ECR 13.2

European Cardiology Review Volume 13 • Issue 2 • Winter 2018

Volume 13 • Issue 2 • Winter 2018

www.ECRjournal.com

Anticoagulation in Patients with Ischaemic Heart Disease and Peripheral Arterial Disease: Clinical Implications of COMPASS study Josep Gradolí, Verónica Vidal, Adrian JB Brady and Lorenzo Facila

Using Pharmacogenetic Testing or Platelet Reactivity Testing to Tailor Antiplatelet Therapy: Are Asians different from Caucasians?

Doreen Tan Su-Yin

Obesity and Weight Loss C Richard Conti

Trimetazidine and Other Metabolic Modifiers Giacinta Guarini, Alda Huqi, Doralisa Morrone, Paola Francesca Giuseppina Capozza and Mario Marzilli

ISSN: 1758-3756

Erectile Dysfunction and IHD

Sub-epicardial Fibrosis of the Left Ventricle Due to Lupus Myocarditis

Inhibiting Thrombotic Formation

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Lugano

Meeting of the 24th Scientific International Society of

Cardiovascular Pharmacotherapy (ISCP) Palazzo dei Congressi, Lugano, Switzerland

May 9th–10th

2019

The educational and scientific programme covers a wide spectrum of cardiovascular pharmacotherapy and is addressed to cardiologists as well as general internists.

Accreditation Swiss Society of Cardiology: 14 credits

World epidemics – Joint session with ESC Working Group on Cardiovascular Pharmacotherapy

The Polypill: A simple, inexpensive approach to reduce mortality and morbidity worldwide

A changing paradigm in management of dyslipidaemia

Atrial fibrillation

Acute heart failure

Anti-inflammatory treatment

How low to go with glucose, cholesterol and blood pressure in primary prevention of CVD

Medical vs invasive treatment strategies in stable CAD

Diabetes and cardiovascular disease

Emerging indications for new oral anticoagulation in CAD For information about the scientific programme, abstract submission, registration, accommodation and travelling to Lugano, visit

Organized in collaboration with

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Chronic heart failure: a paradigm shift

The emerging role of PCSK9 inhibitors after Odyssee

Working Group on Cardiovascular Pharmacaotherapy (European Society of Cardiology)

Arterial hypertension

www.iscp2019.com Swiss Atherosclerosis www.agla.ch

13/12/2018 00:05

Volume 13 • Issue 2 • Winter 2018

www.ECRjournal.com Editor-in-Chief Juan Carlos Kaski

St George’s University of London, London, UK

Senior Associate Editors Richard Conti

Wolfgang Koenig

Giuseppe Mancia

Mario Marzilli

Hiroaki Shimokawa

University of Florida, Gainesville, USA

Technical University of Munich, Munich, Germany

University of Milano-Bicocca, Milan, Italy

University of Pisa, Pisa, Italy

Tohoku University, Sendai, Japan

Pablo Avanzas

Michael Fisher

Alberto Lorenzatti

Giuseppe Rosano

University Hospital of Oviedo, Oviedo, Spain

Royal Liverpool University Hospital, Liverpool, UK

Hospital Córdoba, Córdoba, Argentina

IRCCS San Raffaele, Rome, Italy

Augusto Gallino

Angela Maas

Magdi Saba

Radboud University Medical Center, Nijmegen, the Netherlands

St George’s University of London, London, UK

Aneil Malhotra

Gianluigi Savarese Karolinska Institute, Stockholm, Sweden

Roxy Senior Imperial College, London, UK

Debasish Banerjee St George’s University of London, London, UK

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Vinayak Bapat Columbia University Medical Centre, New York, USA

Robert Gerber Conquest Hospital, Hastings, UK

St George’s University of London, London, UK

Velislav Batchvarov

Bernard Gersh

Olivia Manfrini

St George’s University of London, London, UK

Mayo Clinic, Minnesota, USA

University of Bologna, Bologna, Italy

Antoni Bayés-Genís

David Goldsmith

Felipe Martinez

St George’s University of London, London, UK

National University of Cordoba, Cordoba, Argentina

Tommaso Gori

Antoni Martínez-Rubio

University of Adelaide, Adelaide, Australia

Johannes Gutenberg University Mainz, Mainz, Germany

University Hospital of Sabadell, Sabadell, Spain

Christopher Cannon

Kim Greaves

Noel Bairey Merz

Italian National Research Council, Italy

Harvard Medical School, Boston, USA

Sunshine Coast University Hospital, Sunshine Coast, Australia

Cedars-Sinai Heart Institute, Los Angeles, USA

Iana Simova

Imperial College, London, UK

Eileen Handberg

Argyrios Ntalias University of Athens, Athens, Greece

National Cardiology Hospital, Sofia, Bulgaria

Alberto Cuocolo

University of Florida, Florida, USA

Denis Pellerin

Juan Tamargo

Hospital Germans Trias i Pujol, Barcelona, Spain

John Beltrame

Peter Collins

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

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

Rosa Sicari

St Bartholomew’s Hospital, London, UK

University Complutense, Madrid, Spain

Danderyd University Hospital, Danderyd, Sweden

Carl Pepine

Konstantinos Toutouzas University of Athens, Athens, Greece

Colentina University Hospital, Bucharest, Romania

Koichi Kaikita

University of Florida, Florida, USAA

Piotr Ponikowski

Isabella Tritto University of Perugia, Perugia, Italy

Ranil de Silva

Mike G Kirby

Wroclaw Medical University, Wroclaw, Poland

Imperial College, London, UK

University of Hertfordshire, Hatfield, UK; The Prostate Centre, London, UK

Dimitrios Tziakas

Eva Prescott

Democritus University of Thrace, Xanthi, Greece

University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan

Polychronis Dilaveris Hippokration General Hospital, Athens, Greece

Carlo Di Mario

Thomas Kahan

Kumamoto University, Kumamoto, Japan

Bispebjerg Hospital, Copenhagen, Denmark

Rao Kondapally St George’s University of London, London, UK

Careggi University Hospital, Florence, Italy

Patrizio Lancellotti

Perry Elliott

Amir Lerman

University College, London, UK

Mayo Clinic, Minnesota, USA

Albert Ferro

José Luis López-Sendón

King’s College London, London, UK

La Paz Hospital, Madrid, Spain

Axel Pries Charité Universitätsmedizin Berlin, Germany

University of Liège, Liège, Belgium

Managing Editor Jonathan McKenna

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Production Aashni Shah

Hari Raju

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Mauricio Wajngarten University of São Paulo, Brazil

Hiroshi Watanabe Hamamatsu University School of Medicine, Hamamatsu, Japan

Macquarie University, Sydney, Australia

Matthew Wright

Robin Ray

St Thomas’ Hospital, London, UK

St George’s University of London, London, UK

Hospital Ramon Y Cajal, Madrid, Spain

Senior Designer Tatiana Losinska

Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing Director Leiah Norcott • Commercial Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O’Neill

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In partnership with

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Editorial Contact jonathan.mckenna@radcliffe-group.com Circulation & Commercial Contact david.ramsey@radcliffe-group.com

Cardiology

Lifelong Learning for Cardiovascular Professionals Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use 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 © 2018 All rights reserved ISSN: 1758–3756 • eISSN: 1758–3764 Cover image www.stock.adobe.com

© RADCLIFFE CARDIOLOGY 2018

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Established: April 2005 Frequency: Bi-annual Current issue: Winter 2018

Aims and Scope

Submissions and Instructions to Authors

• European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiology medicine and practice.

• European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• European Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the and invited by the Editor-in-Chief with support from the Associate Editors and Managing Editor, and guidance from the Editorial Board.

• Following acceptance of an invitation, the author(s) and Managing Editor, in conjuction with the Editor-in-Chief formalise the working title and scope of the article.

• Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details.

• The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details.

The ‘Instructions to Authors’ information is available for download at www.ECRjournal.com.

Structure and Format • European Cardiology Review is a bi-annual journal comprising review articles, editorials, and case reports.

• The structure and degree of coverage assigned to each category of the journal is determined by the Editor-in-Chief, with the support of the Associate Editors and the Editorial Board.

• Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion.

• Each edition of European Cardiology Review is replicated in full online at www.ECRjournal.com

Editorial Expertise uropean Cardiology Review is supported by various levels of expertise: E • Overall direction from an Editor-in-Chief, supported by Associate Editors and an Editorial Board comprising leading authorities from a variety of related disciplines.

• Invited contributors who are recognised authorities from their respective fields.

• Peer review – conducted by experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

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

• The Managing Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind.

• Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations.

Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

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

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

Abstracting and Indexing European Cardiology Review is abstracted, indexed and listed on PubMed, Embase, ESCI, Scopus and Google Scholar. All articles are published in full on PubMed Central one month after publication.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in European Cardiology Review unless otherwise stated.

Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

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

Cardiology

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ESC Congress Paris 2019 Together with

World Congress of Cardiology 31 August - 4 September

Spotlight Global Cardiovascular Health

Abstract submission: December - 14 February Clinical Case submission: Mid January - 1 March Late-Breaking Science submission: Mid March - 21 May Early registration deadline: 31 May Late registration deadline: 31 July

escardio.org/ESC2019

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13/12/2018 00:10 31/10/2018 15:10

Content Contents

Foreword

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Juan Carlos Kaski

Editorial

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Left Ventricular Ejection Fraction in Heart Failure Josep Lupón and Antoni Bayes-Genis

Expert Opinion

93

Obesity and Weight Loss C Richard Conti

Imaging

95

“Save the Last Dance” for Cardiovascular Magnetic Resonance Sophie I Mavrogeni, George Markousis-Mavrogenis and Genovefa Kolovou

Ischaemic Heart Disease: Comorbidity

98

Erectile Dysfunction and Ischaemic Heart Disease Abdalla Ibrahim, Mohamed Ali, Thomas J Kiernan and Austin G Stack

Pharmacotherapy

104

Trimetazidine and Other Metabolic Modifiers

112

Using Pharmacogenetic Testing or Platelet Reactivity Testing to Tailor Antiplatelet Therapy: Are Asians Different from Caucasians?

Giacinta Guarini, Alda Huqi, Doralisa Morrone, Paola Francesca Giuseppina Capozza and Mario Marzilli

Doreen Tan Su-Yin

115

Anticoagulation in Patients with Ischaemic Heart Disease and Peripheral Arterial Disease: Clinical Implications of COMPASS Study Josep Gradolí, Verónica Vidal, Adrian JB Brady and Lorenzo Facila

ISCP 2018 Best Posters

119

23rd Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy

120

ISCP 2018 Best Posters

Koji Hasegawa

Cardiology Masters

134

Dr Renu Virmani

Erratum

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Erratum to: The Inhibitory Effects of Crucumin Glucuronide on p300-HAT Activity and Hypertrophic Phenylephrine- Induced Responses in Cardiomyocytes Mai Genpei, Yoichi Sunagawa, Masafumi Funamoto, Kana Shimizu, Yusuke Miyazaki, Yasufumi Katanasaka, Nobuaki Takahashi, Hideaki Kakeya, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto

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16/12/2018 13:24

S AV E T H E D AT E

Please join us at the 40th Annual Heart Rhythm Scientific Sessions in San Francisco, CA May 8 - 11, 2019.

