ECR 14.2 by Radcliffe Cardiology

Volume 14 â&#x20AC;˘ Issue 2 â&#x20AC;˘ Summer 2019

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Rhythm Control in AF: Have We Reached the Last Frontier? Gheorghe-Andrei Dan

Diagnostic Approach to Patients with Stable Angina and No Obstructive Coronary Arteries Gaetano Antonio Lanza

Anti-inflammatory Action of Curcumin and Its Use in the Treatment of Lifestyle-related Diseases Kana Shimizu, Masafumi Funamoto, Yoichi Sunagawa, Satoshi Shimizu, Yasufumi Katanasaka, Yusuke Miyazaki, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto

Cardiology Masters Featuring: Eugene Braunwald Eugene Braunwald

Chagas disease and the heart

Dilated heart with poor systolic function

Testosterone and PDE5 inhibitors may act synergistically to reduce CV risk

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ABSTRACT THEMES • Acute coronary syndromes • Biomarkers • Cardio-renal syndrome • Clinical trials • Diabetes, NASH, Obesity & related metabolic disorders • Heart Failure and Cardiomyopathies • Hypertension • Lipid therapy, anti-inﬂammatory therapy • Management of Arrhythmias • Peripheral arterial and venous disease • Prevention of cardiovascular disease • Pulmonary hypertension ©overcome

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w w w. i s c p 2 0 2 0 . c o m

MAY 7-9

2020

Volume 14 • Issue 2 • Summer 2019

www.ECRjournal.com Official journal of

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

Associate Editor Pablo Avanzas

University Hospital of Oviedo, Oviedo

International Advisers Richard Conti

University of Florida, Gainesville

Wolfgang Koenig

Giuseppe Mancia

Mario Marzilli

Hiroaki Shimokawa

Genetics and Cardiovascular Disease Eliecer Coto

Cardiovascular Disease in Women Angela Maas

Hypertension Maria Lorenza Muiesan

Epidemiology: Meta-analyses Gianluigi Savarese

Technical University of Munich, Munich

University of Milano-Bicocca, Milan

University of Pisa, Pisa

Tohoku University, Sendai

Section Editors Cardiac Imaging John Baksi Royal Brompton Hospital, London

Arrhythmias David Calvo

Hospital Universitario Central de Asturias

Genética Molecular-Laboratorio Medicina, HUCA, Oviedo

Structural Heart Disease: Cardiac Intervention Giuseppe Ferrante

Humanitas Research Hospital, Humanitas University, Milan

Radboud University, Nijmegen

Cardiomyopathies and Athletes Heart Disease Aneil Malhotra St George’s University of London, Londonw

University of Brescia, Brescia

Ischaemic Heart Disease Giampaolo Niccoli

Catholic University of the Sacred Heart, Rome

Karolinska Institutet, Karolinska University Hospital, Stockholm

Pharmacotherapy Juan Tamargo

Universidad Complutense, CIBERCV, Madrid

Editorial Board Debasish Banerjee

Carlo Di Mario

Thomas Kahan

Antoni Martínez-Rubio

Giuseppe Rosano

St George’s University of London, London

Careggi University Hospital, Florence

Danderyd University Hospital, Danderyd

University Hospital of Sabadell, Sabadell

IRCCS San Raffaele, Rome

Vinayak Bapat

Perry Elliott

Koichi Kaikita

John McNeill

Magdi Saba

Columbia University Medical Centre, New York

University College, London

Monash University, Melbourne

St George’s University of London, London

Velislav Batchvarov St George’s University of London, London

Antoni Bayés-Genís Hospital Germans Trias i Pujol, Barcelona

John Beltrame University of Adelaide, Adelaide

Christopher Cannon Harvard Medical School, Boston

Peter Collins Imperial College, London

Alberto Cuocolo University of Naples Federico II, Naples

Gheorghe Andrei Dan Colentina University Hospital, Bucharest

Ranil de Silva

King’s College London, London

Michael Fisher

Mike G Kirby University of Hertfordshire, Hatfield

Keld Per Kjeldsen

Royal Liverpool University Hospital, Liverpool

Copenhagen University Hospital (Holbaek Hospital), Holbæk

Augusto Gallino

Rao Kondapally

Ente Ospedaliero Cantonale, Bellinzona

Robert Gerber Conquest Hospital, Hastings

Bernard Gersh Mayo Clinic, Minnesota

David Goldsmith St George’s University of London, London

Tommaso Gori Johannes Gutenberg University Mainz, Mainz

Diana Gorog

St George’s University of London, London

Patrizio Lancellotti

Noel Bairey Merz Cedars-Sinai Heart Institute, Los Angeles

Roxy Senior

Argyrios Ntalias

Imperial College, London

University of Athens, Athens

Nesan Shanmugam

Peter Ong

St George’s University of London, London

Robert-Bosch-Krankenhaus, Stuttgart

Sanjay Sharma

Denis Pellerin St Bartholomew’s Hospital, London

University of Liège, Liège

Carl Pepine

Gaetano Lanza

University of Florida, Florida

Università Cattolica del Sacro Cuore, Rome

Piotr Ponikowski

Amir Lerman

Wroclaw Medical University, Wroclaw

Mayo Clinic, Minnesota

Eva Prescott

Basil S Lewis

Bispebjerg Hospital, Copenhagen

Lady Davis Carmel Medical Center, Haifa

Axel Pries

José Luis López-Sendón La Paz Hospital, Madrid

Charité Universitätsmedizin, Berlin

Valentina Puntmann

Imperial College, London

University of Hertfordshire, Hatfield, Hertfordshire

Alberto Lorenzatti Hospital Córdoba, Córdoba

Goethe University Hospital Frankfurt, Frankfurt

Marcelo Di Carli

Kim Greaves

Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

Sunshine Coast University Hospital, Queensland

Silvia Maffei

Hari Raju

Derek Connolly

Eileen Handberg

Sandwell & West Birmingham Hospitals NHS Trust, Birmingham

University of Florida, Florida

Olivia Manfrini University of Bologna, Bologna

Polychronis Dilaveris

Koji Hasegawa National Hospital Organization Kyoto Medical Center, Fushimi-ku, Kyoto

Hippokration General Hospital, Athens

Cover image © AdobeStock

Albert Ferro

Kumamoto University, Kumamoto

National Research Council, Pisa

Aneil Malhotra St George’s University of London, London

Felipe Martinez National University of Cordoba, Cordoba

Macquarie University, Sydney

Robin Ray St George’s University of London, London

Alejandro Recio UICE-HP Cardiología, HU Virgen Macarena, Sevilla

St George’s University of London, London

Rosa Sicari Italian National Research Council, Rome

Iana Simova National Cardiology Hospital, Sofia

Konstantinos Toutouzas University of Athens, Athens

Isabella Tritto University of Perugia, Perugia

Dimitrios Tziakas Democritus University of Thrace, Xanthi

Mauricio Wajngarten University of São Paulo

Hiroshi Watanabe Hamamatsu University School of Medicine, Hamamatsu

Matthew Wright St Thomas’ Hospital, London

José Luis Zamorano Hospital Ramón y Cajal, Madrid

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 1758–3756 • eISSN: 1758–3764

Established: April 2005 | Frequency: Tri-annual | Current issue: Summer 2019

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• 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 Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.ECRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Ashlynne Merrifield ashlynne.merrifield@radcliffe-group.com

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

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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 & Electrophysiology Review, Cardiac Failure Review, Interventional Cardiology Review and US Cardiology Review. n

Cardiology

Lifelong Learning for Cardiovascular Professionals

Contents

Foreword Juan Carlos Kaski

DOI: https://doi.org/10.15420/ecr.2019.14.2.FO1

Heart Failure, Arrhythmias and Cardiomyopathies Rhythm Control in AF: Have We Reached the Last Frontier?

Gheorghe-Andrei Dan DOI: https://doi.org/10.15420/ecr.2019.8.1

Chagas Disease and Heart Failure: An Expanding Issue Worldwide

Felipe Martinez, Eduardo Perna, Sergio V Perrone and Alvaro Sosa Liprandi DOI: https://doi.org/10.15420/ecr.2018.30.2

Hidden in Heart Failure

Douglas Ewan Cannie, Mohammed Majid Akhtar and Perry Elliott DOI: https://doi.org/10.15420/ecr.2019.19.2

Ischaemic Heart Disease, Stroke and Risk Factors Diagnostic Approach to Patients with Stable Angina and No Obstructive Coronary Arteries

Gaetano Antonio Lanza DOI: https://doi.org/10.15420/ecr.2019.22.2

Testosterone and the Heart

103

Michael Kirby, Geoffrey Hackett and Sudarshan Ramachandran DOI: https://doi.org/10.15420/ecr.2019.13.1

Hypertension and Stroke: Update on Treatment

111

Mauricio Wajngarten and Gisele Sampaio Silva DOI: https://doi.org/10.15420/ecr.2019.11.1

Cardiovascular Pharmacotherapy Cardiovascular Pharmacotherapy Focus

116

Pablo Avanzas DOI: https://doi.org/10.15420/ecr.2019.14.2.GE1

Anti-inflammatory Action of Curcumin and Its Use in the Treatment of Lifestyle-related Diseases

117

Kana Shimizu, Masafumi Funamoto, Yoichi Sunagawa, Satoshi Shimizu, Yasufumi Katanasaka, Yusuke Miyazaki, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto DOI: https://doi.org/10.15420/ecr.2019.17.2

The Effect of Statins on the Functionality of CD4+CD25+FOXP3+ Regulatory T-cells in Acute Coronary Syndrome: A Systematic Review and Meta-analysis of Randomised Controlled Trials in Asian Populations

123

Nilofer Sorathia, Hussein Al-Rubaye and Benham Zal DOI: https://doi.org/10.15420/ecr.2019.9.2

Cardiology Masters Featuring: Eugene Braunwald

130

Eugene Braunwald DOI: https://doi.org/10.15420/ecr.2019.14.2.CM1

Â© RADCLIFFE CARDIOLOGY 2019

Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), UK, Honorary Consultant Cardiologist at St George’s Hospital NHS Trust, London, and immediate past director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Professor Kaski is a Doctor of Science, University of London, an immediate past president of the International Society of Cardiovascular Pharmacotherapy (ISCP), and an editorial board member and associate editor of numerous peer-review journals. He is also fellow of the European Society of Cardiology (ESC), American College of Cardiology (ACC), American Heart Association (AHA), Royal College of Physicians (RCP) and more than 30 other scientific societies worldwide. Professor 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. Professor Kaski has published more than 450 papers in peerreviewed journals, more than 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

he readership of European Cardiovascular Review continues to increase rapidly as a result of the excellent quality of the articles submitted by our contributors and the hard work of our editorial board. The current issue offers an array of extremely important manuscripts, grouped under three main sections – ischaemic heart disease, heart failure and cardiovascular pharmacotherapy.

In the heart failure, cardiomyopathies and arrhythmias section, Gheorghe-Andrei Dan discusses whether we have reached the end of the road regarding rhythm management in AF, while Martinez et al. review different aspects of Chagas disease, an intriguing form of cardiomyopathy. In the same section, Elliott and colleagues explore different ‘hidden’ conditions in heart failure. Scholarly articles providing great insight into topics such as microvascular angina (Gaetano Antonio Lanza), testosterone and the heart (Kirby et al.), and management of hypertension for the prevention of stroke (Wajngarten et al.) are proudly presented in the ischaemic heart disease section. The cardiovascular pharmacotherapy section, edited by the International Society of Cardiovascular Pharmacotherapy, boasts a variety of manuscripts on intriguing and challenging topics, including the anti-inflammatory effects of curcumin by Morimoto et al. and the effects of statins on T-cell function in acute coronary syndrome in Asian populations by Sorathia et al. The Cardiology Masters section in this issue is devoted to Dr Eugene Braunwald, a true cardiology giant and one of the most influential cardiologists of our generation. His now legendary Cardiology textbook and more than 1,000 original manuscripts have informed several generations of cardiologists the world over. As with previous issues, I have very much enjoyed editing this current issue; in particular, I very much value the interaction with authors and reviewers, as well as with members of the editorial team, all of whom contribute greatly to the success of European Cardiovascular Review. I trust you will find this issue to be truly outstanding and enjoyable to read. I wish you every success in your endeavours and a good summer holiday – if you manage to have one! Do come and visit us at the Radcliffe booth at ESC 2019 in Paris, if you are attending the congress.

DOI: https://doi.org/10.15420/ecr.2019.14.2.FO1

Access at: www.ECRjournal.com

Heart Failure, Arrhythmias and Cardiomyopathies

Rhythm Control in AF: Have We Reached the Last Frontier? Gheorghe-Andrei Dan 1,2 1. Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; 2. Colentina University Hospital, Bucharest, Romania

Abstract AF is a worldwide epidemic, affecting approximately 33 million people, and its rising prevalence is expected to account for increasing clinical and public health costs. AF is associated with an increased risk of MI, heart failure, stroke, dementia, chronic kidney disease and mortality. Preserving sinus rhythm is essential for a better outcome. However, because of the inherent limits of both pharmacological and interventional methods, rhythm strategy management is reserved for symptom and quality-of-life improvement. While ‘classical’ antiarrhythmic drug therapy remains the first-line therapy for rhythm control, its efficacy and safety are limited by empirical use, proarrhythmic risk and organ toxicity. Ablative techniques have had an impressive development, but AF ablation still failed to demonstrate a significant impact on hard endpoints. Understanding of the complex mechanisms of AF will help to develop new vulnerable targets to therapy. Promising molecules are under development, intended to fill the gap between the current pharmacological treatment aimed at maintaining sinus rhythm and the expectations from rhythm strategy.

Keywords AF, antiarrhythmic drugs, AF ablation, rhythm strategy, remodelling, atrial cardiomyopathy, ion channels, calcium handling, atrial fibrosis Disclosure: The author has no conflicts of interest to declare. Received: 16 January 2019 Accepted: 26 March 2019 Citation: European Cardiology Review 2019;14(2):77–81. DOI: https://doi.org/10.15420/ecr.2019.8.1 Correspondence: Gheorghe-Andrei Dan, Carol Davila University of Medicine and Pharmacy, 22 Kiseleff Blvd, Bucharest, Romania. E: andrei.dan@gadan.ro Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

“The tragedy of science is the slaying of a beautiful hypothesis by ugly facts.” – Thomas Huxley The 2016 AF European guidelines specifies that the rhythm control strategy – irrespective of method – exclusively addresses the control of symptoms and improvement of quality of life, autonomy and social functioning.1 The exception, obviously, is the vital indication of acute rhythm restoration in the case of the haemodynamically compromised patient.

ejection fraction (LVEF) improved significantly at 6 months in patients who underwent catheter ablation of AF compared with patients treated with rate control therapy (mean difference in ejection fraction 14%; 95% CI [8.5–19.5%]). However, this important study has shown that the improvement was obtained mainly in patients with minimal ventricular fibrotic myocardial remodelling, as demonstrated by late gadolinium enhancement during MRI examination. The study underlines the importance of the morphologic modification of the substrate such that the benefit of maintaining SR should be extended beyond symptom control.

The guidelines statement may generate puzzling reactions. First, despite scientific evidence showing no difference in outcomes between rate and rhythm strategies, many practitioners believe that maintaining sinus rhythm (SR) improves outcomes in AF patients. Second, the false impression that SR and AF are equivalent in terms of heart function and outcome may be deduced. The subanalysis from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study clearly demonstrated that preservation of SR is accompanied by better survival (risk reduction is approximately 46%).2 However, antiarrhythmic drugs (AAD) used for SR preservation induce an almost equivalent increase in mortality, so it is not the preservation of the SR under question but the tools available to accomplish this target.

There are important limitations regarding pharmacological restoration and maintenance of SR in patients with AF. The efficacy of AAD to convert AF and maintain SR is low. The real efficacy of AAD in conversion of AF is further biased by the fact that more than half of AF episodes convert spontaneously in 24 hours.4,5 The efficacy of AAD in maintaining SR is also modest – ranging from 19% to 60%, depending on the type of drug – and clinically efficient AAD therapy is reflected more in reduction of the AF burden (number and symptoms of AF episodes) than elimination of the arrhythmia.6 Moreover, there are important safety issues with AAD, including the high rate of proarrhythmia and drug withdrawal; sotalol accounts for the greatest mortality rate when compared with dronedarone or flecainide.6–8

The recent Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) study emphasised the importance of SR for optimising LVF in patients with systolic dysfunction of uncertain aetiology.3 In this study, the left ventricular

However, it should be emphasised that the interpretation of drug safety is dependent on study design. Good examples are A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA) and Permanent Atrial fibriLLAtion Outcome Study

Access at: www.ECRjournal.com

Heart Failure, Arrhythmias and Cardiomyopathies Using Dronedarone on Top of Standard Therapy (PALLAS), both with dronedarone in AF patients.9–11 ATHENA included high-risk patients with paroxysmal or persistent AF and demonstrated a decrease in cardiovascular hospitalisations and death, while PALLAS included ill patients with permanent AF and showed increased rates of heart failure (HF), stroke and death. There are important safety concerns regarding the use of AAD in patients with concomitant structural diseases, which considerably limits the available adequate pharmacological solutions, i.e. either dronedarone, sotalol or amiodarone for patients with significant left ventricular hypertrophy and coronary artery disease, or only amiodarone for HF patients. This is concordant with the limited awareness of optimal drug therapeutic solutions; over one-third of cardiologists admit insufficient knowledge to assess the indication for rhythm control.12 The aforementioned limitations translate into practical use of AAD that is inconsistent with guidelines, excessive use of amiodarone despite well-known extracardiac side-effects and unexpectedly high rates of drug discontinuation.13,14 In the early 1990s, the Sicilian Gambit investigators created a complex concept for understanding the electrophysiological and clinical requirement for efficient and safe AAD use. Unfortunately this was considered “clinically unwieldy and... never fully accepted”.15,16 It became evident that the classical ADD-based therapy is empirical and drug/electrophysiological action centred, not arrhythmia and patient focused.17 Also, the classical AAD combine positive effects on arrhythmia with negative ones; for example, Class III Singh-Vaughan-Williams AAD have antifibrillatory properties by opposing the shortening of the action potential duration, but this is blunted by the increase in the chance of triggered activity. None of the classical AAD specifically address the vulnerable parameter of AF, as defined by the Sicilian Gambit investigators. However, the gap between available AAD and the expectations of pharmacological rhythm control in AF was partly overshadowed by the increasing interest in interventional electrophysiology and its tremendous development.

AF Ablation: The Last Frontier? Catheter ablation techniques have diversified and refined during the last decade. Classical radiofrequency energy source and newer cryoablation source demonstrated similar success rates.18 Overall, AF ablation is accompanied by freedom from AF recurrences of more than 60% (without AAD) in the first year.19 However, this benefit is significantly blunted during longer follow up, reaching 40% at 5 years.20,21 The most important aspect of the superiority of AF ablation when compared with AAD therapy is conferred by symptom control and improvement in quality of life and functional capacity. There are no convincing data regarding the general impact of AF ablation on hard endpoints such as mortality or major adverse cardiac effects. The results and rates of success of AF ablation studies are heterogeneous because important differences exist between specific populations with AF. Persistent and permanent forms of AF are less susceptible to consistent effects because of important cardiac remodelling. The success of a single procedure in persistent AF is as low as 43%; however, repeated procedures and novel sophisticated techniques – complex fractionated electrograms, linear ablation in the left atrium, rotor mapping and ablation or substrate modification – can improve the outcome.22,23

Safety issues are linked to procedure complexity, patients’ associated comorbidities and experience of ablation centres.24 Although there is a temporal decrease in complication rates, the number of adverse events remains high even in experienced, high-volume centres, with elderly and HF patients being more exposed.25 A recent meta-analysis/ meta-regression investigation showed that AF ablation is superior to AAD therapy in terms of AF recurrences but non-superior in terms of adverse effects.26 Moreover, the authors noted a regression in efficacy since 2011. The position of the guidelines regarding AF ablation has been reconsidered and upgraded as first alternative of rhythm control therapy in all forms of symptomatic AF (grade 2a for paroxysmal and persistent AF and 2b for long-standing AF).27 However, the place of AF ablation as first-line therapy versus AAD therapy is still a subject of debate, and insights into this subject will be offered by the Early Treatment of Atrial fibrillation for Stroke Prevention Trial (EAST).28,29 The success rate of AF ablation is significantly increased by concomitant use of AAD, but the residual recurrence risk remains high over time.19 Short-term AAD therapy is also used to avoid early AF recurrences after catheter ablation; however, the benefit is still debatable.30–33 Longterm use of AAD therapy post-ablation remains an important tool for preserving SR in patients using previously ineffective AAD.34 Several reasons indicate that HF patients are a particular target for AF ablation. More than 30% of HF patients have AF. Traditional drug therapy with beta-blockers was not associated with a significant reduction in mortality in patients with concomitant AF and systolic HF.35 Data have shown that AF ablation reduced the risk of cardiac hospitalisation and recurrent atrial arrhythmia in subjects with HF and in subjects without HF; however, the reduction in all-cause mortality was noticed only in subjects with HF.36 Two contemporary studies have raised enthusiasm and hope but also scepticism. The Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) study included 394 patients – from 3,013 screened – with HF with reduced ejection fraction (ejection fraction <35%) and symptomatic paroxysmal or persistent AF.37 Patients were randomised for ablation (179 admitted, 21 excluded; patients underwent isolation of pulmonary veins, additional lesion lines and repeated procedure after blanking period, all being permitted) or conventional therapy (184 patients admitted, 13 excluded; 70% of them receiving a rate control strategy, AAD being discouraged and 30% receiving rhythm control strategy, mainly based on amiodarone). A crossover of 26 patients in the ablation group and 18 patients in the conventional therapy group was reported. Mean follow up was 37.8 months and the primary endpoint was all-cause mortality and hospital admission for worsening HF. The results showed an important reduction in the primary composite endpoint (38% risk reduction) and in the secondary endpoint of all-cause mortality (47% relative risk reduction). The AF burden was also significantly decreased in the ablation group. The benefit on mortality only emerged after 36 months, pointing to a sufficiently long time to observe the benefit in ablation trials. Despite the impressive results, apparent study limitations and commentaries invite moderation when interpreting the findings.38 The study group included mostly young patients, almost exclusively male, with less severe disease (New York Heart Association class I and II). On the contrary, in the conventional therapy group patients

EUROPEAN CARDIOLOGY REVIEW

Rhythm Control in AF had a trend for more severe disease (more diabetes, more ischaemic, more taking digoxin). The results could also be biased by the fact that 13% of patients in the ablation group were lost to follow up, compared with only 5% in the conventional group. A query regarding the patient selection for this study is also raised by the fact that the number of screened patients was 10 times higher than that of included patients, with one patient included per site and per year. When looking at subgroup analysis, the benefit does not translate to females, patients aged >65 years, those with LVEF <25% or those with previous ventricular tachycardia/VF. The number of patients with missing or excluded data or events in the ablation group was almost double that of the conventional group, which also influences the interpretation of results. There are no detailed data about how HF was treated according to modern guidelines in the two groups, or about how symptomatic AF was defined to exclude symptoms caused by HF. Finally, the number of events during the study was 32% less than prespecified by the power calculation. The long-awaited Catheter ABlation versus ANtiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) study included 2,204 patients with new-onset or untreated AF and increased cardiovascular risk randomly assigned to either catheter ablation or drug therapy.39 This study had a primary composite endpoint of all-cause mortality, disabling stroke, serious bleeding and cardiac arrest. Initially, the primary endpoint was all-cause mortality but because of the lowerthan-expected number of events and inclusion rate, it was changed and the sample size was reduced to 2,200 patients. The alternative design adopted was characterised by Milton Packer as “the terrifying power of self-deception”.40 Despite this change, the study failed to demonstrate any benefit in intention-to-treat analysis of the primary endpoint, or of all-cause mortality. There was a significant reduction in the combined endpoint of cardiovascular death and hospitalisations. However, this could be better explained by the decrease in readmissions for AF.41 This study also included relatively young patients of whom only 25% had previously diagnosed HF. Bleeding contributed to more than 40% of the composite endpoint – probably to the same extent in both groups – and all-cause mortality was low.42 Had this been a trial for a new drug, the on-treatment analyses would probably have been rejected as a result of all their sources of bias.41 Despite significant limitations, both studies are important to clinical practice; they do not change the actual guidelines but reinforce them. They confirm the safety and the efficacy of ablation and warrant the use of this procedure in the early stages of HF and in patients where at least one AAD has failed.

Complexity of AF: The Secrets of Present Failure and the Future Success of Rhythm Control The existing limitations of the rhythm control strategy in AF – irrespective of the methodology – are a result of the complexity of arrhythmia. AF is a multifactorial arrhythmic syndrome with a common electrical phenotype. It is a marker – a witness of the disease and/or its severity – and a risk factor for cardiovascular disease (CVD) with causal implications. As such, rhythm control as a part of the management of AF considered as a risk factor implies prevention of CVD or its progression (Figure 1).43 The key element for AF initiation and perpetuation is represented by substrate remodelling under the influence of traditional risk factors and under the influence of the genetic susceptibility (the two-hit

EUROPEAN CARDIOLOGY REVIEW

Figure 1: AF as a Marker and Factor of Risk Risk factors

Multifactorial pathways

Risk factor

MARKERS MODULATORS Substrate remodelling

Common pathway Marker of risk

AF Source Dan 2014.43 Reproduced with permission from Springer Nature.

Figure 2: Progression of AF as a Function of Atrial Remodelling and Strategies for Prevention ECV/maintain SR to prevent remodelling

Early prevention

Secondary prevention AADs

Upstream therapy

Ablation ECV

Risk factor management

ECV

Paroxysmal Persistent

Permanent

Primary prevention Remodelling Years

+10

+15

+20

Progressive disease/constant thromboembolic risk AADs = antiarrhythmic drugs; ECV = electrical cardioversion; SR = sinus rhythm. Source: Cosio et al. 2008.45 Reproduced with permission from Oxford University Press.

Figure 3: The Concept of Atrial Cardiomyopathy

Risk factors, e.g. age, sex, hypertension, obesity, diabetes, inflammation Genetic factors Cardiac diseases, e.g. ventricular dysfunction, infiltrative disorders, valvular diseases, and so on

Fibrosis AF progression Cardiovascular dysfunction (remodelling, Atrial stiffness, cardiomyopathy RAAS activation, and so on)

Electrical dysfunction

Mechanical dysfunction Thromboembolism

Non-cardiac diseases, e.g. endocrine diseases, drug toxicity

Procoagulant state

RAAS = renin–angiotensin–aldosterone system.

hypothesis).44 The remodelling process involves electrical substrate (ion channels), functional substrate, morphological substrate (fibrosis) and the intracellular calcium handling (responsible for triggered and ectopic activity). Substrate remodelling and triggered activity – essential for AF initiation and perpetuation – are the vulnerable targets for the efficient rhythm control. ‘AF begets AF’ is a phrase pointing to AF-induced fibrotic remodelling. However, the remodelling process is more complex including, as previously shown, the contribution of genetic factors, age and associated diseases or risk factors. The success of strategies aimed at maintaining the

Heart Failure, Arrhythmias and Cardiomyopathies Table 1: Old and New Targets for Antiarrhythmic Drug Therapy Therapeutic target

Current drugs/targets

New drugs/targets

ERP and re-entry

Class III AAD: dofetilide; sotalol; amiodarone; dronedarone

Atrial-specific ion channel modulation (IKur, IKAch, IK2P- TASK-1, SK channels)

Triggered activity (excitability and ectopy)

Class IC: flecainide, propafenone; vernakalant; ranolazine

Atrial-selective INaL inhibition; Calcium handling (Ry2, CaMKII, FKBP 12.6) NCX

Remodelling

Upstream therapies (ACE inhibitors, angiotensin II receptor blockers, statins) Amiodarone

Ca2+ signalling (calpains, calcineurin); kinases and phosphatases; TRP channels; microRNAs; NLRP3 inflammasome

AAD = anti-arrythmic drug; ACE = angiotensin-converting enzyme; CaMKII = Ca2+-calmodulin-dependent protein kinase; ERP = effective refractory period; FKBP = FK506-binding protein; IKAch = acetylcholine-dependent potassium current; INaL = late sodium current; IKur = ultrarapid potassium current; IK2P- TASK-1 = two-pore-domain TASK family potassium current; NCX = Na+/Ca2+ exchanger; Ry2 = ryanodine receptor; SK = small-conductance calcium dependent potassium current; TRP = transient receptor potential.

SR is highly dependent on timely intervention and the degree of substrate modification (Figure 2).45 The Routine Versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure (RACE 3) study demonstrated that targeted therapy of underlying diseases improves SR maintenance in patients with persistent AF.46 The fibrotic remodelling may have mechanisms independent of AF and may precede it.47,48 The generic term ‘atrial cardiomyopathy’ was created to define the entire spectrum of processes involved in atrial remodelling including electrical, functional, morphologic and procoagulant dysfunction to which AF is associated (Figure 3).49,50 Both interventional and pharmacological therapy need to consider the acquired progress in understanding AF mechanisms. New targets for AAD may be represented by specific atrial currents, remodelled in AF, such as the ultrarapid potassium current (IKur), the acetylcholinedependent potassium current (IKAch), the two-pore-domain TASK family potassium currents (IK2P) or the small-conductance calcium dependent potassium currents (SK).17 Obviously, targeting specific

irchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines K for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609–78. https:// doi.org/10.1093/europace/euw295; PMID: 27567465. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1509–13. https://doi. org/10.1161/01.CIR.0000121736.16643.11; PMID: 15007003. Prabhu S, Taylor AJ, Costello BT, et al. Catheter Ablation versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: the CAMERA-MRI Study. J Am Coll Cardiol 2017;70:1949–61. https://doi.org/10.1016/j.jacc.2017.08.041; PMID: 28855115. Dan GA, Iliodromitis K, Scherr D, et al. Translating guidelines into practice for the management of atrial fibrillation: Results of an European Heart Rhythm Association survey. Europace 2018;20:1382–7. https://doi.org/10.1093/europace/euy094; PMID: 29893840. Boriani G, Diemberger I, Biffi M, et al. Pharmacological cardioversion of atrial fibrillation: current management and treatment options. Drugs 2004;64:2741–62. https://doi. org/10.2165/00003495-200464240-00003; PMID: 15563247. Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2015;3:CD005049. https://doi.org/10.1002/14651858. CD005049.pub4; PMID: 25820938. Reimold FR, Reynolds MR. Proarrhythmia and death with antiarrhythmic drugs for atrial fibrillation, and the unfulfilled promise of comparative effectiveness research. Am Heart J 2018;205:128–30. https://doi.org/10.1016/j.ahj.2018.08.011; PMID: 30290878. Friberg L. Ventricular arrhythmia and death among atrial fibrillation patients using anti-arrhythmic drugs. Am Heart J 2018;205:118–27. https://doi.org/10.1016/j.ahj.2018.06.018; PMID: 30236980. Hohnloser SH, Connolly SJ, Crijns HJ, et al. Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400

10.

11.

12.

13.

14.

15.

16.

17.

