptions relating to the life years saved by identifying a potentially life-threatening condition. In most countries where the health service is already burdened by limited finances and resources, the implementation of a state-funded, national screening programme to identify silent cardiac diseases in young athletes seems unattainable.

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Sudden Cardiac Death in Athletes

Figure 3: Pre-participation Screening Protocols for Young Competitive Athletes (A) and Older Adults (B) Undertaking High-intensity Physical Activity A

B Young competitive athletes

ACTIVE Adult/senior

Family and personal history, physical examination, 12-lead ECG

High-intensity activity

Negative findings

Eligible for competition

Positive findings

No evidence of cardiovascular disease

Screening by physician • History • Physical examination • Risk SCORE • Rest ECG

Further examinations (echo, stress test, 24-h Holter, cardiac MRI, angio/EMB, EPS) Negative

Positive

Diagnosis of cardiovascular disease

Management according to established protocols

Max exercise testing

Eligible for moderate/high exercise training

Negative

Positive

Further evaluation, appropriate treatment and individually prescribed PA EMB = endomyocardial biopsy; EPS = electrophysiological study; PA = physical activity; SCORE = Systematic Coronary Risk Evaluation. Reproduced with permission from Corrado et al.46 and adapted from Borjessen et al.37

There are, however, convincing arguments for alternative funding sources, with charitable organisations subsidising the screening of young athletes who wish to be screened for self-protection.35

Figure 4: Differences Between the Autopsy Conclusions of Referring General Pathologists and an Expert Cardiac Pathologist General pathologist

Pre-participation Cardiac Evaluation of Older Athletes The rapidly expanding population of older veteran or amateur athletes who compete in high-intensity events underscores the importance of preventing SCD in this age group. The resting 12-lead ECG is of limited value in screening senior athletes, as CAD is the main cause of SCD.36 The Sports Cardiology section of the European Association of Cardiovascular Prevention and Rehabilitation published recommendations relating to screening practices, which take into account the burden of cardiovascular risk factors, pre-existing fitness levels and intended level of exercise.37 The assessment of athletes undertaking high intensity physical activity incorporates the assessment of cardiovascular risk factors, symptoms and family history; physical examination; resting 12-lead ECG; and the Systematic Coronary Risk Evaluation (SCORE) to assess the 10-year risk of a fatal cardiovascular event. Any abnormalities arising from this initial assessment, including a SCORE 10-year risk of ≥5 %, requires maximal exercise ECG testing. However, it is well recognised that the sensitivity of exercise ECG stress testing in a screening setting with predominantly asymptomatic individuals is poor (25 %)38 and the false-positive rates are high, particularly in women.39 Nevertheless, a negative maximal exercise ECG stress test provides eligibility for moderate/high exercise training and a positive test result will require further investigation for underlying CAD, the gold standard test being invasive coronary angiography (see Figure 3B). An area deserving further consideration is whether computed tomography coronary artery calcium scoring (CACS) can provide a

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Papadakis_FINAL.indd 51

Cardiac pathologist

17 %

ARVC HCM

14 %

46 %

13 % 66 %

12 % 4 %7 %

4% 4%

LVH Inflammation Valve Normal

ARVC = arrhythmogenic cardiomyopathy; HCM = hypertrophic cardiomyopathy; LVH = left ventricular hypertrophy. Data taken from de Noronha et al.41

better risk prediction of serious cardiovascular events, as high calcium scores appear to predict increased risk for cardiovascular events in the general population,24 including asymptomatic individuals.40 Obstacles to the wider implementation of CACS as a screening tool include radiation exposure (though minimal at 1.5–3.0 mSv), availability and cost.

Evaluation of the Patient and the Family The inherited nature of most conditions predisposing to SCD in young athletes highlights the importance of comprehensive post-mortem evaluation of the index case as well as cardiovascular screening of first-degree relatives. The importance of a histopathological examination by a cardiac pathologist with expertise in the morphological adaptations of the athletic heart and disease phenotypes implicated in SCD in athletes cannot be overstated, as false conclusions may misguide familial evaluation or offer false reassurance to surviving relatives and

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Electrophysiology and Sudden Cardiac Death Figure 5: Principles of Managing SCD

SCD autopsy

Comprehensive PM by expert cardiac pathologist + molecular autopsy

Familial evaluation

Diagnose cause of death Identify others at risk

Secondary Prevention Strategies Emergency Response Planning

PM = post mortem; SCD = sudden cardiac death

dissuade physicians from initiating familial screening. When comparing the cause of death attributed to a series of SCDs, there was a disparity in 41 % of cases between the referring pathologists and the specialist pathologist41. Referring pathologists were more inclined to diagnose cardiomyopathy than morphologically normal heart, with only 63 % of normal hearts being described correctly (see Figure 4). Examples of misdiagnoses can include post-mortem coronary artery collapse with mild atheroma being mislabelled as CAD; overdiagnosis of ARVC where right ventricular fatty infiltration is related to obesity, alcohol misuse or other causes; and overdiagnosis of HCM in hypertrophied hearts despite the absence of myocyte diasarray.18 A guideline has been developed by the Association for European Cardiovascular Pathology to reduce variation in practice and to provide a minimum standard, ensuring accurate, systematic examination and sampling in the autopsy investigation of SCD.42 The retention at post mortem of blood or splenic tissue allows for genetic testing, which is referred to as molecular autopsy. Genetic mutations can be identified and may be highly relevant and potentially informative as to the possible cause of SCD, and can facilitate clinical and genetic screening of family members to identify those at risk. Molecular autopsy opens the possibility to investigate ion-channel disorders such as long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome at post mortem, where the heart is unlikely to demonstrate any structural abnormality, also referred to as SADS. Complementary to the process of establishing an accurate cause of death is the process of investigating first-degree family members (see Figure 5). Where a clear cause of death is established by histopathological examination or molecular autopsy, targeted investigations suited to the detection of that condition can be applied to the relatives of the SCD patient. In cases where no clear cause has been found at autopsy, or the autopsy revealed a morphologically normal heart, investigations are used sequentially to assess for the presence of cardiomyopathy or an inheritable arrhythmogenic condition. First-line assessment

Nocon M, Hiemann T, Muller-Riemenschneider F, et al. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and metaanalysis. Eur J Cardiovasc Prev Rehabil 2008;15 (3):239–46. Chakravarty EF, Hubert HB, Lingala VB, Fries JF. Reduced disability and mortality among aging runners: a 21-year longitudinal study. Arch Intern Med 2008;168 (15):1638–46. Armstrong ME, Green J, Reeves GK, et al. Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United kingdom. Circulation 2015;131 (8):721–9. Schnohr P, O’Keefe JH, Marott JL, et al. Dose of jogging and long-term mortality: the Copenhagen City Heart Study. J Am Coll Cardiol 2015;65 (5):411–9. Van Camp SP, Bloor CM, Mueller FO, et al. Nontraumatic

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includes history, physical examination, resting 12-lead ECG, transthoracic echocardiography, exercise tolerance testing and 24h-Holter ECG monitoring. The use of further tests is predicated upon the findings of the first-line assessment. Up to 25 % of relatives of patients with SADS are diagnosed with a previously unsuspected inherited cardiac condition17 and interventions ranging from simple lifestyle modification advice to the implantation of a prophylactic implantable cardioverterdefibrillator can reduce the risk of further fatalities.

A comprehensive medical action plan that is rehearsed on a regular basis is essential to ensure the best possible outcome in the context of SCA in sports arenas.43 The importance of an effective emergency response plan is underscored by studies that have demonstrated that prompt CPR and defibrillation of athletes (within 5 minutes) resulted in survival rates in excess of 60 %.6 The same message is reiterated by studies of sports-related SCA in the general population, where a witnessed event, prompt CPR and the use of a cardiac defibrillator ventricular fibrillation were associated with higher survival to hospital discharge.11,12 The Fédération Internationale de Football Association (FIFA) support and promote a standardised and consistent level of advanced life support and emergency medical care on the football field, including a FIFA universal medical emergency bag and an ‘11-step plan to prevent SCD’. The ‘FIFA 11 steps’ include primary prevention with PPS, training of personnel on CPR, availability of AEDs, rehearsal of the emergency medical plan on an annual basis, equipment checks, logistical planning and protocols designed to enhance the resuscitation team’s performance.44

Conclusion Exercise confers substantial health benefits to the vast majority of individuals but may serve as a trigger for arrhythmic death in a small minority who harbor an occult pathological substrate. Currently, PPS of young competitive athletes is recommended and supported by many societies, associations and sporting bodies around the world. Groups, arguably at greater risk of SCD, not receiving as much attention and having less access to screening include school children playing sport, senior athletes and those undertaking grassroots, amateur and recreational sports. The aspiration is that future research in this area will improve prediction tools for SCD risk in athletes and institute tailored management, including individualized exercise prescription, to prevent fatalities. However, there will always be a need to ensure that, in the event of SCA, an appropriate emergency response plan is in place and a defibrillator is readily accessible. Finally, the SCA or SCD of a young individual should instigate comprehensive evaluation of the patient and the family to ensure that relatives at potential risk are identified and treated appropriately. n

sports death in high school and college athletes. Med Sci Sports Exerc 1995;27 (5):641–7. Drezner JA, Rao AL, Heistand J, et al. Effectiveness of emergency response planning for sudden cardiac arrest in United States high schools with automated external defibrillators. Circulation 2009;120 (6):518–25. Corrado D, Basso C, Rizzoli G, et al. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42 (11):1959–63. Corrado D, Basso C, Pavei A, et al. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA 2006;296 (13):1593–601. Papadakis M, Sharma S, Cox S, et al. The magnitude of sudden cardiac death in the young: a death certificate-based

review in England and Wales. Europace 2009;11 (10):1353–8. 10. Harmon KG, Asif IM, Klossner D, Drezner JA. Incidence of sudden cardiac death in national collegiate athletic association athletes. Circulation 2011;123 (15):1594–600. 11. Marijon E, Tafflet M, Celermajer DS, et al. Sports-related sudden death in the general population. Circulation 2011;124 (6):672–81. 12. Marijon E, Uy-Evanado A, Reinier K, et al. Sudden cardiac arrest during sports activity in middle age. Circulation 2015;131 (16):1384–91. 13. Harmon KG, Drezner JA, Maleszewski JJ, et al. Pathogeneses of sudden cardiac death in national collegiate athletic association athletes. Circ Arrhythm Electrophysiol 2014;7(2):198–204. 14. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United

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Sudden Cardiac Death in Athletes

States, 1980-2006. Circulation 2009;119(8):1085–92. 15. de Noronha SV, Sharma S, Papadakis M, et al. Aetiology of sudden cardiac death in athletes in the United Kingdom: a pathological study. Heart 2009;95 (17):1409–14. 16. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Intern Med 2004;141 (11):829–34. 17. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008;29 (13):1670–80. 18. Papadakis M, Raju H, Behr ER, et al. Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous interpretation. Circ Arrhythm Electrophysiol 2013;6 (3):588–96. 19. Yankelson L, Sadeh B, Gershovitz L, et al. Life-threatening events during endurance sports: is heat stroke more prevalent than arrhythmic death? J Am Coll Cardiol 2014;64 (5):463–9. 20. Maron BJ, Epstein SE, Roberts WC. Causes of sudden death in competitive athletes. J Am Coll Cardiol 1986;7 (1):204–14. 21. Koenig W, Ernst E. Exercise and thrombosis. Coron Artery Dis 2000;11 (2):123–7. 22. Chugh SS, Weiss JB. Sudden cardiac death in the older athlete. J Am Coll Cardiol 2015;65 (5):493–502. 23. Tabib A, Miras A, Taniere P, Loire R. Undetected cardiac lesions cause unexpected sudden cardiac death during occasional sport activity. A report of 80 cases. Eur Heart J 1999;20 (12):900–3. 24. Möhlenkamp S, Lehmann N, Breuckmann F, et al. Running: the risk of coronary events: Prevalence and prognostic relevance of coronary atherosclerosis in marathon runners. Eur Heart J 2008;29 (15):1903–10. 25. Sheppard MN. Aetiology of sudden cardiac death in sport: a histopathologist’s perspective. Br J Sports Med 2012;46 (Suppl 1):i15–21. 26. Maron BJ, Shirani J, Poliac LC, et al. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA 1996;276 (3):199–204. 27. Steinvil A, Chundadze T, Zeltser D, et al. Mandatory electrocardiographic screening of athletes to reduce their risk for sudden death proven fact or wishful thinking?