M P ONonmember R TA N T Registration D AT E S : January 8,I 2019 and Housing Opens Abstract Submission Site Closes December 7, 2018 February 1, 2019 Late-Breaking Clinical Trial Submission Site Opens Member Registration Opens December 18, 2018 March 8, 2019 Late-Breaking Clinical Trial Submission Site Closes Nonmember Registration Opens January 8, 2019 April 8, 2019 Deadline to Register to Receive Early Registration Discounts Late-Breaking Abstract February 1, 2019 Submission Site Opens April 30, 2019 Deadline to Join to Receive Member Registration Discounts Abstract May Late-Breaking 7, 2019 Registration at theMarch Moscone 8, 2019 Submission Site Closes Center in San Francisco Opens

LEARN MORE AT HRSsessions.org REGISTER TODAY! HRSsessions.org Untitled-2 1

16/12/2018 13:32

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 over 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 peer-reviewed journals, more than 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

T

his is a particularly exciting time for European Cardiology Review. It gives me great pleasure to announce that the journal is now indexed in PubMed. This outstanding achievement is the result of the extremely hard work of everyone involved in the journal in different capacities, in particular the publisher, Radcliffe Cardiology.

The current issue includes insightful contributions on heart failure (Lupón and Bayes-Genis), cardio-rheumatology (Mavrogeni et al.) and obesity (Conti) by international leaders in their fields.

Also, Ibrahim et al discuss the mechanisms and management of erectile dysfunction, an important condition linked to ischaemic heart disease (IHD) that affects an increasingly large proportion of individuals worldwide.

The Pharmacotherapy section of the journal is of utmost interest, featuring the pharmacogenomics of antiplatelet agents (Tan Su-Yin), whilst Guarini et al. address many novel therapeutic issues related to the use of metabolic modulators, and Facila Rubio et al. examine non-vitamin K antagonists for prevention of cardiovascular events in high-risk patients with documented IHD and those with peripheral artery disease.

Hasegawa edits a section that presents the best abstracts from the ISCP Annual Scientific Meeting 2018, which took place in Kyoto in May. Last but not least, the Cardiology Masters section in this issue portrays the professional life of one of the most outstanding female scientists of our time, cardiac pathologist Dr Renu Virmani.

I have truly enjoyed editing this issue and hope you too will enjoy its content. With the end-of-year festivities upon us, I would like to wish you all a peaceful and prosperous New Year. n

DOI: https://doi.org/10.15420/ecr.2018.13.2.FO

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Editorial

Left Ventricular Ejection Fraction in Heart Failure Josep Lupón 1 and Antoni Bayes-Genis 2 1. Heart Institute, Germans Trias i Pujol University Hospital, Badalona, Spain; 2. Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain.

Disclosures: Antonio Bayes-Genis was supported by grants from CIBER Cardiovascular (CB16/11/00403) and AdvanceCat 2014-2020. The authors have no other relevant conflicts of interest to declare.

Received: 15 October 2018 Accepted: 23 October 2018 Citation: European Cardiology Review 2018;13(2):91–2. DOI: https://doi.org/10.15420/ecr.2018.13.2.GE1 Correspondence: Antoni Bayes-Genis, Head of Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n 08916, Barcelona, Spain.

E: abayesgenis@gmail.com

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he left ventricular ejection fraction (LVEF) – calculated as the stroke volume (end-diastolic volume minus end-systolic volume) divided by the end-diastolic volume – remains the main driver for categorising heart failure (HF) and it is a cornerstone in all randomised clinical trials for patients with HF. Although LVEF has many acknowledged limitations, it remains key for the classification, stratification, management and surveillance of HF during followup because it is easy to obtain and non-invasive.1 LVEF is a pivotal measure for managing HF by HF specialists and general cardiologists, but beyond cardiologists, it is well known and understood by a majority of internists, general practitioners and geriatricians.1 Traditionally, patients with HF have been divided into those with reduced LVEF (HFrEF) and preserved LVEF (HFpEF). The HFrEF group tends to be younger and has a higher frequency of coronary artery disease (CAD) than the HFpEF group. Conversely, the HFpEF group tends to be older, female, and has a higher frequency of hypertension, obesity, diabetes, metabolic syndrome, AF, anaemia and chronic kidney disease.2 The 2016 European Society of Cardiology guidelines on HF officially adopted the term ‘HFmrEF’ to introduce a new HF phenotype (LVEF 40–49 %),2 which mostly represents an intermediate phenotype between HFrEF and HFpEF. In HFmrEF, CAD prevalence might be similar to that observed in HFrEF.3 However, recent research has emphasised the novel concept that, in many instances, HFmrEF may be a transition phenotype that appears in patients with HFrEF who are recovering or in patients with HFpEF who are declining (most likely less frequent in our series).4 It is well known that contemporary HF treatments may achieve an increase or even normalisation of LVEF in a substantial number of patients during the first years of the disease.5 However, we lack longterm longitudinal analyses of LVEF trajectories over time.

Recently, Lupón et al. elegantly showed the dynamic changes of LVEF over a 15-year follow-up.6 Here, we prospectively examined LVEF trajectories in 1,160 HF patients with LVEFs <50 % that arose from diverse aetiologies. We found that LVEF trajectory variations among HF cases depended on a number of disease modifiers including aetiology, HF duration, sex and baseline LVEF. However, globally, in HF, the LVEF significantly improves at one year, it then plateaus for up to

© RADCLIFFE CARDIOLOGY 2018

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a decade before slowly declining. This trajectory forms an inverted U-shape, with lower LVEF levels at both ends of the distribution.

These data supported the hypothesis that, in most patients, LVEF improvement represented a myocardial remission rather than a true myocardial recovery or a ‘myocardial cure’. In the longer-term, our data also indicated that neurohormonal blockade – a key mechanism of contemporary pharmacologic treatment for HF – might simply delay further progression of myocardial damage and deterioration. We also speculate that a neurohormonal blockade might rejuvenate the heart, at least temporarily; however, support for this hypothesis will require further investigation.

The mean age of patients at admission in this study was 64.9 ± 12.3 years; only 21 % were over the age of 75 years. At death, the mean age was 75.0 ± 10.0 years (median 77 years) and 25 % of patients died at ages >82 years. Remarkably, older patients (those ≥75 years at baseline) had at least the same degree of LVEF improvement during the first year and a subsequent similar trajectory up to 7 years (unpublished data). Except for a shorter follow-up found in older patients relative to younger patients (4.6 ± 2.6 versus 7.0 ± 4.1 years, respectively p<0.001), driven by a higher mortality rate among older patients (66.3 % versus 40.1 % respectively, p<0.001), no significant differences were found in LVEF trajectories (p=0.6). Baseline LVEF was 31.2 % ± 8.4 in older and 30.1 % ± 8.4 in younger patients (p=0.06), while at 7 years it was 44.0 % ± 12.5 and 42.4 % ± 12.3, respectively (p=0.53). This study also found that a declining LVEF in the preceding period was associated with higher mortality. Indeed, patients who died had lower final LVEFs and worse LVEF dynamics in the immediately preceding periods, compared with survivors.6 Whether ageing might impact the LVEF decline remains to be demonstrated.

Notwithstanding, mortality as a result of HF progression was similar (27.2 % of deaths) between patients older and those younger than 75 years at study entry.6 We must bear in mind that it has been postulated that HF is a disease of accelerated ageing and telomere shortening is an accepted surrogate biomarker of ageing. In a previous study, we found accelerated telomere length attrition in patients with HF (by ~22 % at one year), but we did not observe a relationship between telomere length and LVEF.7 Whether accelerated telomere attrition in HF might be partially linked to myocardial ageing and deterioration remains speculative and requires further investigation.

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Editorial 1.

2.

L upón J, Bayés-Genís A. Left ventricular ejection fraction in heart failure: a clinician’s perspective about a dynamic and imperfect parameter, though still convenient and a cornerstone for patient classification and management. Eur J Heart Fail 2018;20:433–5. https://doi.org/10.1002/ejhf.1116; PMID: 29251402.

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ ejhf.592; PMID: 27207191.

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3.

4.

5.

oh AS, Tay WT, Teng TH, et al. A comprehensive population‐ K based characterization of heart failure with mid‐range ejection fraction. Eur J Heart Fail 2017;19:1624–34. https://doi. org/10.1002/ejhf.945; PMID: 28948683.

Bayes-Genis A, Núñez J, Lupón J. Heart failure with mid‐range ejection fraction: a transition phenotype?

Eur J Heart Fail 2017;19:1635–7. https://doi.org/10.1002/ ejhf.977.

Lupón J, Díez-López C, de Antonio M, et al. Recovered heart failure with reduced ejection fraction and outcomes: a

6.

7.

prospective study. Eur J Heart Fail 2017;19:1615–23. https://doi. org/10.1002/ejhf.824; PMID: 28387002.

Lupón J, Gavidia-Bovadilla G, Ferrer E, et al. Dynamic trajectories of left ventricular ejection fraction in heart failure.

J Am Coll Cardiol 2018;72:591–601. https://doi.org/10.1016/j. jacc.2018.05.042; PMID: 30071987.

Teubel I, Elchinova E, Roura S, et al. Telomere attrition in heart failure: a flow-FISH longitudinal analysis of circulating monocytes. J Transl Med 2018;16:35. https://doi.org/10.1186/ s12967-018-1412-z; PMID: 29463269.

EUROPEAN CARDIOLOGY REVIEW

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Expert Opinion

Obesity and Weight Loss C Richard Conti Professor Emeritus of Medicine, Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA

Abstract The entire world is becoming overweight. Most people are motivated to try to lose weight for cosmetic reasons. Weight loss can decrease health risk factors and possibly improve prognosis. Weight loss can be difficult in people who are trying to stop smoking, as they tend to gain weight. Many weight loss systems are available and are not inexpensive. Athletes who are obese and fit must lose weight after retirement or suffer the consequences related to risk factors. Bariatric surgery seems to be the best way for morbidly obese patients to lose weight, assuming that they adhere to principles of risk factor modulation. Weight-loss medications work in most patients who also comply with lifestyle changes, but these drugs have a number of side-effects.

Keywords Obesity, weight loss, bariatric surgery, fatness and fitness, weight loss systems, risk factors Disclosure: The author has no conflicts of interest to declare.

Received: 21 October 2018 Accepted: 24 October 2018 Citation: European Cardiology Review 2018;13(2):93–4. DOI: https://doi.org/10.15420/ecr.2018.13.2.EO1 Correspondence: C Richard Conti, Division of Cardiovascular Medicine, University of Florida, PO Box 100277, Gainesville, FL 32610, USA. E: richard.conti@medicine.ufl.edu

T

here is no question that Americans are more obese than they were 50 years ago. However, this is also true of the entire world.1

Why Lose Weight?