18.

atrial currents will increase AAD safety, diminishing the risk of ventricular proarrhythmia. Another important target for modern AAD is represented by the components of altered intracellular calcium handling (ryanodine receptors Ry2, Ca2+-calmodulin-dependent protein kinase [CaMKII] or calstabin [FKBP12.6]). Other possible targets – non-coding microRNAs and, unexpectedly, components of the inflammatory chain, such as the NLRP3 inflammasome system – recently demonstrated contribution to atrial remodelling. Unfortunately, because of social and economic reasons the gaps between what we can do and what we should do remain important, especially concerning pharmacological therapy.51 The perspective on future AAD is summarised in Table 1.52 In clinical practice, pharmacological AAD therapy and ablation are often viewed simplistically as competitors. However, it should be emphasised that ablation and pharmacological therapy are complementary tools – both far from ideal at this moment – and they should develop in parallel with the new paradigm of AF. As Hamlet said: “There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy”.53

mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter. J Cardiovasc Electrophysiol 2008;19:69–73. https://doi. org/10.1111/j.1540-8167.2007.01016.x; PMID: 18031520. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668–78. https://doi.org/10.1056/ NEJMoa0803778; PMID: 19213680. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268–76. https://doi.org/10.1056/NEJMoa1109867; PMID: 22082198. Heidbuchel H, Dagres N, Antz M, et al. Major knowledge gaps and system barriers to guideline implementation among European physicians treating patients with atrial fibrillation: a European Society of Cardiology international educational needs assessment. Europace 2018;20:1919–28. https://doi. org/10.1093/europace/euy039; PMID: 29538637. Allen LaPointe NM, Lokhnygina Y, Sanders GD, et al. Adherence to guideline recommendations for antiarrhythmic drugs in atrial fibrillation. Am Heart J 2013;166:871–8. https:// doi.org/10.1016/j.ahj.2013.08.010; PMID: 24176443. Allen LaPointe NM, Dai D, Thomas L, et al. Antiarrhythmic drug use in patients >65 years with atrial fibrillation and without structural heart disease. Am J Cardiol 2015;115:316–22. https://doi.org/10.1016/j.amjcard.2014.11.005; PMID: 25491240. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991;84:1831–51. PMID: 1717173. Camm AJ. Hopes and disappointments with antiarrhythmic drugs. Int J Cardiol 2017;237:71–4. https://doi.org/10.1016/ j.ijcard.2017.03.056; PMID: 28365182. Dan GA, Dobrev D. Antiarrhythmic drugs for atrial fibrillation: imminent impulses are emerging. Int J Cardiol Heart Vasc 2018;21:11–5. https://doi.org/10.1016/j.ijcha.2018.08.005; PMID: 30225340. Kuck K-H, Fürnkranz A, Chun KRJ, et al. Cryoballoon or

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radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial. Eur Heart J 2016;37:2858–65. https://doi.org/10.1093/eurheartj/ehw285; PMID: 27381589. Arbelo E, Brugada J, Blomström-Lundqvist C, et al. Contemporary management of patients undergoing atrial fibrillation ablation: in-hospital and 1-year follow-up findings from the ESC-EHRA atrial fibrillation ablation long-term registry. Eur Heart J 2017;38:1303–16. https://doi.org/10.1093/ eurheartj/ehw564; PMID: 28104790. Steinberg JS, Palekar R, Sichrovsky T, et al. Very long-term outcome after initially successful catheter ablation of atrial fibrillation. Heart Rhythm 2014;11:771–6. https://doi. org/10.1016/j.hrthm.2014.02.003; PMID: 24508206. Teunissen C, Kassenberg W, van der Heijden JF, et al. Fiveyear efficacy of pulmonary vein antrum isolation as a primary ablation strategy for atrial fibrillation: a single-centre cohort study. Europace 2016;18:1335–42. https://doi.org/10.1093/ europace/euv439; PMID: 26838694. Clarnette JA, Brooks AG, Mahajan R, et al. Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. Europace 2018;20:f366–76. https://doi.org/10.1093/europace/eux297; PMID: 29267853. Wynn GJ, Das M, Bonnett LJ, et al. Efficacy of catheter ablation for persistent atrial fibrillation. Circ Arrhythmia Electrophysiol 2014;7:841–52. https://doi.org/10.1161/CIRCEP.114.001759; PMID: 25132078. Hindricks G, Sepehri Shamloo A, Lenarczyk R, et al. Catheter ablation of atrial fibrillation: current status, techniques, outcomes and challenges. Kardiol Pol 2018:1680–6. https://doi. org/10.5603/KP.a2018.0216; PMID: 30406938. Dagres N, Hindricks G, Kottkamp H, et al. Complications of atrial fibrillation ablation in a high-volume center in 1,000 procedures: still cause for concern? J Cardiovasc Electrophysiol 2009;20:1014–9. https://doi.org/10.1111/j.15408167.2009.01493.x; PMID: 19490383. Liu W, Wu Q, Yang XJ, Huang J. The trend of change in catheter ablation versus antiarrhythmic drugs for the management

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Heart Failure, Arrhythmias and Cardiomyopathies

Chagas Disease and Heart Failure: An Expanding Issue Worldwide Felipe Martinez, 1,2 Eduardo Perna, 3 Sergio V Perrone 4,5 and Alvaro Sosa Liprandi 6,7 1. Cordoba National University, Instituto DAMIC, Córdoba, Argentina; 2. Docencia, Asistencia Médica e Investigación Clínica (DAMIC) Medical Institute, Rusculleda Foundation for Research Córdoba, Argentina; 3. Coronary Care Unit and Heart Failure Division, Juana Cabral Cardiovascular Institute, Corrientes, Argentina; 4. El Cruce Hospital, Buenos Aires, Argentina; 5. Argentine Catholic University, Buenos Aires, Argentina; 6. Cardiovascular Division, Sanatorio Güemes Hospital, Buenos Aires, Argentina; 7. Postgraduate Medical School in Cardiology, Universidad de Buenos Aires, Argentina

Abstract Chagas disease, originally a South American endemic health problem, is expanding worldwide because of people migration. Its main impact is on the cardiovascular system, producing myocardial damage that frequently results in heart failure. Pathogenic pathways are mainly related to inmunoinflamatory reactions in the myocardium and, less frequently, in the gastrointestinal tract. The heart usually shows fibrosis, producing dilatation and damage of the electrogenic cardiac system. These changes result in cardiomyopathy with heart failure and frequent cardiac arrhythmias and heart blocks. Diagnosis of the disease must include a lab test to detect the parasite or its immune reactions and the usual techniques to evaluate cardiac function. Therapeutic management of Chagas heart failure does not differ significantly from the most common treatment for dilated cardiomyopathy, with special focus on arrhythmias and several degrees of heart block. Heart transplantation is reserved for end-stage cases. Major international scientific organisations are delivering recommendations for prevention and early diagnosis. This article provides an analysis of epidemiology, prevention, treatment and the relationship between Chagas disease and heart failure.

Keywords Cardiomyopathy, Chagas disease, heart failure, immunoinflammation, roadmap Disclosure: FM, EP and ASL have no conflicts of interest to declare. SVP is a member of advisory groups for Novartis, Ferrer, Abbott and Servier, and has received conference fees from these companies. Received: 10 December 2018 Accepted: 1 April 2019 Citation: European Cardiology Review 2019;14(2):82–8. DOI: https://doi.org/10.15420/ecr.2018.30.2 Correspondence: Felipe Martinez, Cordoba National University, Av Colón 2057, Cordoba X5003DCE, Argentina. E: dr.martinez@usa.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Chagas disease was initially described as an endemic health problem in a few countries in South America – mainly Argentina and Brazil – and one of the consequences of the disease, heart damage, made it an interesting issue for healthcare professionals, from epidemiologists to cardiologists.1 Chagas cardiomyopathy (ChCM) is now recognised as a cardiovascular disorder, diagnosed and treated not only in the original region, but also in Europe, North America and even in Asia (Figure 1). This is a result of increased migration around the world.2–4 It is estimated that Chagas disease affects 6–7 million people in Latin America and more than 300,000 people in the US.5,6 The natural history of the disease shows that after two to three decades up to 30% of infected individuals exhibit evidence of chronic cardiomyopathy and a proportion of these develop heart failure (HF) with reduced ejection fraction (HFrEF).7 Despite the high prevalence of Chagas disease, little is known about morbidity and mortality in patients with HFrEF caused by Chagas disease, compared with other aetiologies, especially in the modern era of HF therapies.8,9 Future trials should consider recruiting larger numbers of patients with ChCM to allow adequately powered subgroup analysis. We still treat patients with HF caused by ChCM empirically with therapies recommended by guidelines and this is another reason to specifically promote more research in ChCM.10 This article will analyse and

Access at: www.ECRjournal.com

discuss Chagas disease and HF, from epidemiology through to the latest treatment and prevention strategies.

The Expanding Epidemiology Chagas disease is an important public health problem, with a frequency 140 times higher than HIV. Initiatives in the Americas have helped to achieve significant reductions in the number of acute cases of Chagas disease and the presence of domiciliary triatomine vectors in endemic areas. The estimated number of people infected with Trypanosoma cruzi worldwide dropped from 30 million in 1990 to 8–10 million in 2010, the annual incidence of infection decreased from 700,000 to 28,000 new cases over the same period and the burden of disease decreased from 2.8 million disability-adjusted life-years lost to <0.5 million years between 1990 and 2006.11 Approximately 108 million people are exposed to Chagas disease in 21 South American countries, with 8 million infected and 41,200 new cases per year. About 20–40% of infected people will develop cardiac damage.12–14 The prevalence of Chagas disease varies between countries, from 1.3% in Brazil to 20.0% in Bolivia. In the US, estimates claim that over 0.5 million immigrants are infected with T cruzi. The number of houses infested by triatomine vectors has been reduced as a result of campaigns and the work of teams throughout South America. Vectorial transmission has been stopped in Uruguay,

Chagas Disease and Heart Failure Chile and Brazil, and in large areas of Argentina and Venezuela, achieving an average reduction in prevalence and incidence of 70%. Chagas disease is an important cause of dilated cardiomyopathy in Latin America, where the disease is endemic.15,16 Chagas heart disease (ChHD) commonly presents with symptomatic ventricular arrhythmias, symptomatic bradyarrhythmias, sudden death, HF, embolic events, chest pain and high susceptibility to proarrhythmia.15 The clinical picture mimics that of coronary artery disease and idiopathic dilated cardiomyopathy. The prognosis is poor for patients with malignant ventricular arrhythmias, HF, left ventricular aneurysm or global systolic dysfunction.16 Moreover, in an Argentinian survey, HF was the most frequent finding, leading clinicians to suspect Chagas disease.17 HF may occur in approximately 10% of subjects who have Chagas disease with cardiac involvement.18,19 A meta-analysis of 143 studies of HF from Latin America reported the incidence of HF in Chagas disease to be 137 per 100,000 people per year and annual mortality to be 1.12–7.18 per 100,000 people per year. Higher in-hospital mortality was also found in patients with Chagas disease, compared with a nonChagas disease aetiology, representing 36% of the aetiology of HF.20 The estimated prevalence of Chagas disease within HF populations in Argentina is about 15%.21 However, data from different surveys reveal a Chagas disease prevalence of 4.0–6.0% in outpatient registries and 1.3–8.4% in decompensated HF settings in Argentina, and of 0.6–20.0% in Latin American registries.22–24 This discrepancy may be attributable to actual lower prevalence, underrepresentation of rural inhabitants in the surveys, low use of screening tests or because some cases of Chagas disease might represent a comorbidity. The Grupo de Estudio de la Sobrevida en la Insuficiencia Cardíaca en Argentina (GESICA) Registry has shown a prevalence of true ChCM of 6.4%.25 Patients with Chagas disease had a different clinical profile from, and were treated differently to, those without Chagas disease. Patients with ChCM were admitted more frequently for decompensated HF than other patients.26 It has been reported that long-term outcomes in patients with chronic systolic HF secondary to ChCM are poorer than those in patients with idiopathic and ischaemic aetiologies.27,28 Acute decompensated HF (ADHF) is a common clinical condition in ChCM. A study has shown that patients with ChCM had the highest proportion of hospital admissions for cardiogenic shock and arrhythmia, with lower systolic blood pressure and a higher proportion of right ventricular HF than other aetiologies.29 Outcomes were also influenced by aetiology, and ChCM had the lowest proportion of hospital discharge and the highest proportion of cardiac transplant when compared with other aetiologies, mainly in Latin American countries. So, the poorer prognosis of ChCM in comparison with other common causes of cardiomyopathy is also applicable to vulnerable ADHF, related to the severity of presentation and other issues, including socioeconomic factors.

Figure 1: Worldwide Expansion of Chagas Disease

Worldwide expansion of Chagas disease (estimated cases)

North America 300–500,000

Europe 70–120,000

South America 8–10 million

Japan 3,000

Australia 1,500

Source: Mitelman.79 Reproduced with permission from the Inter-American Society of Cardiology.

Main Pathophysiologic Pathways Chagas disease may be diagnosed in the infected patient in either acute or chronic clinical presentation. In some cases, the acute phase is light and can go undiagnosed by the patient and the medical team. Acute Chagas disease is an immunological reaction typically characterised by diffuse lymphadenopathy, hepatomegaly and splenomegaly. In this period the myocardium and the gastrointestinal system are severely infected by the parasite and show important tissue inflammation.30 Sometimes, acute myocarditis may be diagnosed with signs of cardiac dilatation and pericardial effusion. The most severe presentations may produce pancarditis and even vasculitis. In these cases, development of acute HF is frequent and the prognosis is usually poor because multiorgan involvement may occur.31,32 Development of HF linked to Chagas disease most commonly presents chronically. The typical dilated cardiomyopathy observed in most patients with chronic HF related to Chagas disease consists of chronic myocarditis producing fibrosis with particular invasion of His bundle branches, causing different types and grades of cardiac block and progressive dysfunction.33 The exact mechanism whereby parasitism causes tissue damage in the chronic phase is not clear and could be related to chronic immune reactions. The severity and extension of the inflammation and fibrosis depend on many factors, mainly the aggressiveness of the parasite, the immunologic reaction of the patient and the concomitant cardiovascular risk factors.34–36 Some patients with ChHD may also have digestive disturbances, often dysfunctions in the oesophagus and bowel as a result of inmunoinflammatory reactions in these organs, which ends in megaoesophagus, megacolon and/or megarectum.37

An Update on Diagnosis Typically, the clinical profile of ChCM includes younger people, more often women, with lower prevalence of hypertension, diabetes and renal impairment, compared with non-ChCM patients. In contrast, health-related quality of life was worse and the prevalence of stroke and pacemaker implantation were higher in ChCM compared with non-ChCM aetiologies. Despite these differences, the rates of cardiovascular death, HF hospitalisation and all-cause mortality were higher in patients with Chagas disease than other non-ischaemic and ischaemic patients.9

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In the acute phase of Chagas disease, the diagnosis might be suspected, taking account of the different transmission forms and patient history. Most patients are oligosymptomatic with non-specific symptoms of weakness, fever and malaise. Patients could present with the pathognomonic chagoma or unilateral eyelid swelling, which is often treated as viral conjunctivitis. In some cases – mainly in immunocompromised patients or in those who were infected with T cruzi through oral transmission – fulminant disease is present with acute myocarditis, pericardial effusion or meningoencephalitis.38–40

Heart Failure, Arrhythmias and Cardiomyopathies After the acute phase of infection, most patients develop the chronic form. This is defined by positive serology and slow progression or even absence, during a non-specific period of time, of physical signs or symptoms of cardiac electrogenic conduction abnormalities, myocardial contractile dysfunction, arrhythmias thromboembolism, colon, rectum or oesophagus abnormalities.41–46 ChCM is the most important clinical manifestation of Chagas disease, resulting in the majority of Chagas disease morbidity and mortality.39,41,47,48

ECG and Holter monitor The ECG and Holter monitor may show tachycardia (out of proportion to fever), different degrees of atrioventricular (AV) block, QT prolongation, low voltage and repolarisation abnormalities in the acute phase of the disease. Later in the disease progression, the ECG plays an important role in diagnosis and prognosis of ChCM. It could be normal, with slight abnormalities, premature ventricular beats, ventricular tachycardia, AF or flutter, complete AV block, anterior and inferior fibrosis, complete right bundle branch block alone or in combination with left anterior fascicular block, with or without different degrees of AV block.49

Radiology X-ray is useful in assessment and follow-up of Chagas disease. Enlargement of all four cardiac chambers with or without signs of pulmonary congestion suggests ChCM.41 X-ray is also useful in the diagnosis of megacolon and megaoesophagus, which can be corroborated with endoscopy.

Parasitaemia In the acute phase of Chagas disease, parasitaemia can be observed with a microscopic blood examination.49 Microhaematocrit is a widely used method of identifying congenital infection. The trypomastigotes present in the blood can be seen during the first 8–12 weeks and, after that, parasitaemia falls below detectable levels.50

Serology and C-reactive Protein Indirect immunofluorescence, haemagglutination, and enzyme-linked immunosorbent assays are commonly used in screening for Chagas disease.51–53 The WHO recommends diagnosing Chagas disease with two conventional laboratory tests and doing a third test in cases of discordance. C-reactive protein testing is the most sensitive test in acute infection or reactivation in patients with Chagas disease who are organ recipients or are otherwise immunocompromised.54–56

Echocardiography Echocardiography may find segmental wall motion abnormalities, including akinesia, hypokinesia or dyskinesia with preserved septal contraction, left ventricular aneurysm (most common in apex), left ventricular diastolic dysfunction, dilated cardiomyopathy involving both ventricles, and mural thrombus, mitral and tricuspid regurgitation. Assessment of myocardial strain through speckle tracking could help to detect myocardial damage in early periods of the disease, and some authors describe decreased global radial strain during the indeterminate stage, even in patients with a normal ECG and common echocardiogram.57–59 Left ventricular global dysfunction with low ejection fraction is one of the most important predictors of death in ChCM.57,59–61

Multigated Radionuclide Ventriculography Multigated radionuclide ventriculography can be particularly helpful for the assessment of biventricular systolic function in patients with poor echocardiographic windows and a contraindication to cardiac MRI. It is an excellent method for providing LVF information in patients with Chagas disease.62,63 It can also provide us with quantification of right ventricular function – although this is less precise – and with echocardiographic analysis can be used to qualitatively assess ventricular dyssynchrony.64–66 These data could all be improved with myocardial perfusion assessment.67

PET PET is not included as a routine investigation in Chagas disease but perfusion defects and areas of fibrosis can be detected with PET in early stages and they correlate with ventricular wall motility abnormalities in the absence of coronary artery lesions.68,69 The presence of chest pain – mostly non-typical angina pectoris – in patients with Chagas disease could be attributable to microvascular perfusion abnormalities.69,70

Cardiac MRI Cardiac MRI with or without gadolinium is useful to obtain more precise information about left ventricular ejection fraction and right ventricular ejection fraction, thrombus and fibrosis, giving us a good diagnostic and prognostic base.17,71–74

Cardiac Catheterisation Although most patients with Chagas disease have normal epicardial coronary arteries, cardiac catheterisation is necessary to rule out epicardial coronary artery disease, which could coexist with Chagas disease, even in patients without angina pectoris or with noncharacteristic chest pain. Ventriculography allows the detection small aneurysms, which would not be detected with echocardiography, and left ventricular wall motion abnormalities. Right and left cardiac catheterisation is also indicated in patients with advanced HF to assess and more effectively tailor therapy and determine the feasibility of cardiac transplantation or the implant of a ventricular assist device. In addition, continuous ambulatory pulmonary pressure monitoring could reduce decompensation episodes and reduce the number of hospitalisations in patients with HF.75–77

Drug Heart Failure Management: Similar or Different? This update is specifically focused on the management of HF and not on the parasite-related therapeutic issues, nor on the other organs damaged by Chagas disease. Treatment of cardiac dysfunction should be similar in populations with and without Chagas disease, as the haemodynamics and pathophysiology are similar. Treatment approaches have been based on evidence from other forms of HF and most clinical trials confirming a survival advantage did not include Chagas disease. So, information about treatment in patients with Chagas disease and HF derives from non-randomised studies or clinical trials of HF that included only small proportion of ChCM.78 Consequently, there are few therapies with strong recommendations and

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Chagas Disease and Heart Failure Table 1: Recommendations of Argentinean Consensus of Chagas Disease Drug

Clinical Scenario

Recommendation

Level of evidence

ACE inhibitors

• EF <40%, FC I–IV, stages B, C and D

Angiotensin receptor blockers

• EF <40%, FC I–IV, stages B, C and D, ACE inhibitor intolerant • EF <40% and symptomatic HF, optimal treatment with ACE inhibitor and beta-blocker

I IIb

B B

Beta-blockers

• EF <40%, FC II–IV, stages B, C and D • Contraindications: bronchospasm, AV block, sinus sick syndrome, symptomatic bradychardia (<50)

IIa III

B B

Mineralocorticoid receptor antagonist

• EF <35% and FC III–IV • Moderated HF (FC II, stage C)

I IIa

B C

Digoxin

• • • •

I IIa IIb III

C C B B

Diuretics

• HF and clinical congestion; FC II–IV, stages C and D

AF with high ventricular rate AF with moderated ventricular rate, and FC III–IV Sinus rhythm, EF <40%, FC III–IV, optimal treatment Contraindications: AF with low ventricular rate, bronchospasm, AV block, sinus sick syndrome, and severe conduction system abnormalities

ACE = angiotensin-converting enzyme; AV = atrioventricular; EF = ejection fraction; FC = functional class; HF = heart failure.

most of therapies are based on evidence from small trials and expert opinions.

authors found that the available evidence was low quality and there were no conclusive data to support or reject the use of carvedilol.

While specific pharmacological treatment of HF is common to other aetiologies, there are some significant features in the context of HF as a result of ChCM that should be considered. Table 1 shows the main recommendations from the Argentinian consensus document on Chagas disease.79

Diuretics should be used at the lowest possible dosage to obtain a negative balance, thus avoiding electrolyte and metabolic disorders caused by high dosages. Furosemide has the strongest diuretic effect and electrolytes should be checked frequently because excessive depletion can generate malignant arrhythmia.

Routinely, beta-blockers, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers and mineralocorticoid receptor antagonists (MRA) represent the ideal combination in subjects with reduced ejection fraction, in the absence of any contraindications. In addition, digoxin, diuretics and anticoagulation are used as needed.80,81 Small trials in patients with cardiomyopathy have shown that these treatments can improve functional class, lower BNP and have a beneficial effect on neurohormones with a reduction in heart rate and decreased incidence of ventricular arrhythmias.3,82 Evidence for the role of angiotensin receptor neprilysin inhibitors (ARNI) is lacking and only 7.6% of 2,552 Latin American patients with HFrEF randomised in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial and Aliskiren Trial of Minimizing OutcomeS in Patients With HEart Failure (ATMOSPHERE) had ChCM.83 Compared with other aetiologies, patients with ChCM less frequently received beta-blockers and digitalis, but a higher proportion were treated with amiodarone, MRA and anticoagulants, with no differences in the use of ACEI.

Patients with severe HF as a result of heart disease not related to Chagas disease have shown improvement in quality of life and fewer hospitalisations when treated with digoxin, compared with placebo. However, ChCM has been associated with changes in automaticity and conduction related to malignant ventricular arrhythmia, and dysautonomia favours the appearance of bradycardic rhythms. Consequently, as digoxin can aggravate these disorders of rhythm and conduction, it has a restricted use in Chagas disease. Low-dose amiodarone has been associated with reduced HF mortality and sudden death in an Argentinian study that included patients with ChCM. A such, amiodarone can be safely used in the presence of arrhythmias. Anticoagulation in ChCM shares its common indication with other aetiologies, including permanent or paroxysmal episodes of AF, a previous thromboembolic event, the presence of a cardiac thrombus and apical aneurysms. A subanalysis of the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) reported that ivabradine was effective in reducing heart rate in ChCM and improving functional class, suggesting that ivabradine may have a favourable benefit-risk profile in this population.85 Specific drugs to eliminate the parasite or its reactions and non-pharmacological or invasive therapies are explained in the following section.

Although several clinical trials have demonstrated the utility of adrenergic blockers in dilated cardiomyopathy different from Chagas disease in terms of reducing mortality and the number of hospitalisations, in ChCM, the presence of significant bradycardia and autonomic nervous system disorders with central and peripheral dysautonomia lead to greater precautions for routine use. The most used drug in this condition is carvedilol. Three trials evaluating carvedilol in ChCM were identified, with a total of 108 participants.84 A lower proportion of all-cause mortality was found in the carvedilol groups compared with the placebo groups (RR 0.69; 95% CI [0.12– 3.88]), with no difference in hospital readmissions. However, the

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Specific Antitrypanosomal Therapy Treatment for Chagas disease is mainly non-invasive in the early stages, when nifurtimox or benznidazole are used. More invasive procedures could be applied in advanced stages of the pathology, for example, where there is pericardial effusion, cardiac tamponade, arrhythmia and HF. Benznidazole is a nitroimidazole with antiparasitic effects. The sideeffects include rash, numbness, fever, muscle pain, anorexia and weight

Heart Failure, Arrhythmias and Cardiomyopathies loss, nausea, vomiting and insomnia, plus a rare but important symptom, bone marrow suppression, which can lead to low blood cell levels.

with ChCM and right bundle branch block or its combination with left anterior fascicular block, where experience is not conclusive.101,102

Nifurtimox forms a nitro-anion radical metabolite that reacts with parasite nucleic acids causing significant DNA breakdown. It is used as a second specific treatment option in early Chagas disease because it has more serious side-effects than benznidazole, including anorexia, weight loss, nausea, vomiting, headache, dizziness, amnesia, rash, depression, anxiety, confusion, fever, sore throat, chills, seizures, impotence, tremors, muscle weakness and numbness.

Ambulatory Pulmonary Pressure Monitoring

Invasive Treatment of Gastrointestinal Chagas Disease Invasive procedures to treat megacolon and megaoesophagus may be necessary. Megacolon can be treated with the Duhamel procedure or a modified version of the procedure, introduced by Haddad.86–88 Laparoscopic procedures could also be applied. Megaoesophagus can be treated with wide oesophago-cardiomyectomy on the anterior oesophagogastric junction, combined with an antireflux valvuloplasty procedure or oesophagogastroplasty through the oesophageal bed.89 These procedures could be extremely useful when advanced stages of HF are present and it is necessary to offer more invasive procedures.

Invasive Treatment of Cardiovascular Chagas Disease Cardiac manifestations of Chagas disease may also need invasive surgical procedures to preserve the patient’s life or improve their functional class. Clinical management of patients with chronic Chagas disease requires proper clinical risk stratification and the identification of patients at high risk of sudden cardiac death (SCD). Recognising high-risk patients who require specific therapies – especially invasive procedures such as the implantation of pacemakers, automatic ICDs, ablative procedures and even cardiac resynchronisation therapy (CRT) – is a major challenge in clinical practice.90

Pacemakers Electrophysiological abnormalities of sinus node, AV node and HisPurkinje conduction can be detected in about one-third of patients with Chagas disease and pacemakers have shown utility in patients with this manifestation, but in some places this is still an unmet need.91–93 AV block and symptomatic sinus sick syndrome are the main indications for pacemaker implantation in these patients, preferably electrode implantation in the mid-septal of the right ventricle to the apical site.94

Automatic ICDs Malignant ventricular arrhythmia and SCD are more frequent in patients with Chagas disease.91,95,96 Automatic ICDs may be used in the treatment of severe arrhythmias with high risk of SCD.97 Primary or secondary prevention should be a routine indication for patients with Chagas disease with malignant arrhythmias.98 The combination of ablation procedures, amiodarone and/or beta-blockers might be considered in special cases to reduce the number of automatic ICD therapies, as in other types of cardiomyopathy.99

Other less invasive procedures such as ambulatory pulmonary pressure monitoring, which are useful in patients with HF, need to be tested in patients with Chagas disease HF and could probably prevent recurrent episodes of decompensation.75,77

Heart Transplant Heart transplantation and left ventricular assist devices (LVAD) have an important place in the treatment of irreversible HF in patients with Chagas disease. Chagas disease was initially considered a contraindication for transplant because of the possible reactivation after transplantation and immunosuppression, but advances in immunosuppression programmes since the 1990s mean that there is now a similar survival and quality of life in HF patients with Chagas cardiomyopathy.103 Selection criteria are similar to those for general heart transplant, including pulmonary artery pressures that could be elevated in some cases as a result of chronic left ventricular failure or undiagnosed pulmonary microembolism. However, the clinician also needs to consider the presence of megaoesophagus or megacolon, which could constitute a contraindication because of the possibility of complications (perforation) with the use of antiproliferative therapy such as mycophenolic acid derivatives or mammalian target of rapamycin inhibitors. The administration of prophylactic antitrypanosomal therapy is not recommended because of the higher risk of malignant neoplasms after transplant in patients who received reactivation prophylactic antitrypanosomal therapy.104 The lowest immunosuppression regimen, high suspicion of possible reactivation and early detection and introduction of medical treatment with benznidazole offer a secure treatment of Chagas disease reactivation after transplant. Lifelong T cruzi monitoring is required, mainly during increased immunosuppression therapy for transplant organ rejection.105,106

Circulatory Assist Devices Different devices for cardiac assist could be used in patients with endstage HF as a result of Chagas disease. These could be applied as a bridge to transplant, a bridge to recovery during the acute period or as a bridge to decision, or even as destination therapy depending on the general state of the patient and meticulous clinical evaluation of the possibility of survival and better quality of life.107–110 As in the transplant population, previous evaluation of the pulmonary pressures plus poor right ventricular function could be a contraindication for LVAD alone.

Global Action on Chagas Disease ChHD is a preventable non-communicable disease (NCD) that mainly affects the poorest and most vulnerable populations of South America. Driven by poverty, poor access to health services and other health system weaknesses, the majority of people with this condition live in low- and middle-income countries.

Ablation Therapy Ablation ventricular tachycardia therapy should be considered after oral medication failure.100 CRT could be used in the treatment of patients with severe HF and left bundle branch block but there is scarce evidence to support resynchronisation therapy for patients

The need for concerted global action to control NCDs is a high priority on the global health agenda. This is evident in the UN political declarations on the prevention and control of NCDs – the 25×25 target aims for a 25% reduction in premature mortality from NCDs

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Chagas Disease and Heart Failure by 2025 – the WHO Global NCD Action Plan, and the UN Sustainable Development Goals.111,112 Cardiovascular disease (CVD) is the leading cause of premature mortality worldwide and with more than 80% of deaths occurring in low- and middle-income countries, leading the World Heart Federation (WHF) to launch its Roadmap Initiative in 2014 to guide and support those seeking to improve CVD control.

of CVD, rheumatic heart disease, cholesterol, AF, diabetes and HF. The ChHD Roadmap is a resource to raise the profile of ChHD and provides a framework to guide and support the strengthening of national, regional and global ChHD control efforts. The process also requires a range of local expertise, including knowledge of medicine, cardiology, cultural and social contexts, prevention, health promotion, health systems, economics and government priorities.

Conclusion The WHF Roadmaps are global implementation strategies designed to help governments, employers, non-governmental organisations, health activists, academic and research institutions, healthcare providers and people affected by CVD, take action to better prevent and control CVD.113,114 The Roadmaps synthesise existing evidence on the efﬁcacy, feasibility and cost-effectiveness of various strategies. They also identify potential barriers (roadblocks) to implementation and propose solutions to bypass them. The WHF and Inter-American Society of Cardiology Roadmap for reducing morbidity and mortality through improved prevention and control of ChHD complements existing Roadmaps on tobacco control, hypertension, secondary prevention

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Chagas disease – originally a South American endemic health problem – is expanding worldwide as a result of people migrating. The pathology of Chagas disease is based in an inmunoinflammatory reaction producing fibrosis and remodelling, mainly in the myocardium. In many cases these mechanisms result in a dilated cardiomyopathy with HF and reduced ejection fraction, frequent cardiac arrhythmias and different types of heart block. The diagnosis and treatment of HF as a result of Chagas disease include the usual steps for other aetiologies, plus the need for laboratory techniques for parasite-related issues. International scientific organisations are concerned about this health problem and about delivering recommendations for prevention and early diagnosis.

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Screening and treatment of Chagas disease in organ transplant recipients in the United States: recommendations from the Chagas in transplant working group. Am J Transplant 2011;11:672–80. https://doi.org/10.1111/j.1600-6143.2011.03444.x; PMID: 21401868. 55. Tohidpour A, Morgun AV, Boitsova EB, et al. Neuroinflammation and infection: molecular mechanisms associated with dysfunction of neurovascular unit. Front Cell Infect Microbiol 2017;7:276. https://doi.org/10.3389/ fcimb.2017.00276; PMID: 28676848. 56. de Freitas VL, da Silva SC, Sartori AM, et al. Real-time PCR in HIV/Trypanosoma cruzi coinfection with and without Chagas disease reactivation: association with HIV viral load and CD4 level. PLoS Negl Trop Dis 2011;5:e1277. https://doi.org/10.1371/ journal.pntd.0001277; PMID: 21912712. 57. Macedo CT, Larocca TF, Noya-Rabelo M, et al. Assessment of speckle tracking strain predictive value for myocardial fibrosis in subjects with Chagas disease. 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Cardiac autonomic impairment and early myocardial damage involving the right ventricle are independent phenomena in Chagas’ disease. Int J Cardiol 1998;65:261–9. https://doi. org/10.1016/S0167-5273(98)00132-6; PMID: 9740483. 66. Marin-Neto JA, Marzullo P, Sousa AC, et al. Radionuclide angiographic evidence for early predominant right ventricular involvement in patients with Chagas’ disease. Can J Cardiol 1988;4:231–6. PMID: 3136900. 67. Nivardo Sobrino A, Jimenez-Angeles L, Bialostozky D, et al. Evaluation of the function and ventricular synchrony in patients with latency stage of Chagas’ disease. Arch Cardiol Mex 2009;79:243–8 [in Spanish]. PMID: 20191983. 68. Peix A, Garcia R, Sanchez J, et al. Myocardial perfusion imaging and cardiac involvement in the indeterminate phase of Chagas disease. Arq Bras Cardiol 2013;100:114–7. https://doi. org/10.5935/abc.20130023; PMID: 23503819. 69. Abuhid IM, Pedroso ER, Rezende NA. Scintigraphy for the detection of myocardial damage in the indeterminate form of Chagas disease. Arq Bras Cardiol 2010;95:30–4. https://doi.org/10.1590/S0066-782X2010005000064; PMID: 20563520. 70. Marin-Neto JA, Marzullo P, Marcassa C, et al. Myocardial perfusion abnormalities in chronic Chagas’ disease as detected by thallium-201 scintigraphy. Am J Cardiol 1992;69:780–4. https://doi.org/10.1016/0002-9149(92)90505-S; PMID: 1546653.