EUROPEAN CARDIOLOGY REVIEW

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J Am Coll Cardiol 2011;57 (11):1291–6. 28. Pelliccia A, Fagard R, Bjornstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26(14):1422–45. 29. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287 (10):1308–20. 30. Marcus FI. Electrocardiographic features of inherited diseases that predispose to the development of cardiac arrhythmias, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy/dysplasia, and Brugada syndrome. J Electrocardiol 2000;33 Suppl:1–10. 31. Goldenberg I, Horr S, Moss AJ, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol 2011;57 (1):51–9. 32. Gati S, Sheikh N, Ghani S, et al. Should axis deviation or atrial enlargement be categorised as abnormal in young athletes? The athlete’s electrocardiogram: time for re-appraisal of markers of pathology. Eur Heart J 2013;34 (47):3641–8. 33. Zaidi A, Ghani S, Sheikh N, et al. Clinical significance of electrocardiographic right ventricular hypertrophy in athletes: comparison with arrhythmogenic right ventricular cardiomyopathy and pulmonary hypertension. Eur Heart J 2013;34 (47):3649–56. 34. Sheikh N, Papadakis M, Ghani S, et al. Comparison of electrocardiographic criteria for the detection of cardiac abnormalities in elite black and white athletes. Circulation 2014;129 (16):1637–49. 35. Papadakis M, Carre F, Kervio G, et al. The prevalence, distribution, and clinical outcomes of electrocardiographic repolarization patterns in male athletes of African/AfroCaribbean origin. Eur Heart J 2011;32 (18):2304–13. 36. La Gerche A, Baggish AL, Knuuti J, et al. Cardiac imaging and stress testing asymptomatic athletes to identify those at risk of sudden cardiac death. JACC Cardiovasc Imaging 2013;6 (9):993–1007. 37. Borjesson M, Urhausen A, Kouidi E, et al. Cardiovascular evaluation of middle-aged/ senior individuals engaged in

38.

39.

40.

41.

42.

43.

44.

45.

46.

leisure-time sport activities: position stand from the sections of exercise physiology and sports cardiology of the European Association of Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc Prev Rehabil 2011;18 (3):446–58. Froelicher VF, Fearon WF, Ferguson CM, et al. Lessons learned from studies of the standard exercise ECG test. Chest 1999;116 (5):1442–51. Gianrossi R, Detrano R, Mulvihill D, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis. Circulation 1989;80 (1):87–98. Nasir K, Clouse M. Role of nonenhanced multidetector CT coronary artery calcium testing in asymptomatic and symptomatic individuals. Radiology 2012;264 (3):637–49. de Noronha SV, Behr ER, Papadakis M, et al. The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths. Europace 2014;16 (6):899–907. Basso C, Burke M, Fornes P, et al. Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch 2008;452 (1):11–8. Borjesson M, Dugmore D, Mellwig KP, et al. Time for action regarding cardiovascular emergency care at sports arenas: a lesson from the Arena study. Eur Heart J 2010;31 (12):1438–41. Dvorak J, Kramer EB, Schmied CM, et al. The FIFA medical emergency bag and FIFA 11 steps to prevent sudden cardiac death: setting a global standard and promoting consistent football field emergency care. Br J Sports Med 2013;47 (18):1199–202. van der Werf C, Hofman N, Tan HL, et al. Diagnostic yield sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. Heart Rhythm 2010;7 (10):1383–9. Corrado D, Pelliccia A, Bjornstad HH, et al. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol. Consensus Statement of the Study Group of Sport Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26 (5):516–24.

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The Diagnosis and Clinical Implications of Interatrial Block Ant onio Ba y és de Luna , Alb e r t M a s s ó - v a n Ro e s s e l , a n d L u i s A l b e r t o E s c o b a r Ro b l e d o Cardiovascular Research Center, CSIC-ICCC, St Pau Hospital, Barcelona, Spain

Abstract Impaired interatrial conduction or interatrial block is now well-documented but is not described as an individual electrocardiographic (ECG) pattern in the majority of ECG literature. In fact the term atrial abnormality has been adopted to encompass both left atrial enlargement (LAE) and interatrial block. In this paper, we maintain that interatrial blocks and atrial enlargement are separate entities, and that interatrial blocks, similar to other types of blocks at sinoatrial, AV junctional, and ventricular level, exhibit a specific ECG pattern that may present first, second, and third degree types of conduction block. The third degree or advanced interatrial block (A-IAB) is frequently associated with atrial fibrillation/atrial flutter (AF/AFl), and constitutes a true newly-described syndrome.

Keywords Bayes Syndrome, paroxysmal AF and interatrial block, P plus/minus in II, III, and VF, prevalence of Interatrial block Disclosure: The authors have no conflict of interest to declare. Received: 22 June 2015 Accepted: 16 July 2015 Citation: European Cardiology Review, 2015;10(1):54–9 Correspondence: Antoni Bayés de Luna, Catalan Institute of Cardiovascular Sciences – ICCC, C/ Sant Antoni Ma Claret, 167, 08025 Barcelona, Spain. E: abayes@csic-iccc.org

It has been considered that an interatrial block exists when there is a delay of conduction in some part of the Bachmann’s bundle zone.1 The interatrial blocks are the most frequent and well-known blocks at atrial level. These are expressed in the electrocardiogram (ECG) by the presence of a P wave duration that equals or exceeds 120 milliseconds and presents usually a bimodal morphology, especially in leads I, II, VL or inferior leads. This represents partial IAB (P-IAB). If there is a P wave morphology ± in II, III, and VF with duration ≥120 ms, we speak about advanced interatrial block (A-IAB) (see Figure 1)1-3.

Which are the P wave ECG Patterns that Meet the Criteria for Interatrial Block? The P wave ECG Pattern of Interatrial Block May be Transient The presence of transient deterioration of interatrial conduction, that is interatrial block, of first or third degree may appear in the same ECG recording on a beat-by-beat basis or in separate recordings. The first case may be considered as a part of the concept of atrial aberrancy, a term first coined by Chung4 in 1972, similar to ventricular aberrancy (see later)2,4.

The P wave ECG Pattern of Interatrial Block May Appear without Associated Atrial Enlargement The prolonged P wave duration (P-wave duration ≥120 milliseconds) may be present in the elderly but can also be a consequence of acute illness, such as pericarditis or acute myocardial infarction without atrial enlargement (ECG pattern of partial interatrial block P-IAB). In fact, in these cases, the duration of P wave may be as long as in left atrial enlargement (LAE), but the P loop does not move so clearly backwards, as in a figure 8 shape, which results in a much smaller negative P wave component in lead V1 (see Figure 2). The combination of LAE with advanced interatrial block (A-IAB) (wide P wave ≥120 milliseconds and ± in leads,

Luna_FINAL.indd 54

II, III, and VF) is very common but isolated cases of A-IAB may be seen. As the P wave often looks flat, to be accurate in the measurement in both types of IAB it is necessary to trace lines, as seen in Figures 4 and 6.

The P wave ECG Pattern May be Reproduced Experimentally (see Figure 3) Experimental studies5 have demonstrated that cutting the Bachmann’s bundle at either the right or left atrial side results in a typical ECG pattern with wide P wave with biphasic ± morphology in inferior leads. It was also demonstrated6 that an attenuation of interatrial conduction, without affecting atrioventricular conduction, may occur after ablation of interatrial conduction zones along the right atrial septum. This intervention produces partial interatrial conduction block with an increase of P wave duration.

Interatrial Blocks May be of First, Second, and Third Degree The interatrial blocks, by analogy with other types of block, (sinoatrial, atrioventricular, and/or bundle-branch block at the ventricular level), may be of first (partial), second (transient interatrial block is part of atrial aberrancy), or third degree (advanced).

Electrocardiographic Pattern of First-degree (Partial) Interatrial Block (see Figures 1-B, 4) The P wave has a normal electrical axis. The electrical impulse is conducted from the right to the LA through the normal propagation route but with a delay. The endocardial recording confirms that the coronary sinus activation time is delayed. The ECG shows that (a) a P wave of 120 milliseconds or more, usually bimodal, is especially visible in leads I, II, or III, and (b) the P wave morphology in V1 in the absence of left atrial enlargement (LAE)

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The Diagnosis and Clinical Implications of Interatrial Block

presents a P wave negative mode that is less evident than in cases of LAE, because in the absence of LAE, the P loop is directed in a less backward direction (see Figures 2 and 4). However, in the instance of P wave duration of 120 milliseconds or more the presence of LAE is common. In fact, it has been considered that the wide and bimodal P wave of LAE is better explained in terms of underlying interatrial block rather than the longer distance that the impulse has to travel7. LAE is often found in the elderly8, in patients with heart failure9 and those with other advanced heart diseases. We also demonstrated that it is a risk marker of atrial fibrillation/atrial flutter (AF/Afl)10.

Electrocardiographic Pattern of Second-degree Interatrial Block (see Figure 5) Similar to the conduction block at the level of AV junction, SA junction, or the ventricles, the interatrial block may occur transiently on a beatby-beat basis or may be recorded momentarily. In a typical case, the morphology of the P wave may change in the same recording from interatrial block pattern (first or third degree) to normal pattern, usually transiently in relation to the preceding premature beats, before then again presenting the pattern of interatrial block. These changes may be considered as atrial aberrancy, similar to ventricular aberrancy2,4.

Table 1 : Prevalence of IAB in a Cohort of Global Population of 70–80 Years and 100 Years Normal P

70-80 years 100 years (n=195) (n=81) 101 of 195 (51.7 %) 23 of 81 (28.4 %)

p < 0.01

Pa-IAB

58 of 195 (29.7 %)

16 of 81 (19.7 %)

p = 0.09

Ad-IAB

15 of 195 (7.7 %)

21 of 81 (19.7 %)

p < 0.01

At Fr/Fl

21 of 195 (10.8 %)

21 of 81 (19.7 %)

p < 0.01

17 of 60 (28.3 %)

p < 0.01

Atrial Premature Beats 15 of 174 (8.6 %)

P Value

Pa-IAB (partial interatrial block) Ad-IAB (advanced interatrial block) At Fr/Fl (atrial fibrillation/flutter)

Figure 1: Left: Scheme of Atrial Activation in a Normal P wave (A), in Presence of Partial IAB (B), and of Advanced IAB (C). Right: Characteristics of the P loop and P wave in Each Case A

Scheme of atrial activation

P loop in FP Y

Normal atrial block

0.10 s

B Partial interatrial block Advanced interatrial block with left atrial retrograde activation

P loop in VF

X 0.12 s

C E

X 0.12 s

Atrial aberrancy may also present a transient bizarre P wave without the morphology of interatrial block. In these cases, the location of the block is usually the right atrium.