Unfortunately, for most people, the main motivation for losing weight seems to be cosmetic. Everyone wants to look like a movie star. Most (but not all) individuals want a slimmer body. For the most part, the individual who wishes to lose weight is focused on weight loss over the next several months, not years, and seems more concerned about today than future prognosis. However, I will admit that some do care about the future.

on the diet recommendations (and these products, by the way, are not cheap). There is no question that these and many other weight loss systems can result in a loss of abdominal fat and, in the view of many, a more attractive appearance than before they started the programme. However, to reduce the unwanted consequences of obesity, a multimodal approach to weight loss is required (alter eating habits and exercise) to slow down development of risk factors and the progression of cardiovascular disease.

In my view, it is relatively easy to lose weight on any diet plan. The problem is keeping the weight from returning.

Smoking Cessation and Weight Weight loss advertisements indicate that people may improve their appearance and confidence if they stay slim. One needs only to turn on the TV to see ads featuring people who say they have lost weight and now look and feel better. In contrast, physicians’ concerns related to weight loss are to prevent or at least slow down major risk factors for adverse cardiac events, such as systemic hypertension, left ventricular hypertrophy, diabetes, dyslipidaemia, sleep-disordered breathing, diastolic dysfunction and others, and, by doing this, possibly decrease morbidity and mortality in the long term.

Cigarette smoking is a well-known risk factor for cardiovascular and other disease, but many ignore the advice of physicians to stop smoking because people who quit smoking tend to gain weight – 5 kg, on average. Therefore, it is difficult to convince a lifelong smoker who wants to lose weight to stop smoking. Smoking cessation is not easy, no matter the circumstances, and is especially difficult in someone who wishes to lose weight. It is important to point out to the patient that smoking cessation is a lifelong process, but they will achieve their goal of smoking cessation and weight loss if they persist with a prudent diet.

Food Products and Diet Plans There are many examples of food products and diet plans that claim weight loss benefits, including SlimFast, South Beach, Slimming World, and many other systems that work – so long as the person stays

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Fatness and Fitness The average weight of an offensive lineman in the US National Football League is 141.5 kg in a 195.5 cm person, while sumo wrestlers can

Access at: www.ECRjournal.com

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Expert Opinion weigh up to 270 kg, although they are generally about 150 kg. During their sporting careers, they have a BMI which indicates they are obese (the lineman would have a BMI of 37), but they must be fit to compete with others who are also heavy and fit. After they retire, they may not stay as fit, but do not reduce their weight, so are exposed to all of the cardiovascular risk factors of overweight people.

Bariatric Surgery Bariatric surgery is not for the person who wants to lose a few pounds, but needs to be considered as an option for many reasons for the morbidly obese patient. Many morbidly obese patients have cardiac disease and need risk factor modulation to improve prognosis, and weight loss will help with this in the long term.

I do not doubt that much of their weight is related to fluid retention, but many of these patients are obese as well as being in heart failure.

They often need to lose around 45–135 kg and there is no easy way to lose this amount of weight. Granted, it can be done with dietary management, but it is very difficult and most patients who try do not achieve the goal. However, in morbidly obese patients who are usually refractory to lifestyle modification including diet and exercise, lifestyle modification may work and must be tried.

I personally believe that bariatric surgery along with lifestyle modification may be an answer to some of these patients’ problems.

However, some bariatric surgeons insist that patients show evidence of attempted weight loss and be motivated to continue on a weight reduction programme both before and after bariatric surgery. For

1.

2.

3.

example, the UK’s NHS has a number of criteria which must be fulfilled before bariatric surgery is considered.2 Bariatric surgery may play a role in these particular patients, since these procedures produce marked weight loss as well as a reduction in risk factors such as hypertension, diastolic dysfunction, diabetes, dyslipidaemia and sleep-disordered breathing, which overall probably decrease cardiac morbidity and mortality.3

Weight-loss Drugs The US Food and Drug Administration has approved five drugs for weight loss and maintenance – orlistat, naltrexone/bupropion, liraglutide, lorcaserin and phentermine/topiramate. However, the European Medicines Agency has only given marketing authorisations to three of these – orlistat, liraglutide and naltrexone/bupropion.

Phentermine/topiramate was declined due to concerns about side-effects, including its possible long-term effects on the heart and blood vessels, while the manufacturer of lorcaserin withdrew the application as indications were that it would not receive a marketing authorisation, again due to side-effects (tumours, psychiatric disorders and valvulopathy). These medications have a number of other side-effects, including oily stools, nausea, diarrhoea, vomiting, depression, anxiety and cognitive effects.

Many patients using weight-loss drugs along with lifestyle modifications lose weight. However, the risk factors return if the weight is gained back. Patients should be advised to alter eating and exercise habits to maintain the weight loss.

L avie CJ, Laddu D, Arena R, et al. Healthy weight and obesity prevention: JACC Health Promotion Series. J Am Coll Cardiol 2018;72:1506–31. https://doi.org/10.1016/j.jacc.2018.08.1037; PMID: 30236314.

NHS. Overview: Weight-loss surgery. Available at: www.nhs.uk/conditions/weight-loss-surgery (accessed 13 November 2018).

Benraouane F, Litwin SE. Reductions in cardiovascular risk after bariatric surgery. Curr Opin Cardiol 2011;26:555–61. https://doi.org/10.1097/HCO.0b013e32834b7fc4; PMID: 21934498.

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Imaging

“Save the Last Dance” for Cardiovascular Magnetic Resonance Sophie I Mavrogeni, George Markousis-Mavrogenis and Genovefa Kolovou Onassis Cardiac Surgery Centre, Athens, Greece

Abstract Despite high mortality, cardiovascular disease (CVD) is underestimated in autoimmune rheumatic diseases (ARDs), due to its atypical presentation. The multi-faceted nature of CVD in ARDs created the need of a dedicated outpatient cardio-rheumatic clinic. Clinical examination, rest/exercise ECG, echocardiography, nuclear techniques and cardiac catheterisation were used as first-line diagnostic tools. Although the currently used non-invasive modalities perform well in cardiology, they are unable to diagnose the complex CVD pathophysiology of ARDs. The application of cardiovascular magnetic resonance (CMR) offers some significant advantages. CMR is versatile and can be used to perform functional, stress-rest perfusion, fibrosis and evaluation of great, peripheral and coronary vessels patency, without the use of ionising radiation, allowing early diagnosis of CVD and prompting modifications of anti-rheumatic and cardiac treatment.

Keywords Echocardiography, cardiovascular magnetic resonance, nuclear imaging, myocardial perfusion-fibrosis, coronary artery disease, vasculitis, rheumatic cardiovascular disease, spondyloarthropathy, myocarditis Disclosure: The authors have no conflicts of interest to declare.

Received: 14 September 2018 Accepted: 16 November 2018 Citation: European Cardiology Review 2018;13(2):95–7. DOI: https://doi.org/10.15420/ecr.2018.19.1 Correspondence: Sophie Mavrogeni, 50 Esperou Street, 175–61 P. Faliro, Athens, Greece. E: soma13@otenet.gr

Rheumatoid arthritis, the spondyloarthropathies, systemic lupus erythematosus, systemic vasculitides, inflammatory myopathies, systemic sclerosis and mixed connective tissue disease are autoimmune rheumatic diseases (ARDs) with high incidence of cardiovascular disease (CVD).1 CVD is usually underestimated in patients with rheumatic diseases, because the main focus of rheumatologists is the signs and symptoms of the systemic disease.

Although targeted treatment has significantly contributed to the decrease in disease-related mortality, life expectancy in people with ARDs remains lower compared to the general population, mainly due to increased cardiovascular involvement.2–7 CVD in ARDs is the result of various pathophysiologic mechanisms including systemic, myocardial, vascular inflammation, macro- and micro-vascular ischemia, abnormal coronary vaso-reactivity and diffuse or replacement myocardial fibrosis.8,9 Irrespective of pathophysiologic background, the symptoms of heart involvement in ARDs are subtle and usually underestimated because they are attributed to the underlying systemic disease. However, the development of clinically overt cardiac signs indicates advanced cardiac disease and carries a poor prognosis.10 The main pathophysiologic phenomena that need to be assessed as early as possible during the course of ARDs include myocardial and vascular inflammation; macro- and micro-vascular vasculopathy; small epicardial, intra-myocardial and/or sub-endocardial fibrosis, due to inflammation and/or MI (Figures 1–3); acuity of heart involvement; angiography of the great vessels; and assessment of the arterial wall inflammatory process.11–15 These cannot be assessed by the currently used imaging modalities. It should be considered that most ARD patients are female and may be unable to exercise, due to arthritis or

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muscular discomfort or weakness and therefore the assessment of myocardial ischemia may be problematic.

The Need for a Cardio-rheumatology Outpatient Clinic The multifaceted presentation of CVD in ARDs created the need for a specific outpatient cardio-rheumatic clinic. Our hospital was among the first in the world to create a dedicated clinic for early diagnosis, management and follow-up of CVD in ARDs. Our outpatient cardiorheumatic clinic works in close collaboration with hospitals that diagnose and treat ARD patients.

Clinical examination, rest ECG, exercise ECG, echocardiography, nuclear techniques and cardiac catheterisation, if needed, are used as diagnostic tools. The exercise electrocardiogram is commonly used first line for diagnosing myocardial ischaemia. It is widely available and inexpensive, but has low sensitivity in women and is not diagnostic in patients with rhythm disturbances.16 The current American Heart Association/American College of Cardiology guidelines recommend the exercise electrocardiogram as the first-line test for known or suspected coronary disease, but only when the patient is able to exercise. However, ARD patients with musculoskeletal impairment are unable to exercise. The exercise electrocardiogram is also less accurate than alternative stress imaging technologies.17 Transthoracic echocardiography (TTE) is currently the cornerstone of diagnosing CVD. Stress echocardiography combines TTE with a physical, pharmacological or electrical stress, inducing higher pulse rate. If coronary stenosis is present, ischaemia of the left ventricular wall may occur, resulting in a transient worsening of left ventricular wall contractility. Stress echocardiography may

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Imaging Figure 1: Sub-epicardial Fibrosis in the Inferior Wall of the Left Ventricle Due to Lupus Myocarditis

Figure 3: Diffuse Sub-endocardial Fibrosis with Normal Left Ventricular Ejection Fraction Due to Microvascular Disease in Systemic Sclerosis

Figure 2: Transmural MI of the Interventricular Septum and the Anterior Wall Due to Left Anterior Descending Artery Occlusion in Rheumatoid Arthritis assessment, all in one examination, without the use of ionising radiation.21 Furthermore, it can offer evaluation of the patency of the great, peripheral and coronary vessels. Recently, the use of mapping techniques and extracellular volume fraction has allowed the assessment of myocardial oedema and diffuse fibrosis in patients with renal impairment, which is commonly found in ARDs.21 The superiority of CMR in the diagnosis of CVD in ARDs against the other non-invasive imaging modalities is based on the assessment of: • m yocardial ischaemia and/or sub-endocardial/transmural replacement or diffuse fibrosis, due to either macro- or microvascular coronary artery disease;22–26 • disease acuity, due to macro- or micro-vascular coronary artery disease;22–27 • extent and disease acuity of myocardial/vascular inflammation;27,28 and • aetiology of silent/overt heart failure or rhythm disturbances.29,30 provide similar diagnostic and prognostic accuracy with radionuclide stress perfusion imaging, but at a substantially lower cost, without environmental pollution, and with no bio-effects for the patient and the physician. However, it has the limitation of being an operator and acoustic window dependent technique.