71. R egueiro A, Garcia-Alvarez A, Sitges M, et al. Myocardial involvement in Chagas disease: insights from cardiac magnetic resonance. Int J Cardiol 2013;165:107–12. https://doi. org/10.1016/j.ijcard.2011.07.089; PMID: 21907431. 72. Nunes MC and Acquatella H. Prevalence of right ventricular dysfunction in Chagas disease: does this depend on the method used? Usefulness of cardiac magnetic resonance. Circ Cardiovasc Imaging 2017;10. https://doi.org/10.1161/ CIRCIMAGING.117.006208; PMID: 28289021. 73. Uellendahl M, Siqueira ME, Calado EB, et al. Cardiac magnetic resonance-verified myocardial fibrosis in Chagas disease: clinical correlates and risk stratification. Arq Bras Cardiol 2016;107:460–6. https://doi.org/10.5935/abc.20160168; PMID: 27982271. 74. Mello RP, Szarf G, Schvartzman PR, et al. Delayed enhancement cardiac magnetic resonance imaging can identify the risk for ventricular tachycardia in chronic Chagas’ heart disease. Arq Bras Cardiol 2012;98:421–30. https://doi. org/10.1590/S0066-782X2012005000031; PMID: 22460166. 75. Abraham WT, Adamson PB, Hasan A, et al. Safety and accuracy of a wireless pulmonary artery pressure monitoring system in patients with heart failure. Am Heart J 2011;161:558– 66. https://doi.org/10.1016/j.ahj.2010.10.041; PMID: 21392612. 76. Castro PF, Concepcion R, Bourge RC, et al. A wireless pressure sensor for monitoring pulmonary artery pressure in advanced heart failure: initial experience. J Heart Lung Transplant 2007;26:85–8. https://doi.org/10.1016/j.healun.2006.10.006; PMID: 17234522. 77. Wolfson AM, Fong M, Grazette L, et al. Chronic heart failure management and remote haemodynamic monitoring. Heart 2018;104:1910–9. https://doi.org/10.1136/ heartjnl-2018-313397; PMID: 30121633. 78. Bocchi EA, Bestetti RB, Scanavacca MI, et al. Chronic Chagas heart disease management: from etiology to cardiomyopathy treatment. J Am Coll Cardiol 2017;70:1510–24. https://doi. org/10.1016/j.jacc.2017.08.004; PMID: 28911515. 79. Mitelman J. Consensus statement on Chagas-Mazza disease. Revista Argentina de Cardiologia 2012;79:546–64. 80. Nunes MCP, Beaton A, Acquatella H, et al. Chagas cardiomyopathy: an update of current clinical knowledge and management: a scientific statement from the American Heart Association. Circulation 2018;138:e169–209. https://doi. org/10.1161/CIR.0000000000000599; PMID: 30354432. 81. Andrade JP, Marin Neto JA, Paola AA, et al. I Latin American Guidelines for the diagnosis and treatment of Chagas’ heart disease: executive summary. Arq Bras Cardiol 2011;96:434–42. https://doi.org/10.1590/S0066-782X2011000600002; PMID: 21789345. 82. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly Epidemiol Rec 2015;6:33–44. PMID: 25671846. 83. Botoni FA, Poole-Wilson PA, Ribeiro AL, et al. A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas cardiomyopathy. Am Heart J 2007;153:544 e1–8. https://doi.org/10.1016/j.ahj.2006.12.017; PMID: 17383291. 84. Marti-Carvajal AJ and Kwong JS. Pharmacological interventions for treating heart failure in patients with Chagas cardiomyopathy. Cochrane Database Syst Rev 2016;7:CD009077. https://doi.org/10.1002/14651858.CD009077.pub3; PMID: 27388039. 85. Bocchi EA, Rassi S, Guimaraes GV, et al. Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial. ESC Heart Fail 2018;5:249–56. https://doi.org/10.1002/ehf2.12240; PMID: 29266804. 86. Duhamel B. New operation for congenital megacolon: retrorectal and transanal lowering of the colon, and its possible application to the treatment of various other malformations. Presse Med 1956;64:2249–50 [in French]. PMID: 13419987. 87. Haddad J and Raia A. Complications of recto-colonic anastomosis using Swenson’s and Duhamel’s technics for the treatment of megacolon. (Comparative study). AMB Rev Assoc Med Bras 1969;15:265–70 [in Portuguese]. PMID: 5311491. 88. Haddad J and Raia A. Treatment of acquired megacolon in adults. Considerations on Duhamel’s technic with perineal colostomy. Chirurgie 1973;99:293–8 [in French]. PMID: 4201488. 89. Pinotti HW, Habr-Gama A, Cecconello I, et al. The surgical treatment of megaesophagus and megacolon. Dig Dis 1993;11:206–15. https://doi.org/10.1159/000171413; PMID: 8222303. 90. Cardinalli-Neto A, Lorga-Filho AM, Silva EF, et al. Clinical predictors of inducible sustained ventricular tachycardia during electrophysiologic study in patients with chronic Chagas’ heart disease. Int J Cardiol Heart Vasc 2015;9:85–8. https://doi.org/10.1016/j.ijcha.2015.10.001; PMID: 28785714. 91. Hernandezpieretti O, Moralesrocha J, Acquatella H, et al. Pacemaker Implantation in Chronic Chagas’ Heart Disease Complicated by Adams-Stokes Syndrome. Am J Cardiol 1965;16:114–7. https://doi.org/10.1016/0002-9149(65)90015-9; PMID: 14314194. 92. Cardoso R, Sa LB, Garcia D, et al. Quality of life determinants in a population of pacemaker patients with a high prevalence of Chagas disease. Int J Cardiol 2014;177:1137–9. https://doi. org/10.1016/j.ijcard.2014.08.046; PMID: 25168101. 93. Clark EH, Sherbuk J, Okamoto E, et al. Hyperendemic Chagas

disease and the unmet need for pacemakers in the Bolivian Chaco. PLoS Negl Trop Dis 2014;8:e2801. https://doi.org/10.1371/ journal.pntd.0002801; PMID: 24901942. 94. da Silva Junior O, Borges MC, de Melo CS, et al. Alternative sites for right ventricular pacing in Chagas disease: a comparative study of the mid-septum and inflow tract. Pacing Clin Electrophysiol 2014;37:1166–73. https://doi.org/10.1111/ pace.12368; PMID: 24588623. 95. Stein C, Migliavaca CB, Colpani V, et al. Amiodarone for arrhythmia in patients with Chagas disease: A systematic review and individual patient data meta-analysis. PLoS Negl Trop Dis 2018;12:e0006742. https://doi.org/10.1371/journal. pntd.0006742; PMID: 30125291. 96. Healy C, Viles-Gonzalez JF, Saenz LC, et al. Arrhythmias in chagasic cardiomyopathy. Card Electrophysiol Clin 2015;7:251–68. https://doi.org/10.1016/j.ccep.2015.03.016; PMID: 26002390. 97. Cardinalli-Neto A, Greco OT, Bestetti RB. Automatic implantable cardioverter-defibrillators in Chagas’ heart disease patients with malignant ventricular arrhythmias. Pacing Clin Electrophysiol 2006;29:467–70. https://doi. org/10.1111/j.1540-8159.2006.00377.x; PMID: 16689840. 98. Barros MV. New predictors of malignant ventricular arrhythmias in Chagas disease: searching for the holy grail. Rev Soc Bras Med Trop 2015;48:1–3. https://doi. org/10.1590/0037-8682-0059-2015; PMID: 25860457. 99. Bunch TJ, Anderson JL. Adjuvant antiarrhythmic therapy in patients with implantable cardioverter defibrillators. Am J Cardiovasc Drugs 2014;14:89–100. https://doi.org/10.1007/ s40256-013-0056-x; PMID: 24288157. 100. Scanavacca M, Sosa E. Catheter ablation to treat sustained ventricular tachycardia in patients with Chagas cardiomyopathy and implantable cardioverter-defibrillator. J Am Coll Cardiol 2014;63:1028–9. https://doi.org/10.1016/ j.jacc.2013.10.078; PMID: 24345594. 101. Atie J, Steinberg JS. A cohort study of cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy. Europace 2018;20:1717–8. https://doi.org/10.1093/europace/ euy027; PMID: 29509893. 102. Menezes Junior ADS, Lopes CC, Cavalcante PF, Martins E. Chronic Chagas cardiomyopathy patients and resynchronization therapy: a survival analysis. Braz J Cardiovasc Surg 2018;33:82–8. https://doi.org/10.21470/1678-9741-20170134; PMID: 29617506. 103. Bestetti RB, Theodoropoulos TA. A systematic review of studies on heart transplantation for patients with end-stage Chagas’ heart disease. J Card Fail 2009;15:249–55. https://doi. org/10.1016/j.cardfail.2008.10.023; PMID: 19327627. 104. Bocchi EA, Higuchi ML, Vieira ML, et al. Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas’ heart disease. J Heart Lung Transplant 1998;17:399–405. PMID: 9588585. 105. Bacal F, Silva CP, Pires PV, et al. 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EUROPEAN CARDIOLOGY REVIEW

Heart Failure, Arrhythmias and Cardiomyopathies

Hidden in Heart Failure Douglas Ewan Cannie, 1,2 Mohammed Majid Akhtar 1,2 and Perry Elliott 1,2 1. University College London Institute for Cardiovascular Science, London, UK; 2. Barts Heart Centre, Barts Health NHS Trust, London, UK

Abstract Current diagnostic strategies fail to illuminate the presence of rare disease in the heart failure population. One-third of heart failure patients are categorised as suffering an idiopathic dilated cardiomyopathy, while others are labelled only as heart failure with preserved ejection fraction. Those affected frequently suffer from delays in diagnosis, which can have a significant impact on quality of life and prognosis. Traditional rhetoric argues that delineation of this patient population is superfluous to treatment, as elucidation of aetiology will not lead to a deviation from standard management protocols. This article emphasises the importance of identifying genetic, inflammatory and infiltrative causes of heart failure to enable patients to access tailored management strategies.

Keywords Heart failure, rare disease, dilated cardiomyopathy, genetic cardiomyopathy, myocarditis, cardiac amyloidosis. Disclosure: The authors have no conflicts of interest to declare. Received: 22 March 2019 Accepted: 6 June 2019 Citation: European Cardiology Review 2019;14(2):89–96. DOI: https://doi.org/10.15420/ecr.2019.19.2 Correspondence: Perry Elliott, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. E: perry.elliott@ucl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure is a global health challenge, affecting 1–2% of the population and up to an estimated 64 million people worldwide.1,2 In the UK, just under 1 million people have heart failure, with approximately 350 new diagnoses each year per 100,000 population.3 The lifetime risk of developing heart failure at 55 years of age is 33% for men and 28% for women.4 The heart failure population is heterogenous with 17 aetiologies defined in the Lancet Global Burden of Disease studies.5 Ischaemic heart disease predominates, accounting for 40–50% of cases, with hypertensive and valvular disease accounting for a further 15%.6,7 About one-third of heart failure patients are labelled as having idiopathic dilated cardiomyopathy (DCM). Global studies highlight a significantly higher burden of non-ischaemic heart failure outside of western Europe and the US.8–10 Patients attending a heart failure clinic undergo a clinical history and examination as per clinical practice guidelines. They will have a 12-lead ECG, echocardiography and serological tests to determine full blood count, renal function, thyroid function and selected cardiac biomarkers. Patients are classified using left ventricular ejection fraction (LVEF) into having heart failure with reduced ejection fraction (HFrEF; LVEF <40%), mid-range ejection fraction (HFmrEF; LVEF 40–49%) or preserved ejection fraction (HFpEF; LVEF ≥50%).11 For patients with a reduced or mid-range EF, further investigation aims to rule out ischaemic, valvular and hypertensive heart disease. Where these tests are negative, patients are frequently given a diagnosis of idiopathic DCM, with emphasis on prompt initiation and uptitration of evidencebased pharmacological treatment and consideration of device therapy. In recent years, this approach has been augmented by improved community heart failure services and the introduction of newer pharmacological therapies.12–14 However, trends in survival rates have

shown only a modest improvement, particularly when compared to fields such as oncology.15 Current diagnostic strategies fail to identify the presence of rare disease in the heart failure population. The EU defines rare disease as one that is present in fewer than 1 in 2,000 of the population. However, with as many as 8,000 recognised rare diseases, the cumulative burden of rare disease affects more than 30 million people in Europe alone. Those affected frequently suffer from delays in diagnosis with a significant impact on quality of life and, potentially, prognosis.16,17 Rarer causes of common presentations are seldom considered in everyday clinical practice. The diagnostic process often places too much emphasis on clinical traits such as LVEF, to the exclusion of a more nuanced approach. Traditional rhetoric argues that delineation of the idiopathic DCM population is superfluous to their treatment, as elucidation of aetiology will not lead to a deviation from standard management protocols. Increasingly, it is recognised that identification of an underlying genetic, inflammatory or infiltrative cause of heart failure can have profound implications for the patient and – where hereditary – their relatives.18–20

Genetic Cardiomyopathies A significant proportion of people with idiopathic DCM have familial disease, with estimates typically in the region of 30–50%.21,22 A large scale meta-analysis, including 23 studies published from 1980 to 2010, resulted in a combined prevalence estimate of 23% with a large range (2–65%), highlighting significant heterogeneity across studies.21 The estimated prevalence of familial DCM increased with publication year, suggesting that greater awareness and access to screening has increased the number of recognised cases. A recent study identified

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Heart Failure, Arrhythmias and Cardiomyopathies Figure 1: A Case of Breathlessness and Peripheral Oedema

Died aged 78

Died aged 64

Died aged >85

Died aged 75

Died aged 89

Died aged 90

Aged 61 To be screened

Aged 42 To be screened

Died suddenly aged 55 ‘Weak heart’

Aged 66 Heart failure FLNC mutation

Died aged 76 CVA x 2

Died suddenly in childhood Cause unknown

Aged 57 To be screened

Aged 26 To be screened

A 66-year-old man presented with a 3-month history of breathlessness and peripheral oedema. He had suffered rheumatic fever as an adolescent and had been told at the time he had atrioventricular block and mitral valve changes. His ECG showed left ventricular hypertrophy and a QRS of 134 ms. Transthoracic echocardiography was technically difficult, but demonstrated an enlarged heart with severe left ventricular systolic dysfunction and no significant valvular abnormalities. A coronary angiogram showed normal coronary arteries. He was initially managed with heart failure medications. Cardiac MRI confirmed a dilated heart with poor systolic function and mid-wall late gadolinium enhancement at the basal anteroseptum and inferior wall (red arrows). On subsequent questioning, a thorough family history identified that the patient’s mother had died at a young age with a ‘weak heart’. Other family members had died in childhood of causes unknown. Genetic analysis showed a mutation in the filamin C gene. This mutation should prompt early consideration of ICD implantation, clinical screening of first degree relatives and cascade genetic screening.

familial disease in 26% of idiopathic DCM patients listed for cardiac transplantation.23 Using these data, we can conservatively estimate that 10% of an undifferentiated heart failure population may have familial disease, emphasising the importance of a detailed family history.24 This has implications for patients and their families and should prompt consideration of family screening and genetic testing.25,26 Panelbased, next-generation sequencing has shown a pathogenic or likely pathogenic variant in almost 50% of patients with familial DCM and 25% in those with sporadic disease.27,28 The yield from genetic testing will change with a better understanding of variant pathogenicity and the discovery of new disease genes. Identification of a definite genetic cause can have profound implications for the patient and their family (Figure 1). Mutations in the gene coding for lamins A and C (LMNA) are well recognised as predictors of a malignant clinical course with progressive conduction disease and arrhythmia, even where left ventricular systolic impairment is mild.29 Patients with an LMNA mutation must be considered for prophylactic ICD implantation at an early stage of disease.30 Filamin C (FLNC) mutations are similarly predictive of a high risk of arrhythmogenic complications. A recent study has found that 85% of DCM patients with truncating FLNC variants had either ventricular arrhythmias or sudden cardiac death.31,32 Pathogenic variants in SCN5A (encoding for the cardiac sodium channel), RMB20 (encoding for the RNA binding motif protein 20) and BAG3 (encoding for an antiapoptotic protein on the sarcomere Z-disc) have also been identified as carrying an increased risk of ventricular arrhythmia or progressive heart failure.33–37

Myocarditis Regardless of aetiology, myocardial injury often prompts an inflammatory response and cardiac autoantibodies are found in high levels in patients with both ischaemic and non-ischaemic end-stage

heart failure.38–41 However, care should be taken to differentiate between cardiac injury leading to inflammation and cardiac dysfunction driven by inflammation. The term inflammatory cardiomyopathy has been used to describe myocarditis that leads to impaired function. Causes of myocarditis are numerous, with viral infection being the most common and parvovirus B19, human herpes virus 6 and enteroviruses the most frequently implicated.42,43 Bacteria, parasites, protozoa and many toxic agents and autoimmune disorders also contribute.44 Histological evidence for myocarditis in patients with DCM and heart failure is frequently reported. In a study of 1,278 patients with congestive cardiac failure and DCM, 24% had an underlying diagnosis confirmed on endomyocardial biopsy that could be attributed to an inflammatory cause.45 Inflammatory disease may be particularly common in patients with idiopathic DCM and ventricular arrhythmia. A study of 103 non-ischaemic cardiomyopathy patients presenting with monomorphic or polymorphic ventricular tachycardia, or with premature ventricular complexes, found that just under 50% had ongoing focal myocardial inflammation on fluorodeoxyglucose PET (FDG-PET). Immunosuppressive therapy was associated with an improvement in ejection fraction, particularly in those identified at an early stage of the disease process. A third of those with a positive scan were subsequently diagnosed with sarcoidosis by tissue biopsy.46 The prevalence of myocarditis remains elusive due to the heterogeneity of aetiologies and modes of presentation. In approximately 50% of cases, acute myocarditis resolves in 2–4 weeks. However, up to 25% develop persistent cardiac dysfunction and 12–25% may acutely deteriorate or progress to end-stage DCM.47 Histological studies suggest that between 10–52% of patients with acute viral myocarditis progress to a DCM and biopsy-based analysis shows that viral persistence is associated with progressive LV dysfunction.48–51 Recent data suggest that more than half of patients presenting with

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Hidden in Heart Failure acute lymphocytic myocarditis and an LVEF <50% suffer persistent left ventricular systolic dysfunction.52 Immunohistological analysis of biopsy material from patients with chronic DCM shows that 40% have evidence of myocardial inflammation.53 The subclinical nature of myocardial inflammation is well recognised in children and adults.54–56 That inflammatory cardiomyopathy exists within the heart failure population seems irrefutable. Identifying these patients offers the opportunity to significantly alter the course of the disease. For example, immunosuppression in patients with virus-negative, chronic inflammatory cardiomyopathy can result in a mean improvement in LVEF from 26% to 46%.57 It also improves rates of transplant-free survival.58 Independent of virus-status, DCM patients with increased human leukocyte antigen (HLA) system expression have also demonstrated significant improvements in LVEF with immunosuppression.53

Systemic Autoimmune Disorders Systemic autoimmune disorders frequently affect the heart and autoimmunity plays a pivotal role in myocarditis and in DCM.59 Systemic lupus erythematosus (SLE) is associated with numerous cardiac disorders and carries a high risk of developing myocarditis, with clinical detection rates in the region of 3–15%.60 African-American people are particularly at risk.61 The inflammatory process is driven by immune complex and complement deposition in the myocardium leading to cardiac dysfunction, DCM and heart failure. SLE may present with myocarditis or with heart failure, which can rapidly progress.62,63 A low threshold of suspicion must be maintained, with awareness that cardiac biomarkers and ECG results may be normal.64 An echocardiogram may demonstrate regional or global ventricular dysfunction, with strain techniques offering earlier diagnosis.65 Cardiac MRI can detect subclinical inflammation in SLE.66,67 Recommended treatment is corticosteroids and immunosuppressive agents such as cyclophosphamide.68 Myocarditis in SLE is associated with lower survival rates.61 Rheumatoid arthritis and systemic sclerosis-associated myocarditis are diagnosed less frequently. However, cardiac MRI studies of these patient populations suggest a high prevalence of myocardial involvement, with half of patients demonstrating evidence of myocardial fibrosis with late gadolinium enhancement.69,70 Cardiac involvement is found in 27–47% of patients with eosinophilic granulomatosis with polyangiitis, previously called Churg-Strauss syndrome, with myocarditis one of the most common cardiac manifestations.71–73 Myocarditis is also seen in Behcet’s disease, Takayasu arteritis, dermatomyositis and polymyositis. It tends to be associated with poorer outcomes and treatment is with steroids and immunosuppression.44,68

black people.74 Higher incidence rates are reported in people from Scandinavia and Japan.75 Cardiac manifestations are seen in only 2–5% of patients with systemic sarcoidosis but there is a significantly higher proportion of subclinical cardiac disease.76,77 At autopsy, cardiac involvement was observed in 14% of white people, 21% of black people and 68% of Japanese people with sarcoidosis.78 The aetiology is poorly understood. Environmental exposures and infectious organisms have been implicated and the involvement of genetic factors is supported by twin studies and familial clustering.79 Cardiac sarcoidosis is frequently asymptomatic but may present with conduction defects, arrhythmias or heart failure. Clinical clues include bilateral hilar lymphadenopathy on chest X-ray and elevated levels of serum angiotensin converting enzyme and serum calcium. The ECG may highlight conduction defects or repolarisation abnormalities, but is abnormal in less than 10% of people with clinically silent disease.74 An echocardiogram with longitudinal strain parameters is useful in identifying cardiac involvement and in predicting major cardiovascular events.80,81 Imaging techniques such as FDG-PET and cardiac MRI with gadolinium contrast offer a high degree of diagnostic accuracy, but diagnostic criteria either fail to recognise the benefits of advanced imaging or rely heavily on biopsy results.82–85 Corticosteroids remain the mainstay of treatment for cardiac sarcoidosis. Data is sparse and conflicting, but indicate a beneficial effect on left ventricular function, reduced heart failure admissions and improved long-term clinical outcomes.86,87 Early diagnosis and initiation of therapy is important and titration of immunosuppression can be guided by FDG-PET.87–89

Cardiac Infiltration Heart failure with preserved ejection fraction remains poorly understood. However, recent evidence suggests that there is a subset of cardiomyopathies caused by cardiac amyloidosis in this patient group. Moreover, better understanding of these conditions is yielding disease-modifying treatments, placing a greater emphasis on early identification of these patients. The term amyloidosis describes a condition in which structurally unstable proteins misfold and aggregate to form fibrils that are deposited in organs and tissues. The misfolding and deposition of two proteins results in the vast majority of cardiac amyloidosis: immunoglobulin light chain (AL) and transthyretin (ATTR). Transthyretin can be further classified into wild type (ATTRwt) and that due to a mutation in the gene encoding transthyretin (ATTRm).90

Giant Cell Myocarditis

Systemic Light-chain Amyloidosis

Giant cell myocarditis is a disease that predominantly affects young people. It typically presents with acute heart failure and ventricular arrhythmias. Approximately 20% of patients have a pre-existing autoimmune disorder and the severe inflammation appears to be mediated predominantly by a T-cell response. Early diagnosis is key as median survival without transplant or immunosuppression is less than 3 months.44

Sarcoidosis

Systemic AL amyloidosis is a rare disease with a yearly incidence estimated at 3 per million in the UK and 8.9 per million, or 3,000 new cases per year, in the US.91,92 Approximately 30–50% of sufferers have cardiac involvement with 5% having isolated cardiac involvement. The average time from initial symptoms to diagnosis is 2 years, with nearly a third of patients requiring review by five physicians before receiving a diagnosis of amyloidosis.90 Cardiologists were consulted more than haematologists, nephrologists and oncologists, but rarely made the diagnosis.93

Sarcoidosis is an inflammatory, non-caseating granulomatous disease affecting multiple organ systems including the skin, eyes, lungs, heart and the nervous system. The incidence rate in the US has been reported at 10.9 per 100,000 in white people and 35.5 per 100,000 in

Proteinuria or hepatomegaly in combination with heart failure should raise the suspicion of AL amyloidosis.94 Macroglossia and periorbital purpura are highly specific but present only in a minority of cases.90

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Heart Failure, Arrhythmias and Cardiomyopathies Figure 2: A Case of Worsening Breathlessness

A 72-year-old African-Caribbean man presented with a 6-month history of worsening breathlessness. The only past medical history of note was bilateral carpal tunnel decompression. Blood tests demonstrated elevated brain natriuretic peptide levels at 4430 ng/l and evidence of chronic kidney disease with an estimated glomerular filtration rate of 38 ml/min. A 12-lead ECG showed sinus rhythm with a prolonged PR interval, broadening QRS complex and left axis deviation. Echocardiography highlighted a bright, speckled myocardium with left ventricular hypertrophy and reduced longitudinal strain with an apical-sparing pattern. Cardiac MRI demonstrated significant, diffuse late gadolinium enhancement. Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy showed Perugini grade 2 cardiac uptake consistent with cardiac transthyretin amyloidosis. There was no uptake on serum amyloid P scintigraphy and there was no underlying plasma cell dyscrasia. Transthyretin gene sequencing confirmed a wild-type gene and the patient is due to start treatment with tafamidis.

Patients with significant cardiac involvement are unable to tolerate the preferred treatment of high-dose chemotherapy with autologous stem cell transplantation, emphasising the importance of early diagnosis.95 Mortality at 6 months remains high at 24%, but is improving as patients are diagnosed earlier with less severe cardiac involvement.96

myocardium, and 32% of patients aged 75 years or older with HFpEF demonstrate myocardial TTR amyloid deposits.111,112 Technetium-99mlabelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy reliably detects TTR-CM. Its use highlights a prevalence of 13% of TTR-CM in patients admitted to hospital with HFpEF.113–116

Transthyretin Amyloidosis

Effective treatment may soon be available for TTR-CM. TTR is a 55-kD protein with a tetrameric structure that transports thyroxine and vitamin A complex. Amyloidogenesis occurs when the tetrameric structure dissociates resulting in the formation of intermediates that then deposit and polymerise as amyloid fibrils in the myocardium. The discovery of a stabilising polymorphism in the TTR gene has led to the discovery of tafamidis, a nonsteroidal anti-inflammatory drug benzoxazole derivative that adheres to the thyroxine binding sites and inhibits tetramer dissociation. Tafamadis has been shown to be superior to placebo in reducing the risk of death and cardiovascularrelated hospitalisations and it reduces the decline in functional capacity and quality of life.117

ATTR amyloidosis is a multisystem disorder caused by aggregation of TTR amyloid fibrils.97–100 TTR cardiomyopathy (TTR-CM) is usually a lateonset disease found in older men, with patients typically presenting aged 60 years or older.101 Symptoms include dyspnoea, fatigue and orthostatic hypotension. Signs of heart failure predominate in TTR-CM, often with a preserved ejection fraction. Clinical clues to its presence involve extra-cardiac amyloid deposition including carpal tunnel syndrome and peripheral neuropathy (Figure 2).102 TTR-CM can be hereditary or non-hereditary. The non-hereditary form of the disease is caused by aggregation of ATTRwt. The hereditary form of the disease can be caused by more than 100 mutations in the TTR gene, of which at least 22 are associated predominantly with TTR-CM.103–5 The point mutation valine 122 to isoleucine (Val122Ile) is the most common TTR-CM variant, with a prevalence of about 3–4% in the African-American population. The proportion that develop clinical disease is much smaller.106–108 In patients with ATTRwt-CM, median survival ranges from 26–67 months from diagnosis and 72 months from symptom onset. Patients with Val122Ile ATTRm-CM have a median survival time from diagnosis ranging from 36 months to 43 months. Death in most patients with TTR-CM is from sudden death or progressive heart failure.109,110 Recent data suggest that the prevalence of TTR-CM in older people has been under-appreciated. Autopsy data demonstrate that 25% of adults older than 80 years have TTR amyloid deposition in the

Disorders of Metabolism Anderson-Fabry Disease Anderson-Fabry disease (AFD) is an X-linked recessive disorder caused by mutations in the GLA gene leading to reduced or absent activity of the enzyme alpha-galactosidase A. This deficiency leads to accumulation of glycosphingolipids in lysosomes in various tissues, including the heart. It results in myocardial remodelling and left ventricular hypertrophy and manifests as systolic and diastolic dysfunction, valvular abnormalities and conduction disease. Presentation of AFD is typically in the first decade, with gastrointestinal symptoms, angiokeratomas or pain caused by a small-fibre neuropathy. However, up to 10% of patients can present with cardiac involvement, highlighting the importance of adopting a low-threshold of suspicion, particularly for patients with left ventricular hypertrophy. 118,119

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Hidden in Heart Failure Figure 3: Flow Diagram Illustrating a Proposed Diagnostic Algorithm for Patients Presenting to Heart Failure Clinic Patient with a new diagnosis of heart failure seen in clinic

Red Flags During Level 1 analysis: • Presentation at young age • Viral prodrome • Peripheral myopathy • Haematological, connective tissue or autoimmune disease • Bilateral carpal tunnel syndrome • Conduction disease • Ventricular arrhythmia • Recent pregnancy • Elevated CK • Family history: cardiomyopathy, sarcoid, PPM, SCD or heart transplant

Level 1 analysis History, clinical examination and family pedigree. Serology,* ECG +/− Holter monitor, transthoracic echocardiogram, CXR, urinary analysis +/− CMR scan

Manage patient as per heart failure, valvular disease, hypertension or coronary artery disease guidelines

Yes

Degree of heart failure explained by IHD, HTN or valve disease? No

Level 1 analysis indicative of inherited cause of heart failure

Level 2 analysis Guided by clinical suspicion following level 1 analysis

Potential diagnoses

Potential management strategies

• CMR scan • Familial screening • Genetic testing • Molecular autopsy from relative with SCD, where able.

• Genetic mutation identified e.g. lamin A/C, desmin, filamin, titin.

• Prognostic heart failure medications • Consider SCD risk based on mutation and familial phenotype • Family screening

Level 1 analysis indicative of inflammatory cause of heart failure

• CMR scan • Infection/immune serology • FDG-PET scan • Endomyocardial biopsy • Extra-cardiac biopsy

• Autoimmune disorder • Connective tissue disorder • Inflammatory cardiomyopathy

• Prognostic heart failure medications • Immunology/ virology/rheumatology opinion • Consider immunosuppression • Consider antiviral therapy

Level 1 analysis indicative of infiltrative/ metabolic cause of heart failure

Level 1 analysis indicative of acquired cause of heart failure

• Symptomatic management • Enzyme replacement therapy • Iron chelation therapy • Chemotherapy • Tafamidis • Close monitoring for pacing requirement • Family screening

CMR evidence of: • Myocardial inflammation • Non ischaemic late gadolinium enhancement Further investigation in the form of CTCA, nuclear imaging, CMR with stress or angiography may be needed to confirm IHD diagnosis. Ambulatory blood pressure monitoring may be required to confirm hypertensive heart disease.

• CMR scan • 99mTc-DPD scan • Serum and urinary electrophoresis, serum free light chains, SAP scan • Genetic testing (AFD/hereditary amyloid/GSD) • Endomyocardial biopsy • Extra-cardiac biopsy

• TTR amyloidosis • AL amyloidosis • Glycogen storage disorder • Iron-overload cardiomyopathy

Echo evidence of: • Infiltrative pattern† • Biventricular hypertrophy • RV outflow tract obstruction

• • • • • •

Ethanol Drugs and toxins Peripartum Tachycardia-induced -induced Obesity Endocrine

• Prognostic heart failure medications • Avoid drug/toxin • Counselling where further pregnancy desired • Rate/rhythm control • Weight loss • Endocrinology opinion

Level 2 investigations: FDG PET can identify active myocardial inflammation in acute myocarditis and sarcoidosis. Skeletal muscle biopsy in suspected mitochondrial disorders/peripheral myopathy. Extra-cardiac biopsy can diagnose multi-system disease e.g. skin, kidneys, lymph nodes. DPD scan identifies TTR cardiac amyloidosis. Serum and urinary electrophoresis, free light chains and a SAP scan for investigation of AL amyloidosis.

*Serology to include full blood count, urea and electrolytes, liver function tests, thyroid function tests, creatine kinase and brain natriuretic peptide. †Infiltrative pattern on echocardiography may include a bright, speckled myocardium with left ventricular hypertrophy and reduced global longitudinal strain with apical sparing. 99mTc-DPD = technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid; AFD = Anderson-Fabry disease; AL amyloidosis = primary light chain amyloidosis; CTCA = CT coronary angiogram; CMR = cardiac MRI; CXR = chest X-ray; FDG-PET = fluorodeoxyglucose PET; GSD = glycogen storage disorder; HTN = hypertension; IHD = ischaemic heart disease; PPM = permanent pacemaker; SAP = serum amyloid P; SCD = sudden cardiac death; TTR amyloidosis = transthyretin amyloidosis.

As many as 10% of patients with AFD develop severe heart failure (defined by New York Heart Association classification ≥3) and cardiac disease is the major cause of death, accounting for 38% of all-cause mortality.120,121 Enzyme replacement therapy is the standard treatment for AFD, aiming to compensate for reduced endogenous alphagalactosidase activity with treatment leading to improved cardiac outcomes. It is readily apparent that enzyme replacement therapy started at a younger age leads to better outcomes illustrating the

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importance of identifying these patients at an early stage in the disease process.122–125

Iron-overload Cardiomyopathy Iron-overload cardiomyopathy (IOC) should be considered in any patient with unexplained heart failure. It can be caused by a primary haemochromatosis where iron accumulation occurs through increased gastrointestinal iron absorption, or by secondary iron-overload, most

Heart Failure, Arrhythmias and Cardiomyopathies commonly due to a high frequency of blood transfusions.94 The pathophysiology is complex and not simply related to myocardial iron accumulation with immunoinflammatory, molecular and genetic factors implicated.126 The early stages of IOC are characterised by left ventricular diastolic dysfunction with restrictive physiology.127,128 Progression can lead to a dilated phenotype with biventricular dilatation and systolic dysfunction or to a restrictive phenotype with preservation of LVEF, pulmonary hypertension and right ventricular dilatation.129–131 It can also present with acute heart failure.132 Serum ferritin and transferrin saturation should be included in the initial investigation of any patient with newly diagnosed heart failure.11 Echocardiography may help with ventricular assessment and an estimation of pulmonary pressures, however cardiac MRI with T2* is able to quantitatively assess myocardial iron content and predict progression to heart failure within one year.133,134 Identification of patients with an IOC is imperative as both iron removal using phlebotomy and chelation therapy have been shown to improve heart function.135–138 With the introduction of chelation therapies and MRI with T2* there has been a significant improvement in mortality rates, predominantly driven by reductions in death due to cardiac iron overload.139 Early initiation of therapy is therefore crucial.