We want to note that in normal conditions, the breakthrough in left atrium also occurs at the level of coronary sinus. The dotted line shows that the Bachmann’s bundle is the preferential route of interatrial conduction. The remaining atrial activation is performed without preferential pathways. The primary left atrium breakthrough is in the Bachmann’s bundle, and also often in the fossa ovalis area (see arrow).

Electrocardiographic Pattern of Third-degree (advanced) Interatrial Block (Figures 6–8)

Figure 2: (A and B) P wave Morphology in V1 and P loop in a Case of Isolated Partial Interatrial Block (B) and Associated with Left Atrial Enlargement (A)

The electrical impulse is blocked especially in the upper and middle part of the interatrial septum, in the Bachmann’s bundle zone, and/or in the upper part of LA so that retrograde left atrial activation occurs mainly via muscular connections in the vicinity of coronary sinus 2,3,11,12. In rare occasions, the right atrium and LA can demonstrate dissociated electrical activity.

The ECG shows that (a) P wave duration of 120 milliseconds or more and (b) the morphology of P wave are usually bimodal in lead I and biphasic [±] in leads II, III, and VF because of caudocranial activation of the LA, and also often in V1 to V3–V5 (see Figure 6). The electrophysiological mechanism underlying this ECG pattern has been explained using deductive ECG-VCG data correlated with recordings obtained from the high and low right atrium, coronary sinus, right pulmonary artery, and oesophagus and also with electroanatomic mapping11,12 (see Figures 7 and 8). It has been also demonstrated that the block may be located in the LA not affecting conduction through the proximal Bachmann’s bundle. However, this does not modify the terminal inferosuperior activation of the LA that explains the typical morphology ± in II, III, and VF. In fact, in dogs, the same ± morphology appears after cutting the Bachmann’s bundle at the right and left sides of the septum5 (see Figure 3). Bayés de Luna et al13 defined the ECG-VCG criteria and demonstrated that this type of block is a very specific (90 %) but insensitive

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The ECG has to be recorded with the electrode of V1 accurately located because if it is in a high location (3rd-2nd intercostal space) the depth of negativity in P and V1 is higher.

marker of LAE. The duration of P wave is 120 milliseconds or more (120–170 milliseconds in this sample of 83 cases). However, it is the morphology of the P wave (± in inferior leads) that pinpoints that there is a retrograde activation of the LA. The positive mode of P waves in leads II, III, and VF is at times not well-observed, probably because of fibrosis, and the diagnosis of junctional rhythm due to an apparently negative P wave in II, III, and VF may be made. It was demonstrated that this type of block is very frequently accompanied by paroxysmal atrial arrhythmia, especially atypical atrial flutter in patients with valvular heart diseases and cardiomyopathies. As a result, this association is considered an ECG clinical syndrome10,14.

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Electrophysiology and Sudden Cardiac Death Figure 3: Adapted from Experimental Bachmann’s Bundle Block (Waldo et al. 1971) A

In an in-hospital population, Spodick, using as a criterion of IAB the presence of P wave ≥100 ms, identified the prevalence of IAB (most likely partial IAB) in 47 % of the screened population (1,000 patients), being highly prevalent in the subgroup above 60 years of age15.

The prevalence of partial (P) and advanced A–IAB is rare before the age of 50. In our experience8 (see Table I), the prevalence is much higher with advancing age. In centenarians the prevalence of A-IAB is higher than that of P-IAB. Also ageing increases the prevalence of AF/Afl, being 10 % at ages 70–80 and 26 % in centenarians.

B S

20 msec

20 msec A

Prevalence of IAB

B S

Recently, we have found in patients with heart failure a prevalence of A-IAB of 10 %9. After BB (RA) lesion

After BB (LA) lesion

(A) Control P wave recorded in ECG lead II when the atrial were paced from the right atrium. See the change of morphology after Bachmann’s bundle lesion in the right sife. (B) P wave recorded in lead II after the creation of a lesion in the left atrial (LA) portion of Bachmann’s bundle (BB). In both cases the changes in conduction time and morphology after block are shown. (Adapted with permission from Waldo (1971)).

Figure 4: This is an Example of Partial Interatrial Block without Left Atrial Enlargement

Identification of the Syndrome Bayés de Luna et al10 reported on a single sample of patients with long-term follow-up to better characterise the incidence of atrial tachyarrhythmias in patients with advanced IAB (16 patients) and compared them with patients with partial IAB (22 patients) but similar echocardiographic parameters. The advanced IAB group presented a higher incidence of atrial flutter/fibrillation (15/16, 93.7 %) during a 30-month follow-up compared with the control group with partial IAB (6/22, 27.7 %) (p < 0,0001). At one year of follow-up, the incidence of arrhythmias was 80 % and 20 % respectively (see Figures 10 and 11). Additionally, Holter monitoring showed that the prevalence of frequent premature atrial contractions (more than 60/h) was much more frequent in advanced (75 %) than in partial (25 %) IAB. In 1998 Bayés de Luna, et al published a review paper in which they summarised all previous research published in this topic; suggesting that the association between advanced IAB and atrial tachyarrahythmias constitute a true syndrome14. Since then, different groups have confirmed this association16–18 and a recent consensus on IAB has accepted the diagnostic criteria and clinical association of advanced IAB with atrial arrhythmias3. This association is now considered a unique syndrome that should be known as Bayes’ Syndrome19,21.

Should we Prevent Atrial Arrhythmias in Patients with IAB? See the wide P wave duration (around 150 ms) in aVF and the predominant positivety of the P wave in V1. In cases of IAB, very often due to the presence of atrial fibrillation, the P wave is flat and difficult to measure. Therefore in some leads (in the figure for instance) P wave in V1 looks much shorter.

Figure 5: A Clear Example of Second-degree Advanced IAB

The ± P wave pattern is clearly seen in II in the first two complexes, then a PVC and after a long pause the refractory period of the atria is finished, and the next the P wave is normal. Later the ECG pattern of A-IAB again appears.

During long-term follow-up, especially in patients with mitral valve disease or cardiomyopathy, the successive appearance of first-degree and later third-degree interatrial block may be seen (see Figure 9).

Luna_FINAL.indd 56

The strong relationship between advanced IAB and atrial flutter/ fibrillation led us to investigate the possible role of preventing atrial arrhythmias using antiarrhythmic drugs22. A small comparative trial of patients with advanced IAB received either an antiarrhythmic drug or a placebo. A significant reduction of AF recurrences was observed at follow-up in the group receiving prophylactic antiarrhythmic medication. Despite the small sample, this study should be considered pioneering by suggesting the treatment of patients early on when advanced IAB is detected, in order to reduce the incidence of atrial arrhythmias. This hypothesis needs to be confirmed with larger studies and samples. We have not tested the possible benefits of antithrombotic therapy in this group of advanced IAB, as currently, the presence of documented AF is still needed, to start anticoagulation medication. However, as an interesting hypothesis, it could be reasonable to consider anticoagulation if the patient presents with advanced IAB and a

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The Diagnosis and Clinical Implications of Interatrial Block

CHA2DS2-vasc score 3 and the patient presents with advanced IAB. The evidence on the one hand shows that in patients with A-IAB there is an LA disfunction with important electromechanical changes23 and on the other that in many instances the AF is a risk factor but not the actual cause of stroke24 and it may be important to consider the possibility of treatment with antithrombotic therapy in patients with A-IAB and a CHA2DS2-vasc score 3, especially if they show atrial arrhythmias in Holter monitoring. This suggested hypothesis needs to be tested before making any convincing recommendations. However, several studies with poor results have tried to resynchronise the atria with bi-atrial pacing. There is still no consensus whether this technique reduces the incidence of AF and this technique did not prove to be superior to sequential pacing3.

Research on this Topic We would like to briefly review some of the important contributions different groups have published on this topic. Special attention should be paid to the group based in the USA and led by Dr Spodick who investigated several aspects of IAB and specifically its relation to stroke and to the electromechanical dysfunction of the left atrium associated with IAB24,25.

Figure 6: Typical ECG of Advanced Interatrial Block (P ± in II, III, and VF and Duration of 180 ms) in a Patient with Ischaemic Cardiomyopathy

When amplified we can see the beginning of P in the three leads.

Figure 7: Above: P-wave ± Morphology in I II and III Typical of Advanced Interatrial Block with Retrograde Conduction to the Left Atrium >0,12 s

-60º H.E.

Daubert’s group from France, studied different aspects of atrial pacing associated with the presence of advanced IAB26. Garcia-Cosio’s group from Spain performed interesting studies using intracardiac mapping, demonstrating the retrograde activation of the left atrium in these patients27. Platonov and Holmqvist studied the characteristics of the P wave morphology according to the manner of atrial activation and the relation of this pattern to atrial fibrillation28,29. In the past three years, the groups of Baranchuk and Conde from Canada and Argentina have added to the knowledge of the syndrome. Those findings considered the most important are: a) the presence of advanced IAB was a strong predictor of new atrial flutter/fibrillation post-cavotricuspid isthmus ablation for typical atrial flutter16; b) the presence of advanced IAB in patients with Chagas disease implanted with defibrillators was a strong predictor of new AF in the follow-up17; c) the presence of advanced IAB is highly prevalent in patients with sleep apnoea and this probably could explain the higher incidence of AF in these patients; d) treatment with CPAP could induce reverse atrial remodelling and resolution of IAB; and e) the presence of advanced IAB predicts new onset AF in patients with severe heart failure and RT18.

I HRA

120º

LRA

III

p a

QRS h

+60º

0,12 mv

RSP

Observe the angle between the direction of the activation in the first and second parts of the P wave measured. To the right, intra-oesophageal ECG (HE) and endocavitary registration high right atrium (HRA); ow right atrium (LRA) demonstrate that the electrical stimulus moves first downwards (HRA-LRA) and then upwards (LRA-HE). Below: P loop morphology in the three planes with the inscription of the second part moving upwards.

Figure 8: Virtual Anatomic Rendering of the LA in a Patient with Typical Biphasic (±) Pwave in Leads II, III, and a VF Typical of Bachmann’s Bundle Block

Future Directions It is our intention to highlight the association of advanced IAB, which can be easily recognised in a surface 12-lead ECG, with atrial arrhythmias (specifically AF). Future investigations (some of them ongoing studies of our international collaboration group) should be considered:

Note that early left atrial activation (white) occurs at the high septal wall, as expected for Bachmann’s bundle conduction. Activation does not progress through the left atrial roof because of the presence of a large zone of low voltage (grey) that diverts activation toward the low septal (orange-yellow), then the low posterior (green) and finally the high posterior (violet) left atrial wall.