Stress myocardial perfusion scintigraphy (MPS) is a useful non-invasive imaging modality for diagnosing patients with suspected coronary artery disease.18,19 However, has serious limitations, including high radiation exposure, imaging artefacts and low spatial resolution that does not allow the detection of small areas of myocardial ischemia and scars.20 It became clear that all the above-mentioned modalities, although useful in cardiology, were unable to diagnose the multifaceted cardiac involvement in asymptomatic ARD patients.21 This discrepancy motivated the application of cardiovascular magnetic resonance (CMR). Compared with other non-invasive imaging modalities, CMR has the advantage of high spatial resolution capable of assessing slight tissue changes occurring during the course of ARDs. Additionally, CMR is versatile and can be used to perform functional, stress-rest perfusion, replacement and diffuse fibrosis

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The disadvantages of CMR are that it is contraindicated in patients with non-MRI compatible devices or metallic clips and in people with claustrophobia. However, all coronary artery stents, currently implanted valves and MRI-conditioned devices can be safely scanned. In patients with renal failure, the use of gadolinium is contraindicated, due to the risk of nephrogenic fibrosis. In these patients, we can apply non-contrast imaging protocols and perform both function and tissue characterisation evaluation. Additionally, CMR performs less well in patients with severe arrhythmia and who are unable to hold their breath.21

Role of CMR in the Evaluation of Anti-rheumatic and Cardiac Treatment There are only a few studies supporting a role for CMR in the evaluation of anti-rheumatic and cardiac treatment in ARDs. A previous study by our group documented that CMR can detect early silent cardiovascular (CV) lesions, assess disease acuity and successfully evaluate the effect of both cardiac and anti-rheumatic medication on the CV system.31 In another study, the CMR findings of 246 ARD patients with typical cardiac symptoms (n=146) or atypical cardiac symptoms (n=100)

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Cardiovascular Magnetic Resonance were retrospectively evaluated. CMR in symptomatic ARD patients with normal echocardiographic findings assessed disease acuity and identified vasculitis, myocarditis and MI that influenced the CV risk stratification of ARD patients.11 Furthermore, occult CMR lesions, including myocardial oedema, myocarditis, diffuse sub-endocardial fibrosis and MI, were not unusual in treating naïve ARDs and may be reversed with appropriate treatment.32 Additionally, stress CMR has successfully detected silent myocardial Raynaud phenomena in patients with ARDs and known peripheral Raynaud phenomena, and thus motivated the early start of relevant cardiac treatment.33 CMR offers the potential to identify ARD patients at high risk of ventricular tachycardia or VF, thus influencing both cardiac and anti-rheumatic treatment and possibly modifying the criteria for ICD implantation.34 Although the role of cardiac treatment is established for early morphologic or functional cardiac changes,35 clear guidelines for anti-rheumatic treatment are still missing.

According to our experience, a baseline study, including clinical, ECG and TTE evaluation, should be performed at diagnosis of ARDs and a CMR should then be recommended if:

1.

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4.

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6.

7.

8.

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13.

ohl D, Benseler S. Systemic inflammatory and autoimmune P disorders. Handb Clin Neurol 2013;112:1243–52. https://doi. org/10.1016/B978-0-444-52910-7.00047-7; PMID: 23622335.

Aviña-Zubieta JA, Choi HK, Sadatsafavi M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59:1690–7. https://doi.org/10.1002/art.24092; PMID: 1903541.

Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol 2006;2:99–106. https://doi.org/10.1038/ncprheum0092; PMID: 16932663.

Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann. Rheum Dis 2011;70:8–14. https://doi.org/10.1136/ard.2010.142133; PMID: 21109513.

Hollan I, Meroni PL, Ahearn JM, et al. Cardiovascular disease in autoimmune rheumatic diseases. Autoimmun Rev 2013;12:1004–15. https://doi.org/10.1016/j.autrev.2013.03.013; PMID: 23541482.

Björnådal L, Yin L, Granath F, et al. Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population based study 1964–95. J Rheumatol 2004;31:713–9. PMID: 15088296.

Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 2011;7:399–408. https://doi.org/10.1038/nrrheum.2011.75; PMID: 21629241.

Gasparyan AY. Cardiovascular risk and inflammation: pathophysiological mechanisms, drug design, and targets. Curr Pharm Des 2012;18:1447–9. https://doi. org/10.2174/138161212799504777; PMID: 22364139.

Dimitroulas T, Giannakoulas G, Karvounis H, et al. Micro- and macrovascular treatment targets in scleroderma heart disease.

Curr Pharm Des 2014;20:536–44. https://doi.org/10.2174/138161 28113199990555; PMID: 23565639.

Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum 2010;39:269–77. https://doi.org/10.1016/ j.semarthrit.2008.06.002; PMID: 18706680.

Mavrogeni S, Sfikakis PP, Gialafos E, et al. Cardiac tissue characterization and the diagnostic value of cardiovascular magnetic resonance in systemic connective tissue diseases.

Arthritis Care Res (Hoboken) 2014;66:104–12. https://doi. org/10.1002/acr.22181; PMID: 24106233.

Mavrogeni S, Spargias K, Markussis V, et al. Myocardial inflammation in autoimmune diseases: investigation by cardiovascular magnetic resonance and endomyocardial biopsy. Inflamm Allergy Drug Targets 2009;8:390–7. https://doi.org/ 10.2174/1871528110908050390; PMID: 20025587.

Mavrogeni S, Manoussakis MN. Myocarditis and subclavian

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14.

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17.

18.

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21.

22.

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• t here is a mismatch between clinical findings and imaging/ laboratory findings; • there is new onset heart failure; • if there is any kind of arrhythmia; • if the rheumatologist plans to change treatment, especially if there is a plan to initiate biologic agents; • if there is any increase in troponin, brain natriuretic peptide or D-dimers, even if there are only subtle symptoms; • if the patient is being treated with hydroxyl-chloroquine or biologic agents; or • if the patient notes any kind of typical or atypical cardiac symptoms and the routine cardiac evaluation is normal.

Conclusion CMR allows the early diagnosis of various CV pathophysiologic phenomena in ARDs. Preliminary studies suggest it has a promising role in prompting modifications of anti-rheumatic and cardiac treatment in ARDs with CVD. The diagnostic potential of CMR strongly supports the view that we should “save the last dance” for CMR in early diagnosis, risk stratification and treatment follow-up of CVD in ARDs.

stenosis in Takayasu arteritis. Int J Cardiol 2011;148:223–4. https://doi.org/10.1016/j.ijcard.2009.05.008; PMID: 19482365.

Mavrogeni S, Sfikakis PP, Gialafos E, et al. Diffuse, subendocardial vasculitis. A new entity identified by cardiovascular magnetic resonance and its clinical implications. Int J Cardiol 2013;168:2971–2. https://doi. org/10.1016/j.ijcard.2013.04.116; PMID: 23647593.

Raman SV, Aneja A, Jarjour WN. CMR in inflammatory vasculitis. J Cardiovasc Magn Reson 2012;14:82. https://doi. org/10.1186/1532-429X-14-82; PMID: 23199343.

Meyers HP, Jaffa E, Smith SW, et al. Evaluation of T-wave morphology in patients with left bundle branch block and suspected acute coronary syndrome. J Emerg Med 2016;51: 229-37. https://doi.org/10.1016/j.jemermed.2016.05.004; PMID: 27318856.

Gibbons RJ, Balady GJ, Beasley JW et al. ACC/AHA guidelines for exercise testing. J Am Coll Cardiol 1997;30:260–311. PMID: 9207652. https://doi.org/10.1016/j.jemermed.2016.05.004; PMID: 27318856.

Sicari R, Nihoyannopoulos P, Evangelista A, et al. European Association of Echocardiography. Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE). Eur J Echocardiogr 2008;9:415–37. https://doi.org/10.1093/ejechocard/jen175; PMID: 18579481.

Hachamovitch R, Berman DS, Kiat H, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery disease. Circulation 1996;93:905–14. PMID: 8598081.

Iskander S, Iskandrian AE. Risk assessment using singlephoton emission computed tomography technetium-99m sestamibi imaging. J Am Coll Cardiol 1998;32:57–62. https://doi. org/10.1016/S0735-1097(98)00177-6; PMID: 9669249.

Mavrogeni SI, Kitas GD, Dimitroulas T, et al. Cardiovascular magnetic resonance in rheumatology: Current status and recommendations for use. Int J Cardiol 2016;217:135–48. https://doi.org/10.1016/j.ijcard.2016.04.158; PMID: 27179903.

Mavrogeni S, Sfikakis PP, Gialafos E, et al. Cardiac tissue characterization and the diagnostic value of cardiovascular magnetic resonance in systemic connective tissue diseases.

Arthritis Care Res (Hoboken) 2014;66:104–12. https://doi. org/10.1002/acr.22181; PMID: 24106233.

Mavrogeni S, Markousis-Mavrogenis G, Koutsogeorgopoulou L, et al. Cardiovascular magnetic resonance imaging pattern at the time of diagnosis of treatment naïve patients with connective tissue diseases. Int J Cardiol 2017;236:151–6. https:// doi.org/10.1016/j.ijcard.2017.01.104; PMID: 28185705.

Chraibi S, Ibnabdeljalil H, Habbal R, et al. Pericardial tamponade as the first manifestation of dermatopolymyositis.

Ann Med Interne (Paris) 1998;149:464–6. PMID: 9921402.

Mavrogeni S, Bratis K, Sfendouraki E, et al. Myopericarditis,

26.

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29.

30.

31.

32.

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34.

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as the first sign of rheumatoid arthritis relapse, evaluated by cardiac magnetic resonance. Inflamm Allergy Drug Targets 2013;12:206–11. https://doi.org/10.2174/18715281113120300 08; PMID: 23547732.

Mavrogeni SI, Schwitter J, Gargani L, et al. Cardiovascular magnetic resonance in systemic sclerosis: “Pearls and pitfalls”. Semin Arthritis Rheum 2017;47:79–85. https://doi. org/10.1016/j.semarthrit.2017.03.020; PMID: 28522072.

Kouranos V, Tzelepis GE, Rapti A, et al. Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis. JACC Cardiovasc Imaging 2017;10:1437–47. https://doi.org/10.1016/j.jcmg.2016.11.019; PMID: 28330653.

Raman SV, Aneja A, Jarjour WN. CMR in inflammatory vasculitis. J Cardiovasc Magn Reson 2012;14:82. https://doi. org/10.1186/1532-429X-14-82; PMID: 23199343.