Improving the Detection of Actionable Diagnoses The definition of heart failure rests on a constellation of typical symptoms and an underlying structural or functional cardiac abnormality leading to deranged cardiac physiology. This definition captures a patient cohort that, historically, have been managed with a simple treatment algorithm; a ‘one-size-fits-all’ approach. A third of these patients are categorised as suffering an idiopathic DCM. We contend that rare but readily identifiable aetiologies reside within this group and, more importantly, that they are actionable diagnoses leading to targeted therapies. The diagnosis of rare disease among people with heart failure may be challenging, particularly where resources are constrained and access to specialist cardiac investigations limited. Diagnoses are often made following a conspicuous event such as unexplained syncope or sudden death in a relative. On other occasions, diagnoses are delayed and are reached only with retrospective recognition of atypical features. Elucidating the rarer causes of heart failure may need specialised knowledge or access to investigations such as genetic testing. We argue, however, that a diagnostic ‘red flag’ approach to clinical assessment in the heart failure clinic, combined with routinely available tests, can act as an initial filter to more readily identify uncommon disease. This approach begins with a thorough,

os T, Alemu Abajobir A, Hassen Abate K, et al. Global, V regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017: 390:1211–59. https://doi. org/10.1016/S0140-6736(17)32154-2; PMID: 28919117. Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol 2016;13:368–78. https://doi.org/10.1038/ nrcardio.2016.25; PMID: 26935038. Conrad N, Judge A, Tran J, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 2018;391:572–80. https://doi. org/10.1016/S0140-6736(17)32520-5; PMID: 29174292.

hypothesis-driven clinical and family history and incorporates basic serology, an ECG and baseline imaging (Figure 3).18 Ischaemic, valvular and hypertensive heart disease should be managed as per guidelines.140–142 Acquired and reversible causes of heart failure such as alcohol excess and prolonged tachycardia are readily identifiable with thorough clinical assessment and routine investigations.11 Cardiooncology is a growing sub-specialty, with increasing recognition of the cardiotoxic effects of both established chemotherapy agents and newer immunotherapies and targeted therapies. Left ventricular dysfunction and heart failure are relatively common and serious sideeffects of cancer treatment.143 After preliminary assessment, patients without an obvious cause for heart failure can be directed to one of three investigative streams: genetic, inflammatory or infiltrative/metabolic.24,144,145 Awareness of dual pathologies is important as, for example, hypertension may coexist with infiltrative disease in a patient with left ventricular hypertrophy.146

Precision Medicine in Heart Failure NHS England embraces the concept of personalised, precision medicine recognising that “complex diseases should no longer be considered a single entity” and that “different subtypes of patients within a given condition can be identified and treatment can be tailored to the underlying cause”. It urges more precise diagnoses and emphasises the usefulness of genomic medicine.147 The field of oncology offers a paradigm of the precision medicine approach. Where previously cytotoxic treatments with severe sideeffects were the norm, we now see therapies designed to precisely target cancer cells. This is chiefly through two methods: pathwaytargeted therapy and immunotherapy.148 These approaches seem particularly well-suited to future treatment of inflammatory and infiltrative heart disease. The one-size-fits-all approach continues to prevail in the modern management of heart failure. This article highlights the diverse pathogeneses of the heart failure syndrome and how it could benefit from a precision medicine approach. The underlying biology of the conditions outlined is increasingly well described, resulting in the development of new therapies that offer significant clinical benefit, particularly when instituted at an early stage in the disease process. Furthermore, these conditions, traditionally thought of as rare, are more common than first thought and, in combination, account for a significant burden of disease. We offer a diagnostic algorithm that aims to co-opt principles of precision medicine into heart failure clinics. If adopted, we hypothesise that the population prevalence of idiopathic DCM would decline as patients are given aetiology-specific diagnoses with accompanying disease-modifying treatments.

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Circulation 2007;115:1876–84. https://doi. org/10.1161/CIRCULATIONAHA.106.648790; PMID: 17372174. 139. Modell B, Khan M, Darlison M, et al. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2008;10:42. https://doi.org/10.1186/1532-429X-10-42; PMID: 18817553. 140. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619. 141. Task Force Members, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J 2013;34:2949–3003. https://doi. org/10.1093/eurheartj/eht296; PMID: 23996286. 142. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104. https://doi.org/10.1093/eurheartj/ ehy339; PMID: 30165516. 143. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J 2016;37:2768–801. https:// doi.org/10.1093/eurheartj/ehw211; PMID: 27567406. 144. Milandri A, Longhi S, Gagliardi C, et al. Prevalence, risk factors and correlation with cardiac involvement of carpal tunnel syndrome in amyloidosis. Orphanet J Rare Dis 2015;10:P32. https://doi.org/10.1186/1750-1172-10-S1-P32. 145. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid 2016;23:58–63. https://doi. org/10.3109/13506129.2015.1135792; PMID: 26852880. 146. Terryn W, Deschoenmakere G, De Keyser J, et al. Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy. Int J Cardiol 2013;167:2555–60. https://doi.org/10.1016/j. ijcard.2012.06.069; PMID: 22805550. 147. NHS England. Improving outcomes through personalised medicine: working at the cutting edge of science to improve patients’ lives. Leeds: NHS England, 2016. Available at: https://www.england.nhs. uk/wp-content/uploads/2016/09/improving-outcomespersonalised-medicine.pdf (accessed 19 June 2019). 148. Dugger SA, Platt A, Goldstein DB. Drug development in the era of precision medicine. Nat Rev Drug Discov 2018;17:183–96. https://doi.org/10.1038/nrd.2017.226; PMID: 29217837.

EUROPEAN CARDIOLOGY REVIEW

Ischaemic Heart Disease, Stroke and Risk Factors

Diagnostic Approach to Patients with Stable Angina and No Obstructive Coronary Arteries Gaetano Antonio Lanza Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Cardiology Institute, Rome, Italy

Abstract The diagnosis of microvascular angina (MVA) is usually considered in patients presenting with angina symptoms and evidence of MI on non-invasive stress tests but normal coronary arteries at angiography. A definitive diagnosis of MVA, however, would require the presence of coronary microvascular dysfunction. Several invasive (e.g. intracoronary Doppler wire recording and thermodilution) and non-invasive (e.g. PET, cardiac MRI, transthoracic Doppler echocardiography) methods can be applied to obtain a diagnosis. Both endotheliumdependent and -independent coronary microvascular dilator function, as well as increased microvascular constrictor activity, should be investigated. The main issues in the assessment of clinical and diagnostic findings in patients with suspected MVA are discussed and a diagnostic approach is suggested.

Keywords Microvascular angina, stable angina, normal coronary arteries, coronary microvascular dysfunction, endothelium-dependent vasodilatation, endothelium-independent vasodilatation, coronary flow reserve, diagnostic methods Disclosure: The author has no conflicts of interest to declare. Received: 1 April 2019 Accepted: 4 June 2019 Citation: European Cardiology Review 2019;14(2):97–102. DOI: https://doi.org/10.15420/ecr.2019.22.2 Correspondence: Gaetano A Lanza, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, Istituto di Cardiologia, Largo A Gemelli, 8, 00168 Rome, Italy. E: aetanoantonio.lanza@unicatt.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Up to 50% of patients who undergo elective coronary angiography for stable chest pain symptoms that are mainly related to exercise and typical enough to suggest the presence of obstructive coronary artery disease (CAD) are found to have normal or near-normal coronary arteries.1 The mechanisms responsible for angina chest pain in these patients are heterogeneous; accordingly, their identification is crucial for the tailored management of individual patients.

whereas non-cardiac causes include gastro-oesophageal disorders, in particular gastro-oesophageal reflux,5 as well as musculoskeletal and psychosomatic causes. However, a definitive diagnosis of MVA requires the documentation of functional abnormalities of the coronary microcirculation.

Methods to Assess Coronary Microvascular Function A large number of studies have shown that most of these patients display abnormalities in the regulation of coronary blood flow (CBF) and coronary vascular resistance (CVR), suggesting that abnormalities of small coronary artery vessels are the cause of symptoms, a condition which is defined as primary stable microvascular angina (MVA), in the absence of other heart disease.2,3

Several methods have been proposed to assess coronary microvascular function.6,7 Independent of the method applied, the assessment of the functional state of coronary microcirculation is based on the measurement of CBF and/or CVR at rest and following the administration of vasoactive stimuli, with the effect expressed as the ratio of peak-to-basal values or the percent of variation.

This article focuses on how a diagnosis of MVA could be achieved or excluded in patients presenting with angina chest pain but with an absence of obstructive coronary lesions, and examines issues related to the diagnostic process.

Invasive methods are considered the gold standard to measure the response to vasoactive stimuli of the coronary microcirculation. CBF has classically been derived from CBF velocity measured by intracoronary Doppler wires.8 More recently, an intracoronary thermodilution-derived method has been introduced to measure CBF using a wire that also allows the simultaneous measurement of intracoronary pressure and the calculation of an index of coronary microvascular resistance. In some studies, this method has been found to achieve more reproducible results.9 However, recent data have shown a better correlation of Doppler-derived measurements of coronary flow reserve (CFR) compared with thermodilution-derived measurements, with CFR assessed by non-invasive methods, such as PET and cardiac MRI (CMR;

The Diagnosis of Microvascular Angina Since small coronary arteries cannot be assessed at angiography, in clinical practice the diagnosis of MVA is usually hypothesised after the exclusion of other possible causes of symptoms, both cardiac and non-cardiac. Cardiac causes include both ischaemic (e.g. epicardial spasm; see later) and non-ischaemic diseases (e.g. inflammatory diseases, abnormal stimulation of cardiac nociceptors),4

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Ischaemic Heart Disease, Stroke and Risk Factors see later) suggesting that they show more reliable results on coronary microvascular function.10,11 Invasive methods, however, present with some limitations, including the prolongation of diagnostic angiography and an increase in cost and risk. In the absence of obstructive CAD, coronary microvascular dilator function can reliably be investigated by several non-invasive methods that allow measurement of CBF. Cardiac PET is perhaps the most reliable method at present, and has been applied in several studies in patients with suspected MVA.12,13 PET allows quantitative measurements of myocardial blood flow (MBF; both global and regional) using myocardial distribution and radioactivity of tracers such as 15O-water, 13N-ammonia, and 82rubidium.6,7,10 CMR also allows for reliable assessment of coronary microvascular function in patients with angina and normal/near-normal coronary arteries, using the paramagnetic contrast medium gadolinium to measure MBF.11,14,15 Compared with PET, CMR has the advantage of being radiation free and having a higher spatial resolution; however, post-acquisition processing is more complicated, artefacts are more frequent, and gadolinium should be avoided in patients with renal failure.6,7 The use of PET and CMR to routinely assess coronary microvascular function in clinical practice is mainly challenged by limited availability and high costs. Myocardial contrast echocardiography is an attractive method used to assess coronary microvascular function, as it is based on using gas-filled microbubbles as echo-contrast, a largely available and inexpensive echocardiographic technique used to measure MBF. Although found to be reliable in some studies, its diffusion has been restrained by some limitations, including operator dependence, difficulty in obtaining reliable images in some conditions (e.g. obesity, pulmonary disease), and some unresolved technical issues.6,7,16,17 In some studies on patients with suspected MVA, coronary microvascular function has been assessed using transthoracic Doppler echocardiography.17,18 In this method, blood flow in the mid-part of the left anterior descending coronary artery is imaged by colourDoppler using a high-frequency ultrasound probe (7–10 MHz) and CBF velocity is measured by the pulsed Doppler technique. Transthoracic Doppler echocardiography is a potentially largely applicable method as it is easily available and inexpensive.19 Limitations include operator dependence and the inability to obtain good echocardiographic windows in some patients.6

Assessment of Coronary Microvascular Dilatation Since chest pain in patients with a suspected stable MVA is mainly induced by physical efforts, it seems reasonable to investigate whether an impairment of dilatation of resistance coronary arteries, limiting the increase of CBF required to match the enhanced myocardial oxygen requirements, is present. CBF is regulated at the microvascular level by multiple mechanisms, including metabolic, neural, humoral, and mechanical (shear stress) factors.20 When required, coronary microvascular dilatation can be achieved by using various substances to induce a direct relaxant effect on the smooth muscle cells (SMCs) of resistance arteries. Other stimuli, however, result in microvascular dilatation indirectly by inducing the release of dilator substances from the endothelium (mainly nitric oxide

[NO]) that eventually act on SMCs. Thus, an impairment of maximal dilatation of the coronary microcirculation may result from either a reduced response of SMCs to dilator stimuli, impaired production and/ or release of dilator substances by the endothelium (endotheliumdependent dilatation), or both.5 In typical patients with a suspicion of MVA, an assessment of CBF response to exercise would be ideal to assess coronary microvascular dilatation. However, the measurement of CBF during maximal exercise presents practical issues, both with invasive and non-invasive methods. Atrial pacing might be an alternative stimulus to assess CBF response to increased myocardial oxygen consumption, but it also presents with practical issues. Thus, coronary microvascular dilatation is usually assessed by measuring CBF in response to dilator pharmacologic substances.

Endothelium-independent Coronary Microvascular Dilatation Although various substances (e.g. papaverine, dobutamine, organic nitrates) have been used to investigate the intrinsic dilator capacity of the coronary microcirculation, the arteriolar dilator adenosine and its agonists, dipyridamole and (more recently) regadenoson, are used most frequently (Table 1).21–23 A CFR (ratio between CBF at peak drug administration and at baseline) <2.0 definitively identifies coronary microvascular dysfunction (CMD), whereas an increase in CBF between >2.0 and <2.5 is of borderline significance. It should be underscored that impaired dilatation of small coronary arteries might originate from functional abnormalities, structural alterations (e.g. SMC hypertrophy, medial fibrosis, intimal thickening), or both.24,25

Endothelium-dependent Coronary Microvascular Dilatation Endothelium-dependent coronary microvascular dilatation is usually assessed invasively using an acetylcholine test (Table 1). In normal subjects, intracoronary acetylcholine at low-medium doses (usually 10–50 µg) causes microvascular dilatation through the release of NO by endothelial cells,26 with a mild dilator effect also seen on epicardial vessels. In patients with endothelial dysfunction, the release of NO induced by acetylcholine is impaired, thus resulting in lower degrees of dilatation of small coronary arteries, as indicated by a lower increase in CBF and/or reduction in CVR. Moreover, in case of severe endothelial dysfunction, acetylcholine may actually cause microvascular constriction, as documented by a reduction in CBF and/ or increase in CVR.27,28 Through stimulation of muscarinic receptors, acetylcholine also exerts a direct vasoconstrictor effect on SMCs that in normal subjects is masked by the prevailing endotheliummediated dilatation, but which may become apparent in case of severe endothelial dysfunction.29 There is no clear definition of impaired endothelium-dependent coronary microvascular dilatation with the acetylcholine test, but it has been suggested that failure to increase CBF by >50% should be considered indicative of an impaired dilator response of the coronary microcirculation.30,31

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Diagnostic for Stable Angina and No Obstructive Coronary Arteries Table 1: Substances Most Frequently Used to Assess Coronary Microvascular Function Dose

Mechanism

Main Effects

Side Effects

Adenosine

140 mg/kg/min, IV 2–16 µg/kg/min, IC

Activation of A2A receptors on SMCs

Arteriolar dilatation

Bradycardia, flushing bronchoconstriction

Dipyridamole

0.56–0.84 mg/kg, IV

Inhibition of adenosine degradation

Arteriolar dilatation

Headache, flushing, hypotension

Regadenoson

0.4 mg, IV

Activation of A2A receptors on SMCs

Arteriolar dilatation

Headache, flushing, hypotension, hypertension

Acetylcholine

10–200 µg, IC

NO release from endothelial cells Stimulation of muscarinic M3 receptors on SMCs

ED coronary dilatation Direct coronary constriction

Bradyarrhythmias, hypotension broncho-constriction

Ergonovine maleate Methyl-ergometrine

10–50 µg, IV 8–64 µg, IC 1–3 µg/kg/min IV 8, 16, 32 µg, IC

Alpha and serotonin receptor agonists on SMCs

Coronary vasoconstriction

Diffuse vasospasm, nausea, headache, hypertension

ED = endothelium dependent; IC = intracoronary; IV = intravenous; NO = nitric oxide; SMC = smooth muscle cell.

Coronary microvascular endothelial function has also been assessed using other stimuli, in particular the cold pressor test (CPT), which comprises placing a hand in ice for 90 to 120 seconds. The sensation of cold and the accompanying hand pain cause a mild sympathetic activation that slightly increases heart rate and blood pressure; the resulting mild increase in myocardial oxygen consumption determines arteriolar dilation and flow-mediated (endothelium-dependent) dilatation of pre-arteriolar vessels. Furthermore, NO release may also result from the stimulation of endothelial alpha-adrenergic receptors.32 Normal values of CBF response to the CPT have also not been well defined, but we have found that a CBF velocity increase on transthoracic Doppler echocardiography >1.56 allowed a clear discrimination between healthy subjects and MVA patients.17

Microvascular Versus Epicardial Spasm Some studies have suggested that, at least in some patients, stable MVA might be related to increased coronary microvascular constriction/ spasm rather than impaired dilatation. A significant reduction in CBF or increase in CVR has been shown in response to potentially constrictive stimuli, including acetylcholine, hyperventilation, and mental stress, in the absence of any flow-limiting epicardial constriction.27,28,33 Importantly, some studies have recently shown that a sizeable proportion of patients with a suspicion of stable MVA develop typical angina and ischaemic electrocardiographic (ECG) changes in the absence of any significant epicardial spasm in response to higher doses of acetylcholine (up to 200 µg), indicating the induction of coronary microvascular spasm.34–36 Accordingly, it has been suggested that the identification of microvascular spasm as a mechanism of angina symptoms should be achieved by this method rather than by CBF/CVR measurements.37 Importantly, the same doses of acetylcholine have been shown to trigger epicardial spasm in more than 60% of patients, suggesting that this mechanism – rather than microvascular spasm – could be a cause of angina symptoms in a subgroup of patients.34–36 ,8 Of note, the fact that both coronary microvascular and epicardial spasm have been described in patients with stable angina but no obstructive CAD makes it necessary to perform vasoconstrictive tests during invasive coronary angiography to establish the site of the spasm. The tendency towards coronary spasm might also be assessed non-invasively (e.g. by ergonovine test; Table 1), although in this case a positive test will leave doubts about the site of the spasm.39,40

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Combined Functional Coronary Alterations Current data suggest that most patients with angina and no obstructive CAD present with a variable combination of abnormal dilator and constrictive provocative tests. In a 2011 study, we found an impairment of coronary microvascular dilatation to both adenosine and CPT in 44% of 71 patients with a suspicion of MVA, whereas 21% and 10% of patients presented with an impairment of coronary microvascular dilatation in response to either adenosine or CPT, respectively.17 In a study by Sara et al., an abnormal coronary microvascular response to both adenosine and acetylcholine was found in 36.1% of 1,439 patients, whereas a discordant response was found in 45.2% of patients.41 Finally, in the recently published CORonary MICrovascular Angina (CorMicA) trial, 20.5% of patients had evidence of both impaired response to adenosine and a positive acetylcholine test, while epicardial spasm was induced in 16.5% and CMD (either impaired dilatation or microvascular spasm) in 51.6% of 151 patients.36 Thus, a complete characterisation of CMD and functional abnormalities of coronary circulation in individual patients requires assessment of all the types of tests described above, which might have implications on the choice of specific or combined forms of treatment.

Limitations in the Interpretation of Provocative Tests We should be aware that, in contrast to current beliefs, there are significant pitfalls in the interpretation of provocative coronary tests and, therefore, the accurate characterisation of coronary alterations. Thus, the stimuli used to assess endothelium-dependent dilatation are not specific to these tests. Acetylcholine, as discussed above, has also vasoconstrictor effects, and it is not possible to exclude that this effect contributes to the abnormal coronary microvascular response detected by its administration in MVA patients, possibly resulting from an increased reactivity of SMCs. Similar considerations apply to other endothelium-dependent dilator stimuli, such as the CPT, which might trigger spasm in hyperreactive coronary segments through adrenergic activation.42 It should be also observed that, in the presence of a global impairment of SMC relaxation in response to vasodilator substances, normal endothelial release of NO also results in a lower dilator response, thus leading to an erroneous diagnosis of impaired endotheliumdependent dilatation.

Ischaemic Heart Disease, Stroke and Risk Factors Figure 1: Diagnostic Approach to Patients With Stable Angina Chest Pain and No Obstructive Coronary Artery Disease Stable angina pain

• Clinical features • Echo-stress • Nitrate EST

Strong suspicion of MVA

Although a differentiation between classical stable angina and stable MVA is often difficult, a few documented clinical features and results of non-invasive diagnostic tests may help orient the diagnosis towards one of the two forms of angina.

Yes

Invasive CA

Diagnosis of primary stable MVA presupposes a lack of obstructive CAD in patients with a stable pattern of chest pain. Importantly, while until a few years ago this could be achieved only by invasive coronary angiography, the documentation of normal (or near-normal) coronary arteries can now reliably be obtained by non-invasive angio-CT scan. Accordingly, in clinical practice, a non-invasive CT coronary angiography can be recommended to define the coronary picture in symptomatic patients with a high probability of MVA. This would avoid the small risk as well as higher costs related to a more invasive procedure. As suggested above, the documentation of CMD to support the diagnosis of MVA may in these cases be achieved by non-invasive methods (see above).

Exclude non-cardiac causes

Microvascular Angina Versus Stable Angina

CT-CA

Clinical Features NO-CAD

NO-CAD TTDE CMR PET MCE

ICDW MRI

Assessment of CMV dilatation

While chest pain in MVA patients is often indistinguishable from that of CAD patients, two main features, when present, strongly suggest MVA: the persistence of dull chest discomfort several minutes after stopping exercise, in spite of the resolution of typical chest pain; and slow resolution of chest pain after taking a short-acting nitrate.46

Non-invasive Diagnostic Tests ECG Exercise Stress Test

Assessment of CMV constriction *Consider indication to invasive CA if CT-CA inconclusive. CA = coronary angiography; CMR = cardiac MRI; CMV = coronary microvascular; CT-CA = CT-coronary angiography; EST = exercise stress test; ICDW = intracoronary Doppler wire; MVA = microvascular angina; NO-CAD = no obstructive coronary artery disease; TTDE = transthoracic Doppler echocardiography. Adapted from: Lanza.60 Used with permission from Springer Nature.

On the other hand, the increase in CBF determined by direct arteriolar vasodilators may also depend on endothelium-dependent, flow-mediated pre-arteriolar dilatation, and adenosine, in particular, may in part also act through endothelial NO release.43 Thus, in most cases it is not possible to attribute CMD with certainty to only one of the specific mechanisms that can be responsible for its occurrence. Finally, it should be observed that, while the induction of epicardial or microvascular spasm in patients with stable angina and no obstructive CAD indicates the presence of an abnormal coronary reactivity, the actual role that these abnormal responses have in determining the angina symptoms in individual patients remains to be demonstrated, particularly when considering epicardial spasm induced by high doses of acetylcholine. Of note, being a vagal neuromediator, acetylcholine is not an ideal stimulus to prove that clinical exercise-induced angina is related to spasm. Some studies have assessed the effect of exercise on coronary vascular reactivity in patients with suspected MVA, consistently showing some degree of vasoconstriction in epicardial vessels in subgroups of patients; none, however, reported exercise-induced occlusive/ subocclusive epicardial spasm. 44,45 Thus, to avoid false-positive diagnoses of epicardial spasm, only low-to-medium doses of acetylcholine should be used to assess the functional abnormalities of coronary circulation in stable angina patients with no obstructive CAD.

100

While the characteristics of ST-segment changes induced during an exercise stress test do not usually allow for a reliable distinction between MVA and CAD patients, the lack of improvement or, even more, a worsening of ischaemic changes during the exercise stress test performed after a preventive administration of short-acting nitrates, would strongly suggest MVA.47,48 For example, in a recent study we found that the time and/or rate pressure product at the ischaemic threshold (1 mm ST-segment depression) was lower than ≥60 s >1,500 BPM*mmHg on the post-nitrate exercise stress test, compared with a baseline test, in 24% of MVA patients, but this was not the case in any CAD patients.49

Echocardiographic Stress Tests Significant clues to the differential diagnosis of MVA and stable CAD may come from echocardiographic exercise or a pharmacological stress test. The induction of angina and ischaemic ST-segment depression in the absence of reversible regional left ventricle wall motion abnormalities strongly supports the diagnosis of MVA.50–52 The reason for the variable behaviour of left ventricle contraction in the two conditions can be related to the fact that myocardial ischaemia caused by obstructive stenoses of epicardial vessels usually involves large myocardial regions, resulting in an appreciable impairment of regional contractility. Conversely, CMD responsible for MVA can be patchily distributed in the myocardium, resulting in sparse small myocardial ischaemic spots that cannot usually determine detectable regional abnormalities in left ventricle contractility.53 However, regional left ventricle dysfunction at echocardiography may also be undetectable in some patients with minor degrees of obstructive CAD,54 while, on the other hand, reversible wall motion abnormalities have been reported in patients with MVA in a few studies.55,56

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Diagnostic for Stable Angina and No Obstructive Coronary Arteries Radionuclide Stress Tests Radionuclide stress tests also show similar reversible myocardial perfusion defects caused by CMD or obstructive CAD.57,58 A totally negative myocardial perfusion stress test in the presence of chest pain and ischaemic ST-segment changes might suggest MVA with diffuse CMD. A similar finding, however, may sometimes also be found in patients with multivessel obstructive CAD.59

Advanced Imaging Stress Tests Stress tests with PET, CMR or myocardial contrast echocardiography can be used to detect abnormalities in myocardial perfusion and ischaemia, but may present similar issues as those described for myocardial scintigraphy. As discussed above, these methods can instead be significant for the assessment of CMD in NO-CAD patients.

(or near-normal) coronary arteries. The demonstration of CMD might be achieved through a systemic pharmacologic vasodilator test (adenosine/dipyridamole/regadenoson), with the diagnostic method chosen according to the availability and expertise of the single centres. An ergonovine test might be performed when vasodilator tests are negative or to fully characterise the functional abnormalities of coronary circulation, although with the caveat that the site of vasoconstriction (microvascular or epicardial) cannot be established with certainty.

Diagnostic Algorithm

Invasive coronary angiography, on the other hand, should be directly recommended in angina patients with only a low-to-moderate probability of MVA. Provocative tests should only be performed during the invasive diagnostic procedure in case of detection of normal or near-normal coronary arteries.

Figure 1 shows a schematic diagnostic approach for patients with a suspicion of primary stable MVA, as well as MVA occurring in other clinical contexts.60 When clinical and non-invasive assessment of the angina patient suggests CMD rather than obstructive CAD, a CT coronary angiography could be recommended to document normal

Whether careful characterisation of functional abnormalities of coronary circulation (and CMD in particular) by this approach will impact the therapeutic management of patients needs to be ascertained in adequately designed randomised studies.

10.

11.

12.

13.

14.

atel MR, Peterson ED, Dai D, et al. Low diagnostic yield of P elective coronary angiography. N Engl J Med 2010;362:886–95. https://doi.org/10.1056/NEJMoa0907272; PMID: 20220183. Cannon RO 3rd, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 1988;61:1338–43. https://doi. org/10.1016/0002-9149(88)91180-0; PMID: 3287885. Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation 2010;121:2317–25. https://doi. org/10.1161/CIRCULATIONAHA.109.900191; PMID: 20516386. Cannon RO, Quyyumi AA, Schenke WH, et al. Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J Am Coll Cardiol 1990;16:1359–66. https://doi. org/10.1016/0735-1097(90)90377-2; PMID: 2229787. Herregods TV, van Hoeij FB, Oors JM, et al. Effect of running on gastroesophageal reflux and reflux mechanisms. Am J Gastroenterol 2016;111:940-6. https://doi.org/10.1038/ ajg.2016.122; PMID: 27068716. Lanza GA, Camici PG, Galiuto L, et al. Methods to investigate coronary microvascular function in clinical practice. J Cardiovasc Med (Hagerstown) 2013;14:1–18. https://doi. org/10.2459/JCM.0b013e328351680f; PMID: 23222188. Feher A, Sinusas AJ. Quantitative assessment of coronary microvascular function. dynamic single-photon emission computed tomography, positron emission tomography, ultrasound, computed tomography, and magnetic resonance imaging. Circ Cardiovasc Imaging 2017;10:e006427. https://doi. org/10.1161/CIRCIMAGING.117.006427; PMID: 28794138. Joye JD, Schulman DS. Clinical application of coronary flow reserve using an intracoronary Doppler guide wire. Cardiol Clin 1997;15:101–29. https://doi.org/10.1016/S07338651(05)70321-0; PMID: 9085755. Fearon WM, Kobayashi Y. Invasive assessment of the coronary microvasculature: the index of microcirculatory resistance. Circ Cardiovasc Interv 2017;10:e005361. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005361; PMID: 29222132. Everaars H, de Waard GA, Driessen RS, et al. Doppler flow velocity and thermodilution to assess coronary flow reserve: a head-to-head comparison with [15O]H2O PET. JACC Cardiovasc Interv 2018;11:2044–54. https://doi.org/10.1016/j. jcin.2018.07.011; PMID: 30268877. Williams RP, de Waard GA, De Silva K, et al. Doppler versus thermodilution-derived coronary microvascular resistance to predict coronary microvascular dysfunction in patients with acute myocardial infarction or stable angina pectoris. Am J Cardiol 2018;121:1–8. https://doi.org/10.1016/j. amjcard.2017.09.012; PMID: 29132649. Bøttcher M, Botker HE, Sonne H, et al. Endotheliumdependent and -independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X. Circulation 1999;99:1795–801. PMID: 10199874. de Vries J, De Jongste MJ, Jessurun GA, et al. Myocardial perfusion quantification in patients suspected of cardiac syndrome X with positive and negative exercise testing: a 13N-ammonia positron emission tomography study. Nucl Med Commun 2006;27:791–4. https://doi.org/10.1097/01. mnm.0000237984.46844.42; PMID: 16969261. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948–53. https://doi.org/10.1056/NEJMoa012369;

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PMID: 12075055. 15. L iu A, Wijesurendra RS, Liu JM, et al. Diagnosis of microvascular angina using cardiac magnetic resonance. J Am Coll Cardiol 2018;71:969–79. https://doi.org/10.1016/j. jacc.2017.12.046; PMID: 29495996. 16. Galiuto L, Sestito A, Barchetta S, et al. Noninvasive evaluation of flow reserve in the left anterior descending coronary artery in patients with cardiac syndrome X. Am J Cardiol 2007;99:1378–83. https://doi.org/10.1016/j. amjcard.2006.12.070; PMID: 17493464. 17. Sestito A, Lanza GA, Di Monaco A, et al. Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. J Cardiovasc Med (Hagerstown) 2011;12:322–7. https://doi.org/10.2459/ JCM.0b013e3283406479; PMID: 21135582. 18. Michelsen MM, Pena A, Mygind ND, et al. Coronary flow velocity reserve assessed by transthoracic Doppler: the iPOWER study: factors influencing feasibility and quality. J Am Soc Echocardiogr 2016;29:709–16. https://doi.org/10.1016/j. echo.2016.02.011; PMID: 27038514. 19. 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. https://doi.org/10.1093/ ejechocard/jen004; PMID: 18296409. 20. Crea F, Lanza GA, Camici PG. Coronary Microvascular Dysfunction. Milan: Springer, 2013. 21. Berne RM. The role of adenosine in the regulation of coronary blood flow. Circ Res 1980;47:807–13. PMID: 6254686. 22. Ghimire G, Hage FG, Heo J, et al. Regadenoson: a focused update. J Nucl Cardiol 2013;20:284–8. https://doi.org/10.1007/ s12350-012-9661-3; PMID: 23229649. 23. Wang T, Mentzer JRM Jr, Van Wylen DG. Interstitial adenosine with dipyridamole: effect of adenosine receptor blockade and adenosine deaminase. Am J Physiol 1992;263(2 Pt 2):H552–8. https://doi.org/10.1152/ajpheart.1992.263.2.H552; PMID: 1510152. 24. Opherk D, Zebe H, Weihe E, et al. Reduced coronary dilator capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation 1981;63:817–25. PMID: 7471337. 25. Mosseri M, Yarom R, Gotsman MS, et al. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries. Circulation 1986;74:964–72. PMID: 3769180. 26. Quyyumi AA, Dakak N, Mulcahy D, et al. Nitric oxide activity in the atherosclerotic human coronary circulation. J Am Coll Cardiol 1997;29:308–17. https://doi.org/10.1016/S07351097(96)00472-X; PMID: 9014982. 27. Al Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronay artery disease and endothelial dysfunction. Circulation 2000;101:948–54. PMID: 10704159. 28. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106:653–8. PMID: 12163423. 29. Ren LM, Nakane T, Chiba S. Muscarinic receptor subtypes mediating vasodilation and vasoconstriction in isolated, perfused simian coronary arteries. J Cardiovasc Pharmacol 1993;22:841–6. PMID: 7509902. 30. Hasdai D, Holmes DR Jr, Higano ST, et al. Prevalence of coronary blood flow reserve abnormalities among

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55. F ragasso G, Chierchia SL, Lu C, et al. Left ventricular dysfunction during dobutamine stress echocardiography in patients with syndrome X and positive myocardial perfusion scintigraphy. G Ital Cardiol 1999;29:383–90. PMID: 10327315. 56. Cadeddu C, Nocco S, Deidda M, et al. Altered transmural contractility in postmenopausal women affected by cardiac syndrome X. J Am Soc Echocardiogr 2014;27:208–14. https://doi. org/10.1016/j.echo.2013.09.014; PMID: 24161482. 57. Kaul S, Newell JB, Chesler DA, et al. Quantitative thallium imaging findings in patients with normal coronary angiographic findings and in clinically normal subjects. Am J Cardiol 1986;57:509–12. https://doi.org/10.1016/00029149(86)90825-8; PMID: 3953433. 58. Cavusoglu Y, Entok E, Timuralp B, et al. Regional distribution and extent of perfusion abnormalities, and the lung to heart uptake ratios during exercise thallium-201 SPECT imaging in patients with cardiac syndrome X. Can J Cardiol 2005;21:57–62. PMID: 15685304. 59. Diamond JA, Makaryus AN, Sandler DA, et al. Normal or near normal myocardial perfusion stress imaging in patients with severe coronary artery disease. J Cardiovasc Med (Hagerstown) 2008;9:820–5. https://doi.org/10.2459/ JCM.0b013e3282f88bc5; PMID: 18607248. 60. Lanza GA. Angina pectoris and myocardial ischemia in the absence of obstructive coronary artery disease: role of diagnostic tests. Curr Cardiol Rep 2016;18:15. https://doi. org/10.1007/s11886-015-0688-3; PMID: 26768741.