• To create an international register that would allow for longitudinal follow-up of these patients. • To perform studies to evaluate the prevalence of IAB and its association with atrial arrhythmias in different clinical settings including: a) after electrical cardioversion (larger observational studies)(ongoing); b) cardiac surgery for aortic and mitral valve replacement (ongoing); c) in

patients with heart failure (ongoing); d) in patients with hypertrophic cardiomyopathy and other forms of less frequent cardiomyopathies and e) in athletes. • To determine the prevalence of IAB in special populations (i.e. atrial septum abnormalities, haemodialysis (ongoing), cryptogenec stroke, patients with fibrotic diseases).

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Electrophysiology and Sudden Cardiac Death Figure 9: Progressive Interatrial Block – Three ECGs from a Patient with Mitro-aortic Valve Disease

Figure 11: Two Atrial Flutter Morphologies in the Same Patient: Typical Atrial Flutter with Negative F Wave with Saw-teeth Morphology (b) and a Typical Atrial Flutter (a) with Positive F Wave

Observe the angle between the direction of the activation in the first and second parts of the P wave measured. To the right, intra-oesophageal ECG (HE) and endocavitary registration high right atrium (HRA); low right atrium(LRA) demonstrate that the electrical stimulus moves first downwards (HRA-LRA) and then upwards (LRA-HE). Below: P loop morphology in the three planes with the inscription of the second part moving upwards.

(A) P wave in II, III, and VF with normal atrial duration (P=105 ms) and P wave of pseudo P pulmonary type- (B) Four years later an intermediate morphology that corresponds to a first-degree interatrial block (P=135 ms) is recorded. (C) A typical advanced interatrial block appearing after five years with P ± morphology in II, III, and VF (P= 145 ms).

Probability of remaining free of supraventricular tachyarrythmias

Figure 10: Life Table Analysis of the Probability of Remaining Free of Supraventricular Tachyarrhytmias in Patients with Advanced Interatrial Block (IAB) and Retrograde Activation of the Left Atrium (RALA) and Controls 1

Conclusion

0.9 0.8 0.7 0.6 0.5

P<0.001

0.4

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Although all IABs are more frequently associated with atrial arrhythmia, its incidence is much higher in advanced IABs when compared with partial IABs. The presence of advanced IAB associated with supraventricular arrhythmias constitutes a true syndrome, named as Bayes’ Syndrome.

0.3

IAB + RALA 0.2 0.1

Follow-up (months)

Interatrial blocks are a separate entity from atrial enlargement and may be of first (partial), second degree (intermittent) or third degree (advanced). This ECG pattern may be transient, it may present simultaneously without left atrial enlargement (or not), and it may be reproduced experimentally. Advanced interatrial block presents a clear ECG pattern (P ≥120 ms with a ± morphology in leads II, III and VF).

Control G

• To study the correlation by cardiac MR between advanced IAB ECG pattern and extension of atrial fibrosis. • To confirm the hypothesis that early intervention with arntiarrhythmic drugs may represent a reduction in the incidence of new AF. • To determine whether patients with CHA2DS2-score > 3 and advanced IAB, regardless of the documentation of AF, would benefit from oral anticoagulation. • To determine if there are any genetic influences.

Further studies will help in characterising the syndrome in different clinical scenarios. n

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The Diagnosis and Clinical Implications of Interatrial Block

Bayés de Luna A, Clinical Electrocardiology: a textbook. Chichester, West Sussex, UK: Wiley-Blackwell 2012. Bayés de Luna A. Bloqueo a nivel auricular, Rev Esp Cardiol . 1979;39:5–10. 3. Bayés de Luna A, Platonov P, Garcia Cosio F, et al. Interatrial blocks. A separate entity from Leith atrial enlargement: a consensus report. Journal of Electrocardiology . 2012;45:445–51. 4. Chung E. Aberrant atrial conduction. Br Heart J .1972;34:341. 5. Waldo A, Hurry L, Bush J, et al. Effects on the canine P waves of discrete lesions in the specialised atrial tracts. Circulation Res. 1971;29:452. 6. Schwartzman D, Warman EN, Devine WA, et al. Attenuation of interatrial conduction using right atrial septal catheter ablation. J Am Coll Cardiol . 2001;38:892. 7. Josephson ME, Kastor JA, Morganroth J. Electrocardiographic left atrial enlargement. Electrophysiologic, echocardiographic and haemodynamic correlates. Am J Cardiol. 1977;39:967. 8. Martínez-Sellés M, Massó-van Roessel A, Alvarez-Garcia J, et al. The ECG atrial activity in centenarians. Malt meeting . Abstract book p.8 9. Alvarez-Garcia J, Massó-van Roessel A, Goldwasser D, et al. The ECG atrial activity in patients with heart failure. Int-Congress ISHNE . Abstract book p. 4 10. Bayés de Luna A, Cladellas M, Oter R, et al. Interatrial conduction block and retrograde activation of the left atrium and paroxysmal supraventricular tachyarrthymias. Eur Heart J . 1988;9:1112. 11. Holmqvist F, Husser D, Tapanainen JM, et al., Interatrial conduction can be accurately determined using standard 12-lead electrocardiography: validation of P wave morphology using electroanatomic mapping in man. Heart Rhythm. 2008;5:413. 2.

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12. C osio FG, Martín-Peñato A, Pastor A, et al. Atrial activation mapping in sinus rhythm in the clinical electrophysiology laboratory. Observations in Bachmann’s bundle block. J Cardiovasc Electrophysiol. 2004;15:524. 13. Bayés de Luna A, Fort de Ribot R, Trilla E, et al. Electrocardiographic and vectorcardiographic study of interatrial conduction disturbances with left atrial retrograde activation. J Electrocardiol . 1985;18:1. 14. Bayés de Luna A, Guindo J, Viñolas X, et al. Third-degree interatrial block and supraventricular tachyarrhythmias. Europace. 1999;1:43. 15. Spodick D, Ariyarajah V. Interatrial block; a prevalent widely neglected and portentous abnormality. JECG . 2008;41:61. 16. Enriquez A, Sarrias A, Villuendas R, et al. New-onset atrial fibrillation after cavotricuspid isthmus ablation. Identification of advanced interatrial block is key. Europace on line . February 10, 2015. 17. Enriquez A, Conde D, Femenia F, et al. Relation of interatrial block to new-onset atrial fibrillation in patients with Chagas cardiomyopathy and implantable cardioverter-defibrillators. Am J Cardiol . 2014;113:1740–3. 18. Sadiq Ali F, Enriquez A, Conde D, et al. Advanced Interatrial block predicts new onset atrial fibrillation in patients with severe heart failure ad cardiac resynchronisation therapy. Ann Noninvasive Electrocardiol . 2015;00:1–6. 19. D Conde, A Baranchuk. What a cardiologist must know about Bayes’ Syndrome. Rev Argent Cardiol . 2014;82:220–2. 20. D Conde, A Baranchuk. Bloqueo interauricular como sustrato anatómico-eléctrico de arritmias supraventriculares: syndrome de Bayés. Arch Cardiol Mex . 2014;84(1):32–40.

21. B acharova L, Wagner G. The time for naming the interatrial block syndrome: Bayes’ Syndrome. Journal of Electrocardiology . 2015;48:133–4. 22. Bayés de Luna A, Cladellas M, Oter R, et al. Interatrial conduction block with retrograde activation of the left atrium and paroxysmal supraventricular tachyarrhythmias: influence of preventive antiarrhythmic treatment. Int J of Cardiology. 1989;22:147–50. 23. Martin D, Bersohn M, Waldo A, et al. Randomised trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronisation devices. European Heart Journal on line , April 23, 2015. 24. Ariyarajah V, Apiyasawat S, Najjar H, et al. Frequency of interatrial block in patients with sinus rhythm hospitalised for stroke and comparison to those without interatrial block. Am J Cardiol . 2007;99:49–52. 25. Goyal S, Spodick D. Electromechanical dysfunction of the left atrium associated with interatrial block. Am Heart J . 2001;142:823–7. 26. Daubert JC, Pavin D, Jauvert G, Mabo P. Intra-and interatrial conduction delay: implications for cardiac pacing. Pacing Clin Electrophysiol , 2004;27:507–25. 27. Garcia Cosio F, Martín-Peñato A, Pastor A, et al. Atrial activation mapping in sinus rhythm in the clinical electrophysiology laboratory: observations during Bachmann’s bundle block. J Cardiovasc Electrophysiol . 2004;15:524–31. 28. Holmqvist F, Platonov PG, Mcnitt S, et al. Abnormal P wave morphology is a predictor of atrial fibrillation in MADIT II patients. Ann Noninvasive Electrocardiol . 2010;15:63–72. 29. Platonov PG. Atrial conduction and atrial fibrillation. What can we learn from ECG? Cardiol J . 2008;15:402–7.

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Atherosclerotic Disease Prevention

At the Heart of Brain Disorders – Preventing Cognitive Decline and Dementia Augusto Vicario and Gustavo H. Cerezo Buenos Aires Cardiovascular Institute, Argentina

Abstract Vascular risk factors are shared by heart and brain. Vascular brain injury (small vessel disease, stroke) alone or combined with neurodegenerative pathology (β-amyloid depositions) brings about either cognitive decline and vascular dementia or Alzheimer’s disease. Long-term exposure to vascular risk factors precedes the onset of neurocognitive diseases by one or two decades. Early detection and control of modifiable vascular risk factors seem to be the only current strategies to prevent cognitive impairment and dementia.

Keywords Cognitive impairment, dementia, Alzheimer’s disease, vascular dementia, vascular risk factors, cardiovascular prevention. Disclosure: The authors have no conflict of interests to declare. Received: 14 April 2015 Accepted: 10 July 2015 Citation: European Cardiology Review, 2015;10(1):60–3 Correspondence: Augusto Vicario, Heart-Brain Unit, Department of Clinical Cardiology, Buenos Aires Cardiovascular Institute, Blanco Encalada 1543/47, Buenos Aires, Argentina. E: augusto.vicario@gmail.com

Heart-brain interaction is an indisputable fact. The connection between vascular risk factors and/or cardiovascular disease and cognitive impairment and dementia has been supported by countless publications in the past 30 years. The most important studies concluded that vascular brain injury exacerbates cognitive ageing, and increases the risk for dementia both in its vascular type and in its degenerative type (Alzheimer’s disease). However, the negative impact of vascular risk factors depends on, first, the length of exposure to vascular injury, and second, the burden of vascular injury accumulated over time. This connection, complex in essence, is actually an inverse problem because the aim is to identify the past circumstances that have led to heart and/or brain disease. A myriad of strategies for controlling the problem may arise from the interpretation of the facts and the plausible associations derived from scientific observation. Over the past 50 years, vascular medicine – based on major technological developments – has significantly extended lifespan, but has failed to put forth prevention strategies to reduce heart and cerebrovascular morbimortality. Timely intervention on modifiable vascular risk factors might diminish the prevalence of both cardiovascular and neurocognitive diseases, and place prevention at the core of the matter. A deep understanding of the heart-brain interaction will enable the implementation of health policies that ensure normal brain ageing, and thus longer preservation of intellectual capacity and autonomy. This review intends to discuss this heart-brain connection, describe how uncontrolled vascular disease impacts on cognition, and emphasise the importance of prevention and health promotion messages. This review is based on bibliographic consultations in: MEDLINE, SciELO, EMBASE, LILACS, and other data sources. The terms employed for the search were: cognitive impairment, dementia, Alzheimer’s disease,

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vascular risk factors, and cardiovascular prevention. Bibliography from the past 10 years was examined including review studies, original research papers, population-based epidemiological studies, and intervention studies.