Mavrogeni S, Sfikakis PP, Karabela G, et al. Cardiovascular magnetic resonance imaging in asymptomatic patients with connective tissue disease and recent onset left bundle branch block. Int J Cardiol 2014;171:82–7. https://doi. org/10.1016/j.ijcard.2013.11.059; PMID: 24331867.

Kobayashi Y, Kobayashi H, Giles JT, et al. Association of tocilizumab treatment with changes in measures of regional left ventricular function in rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging. Int J Rheum Dis 2016;19:1169–74. https://doi.org/10.1111/1756-185X.12632; PMID: 26480957.

Mavrogeni S, Markousis-Mavrogenis G, Koutsogeorgopoulou L, Kolovou G. Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases. J Inflamm Res 2017;10:55–61. https://doi.org/10.2147/ JIR.S115508; PMID: 28546762.

Mavrogeni S, Markousis-Mavrogenis G, Koutsogeorgopoulou L, et al. Cardiovascular magnetic resonance imaging pattern at the time of diagnosis of treatment naïve patients with connective tissue diseases. Int J Cardiol 2017;236:151–6. https:// doi.org/10.1016/j.ijcard.2017.01.104; PMID: 28185705.

Mavrogeni S, Bratis K, Koutsogeorgopoulou L, et al.

Myocardial perfusion in peripheral Raynaud’s phenomenon.

Evaluation using stress cardiovascular magnetic resonance.

Int J Cardiol 2017;228:444–8. https://doi.org/10.1016/j. ijcard.2016.11.242; PMID: 27870974.

Mavrogeni SI, Sfikakis PP, Dimitroulas T, et al. Prospects of using cardiovascular magnetic resonance in the identification of arrhythmogenic substrate in autoimmune rheumatic diseases. Rheumatol Int 2018;38:1615–21. https://doi. org/10.1007/s00296-018-4110-5; PMID: 30043238.

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ ejhf.592; PMID: 27207191.

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Ischaemic Heart Disease: Comorbidity

Erectile Dysfunction and Ischaemic Heart Disease Abdalla Ibrahim, 1 Mohamed Ali, 2 Thomas J Kiernan 1 and Austin G Stack 3 1. Cardiology Department, University Hospital Limerick, Limerick, Ireland; 2. Cardiology Department, St James’s Hospital, Dublin, Ireland; 3. Division of Nephrology, University Hospital Limerick, Limerick, Ireland

Abstract Erectile dysfunction (ED) is a common disorder that affects the quality of life of many patients. It is prevalent in more than half of males aged over 60 years. Increasing evidence suggests that ED is predominantly a vascular disorder. Endothelial dysfunction seems to be the common pathological process causing ED. Many common risk factors for atherosclerosis such as diabetes, hypertension, smoking, obesity and hyperlipidaemia are prevalent in patients with ED and so management of these common cardiovascular risk factors can potentially prevent ED. Phosphodiesterase type 5 inhibitors provide short-term change of haemodynamic factors to help initiate and maintain penile erection. They have been shown to be an effective and safe treatment strategy for ED in patients with heart disease, including those with ischaemic heart disease and hypertension.

Keywords Atherosclerosis, endothelial dysfunction, erectile dysfunction, ischaemic heart disease, phosphodiesterase inhibitors Disclosure: The authors have no conflicts of interest to declare.

Received: 16 October 2017 Accepted: 9 October 2018 Citation: European Cardiology Review 2018;13(2):98–103. DOI: https://doi.org/10.15420/ecr.2017.21.3 Correspondence: Abdalla Ibrahim, Cardiology Department, University Hospital Limerick, St Nessan’s Road, Dooradoyle, Co. Limerick V94 F858, Ireland.

E: abdalla.ibrahimmd@gmail.com

Erectile dysfunction (ED) is generally defined as the persistent (at least 6 months) inability to achieve and maintain penile erection sufficient to allow satisfactory sexual performance.1 It is a common condition, and recent studies predict a higher prevalence of ED in the future.2 It is estimated that ED has affected more than 150 million men worldwide and this number will reach approximately 322 million by 2025.2,3 It has affected 30 million men in the US alone.4 Ischaemic heart disease (IHD), also known as coronary artery disease (CAD), is a predominant manifestation of cardiovascular disease (CVD).

CVD is the leading cause of morbidity and mortality, accounting for 17.3 million deaths globally every year; this figure is expected to grow to 23.6 million by the year 2030. Eighty per cent of these deaths occur in lower- and middle-income countries.5 ED and IHD are highly prevalent and occur concomitantly because they share the same risk factors, including diabetes, hypertension, hyperlipidaemia, obesity and smoking.

The incidence of ED is 42.0–57.0 % in men with CAD and 33.8 % in those who have diabetes with silent ischaemia, compared with 4.7 % in men without silent ischaemia.6 The prevalence of ED is likely to be higher than the reported figures, because men generally do not seek medical advice for ED.6 Erection is thought to be a process that is regulated by hormones and neurovascular mechanisms in cerebral and peripheral levels.7 Causes of ED may be of primary developmental origin or secondary.

Lack of sex hormone in the early developmental stage of male children is the major cause of primary ED. The secondary cause of ED involves arteriosclerosis, diabetes or psychogenic disturbances. Other secondary factors may include hypertension, hyperlipidaemia, obesity

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and tobacco use. The primary causes of ED are beyond the scope of this review; we will not be discussing the neurovascular mechanisms pertaining to ED and will focus on the relationship between IHD and ED.

Association Between ED and IHD The association of ED and IHD has been a constant matter of study.

Many previous studies have documented that IHD and ED are linked.

IHD can be used to predict the risk of ED because both conditions have the same risk factors. Conversely, ED may trigger events that further lead to IHD. ED is generally associated with significant changes in established cardiovascular risk factors. Atherosclerosis is the main cause of ED development in both the general population and patients with diabetes.

However, the prevalence of ED is greater in patients with diabetes than in the general population.8 ED has been shown to occur at rates as high as 50 % in patients with CAD.9 A meta-analysis of 12 prospective cohort studies has provided evidence that ED is a predictor of IHD associated with an increased risk of CVD, stroke and all-cause mortality.10 Previous studies reported that there is a strong chance of future cardiac events when ED occurs in younger men compared with older men.11 Another study suggested that there is consistent association across age groups.12 A study of men with diabetes found that ED acts as an indicator of cardiovascular events after adjusting for other illnesses, psychological aspects and the usual cardiovascular risk factors.13 Another large-scale study comprising 25,650 men with preexisting ED suggested that these men had a 75 % increased risk of peripheral vascular disease.14 Moreover, some studies demonstrated a relationship between ED score and number of diseased coronary arteries and plaque burden in coronary arteries.2,15

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Erectile Dysfunction in Ischaemic Heart Disease A study that examined the association between ED and asymptomatic CAD showed that 67 % of patients had ED for a mean 38.8 months before developing symptoms of CAD.16 Interestingly, all patients with type 1 diabetes in this study had ED well before symptoms of CAD. Artery size also explains the onset of ED before occurrence of CAD. Coronary arteries are 3–4 mm in diameter, while the penile artery is 1–2 mm in diameter.17 Endothelial dysfunction and plaque burden in the small arteries may cause symptoms of ED before they affect blood flow in large arteries. Also, an asymptomatic lipid-rich plaque in the coronary arteries carries the risk of rupture that leads to acute coronary syndrome or death, so ED may be predictive of these serious events without warning cardiac symptoms.17 Some commonly prescribed cardiovascular drugs (beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, etc.) contribute to ED.18 Previous studies have shown a strong association between ED and diuretics in patients treated with hydrochlorothiazide or chlorthalidone.19,20 It has also been shown that patients treated with first-generation non-selective beta-blockers, such as propranolol, had more frequent ED than those treated with a placebo.21 Second-generation cardioselective beta-blockers (atenolol, metoprolol, bisoprolol, etc.) can also lead to ED. Atenolol was shown to cause significant reduction of sexual activity compared with placebo in a double-blind, parallel-arm study.22 The same study also showed a significant reduction in testosterone levels with atenolol versus valsartan. An open, prospective study of hypertensive men treated with atenolol, metoprolol and bisoprolol for at least 6 months showed high prevalence of ED – approaching 66 % – in these patients.23 The impact of third-generation cardioselective beta-blockers such as carvedilol and nebivolol has also been investigated. Fogari et al. investigated the effect of carvedilol on erectile function in a double-blind crossover study involving 160 men newly diagnosed with hypertension and found chronic worsening of sexual function in those treated with carvedilol compared with valsartan and placebo.24 Nebivolol seems to have an advantage over other beta-blockers when used to treat men with hypertension and ED. It has additional vasodilating effects because it stimulates endothelial release of nitric oxide (NO), resulting in relaxation of smooth muscle in the corpus cavernosum, allowing penile erection.25 Despite limited studies, nebivolol does not seem to worsen erectile function and some studies have demonstrated significant improvement in erectile function with nebivolol compared with second-generation cardioselective beta-blockers.23,26–28 Most studies into the effect of beta-blockers on ED point to negative effects of first- and second-generation beta-blockers, while betablockers with vasodilating effects can improve erectile function.

Alpha-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors seem to have a neutral effect on erectile function.

Multiple previous studies have demonstrated a beneficial effect of angiotensin receptor blockers on erectile function and they should probably be the favoured antihypertensive agents in patients with ED.29

Aetiology In most men, ED is recognised as sharing vascular aetiology with IHD.17 ED and IHD share common risk factors, such as hypertension,

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Figure 1: Risk Factors Associated with Erectile Dysfunction and Ischaemic Heart Disease

Endothelial dysfunction

Erectile dysfunction

Coronary artery disease/ischaemic heart disease

Cardiovascular risk factors: age, smoking, obesity, hyperlipidaemia, diabetes, hypertension, depression

hyperlipidaemia, diabetes, obesity, lack of physical exercise, cigarette smoking, poor diet, excess alcohol consumption and psychological stress, including depression.30 Endothelial dysfunction has been implicated as a common mechanism between CAD and ED and it has an important role in the development of atherosclerosis.31 The role of endothelial dysfunction in CAD is well known.32,33 Also, endothelial-derived NO induces vasodilatation, which in turn is an important event to achieve normal erectile function.34–36 Moreover, systemic endothelial-dependent vasodilatation has been shown to be reduced in men with ED.37,38

Risk Factors ED and IHD share the same risk factors (Figure 1). Endothelial dysfunction is the common link between ED and IHD.5

Age Age is a critical risk factor for the development of ED and endothelial dysfunction.4,5 ED is the most common condition occurring in middle-aged and older men. 5 Kinsey et al. reported that 25 % of 65-year-old men and 75 % of ≥80-year-old men have ED.39 Moreover, ageing also decreases endothelial function, which is responsible for IHD.5 The incidence and severity of ED increases with age (a man aged 70 years is three-times more likely to have ED than a man aged 40 years). 40

Blood Pressure Hypertension can affect endothelial function in many ways.