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Ischaemic Heart Disease, Stroke and Risk Factors

Testosterone and the Heart Michael Kirby 1 , Geoffrey Hackett 2,3 and Sudarshan Ramachandran 4,5 1. University of Hertfordshire, Hatfield, UK; 2. Spire Little Aston Hospital, Sutton Coldfield, UK; 3. Aston University, Birmingham, UK; 4. Department of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 5. Department of Clinical Biochemistry, University Hospitals of North Midlands/Keele University/Staffordshire University, Staffordshire, UK

Abstract The development of a subnormal level of testosterone (T) is not universal in ageing men, with 75% of men retaining normal levels. However, a substantial number of men do develop T deficiency (TD), with many of them carrying a portfolio of cardiovascular (CV) risk factors, including type 2 diabetes (T2D) and the metabolic syndrome. TD increases the risk of CV disease (CVD) and the risk of developing T2D and the metabolic syndrome. The key symptoms suggesting low T are sexual in nature, including erectile dysfunction (ED), loss of night-time erections and reduced libido. Many men with heart disease, if asked, admit to ED being present; a problem that is often compounded by drugs used to treat CVD. A large number of studies and meta-analyses have provided evidence of the link between TD and an increase in CVD and total mortality. Patients with chronic heart failure (CHF) who have TD have a poor prognosis and this is associated with more frequent admissions and increased mortality compared with those who do not have TD. Conversely, in men with symptoms and documented TD, T therapy has been shown to have beneficial effects, namely improvement in exercise capacity in patients with CHF, improvement of myocardial ischaemia and coronary artery disease. Reductions in BMI and waist circumference, and improvements in glycaemic control and lipid profiles, are observed in T-deficient men receiving T therapy. These effects might be expected to translate into benefits and there are more than 100 studies showing CV benefit or improved CV risk factors with T therapy. There are flawed retrospective and prescribing data studies that have suggested increased mortality in treated men, which has led to regulatory warnings, and one placebo-controlled study demonstrating an increase in coronary artery non-calcified and total plaque volumes in men treated with T, which is open for debate. Men with ED and TD who fail to respond to phosphodiesterase type 5 (PDE5) inhibitors can be salvaged by treating the TD. There are data to suggest that T and PDE5 inhibitors may act synergistically to reduce CV risk.

Keywords Testosterone deficiency, erectile dysfunction, cardiovascular risk, chronic heart failure, myocardial ischaemia, coronary artery disease, reduced libido, night time erections, cardiovascular risk factors, PDE5 inhibitors Disclosure: MK has received funding for research, lecturing, advice and conference attendance from the pharmaceutical industry. He serves as a member of the Prostate Cancer Risk Management Scientific Advisory Group, and the National Prostate Cancer Audit group. All other authors have no conflicts of interest to declare. Received: 10 February 2019 Accepted: 14 May 2019 Citation: European Cardiology Review 2019;14(2):103–10. DOI: https://doi.org/10.15420/ecr.2019.13.1 Correspondence: Mike Kirby, Faculty of Health and Human Sciences, Centre for Research in Primary and Community Care, 30 Wedon Way, Bygrave, Baldock, Herts SG7 5DX, UK. E: kirbym@globalnet.co.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Testosterone deficiency (TD) is a well-established and significant medical condition.1,2 It has been defined as a clinical and biochemical syndrome, associated with older age and comorbidities. 3 It is characterised by a deficiency in serum androgen levels, with or without reduced genomic sensitivity to androgens.2 The latter relates to the functionality of androgen receptors. For example, if there is CAG repeat polymorphism on exon 1 of the androgen receptor gene, the response to any given serum testosterone (T) concentration is reduced as the number of CAG repeats increases.4–8 Biochemical TD must be associated with relevant signs and symptoms for a diagnosis to be made. The hormone has important physiological functions and deficiency can adversely affect the brain, peripheral nerves, muscle, fat, bone, the cardiovascular (CV) system and especially the male genital and reproductive systems. T is important for the regulation of carbohydrate metabolism, lipids and proteins, and

positively affects glucose control, liver fat, cardiac biomarkers, muscle growth and adipogenesis.1,9–15

Epidemiology Epidemiological studies vary regarding the prevalence of TD. Perhaps the most useful study is the European Male Ageing Study, which evaluated more than 3,000 men between the ages of 40 and 79 years, recording biochemistry results and symptoms. An overall prevalence of 2.5% was reported and rates varied from 0.1% in men aged 40–49 years to 5.1% in those aged 70–79. In this study, TD was defined as three or more sexual symptoms associated with a total T (TT) level <11 nmol/l and a free T (FT) level less than 0.22 nmol/l.16 Three-quarters of men maintained normal T levels into old age. Based on biochemical levels, the prevalence of secondary TD was 11.8%, primary TD 2.0% and compensated (subclinical) TD 9.5% (worthy of observation but not treatment).17

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Ischaemic Heart Disease, Stroke and Risk Factors Table 1: Clinical Signs and Symptoms Suggestive of Testosterone Deficiency 1–3,21–23 Sexual

Physical

Delayed puberty

Decreased body hair

Small testes

Gynaecomastia

Infertility

Decreased muscle mass and strength

Decreased sexual desire and activity

Hot flushes or sweats

Erectile dysfunction

Sleep disturbances

Delayed ejaculation

Fatigue

Decreased volume of ejaculate Osteoporosis/height loss/low-trauma fractures Decreased or absent morning/ night-time erections Cardiometabolic

Psychological

Increased BMI/obesity

Changes in mood, e.g. anger, irritability, sadness, depression

Visceral obesity

Decreased wellbeing or poor self-rated health

Metabolic syndrome

Decreased cognitive function (including impaired concentration, verbal memory and spatial performance)

Source: Hackett et al. 2017.1 Reproduced with permission from Elsevier.

Aetiology Normal T levels depend on a healthy hypothalamic–pituitary– gonadotropin axis. Primary TD results from disruption at the level of the testes, secondary TD from disruption at the level of the hypothalamus and pituitary and combined TD from disruption at both these levels.3 Secondary TD is the most common form.17,18 Pituitary tumours can cause centrally mediated TD. Primary testicular failure may result from orchitis, Klinefelter’s syndrome, chemotherapy or radiation. Additional causes of TD include obesity, diabetes, metabolic syndrome, HIV infection, chronic renal failure, and chronic glucocorticoid and opioid use.19,20

Making the Diagnosis The signs and symptoms of TD are shown in Table 1. Sexual symptoms are the most common, but there are many less specific symptoms such as fatigue, sleep disturbance, visceral obesity, loss of physical strength, decreased muscle mass, decreased energy and motivation, hot flushes, changes in cognition and memory, depression and decreases in bone mineral density.1–3,21–23 The patient should be asked if they are taking any medications – prescription or otherwise – that can lower T levels, e.g. corticosteroids or opiates, or drugs that can cause erectile dysfunction (ED), and if they have previously taken T therapy.1,21 Physical examination should include height, weight, BMI and waist circumference, together with an assessment of body hair, any significant breast enlargement and the appearance of the penis and testicles.1,21,22,24 A prostate examination is also recommended.1,21 The British Society for Sexual Medicine (BSSM) recommendations for case finding are to test for TD in adult men with persistent and multiple signs of TD and to screen for TD in all men presenting

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with ED, loss of spontaneous erections or low sexual desire, type 2 diabetes (T2D), BMI >30 kg/m 2 or waist circumference >102 cm and those on long-term opiate, antipsychotic or anticonvulsant medications.1 T has a diurnal rhythm in younger men, which may become less marked with age but not invariably so.22 Thus, the recommendation is to measure T between 7 am and 11 am on at least two occasions, with a reliable method, preferably 4 weeks apart and, if possible, not during an acute illness.1 A fasting sample is generally advised because T levels are influenced by insulin and glucose, and this is particularly important for the second test.25 If the first result was close to the lower normal range (8–12 nmol/l), it is advised to include levels of sex hormone binding globulin (SHBG).1 The bioavailable forms of T are those not bound to SHBG, known as FT, and this may provide the most reliable clinical androgen status in some patients.16 FT may be calculated using the equation of Vermeulen et al.26 Online FT calculators are provided by the International Society for the Study of the Aging Male (ISSAM), available at: http://issam.ch/freetesto.htm and the Primary Care Testosterone Advisory Group (PCTAG), available at: http://www.pctag.uk/testosterone-calculator/. Reference ranges quoted by laboratories represent the normal population and these are often much lower than the advised action levels recommended by the various guideline groups. The BSSM and International Society for Sexual Medicine (ISSM) recommend the following action levels:1,27 • TT less than 8.00 nmol/l, or FT less than 0.18 nmol/l (based on two separate levels taken between 8 am and 11 am) usually requires T therapy. • TT higher than 12.00 nmol/l, or FT higher than 0.225 nmol/l does not require T therapy. • TT levels between 8.00 nmol/l and 12.00 nmol/l may require a trial of T therapy, for a minimum of 6 months, according to symptoms. The BSSM and ISSAM also recommend the following:1,22 • Increased luteinising hormone (LH) levels and T levels below normal or in the lower quartile range indicates testicular failure, so T therapy should be considered.28 • Men with increased LH levels, normal T levels but TD symptoms should be considered to have TD. European Male Ageing Study data demonstrated that clinical symptoms were more closely related to calculated FT than TT.29

Testosterone Levels in Men Ruige et al. demonstrated that higher T levels were associated with a decreased risk for CV events in men aged >70 years (HR 0.84; 95% CI [0.76–0.92]) but this was not the case in younger men (HR 1.01; 95% CI [0.95–1.08]).30 Araujo et al. performed a meta-analysis that included 18 studies and more than 22,000 subjects and concluded that both overall and CV mortality were related to T levels.31 Corona et al. comprehensively reviewed 1,178 articles and included 70 in their meta-analysis. They demonstrated a clear association between

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Testosterone and the Heart low T/high oestradiol levels and CV disease (CVD). They made the point that longitudinal studies demonstrated that overall mortality and CV mortality were highest in those with lowest T levels.32

Coronary Artery Disease and Testosterone Deficiency

All-cause Mortality, Cardiovascular Mortality and Testosterone Deficiency Long-term studies, reviews and meta-analyses have supported the association between TD and increased all-cause and CV mortality.2,30,31,57–60

Clinical studies show favourable effects of short- or long-term exposure to T therapy on coronary and peripheral vasomotion and peripheral arterial stiffness.33–35 Physiological concentrations of intracoronary T cause epicardial coronary artery dilatation and increases in volume blood flow in men with coronary artery disease (CAD).33

A meta-analysis by Araujo et al. included 12 studies involving more than 17,000 participants. Although there was considerable heterogeneity in these studies resulting from study and subject characteristics, low endogenous T levels were associated with both overall and CV mortality.31

T therapy in hypogonadal men delays time to ischaemia, improves mood and is associated with potentially beneficial reductions in biomarkers, total cholesterol and serum tumour necrosis factor-alpha.13,36

Corona et al. included 70 papers in their meta-analysis and showed a clear association between low T/high oestradiol levels and increased risk of CVD and CV mortality.32

Three early randomised, placebo-controlled trials demonstrated that administration of T improves myocardial ischaemia in men with CAD. All three trials found that in men with CAD, T prolongs the time to exercise-induced ST-segment depression as measured on treadmill stress testing.37–39

Muraleedharan et al. studied 581 men with T2D who were followed up for a mean of 5.8 years. Low T was defined as less than 10.4 nmol/l. A total of 51 men received T therapy for at least 2.0 years. Mortality rates were 20.0% in the low T group versus 9.1% in the normal T group, independent of comorbidities and other therapies, and T therapy reduced mortality similar to the controls.58

Numerous studies have demonstrated a negative correlation between endogenous T levels and intima-media thickness of the carotid arteries, abdominal aorta and thoracic aorta, which suggests that men with lower levels of endogenous T may be at a higher risk of developing more generalised atherosclerosis.40–47 Evidence also suggests that men with lower T levels are more likely to develop CAD during their lifetime and CAD severity has been shown to correlate with the degree of TD.48–55

Daka et al. demonstrated that low concentrations of T predicted acute MI in men with T2D.60

Budoff et al. studied 170 T deficient men over the age of 65 years in a double-blinded, placebo-controlled trial setting in the US.56 Men with symptoms suggestive of hypogonadism were enrolled in the study between June 2010 and June 2014. Treatment was with T gel, with the dose adjusted to maintain the T level in the normal range for young men, or placebo gel for 12 months. Plaque volume was determined by coronary CT angiography. For the primary outcome, T therapy compared with placebo was associated with a significantly greater increase in non-calcified plaque volume from baseline to 12 months. There were no major adverse CV events in either group.

A review by Muraldeedharan et al. raised the issue that these studies do not prove a pathogenic link, but low T may simply be a marker of illness.61

The authors point out that this trial had several strengths, including a placebo-controlled design, selection of men with unequivocally low T and a relatively high retention rate. However, they also point out that the study had some limitations. The assumptions about the composition of plaque components as detected by coronary CT angiography were not confirmed by direct radiological and pathological studies. Furthermore, the volume and radiological characteristics of coronary artery plaques are only surrogate outcomes and do not account for other factors that can influence the frequency and extent of plaque rupture and thrombosis. In fact, T therapy was associated with a significant increase in the volume of fibrous plaque, which may be more stable than other types of plaque. The major limitation is that the trial was not large enough or long enough to draw conclusions about the risk of T therapy on major adverse CV events. Larger studies are needed to understand the clinical implications of this finding.

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Yeap et al. studied 3,690 older men over 10 years, TT and FT levels in the normal range were associated with reduced all-cause and CV mortality. Interestingly, both low and high levels of T were associated with all-cause mortality, and higher levels of dihydrotestosterone reduced ischaemic heart disease mortality.59

Testosterone Therapy and Cardiovascular Risk T therapy has been controversial, with worries that treatment will increase CV risk. An extensive review of the literature published between 1940 and 2014 found only four studies that reported increased CV risk.62 The authors concluded that two of these were retrospective analyses with serious methodological limitations; one was a prospective trial with only four major adverse CV events and the other a meta-analysis that was criticised for using few studies and CV endpoints of questionable clinical importance, e.g. non-specific ECG findings and palpitations.63–66 The study by Vigen et al. was indeed retrospective, involving 8,709 men with a baseline TT level no higher than 10.4 nmol/l.63 These men were undergoing angiography and were followed up for a mean of 840 days. Results showed 681 of the 7,486 patients who did not receive T therapy died, 420 had a MI and 486 had a stroke. Of the remaining 1,233 patients receiving T therapy, only 67 died, 23 had a MI and 33 had a stroke. The authors then performed a complex statistical analysis using more than 50 covariates and concluded that there was a greater risk in the T therapy group. Some 1,132 patients were excluded because they were prescribed T therapy after the event when they should have been included in the untreated group, which falsely increased the events by 70%. When challenged, the investigators revised the number to 132 but admitted that 104 women had been mistakenly included in the results.

105

Ischaemic Heart Disease, Stroke and Risk Factors Figure 1: Men Stratified by Testosterone Replacement Therapy 60

Low T/untreated Low T/untreated + 95% CI Low T/untreated – 95% CI Low T/treated Low T/treated + 95% CI Low T/treated – 95% CI

50 Probability of mortality (%)

not presented. The lack of mortality data fails to recognise that any treatment that decreases mortality is, of course, likely to increase nonfatal events. The design was not prospective and although used as evidence against T therapy, it has been discredited by several design flaws and statistical analyses.62 Following these publications, in January 2014 the US Food and Drug Administration (FDA) convened an advisory committee meeting to review CV risks of T therapy. Subsequently, the FDA expanded the stated purpose of this committee to include a review of the suitable populations for T therapy. On 17 September 2014, the advisory committee voted to restrict therapeutic indications for T therapy and requested that the pharmaceutical industry perform a CV safety study. In March 2015, all US commercial T products underwent a mandatory label change that restricted the indicated population and warned against the possible risk of MI and stroke.67

0 50

Age (years) The estimated mortality probability and 95% CI from the fitted logistic regression: men stratified by testosterone replacement therapy. T = testosterone. Source: Hackett et al. 2017.71 Reproduced with permission from Baishideng Publishing Group.

Figure 2: Men Stratified by Phosphodiesterase Type 5 Inhibitor Treatment 35

Probability of mortality (%)

Testosterone Therapy and Decreased Cardiovascular Risk There are more than 100 studies showing CV benefits of higher endogenous T levels or improved CV risk factors with T therapy.69 This may not be surprising because long-term T therapy reduces fat mass, increases lean mass, improves glycaemic control, reduces insulin resistance and waist circumference and improves the ability to exercise.

PDE5 inhibitor/untreated PDE5 inhibitor/untreated + 95% CI PDE5 inhibitor/untreated – 95% CI PDE5 inhibitor/treated PDE5 inhibitor/treated + 95% CI PDE5 inhibitor/treated – 95% CI

The EU and Health Canada also issued warnings regarding T therapy and potential CV risk. A review by the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee recommended updating the product information warning about the potential increased CV risk in hypogonadal men using T therapy, but did not confirm an increase in heart problems with T medicines.68 These label changes have led to significant media coverage, which is ongoing.

In a retrospective observational study involving 1,031 hypogonadal men aged over 40 years, 398 of whom took T therapy, the cumulative mortality was 21% in the untreated group versus 10% in the treated group (p<0.0001). The mortality rates were 3.4 deaths per 100 personyears for T-treated men and 5.7 deaths per 100 person-years in men not treated with T. The greatest effect was observed in younger men and those with T2D.70

Age (years) The estimated mortality probability and 95% CI from the fitted logistic regression: men stratified by testosterone replacement therapy. PDE5 = phosphodiesterase type 5. Source: Hackett et al. 2017.71 Reproduced with permission from Baishideng Publishing Group.

Worryingly, there were no data confirming the correct diagnosis of TD syndrome or T therapy and duration of therapy.62 The Finkle et al. study provided prescribing data in men treated with T, but there were no records of T blood results or the patients’ symptoms.64 The researchers defined non-fatal coronary events as the major endpoint assessed in the 12 months before and 3 months after therapy. This is clearly a major weakness because the benefits of T therapy would take longer than this to appear and many other studies have excluded the first 3 months of treatment from analysis because of the likelihood of events relating to the pre-existing condition. In addition to this, data on fatal CV events and all-cause mortality were not collected and 12-month post-treatment data were collected but

106

In a prospective study, 581 men with T2D and low T (defined as TT <10.4 nmol/l) were followed up for a mean of 5.8 years. Fifty-one men were treated for at least 2.0 years. Mortality rates were 20.0% in the low T group versus 9.1% in the normal T group, independent of comorbidities and therapies, and 9.4% in those with TD in the treated group.58 Both studies demonstrated that mortality was reduced by approximately half in those who received T therapy compared with those who did not. A retrospective study followed up 857 men with T2D for 4 years after baseline T measurements. Patients were randomised to long-acting T undecanoate or placebo. Low baseline TT and FT levels were associated with increased all-cause mortality. T therapy and phosphodiesterase type 5 (PDE5) inhibitor use were independently associated with lower all-cause mortality (Figures 1–4).71 Interestingly, the greatest benefits from the two treatments were seen in older men (Figure 5).72 This finding regarding PDE5 inhibitor treatment was supported by two database studies demonstrating CV and mortality benefits.73,74

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Testosterone and the Heart Figure 3: Long-term Mortality Data in Diabetes 25.0

Mortality (%)

A large retrospective study examined 83,010 male veterans with low TT levels who were categorised into three groups:76 • group 1: T therapy resulting in normalisation of T levels; • group 2: T therapy without normalisation of T levels; and • group 3: did not receive T therapy.

15.0

14.7

10.0

8.9

5.0

1.7

hi in

Long-term mortality data in diabetes: the BLAST long-term study (n=857). Source: Hackett et al. 2017.71 Reproduced with permission from Baishideng Publishing Group.

Figure 4: Men on All or No Treatments

Not on any treatment Not on any treatment + 95% CI Not on any treatment – 95% CI All 3 treatments All 3 treatments + 95% CI All 3 treatments – 95% CI

90 80 Probability of mortality (%)

A virtual controlled study examined electronic medical records from 1996 to 2011 to identify 5,695 men who had a low initial TT level, a subsequent T level and up to 3 years of follow-up. It demonstrated a positive impact of T therapy – particularly on mortality – and there was no suggestion of increased risk with sustained higher serum levels.78 In a more recent study, the same group reported a significant reduction in CV events in a cohort of hypogonadal men with angiographically confirmed CAD.79

1.6

0.0

100

A further large study compared acute MI rates in 6,355 men aged 66 years and older who received at least one T injection, compared with a matched placebo group over an 8 year period. It found no overall increase in events, those at greatest risk experienced a significant reduction in events and mortality and there was no increased risk from thromboembolism.77

4.8

3.6 1.7

PD E5

All-cause mortality (HR 0.44; 95% CI [0.42–0.46]), risk of MI (HR 0.76; 95% CI [0.63–0.93]) and stroke (HR 0.64; 95% CI [0.43–0.96]) were significantly lower in group 1 (n=43,931, median age 66.0 years, mean follow-up 6.2 years) than group 3 (n=13,378, median age 66.0 years, mean follow-up 4.7 years). Similarly, all-cause mortality (HR 0.53; 95% CI [0.50–0.55]), risk of MI (HR 0.82; 95% CI [0.71–0.95]) and stroke (HR 0.70; 95% CI [0.51–0.96]) were significantly lower in group 1 than group 2 (n=25,701, median age 66.0 years, mean follow-up 4.6 years). There was no difference in the risk of MI or stroke between groups 2 and 3.76

22.4

20.0

bi to rs PD n=6 – u 82 nt E5 , f rea in ol te hi lo d bi w- (a up ll n= tors : pa 17 – 5, tre 3.8 tien y fo a t llo ed ear ts, s) w- (a PD up ll E5 : 3 pa tie in . 9 hi ye nts bi ar , to s) rs PD n= – u 11 nt E5 2, rea in f t ol ed hi lo bi w- (50 to up –6 n= rs – : 0 PD t 6 1, rea 4.1 yea E5 ye rs fo te in l l hi ow d (5 ars , bi ) -u 0– to p: 60 rs 3. y PD n= – u 7 e 23 nt ye ars E5 6, rea ar , in s) fo te hi llo d bi w- (60 to up –7 rs n : =5 – t 0 PD 8, rea 3.9 yea E5 ye rs fo te in a , llo d hi w- (50 rs) bi to up –6 rs :3 0 – PD n= u .9 ye 20 nt ye ars E5 1, rea ar , in s) f t hi bi ollo ed to w- (70 r up –8 n= s – 21 tre : 3. 0 y 7 e , f at ol ed ye ars a , lo w- (70 rs) up –8 :3 0 .9 ye ye ars ar , s)

Registry data provide useful evidence where parenteral T undecanoate was used for up to 10 years in 656 men with a mean age of 60.7 years. Long-term treatment was well tolerated, with excellent adherence. Importantly, mortality related to CVD was significantly decreased in the group taking T versus the untreated group.75

70 60 50 40 30 20 10 0

Age (years)

Wallis et al. compared 10,311 T-treated men with 28,029 controls. They found a reduction in all-cause and CV mortality with T therapy. They also found an increase in mortality in the first 6 months compared with normal, which was attributed to the impact of underlying undertreated TD. Reassuringly, this study also reported a 40% reduction in new diagnoses of prostate cancer in the treated group versus the control group.80 Lastly, a study comparing 8,808 T-treated men with 35,527 untreated men with low T reported a 33% reduction in cardiac events associated with T therapy.81 These results corroborate those of registry studies, which have published data collected over 6 years of follow-up, with no suggestion of increased mortality.82

Heart Failure TD is common during the course of chronic heart failure (CHF). Reduction in circulating T level predicts a deterioration of functional capacity and suggests a role for managing TD in CHF. T is a determinant of exercise capacity, muscle mass and strength. TD is involved in the pathophysiology of CHF, contributing to some features of this

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The estimated mortality probability and 95% CI from the fitted logistic regression comparing men on all three treatments (testosterone, phosphodiesterase type 5 inhibitor and statin) and on none of the treatments. Source: Hackett et al. 2017.71 Reproduced with permission from Baishideng Publishing Group.

syndrome such as reduced muscle mass, abnormal energy handling, fatigue, dyspnoea and, ultimately, cachexia.83–85 Approximately 25% of patients affected by CHF have T levels below normal ranges and this is related to disease progression. In addition, reduction of circulating T levels may contribute to some specific features of CHF, such as abnormal energy handling, weakness, dyspnoea and cachexia in particular. T therapy may improve muscle strength and functional pulmonary capacity in (CHF) in men with TD.86 Jankowska et al. studied 208 men with CHF and 366 healthy male controls.87 Low T levels were found in all New York Heart Association (NYHA) classes of heart failure. It has also been shown that reduced T levels in men with CHF indicates a poor prognosis and is associated with increased hospital admissions and mortality.88,89 A meta-analysis of a small number of randomised controlled trials studied the effect of T therapy on exercise capacity in HF patients.90

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Ischaemic Heart Disease, Stroke and Risk Factors Figure 5: Mortality of Men with Type 2 Diabetes Not Receiving Phosphodiesterase Type 5 Inhibitors Eugonadal untreated

Hypogonadal untreated

(129 seconds in T patients versus 12 seconds in placebo patients, p=0.020).

Hypogonadal treated

30.0 25.2

25.0

22.8 19.7

20.0 15.0

Contraindications to Testosterone Therapy

13.3 10.3 10.4

10.0 5.0

Nevertheless, it would seem sensible to be cautious in patients with CVD in an unstable state and approach replacement therapy in the same way as the correction of hypothyroidism, by slowly titrating the dose up to normal over 3 months.

3.6

2.6

5.3

4.2 4.0

2.3

The main contraindications to T therapy are a haematocrit >54%, male breast cancer, locally advanced or metastatic prostate cancer, an active desire to have children (T therapy reduces spermatogenesis) and severe CHF (NYHA class IV).1,21

0.0 Total group

50–60 years

60–70 years

70–80 years

Mortality data of men with type 2 diabetes who were not receiving phosphodiesterase type 5 inhibitors followed for approximately 4 years (n=682). Source: Hackett et al. 2016.72 Reproduced with permission from Wiley.

The four studies (n=198; men, 84%; mean age 67 years) tested either transdermal or intramuscular T, given between 12 weeks and 12 months. The endpoints were 6-minute walk test (6MWT), incremental shuttle walk test, or peak VO2 by cardiopulmonary exercise test. The 6MWT increased by 54.0 metres, incremental shuttle walk test increased by 46.7 metres, and peak VO2 increased by 2.7 ml/kg/min in the T-treated patients versus placebo. The increase in peak VO2 and distance walked in the T-treated group correlated with the increase in FT. This degree of improvement in the 6MWT is similar to that seen with other therapies in patients with HF. The NYHA functional class improved by ≥1 grade in 9.8% of patients in the placebo group versus 35.0% of patients in the T therapy group. There were no significant differences in major adverse cardiac events between the T therapy and placebo groups.90

Concern About Prostate Cancer There is no compelling evidence that T therapy is associated with an increased risk of prostate cancer. This statement is supported by guidelines from the European Association of Urology, the BSSM, the International Consultation on Sexual Medicine (ICSM) and the ISSM.1,3,21,23 The ISSAM states that there is no evidence that T therapy converts subclinical prostatic lesions into clinically detectable prostate cancer, and the ICSM states that there is no compelling evidence that T therapy is associated with prostate cancer progression.3,22 T therapy may make occult prostate cancer cases detectable within an early phase of treatment and present a beneficial effect in relation to early detection. Future longitudinal studies are needed to confirm these findings.91

Testosterone Therapy The choice of therapy lies between the transdermal route and long-acting T undecanoate injection, depending on patient choice. Adverse events related to T therapy are relatively rare, but follow-up is important because T therapy – especially shorter-acting injections – can increase the haematocrit.92

Additional contraindications include an unevaluated prostate nodule or induration, prostate specific antigen >4 ng/ml (or >3 ng/ml in those at high risk of prostate cancer), severe untreated sleep apnoea and severe lower urinary tract symptoms associated with benign prostatic hyperplasia.1,3,22,24

Discussion Both ED and TD are now regarded as independent CV risk factors.94–96 ED is common in cardiac patients and virtually all international guidelines recommend testing for TD in men with ED.97 PDE5 inhibitors are first-line therapy for men with ED.98 Patients unresponsive to PDE5 inhibitors may be rescued with T therapy, especially if their T level is less than 8 nmol/l.99 The Birmingham, Lichfield, Atherstone, Sutton and Tamworth (BLAST) study found that in patients with T2D, T therapy, PDE5 inhibitors and statin therapy appeared to be synergistic and independent in preventing morbidity and mortality. T therapy and PDE5 inhibitors were independently associated with reduced all-cause mortality, with the greatest benefit from both treatments being seen in older men.71,72 Evidence also suggests that PDE5 inhibitors improve insulin sensitivity.100,101 These findings of reduced mortality in men taking PED5 inhibitors are in close agreement with Anderson et al., who followed up 5,956 UK men with T2D over 6.9 years. A 31.0% reduction in all-cause mortality and a 26.0% reduction in MI were reported with a low rate of PDE5 inhibitor prescribing at 22.8%.73 PDE5 inhibitors protect against endothelial reperfusion injury, improve endothelial function and reduce systemic and pulmonary blood pressure.101 Andersson et al. followed up 43,415 Swedish men after first MI for 5 years and found a significant reduction in all-cause and CV mortality and a 30% reduction in new diagnoses of heart failure and related admissions in men prescribed PDE5 inhibitors.74 T levels were not recorded and the benefits of PDE5 inhibitors appeared dose related and were not seen with other treatments for ED. An assessment of CV risk is inadequate and inaccurate if a question regarding ED is not included in the risk calculation, as in QRISK®3.95

Conclusion In patients with TD, ischaemia should be addressed wherever possible and underlying risk factors corrected. Mathur et al. tested the effect of T therapy on ischaemia during 12 months of treatment.93 Long-term treatment with T increased time to develop ischaemia on a treadmill

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The balance of evidence is that T therapy does not increase CV risk. Many studies have demonstrated that a low serum T concentration is associated with increased CV risk and mortality and that T therapy may have clinically relevant CV benefits.

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Testosterone and the Heart Evidence demonstrates reduced CV risk with a higher endogenous T concentration, evidence of improvement of known CV risk factors with T therapy and reduced mortality in T deficient men who received T therapy versus untreated men, evidence of improvement of myocardial ischaemia in men with CAD, improved exercise capacity in men with CHF and improvement in serum glucose levels, HbA1c and insulin resistance in men with diabetes and prediabetes. Bearing these facts in mind, when dealing with cardiac patients clinicians need to be alert to the possibility of undisclosed sexual problems and underlying TD, which are amenable to treatment. The following statements are the conclusions of the BSSM:1 • Other benefits of replacing T in deficient men are that beyond 6 months there is evidence of benefit of T therapy in terms of body composition, features of the metabolic syndrome and bone mineralisation.

10.

11.

12.

13.

14.

15.

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• T therapy also improves sexual desire, erectile function and sexual satisfaction. Reductions in BMI and waist circumference, and improvements in glycaemic control and lipid profiles, are observed in hypogonadal men receiving T therapy. • Trials of T therapy should extend beyond 6 months and maximal benefit is often seen after 12 months. • Patients should be informed about the benefits and side-effects of therapy to allow a joint decision regarding the appropriateness of treatment. • The adverse effects of T therapy should be fully discussed and, where appropriate its potential effect on future fertility for each patient and his partner. • When T therapy is prescribed, it should be accompanied by weight loss and lifestyle advice as standard management. • For patients who are severely symptomatic, with T levels <8 nmol/l, dietary and lifestyle advice alone is unlikely to produce meaningful improvement within a relevant clinical period.