Vascular Risk in Cognitive Diseases In 2010, the joint report of the World Health Organisation and Alzheimer’s Disease International claimed that there were 35.6 million people with dementia in the world, and anticipated that the figure would almost triple by 2050 (115 million)1. Four years later, the projection was increased by 15 % (135 million people with dementia)2. Longer life expectancy has contributed to this epidemic growth, especially in the population aged 60 or over, and particularly in the over-80 age group. According to the World Health Organisation, in high-income countries, average life expectancy is 8.7 years for 80-year-old men and 11 years for 80-year-old women, (30 % more than three decades ago)3. The main reason for this occurrence is the continuing drop in mortality rate from heart and cerebrovascular diseases due to the technological advances of the past 50 years. Identification of vascular risk factors, new drugs that have been developed and new techniques, such as coronary artery bypass grafting, balloon angioplasty and stent implants, paradoxically seem to have contributed to the main risk factor for dementia in old age. Medicine has improved the prognosis of manifest vascular disease, and it has also prolonged life expectancy; however, heart and cerebrovascular diseases are still the main cause of death throughout the world (≈30 %)4. The same vascular risk factors that affect cardiovascular health also compromise cerebrovascular health. Vascular brain injury and the resulting cellular damage (oxidative stress, swelling) appear to be the causes of the altered brain ageing process, leading to increased risk for stroke, cognitive decline, dementia, depression, and other neurological problems, such as gait disorders.

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Preventing Cognitive Decline and Dementia

From this perspective, the prevalence of dementia will continue to increase as long as the scientific method is systematically focused on the treatment for the dementia syndrome and not on its prevention. The only way to reduce or eradicate its incidence is by implementation of preventative approaches. In accordance with the World Health Organisation definition, prevention covers measures which not only to prevent the occurrence of disease, but also arrest its progress and reduce its effects once established, thus, it is imperative to appraise population vulnerability; i.e. ascertain what it is we have to prevent.

Figure 1. Connection between Vascular Disease and Cognitive Disease.

Hypertension or VRF, CV disease

Stroke

β-amyloid

SVD

Cardiovascular Health and Incidence of Dementia Decline Despite the fact that dementia has reached epidemic levels due to the increasing number of people that are affected by it, recent publications have reported its incidence is actually declining. This trend may follow improvements in education quality and more effective control of vascular risk factors. Both the Mayo Clinic Study (2005)5 and the Health and Retirement Study (2008)6 informed a 50 % drop in the prevalence of cognitive decline (from 5.7 % to 2.9 %) in a 17-year period, and a 29 % drop (from 12.2 % to 8.7 %) in a nine-year period. The retrospective interpretation of these results is that this decrease stems from a reduction of the stroke rate, improvements in health education and favourable changes in lifestyle (i.e. control of vascular risk factors). Three European studies (Rotterdam Study, Cognitive Function and Ageing Study I-II and a study carried out in the Swedish population)7,8,9, with similar results, agree that the explanation may be better control of vascular disease and vascular risk factors. The comparison of two sub-cohorts in the Rotterdam study (10 years apart) underscored the finding that in the most recent cohort, the incidence of dementia was lower, the participants’ brains were bigger (i.e. less atrophy) with fewer white matter lesions7 , and this was attributed to the fact that this group took more antihypertensive and antithrombotic (aspirin) drugs and statins. In a nutshell, “…there is evidence from various studies that in highincome countries, the incidence of dementia is decreasing due to high levels of education and improvement in cardiovascular health.” (Alzheimer’s Report 2014)2. In essence, every case of vascular disease will be somehow associated with vascular brain injury and, consequently, with neurocognitive diseases. Middle-age hypertension is related to the progression of white matter lesions, cognitive impairment and mood disorders10,11, diabetes seems to add loss of brain volume to vascular lesions, and obesity has also been associated with higher risk for dementia13. Cognitive impairment in patients with metabolic syndrome appears to be directly linked to the number of components encompassed in the particular syndrome and the metabolic disorder involved14; smoking more than two packs of cigarettes a day increases the risk for dementia 20 years later15, and atrial fibrillation with inadequate anticoagulation therapy increases the risk for stroke and dementia (Alzheimer’s disease) irrespective of vascular disease16,17 (see Table 1). New studies have reported that aggregate exposure to vascular risk factors since early stages in life is also associated with worsening cognition in mid-life 18. Accordingly, identification of

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Vascular cognitive impairment

Dementia; vascular or Alzheimer

Neurodegenerative brain lesion

Hypertension alone or associated with other vascular risk factors (VRF), or cardiovascular disease (CVD) are responsible for both cerebral small vessel disease (SVD) and stroke. This vascular brain injury either results in vascular dementia or exacerbates neurodegenerative pathology (β-amyloid) thus hastening the onset of Alzheimer’s disease. Nowadays, most types of dementia are considered mixed forms that share pathological mechanisms and risk factors.

vascular risk factors and the duration of exposure when they may have had a negative impact on health can be considered targets for prevention.

Physiopathological Heart – Brain Connection There are three disorders through which vascular disease brings on mild cognitive decline or dementia: i) stroke, ii) small vessel disease, and iii) β-amyloid depositions (Aβ) that contribute to neurodegenerative phenomena. (see Figure 1)

Stroke Fifty per cent of strokes may be attributed to hypertension, and they constitute the main risk factor for cognitive impairment or post-stroke dementia. The prevalence of post-stroke cognitive decline has a broad range, from 20 % to 80 %19. This variability depends on the diagnostic tools and the criteria employed, on the extent of the vascular and neurodegenerative pathologies before the stroke, on the cognitive status, on the stroke extension (volume) and topography (i.e. strategic areas such as frontal cortex, hippocampus or white matter). Cerebral blood flow self-regulation alterations induced by brain ageing, vulnerability to hypoperfusion and hypoxia, lacunar infarcts (responsible for 70–90 % of vascular cognitive impairment), micro-haemorrhages, and neuron damage (protein synthesis and synaptic plasticity) account for the complex association between stroke and cognition. Post-stroke cognitive status is not confined to vascular cognitive impairment or vascular dementia; it may also play a role in the genesis of Alzheimer’s disease and mood disorders (depression). The Nun’s Study has shown that lacunar infarcts cause a 20-fold increase in the risk for Alzheimer’s disease20, and the PROGRESS Study (Perindopril Protection against Recurrent Stroke Study) has indicated that hypertension treatment reduces the risk for poststroke dementia in 34 %21. Depression in older adults is closely related to subcortical vascular pathology, thus supporting the vascular depression hypothesis22. This syndrome presents a high post-stroke prevalence that ranges from 35 % to 50 %.

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Atherosclerotic Disease Prevention Table 1. Modifiable risk factors that increase the risk for dementia; length of exposure and preventive measures.

Modifiable Risk Factors

Length of Exposure Age (years) Preventive Measures

Comments

Education

Childhood–adolescence (5–20)

Risk reduction RR≈40 %

Health promotion formal education Education policy

CV Risk Factors Hypertension

Midlife (40–50)

Prevention, detection and control

Probably substantial impact on prevalence of dementia (VD)

Diabetes

Midlife and late-life (60 –70)

Prevention, detection and metabolic control

Both types of dementias (VD or AD)

Obesity

Midlife

Weight loss, physical activity and diet

No strong evidence

Hypercholesterolemia

Midlife

Treatment

Increased risk (AD)

From childhood, adulthood

Physical activity, exercise according to

Protective effect risk reduction + 40 %

Lifestyle Physical inactivity

age and fitness Smoking

Midlife and late-life

Smoking cessation

14 % of dementia attributable to smoking

Abbreviations: VD, vascular dementia; AD Alzheimer’s disease.

Small Vessel Disease Small vessel disease is essentially associated with hypertension. The blood vessels supplying the white matter (penetrating arteries, branches of subarachnoid and subependymal arteries) are terminal arteries. The absence of collateral circulation renders the periventricular regions vulnerable to atherosclerotic ischaemic damage. The ischaemic episodes and the reactive gliosis lead to a process called araiosis (rarefaction) that damages the nerve myelin. White matter hyperintensities (leucoaraiosis) and lacunar infarcts seen in neuroimages are the objective signs of these vascular abnormalities that cause white matter demyelination and subcortical-cortical disconnection or desaferentisation syndrome. The disconnection of the dorsolateral prefrontal cortex – the most affected circuit –gives rise to a cognitive syndrome called executive dysfunction, a distinctive feature of vascular brain injury and commonly seen in hypertensive patients23,24. On the other hand, selective neocortical atrophy (grey matter volume in the frontal lobes) may also contribute to the executive dysfunction25.

which, in turn, leads to its clinical expression (dementia), supporting the hypothesis that vascular and neurodegenerative injuries are the extreme points of a spectrum, within which most of the various forms of dementia can be found. Neurodegenerative pathology seems to be a necessary but not sufficient condition. The vascular damage (endothelial dysfunction, ischaemia, blood-brain barrier disruption) alters the balance between Aβ production and clearance, thus increasing Aβ levels in the brain with the toxic consequences (reactive oxygen species production and inflammatory response)30. Recent publications report that patients with treated but uncontrolled hypertension increase their brain Aβ depositions31,32,33. Knowledge of the role vascular injury plays in the clinical expression of Alzheimer’s disease may open up new avenues to explore in the search for dementia prevention by employing strategies that either treat or prevent the vascular cause.

Vascular Prevention of Cognitive Diseases Our group has shown that patients with hypertension have a five-fold increased risk for executive dysfunction in the course of the disease26. Early detection of this syndrome is important because it increases the risk for conversion to dementia27 and/or to major depression22. White matter disease, microinfarctions and micro-bleedings may have an impact on the onset of cognitive dysfunction. The volume or burden of white matter lesions, along with their progression and their location determine the clinical expression of the cognitive impairment and increase the risk for stroke. Limits to progression and burden depend on effective blood pressure control28.

β-amyloid depositions β-amyloid is a protein that accumulates in brain extracellular spaces (neuritic plaques) and on the blood vessel walls (cerebral amyloid angiopathy). It results from the abnormal cleavage of a transmembrane precursor protein and constitutes the neuropathological basis of Alzheimer’s disease29, along with the neurofibrillary tangles (protein aggregates of hyperphosphorylated tau protein). The vascular damage observed in almost 90 % of the brains of patients with Alzheimer’s disease contributes to the progress of the neurodegenerative process

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For more than two decades, vascular disease has been gaining ground within neurodegenerative diseases, among which dementias have a significant place. Risk factors that impair vascular health – hypertension, hypercholesterolaemia and diabetes – contribute to hastening and compounding dementia and worsen its prognosis. Considering the above hypotheses and published research devoted to investigating the link between vascular disease, cognitive decline and dementia, we can conclude that: i) patients with hypertension, whether isolated or associated with other vascular risk factors, present vascular brain injury and greater risk for dementia than the vascular diseasefree population; ii) cases of Alzheimer’s disease are paradoxically more frequent than cases of vascular dementia among patients with vascular risk factors and vascular disease; iii) the association of vascular brain injury and brain neurodegenerative disorder is clinically expressed by greater cognitive decline; and iv) some studies have proved that the preservation and enhancement of vascular health through rigorous control of risk factors may prevent or delay the onset of dementia, and in those already diagnosed, may contribute to slowing of cognitive decline. Therefore, the promotion of vascular health becomes the focal point of primary and secondary prevention of dementias34.