It can reduce endothelium-dependent vasodilatation by increasing the vasoconstrictor tone as a result of increased peripheral sympathetic activity.41–43 Another mechanism is hypertension-induced increase in cyclooxygenase activity that leads to an increase in reactive oxygen species; these in turn damage endothelial cells and disrupt their function.44–46 In some cases, endothelial NO synthase (eNOS) gene variations may relate to hypertension-associated endothelial dysfunction.6

Cholesterol High cholesterol level is an independent risk factor for ED. A 22-month follow-up study estimated that each mmol/l increase in baseline total cholesterol level increases the risk of ED by 1.32 times.4 In a study by Seftel et al., 42 % of men with ED also had hyperlipidaemia.47 In another study, 114 patients with ED had elevated LDL cholesterol.48

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Ischaemic Heart Disease: Comorbidity Figure 2: Pathophysiology of Erectile Dysfunction and Ischaemic Heart Disease

Atherosclerosis

Diabetes, hypertension, dyslipidaemia

Impaired endotheliumdependent relaxations

Arterial stenosis

Arterial insufficiency

Impaired vasodilatation

Reduced blood flow to the penis

Erectile dysfunction

Smoking Smoking is an independent risk factor for ED. Tobacco smoking causes direct toxicity to endothelial cells, including decreased eNOS activity, increased adhesion expression and impaired regulation of thrombotic factors.6 A meta-analysis of 19 studies by Tengs and Osgood suggested that 40 % of the impotent men studied were current smokers compared with 28 % who had never smoked.49

Obesity Obesity is a strong predictor of ED as it is associated with other risk factors, such as diabetes, hyperlipidaemia and hypertension.4 Obesity increases the risk of ED by 30–90 % and acts as an independent risk factor for CVD. Obese men with ED have greater impairment in endothelial function than non-obese men with ED.5 Moreover, high BMI causes low testosterone levels, which in turn leads to ED, as observed in a prospective trial involving 7,446 participants.50

touching the shaft of the penis, while psychogenic erection occurs by erotic or emotional stimuli. ED is a condition where erection does not take place by either mechanism. ED can occur because of hormonal imbalance, neural disorders or lack of adequate blood supply to the penis.54 Lack of blood supply can be a result of impaired endothelial function associated with CAD.54 The vascular endothelium has an important role in angiogenesis and vascular repair by producing regulatory substances, including NO, prostaglandin, endothelins, prostacyclin and angiotensin II. These regulatory factors regulate the blood flow to the penis by controlling smooth muscle contractility and subsequent vasoconstriction and vasodilatation. Generally, in erectile tissue, increased blood flow through the cavernosal artery increases shear stress and produces NO, which further relaxes the vascular smooth muscles and increases blood flow in the corpora cavernosa.54 These events cause penile erection. However, in ED, endothelial NO synthesis is reduced and there is increased endothelial cell death (Figure 2).55 Myocardial ischaemia is caused by the reduction of coronary blood flow as a result of fixed or dynamic epicardial coronary artery stenosis, abnormal constriction or deficient relaxation of coronary microcirculation, or because of reduced oxygen-carrying capacity of the blood.56 Atherosclerosis is the major cause of myocardial ischaemia.

Plaque that develops in atherosclerosis can rupture causing platelet aggregation and subsequent thrombus formation, which leads to MI. The other mechanisms of myocardial ischaemia are encountered far less than atherosclerosis. Endothelial dysfunction has an important role in the progression of atherosclerosis. Endothelial dysfunction enhances the intimal proliferation and malregulation that results in plaque destabilisation in the arteries.6 This process, coupled with paradoxical vasoconstriction, can result in major cardiovascular events such as MI.32

Psychological A considerable number of patients with ED can have psychogenic factors as the only cause, or in combination with organic causes of ED. Depression, low self-esteem and social stresses are among the psychogenic factors that can lead to ED. Depression is an independent risk factor for both ED and IHD; these three disease conditions are interlinked.51 Psychogenic ED can be managed by multiple psychological interventions such as cognitive behavioural therapy, couples counselling and guided sexual stimulation techniques.52

Diabetes ED is a common complication of diabetes and people with diabetes are also prone to developing cardiovascular complications.48 The risk of ED is relatively high in patients with known CVD. This was supported by a study of men with known CVD, in which ED was substantially predictive of all-cause mortality and the composite of CVD death, admission for heart failure, MI and stroke.17 Macroangiopathy, microangiopathy and endothelial dysfunction are among the mechanisms by which diabetes causes ED. Subnormal testosterone levels have also been observed in patients with diabetes and this is thought to be either autoimmune or a result of low levels of sex hormone binding globulin secondary to insulin resistance.53

Pathophysiology of Erectile Dysfunction and Ischaemic Heart Disease Normal penile erection is controlled by two mechanisms: reflex erection and psychogenic erection. Reflex erection occurs by directly

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Treatment of Erectile Dysfunction in Men with Ischaemic Heart Disease The third Princeton Consensus (Expert Panel) Conference recommends assessing cardiovascular risk in all patients with ED and CVD. This refers to estimating the risk of mortality and morbidity associated with sexual activity. The current recommendations classify patients into low-, intermediate- and high-risk, based on their New York Heart Association class.57 The consensus also recommended that all patients with ED and CVD should undergo lifestyle changes, such as exercise, smoking cessation, healthy diet and weight reduction. These measures are likely to reduce cardiovascular risk and improve erectile function.58 Patients with ED at high risk of cardiovascular events should refrain from sexual activity until they are stable from a cardiovascular point of view. Their management should be under close supervision from a cardiologist.58

PDE5 Inhibitors Guidelines recommend that phosphodiesterase type 5 (PDE5) inhibitors are the first-line drug for the treatment of ED (Table 1).

Sildenafil citrate was the first oral drug approved for ED in the US.59 The newer PDE5 inhibitors include vardenafil, tadalafil and avanafil.

The inhibition of PDE5 enhances cyclic guanosine monophosphate (cGMP)-NO-mediated vasodilatation by preventing PDE5 catabolism of cGMP and so delaying detumescence. PDE5 inhibitors increase the number and duration of erections, as well as the percentage of successful sexual intercourse.60

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Erectile Dysfunction in Ischaemic Heart Disease PDE5 inhibitors are commonly prescribed to treat ED. The second Princeton Consensus Conference reviewed their appropriate use and recent studies of placebo-controlled and post-marketing surveillance data have confirmed their safety regarding cardiovascular events.61–63 Olsson et al. conducted a randomised, double-blind, placebocontrolled, parallel group, and flexible dose study in 224 men with ED and one CVD, including IHD (20 %) and hypertension (80 %).

This study reported that the sildenafil-treated group showed 71 % improvement in ED compared with the placebo-controlled group (24 %).64 Furthermore, no treatment-related cardiovascular adverse events were reported.65 Conti et al. showed in an early study that sildenafil is an effective treatment for ED in patients with IHD; the majority of patients reported improvement in penile erection with it.66 Another double-blind, placebo-controlled study of patients with ED and stable CAD showed statistically significant improvement with sildenafil versus placebo in both the frequency of penetration and frequency of maintained erections after penetration.67 However, sildenafil should be used carefully with nitrates because their combination can result in severe hypotension and death.68 Both short- and long-acting nitrates are commonly prescribed to treat angina, but they have no prognostic benefit. In addition, there are numerous alternatives to treat angina, such as ranolazine and ivabradine, which do not interact with PDE5 inhibitors. As a result, patients with ED wishing to take PDE5 inhibitors can safely discontinue their nitrates and replace this treatment with the other anti-anginal agents.68 The safety of PDE5 inhibitors in patients with IHD has been shown in multiple trials. Arruda-Olson et al. investigated the safety of sildenafil during exercise stress tests in patients with IHD to ascertain whether the drug induces or exacerbates myocardial ischaemia. This was a prospective, randomised crossover study that demonstrated safety of sildenafil when given 1 hour before an exercise stress test.69 Another study that investigated 120 trials of sildenafil revealed that the rates of MI and cardiovascular death with sildenafil are as low as with placebo.70 The recommended dosage of sildenafil is 50 mg/day, usually taken 1 hour before sexual activity. This dose may be increased to 100 mg or decreased to 25 mg based on side-effects.6 PDE5 inhibitors also have a beneficial effect in the treatment of heart failure with reduced ejection fraction as well as pre- and post-capillary pulmonary hypertension. The use of PDE5 inhibitors in the treatment of right heart failure and left ventricular failure associated with combined pre- and post-capillary pulmonary hypertension has been well studied.71,72

Vacuum Devices Vacuum erection devices are an effective first-line treatment for ED, regardless of the underlying cause. They can be used in combination with PDE5 inhibitors and they have high reported satisfaction rates.

They are generally well tolerated, with minor adverse effects such as bruising, pain and failure to ejaculate.73

Testosterone It is recommended that testosterone be measured in patients with ED because low levels are a reliable measure of hypogonadism.

Hypogonadism is not only a treatable cause of ED, but can also lead

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Table 1: Treatment Options for Erectile Dysfunction Therapy Stage

Treatment Options

First line

1. Phosphodiesterase type 5 inhibitors 2. Vacuum erection devices

Second line

1. Intracavernosal and intraurethral injections 2. Topical creams 3. Low-intensity extracorporeal shockwave therapy

Third line

Penile prosthesis

to reduced or lack of response to PDE5 inhibitors.73 Testosterone deficiency is also associated with increased cardiovascular and allcause mortality.74 Levels >350 ng/dl do not usually require replacement, but in patients with testosterone <230 ng/dl, replacement can usually be beneficial.57 In patients with congestive heart failure, testosterone replacement can lead to fluid retention, so caution is advised. In these patients, the aim should be to keep testosterone levels in the middle range, i.e. 350–600 ng/dl.57 Testosterone cypionate and testosterone enanthate injections are used for replacement therapy in patients with low testosterone.

Other formulations, such as gels and patches, are recommended in older patients with chronic conditions.57 Serum prostate specific antigen should be measured before starting testosterone replacement, then 3–6 months after starting the treatment, followed by annual measurement.74 The benefits of testosterone replacement and the potential cardiovascular risks need to be thoroughly investigated, ideally through randomised controlled trials.