A Biol Sci Med Sci 2013;68:954–9. https://doi.org/10.1093/ gerona/gls259; PMID: 23292288. 16. W u FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363:123–35. https://doi.org/10.1056/NEJMoa0911101; PMID: 20554979. 17. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab 2010;95:1810–8. https://doi.org/10.1210/ jc.2009-1796; PMID: 20173018. 18. Corona G, Maseroli E, Rastrelli G, et al. Characteristics of compensated hypogonadism in patients with sexual dysfunction. J Sex Med 2014;11:1823–34. https://doi. org/10.1111/jsm.12549; PMID: 24774537. 19. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008;93:2737–45. https://doi.org/10.1210/ jc.2007-1972; PMID: 18270261. 20. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab 2011;96:2341–53. https://doi.org/10.1210/jc.2011-0118; PMID: 21646372. 21. Dohle GH, Arver S, Bettocchi C, et al. Guidelines on male hypogonadism. The Netherlands: European Association of Urology, 2017. Available at: http://uroweb.org/guideline/malehypogonadism/ (accessed January 2019). 22. Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male 2015;18:5–15. https://doi.org/10.3109/13685538.2015.1004049; PMID: 25657080. 23. Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med 2015;12:1660–86. https://doi.org/10.1111/ jsm.12952; PMID: 26081680. 24. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59. https://doi.org/10.1210/jc.2009-2354; PMID: 20525905. 25. Caronia LM, Dwyer AA, Hayden D, et al. Abrupt decrease in serum testosterone levels after an oral glucose load in men: implications for screening for hypogonadism. Clin Endocrinol (Oxf) 2013;78:291–6. https://doi.org/10.1111/j.13652265.2012.04486.x; PMID: 22804876. 26. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–72. https://doi. org/10.1210/jc.84.10.3666; PMID: 10523012. 27. International Society for Sexual Medicine. ISSM quick reference guide on testosterone deficiency for men. Wormerveer, the Netherlands: ISSM, 2015. Available at: https://professionals. issm.info/wp-content/uploads/sites/2/2018/05/ISSM-QuickReference-Guide-on-TD.pdf (accessed 14 June 2019). 28. Tajar A, McBeth J, Lee DM, et al. Elevated levels of gonadotrophins but not sex steroids are associated with musculoskeletal pain in middle-aged and older European men. Pain 2011;152:1495–501. https://doi.org/10.1016/j. pain.2011.01.048; PMID: 21421286. 29. Antonio L, Wu FC, O’Neill TW, et al. Low free testosterone is associated with hypogonadal signs and symptoms in men with normal testosterone. J Clin Endocrinol Metab 2016;101:2647– 57. https://doi.org/10.1210/jc.2015-4106; PMID: 26909800. 30. Ruige JB, Mahmoud AM, De Bacquer D, et al. Endogenous testosterone and cardiovascular disease in healthy men: a

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82. H aider A, Yassin A, Dorros G, et al. Effects of long-term testosterone therapy on patients with ‘diabesity’: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. men with type 2 diabetes. Int J Endocrinol 2014;2014:683515. https://doi. org/10.1155/2014/683515; PMID: 24738000. 83. Volterrani M, Rosano G, Iellamo F. Testosterone and heart failure. Endocrine 2012; 42:272–7. https://doi.org/10.1007/ s12020-012-9725-9; PMID: 22729951. 84. Malkin CJ, Jones TH, Channer KS. Testosterone in chronic heart failure. Front Horm Res 2009;37:183–96. https://doi. org/10.1159/000176053; PMID: 19011297. 85. Pugh PJ, Jones RD, West JN, et al. Testosterone treatment for men with chronic heart failure. Heart 2004;90:446–7. https:// doi.org/10.1136/hrt.2003.014639; PMID: 15020527. 86. Giagulli VA, Guastamacchia E, De Pergola G, et al. Testosterone deficiency in male: a risk factor for heart failure. Endocr Metab Immune Disord Drug Targets 2013;13:92–9. https://doi. org/10.2174/1871530311313010011; PMID: 23369141. 87. Jankowska EA, Biel B, Majda J, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 2006;114:1829–37. https://doi. org/10.1161/CIRCULATIONAHA.106.649426; PMID: 17030678. 88. Wehr E, Pilz S, Boehm BO, et al. Low free testosterone is associated with heart failure mortality in older men referred for coronary angiography. Eur J Heart Fail 2011;13:482–8. https://doi.org/10.1093/eurjhf/hfr007; PMID: 21339189. 89. Dos Santos MR, Seyegh AL, Groehrs RV, et al. Testosterone deficiency increases hospital readmission and mortality rates in male patients with heart failure. Arq Bras Cardiol 2015;105:256–64. https://doi.org/10.5935/abc.20150078; PMID: 26200897. 90. Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail 2012;5:315–21. https://doi.org/10.1161/ CIRCHEARTFAILURE.111.965632; PMID: 22511747. 91. Zhang X, Zhong Y, Saad F, et al. Clinically occult prostate cancer cases may distort the effect of testosterone replacement therapy on risk of PCa. World J Urol 2019. https:// doi.org/10.1007/s00345-018-02621-6; PMID: 30659301; epub ahead of press. 92. Jones SD, Dukovac T, Sangkum P, et al. Erythrocytosis and polycythemia secondary to testosterone replacement therapy in the aging male. Sex Med Rev 2015;3:101–12. https://doi. org/10.1002/smrj.43; PMID: 27784544. 93. Mathur A, Malkin C, Saeed B, et al. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol 2009;161:443–9. https://doi. org/10.1530/EJE-09-0092; PMID: 19542238. 94. Hackett G, Kirby M. Erectile dysfunction and testosterone deficiency as cardiovascular risk factors? Int J Clin Pract 2017;72:e13054. https://doi.org/10.1111/ijcp.13054; PMID: 29381240. 95. Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ 2017;357:j2099. https://doi.org/10.1136/bmj.j2099; PMID: 28536104. 96. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA Guideline. J Urol 2018;200:423–32. https://doi.org/10.1016/j.juro.2018.03.115; PMID: 29601923. 97. Hodges LD, Kirby M, Solanki J, et al. The temporal relationship between erectile dysfunction and cardiovascular disease. Int J Clin Pract 2007;61:2019–25. https://doi.org/10.1111/j.17421241.2007.01629.x; PMID: 17997808. 98. Hackett G, Kirby M, Wylie K, et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men – 2017. J Sex Med 2018;15:430–57. https:// doi.org/10.1016/j.jsxm.2018.01.023; PMID: 29550461. 99. Hackett G, Cole N, Saghir A, et al Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study. BJU International 2016;118:804–13. https://doi.org/10.1111/bju.13516; PMID: 27124889. 100. Ramirez CE, Nian H, Yu C, et al. Treatment with sildenafil improves insulin sensitivity in prediabetes: a randomized, controlled trial. J Clin Endocrinol Metab 2015;100:4533–40. https://doi.org/10.1210/jc.2015-3415; PMID: 26580240. 101. Pofi R, Gianfrilli D, Badagliacca R, et al. Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask): How do they work? J Endocrinol Invest 2016;39:131–42. https://doi.org/10.1007/ s40618-015-0339-y; PMID: 26142740.

EUROPEAN CARDIOLOGY REVIEW

Ischaemic Heart Disease, Stroke and Risk Factors

Hypertension and Stroke: Update on Treatment Mauricio Wajngarten 1 and Gisele Sampaio Silva 2,3 1. Sao Paulo University Medical School, Brazil; 2. Neurology and Neurosurgery Department, Federal University of São Paulo, Brazil; 3. Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil

Abstract Stroke is the second most common cause of mortality worldwide and the third most common cause of disability. Hypertension is the most prevalent risk factor for stroke. Stroke causes and haemodynamic consequences are heterogeneous which makes the management of blood pressure in stroke patients complex requiring an accurate diagnosis and precise definition of therapeutic goals. In this article, the authors provide an updated review on the management of arterial hypertension to prevent the first episode and the recurrence. They also present a discussion on blood pressure management in hypertensive urgencies and emergencies, especially in the acute phase of hypertensive encephalopathy, ischaemic stroke and haemorrhagic stroke.

Keywords Hypertension, stroke, treatment, prevention, emergency, public health Disclosure: The authors have no conflicts of interest to declare. Received: 11 February 2019 Accepted: 14 May 2019 Citation: European Cardiology Review 2019;14(2):111–5. DOI: https://doi.org/10.15420/ecr.2019.11.1 Correspondence: Mauricio Wajngarten, Alameda Franca 1433, Apartamento 121, São Paulo SP, Brazil, CEP 01422001. E: mauricio@w123.com.br Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Stroke is the second most common cause of mortality worldwide and the third most common cause of disability.1 Although there has been a global trend towards a reduction in stroke incidence, prevalence and mortality since the 1990s, the overall stroke burden in terms of absolute number of people affected continues to increase.2 More than 1 million people have a stroke every year in Europe and that figure is estimated to rise to 1.5 million by 2025, due to the ageing population.3 There are three main types of stroke: ischaemic, intracebral and subarachnoid haemorrhage. In the US, the proportion of ischaemic strokes, intracerebral haemorrhage and subarachnoid haemorrhage is 87%, 10% and 3%, respectively.4 These percentages seem to be similar globally, with a trend of a higher increase in the frequency of haemorrhage in developed countries in relation to developing countries, while death rate is significantly higher in developing countries compared with developed countries.5–7 Men have a higher incidence of stroke than women at younger ages, with the incidence reversed by the age of 75 years, although recent data suggests this may not be the case for black people as the stroke risk for black women aged 65 to 74 years was similar when compared with black men.4,8 The finding could be driven by race and sex group differences for stroke risk factors, mainly hypertension.8 Hypertension is the most prevalent risk factor for stroke, based on data from 30 studies, and has been reported in about 64% of patients with stroke.2,9 In low-income countries, the reported prevalence of risk factors among patients with stroke is lower, however patients have the highest in-hospital mortality, probably due to delays in presentation for

seeking acute stroke care, differences in health system response and acute stroke management.10 The cause of stroke and haemodynamic consequences are heterogeneous across stroke subtypes and timing of disease presentation. Thus, the management of blood pressure (BP) in stroke patients is complex and requires an accurate diagnosis and precise definition of therapeutic goals. The present review will address the management of BP in patients with stroke, mostly based on recent published guidelines. In general, guideline recommendations from different countries are similar, including the gaps in evidence and suggestions for the need for further studies (Figure 1).11–15

Blood Pressure and Primary Prevention of Cardiovascular Disease and Stroke There is robust evidence that screening and treatment of hypertension prevents cardiovascular disease (CVD) and reduces mortality in the middle-aged population (50–65 years). Even in older adults, lowering BP is likely to be beneficial provided that treatment is well tolerated, despite a lack of studies to support this. However, there is a lack of high-quality evidence for a favourable harm–benefit balance of antihypertensive treatment among older adults, especially among the oldest age groups (>80 years).16 There has been a debate about how far BP should be lowered. The American Guidelines for Management of Hypertension, influenced by the results of the Systolic Blood Pressure Intervention Trial (SPRINT) recommends a reduction of the treatment target from 140/90 mmHg to 130/80 mmHg, including for the very old.17-19 However, some authors emphasised that there is a greater potential for harm to exceed benefit when BP targets are lowered.20

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Ischaemic Heart Disease, Stroke and Risk Factors Figure 1: Blood Pressure Levels in Patients with Stroke Suggested by the Current Clinical Guidelines

Primary Prophylaxis

Acute Ischaemic Stroke

Patients with hypertension should be treated with antihypertensive drugs to a target BP of <140/90 mmHg

Patients with elevated BP who are eligible for treatment with IV alteplase should have their BP carefully lowered to a systolic BP <185 mmHg and diastolic BP <110 mmHg before IV fibrinolytic therapy is initiated. In patients not treated with IV thrombolytic therapy for whom intra-arterial therapy is planned, it is reasonable to maintain BP ≤ 185/110 mmHg before the procedure

Blood Pressure and Stroke Acute Haemorrhagic Stroke

Secondary Prophylaxis

In patients with systolic BP 150–220 mmHg and without contraindication to acute BP treatment, acute lowering of systolic BP to 140 mmHg is safe

BP therapy is indicated for previously untreated patients with ischaemic stroke or TIA who after the first several days, have an established BP ≥140 mmHg systolic or ≥90 mmHg diastolic

In patients presenting with systolic BP >220 mmHg, it may be reasonable to consider aggressive reduction of BP with continuous IV infusion and frequent BP monitoring

Goals for target are uncertain and should be individualised, but it is reasonable to achieve a systolic pressure <140 mmHg and a diastolic pressure <90 mmHg. For patients with a recent lacunar stroke, a systolic BP of <130 mmHg might be reasonable to target.

BP = blood pressure

The European Guidelines for the Management of Arterial Hypertension recommend lowering systolic BP to <140 mmHg for all patient groups, including independent older patients, with a target of 130 mmHg for most patients if tolerated. That level is lower than the one recommended in previous guidelines. Even lower systolic BP levels (<130 mmHg) are recommended for some patients, especially to further reduce the risk of stroke. However, the European guidelines recommend against the reduction of systolic BP to <120 mmHg because of a possible increase in harm. According to the same guideline, BP targets in old and very old patients (above 80 years) with dependence, frailty and comorbidities may be higher.12

Blood Pressure Management for Patients with Stable Cardiovascular Disease There is little evidence for the benefits in total mortality, serious adverse events, or total cardiovascular events for people with hypertension and cardiovascular disease treated to lower than target BP. Also, there is very limited evidence on adverse events associated with lower BP targets, which leads to high uncertainty. At present, evidence is insufficient to justify lower BP targets (≤135/85 mmHg) in people with hypertension and established cardiovascular disease. Further randomised clinical trials are needed to address this question.21

Hypertensive Urgencies and Emergencies Hypertensive urgencies are situations associated with severe BP elevation in otherwise stable patients without acute or impending change in target organ damage or dysfunction.11 Many of these patients have withdrawn from or are noncompliant with antihypertensive therapy and do not have clinical or laboratory evidence of acute target organ damage. These patients should not be considered as having a hypertensive emergency and instead should be treated by reinstituting or intensifying their antihypertensive drug therapy and treatment of anxiety, as applicable.12,13 There is no indication for referral to emergency departments, immediate reduction of BP or hospitalisation for these patients. Hypertensive emergencies are defined as severe elevations in BP (>180/120 mmHg) associated with evidence of new or worsening target

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organ damage. People with chronic hypertension can often tolerate higher BP levels than those who were previously normotensive. However, if the emergency is left untreated, the one-year death rate associated with hypertensive emergencies is higher than 79% and the median survival is 10.4 months.12,13 The most common emergency symptoms will depend on the organs affected but may include headache, visual disturbances, chest pain, dyspnoea, dizziness and other neurological deficits.22 Acute stroke, especially intracerebral haemorrhage, when associated with severe hypertension has often been termed a hypertensive emergency, but a more cautious approach is recommended for acute lowering of BP in the emergency setting for acute ischaemic stroke.12,14 Paradoxically, there is no evidence from randomised controlled trials that antihypertensive drugs reduce morbidity or mortality in patients with hypertensive emergencies. However, from clinical experience, it is highly likely that reduction of BP (not necessarily to normal) prevents or limits further target organ damage. There is also no robust evidence to suggest which first-line antihypertensive drug class provides more benefit than harm in hypertensive emergencies.12,13,22 For most hypertensive emergencies, IV administration of a short half-life drug under continuous haemodynamic monitoring is recommended to allow careful titration of the response to treatment. Esmolol, metoprolol, labetalol, fenoldopam, clevidipine, nicardipine, nitroglycerine, nitroprusside, enalaprilat, urapidil, clonidine and phentolamine are all recommended. In general, use of oral therapy is discouraged.11,13 If conditions requiring rapid lowering of systolic BP, such as aortic dissection or pheochromocytoma, are not present, the recommendation is to reduce blood pressure by a maximum of 25% over the first hour, then to 160/100–160/110 mmHg over the next 2–6 hours, then to normal over the next 24–48 hours.12 The survival of patients with hypertensive emergencies has improved dramatically over the past decades. However, these patients still have a

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Hypertension and Stroke high mortality risk and should be screened for secondary hypertension. Careful long-term follow up is also of utmost importance.11

Blood Pressure Management in Hypertensive Emergencies Involving Brain Damage BP management in hypertensive emergencies involving brain damage (hypertensive encephalopathy, intracerebral hemorrhage and acute ischaemic stroke) should consider that the pathophysiology of brain damage is unique to each condition.12,14 Management should be tailored according to the disease and there is not a single recommendation that fits all. Consequently, the right diagnosis is crucial based upon clinical features, brain imaging, neurovascular evaluations and cardiac tests.

Hypertensive Encephalopathy The diagnosis of hypertensive encephalopathy is based on the presence of vague neurologic symptoms, headache, confusion, visual disturbances, seizures, nausea and vomiting. The onset of symptoms usually occurs over 24–48 hours with neurological progression. The examination can show retinopathy (haemorrhages, exudates and papilledema), transient and migratory neurological nonfocal deficits ranging from nystagmus to weakness and an altered mental state ranging from confusion to coma.22,23 Complications can result in neurological deficits from intracranial haemorrhage. Focal neurological lesions are rare and should raise the suspicion of stroke.23 Symptoms are usually reversible with prompt initiation of therapy. It is usually safe to reduce mean arterial pressure by 20–25% and to lower the diastolic BP to 100–110 mmHg using labetalol, nicardipine or nitroprusside. Agents that affect the central nervous system, such as clonidine, reserpine and methyldopa, and diuretics should be avoided.13

In the acute phase of ischaemic stroke, early initiation or resumption of antihypertensive treatment is indicated only in patients treated with recombinant tissue-type plasminogen activator or if hypertension is extreme. For patients eligible for IV thrombolysis, antihypertensive treatment is recommended so that systolic blood pressure is ≤185 mmHg and diastolic blood pressure is ≤110 mmHg before treatment and <180/105 mmHg for the first 24 hours after treatment.14 A recently published clinical trial evaluating more strict BP targets after IV thrombolysis for acute ischaemic stroke did not show longterm benefits in independence or survival, however lower BP levels were associated with lower rates of haemorrhagic transformation.26 The benefit of acute BP lowering in patients with acute ischaemic stroke who do not receive thrombolysis is uncertain. Initiation of treatment for these patients is suggested only if the systolic blood pressure is >220 mmHg or diastolic blood pressure is >120 mmHg or if the patient has another clear indication.14 Rapid reduction of BP, even to lower levels in the hypertensive range, can be detrimental. Therefore, if indicated, BP should be lowered cautiously, by about 15% during the first 24 hours after the onset of stroke.14 Patients with acute ischaemic stroke and a BP lower than 180/105 mmHg in the first 72 hours after stroke do not seem to benefit from the introduction or reintroduction of BP-lowering medication. For stable patients who remain hypertensive (≥140/90 mmHg) more than three days after an acute ischaemic stroke, initiation or reintroduction of BP-lowering medication should be considered. Restarting BP control is reasonable after the first 24 hours for hypertensive patients who are stable.14

Haemorrhagic Stroke Posterior reversible encephalopathy syndrome (PRES) has been increasingly recognised as a complication of hypertensive encephalopathy. Hypertension with failed autoregulation, dysfunction of the blood brain barrier, arteriolar dilatation and hyperperfusion leading to vasogenic oedema have all been implicated in its pathophysiology. The clinical presentation can be very similar to a hypertensive encephalopathy including headache, nausea, hemiparesis, hemianopsia, seizures and coma. Findings from brain MRI are typical and show symmetric hyperintensities in the subcortical white matter of the posterior temporal and occipital lobes in the fluid-attenuated inversion recovery sequences. Some patients can also present with string-of-beads and focal vasodilatation-vasoconstriction areas in the cerebral angiogram, a finding compatible with reversible cerebral vasoconstriction syndrome. However, PRES can also occur in patients without elevated BP levels, including those using immunosuppressive drugs, after organ and bone marrow transplantation and in patients with sepsis and multiorgan failure.24

Ischaemic Stroke Acute ischaemic strokes occur due to an occlusion of an intracranial or cervical artery with consequent deprivation of blood and oxygen to a brain territory. A few minutes after an arterial occlusion in the brain, a core ischaemic lesion is established, however a larger area at risk of hypoperfusion can be salvageable if recanalisation therapies are administered. The salvageable area or ischaemic penumbra is largely dependent on collateral blood flow and acute reductions of BP can threaten perfusion in critical areas.25

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Spontaneous, non-traumatic intracerebral haemorrhage is the second most common cause of stroke after ischaemic stroke. The most common causes are hypertension, bleeding diatheses, amyloid angiopathy, drug misuse and vascular malformations.27 Subarachnoid haemorrhage is another subtype of haemorrhagic stroke. The two major causes of subarachnoid haemorrhage are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface.28,29 In patients with intracerebral haemorrhage, BP is often elevated and hypertension is linked to greater haematoma expansion, neurological deterioration and worse prognosis. However, the management of hypertension is complicated by competing risks (reducing cerebral perfusion pressure in patients with intracranial hypotension) and potential benefits (reducing further bleeding).30,31 Intensive BP lowering (<140 mmHg) in patients with intracerebral haemorrhage had no clear benefits on clinical prognosis but was safe and associated with a modest better functional recovery in patients who survived a stroke in a large randomised clinical trial. A favourable trend was also seen toward a reduction in the conventional clinical end point of death and major disability.32 However, more intense BP lowering (<120 mmHg) not only did show not clinical benefits and was associated with more renal adverse events in another clinical trial using intravenous nicardipine.33 The American Heart Association guidelines recommend that for patients with intracerebral haemorrhage presenting with systolic BP 150–220 mmHg and without

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Ischaemic Heart Disease, Stroke and Risk Factors contraindication to acute BP treatment, acute lowering of systolic BP to 140 mmHg is safe and can be effective for improving functional outcome.27 A subsequent study, in which SBP was immediately reduced from a mean of 200 mmHg to two different target intervals (140–170 versus 110–139 mmHg), showed that more intensive BP lowering had no benefit on disability or death and was associated with more renal adverse events.34 Intracranial pressure is another important parameter to be considered in patients with intracerebral haemorrhage. If the systolic BP is higher than 180 mmHg and there is evidence or suspicion of elevated intracranial pressure, it is recommended to keep cerebral perfusion pressure at 61–80 mmHg. If there is no evidence or suspicion of elevated intracerebral pressure, a modest reduction of BP (160/90 mmHg) is recommended. If the systolic BP is 150–200 mmHg, acute lowering to 140 mmHg is probably safe.27 Drugs that may cause prolonged or precipitous decline in BP should be avoided. The management of BP in the acute phase of subarachnoid haemorrhage is based on even less clinical evidence. Observational studies suggest that aggressive treatment of BP may reduce the risk of aneurysmal rebleeding, but with an increased risk of secondary ischaemia. Guidelines from different clinical societies agree that is reasonable to treat BP if the aneurysm is not yet secured, although the levels recommended in the guidelines differ. The American Stroke Association recommends <160 mmHg of SBP, the Neurocritical Care Society says <110 mmHg of mean arterial pressure,28,29 while the European Stroke Organisation found moderate-quality evidence to support weak recommendations for intensive lowering of SBP to <140 mmHg within 6 hours of intracraneal hemorragic stroke onset.35

Blood Pressure Management to Prevent Stroke Recurrence About 25% of strokes are recurrent, the annual risk of recurrence is about 4% and the mortality rate after a recurrent stroke is 41%.12,13 In the North Dublin Population Stroke Study, the cumulative 2-year stroke recurrence rate was 10.8% and case fatality was 38.6%.36 The risk is also high after a transient ischaemic attack (TIA) or a minor ischaemic stroke. Data from a registry of TIA clinics in 21 countries that enrolled 4,789 patients showed that at 1-year follow-up, the rate of cardiovascular events including stroke was 6.4% in the first year and 6.4% in years 2–5.37 There are gaps in the evidence for the management of BP for secondary prevention of stroke and there is a need for further studies. BP-lowering therapy should be considered in patients with stable neurological status, 72 hours after onset of neurologic symptoms, or immediately after TIA, for previously treated or untreated patients with hypertension, except in patient with large vessel occlusion and fluctuating clinical symptoms.14,38 A Cochrane review of randomised controlled trials investigating BP-lowering treatment for the prevention of recurrent stroke, major vascular events and dementia in patients with a history of stroke or TIA. The BP-lowering drugs started at least 48 hours after stroke or TIA. The authors concluded that the results support the use of BP-lowering drugs in people with stroke or TIA for reducing the risk of recurrent stroke and that the current evidence is primarily derived from trials studying an ACE inhibitor or a diuretic and that no definite conclusions

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can be drawn from current evidence regarding an optimal systolic BP target after stroke or TIA.39 Reducing BP appears to be more important than the choice of agents and the effectiveness of the BP reduction diminishes as initial baseline BP declines. Angiotensin inhibitors, calcium channel blockers and diuretics are reasonable options for initial antihypertensive monotherapy and may be used in such patients. Beta-blockers should not be given unless there is a compelling indication for their use, particularly as the most common recurrent event after stroke is a further stroke rather than MI.39 The appropriate BP targets to prevent recurrent stroke are uncertain and depend upon the patient’s history. • In patients with underlying hypertension, a goal BP of <140/90 mmHg or systolic pressure <130–135 mmHg is recommended by the current guidelines. A systolic BP level <130 mmHg was not associated with a lower stroke risk.38 • For patients with recent small vessel (lacunar) ischaemic stroke, lowering the systolic BP <130 mmHg may reduce the risk of a future intracerebral haemorrhage.40 • In patients with haemodynamically significant large artery disease, BP lowering should be used cautiously as tolerated, without a specific goal other than a minimum reduction of 10/5 mmHg.38 • In patients who develop recurrent neurologic symptoms referable to a stenotic artery when the BP is lowered below a threshold, the suggested management is to maintain BP above that threshold.38

Conclusion Projections show that by 2030, an additional 3.4 million US adults aged ≥18 years, representing 3.88% of the adult population, will have had a stroke – a 20.5% increase in prevalence from 2012.41 BP is a powerful determinant of risk for ischaemic stroke and intracranial haemorrhage and there is evidence that controlling BP levels to <150/90 mmHg reduces the risk of stroke. Evidence of the benefits are weaker for lower BP targets obtained with intensive BP lowering, especially in older patients.42,43 The management of BP in adults with stroke is complex and challenging because of its heterogeneous causes and haemodynamic consequences. Future studies should focus on optimal timing and targets for BP reduction, as well as ideal antihypertensive agent therapeutic class by patient type and event type. New strategies to identify and reduce stroke risk and improve management of acute stroke are necessary. Markers for increased risk may improve prevention. For example, in a study involving Chinese adults with hypertension, the subgroup with a low platelet count and high homocysteine levels had the highest risk of first stroke, and this risk was reduced by 73% with folic acid treatment.44 About 90% of the stroke burden is attributable to modifiable risk factors, with about 75% being due to behavioural factors such as smoking, poor diet and low physical activity. Achieving control of behavioural and metabolic risk factors could avert more than threequarters of the global stroke burden.45 Health promotion strategies for positive cardiovascular health should be emphasised, in addition to the treatment of established CVD. The

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Hypertension and Stroke concept of cardiovascular health is characterised by seven metrics (Life’s Simple 7 defined by the American Heart Association).46 Ideal cardiovascular health involves the absence of clinically manifest CVD together with the simultaneous presence of optimal levels of all seven metrics, including not smoking and having a healthy diet pattern, enough physical activity, a healthy body weight and normal levels of total cholesterol, blood pressure and fasting blood glucose, in the absence of drug treatment.46 Unfortunately, the number of people – even young people – who have far from ideal cardiovascular health is still high. A survey of 550 physicians in 11 European countries found that primary care doctors reported that less than 30% of patients >40 years old were screened for blood pressure, whereas even fewer were screened for AF.47

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Programmes to improve patients’ and health providers’ education and communication are needed, and several are being studied and show promise.48 Patients should increase adherence to medical treatments and adopt a healthy lifestyle. Healthcare providers should have tools for quality improvement interventions on adherence to evidencebased therapies.49 Primordial prevention strategies that prevent the emergence of stroke risk factors should be the ultimate goal. Measures such as salt reduction and dietary interventions, implementation of tobacco control and support to the development of healthy environment are crucial for reducing the burden of cardiovascular diseases. This endeavour needs close collaboration between healthcare professionals, institutions and governments.50

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35. S teiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014;9:840– 55. https://doi.org/10.1111/ijs.12309; PMID: 25156220. 36. Callaly E, Ni Chroinin D, Hannon N, et al. Rates, predictors, and outcomes of early and late recurrence after stroke: the north Dublin population stroke study. Stroke 2016;47:244–6. https://doi.org/10.1161/STROKEAHA.115.011248; PMID: 26585395. 37. Amarenco P, Lavallee PC, Monteiro Tavares L, et al. Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med 2018;378:2182–90. https://doi.org/10.1056/NEJMoa1802712; PMID: 29766771. 38. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2014;45:2160–36. https://doi. org/10.1161/STR.0000000000000024; PMID: 24788967. 39. Zonneveld TP, Richard E, Vergouwen MD, et al. Blood pressure-lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack. Cochrane Database Syst Rev 2018;7:CD007858. https://doi. org/10.1002/14651858.CD007858.pub2; PMID: 30024023. 40. 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. https://doi.org/10.1016/ S0140-6736(01)06178-5; PMID: 11589932. 41. Ovbiagele B, Goldstein LB, Higashida RT, et al. Forecasting the future of stroke in the United States. Stroke 2013;44:2361–75. https://doi.org/10.1161/STR.0b013e31829734f2; PMID: 23697546. 42. Weiss J, Freeman M, Low A, et al. Benefits and harms of intensive blood pressure treatment in adults aged 60 years or older: a systematic review and meta-analysis. Ann Intern Med 2017;166:419–29. https://doi.org/10.7326/M16-1754; PMID: 28114673. 43. Messerli FH, Bangalore S. Blood pressure and stroke: findings from recent trials. J Am Coll Cardiol 2011;57:114–5. https://doi. org/10.1016/j.jacc.2010.06.054; PMID: 21185511. 44. Kong X, Huang X, Zhao M, et al. Platelet count affects efficacy of folic acid in preventing first stroke. J Am Coll Cardiol 2018;71:2136–46. https://doi.org/10.1016/j.jacc.2018.02.072; PMID: 29747834. 45. Feigin VL, Roth GA, Naghavi M, et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease study 2013. Lancet Neurol 2016;15:913–24. https://doi.org/10.1016/ S1474-4422(16)30073-4; PMID: 27291521. 46. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation 2010;121:586–613. https://doi.org/10.1161/ CIRCULATIONAHA.109.192703; PMID: 20089546. 47. Karnad A, Pannelay A, Boshnakova A, et al. Stroke prevention in Europe: how are 11 European countries progressing toward the European Society of Cardiology (ESC) recommendations? Risk Manag Healthc Policy 2018;11:117–25. https://doi.org/10.2147/RMHP.S163439; PMID: 30197544. 48. Machline-Carrion MJ, Santucci EV, Damiani LP, et al. An international cluster-randomized quality improvement trial to increase the adherence to evidence-based therapies for acute ischemic stroke and transient ischemic attack patients: Rationale and design of the BRIDGE STROKE trial. Am Heart J 2019;207:49–57. https://doi. org/10.1016/j.ahj.2018.09.009; PMID: 30415083. 49. Vinereanu D, Lopes RD, Bahit MC, et al. A multifaceted intervention to improve treatment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international, clusterrandomised trial. Lancet 2017;390:1737–46. https://doi. org/10.1016/S0140-6736(17)32165-7; PMID: 28859942. 50. Pandian JD, Gall SL, Kate MP, et al. Prevention of stroke: a global perspective. Lancet 2018;392:1269–78. https://doi. org/10.1016/S0140-6736(18)31269-8; PMID: 30319114.

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Cardiovascular Pharmacotherapy

Cardiovascular Pharmacotherapy Focus Pablo Avanzas 1,2,3 1. Hospital Universitario Central de Asturias, Oviedo, Spain; 2. Universidad de Oviedo, Oviedo, Spain; 3. Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain

Citation: European Cardiology Review 2019;14(2):116. DOI: https://doi.org/10.15420/ecr.2019.14.2.GE1 Correspondence: Pablo Avanzas, Hospital Universitario Central de Asturias, Av. Roma, s/n, 33011 Oviedo, Spain. E: avanzas@secardiologia.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

t is a great pleasure for me to introduce the International Society of Cardiovascular Pharmacotherapy (ISCP) section on cardiovascular pharmacotherapy. This issue features a variety of excellent manuscripts on intriguing topics, including the anti-inflammatory effects of curcumin, the effects of statins on T-cell function in acute coronary syndrome in Asian populations, and the cost-effectiveness of tailored antiplatelet treatments. Kana Shimizu and colleagues summarise available data on the anti-inflammatory properties of curcumin, a polyphenol found in turmeric that is used as a ‘natural’ pharmacological agent.1,2 Curcumin has several physiological actions that can make it useful in the management of ischaemic heart disease, including anti-inflammatory and antioxidant properties.3 The authors review the available clinical evidence on curcumin use for treating different lifestyle-related diseases, such as atherosclerotic vascular disease, myocarditis and heart failure, dementia, ischemic myocardial injury, chronic obstructive pulmonary disease, obesity and diabetes. All the clinical trials reviewed in the paper have been registered at Clinicaltrials.gov and a large body of evidence is expected

himizu K, Funamoto M, Sunagawa Y, et al. Anti-inflammatory S action of curcumin and its use to treat lifestyle-related diseases. Eur Cardiol 2019;14:117–22. https://doi.org/10.15420/ ecr.2019.17.2. Tsuda T. Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future

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to continue to accumulate over the coming years, with many trials still ongoing.1 It is known that the therapeutic effects of statins are not solely due to the reduction of LDL cholesterol because these agents have a number of immunomodulatory properties that may contribute to their beneficial effects, although the exact mechanisms involved are still being debated. Sorathia et al. performed a systematic review and meta-analysis to evaluate whether statin therapy enhances the frequency of regulatory T-cells determined by CD4+CD25+FOXP3+.4 Acute coronary syndromes are characterised by a diminished frequency and function of regulatory T-cells, and it has been speculated that their induction could potentially shift the immunomodulatory balance toward an anti-inflammatory state. The article by Sorathia et al. is the first systematic review published on this intriguing topic, compiling results from randomised controlled trials in patients with acute coronary syndromes. I hope you will enjoy reading this ISCP Pharmacotherapy section as much as I did.

perspectives. Food Funct 2018; 9: 705-14. https://doi. org/10.1039/c7fo01242j; PMID: 29206254 Hewlings SJ, Kalman DS. Curcumin: a review of its effects on human health. Foods 2017;6:E92.https://doi.org/10.3390/ foods6100092; PMID: 29065496. Sorathia N, Al-Rubaye H, Zal B. The effect of statins on the

functionality of CD4+CD25+FOXP3+ regulatory T-cells in acute coronary syndrome: a systematic review and meta-analysis of randomised controlled trials in Asian populations. Eur Cardiol 2019;14:123–9. https://doi.org/10.15420/ecr.2019.9.2.

Cardiovascular Pharmacotherapy

Anti-inflammatory Action of Curcumin and Its Use in the Treatment of Lifestyle-related Diseases Kana Shimizu, 1,2 Masafumi Funamoto, 1,2 Yoichi Sunagawa, 1,2 Satoshi Shimizu, 1,2 Yasufumi Katanasaka, 1,2 Yusuke Miyazaki, 1,2 Hiromichi Wada, 2 Koji Hasegawa 1,2 and Tatsuya Morimoto 1,2 1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2. Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Abstract Chronic inflammation plays a significant role in lifestyle-related diseases, such as cardiovascular diseases and obesity/impaired glucose tolerance. Curcumin is a natural extract that possesses numerous physiological properties, as indicated by its anti-inflammatory action. The mechanisms underlying these effects include the inhibition of nuclear factor-kappaB and Toll-like receptor 4-dependent signalling pathways and the activation of a peroxisome proliferator-activated receptor-gamma pathway. However, the bioavailability of curcumin is very low in humans. To resolve this issue, several drug delivery systems have been developed and a number of clinical trials have reported beneficial effects of curcumin in the management of inflammation-related diseases. It is expected that evidence regarding the clinical application of curcumin in lifestyle-related diseases associated with chronic inflammation will accumulate over time.

Keywords Inflammation, curcumin, lifestyle-related diseases, cardiovascular risk factor, natural product Disclosure: The authors have no conflicts of interest to declare. This review was conducted with a research grant from the National Hospital Organization. Received: 28 March 2019 Accepted: 29 May 2019 Citation: European Cardiology Review 2019;14(2):117–22. DOI: https://doi.org/10.15420/ecr.2019.17.2 Correspondence: Tatsuya Morimoto, Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. E: morimoto@u-shizuoka-ken.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Inflammation involves an array of processes in response to tissue damage resulting from oxidative stress or other causes and triggers repair, such as subsequent extracellular matrix remodelling and fibrosis.1–3 Chronic inflammation continues for a prolonged period, lasting from several months to several years, and is characterised by tissue invasion by inflammatory macrophages. This induces the expression of inflammatory cytokines or growth factors, which is associated with the pathophysiology of various lifestyle-related diseases including cardiovascular disease, obesity, diabetes, chronic obstructive pulmonary disease (COPD) and other related diseases, such as dementia.4–6 Atherosclerosis is a chronic illness associated with inflammation and is a major cause of cardiovascular disease.7–10

as 4,000–8,000 mg/kg per day.11 Trials in humans have reported beneficial effects of curcumin and it appears to have a role in treating lifestyle-related diseases associated with inflammation.