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Preventing Cognitive Decline and Dementia

Today we can conclude that vascular risk factors are shared by heart and brain. As a result, if we deem the seventh decade of life as the average age in which late-onset Alzheimer’s disease begins, our preventive attitude should target vascular risk factors 20 years earlier, that is, the mean age in which these factors’ presence becomes relevant. Furthermore, a recent publication points out that more than 30 % of late-onset Alzheimer’s disease cases may be attributed to the combination of vascular risk factors35. Thus, if timely intervention manages to increase the control of vascular risk factors in the vulnerable population by 10 %, the projected effect would be a reduction in the number of cases of Alzheimer’s disease by one million, and by three million if control reaches 25 %. In other words, if we could delay onset of Alzheimer’s disease by five years, cases of dementia would be reduced by half within 10 years36. In 2011, the Alzheimer’s Disease International World Report recommended antihypertensive drugs, statins and physical activity among the most beneficial interventions for dementia prevention. All of these measures are aimed at preserving vascular health37, and do not exclude the need to recognise, reduce and treat vascular risk factors or cardiovascular disease in patients with dementia (see Table 1). Prevention should include health promotion to inspire a change in the population towards healthier lifestyles and behaviours, while also raising awareness among physicians about these factors. In this way,

Chapter 2: Epidemiology of dementia. In Saxena S and Wortmann M: Dementia. A public health priority. Publication of the World Health Organisation available on the WHO website (www.who.int). 2. Dementia and risk reduction: an analysis of protective and modifiable factors. World Alzheimer Report 2014. Available at www.alz.co.uk/research/WorldAlzheimerReport2014.pdf 3. Mathers CD, Stevens GA, Boerma T, et al. Causes of international increases in older aged life expectancy. Lancet. 2015;385 :540–8. 4. Butler D. UN Targets top killers. International Summit considers how to stem the rise in non-communicable diseases. Nature. 2011;477 :260–1. 5. Manton KC, Gu XL, Ukraintseva SV. Declining prevalence of dementia in the US elderly population. Adv Gerontol . 2005;16 :30–7. 6. Langa KM, Larson EB, Karlawish JH, et al. Trends in the prevalence and mortality of cognitive impairment in the United States: is there evidence of a compression of cognitive morbidity? Alzheimer’s Dement. 2008;4 :134–44. 7. Schrijvers EMC, Verhaaren BFJ, Koudstaal PJ, et al. Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology 2012;78 :1456–63. 8. Qiu C, von Strauss E, Backman L, Winblad B, Fratiglioni L. Twenty-year changes in dementia occurrence suggests decreasing incidence in central Stockholm, Sweden. Neurology. 2013;80 :1888–94. 9. Matthews FE, Arthur A, Barnes LE, et al. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet. 2013;382 :1405–12. 10. Launer LJ, Ross GW, Petrovich H,Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the HonoluluAsia aging study. Neurobiol Aging. 2000;21 :49–55. 11. Hajjar I, Quach L, Yang F, Chaves PHM, Newman AB, Mukamal K, Longstreth W, Inzitari m, Lipsitz LA. Hypertension, White matter Hyperintensities, and Concurrent Impairments in Mobility, Cognition and Mood. The Cardiovascular Health Study. Circulation. 2011;123 :858–865. 12. Biessel GJ, Strachan MWJ, Visseren FLJ, et al. Dementia and

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22. 23.

24.

the epidemic levels of dementia currently seen will be effectively managed by a population controlling its own health and through the identification of vulnerable individuals by the healthcare sector. Some of the variables that operate in the clinical expression of dementia escape intervention (e.g. genetics, age), while others are modifiable. However, vascular risk factors that impact negatively on vascular health can be controlled. We cannot limit our efforts and simply wait until a drug treatment that can cure Alzheimer’s disease makes its appearance on the market (although that drug is necessary). Instead, our purpose should be to highlight prevention and promote vascular health as the only effective method for reducing the prevalence of Alzheimer’s disease.

Summary and Final Comments Dementia is, as yet, an incurable disease. There is evidence however to support the idea that targeting the vascular component of the disease with preventative measures may delay the onset of the condition. Translational research involving relevant medical specialties is essential to solving the difficult problem posed by dementia. Vascular risk factor detection, preventative measures and the identification of therapeutic targets during the early stages of life may represent an effective strategy to prevent or delay the onset of cognitive decline and dementia later on. Further research is required to understand the molecular mechanisms of the disease and this will provide the basis for the development of rational treatments. n

Cognitive Decline in type 2 diabetes and pre-diabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol. 2014;2 :246–55. Whitmer RA, Gunderson EP, Barrett-Connor E, et al. Obesity in middle age and future risk of dementia: 27-year longitudinal population-based study. BMJ. 2005;330 :1360–71. Panza F, Solfrizzi V, Logroscino G, et al. Current epidemiological approaches to the Metabolic-Cognitive Syndrome. Journal of Alzheimer’s Disease. 2012;30 :S31–S75. Rusanen M, Kivipelto M, QuesenberryCP, Zhou J, Whitmer RA. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Arch Intern Med. 2011;171 :333–9. Dublin S, Anderson ML, Haneuse SJ, et al. Atrial Fibrillation and Risk of Dementia: A Prospective Cohort Study. J Am Geriatr Soc. 2011;59 :1369–75. Stefansdottir H, Arnar DO, Aspelund T, et al. Atrial Fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarction. Stroke. 2013;44 :1020–5. Yaffe K, Vittinghoff E, Pletcher MJ, et al. Early Adult to Midlife Cardiovascular Risk Factors and Cognitive Function. Circulation. 2014;129 :1560–7. Sun JH, Tan L, Yu JT. Post-stroke cognitive impairment: epidemiology, mechanism and management. Ann Transl Med. 2014;2 :80–96. Snowdon DA, Greiner LH, Mortimer JA, et al. infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277 :813–817. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358 :1033–41. Sneed JR, Culang-Reinlieb ME. The Vascular Depression Hypothesis: an update. Am J Geriatr Psychiatry . 2011;19 :99–103. Vicario A, Martinez CD, Barreto D, Diaz Casale A, Nicolosi L. Hypertension and cognitive decline: Impact on executive function. J Clin Hypertens. 2005;7 :598–604. Vicario A, del Sueldo M, Zilberman J, Cerezo GH. Cognitive evolution in hypertensive patients: a six-years follow-up. Vasc Health Risk Manag. 2011;7 :1–5.

25. Celle S, AnnweilerC, Pichot V, Beauchef O et al. Association between ambulatory 24-hour blood pressure levels and brain volume reduction: a cross-sectional elderly population-based study. Hypertension. 2012;60 :1324–31. 26. 26. Vicario A, del Sueldo M, Fernández RA, et al. Cognition and vascular risk factors: an epidemiological study. J Hypertension. 2012;6 : http://dx.doi.org/10.1155/2012/783696. ID 783696. 27. Oveisgharan S, Hachinski V. Hypertension executive dysfunction and progression to dementia. The Canadian study of health and ageing. Arch Neurol. 2010;67 :187–92. 28. Verhaaren BF, Vernooij MW, de Boer R, et al. High blood pressure and white matter lesion progression in the general population. Hypertension. 2013;61 :1354–9 29. Selkoe DJ. Ageing Brain, Ageing Mind. Scientific American. 1992;267, Issue 3. 30. Iadecola C and Davisson RL. Hypertension and cerebrovascular disfunction. Cell Metabolism. 2008;7 :476–84. 31. Nation DA, Edland SD, Bondi MW, et al. Pulse pressure is associated with Alzheimer disease in cognitively normal older adults. Neurology. 2013;81 :1–4. 32. Rodrigue K. Hypertension could bring increased risk for Alzheimer’s disease. JAMA Neurol . 2013;70 (4):438–9 33. Kester MI, Goos JD, Teunissen CE, et al. Association between cerebral small-vessel disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurol. 2014;71 (7); 855–62 34. Kivipelto M, Solomon A, Ahtilhuoto S, et al. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): Study design and progress. Alzheimer’s & Dementia. 2013;9 :657–65. 35. Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s disease: analysis of populationbased data. Lancet Neurol. 2014;13 :788–94. 36. Barnes D, Yaffe K. The projected effectof risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011;10 :819–28. 37. World Alzheimer Report 2011. The benefits of early diagnosis and intervention. Available atwww.alz.co.uk/research/ WorldAlzheimerReport2011.pdf.

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LE ATION.

Cholesteryl Ester Transfer Protein Inhibitors – Future Soon to be REVEALed Christopher Huggins, Nicoletta Charolidi and Gillian W Cockerill Cardiovascular & Cell Sciences, St George’s, University of London, UK

Abstract Reduction of the remaining residual cardiovascular risk is a clinical unmet need currently being addressed through a combination of further reduction of plasma concentrations of low-density lipoproteins (LDLs) and increasing plasma concentrations of high-density lipoproteins (HDLs). This brief review sets out the so-called HDL hypothesis and summarises the clinical results of the family of drugs, which function to raise plasma HDL concentration through inhibition of cholesteryl ester transfer proteins (CEPT).

Keywords Apolipoprotein AI, cholesteryl ester transfer protein, high-density lipoprotein, low-density lipoprotein Disclosure: The authors have no conflict of interest to declare. Received: 24 June 2015 Accepted: 9 July 2015 Citation: European Cardiology Review. 2015;10(1):64–7 Correspondence: Gillian W Cockerill, Institute of Cardiovascular & Cell Sciences, Professor of Vascular Biology, St George’s, University of London, Cranmer Terrace, London SW17 0RE. E: gcockeri@sgul.ac.uk

The concentration of plasma low-density lipoprotein cholesterol (LDL-C) is reduced, while that of total high-density lipoprotein cholesterol (HDL-C) is increased, following inhibition of cholesteryl ester transfer protein (CETP). This combined effect has made inhibition of CETP an attractive pharmacological approach for reducing the residual incidence of cardiovascular disease (CVD) remaining after optimal LDL-lowering therapy. However, since HDLs represent a complex dynamic heterogeneous family of particles varying in size, composition and function, the concept is not without difficulties. CVD has been shown to alter the particle complexity, in terms of both relative abundance of size/density and composition. The effects of raising the plasma concentration of HDL-C on a background of ‘disease modified’ are largely unknown. Randomised clinical trials to date have failed to provide evidence of benefit for this approach. The CETP inhibitor, dalcetrapib, which showed no harmful effect, also had no ability to reduce LDL-C and the study may be considered as providing strong evidence that HDL raising per se is not an effective approach in reducing CVD. The remaining members of the CETP inhibitor family, currently in Phase III studies, are able to reduce plasma LDL-C and may, thus, provide a beneficial effect on CVD, as long as it is not reduced through the adverse effects of raising plasma HDL-C, which may well be dysfunctional. Subsequent analysis of these large randomised controlled trials, due to be published in 2016/17, may allow us to further understand the effect of CVD on the complex metabolism of HDL-C.