Other Therapies Intracavernosal and intraurethral injections are second-line therapy for patients with ED. Alprostadil is the agent most commonly used for intracavernosal injections. The main adverse effects of intracavernosal injections are painful erection, priapism and development of scarring at the injection site.73 Alprostadil is also available as a topical cream in patients who cannot tolerate injections.75 Another injection option is the combination of phentolamine and aviptadil. This is effective, but requires simultaneous sexual stimulation to achieve its desired effect.73 Side-effects include headache, facial flushing and, rarely, tachycardia and palpitation.73 Intraurethral prostaglandin E1 pellets are suppositories that are inserted into the urethra. These agents act by relaxation of cavernous smooth muscle, which elevates the intracavernosal cGMP and by blocking the local alpha-receptors, resulting in improved erectile function.2 Another second-line treatment is low intensity extracorporeal shockwave therapy. This can be very useful, especially in patients who failed oral therapy, but do not wish to start injections.73 Penile prosthesis is recommended as third-line treatment for patients who are fit for surgery and intolerant of oral medication, injections or external device therapy. A penile prosthesis is particularly useful in patients with severe organic ED, achieving long-term effects and high satisfaction rates without the need for further medication.73

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Ischaemic Heart Disease: Comorbidity Future Treatment Options Gene therapy has the potential to become a future management option for patients with CAD and ED. Animal studies have been conducted to evaluate the effects of gene therapy. A rat model was studied by Bivalacqua et al. to evaluate the effect of the combination of eNOS gene therapy and sildenafil. This research suggested that erectile response was greater in male rats with diabetes treated with combination eNOS gene therapy and sildenafil, compared with male rats with diabetes treated with eNOS gene therapy or sildenafil alone.76–78 Stem cell therapy is an attractive treatment modality and an appealing option for tissue regenerative therapy for ED. Stem cells are pluripotent cells that can be produced from multiple regions within the body. They have the potential to divide and differentiate into numerous kinds of human cells, such as endothelial cells and smooth muscle.79 The efficacy and safety of gene and stem cell therapy in patients with ED

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and IHD need to be extensively investigated because both seem to have the potential to correct underlying abnormalities in ED. This would be a huge development in terms of management options for patients with ED and IHD.

Conclusion ED is a common disease affecting men with IHD. Endothelial dysfunction is the link between ED and IHD and both diseases share the same aetiology, risk factors and pathogenesis. Aggressive control of these risk factors – along with lifestyle modification – is recommended to improve symptoms of ED and reduce cardiovascular risk. PDE5 inhibitors remain the first-choice treatment for ED in IHD patients and they have been shown to be safe and effective. However, PDE5 inhibitors can potentiate the hypotensive effect of nitrates so concomitant administration of sildenafil and nitrates is contraindicated. Gene and stem cell therapy are being investigated as a future therapies for ED.

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66. Conti CR, Pepine CJ, Sweeney M. Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999;83:29C−34. https://doi.org/10.1016/S00029149(99)00045-4; PMID: 10078540.

67. DeBusk RF, Pepine CJ, Glasser DB, et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol 2004;93:147−53. https:// doi.org/10.1016/j.amjcard.2003.09.030; PMID: 14715338 .

68. Kloner RA, Goggin P, Goldstein I, et al. A new perspective on the nitrate-phosphodiesterase type 5 inhibitor interaction.

J Cardiovasc Pharmacol Ther 2018;23:375−86. https://doi. org/10.1177/1074248418771896; PMID: 69. Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease. A randomized crossover trial.

JAMA 2002;287:719−25. https://doi.org/10.1001/jama.287.6.719; PMID: 11851538.

70. Mittleman MA, Glasser DB, Orazem J. Clinical trials of sildenafil citrate demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo. Int J Clin Pract 2003;57:597−600. PMID: 14529061.

71. De Vecchis R, Cesaro A, Ariano C, et al. Phosphodiesterase-5 inhibitors improve clinical outcomes, exercise capacity and

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pulmonary hemodynamics in patients with heart failure with reduced left ventricular ejection fraction: a meta-analysis.

J Clin Med Res 2017;9:488–98. https://doi.org/10.14740/ jocmr3008w; PMID: 28496549.

Assad TR, Hemnes AR, Larkin EK, et al. Clinical and biological insights into combined post- and pre-capillary pulmonary hypertension. J Am Coll Cardiol 2016;68: 2525–36. https://doi.org/10.1016/j.jacc.2016.09.942; PMID: 27931609.

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.

Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine guidelines on adult testosterone deficiency, with statements for UK practice. J Sex Med 2017;14:1504–23. https://doi.org/10.1016/ j.jsxm.2017.10.067; PMID: 29198507.

Anaissie J, Hellstrom WJ. Clinical use of alprostadil topical cream in patients with erectile dysfunction: a review. Res Rep Urol 2016;8:123–31. https://doi.org/10.2147/RRU.S68560; PMID: 27536559.

Bivalacqua TJ, Deng W, Champion HC, et al. Gene therapy techniques for the delivery of endothelial nitric oxide synthase to the corpa cavernosa for erectile dysfunction.

Methods Mol Biol 2004;279:173–85.https://doi.org/10.1385/159259-807-2:173; PMID: 15199245.

Bivalacqua TJ, Usta MF, Champion HC, et al. Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 2004;16:21–9. https://doi.org/10.1038/sj.ijir.3901054; PMID: 14963467.

Bivalacqua TJ, Usta MF, Champion HC, et al. Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozotocin diabetic rats. J Urol 2003;169:1911–7. https://doi.org/10.1097/01. ju.0000051881.14239.4a; PMID: 12686872.

Harraz A, Shindel AW, Lue TF. Emerging gene and stem cell therapies for the treatment of erectile dysfunction. Nat Rev Urol 2010;7:143–52. https://doi.org/10.1038/nrurol.2010.8; PMID: 20157303.

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Trimetazidine and Other Metabolic Modifiers Giacinta Guarini, 1 Alda Huqi, 2 Doralisa Morrone, 1 Paola Francesca Giuseppina Capozza 1 and Mario Marzilli 1 1. Cardiovascular Medicine Division, Cardiothoracic and Vascular Department, University of Pisa, Italy; 2. Cardiovascular Medicine Division, Ospedale della Versilia, Lido di Camaiore, Italy

Abstract Treatment goals for people with chronic angina should focus on the relief of symptoms and improving mortality rates so the patient can feel better and live longer. The traditional haemodynamic approach to ischaemic heart disease was based on the assumption that increasing oxygen supply and decreasing oxygen demand would improve symptoms. However, data from clinical trials, show that about one third of people continue to have angina despite a successful percutaneous coronary intervention and medical therapy. Moreover, several trials on chronic stable angina therapy and revascularisation have failed to show benefits in terms of primary outcome (survival, cardiovascular death, all-cause mortality), symptom relief or echocardiographic parameters. Failure to significantly improve quality of life and prognosis may be attributed in part to a limited understanding of ischaemic heart disease, by neglecting the fact that ischaemia is a metabolic disorder. Shifting cardiac metabolism from free fatty acids towards glucose is a promising approach for the treatment of patients with stable angina, independent of the underlying disease (macrovascular and/or microvascular disease). Cardiac metabolic modulators open the way to a greater understanding of ischaemic heart disease and its common clinical manifestations as an energetic disorder rather than an imbalance between the demand and supply of oxygen and metabolites.

Keywords Chronic stable angina, myocardial ischaemia, cardiac metabolism, metabolic modulation therapy Disclosure: The authors have no conflicts of interest to declare.

Received: 10 May 2018 Accepted: 25 September 2018 Citation: European Cardiology Review 2018;13(2):104–11. DOI: https://doi.org/10.15420/ecr.2018.15.2 Correspondence: Giacinta Guarini, Cardiovascular Medicine Division, Cardiothoracic and Vascular Department, University of Pisa, Via Paradisa n2, 56100 Pisa, Italy.

E: giacinta.guarini@ao-pisa.toscana.it

Although cardiovascular mortality has declined progressively in developed countries, ischaemic heart disease (IHD) and chronic stable angina cause a worse prognosis and poor quality of life and can dramatically increase healthcare costs.1–4 Traditionally, chronic stable angina has been interpreted as reversible episodes of myocardial ischaemia due to the presence of coronary artery disease. Coronary artery disease hampers coronary blood flow augmentation in response to an increase in myocardial oxygen consumption, thus causing myocardial ischaemia. Based on this assumption, myocardial ischaemia is the direct consequence of an imbalance between the demand and supply of oxygen and metabolites. Current guidelines recommend pharmacological agents that can modulate cardiac work, such as betablockers and calcium channel blockers (or modulate coronary blood flow (nitroglycerin), alone or in combination, in addition to percutaneous coronary intervention.1 These strategies were expected to prevent episodes of myocardial ischaemia, improving symptoms and prolonging survival but available data indicates that this approach is not effective and about one-third of patients experience angina despite successful coronary revascularisation, or medical therapy and percutaneous coronary interventions.5–7 The failure of these interventions to improve the prognosis of patients with IHD shows an oversimplified approach to mycoardial ischaemia and its multifactorial aetiology.

Recent research has shown that myocardial ischaemia may be precipitated by several different mechanisms, including coronary stenosis, coronary vasospasm, microvascular dysfunction and mitochondrial dysfunction.8,9 Therefore, a combined approach to

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IHD that targets multiple mechanisms may be a more successful treatment strategy.1,10 Targeting cardiac myocytes, protecting them from ischaemic damage and modulating myocardial metabolism could improve cardiac efficiency and long-term outcomes.11–13 Indeed, studies have shown that metabolic modulation therapy plays a critical role in the acute phase of ischaemic events, affecting the results of acute interventions and the subsequent development of heart failure (HF), stunned and hybernated myocardium, as well as chronic stable angina.14

Heart Metabolism in Health and During Ischaemia The healthy heart derives most of its energy from the free fatty acid pathway that accounts for about two thirds of energy production in the form of adenosine triphosphate (ATP), and the rest is derived from glucose oxidation and lactate. The healthy heart is able to modulate the use of substrates according to availability, general nutritional status and exercise levels. During mild to moderate cardiac ischaemia, myocardial cells respond by accelerating glucose uptake to generate enough ATP to maintain ionic gradients and calcium homeostasis.

Paradoxically, during prolonged and severe ischaemia, the myocardium continues to derive most of its energy from beta-oxidation despite a high rate of lactate production. In this condition, high rates of fatty acid oxidation further inhibit glucose oxidation due to competitive interaction, known as the Randle mechanism.15 Although the complete oxidation of fatty acid produces more ATP than complete oxidation of glucose, a greater amount of oxygen is required. Therefore, for a

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Trimetazidine and Other Metabolic Modifiers given amount of oxygen consumed, glucose metabolism is ‘oxygen sparing’ compared with fatty acid metabolism, producing about 15 % more ATP. Therefore, when there is a low availability of oxygen, fatty acid oxidation has an unfavourable effect on cells requiring more oxygen, producing less ATP and more reactive oxygen species (ROS), further depressing mitochondrial respiratory efficiency. These metabolic changes are responsible for metabolic, morphological and functional alteration of the myocardium leading to arrhythmias and contractive failure.16–18 Figure 1 depicts energy generation in the healthy heart, while Figure 2 shows metabolic derangements occurring during ischaemia.

Coupling glycolysis to glucose oxidation is of pivotal importance due to the link between these enzymes and the activity of two survivalpromoting membrane-bound pumps, namely the sodium-potassium ATPase, and the calcium uptake pump of the sarcoendoplasmic reticulum (SERCA).19 This interplay explains the efficacy of antiischaemic fatty acid inhibitors such as trimetazidine and ranolazine.