Curcumin is a polyphenol found in the spice turmeric that is used as a natural drug.11–13 Curcumin exhibits various physiological activities, including anti-inflammatory, antioxidant and anticancer activities.4,12–14 It inhibits signalling pathways, such as nuclear factor kappa-B (NF-kappaB) and myeloid differentiation protein 2-Toll-like receptor 4 co-receptor pathways, activates peroxisome proliferatoractivated receptor-gamma (PPAR-gamma) and inhibits the production of proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta (Figure 1).4,15

Risk factors associated with atherosclerosis lead to the production of inflammatory cytokines IL-1beta and TNF-alpha in the arterial walls via an increase in lipid peroxides and free radicals. These inflammatory cytokines produce IL-6 and are related to the adhesion and accumulation of inflammatory cells in the vessel walls. 16 Macrophages are the most abundant immune cells in atherosclerotic lesions and they play an important role in every stage of the disease, from lesion formation to plaque rupture. Macrophages are involved in the production of inflammatory cytokines, chemokines and proteases as well as having a role in foam cell formation.17 Numerous prospective cohort studies have reported that various inflammatory markers in the blood, such as C-reactive protein (CRP), are associated with the onset of cardiovascular disease.18

The US Food and Drug Administration has approved curcumin as a compound that is “generally recognised as safe” and a clinical trial reported that it was well tolerated and safe at doses as high

Curcumin and Atherosclerosis Risk factors for atherosclerosis, including hypertension, diabetes and smoking, cause a chronic inflammatory response. Oxidative stress can cause atherosclerotic plaques to become unstable and rupture, possibly triggering thrombosis. Statins are drugs with antiinflammatory effects that are used for treating high cholesterol and various studies have demonstrated their effectiveness in the primary and secondary prevention of cardiovascular events.16

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Cardiovascular Pharmacotherapy Figure 1: Actions of Curcumin on Lifestyle-related Conditions

Inflammatory stimuli

previous administration of curcumin inhibited early growth response 1 expression and reduced the infarct size.25

Curcumin and Myocarditis and Heart Failure Curcumin

Production of pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6)

Lifestyle-related conditions Atherosclerotic vascular disease Ischaemic myocardial injury Myocarditis Heart failure Chronic obstructive pulmonary disease Dementia Obesity Diabetes IL-1beta = interleukin-1beta; IL-6 = interleukin-6; TNF-alpha = tumour necrosis factor-alpha.

Zhang et al. evaluated a model of atherosclerosis in which ApoE knockout (ApoE−/−) mice were fed a high-fat diet. They found that curcumin inhibited the expression of Toll-like receptor 4 in atherosclerotic plaques, macrophage invasion and NF-kappaB activation in the aorta; reduced the level of inflammatory cytokines and adhesion molecules in the aorta and blood; and reduced the size of atherosclerotic regions, inhibiting their expansion.19 Ghosh et al. initiated renal failure in LDL receptor knockout mice via partial nephrectomy. They induced atherosclerosis with a high-fat diet and reported that curcumin reduced the area of atherosclerotic lesions by 63%.20

Curcumin and Ischaemic Myocardial Damage The death of myocytes due to MI temporarily causes an intense inflammatory response via the activation of Toll-like receptors.21 In a rodent model of MI, considerably increased expression of inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, was evident after a few hours in some cases (several hours to 1 day).22 In addition, the generation of reactive oxygen species due to ischaemia is essential in activating inflammatory responses.21

Myocarditis is often induced by a viral infection but has non-infectious causes, including autoimmune disorders.26,27 Heart failure is the final stage of cardiovascular disease. Chronic inflammation and subsequent myocyte death are associated with heart failure. Patients with heart failure have an abnormal immune response that disrupts wound healing and prolongs inflammation, consequently worsening heart failure.28 A high level of the inflammatory cytokine TNF-alpha has been reported in the blood of patients with chronic heart failure.29 The impact of curcumin in myocarditis has been studied using a number of rodent models. In coxsackievirus B3-induced myocarditis, curcumin inhibited the phosphatidylinositol-3 kinase–Akt–NF-kappaB signalling pathway and inhibited the expression of inflammatory cytokines, such as TNF-alpha, IL-6 and IL-1beta, both systemically and in the myocardium; thus, reducing the inflammatory response.30 Hernández et al. evaluated a mouse model of myocarditis caused by the protozoan parasite Trypanosoma cruzi and reported that curcumin inhibited the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in the myocardium as well as inhibiting inflammation in the myocardium and increased the survival rate of mice.31 TNF-alpha and IL-6 are inflammatory cytokines, whereas IL-4 and IL-13 are anti-inflammatory cytokines. Curcumin inhibited the expression of TNF-alpha and IL-6 and increased the expression of IL-4 and IL-13 in autoimmune acute myocarditis induced by cardiac myosin.32 Moreover, curcumin enhanced signal transducer and activator of transcription 6 phosphorylation and induced M2 macrophage polarisation, thus inhibiting myocarditis progression.32 Morimoto et al. studied two rat models of heart failure caused by hypertension and MI and showed that curcumin inhibits p300 histone acetyltransferase activity, thus inhibiting the development of left ventricular hypertrophy and left ventricular systolic dysfunction.33 In a rat model of doxorubicin-induced heart failure, curcumin inhibited the expression of atrial natriuretic factor, brain natriuretic peptide and beta-myosin heavy chain.34 The inhibition of heart failure by curcumin may thus be associated with its anti-inflammatory action.

Several studies suggest that curcumin has an inhibitory effect on NF-kappaB, which is a pivotal mediator of inflammatory responses. Lv et al. assessed a rat model of MI in which they ligated the left anterior descending artery. They found that administering 150 mg/ kg curcumin on the day after ligation significantly inhibited an increase in NF-kappaB expression as a result of MI and increased the PPAR-gamma expression, which is involved in anti-inflammatory signalling, consequently reducing the infarct size.23 In a rabbit model of myocardial ischaemia–reperfusion injury during cardiopulmonary bypass, Saeidinia et al. reported that curcumin inhibited NF-kappaB activation in the nucleus of cardiomyocytes, thus reducing TNFalpha, IL-6 and IL-8 levels in the blood, and that it inhibited monocyte apoptosis.24

Curcumin and Chronic Obstructive Pulmonary Disease

Early growth response 1 plays a key role in the pathophysiology of acute and chronic cardiovascular disease and is associated with induction of TNF-alpha and IL-6 expression. Wang et al. studied a rat model of myocardial ischaemia–reperfusion injury and found that

Several studies have demonstrated the possible benefits of curcumin in COPD. Moghaddam et al. used a mouse model of K-ras-induced lung cancer in which Haemophilus influenzae induced COPD-like airway inflammation and showed that curcumin inhibited neutrophil

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COPD is a family of diseases mainly characterised by airflow obstruction due to airway inflammation and remodelling. Several clinical studies have demonstrated the relationship between COPD and an increase in inflammatory markers, such as TNF-alpha, IL-6 and CRP.35,36 Smoking is the primary cause of COPD, and can cause systemic inflammation, but this is further exacerbated in people with COPD.35,36 COPD causes various complications, including MI, stroke and lung cancer. The most common comorbidity in patients with mild-to-moderate COPD is cardiovascular disease. One study suggested that chronic inflammation due to COPD exacerbates atherosclerosis, both directly and indirectly, and promotes thrombosis by weakening plaque.37

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Curcumin in Lifestyle Diseases Funamoto et al. 201640

Panahi et al. 201860

Vors et al. 201859

Mohammadi et al, 201858

Krishnareddy et al. 201957

Jazayeri-Tehrani et al. 201947

Adibian et al. 201956

Study

To investigate the efficacy of curcuminoids in reducing systemic oxidative burden in people with knee osteoarthritis

To evaluate the efficacy of curcumin using dispersion technology in patients with mild COPD by examining its effects on oxidative stress markers and inflammatory markers

To evaluate the impact of curcuminoids plus piperine administration on glycaemic, hepatic and inflammatory biomarkers in people with type 2 diabetes

To investigate: the bioavailability of resveratrol consumed in combination with curcumin after consumption of a high-fat meal; and the acute combined effects of this combination on the postprandial inflammatory response of subjects with abdominal obesity

To investigate the effects of unformulated curcumin and phospholipidated curcumin on anti-Hsp27 in patients with metabolic syndrome

To investigate the efficacy of a novel food-grade freecurcuminoid delivery system in improving markers of hepatic function (inflammation and oxidative stress) in chronic alcoholics

To determine the effects of nanocurcumin on overweight/ obese non-alcoholic fatty liver disease patients by assessing glucose, lipids, inflammation, insulin resistance and liver function indices, especially through nesfatin

To investigate the effects of curcumin supplementation on systemic inflammation, serum levels of adiponectin and lipid profiles in patients with type 2 diabetes

Purpose

• 117 subjects with metabolic syndrome (according to the National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria) • 500 mg curcuminoids (Curcumin C3 Complex®) co-administered with 5 mg piperine or placebo twice daily for 8 weeks

• 40 patients with mild-to-moderate primary knee osteoarthritis • 1.5 g curcuminoid per day in three divided doses co-administered with 15 mg piperine per day or placebo capsules for a period of 6 weeks

• 39 subjects with stage 1–2 COPD • 9 0 mg curcumin (Theracurmin®) or placebo twice a day for 24 weeks

• 100 patients with type 2 diabetes • C urcuminoids 500 mg/day co-administered with piperine 5 mg/day or placebo for 3 months

• 22 healthy subjects • 2 resveratorol/curcumin capsules (100 mg resveratorol sustained-release complex plus 50 mg curcumin sustained-release complex) or placebo (cellulose) before consuming the high-fat meal

• 120 patients with metabolic syndrome • 1 g curcumin, phospholipidated curcumin per day or placebo for 6 weeks

• 48 subjects with elevated serum transaminase and gamma-glutamyltransferase levels • Placebo or 250 mg curcumin-galactomannoside complex twice daily for 8 weeks

• 84 overweight/obese patients with non-alcoholic fatty liver disease • P lacebo or 40 mg nanocurcumin (Sinacurcumin®) twice a day for 3 months

• 44 people with type 2 diabetes • 1.5 g curcumin or placebo daily for 10 weeks

Subjects and Treatment

Superoxide dismutase, malondialdehyde, hs-CRP

Superoxide dismutase, glutathione, malondialdehyde

C-reactive protein, TNF-alpha, IL-6, SAA-LDL, alpha-1-antitrypsin-LDL

hs-CRP

IL-6, IL-8, MCP-1, C-reactive protein, sVCAM-1, sICAM-1, soluble E-selectin

Anti-Hsp27

IL-6, C-reactive protein, glutathione, superoxide dismutase, glutathione peroxidase

TNF-alpha, hs-CRP, IL-6

hs-CRP

Endpoint

Patients receiving curcumin showed significant reductions in the levels of malondialdehyde, IL-6 and TNF-alpha

Curcuminoid-piperine significantly improved serum superoxide dismutase activities (p<0.001) and reduced malondialdehyde (p<0.001) and C-reactive protein (p<0.001) concentrations compared with placebo

Curcuminoids induced significant elevation in serum superoxide dismutase activities (p<0.001), a borderline significant elevation in glutathione concentrations (p=0.064) and a significant reduction in malondialdehyde concentrations (p=0.044) compared with placebo

Percentage change in alpha1-antitrypsin-LDL level was significantly lower in the curcumin group compared with placebo (p=0.02)

No significant differences in hs-CRP concentrations were observed between curcuminoids and placebo groups

Resveratorol/curcumin significantly decreased the cumulative postprandial response of sVCAM-1 compared to placebo (p=0.01)

Curcumin and phospholipidated curcumin did not modify anti-Hsp27 concentration

Compared to both baseline and the placebo group, curcumin-galactomannoside complex significantly increased levels of glutathione, superoxide dismutase and glutathione peroxidase (p<0.001) and decreased IL-6 and C-reactive protein (p<0.001)

Compared with placebo, nanocurcumin significantly decreased levels of TNF-alpha, hs-CRP and IL-6 (p<0.05)

Compared with control, curcumin decreased hs-CRP significantly (p<0.05)

Results

Table 1:Completed Randomised Trials into Curcurmin

Panahi et al. 201661

To study the effectiveness of supplementation with a bioavailable curcuminoid preparation on measures of oxidative stress and inflammation in patients with metabolic syndrome

• 72 patients with type 2 diabetes Malondialdehyde, IL-6, • 2 NCB-02 capsules (150 mg curcumin) twice daily, TNF-alpha 10 mg atorvastatin once daily or placebo for 8 weeks

Panahi et al. 201562

To compare the effects of NCB-02 (a standardised preparation of curcuminoids), atorvastatin and placebo on endothelial function and its biomarkers in people with type 2 diabetes

Usharani et al. 201863

Anti-Hsp27 = antibody titers to heat shock protein 27; COPD = chronic obstructive pulmonary disease; hs-CRP = high-sensitivity C-reactive protein; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; SAA-LDL = serum amyloid A-LDL complex; sICAM-1 = soluble intercellular adhesion molecule-1; sVCAM-1 = soluble vascular cell adhesion molecule-1; TNF- alpha = tumour necrosis factor-alpha.

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Cardiovascular Pharmacotherapy Table 2: Results of Studies of Curcumin using Drug Delivery Systems to Increase Bioavailability Study

Formulation

Advantage

Application

Outcome

Biodegradable curcumin encapsulated in polylactidepoly(ethylene glycol) copolymer nanoparticles

• Better solubility and stability

Streptozotocin-induced diabetic rats

Enhanced the suppressive effect on markers of hepatitis and oxidative stress

Karri et al. 201665

Curcumin in chitosan nanoparticles impregnated into a collagen-alginate scaffold

• Better solubility and stability • Controlled release • Prevention from rapid clearance

Streptozotocin-induced diabetic rats

Promoted wound healing

Hu et al. 201866

Inhalable curcumin-loaded poly(lactic-co-glycolic) acid large porous microparticles

• Suitable aerodynamic Rat pulmonary fibrosis diameters for inhalation models • Prevention from phagocytosis

Qiao et al. 201767

Amphiphilic curcumin polymer

• Better solubility and stability • Targeting for colonic reducing environment

Dextran sulphate sodium-induced Suppressed the progress of mouse model of inflammatory inflammation in the colon bowel disease

Young et al. 201468

Nano-emulsion curcumin

• Better solubility • Protection from metabolism

Lipopolysaccharide-induced acute Suppressed lipopolysaccharideinflammation model induced blood monocyte mice accumulation

Li et al. 201969

E-selectin-modified atorvastatin calcium-and curcumin-loaded liposome

• Targeted for endothelial cells • Co-delivery

ApoE−/− mice

Suppressed atherosclerosis

Funamoto et al. 201640

Curcumin dispersed with colloidal nanoparticles

• B etter stability and solubility

People with mild chronic obstructive pulmonary disease

Suppressed an increase in alpha1antitrypsin LDL

El-Naggar et al. 2010

migration to the lungs.38 Yuan et al. studied a mouse model of COPD induced by lipopolysaccharide and cigarette smoke, reporting that curcumin inhibited the degradation of IkappaB-alpha protein and the expression of cyclooxygenase-2, thus reducing airway inflammation and remodelling.39 Funamoto et al. conducted a clinical trial including patients with mild COPD in which the oxidised LDL – alpha-1antitrypsin LDL – was significantly decreased in those taking highly absorbable curcumin compared with those taking a placebo.40

Curcumin, Obesity and Diabetes Adipose tissue is a multifunctional endocrine organ that releases various inflammatory and anti-inflammatory cytokines and physiologically active peptides.41,42 Obesity is a risk factor for cardiovascular disease.41,43 The accumulation of pericardial fat and myocardial steatosis is associated with the progression of coronary artery atherosclerosis. In obese patients, the secretion of inflammatory adipocytokines, such as TNF-alpha and IL-6, is increased and the secretion of anti-inflammatory adipocytokines is inhibited in enlarged mast cells in the visceral adipose tissue.42,43 Several rodent studies have assessed the effects of curcumin in models of obesity. In a mouse model of obesity due to a high-fat diet and in a model of genetic obesity, curcumin reduced macrophage invasion of adipose tissue, increased adiponectin production (which has anti-inflammatory and anti-atherosclerotic actions) and inhibited adipose tissue inflammation.44 Pan et al. evaluated a mouse model of obesity due to a high-fat diet and reported that ingestion of curcumin inhibited weight gain, reduced fat accretion due to a high-fat diet and significantly improved the serum lipid profile (including serum levels of triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol and free fatty acids).45 In addition, curcumin increased the adipose triglyceride lipase and hormone-sensitive lipase protein expression by activating PPARgamma/alpha and CCAAT/enhancer binding protein alpha in adipose

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Enhanced antifibrotic activity

tissue. Further, curcumin broke down lipids and improved glycolipid metabolism.45 Curcumin administration via percutaneous absorption in obese rats improved serum leptin levels and reduced adipose tissue volume to a level comparable with that in normal rats.46 Jazayeri-Tehrani et al. conducted a clinical trial involving 84 overweight or obese patients who were diagnosed with nonalcoholic steatohepatitis.47 They noted a decrease in TNF-alpha, high-sensitivity CRP, IL-6 and LDL-cholesterol as well as an increase in HDL-cholesterol in the blood. There was also increased absorption efficiency in patients taking nanocurcumin compared to those taking placebo. Nesfatin, an appetite-regulating protein, is significantly increased in patients taking nanocurcumin. When patients taking placebo were compared with those taking nanocurcumin, the two groups had a similar percentage decrease in BMI, but those taking nanocurcumin had a significantly greater percentage decrease in abdominal circumference.47 In people with type 2 diabetes, trials have shown that curcumin decreased leptin and increased adiponectin in the blood and resulted in improved lipid metabolism.48,49

Curcumin and Dementia Over the past few years, the role of inflammation has been recognised in the onset and progression of dementia.50,51 One study reported that dementia onset may be related to conditions such as hypertension, dyslipidaemia and diabetes, independent of cardiovascular risk factors.52 The onset of Alzheimer’s-type dementia is closely correlated with inflammation and oxidative stress in the brain.50,53 NF-kappaB activation in the glial cells of Alzheimer’s patients induces increased expression of inflammatory cytokines and contributes to neuronal degeneration in the brain.53 Levels of CRP, IL-6 and alpha1-antichymotrypsin in the blood are significantly correlated with the degree of dementia.50

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Curcumin in Lifestyle Diseases Research into the possible impact of curcumin on dementia is currently very limited. However, Liu et al. found that curcumin significantly reduced spatial memory deficit and promoted the function of cholinergic neurons in mice; this improvement was associated with the inhibition of NF-kappaB signalling pathways and enhanced transcription by PPAR-gamma.54 Small et al. reported that highly absorbable curcumin reduced amyloid and tau accumulation in the brains of adults with no cognitive impairment and may consequently improve memory and attention.55

Figure 2: The Mechanisms of Curcumin Action on Inflammation

TLR4 PI3K Cytoplasm

Akt P NF-κB IκB-alpha P

Trials on Anti-inflammatory Effects of Curcumin The anti-inflammatory effect of curcumin forms the basis for its potential clinical applications (Figure 2). A large body of clinical evidence is expected to accumulate in the future. Among trials registered at Clinicaltrials.gov, 162 studies are related to the anti-inflammatory effect of curcumin. Of these, 50 are currently on-going, 70 are complete and 42 have been withdrawn, have unknown status or have been terminated. Of the 50 completed studies, the 10 randomised double-blind and placebo-controlled comparative studies are listed in Table 1. The results of eight of these studies were significant. As the absorption of curcumin is very poor, most studies that reported significant effects used a large dose of curcumin (>1.5 g/day) or employed strategies to increase its absorption, such as using a drug delivery system.

Ligands

Curcumin

Degradation

PPAR-gamma NF-κB Anti-inflammatory cytokine (IL-4, IL-13)

Pro-inflammatory cytokine (IL-1beta, IL-6, TNF-alpha)

COX2 mPGES-1

COX2 = cyclooxygenase-2; IkB = inhibitor of kappaB; IL = interleukin; mPGES-1 = microsomal prostaglandin E synthase-1; NF-kB = nuclear factor-kappaB; PI3K = phosphatidylinositol-3 kinase; PPAR-gamma = peroxisome proliferator-activated receptor-gamma; TLR4 = toll-like receptor 4; TNF-alpha = tumour necrosis factor-alpha.

in alpha1-antitrypsin LDL levels in people with mild COPD.40 The improvement in the bioavailability of curcumin through the development of drug delivery systems may contribute to the successful clinical application of curcumin.

Drug Delivery Systems Curcumin has beneficial effects on the status of various diseases involving chronic inflammation. However, the absorption of curcumin is poor, and even if absorbed into the body it is rapidly metabolised and excreted in faeces.14 To overcome its low bioavailability, various drug delivery systems have been developed (Table 2). These include polymer nanoparticles, chitosan nanoparticles, colloidal nanoparticles, nanoemulsion and ligand-targeted liposomes. The beneficial effects of these drug delivery systems on curcumin bioavailability have been reported in streptozotocin-induced diabetic rats, a pulmonary fibrosis rat model, a dextran sulphate sodium-induced inflammatory bowel disease mouse model and a lipopolysaccharidestimulated acute inflammation mouse model.64–68 E-selectin-modified liposome was effective for ApoE−/− mice.69 Moreover, Funamoto et al. reported that curcumin dispersed with colloidal nanoparticles (Theracurmin®) suppressed an increase

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Conclusion A number of studies have reported the efficacy of curcurmin and the mechanisms by which its anti-inflammatory activity could treat various lifestyle-related conditions associated with chronic inflammation, including atherosclerosis, heart failure, obesity, diabetes and other related diseases, such as dementia. Most of these studies have involved animal experiments; however, there are several reports on the benefits of curcumin use in humans. Because curcumin has extremely low bioavailability in humans, an appropriate drug delivery system is necessary for its clinical application. It is important to study the relationship between the structure and activity of curcumin and to develop novel compounds that are more effective than natural curcumin. Additional clinical trials involving drug delivery systems for curcumin in humans need to be conducted to determine the benefits of curcumin treatment in conditions associated with inflammation.

atherosclerosis: JACC state-of-the-art review. J Am Coll Cardiol 2019;73:1691–706. https://doi.org/10.1016/j.jacc.2018.12.083; PMID: 30947923. Hansson GK. Inflammation and atherosclerosis: the end of a controversy. Circulation 2017;136:1875–7. https://doi.org/10.1161/CIRCULATIONAHA.117.030484; PMID: 28916641. Tsuda T. Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives. Food Funct 2018;9:705–14. https://doi. org/10.1039/c7fo01242j; PMID: 29206254. Rauf A, Imran M, Erdogan-Orhan I, et al. Health perspective of a bioactive compound curcumin: a review. Trends Food Sci Technol 2018;74:33–45. https://doi.org/10.1016/j. tifs.2018.01.016. Liu X, Zhu L, Gao X, et al. Magnetic molecularly imprinted polymers for spectrophotometric quantification of curcumin in food. Food Chem 2016;202:309–15. https://doi.org/10.1016/j. foodchem.2016.02.015; PMID: 26920299. Hewlings SJ, Kalman DS. Curcumin: a review of its effects on human health. Foods 2017;6:E92. https://doi.org/10.3390/ foods6100092; PMID: 29065496. Ghosh S, Banerjee S, Sil PC. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem Toxicol 2015;83:111–24. https://doi. org/10.1016/j.fct.2015.05.022; PMID: 26066364. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk

factor. Circulation 2004;109:II2-10. https://doi.org/10.1161/01. CIR.0000129535.04194.38; PMID: 15173056. 17. C ochain C, Zernecke A. Macrophages in vascular inflammation and atherosclerosis. Pflugers Arch 2017;469:485–99. https://doi. org/10.1007/s00424-017-1941-y; PMID: 28168325. 18. Welsh P, Grassia G, Botha S, et al. Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect? Br J Pharmacol 2017;174:3898–913. https://doi. org/10.1111/bph.13818; PMID: 28409825. 19. Zhang S, Zou J, Li P et al. Curcumin protects against atherosclerosis in apolipoprotein E-knockout mice by inhibiting toll-like receptor 4 expression. J Agric Food Chem 2018;66:449–56. https://doi.org/10.1021/acs.jafc.7b04260; PMID: 29224353. 20. Ghosh SS, Righi S, Krieg R, et al. High fat high cholesterol diet (Western diet) aggravates atherosclerosis, hyperglycemia and renal failure in nephrectomized LDL receptor knockout mice: role of intestine derived lipopolysaccharide. PLoS One 2015;10:e0141109. https://doi.org/10.1371/journal. pone.0141109; PMID: 26580567. 21. Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 2014;11:255–65. https://doi.org/10.1038/nrcardio.2014.28; PMID: 24663091. 22. Nian M, Lee P, Khaper N, et al. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 2004;94:1543– 53. https://doi.org/10.1161/01.RES.0000130526.20854.fa; PMID: 15217919.

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EUROPEAN CARDIOLOGY REVIEW

Cardiovascular Pharmacotherapy

The Effect of Statins on the Functionality of CD4 +CD25 +FOXP3 + Regulatory T-cells in Acute Coronary Syndrome: A Systematic Review and Meta-analysis of Randomised Controlled Trials in Asian Populations Nilofer Sorathia, 1,2,3 Hussein Al-Rubaye 3 and Benham Zal 1,2 1. Medipathways College London, London, UK; 2. University of Buckingham, Buckingham, UK; 3. St George’s, University of London, London, UK

Abstract Acute coronary syndrome (ACS) is characterised by increased effector cells and decreased regulatory T-cells (Tregs). Statins have been shown to be clinically beneficial in ACS patients. This effect could be mediated via the induction of Tregs in ACS patients. The aim of this systemic review and meta-analysis was to evaluate whether statin therapy enhances the frequency of Tregs determined by CD4+CD25+FOXP3+ in this subset of patients. A comprehensive search of PubMed and Embase was performed. Studies were restricted to randomised controlled trials that quantified CD4+CD25+FOXP3+ cell frequency by flow cytometric analysis before and after statin treatment in adults diagnosed with ACS. A minimum of at least two of the conventional markers to identify Tregs was compulsory. Four randomised controlled trials studies (439 participants) were included, all with low-to-moderate risk of bias. Pooled data showed a significant increase in Treg frequency after statin therapy in ACS patients. A further meta-regression and subgroup analysis also showed a negative dose-related effect, and a statin type-related effect (rosuvastatin versus atorvastatin), respectively. The results confirmed that statins positively alter the frequency of Tregs, which may indicate a potential mechanism of their therapeutic effect. However, there was a risk of information bias due to the markers used to identify Tregs, which was not fully explored, therefore, further randomised controlled trials should utilise markers of Tregs, such as the FOXP3 locus (Treg-specific demethylated region), for identification.

Keywords Regulatory T-cells, cluster of differentiation 4 positive, interleukin-2 receptor alpha chain negative, forkhead box P3 positive, acute coronary syndrome, statins, cytotoxic T-lymphocyte-associated protein 4 Disclosure: The authors have no conflicts of interest to declare. Received: 22 January 2019 Accepted: 2 May 2019 Citation: European Cardiology Review 2019;14(2):123–9. DOI: https://doi.org/10.15420/ecr.2019.9.2 Correspondence: Nilofer Sorathia, St George’s, University of London, Cranmer Terrace, Tooting, London SW17 0SZ, UK. E: m1701816@sgul.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Statins are most frequently prescribed for the primary prevention of cardiovascular disease due to their lipid-lowering properties. They are known to exert their effect by competitive inhibition of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase. The reduction in the synthesis of cholesterol induces upregulation of LDL receptors in the liver, resulting in increased clearance and decreased deposits of LDL in blood vessels.1 These LDL deposits are central to the induction of atherogenesis once oxidised by reactive oxygen species.2 Reducing circulating LDL leads to less oxidised LDL, which causes less damage. However, it was discovered that the therapeutic effect of statins is not solely due to the reduction of LDL. This is because statins are able to reduce mortality in healthy individuals with a normal LDL cholesterol profile.3 Similarly, other cholesterol-lowering methods, such as ileal bypass surgery or bile acid sequestrants, do not have an immediate clinically beneficial result, despite the drop in LDL.4 Statins also show a significant reduction in morbidity, mortality, recurrent unstable angina incidents, non-fatal MI after 4 months and reduced rehospitalisation in just 30 days for acute coronary syndrome (ACS) patients.5–9 Studies also demonstrated that the use of a higher

statin dose strategy did not increase the clinical benefit, despite greater LDL reduction.10 Apart from their lipid-lowering ability, statins have various immunomodulatory properties that have recently been identified.11 Inhibition of HMG-CoA reductase not only suppresses cholesterol synthesis, but also various inflammatory pathways due to the intermediates in the mevalonate pathway. Two isoprenoids, farnesylpyrophosphate and geranylgeranyl-pyrophosphate, are involved in post-translational modifications, in particular, the prenylation of GTPases, such as Ras, Rac, Rho and Cdc42.12 These binary switches are involved in various inflammatory pathways activated by their effect on cell signalling via phophatidylinositol-3-kinase, mitogen-activated protein kinase and nuclear factor kappa-light chain-enhancer of activated B-cells. Of note, Rho activates nuclear factor kappa-light-chain-enhancer of activated B-cells, which reduces endothelial nitric oxide synthase.13 Inhibition by statins would increase nitric oxide bioavailability and improve vascular function, which could explain how statins are able to improve vascular endothelial function within 3 hours of treatment

Access at: www.ECRjournal.com

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Cardiovascular Pharmacotherapy Figure 1: Flow Diagram Highlighting the Process of Study Selection for Each Step of the Systematic Review

192 records identified through database searching

4 additional records identified through bibliography

187 records after duplicates removed

187 records screened

177 records excluded 6 full-test articles excluded: - 2 studies were reviews

10 full-text articles assessed for eligibility

4 studies included in qualitative synthesis

- 2 studies did not examine ACS patients - 1 study examined in vitro administration of statins - 1 study did not measure Tregs, only effector t-cells

4 studies included in quantitative synthesis (meta-analysis) ACS = acute coronary syndrome; Tregs = regulatory T-cell.

in healthy patients.14 Inhibition of these pathways also causes a downregulation of vascular cell adhesion protein 1 and tumour necrosis factor-alpha-induced expression of intercellular adhesion molecule 1, reducing the ability of macrophages to bind to endothelial cells.15 Macrophage activity is also disrupted because of the reduction in chemoattractants, such as monocyte chemoattractant protein 1. Statins have also been shown to favour expression of anti-inflammatory cytokines, such as interleukin (IL)-4, IL-10 and transforming growth factor-beta (TGF-beta), while downregulating interferon-gamma (IFNgamma), IL-6, IL-1 and IL-8 due to a shift from T-helper cell type 1 to T-helper cell type 2 response, as shown in a mouse model of autoimmune encephalomyelitis treated with statins.16 A similar milieu of anti-inflammatory mediators was seen to improve graft versus host disease in animal models with the treatment of atorvastatin due to its ability to inhibit protein geranylgeranylation.17

found on classic CD4+ T-cells,24,25 research for a specific marker of Tregs has identified a demethylation site in a 5’untranslated region of FOXP3 called Treg-specific demethylated region, which allows for discrimination of Tregs.26 Tregs are regarded as the master switch of immune system regulation by exerting their effect through the modulation of both adaptive and innate immune responses through multiple mechanisms. The main four mechanisms by which Tregs exert their effects are through the release of inhibitory cytokines, antigen-dependent inhibition of immune responses, and direct contact and inhibition of APC maturation, as well as the interaction with CD80/86 complex on APC via CTLA4. Tregs release immunosuppressive cytokines IL-10, IL-35 and TGF-beta. Secretion of IL-10 by Tregs inhibits synthesis of proinflammatory cytokines (such as IL-6 and IL-2)and expression of major histocompatibility complex class II by APC, preventing antigen presentation.27 IL-35 secretion mediates induction of CD4+ cells into Tregs while also inhibiting proliferation of T-cells.28 TGF-beta released by Tregs decreases CD28 expression (a co-stimulatory molecule required for the activation of T-cells) and induces CD4+ differentiation into Tregs.29 Another functional mechanism of Tregs is antigen-dependent suppression. Tregs can be activated by an antigen via its T-cell receptor, where after it may suppress a T-cell with any antigen specificity.30 Direct contact of Tregs with APC exerts multiple actions. One of them is downregulation of co-stimulatory ligands CD80/CD86, which are required for T-cell activation.31 They also prevent dendritic cell activation by inhibiting effector T-helper cell type 1 cells (reducing IFN-gamma and tumour necrosis factor-alpha production), which is required for antigen presentation.32 Tregs also modulate macrophage activity, in particular, reducing their production of matrix metalloproteinases.33 However, the predominant mechanism by which Tregs exert their inhibitory effect on immune responses is through expression of CTLA4 molecule on its surface. CTLA4 binds the CD80/86 complex on APC, hence preventing CD28mediated activation of CD4+T-helper cells, leading to downregulation of both B-cell and cytotoxic T-lymphocyte (CTL)-mediated inflammatory responses.34 Binding also generates inhibitory signals to decrease the expression of CD28 while enhancing FOXP3 expression.35

Independent of HMG-CoA reductase inhibition, statins have been shown to bind to an allosteric site on lymphocyte function-associated antigen 1, thereby blocking the recruitment of lymphocytes and their cytotoxicity.18 All the effects of statins highlighted demonstrate that statins tilt the balance towards an anti-inflammatory state, so it is not surprising when statins are shown to significantly reduce regulatory T-cells (Tregs) in healthy individuals.19

Finally, CTLA4 and CD80/CD86 binding can also induce expression of indoleamine 2,3-dioxygenase, which catabolises tryptophan into pro-apoptotic mediators.36 Other mechanisms include Treg-mediated cytolysis of B-cells, natural killer cells and CTL via the release of granzyme A and perforin.37 Tregs can also cause metabolic disruption of CTL, as high levels of CD25 on Tregs cause depletion of IL-2 in the local environment, starving the effector T-cells and inducing apoptosis.38 Overall, Tregs play a significant role in the prevention of autoimmunity and induction of peripheral tolerance, but overactivation may also prevent immunity to certain pathogens or tumours.