The Birth of the HDL Hypothesis It is a well-established fact that elevated plasma concentrations of low-density lipoprotein-cholesterol (LDL-C) is one of the most important risk factors for developing coronary artery disease (CAD), and, eventually, coronary heart disease (CHD)1 and other forms of atherosclerotic cardiovascular disease (CVD). Targeting LDL-C

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reduction has been effective in lowering CVD risk, through the use of HMG-CoA reductase inhibitors (statins) for both primary and secondary CVD prevention as the first-line therapy, resulting in reduced CV events and overall mortality2,3. However, despite reduction in LDL-C, 18–41 % with moderate doses of statins and 40–60 % with higher doses or more potent statins, there remains a significant residual cardiovascular risk. In the late 1970s the inverse relationship between plasma concentration of HDL-C and CVD risk was identified4 and subsequent prospective data from the Framingham Heart and ARIC studies further supported this idea5,6. It was proposed that CHD risk was inversely related to plasma concentration of HDL-C, owing to the ability of HDL particles to remove cholesterol from developing atherosclerotic lesions, and thus, the HDL hypothesis was conceived. Subsequent in vivo studies, in which plasma HDL-C was raised by infusion or transgenic expression of human apolipoprotein AI (ApoAI) in rabbit and mouse models of atherosclerosis demonstrated a potent atheroprotective effect7–9. With this wide array of potential benefits, raising plasma HDL-C was seen as a promising new drug target.

Raising Plasma Concentration of HDL-C Although lifestyle changes, such as vigorous exercise, smoking cessation and weight loss have been shown to moderately increase plasma concentrations of HDLs 10–13, individuals with low plasma HDL-C are more likely to respond to pharmacological treatment that increases HDL. Whilst statins, fibrates and some thiazolidenediones have been shown to modestly increase plasma concentrations of HDL-C14–16, nicotinic acid or niacins have been used to provide a more robust increase by 15–16 %17,18. Niacin increases plasma HDL-C by inhibiting the putative hepatocyte HDL-C catabolism receptor, preventing HDL-C catabolism, and thereby increasing the half-life of circulating HDL-C18. However, neither of the two large randomised controlled clinical trials, AIM-HIGH and HPS2-THRIVE, were able to

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demonstrate a difference in the primary end point despite favourable changes in HDL-C concentration17,18. Although these data may question the ability to provide a cardioprotective effect through elevating plasma HDL-C, nicotinic acid and niacins have dramatic side effects, such as flushing, which may well compromise any benefits observed.

Figure 1: Schematic diagram showing activity of CETP VLDL, IDL, LDL

CETP as a Novel Drug Target to Raise Plasma Concentration of HDLs. Development of a novel target for elevating plasma HDL-C concentration was derived from analysis of the understanding of the biochemistry of HDL metabolism and particle dynamics. CETP is a hydrophobic glycoprotein which can catalyse the transfer of cholesteryl esters, generated by lecithin:cholesterol acyltransferase (LCAT), principally in larger α-HDLs, to other lipoproteins in exchange for triglycerides (TGs), derived primarily from very low-density lipoproteins (VLDL) or chylomicrons19 (Figure 1). This process of lipid exchange has been shown to increase the relative abundance of small lipid-poor preβ-HDL particles, which play a primary role in the acquisition of cholesterol from cell membranes via the ABCA1 transporter (reverse cholesterol transport)20. These data seeded the idea that modulation of HDL particle abundance could increase the ability to remove cholesterol from peripheral tissues, and was further supported by numerous in vivo studies where inhibition of CETP in animal models prevented cholesterol-induced atherosclerosis21–23, whilst CETP gene transfer in mice (a species lacking CETP activity) increased lesion formation21. Although these findings were encouraging, subsequent studies in other models did not reiterate the protective effect of CETP inhibition shown previously24–26. However, these data are difficult to compare and may reflect disparity in means by which CETP is modulated and in the mechanisms involved in generating atheromatous lesions in the specific models. In an extremely elegant set of experiments, Brousseau and colleagues were able to show, that raising HDL-C using the CETP-inhibitor drug, torcetrapib, did so through an effect on delaying catabolism27. Both torcetrapib and niacin increase HDL by delaying catabolism, which, in turn, increases the half-life of HDL-C, but neither of these methods have led to a beneficial clinical effect. As HDLs are heterogeneous, dynamic particles, it is likely that their structure and function will be significantly modified by prolonging the circulatory half-life and would depend largely on the effect of the clinical status of the patient.

CETP Inhibition – Effect of Gene Polymorphisms The human CETP gene has been mapped to chromosome 16 on the 16q21 locus, spanning about 25 kb and consisting of 16 exons and 15 introns. The current availability of DNA arrays capable of screening the entire genome for many thousands of SNPs in large cohorts has provided a new tool for studying the aetiology of complex diseases. However, the putative instrumental variables associated with alleles and clinical outcome are not always appropriate and the method is also limited by problems associated with linkage disequilibrium. Voight and colleagues reported a large Mendelian randomisation study confirming that lower CETP activity, when associated with both lower LDL-C and higher HDL-C, is associated with cardiovascular benefit28. Studies of CETP gene polymorphisms have been controversial. The B2 allele of the Taq1B SNP of the CETP gene (which is associated with low CETP activity and raised HDL-C) was found to be accompanied by a lower than average risk of CVD29. Further analysis showed that this association was limited to one ethnic group (Chinese)30. In a 10-year follow-up study of more than 18,000 women, among 350,000 SNPs, it was found that three SNPs in or close to the CETP gene (rs708272,

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CETP

TG HDL3

CETP

HDL2 CETP modulates cholesterol ester (CE) exchange for triglycerides (TG) between HDL particles (homotypic transfer), leading to the larger HDL2 particle, and apoB-containing particles (VLDL, IDL, LDL) (heterotypic transfer).

rs432992 and rs7202364) were associated with an increase in plasma HDL-C and a reduced incidence of myocardial infarction in this population31. Current genetic analysis indicates that a decrease in CETP activity is correlated with a decrease in CVD risk.

Prospective Cohort Studies of CETP and CVD Risk Measuring CETP activity is technically challenging and work by Ritsch and colleagues provides our sole reference data that there is a linear relationship between activity and concentration32. Prospective observational cohort studies to investigate the relationship between the plasma concentration of CETP activity or concentration and the risk of cardiovascular events generally show an inverse correlation, suggesting a negative association with CETP33–38. Of the three studies that evaluated populations free of CVD, two of them assayed CETP activity long-term, with a 10–15-year follow-up33,34, whilst the other study measured concentration and had a two-year follow-up35. The remaining three studies considered patients with clinical CAD or CHD and measured CETP activity36–38. Assessment of CETP activity or mass requires purification from total plasma or serum, which is then a measurement made in the absence of the proper biological complexity of whole blood and its many affecting factors; for example, the presence of ApoC-I, an isoform of apoliprotein C that has been recently demonstrated to be an endogenous inhibitor of CETP activity39. Although these prospective cohort studies are strongly suggestive that low concentrations/activities of CETP may correlate with increased CVD, these data are entirely reductive and do not to address the clinical effect of CETP inhibition in an appropriate patient population. Currently, we have limited and insufficient precise knowledge of the complex dynamics between plasma lipoproteins and activation of vascular cells and cell membranes to explain the apparent paradox between the prospective observational epidemiology and genomewide analysis for the role of CEPT inhibition. To enter into a discourse on whether the disparity is due to confounding effects or reverse causality would be fatuous at this point.

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in July 2004 comparing 15,067 patients randomised to high-intensity statin alone or high-intensity statin plus torcetrapib54. This study was

The potential for disease status to change the structure and, hence, function of HDLs is of paramount importance to our understanding of the subsequent effects of raising HDL-C concentration. Interpretation and prediction of the impact of CETP inhibition is complicated by the growing awareness that the effects of HDL-C may be modified in different clinical settings. Human plasma high-density lipoprotein (HDL) particles constitute a spectrum of pseudo-micellar protein/ lipid complexes, with hydrated densities within the range of 1.063 to 1.210 g/ml40. This spectrum may be further defined by five physicochemically-defined particle subpopulations determined by their buoyant density: HDL2b, 2a, 3a, 3b, and 3c. Compared with other lipoproteins, HDLs are protein-rich, with an average ratio protein:lipid of 1:1. Approximately 70 % of HDL protein mass is Apo AI, with Apo AII accounting for a further 15–20 %. Major components of the remaining 15–20 % of proteins are other amphipathic apolipoproteins (eg., ApoCI, ApoCIV, E, D, M and AIV), enzymes and lipid transfer proteins (eg paraoxonase (PON), PAF-acetlyhydrolase (PAFAH), LCAT, and CETP).

terminated early when it became clear that the drug increased the incidence of the primary CVD endpoint, despite raising HDL-C by 70 % and lowering LDL-C by 20 %. Following analysis of the trial samples collected, the authors concluded that the effect was due to an offtarget rise in the concentration of an aldosterone-like factor, which resulted in an unanticipated increase in blood pressure. However, this is not entirely consistent with the fact that CHD mortality was inversely related to a raised blood pressure and the incidence of stroke was not greater in the treatment group. A second member of the CETP inhibitors, dalcetrapib, presented an opportunity to test the HDL hypothesis as this compound raised plasma HDL-C by 30–40 % but had little or no effect on LDL-C. A Phase III randomised controlled trial (Dalcetrapib: Dal-OUTCOMES; NCT00658515), involving 15,600 patients with recent acute coronary syndrome, began in 2008 but was halted in 2012, because of a perceived lack of efficacy55. Anacetrapib is the most potent CETP inhibitor to date and in the first clinical trial (Anacetrapib: DEFINE; NCT00685776)56 was shown to lower LDL-C by approximately 50 % and increase HDL-C by 140 %. Although, this gross effect may reflect an extreme disturbance of HDL-C metabolism and its consequences,the DEFINE trial did not report any significant increase in CVD in the test arm. However, this study was too small to provide robust information on the clinical events56.

Proteomic analysis of HDLs, on the other hand, has been identifying putative mechanistic information for functional observations reported in previous decades. Recent proteomic studies have identified up to 49 proteins associated with centrifugally-isolated HDL41–44. Studies by Vaisar and colleagues44, investigating both total HDL and HDL3 from normocholesterolaemic control subjects and age-matched patients with CAD, identified a role for HDLs in protease inhibition in addition to an effect on complement activation, supporting findings from ten years earlier45. Data from a meticulous study, in which the proteome of HDL2b, 2a, 3a, 3b, and 3c, also from normocholesterolaemic subjects, were analysed, defined 28 distinct HDL-associated proteins which associated in clusters in subpopulations46. In this study the investigators were able to show that ApoL-I, PON1 and PON3 correlated with the capacity of HDL3 to protect against oxidation, confirming their results through measurement of the ability of HDL3 to reduce the rate of accumulation of conjugated dienes in an LDL oxidation assay. These observations confirm earlier functional studies in which PON was shown to be one of the major proteins responsible for the antioxidative function of HDLs47–49. In a recent report of a 10-year follow up of 88 type 2 diabetic patients, the incidence of cardiovascular events increased in proportion to reduced PON1 levels and activity, suggesting that PON1 may be an independent predictor of cardiovascular events in people with diabetes49. Modulation of the structure and function of HDL-C has been reported, initially with regard to the anti-oxidative function of the particle50, but also with respect to the anti-inflammatory, cholesterol transfer, and anti-thrombotic function of HDL-C51–53. .

Clinical Outcomes, so Far The first Phase III randomised controlled trial for a member of the CETP inhibitor family (Torcetrapib: ILLUMINATE; NCT00134264) began

Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med . 1977;62 :707–14. Baigent C, Keech A, Kearney PM, et al. and Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet . 2005;366 :1267–78. LaRosa JC, He J and Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA . 1999;282 :2340–6. Castelli WP, Doyle JT, Gordon T, et al. HDL cholesterol and other lipids in coronary heart disease. The cooperative

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Conclusion Although two members of the CETP inhibitor drug family have clearly been removed from the drugs cabinet, it is still a fact that we do not know if the remaining members will provide a clinical benefit for patients with CVD/CHD. The two members of this family under clinical investigation, currently in Phase III randomised control trials (Anacetrapib: REVEAL; NCT01252953 and Evacetrapib: ACCELERATE; NCT01687998), are due to report in 2016/17. Results from these highly powered, multi-centre studies, will determine the success or failure of the original hypothesis that CETP inhibition is of benefit to CVD/CHD. Any chance of addressing whether success is through raising HDL-C per se is lost following the failure of Dalcetrapib, the only member of the family that had little effect of plasma LDL-C. Efficacy of either CETP inhibitor remaining in the arena, may be due to the ability of one or other of these drugs to further reduce plasma LDL-C, rather than a benefit of raising HDL-C concentration. Should the drugs fail to give a beneficial effect, the reasons will be largely unknown, but may relate to the altered kinetic of the dynamic effects that increase the circulating half-life and hence complexity of the HDL particles. The results of these studies are anticipated with gathering interest, and an additional benefit will be that they will provide an important opportunity to gain a further understanding of HDL metabolism/catabolism in disease, which will be invaluable in progressing with clinical development of these compounds. n

lipoprotein phenotyping study. Circulation . 1977;55 :767–72. Castelli WP, Anderson K, Wilson PW, et al. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol . 1992;2 :23–8. Sharrett AR, Ballantyne CM, Coady SA, et al. Atherosclerosis Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation . 2001;104 :1108–13. Badimon JJ, Badimon L, Galvez A, et al. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest . 1989;60 :455-61.

Plump AS, Scott CJ and Breslow JL. Human apolipoprotein A-I gene expression increases high-density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A . 1994;91 :9607–11. 9. Rubin EM, Krauss RM, Spangler EA, et al. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature . 1991;353 :265–7. 10. Huttunen JK, Länsimies E, Voutilainen E, et al. Effect of moderate physical exercise on serum lipoproteins. A controlled clinical trial with special reference to serum highdensity lipoproteins. Circulation . 1979;60 :1220–9. 11. Kelley GA, Kelley KS, Roberts S, et al. Efficacy of aerobic exercise and a prudent diet for improving selected lipids

EUROPEAN CARDIOLOGY REVIEW

27/07/2015 22:58

Cholesteryl Ester Transfer Protein Inhibitors

and lipoproteins in adults: a meta-analysis of randomised controlled trials. BMC Med . 2011;9 :74. 12. Moffatt RJ, Chelland SA, Pecott DL, et al. Acute exposure to environmental tobacco smoke reduces HDL-C and HDL2-C. Prev Med . 2004;38 :637–41. 13. Contaldo F, Strazzullo P, Postiglione A, et al. Plasma high-density lipoprotein in severe obesity after stable weight loss. Atherosclerosis . 1980;37 :163–7. 14. Boekholdt SM, Arsenault BJ, Hovingh GK, et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation . 2013;128 :1504–12. 15. Kesäniemi YA and Grundy SM. Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. JAMA . 1984;251 :2241–6. 16. Naoumova RP, Kindler H, Leccisotti L, et al. Pioglitazone improves myocardial blood flow and glucose utilisation in non-diabetic patients with combined hyperlipidaemia: a randomised, double-blind, placebo-controlled study. J Am Coll Cardiol . 2007;50 :2051–8. 17. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med . 2011; 365 :2255–67. 18. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med . 2014;371 :203–12. 19. Fielding CJ and Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res . 1995;36 :211–28. 20. Hennessy LK, Kunitake ST and Kane JP. Apolipoprotein A-Icontaining lipoproteins, with or without apolipoprotein A-II, as progenitors of pre-beta high-density lipoprotein particles. Biochemistry . 1993;32 :5759–65. 21. Marotti KR, Castle CK, Boyle TP, et al. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature . 1993;364 :73–5. 22. Okamoto H, Yonemori F, Wakitani K, et al., A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature . 2000;406 :203–7. 23. Sugano M, Makino N, Sawada S, et al. Effects of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J Biol Chem . 1998;273 :5033–36. 24. Ritterhaus CW, Miller DP, Thomas LJ, et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol . 2000;20 :2106–12. 25. Hayek T, Masucci-Magoulas L, Jiang X, et al. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J Clin Invest . 1995;96 :2071–74. 26. Föger B, Chase M, Amar MJ, et al. Cholesteryl ester transfer protein corrects dysfunctional high-density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol

EUROPEAN CARDIOLOGY REVIEW

Cockerill_FINAL.indd 67

acyltransferase transgenic mice. J Biol Chem. 1999;274 : 36912-20. 27. Brousseau ME, Diffenderfer MR, Millar JS, et al. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism and fecal sterol excretion. Arterioscler Thromb Vasc Biol . 2005;25 :1057–64. 28. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet . 2012;380 :572–80 29. Thompson A, Di Angelantonio E, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels and coronary risk. JAMA . 2008;299 :2777–88. 30. Li YY, Wu XY, Xu J, et al. Apo A5-1131T/C, FgB-455G/A, -148C/ T, and CETP TaqIB gene polymorphisms and coronary artery disease in the Chinese population; a meta-analysis of 15,055 subjects. Mol Biol Rep. 2013;40 :1997–2014. 31. Ridker PM, Paré G, Parker AN, et al. Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18,245 initially healthy women from the Women’s Genome Health Study. Circ Cardiovasc Genet . 2009;2 :26–33. 32. Ritsch A, Auer BM, Föger B, et al. Polyclonal antibody-based immunoradiometric assay for quantitation of cholesteryl ester transfer protein. J Lipid Res . 1993;34 :673–9. 33. Marschang P, Sandhofer A, Ritsch A, et al. Plasma cholesteryl ester transfer protein concentrations predict cardiovascular events in patients with coronary artery disease treated with pravastatin. J Intern Med . 2006;260 :151–9. 34. Vasan RS, Pencina MJ, Robins SJ, et al. Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community. Circulation . 2009;120 :2414–20. 35. Khera AV, Wolfe ML, Cannon CP, et al. On-statin cholesteryl ester transfer protein mass and risk of recurrent coronary events (from the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 [PROVE IT-TIMI 22] study). Am J Cardiol . 2010;106 :451–6. 36. Duwensee K, Breitling LP, Tancevski I, et al. Cholesteryl ester transfer protein in patients with coronary heart disease. Eur J Clin Invest . 2010;40 :616–22. 37. Ritsch A, Scharnagl H, Eller P et al. Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health Study. Circulation . 2010;121 :366–74. 38. Robins SJ, Lyass A, Brocia RW, et al. Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study. Atherosclerosis . 2013;228 :230–6. 39. McNeal CJ, Chatterjee S, Hou J, et al. Human HDL containing a novel apoC-I isoform induces smooth muscle cell apoptosis. Cardiovasc Res . 2013;98 :83–93. 40. Havel RJ, Eder HA and Bragdon JH. The distribution and chemical composition of ultracentrifugally separated

lipoproteins in human serum. J Clin Invest . 1955;34 :1345–53. 41. Karlsson H, Leanderson P, Tagesson C, et al. Lipoproteomics II: mapping of proteins in high-density lipoprotein using two-dimentional gel electrophoresis and mass spectrometry. Proteomics . 2005;5 :1431–45. 42. Heller M, Stalder D, Schlappritzi E, et al. Mass spectrometrybased analytical tools for the molecular protein characterisation of human plasma lipoproteins. Proteomics . 2005;5 :2619-30. 43. Rezaee F, Casetta B., Levels JH, et al. Proteomic analysis of high-density lipoprotein. Proteomics . 2006;6 :721–30. 44. Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the anti-inflammatory properties of HDL. J Clin Invest . 2007;117 ;746–56. 45. Rosenfeld SI, Packman CH and Leddy JP. Inhibition of the lytic action of cell-bound terminal complement components by human high-density lipoproteins and apoproteins. J Clin Invest . 1983;71 ;795–808. 46. Davidson WS, Silva GA, Chantepie S, et al. Proteomic analysis of defined HDL subpopulations reveals particlespecific protein clusters: relevance to antioxidative function. Arterioscler Thromb Vasc Biol . 2009;29 ;870–6. 47. Mackness MI, Durrington PN and Mackness B. How highdensity lipoprotein protects against the effects of lipid peroxidation. Curr Opin Lipidol . 2000;383–8. 48. Laplaud PM, Dantoine T and Chapman MJ. Paraoxonase as a risk marker for cardiovascular disease: facts and hypotheses. Clin Chem Lab Med . 1998;36 ;431–41. 49. Ikeda Y, Inoue M, Suehiro T, et al. Low human paraoxonase predicts cardiovascular events in a Japanese patients with type 2 diabetes. Acta Diabetol . 2009;46 :239–42. 50. Van Lenten BJ, Reddy ST, Navab M et al. Understanding changes in high-density lipoproteins during the acute phase response. Arterioscler Thromb Vasc Biol . 2006;26 :1687–8. 51. Riwanto M and Landmesser U. High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease. J Lipid Res . 2013;54 :3227–43. 52. Bergt C, Pennathur S, Fu X, et al. The myeloperoxidase product hypochlorous acid oxidises HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc Natl Acad Sci U S A . 2004;101 :13032–7. 53. Morgantini C, Natali A, Boldrini B, et al. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes . 2011;60 :2617–23. 54. Barter PJ, Caulfield M, Eriksson M, et al., ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med . 2007;357 :2109-22. 55. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary sydrome. N Eng J Med. 2012; 367:2089-99 56. Cannon CP, Shah S, Dansky HM, et al. Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med . 2010;363 :2406–15.

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THE WORLD’S LARGEST AND MOST INFLUENTIAL CARDIOVASCULAR EVENT ESC Congress 2015 29 August – 2 September

Where cardiology comes together 29 August - 2 September London, UK www.escardio.org/ESC2015

Where cardiology comes together www.escardio.org/ESC2015

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ESC Congress 365

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27 – 31 August www.escardio.org/ESC2016

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European Society of Cardiology

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Program and registration online www.toptencardiology.com

Department of Cardiology An International 1-day Cardiology Meeting

Top Ten in Cardiology 3rd Edition - October 2nd 2015 Lausanne, Switzerland Program Directors : Martin Fromer MD, Pierre Vogt MD

With the contributions of : Thomas Arentz MD, Bad Krozingen University, Germany

Sanjay Sharma MD, St George University of London, United Kingdom

Salim Yusuf, MD McMaster University, Canada

Didier de CanniĂ¨re MD, UniversitĂŠ Libre de Bruxelles, Belgium

Scott D. Solomon MD, Harvard Medical School, USA

Mooly Auerbach MD, Biosense Webster, Israel

John Chapman MD, University Pierre and Marie Curie, France

Hugo Vanermen MD, University of Leuven, Belgium

Alphons Vincent MSc, Medtronic, Switzerland

Yoram Rudy MD, Washington University in St Louis, USA

Michael A Weber MD, Downstate College of Medicine, USA

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