Tregs are a subpopulation of CD4+ T-cells that are induced by an inflammatory stimulus in the peripheries from naive CD4+ cells, but they can also be derived in the thymus as CD4+CD25− cells.20 It has been found that 5–10% of circulating CD4+ T-cells are Tregs.21 They are characterised by the constitutive expression of CD25 and CTLA4 receptors, and FOXP3; a transcription factor that promotes T-cell differentiation into Tregs.22,23 Although these markers may also be

Vascular endothelial injury and dysfunction are the initial stages of coronary atheroma formation. The influx of LDL and its oxidisation within the coronary vessels are followed by activation and recruitment of monocyte-derived macrophages, leading to formation of lipid-laden foam cells in the vessel lumen and early plaque lesions.2 The damaged endothelium and macrophages release cytokines and growth factors including IFN-gamma, platelet-derived growth factor and TGF-beta,

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EUROPEAN CARDIOLOGY REVIEW

Effect of Statins on Regulatory T-cells in Acute Coronary Syndrome Table 1: Characteristics of Included Studies Statin

Author

Control

Xie at al. 201454

Hu et al. 2007

Statin and dose (mg/day)

Length of administration

Treg markers used

Rosuvastatin 40

24 hours

CD4+FOXP3+

Atorvastatin 10

2 weeks

CD4+CD25−

Wang et al. 201552

Atorvastatin 20

4 weeks

CD4+CD25−FOXP3+

Zhang et al. 201151

Atorvastatin 80

3 months

CD4+CD25−FOXP3+

Total

215

224

F = female, M = male, Treg = regulatory T-cell.

which signal for the recruitment of pro-inflammatory T-cells and proliferation of smooth muscle cells.39

meta-analysis compiling results from different randomised controlled trials (RCTs) in ACS patients.

The chronic vicious cycle of inflammation and proliferation of collagensecreting smooth muscle cells gradually leads to the thickening of the lesion and formation of a fibrolipid cap covering a highly thrombogenic necrotic core.40 Such advanced coronary plaques can, however, become destabilised and rupture through multiple inflammatory processes predominantly mediated by T-cells.41

The aim of this systematic review and meta-analysis is to evaluate whether statin therapy enhances the frequency of CD4+CD25+FOXP3+ Tregs in patients with ACS.

In this context, an aggressive and unusual subpopulation of CD4 + T-cells, CD4 +CD28− cells, has been reported to significantly contribute to coronary plaque destabilisation.42 These T-cells are believed to be activated by an auto-antigen, namely, human heat shock protein 60, expressed within the plaque environment. Human heat shock protein 60 is a chaperone stress protein that is constitutively expressed in all cells, and its expression is significantly increased during inflammation.42 Upon antigen exposure and activation, these T-cells are able to directly target and lyse the smooth muscle cell constituent of the plaque through the release of cytotoxic granules, resulting in plaque rupture and exposure of its thrombogenic content to the coronary blood flow. Once activated, CD4 +CD28− cells also produce IFN-gamma, which activates local macrophages, leading to increased secretion of matrix metalloproteinase enzymes. 43,44 These enzymes can gradually degrade the fibrous plaque cap, and contribute to plaque destabilisation and rupture resulting in thrombosis and ACS. ACS is characterised by heightened inflammatory status, and T-cells within the coronary environment, in particular, have been implicated in both disease initiation and progression.43,45 It has been shown that the frequency of Tregs is reduced in patients with non-STsegment elevation MI, ST-segment elevation MI, acute MI and unstable angina.46,47 In addition, Wigren et al. showed that individuals with low levels of Tregs were at increased risk of a first coronary event.48 Furthermore, Tregs are reported to have compromised functional efficacy, increased tendency for apoptosis and reduced responsiveness to T-cell receptor-mediated induction.46,49,50 These findings have led to suggestions that Tregs are unable to modulate coronary disease progression through tilting the internal milieu in support of a proinflammatory state. ACS patients have been shown to benefit from the anti-inflammatory effects of statin treatment; although, the exact mechanisms by which these effects are exerted are still debatable. Since ACS is characterised by diminished frequency and function of Tregs, their induction could potentially shift the immunomodulatory balance to an anti-inflammatory state. To date, there is no systematic review and

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Methods Eligibility Criteria Studies were restricted to RCTs, with no minimum or maximum length of follow-up. Adults diagnosed with ACS were included in this study. Studies that quantified Tregs cell frequency by flow cytometric analysis before and after statin treatment were included. A minimum of at least two of the conventional markers from CD4+CD25+FOXP3+ was compulsory to identify Tregs. The intervention must have been any of the oral tablet forms of statins: simvastatin, atorvastatin, rosuvastatin, pravastatin and fluvastatin, of which at least a minimum of 10 mg and a maximum of 80 mg dosage were prescribed

Search Strategy Studies from all years and languages were allowed for inclusion. MeSH terms were used to add synonyms and to increase the scope of the search (Supplementary Material Appendix 1). Following identification of eligibility criteria and the relevant search terms, the PubMed (1996 to search date) and EMBASE (1947 to search date) databases were searched on 13 June 2017. The detailed search strategy can also be found in Supplementary Material Appendix 2.

Data Collection and Analysis The title and abstract of all studies retrieved were evaluated for relevance to the objective of this review using the population, intervention, comparator, outcomes and study type (Supplementary Material Appendix 1). The piloted spread sheet contained the population, intervention, comparator, outcomes and study type, p-value, power, mean, Treg percentage, SD, 95% CI and length of the study.

Quality Assessment of Included Studies To assess the risk bias of eligible RCTs, authors (NS and HA) used the Cochrane risk of bias tool. The randomisation, allocation concealment, blinding of patients, researchers, outcome, completeness of data reported and selection of biomarkers used to identify Treg cells were evaluated. Studies should state the patient characteristics, exclusion criteria, lost to follow-up and number of patients in each group. If studies did not use all three CD25, CD4 and FOXP3 biomarkers, they were classified as high risk of information bias, as this may increase the probability of an impure yield of Tregs. Studies needed to report that

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Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (detection bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Information bias

Figure 2: Risk of Bias Summary

Hu et al.

−

Wang et al.

−

Xie et al.

−

Zhang et al.

−

of which four met the full eligibility criteria. Figure 1 shows the flow diagram for study selection.

Characteristics of Included Studies There was a total of 439 participants from all the included studies, of which 215 received statin therapy and 224 were part of the control groups. The characteristics of the included studies are summarised in Table 1. All studies were RCTs reported in English. Three studies administered atorvastatin oral tablets, one at a dose of 80 mg, and the rest at 20 mg and 10 mg, respectively.51–53 A study by Xie et al. used rosuvastatin oral tablets at a dose of 40 mg.54 Only studies by Zhang et al. and Wang et al. used placebos in the control group, compared with Hu et al. and Xie et al., who did not administer any medication to the control group, besides conventional ACS medication.51–54

Risk of Bias

+ Low risk of bias ? Unclear (not enough data provided) − High risk of bias

Random Sequence Generation The four studies had a low risk of bias due to randomisation (Figures 2 and 3).51–54

Allocation Concealment Figure 3: Percentage Risk of Bias in Each Domain of the Risk of Bias Assessment of the Studies Included in the Review

None of the studies provided adequate information to assign bias as low or high, consequentially the risk of bias remains unclear.51–54

Blinding Random sequence generation (selection bias)

All studies had a high risk of bias by blinding due to the nature of the study, as blinding was not possible.51–54

Allocation concealment (selection bias) Blinding of participants and personnel (detection bias) Blinding of outcome assessment (detection bias)

Incomplete Outcome Data

Incomplete outcome data (attrition bias) Information bias 0% Low risk of bias

25%

Unclear risk of bias

50%

75% 100%

High risk of bias

All studies included had a low risk of incomplete outcome data, as all results were reported for outcomes identified at the start of the review.51–54

Information Bias division of participants into control or statin therapy groups had been conducted randomly. However, a detailed account of randomisation was not required, as long as the patient characteristics of both groups were included and did not differ significantly (p>0.05).

Synthesis of Results Standardised mean difference (SMD) was used as a summary measure due to the nature of the outcomes. As the data type is continuous, the statistical method to pool the results will be inverse variance.

Assessment of Homogeneity Chi-squared and I-squared were calculated using Review Manager 5.3. Heterogeneity was interpreted according to guidelines by the Cochrane Handbook 5.1.0. A random effects model was used, as the I-squared was significant (>50%). Due to the significant heterogeneity, a subgroup analysis was performed by the type of statin. A metaregression was also performed to see the dose-related effect.

Results

Two studies used the three known markers, CD4, CD25 and FOXP3, to identify Tregs.51,52 Therefore, they had a low risk of bias. In contrast, Hu et al. and Xie et al. only used two markers each – CD4 and CD25, and CD4 and FOXP3, respectively.53,54 Both Hu et al. and Xie et al. used fewer surface markers to identify Tregs, which increased the chance of an impure yield. Further details of the rationale of bias assessment are found in Supplementary Material Appendix 3.

Synthesis of Results There was an increase in the mean frequency of Treg percentage in patients who received statins in all four studies (Table 2). Each study reported a p<0.01 for Treg frequency. Meta-analysis for Treg frequency demonstrated significantly higher values in patients treated with statins (SMD 1.93; 95% CI [1.16–2.71]; p<0.00001; Figure 4).

Heterogeneity of Results The heterogeneity of effect sizes resulted in a I-squared value of 91%. These results signify that the effect sizes are heterogeneous with very high inconsistency in the data.

Study Selection Search Results

Subgroup Analysis

The search results retrieved 192 articles. Four additional records were identified through bibliographies. After duplicates were removed, 187 articles remained. Ten full-text articles were reviewed for inclusion,

A subgroup analysis of studies that only used atorvastatin is shown in Figure 5. This was carried out by removing the study by Xie et al., which used rosuvastatin. The meta-analysis still indicated a

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Effect of Statins on Regulatory T-cells in Acute Coronary Syndrome Table 2: Summary Data of Each Study Included in the Review Study

Statin therapy

Control

Sample size

Mean (%) ± SD [95% CI] of Treg

Sample size

Mean (%) ± SD [95% CI] of Treg

quantity post-intervention

Xie at al. 201454

9.65 ± 2.10 [9.18–10.11]

4.97 ± 0.87 [4.77–5.16]

Hu et al. 200753

6.47 ± 1.75 [5.76–7.17]

3.26 ± 1.71 [2.57–3.94]

6.47 ± 1.75 [6.02–6.91]

3.26 ± 1.71 [2.82–3.69]

7.64 ± 3.16 [6.78–8.49]

4.56 ± 2.05 [2.4–5.07]

Wang et al. 2015

Zhang et al. 201151 Treg = regulatory T-cell.

Figure 4: Forest Plot Showing the Standardised Mean Difference of Regulatory T-cells Frequency in the Control and Statin Groups

Study or subgroup Hu et al. 200753 Wang et al. 201552 Xie et al. 201454 Zhang et al. 201151

Mean

Statins Control SD Total Mean SD Total

6.47 6.47 9.65 7.64

1.75 1.75 2.1 3.16

Total (95% CI)

24 60 79 52

3.26 3.26 4.97 4.56

1.71 1.71 0.87 2.05

215

Weight

24 60 80 60

22.9% 25.7% 25.5% 25.9%

224

100.0%

Std Mean Difference IV, Random, 95% CI 1.82 1.84 2.90 1.17

Std Mean Difference IV, Random, 95% CI

[1.14–2.51] [1.41–2.27] [2.46–3.35] [0.76–1.57]

1.93 [1.16,2.71]

Heterogeneity: tau2 = 0.56; chi2 = 32.15; d.f. = 3 (p<0.00001); I2 = 91% Test for overall effect: Z = 4.89 (p<0.00001)

−4

−2

Control Statins

Figure 5: Forest Plot Showing the Standardised Mean Difference of Regulatory T-cells Frequency in the Control and Atorvastatin Groups, While Excluding Xie et al., Which Used Rosuvastatin

Study or subgroup Hu et al. 200753 Wang et al. 201552 Zhang et al. 201151

Mean

Statins SD

6.47 6.47 7.64

Total (95% CI)

1.75 1.75 3.16

Total Mean 24 60 52 136

3.26 3.26 4.56

Control SD Total

Weight

Std Mean Difference IV, Random, 95% CI

24 60 60

25.5% 36.6% 37.9%

1.82 [1.14, 2.51] 1.84 [1.41, 2.27] 1.17 [0.76, 1.57]

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100.0%

1.58 [1.10, 2.07]

1.71 1.71 2.05

Heterogeneity: tau2 = 0.12; chi2 = 5.91; d.f. = 2 (p=0.05); I2 = 66% Test for overall effect: Z = 6.39 (p<0.00001)

Meta-regression To further explore the high heterogeneity values, dosage-related effect was explored through a meta-regression (Figure 6). The metaregression including all the studies resulted in an R2 value of 0.15 and correlation coefficient of −0.39. The graph showed a dose-related effect; however, there was an outlier – the study by Xie et al. – which used 40 mg of rosuvastatin.54

−4

−2

Control Statins

Figure 6: Meta-regression Evaluating the Dose-related Effect of Atorvastatin on Regulatory T-cells Frequency 3.5 y = –0.0092x + 2.2939 R2 = 0.15451

3 Effect Size (D)

significant increase in Treg frequency compared with the control group (SMD 1.58; 95% CI [1.10–2.07]; p<0.00001). However, pooled results showed a lower SMD than that of all the studies combined. Although this subgroup analysis showed a further decrease in heterogeneity (I-squared from 91% to 66%), it still remained significant.

Std Mean Difference IV, Random, 95% CI

2.5 2 1.5 1 0.5 0 0

Dose (mg)

A meta-regression of the other three studies that used atorvastatin was conducted. It resulted in an R2 value of 0.98 (Figure 7) and correlation coefficient of −0.99. These values are very close to 1, suggesting a strong negative relationship.

Discussion The results of the present review highlighted that statins significantly increase the frequency of Tregs. However, there is a considerable

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amount of heterogeneity in the pooled results, which was explored in terms of the statin type and dosage used. In terms of statin type, three of the studies used atorvastatin in the experimental group, and only Xie et al. used rosuvastatin.54 By removing Xie et al., the heterogeneity decreased, indicating that the effect on the frequency of Tregs varies according to the statin type. The dose-related effect was evaluated by conducting a meta-regression. It was found that there is a negative

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Cardiovascular Pharmacotherapy Figure 7: Meta-regression Evaluating the Dose-related Effect of Atorvastatin on Regulatory T-cells Frequency

impaired Tregs functioning.58 A RCT showed that atorvastatin treatment increases the amount of Tregs in the PBMC of rheumatoid arthritis patients and reduces disease activity.59

2 y = −0.0103x + 2.006 R2 = 0.98256

1.8

Effect Size (D)

1.6

This trend was also seen in people with asthma, for whom statin therapy improved symptom control, and in vitro studies with the incubation of statins and CD4+ T-cells revealing expansion of Tregs.60,61 The effect of statins in upregulating of Tregs and reducing disease burden was also seen in animal models of autoimmune neuritis, experimental autoimmune myasthenia gravis (Li et al.), ischaemia-reperfusion injury and apolipoprotein E (ApoE)−/− model of atherosclerosis.62–65

1.4 1.2 1 0.8 0.6 0.4 0.2 0 0

Dose (mg)

correlation with dose and the frequency of Tregs. However, there were very few studies that used the same statin type and dose, limiting the amount of data available for statistical aggregation. The studies included in the review have a high risk of information. In terms of information bias, the studies by Hu et al. and Xie et al. have a high risk because these did not use all the Tregs markers used to identify Treg cells, which may alter the results.53,54 However, even the studies that used all three or at least two of the classic markers (CD4, FOXP3 and CD25) may also have a risk of bias. This is because conventional CD4+ T-cells express FOXP3 transiently when activated and express CD25 upon stimulation.55–57 ACS patients are known to have heightened CTL, which correlates with the extent of the disease. Therefore, using biomarkers that may detect CTL in such patients could further increase the impurity of the results. However, due to the lack of studies, subgroup analysis could not be performed to measure whether the effect of statins on Tregs correlated with the different patterns of Treg markers used. Future studies need to use a more accurate method in identifying Tregs to produce more reliable results. The use of the FOXP3 locus (Treg-specific demethylated region) is recommended as a specific marker of Tregs rather than the sole use of fluorescence-activated cell sorting.26

However, Hasib et al. demonstrated that patients with ACS had a low baseline frequency of Tregs, and despite 12 months of extensive statin use after an acute event, Treg frequency remained significantly unchanged, which contradicts our findings.66 Although that was an observational study, it did not provide any strong support to the theory that statins exert a pronounced effect on Treg levels in a clinical scenario. Finally, in terms of mechanism, Maussner-Fainberg et al. highlighted the ability of statins to induce FOXP3+ expression from peripheral CD4+CD25−FOXP3−.67 This expression may be induced by inhibition of HMG-CoA reductase, which suppresses intermediates in the mevalonate pathway leading to prenylation of GTPases, such as Ras, Rac, Rho and Cdc42.11–13 These small G proteins are postulated to be the reason for the induction of foxp3+ Tregs.67

Conclusion ACS patients have been shown to clinically benefit from the anti-inflammatory effects of statin therapy through different pharmacological mechanisms. The current literature indicates a significant difference in Treg frequency following statin therapy in ACS patients. It is hypothesised that this is due to the stabilisation of the plaque by decreasing pro-inflammatory mediators involved in plaque destabilisation. It is proposed that future RCTs use accurate methods to identify Tregs and study the dose-related effects.

The present review is only applicable to the Asian population, as all studies were conducted in Asia. Moreover, it can only be applied to countries where the use of rosuvastatin and atorvastatin is approved.

Overall, these results have considerable implications for patients who would benefit from restoring the Treg-induced immunomodulatory balance, with a view to exploring new therapeutic approaches to the management of disease progression in ACS.

Despite the limitations highlighted by the review, the potential of statins in inducing the frequency of Tregs has been shown by different studies with a plausible mechanistic effect. A similar benefit induced by statins was shown in rheumatoid arthritis, which is also characterised by

Despite the limited data available and heterogeneity, the present review highlights areas for improvement, such as using more specific universal markers for Tregs, such as the Treg-specific demethylated region, and determining the statin type and dose-related effect.

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33. T aams LS, van Amelsfort JM, Tiemessen MM, et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 2005;66:222–30. https://doi. org/10.1016/j.humimm.2004.12.006; PMID: 15784460. 34. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyteassociated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000;192:295–302. https://doi. org/10.1084/jem.192.2.295; PMID: 10899916. 35. Oderup C, Cederbom L, Makowska A, et al. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 2006;118:240–9. https://doi.org/10.1111/j.13652567.2006.02362.x; PMID: 16771859. 36. Fallarino F, Grohmann U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206–12.https://doi.org/10.1038/ni1003; PMID: 14578884. 37. Grossman WJ, Verbsky JW, Tollefsen BL, et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 2004;104:2840–8. https://doi.org/10.1182/blood-2004-03-0859; PMID: 15238416. 38. Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007;8:1353– 62. https://doi.org/10.1038/ni1536; PMID: 17982458. 39. Jonasson L, Holm J, Skalli O, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986;6:131–8. https:// doi.org/10.1161/01.ATV.6.2.131; PMID: 2937395. 40. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb 1991;11:1223–30. https://doi.org/10.1161/01. ATV.11.5.1223; PMID: 1911708. 41. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36–44. https://doi.org/10.1161/01. CIR.89.1.36; PMID: 8281670. 42. Zal B, Kaski JC, Akiyu JP, et al. Differential pathways govern CD4+ CD28- T cell proinflammatory and effector responses in patients with coronary artery disease. J Immunol 2008;181:5233–41. https://doi.org/10.4049/ jimmunol.181.8.5233; PMID: 18832677. 43. Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999;100:2135–9. https://doi.org/10.1161/01.CIR.100.21.2135; PMID: 10571971. 44. Huang WC, Sala-Newby GB, Susana A, et al. Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-kappaB. PLoS One 2012;7:e42507. https:// doi.org/10.1371/journal.pone.0042507; PMID: 22880008. 45. Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000;101:2883–8. https://doi. org/10.1161/01.CIR.101.25.2883; PMID: 10869258. 46. Mor A, Luboshits G, Planer D, et al. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 2006;27:2530–7. https://doi. org/10.1093/eurheartj/ehl222; PMID: 16954132. 47. Han SF, Liu P, Zhang W, et al. The opposite-direction modulation of CD4+CD25+ Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 2007;124:90–7. https://doi. org/10.1016/j.clim.2007.03.546; PMID: 17512253. 48. Wigren M, Bjorkbacka H, Andersson L, et al. Low levels of circulating CD4+FoxP3+ T cells are associated with an increased risk for development of myocardial infarction but not for stroke. Arterioscler Thromb Vasc Biol 2012;32:2000–4. https://doi.org/10.1161/ATVBAHA.112.251579; PMID: 22628434. 49. Zhang WC, Wang J, Shu YW, et al. Impaired thymic export and increased apoptosis account for regulatory T cell defects in patients with non-st segment elevation acute coronary syndrome. J Biol Chem 2012;287:34157–66. https://doi. org/10.1074/jbc.M112.382978; PMID: 22872639. 50. Flego D, Severino A, Trotta F, et al. Increased PTPN22 expression and defective CREB activation impair regulatory

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Cardiology Masters

Featuring: Eugene Braunwald

In the Cardiology Masters section of European Cardiology Review, we bring you an insight into the career of a key contributor to the field of cardiology. In this issue, we feature Professor Eugene Braunwald, cardiovascular medicine specialist at Brigham and Women’s Hospital and distinguished Hersey Professor of Medicine at Harvard University, Boston, Massachusetts, US. DOI: https://doi.org/10.15420/ecr.2019.14.2.CM1

Eugene Braunwald is a cardiovascular specialist at Brigham and Women’s Hospital. He studied cardiology at the New York University School of Medicine before completing an internal medicine residency at the Johns Hopkins Hospital and a cardiology residency at Mount Sinai Hospital. He went on to complete cardiology fellowships at Columbia University College of Physicians and Surgeons and the National Heart institute. As the founding chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Prof Braunwald and his colleagues have provided significant insight in to the treatment of patients suffering from acute MI and unstable angina. Prof Braunwald has been listed as the most frequently cited author in cardiology by Science Watch. He has served as an editor of Harrison’s Principles of Internal Medicine for 12 editions and is the founding editor of Braunwald’s Heart Disease, now in its 11th edition, as well as two other prominent cardiovascular textbooks.

was eight and a half years old when the lights of my childhood went out. It was 1938 and my family and I lived in what had been, until then, a pleasant area in the first District of Vienna near the Danube Canal. I went to a special school, took piano and English lessons and had good friends. My mother often took my younger brother and me on walks around the canal. We watched the boats and other activities on the water and had picnics in the park. My father ran a successful wholesale clothing business and he and my mother were devoted opera fans. They began taking me to Vienna State Opera when I was 6 years old, sparking a love of music that I carry with me to this day. It was a wonderful life. I was too young to understand what was happening just across the border in Germany.

Sudden Darkness My memories of how that period ended – on 12 March 1938, with the Anschluss, of Austria – are vivid. The Nazis marched in and, insofar as the Jews were concerned, accomplished in 5 days what had taken 5 years in Germany. The park benches we had sat on were – overnight it seemed – painted with large yellow letters that said, “Jews must not sit here”. I saw elderly Jews, with armed policemen standing over them, being forced to clean the pavements in front of their homes with their toothbrushes. Aware of the growing danger, my parents took me out of school.

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Access at: www.ECRjournal.com

My younger brother Jack and I were largely confined to our home, frustrated and bewildered by this dark change in our lives. A couple of months later, the Nazis came for my father in the middle of the night and my mother woke us up to say goodbye to him. “He’s going away,” she wept. My father, deathly pale, could barely speak. He packed up some belongings and hugged us for what he imagined could be the last time. However, it was not – thanks to my brilliant and quick-thinking mother. The next day, the SS officer who had been liquidating my father’s business (and taking the proceeds) arrived and asked, “Where is the Jew?” My mother, still weeping, explained that he had been taken away, but added, “You still need him! You’ve only liquidated half of the business.” It was true. The SS officer got on the phone and a series of arguments ensued. It seemed the train carrying my father had not left the station. He was brought back to our home. He had been away for less than 10 hours. It was miraculous. However, my parents knew it was only a matter of time before he would be sent to a concentration camp. We had to get out.

Anxious Escape On a Saturday morning in late July 1938, my mother came into our bedroom and said: “Boys, you have to get dressed quickly. We’re

Cardiology Masters: Eugene Braunwald going on a picnic.” That struck me as odd, but when I began to ask questions, she cut me off quickly. “Just do it,” she said. She had a basket of food and the four of us boarded a trolley, then a taxi that took us to the train station. From there we took a train to the Swiss border and, as I recall, were met by a man who – for a significant price, I would guess – saw to it that we got across. It was terribly frightening. At that age, you want to believe your parents are in control, but it was clear to me that they were afraid and certainly not in control of our lives. From Switzerland, we took a train to Paris, then another to Calais. Finally, we ferried across the English Channel and reached London. The whole ordeal lasted about 48 hours.

Figure 1: Dr Braunwald in the 1960s with ECG Tracing

A Year of Stability We arrived in London with the clothes we had on and virtually nothing else. We were met there by representatives of the Jewish Relief Agency, who set us up in a two-room apartment in a low-rent part of the city. Within days, my parents had jobs wrapping packages in the basement of Selfridges department store. I had learned English from my tutor in Vienna, so I was the only one in the family who spoke the language. This meant I was entrusted to negotiate the buying of milk and bread in the grocery shop. However, my parents immediately began taking English lessons and caught up quickly. Our family life was relatively stable again for about a year. Then, in September 1939, World War II began. My brother and I were among the hundreds of thousands of children who were evacuated from London. We were each given a basket with a gas mask and a chocolate bar and then removed to the comparative safety of the English countryside. Jack and I were housed with a family of farmers, the Whites, in a village near Northampton. The accommodation was modest – there was no indoor plumbing – but the family welcomed us and treated us kindly. We were refugees and the UK saved our lives. However, a bureaucratic quirk soon forced us to move again. After a few months, I received a telegram from my father with explicit instructions. I was to buy third-class tickets for my brother and myself and catch a train from Northampton to London, leaving on a specific day and time. My father would meet our train in London and, several days later, we would begin our journey to the US. The reason for this was that Austria had been annexed by Germany, not conquered. As such, we were technically now German citizens, and enemy aliens in the UK. My father was to be placed in an internment camp; not a concentration camp, but a camp surrounded by a barbed wire fence, nonetheless. My parents had arranged with distant relatives of my mother in New York that they would serve as our US sponsors, guaranteeing that we would never become wards of the state. We boarded the President Harding passenger ship and crossed the Atlantic; a trip that would soon be far more treacherous because of the proliferation of German U-boats. Our new home was in Brooklyn.

Source: US National Library of Medicine, National Institutes of Health.

element was lacking. This realisation led me into medicine. I remained interested in pumps and electromagnets. In medicine, you cannot get any closer to engineering than cardiology. From there, I went on to New York University (NYU), where I met my future first wife, Nina Starr, who would become a renowned cardiothoracic surgeon. Together, we went through college and then NYU School of Medicine. We married in June 1952, between graduation and internship.

Better Luck As challenging as my childhood was, I have been extremely lucky since then. From the day I was accepted to medical school – 1 May 1948, almost exactly 10 years after that dark day in Vienna – I have somehow always managed to be in the right place at the right time, with the right people, in the right institution. By the 1960s I was active in research and clinical work, and my family and I moved several times (Figure 1). We started in New York, then spent 13 years in Bethesda, Maryland, where I was the Chief of Cardiology and Clinical Director of the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH). Through Nina, I met the man who was probably my greatest mentor, her boss, Dr Andrew Glenn Morrow.

Aspiring Engineer Our traumas finally behind us, I finished grammar school in Brooklyn and attended Brooklyn Technical High School, an elite high school. The war was nearly over and I was planning to go into engineering, which was the most popular profession of the day. However, after a couple of years, my interest in engineering began to wane; I felt that the human

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Next came 4 years at the University of California (UC), San Diego (1968– 72), where I was the founding Chair of the Department of Medicine. In 1972 I went to Boston as Chair of Medicine at the Brigham and Women’s Hospital and Harvard Medical School (Figure 2). My family and I have lived in Weston, a Boston suburb, since then.

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Cardiology Masters Figure 2: Dr Braunwald in the Early 1970s

My minor achievements fall into three related categories – hypertrophic cardiomyopathy, heart failure and cholesterol.

Hypertrophic Cardiomyopathy The first of my minor achievements is the understanding and treatment of hypertrophic cardiomyopathy. Glenn Morrow and I recognised this as a unique clinical entity in 1959. We came to understand that it is often an inherited condition. It can be benign, but it can also cause ventricular arrhythmias and sudden cardiac death in young people, especially those engaged in vigorous sports. This is why high school and college students should undergo a cardiac examination before going out for football and other physically demanding activities. We showed how beta-blockers can help these patients and Morrow developed a successful operation, ventricular myectomy, which is known as the Morrow procedure. Both of these treatments are still widely used.

Heart Failure My next achievement is in the area of heart failure, a condition I consider to be the price we pay for success. We now know how to treat patients with acute MI and valvular or congenital heart diseases,

Achievements

but typically we cannot cure these conditions. Instead, we prolong patients’ lives, often for as long as 20 or 30 years. However, eventually, their hearts may fail. In fact, heart failure is now the most common diagnosis in hospitalised patients on Medicare.

My name appears on about 1,700 publications in cardiovascular and general medical journals, but this is not something I am particularly proud of. It is not the quantity that counts, it is the quality. When I think about my research, I divide it into one major and three minor achievements.

In 1962, when I was at the NIH, we first described a technique that measures how well the ventricles are pumping blood with each beat. This measurement is known as the ejection fraction and it is now used on most patients suspected of having heart failure.

Time is Muscle My major achievement can be summed up in the phrase ‘time is muscle’. It started with a eureka moment at the NIH. It had long been assumed that MI results from a blood clot in a coronary artery, which suddenly causes necrosis of the muscle perfused by this artery, akin to turning off a light switch. However, something I observed led me to challenge that assumption. I saw the ECG of a patient with acute myocardial infarction showing changes that seemed to be associated with changes in blood pressure, which occurred over the course of several hours. I suspected there might be interventions that could be carried out in patients experiencing MI. The development of an infarction was comparable to a rheostat that could be turned up or down slowly, as opposed to a binary light switch. When I got to UC San Diego, my colleagues and I began experiments in anaesthetised dogs that proved the size of – and damage done by – MI could be reduced after the initial obstruction. We showed that early reperfusion was key and the longer the heart is ischaemic, the more heart muscle dies. These experiments were performed before coronary angioplasty had been developed but, once this new technique was popularised, the concept of infarct size limitation was applied successfully to many patients.

Years later in the late 1970s at Harvard and the Brigham, my colleague Marc Pfeffer and I showed that an angiotensin-converting enzyme inhibitor prolonged life in patients whose ejection fraction had fallen after a myocardial infarction. I am still actively involved in heart failure and we continue to look at new medications. In fact, we have recently finished a trial that showed a new drug, sacubitril/valsartan, is safe and effective in patients hospitalised with acute, decompensated heart failure.

Cholesterol We now know that an elevated level of circulating LDL cholesterol is the most important risk factor for the development of atherosclerosis. My colleagues and I have carried out a series of clinical trials showing that the lower the circulating level of LDL cholesterol, the lower the risk of MI or stroke. Initially, experts were aiming for LDL cholesterol levels below about 3.11 mmol/l. This was later reduced to 2.33 mmol/l. However, we have now shown there may be beneficial effects under 1.30 mmol/l; a concentration once considered to be outrageously low. My colleagues in TIMI have evidence that you can lower LDL cholesterol to <0.52 mmol/l without any apparent ill effects.

Textbook Editing In 1984, I founded the Thrombolysis In Myocardial Infarction (TIMI) Study Group, an academic research organisation at the Brigham. We have run more than 60 clinical trials and have branched out from the original mission to include heart failure and the influence of diabetes on the heart.

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Another of my most gratifying activities has been my work as an editor of two textbooks. The first is on internal medicine (Harrison’s Principles of Internal Medicine). I have had the opportunity to serve as an editor of 12 editions and an editor-in-chief of two of them. In 1980, I decided to edit a textbook of cardiology (Braunwald’s Heart

EUROPEAN CARDIOLOGY REVIEW

Cardiology Masters: Eugene Braunwald Disease), which has completed 11 editions. Both of these books remain popular among trainees worldwide.

Ringside Seat

My days are full. I usually get up at around 7 am, work at home for a while, drive to the hospital and meet with trainees and cardiology fellows to go over their work. I spend a lot of time writing and editing and I attend clinical conferences at the Brigham regularly.

It has been more than 80 years since that dark day in Vienna when everything changed. Nina died in 1992, but my three daughters (Karen, a clinical psychologist; Allison, a physician; and Jill, a lawyer), bring me joy, as do my seven grandchildren and two great-grandchildren. My second wife, Elaine, was a hospital executive. She is supportive and a great companion.

My interest in cardiology began 68 years ago student. I have been privileged to have a enormous life-prolonging advances in this progress represents a great triumph, there is in the field.

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when I was a medical ringside seat to the speciality. While this still much to be done

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Articles inside

Foreword