In line with this, the greatest progress for patients with stable angina came with the use of metabolic therapy, particularly with the advent of direct inhibitors of myocardial fatty acid oxidation, trimetazidine and ranolazine.17

Cardiac Metabolic Modulators

Figure 1: Cardiac Metabolism in Normal Conditions

Glucose

Fatty acids

Glycolysis

Glycolysis

ADP ATP

Beta-oxidation Fatty acid oxidation

Pyruvate Lactate

Glucose oxidation

Pyruvate dehydrogenase Acetyl CoA

Acetyl CoA Krebs cycle

H2O

O2 Electron transport chain

ADP

The heart derives most of its energy from the oxidation of fatty acids, but nutritional status (e.g. fasting, substrate availability) as well as exercise and hormones can modify fuel selection. ADP = adenosine diphosphate; ATP = adenosine triphosphate; CoA = co-enzyme A.

Figure 2: Metabolic Alterations During Sustained Period of Ischaemia

Significant progress has been made since it was acknowledged in 1999 that it was necessary to treat ischaemia, a metabolic disorder, with metabolic therapy.20

Glucose

Fatty acids

Glycolysis

Given the interdependence between fatty acid and glucose oxidation, metabolic modulation therapy with optimisation of the use of energy substrate can be achieved by either inhibiting fatty acid oxidation or stimulating glucose oxidation. This can be achieved through three major strategies:

ADP

Fatty acid oxidation

Beta-oxidation Lactate and H+

Glycolysis

ATP Pyruvate Glucose oxidation

Pyruvate dehydrogenase Acetyl CoA

Acetyl CoA

• d irectly enhancing glucose oxidation; • decreasing the circulating levels of fatty acids and/or their uptake by cardiac myocytes or mitochondrion; and • directly inhibiting the enzymes that participate in fatty acid oxidation.

Contractile function basal metabolism

ATP

Krebs cycle H2O

O2 Electron transport chain

Figure 3 shows the specific mechanism of cardio-metabolic drugs.

ADP

Strategies to Enhance Glucose Oxidation Dicholoroacetate The rate-limiting step for glucose oxidation is catalysed by the pyruvate dehydrogenase (PDH) complex, which consists of PDH, PDH kinase (PDK), and PDH phosphatase (PDHP) enzymes.21 PDH flux is increased in response to increases in glycolysis and an increased generation of pyruvate, while PDH flux is decreased by increased ratios of mitochondrial nicotinamide adenine dinucleotide (NADH/NAD+) and acetyl-coenzyme A (acetyl CoA/CoA).22 PDHP dephosphorylates activate PDH, whereas PDK phosphorylates inhibit it.21 Dichloroacetate improves glycolysis and glucose oxidation coupling and decreases proton production by inhibiting PDK activity and stimulating mitochondrial PDH.23 There are no data available on the use of this approach on patients with heart disease. Despite the promising experimental evidence when used in other pathological conditions, dichloroacetate treatment has been associated with neurotoxicity which has prevented its use in clinical applications.24

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ATP

Glycolysis is the main catabolic pathway during ischaemia, whereas fatty acid oxidation is enhanced in this period. As a consequence, less ATP is generated at the expense of more protons production, which are ultimately responsible for myocardial acidosis and the accumulation of ions (mainly calcium). Purple arrows: enhanced pathway; pale blue arrows: almost abolished pathways. ADP = adenosine diphosphate; ATP = adenosine triphosphate; CoA = co-enzyme A.

Strategies to Reduce Cellular/Mitochondrial Fatty Acid Uptake Carnitine Palmitoyl Transferase Inhibitors: Perhexiline A strategy to inhibit mitochondrial uptake of fatty acids is to suppress the rate-limiting enzyme for the mitochondrial uptake of fatty acids, such as carnitine palmitoyl transferase (CPT) 1 or 2. Perhexiline is a reversible CPT-1 and, to a lesser extent, a CPT-2 inhibitor, and has been shown to relieve angina (Figure 3); it attenuates the increase in diastolic tension associated with myocardial ischaemia, thereby improving myocardial efficiency.25,26 Inhibition of CPT-1/CPT-2 by perhexiline improves the efficiency of myocardial oxygen use by at least 13 %. However, after perhexiline administration, cardiac efficiency increases by about 30 %, suggesting additional mechanisms at work.27

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Pharmacotherapy Figure 3: The Mechanism of Action of Drugs Able to Modulate Cardiac Metabolism Fatty acid

Glucose

Plasma CD36/fatty acid translocase

MCD inhibitor

Glucose transporter 4

MCD Acetyl CoA

Malonyl CoA

Etomoxir, perhexiline

ACC

Fatty acid

Glycolysis

CPT-1 Carnitine acyl transferase

cyl

F

MPC

tine

Fatty acyl CoA

i

carn

Trimetazidine, ranolazine

H+ H+

PDK

II

Cytosol

NADH FADH2 4H+

I

H+

DCA

PDH

2H+

III

Pyruvate

Fatty acid beta-oxidation

Acetyl CoA

ADP H+ 4H+

IV

Lactate

CPT-2

H+

F0/F1 ATPase

LDH

Pyruvate

ATP 3H+

2ATP

Fatty acyl CoA

Fatty acyl carnitine

a atty

Glucose

PDP

Mitochondrial matrix Tricarboxcylic (citric) acid cycle

+

H

ACC = acetyl CoA carboxylase; ATP = adenosine triphosphate; CAT = carnitine acyl transferase CoA = co-enzyme A; CPT = carnitine palmitoyltransferase; DCA = dichloroacetate; FADH2 = flavin adenine dinucleotide; LDH = Lactate dehydrogenase; MCD = malonyl CoA decarboxylase; MPC = mitochondrial pyruvate carrier; NADH = nicotinamide adenine dinucleotide; PDH = pyruvate dehydrogenase; PDK = pyruvate dehydrogenase kinase; PDP = pyruvate dehydrogenase phosphatase.

However, perhexiline has been associated with infrequent but serious hepatotoxicity and neuropathy that necessitates regular monitoring of plasma levels and makes perhexiline unsuitable for use in patients with hepatic or renal dysfunction.28

Malonyl CoA Decarboxylase Inhibitors Malonyl CoA is another potent, endogenous inhibitor of CPT-1 which decreases the uptake of fatty acids into the mitochondria, thereby reducing mitochondrial fatty acid beta-oxidation. Malonyl CoA decarboxylase (MCD) degrades malonyl CoA and this leads to an increase in fatty acid oxidation. Inhibition of MCD significantly increases malonyl CoA levels, therefore causing a significant decrease in fatty acid oxidation rates and a subsequent increase in glucose oxidation rates (Figure 3).

Inhibition of MCD in animal models has led to a significant improvement in cardiac functional recovery of aerobically reperfused ischaemic hearts.29 Inhibition of MCD in the heart appears to be a safe and promising therapeutic target for IHD but it is not yet ready for clinical testing.

Strategies to Reduce Fatty Acid Oxidation The concept of metabolic protection of the ischaemic myocardium is gaining more attention and is supported by clinical studies that have confirmed the beneficial effect of fatty acid oxidation inhibitors such as trimetazidine (TMZ) and ranolazine (RNZ), able to couple glycolysis to glucose oxidation.17

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Trimetazidine Trimetazidine (TMZ) has been the first and, for many years, the only registered drug in this class of anti-anginal agents. The beneficial effect of TMZ as an anti-anginal drug was established before it was discovered that the drug acts via partial inhibition of myocardial fatty acid oxidation.17,30,31 Initial preclinical studies demonstrated that it was cytoprotective in several models of myocardial ischaemia and reperfusion.32 Kantor et al. have shown that TMZ specifically inhibits the long-chain activity of the enzyme acetyl CoA C-acyltransferase; an enzyme that is commonly referred to as 3-KAT. The 3-KAT enzyme catalyses the terminal reaction of fatty acid beta-oxidation, using long-chain 3-ketoacyl CoA as a substrate, to generate acetyl CoA.33 These results suggest that TMZ removes the inhibition on PDH by inhibiting 3-KAT in the mitochondrial matrix, and increases the rate of glucose oxidation (Figure 3). TMZ has been shown to significantly increase the rate of glucose oxidation in rats’ hearts despite only modestly reducing the rate of fatty acid oxidation.33,34 In one study, a single dose of TMZ was shown to increase plasma levels of adenosine, suggesting a preconditioning role for this drug.35–37 Several studies have shown that TMZ alone or in addition to calcium channel blockers can effectively improve symptoms, quality of life and markers of ischaemia on stress tests in patients with chronic stable angina and ischaemic cardiomyopathy when used on top of conventional treatment.38–44 Moreover, clinical trials have proved the efficacy of this

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Trimetazidine and Other Metabolic Modifiers metabolic agent in refractory angina, and have supported the superior benefit associated to the addition of this metabolic agent to classic haemodynamic agents, such as beta-blockers or nitroglycerin.45–47 In the TRIMetazidine in POLand (TRIMPOL) II trial, a randomised, double-blind, placebo-controlled, multicentre study that recruited patients with stable angina, the addition of TMZ (20 mg three times a day) or placebo on top of metoprolol, resulted in an improvement in time to ST segment depression on exercise tolerance testing, total exercise workload, mean nitrate consumption and angina frequency when compared with patients receiving placebo.45 Similar efficacy was observed in the subgroup of patients revascularised with recurrent angina. The time to 1 mm ST-segment depression (STD) was increased with TMZ by 80 seconds and was significantly greater than that recorded in the placebo group (p<0.01). The time to onset of angina was significantly greater for the group treated with TMZ in comparison with placebo (p=0.031). The total duration of exercise was significantly greater than that recorded for patients with placebo plus metoprolol (p=0.048). A similarly significant observation was made regarding workload (p=0.035). The maximum ST-segment depression at peak exercise was significantly smaller in the TMZ group than the placebo group (p<0.01). The mean number of angina attacks per week was also reduced in patients receiving TMZ compared with those treated with placebo (p<0.01).45 The efficacy and acceptability of TMZ in combination with haemodynamic agents (beta-blockers or long-acting nitrates) was tested in the Trimetazidine in Angina Combination Therapy (TACT) study.48 After 12 weeks of therapy, exercise test duration significantly increased in the TMZ group, as well as time to 1 mm STD and time to onset of anginal pain. The mean number of angina attacks per week decreased in the TMZ group, along with mean consumption of short-acting nitrates per week. The addition of TMZ on beta-blockers or longacting nitrates therapy, significantly improved exercise stress test parameters and angina symptoms compared with placebo. In another randomised, double-blind, controlled trial in people with angina who were symptomatic despite taking propranolol, Michaelides et al. demonstrated that the addition of TMZ significantly decreased the mean number of angina attacks twice as much as isosorbide dinitrate alone.49 Similar results were also observed in the Efficacy of Trimetazidine on Functional Capacity in Symptomatic Patients with Stable Exertional Angina (VASCO-angina) study. This was a randomised, double-blind, placebo-controlled trial, which assessed the anti-anginal efficacy and safety of standard and high-dose modified-release TMZ (70 mg per day and 140 mg per day) in symptomatic and asymptomatic patients with chronic IHD receiving 50 mg per day of atenolol, on exercise test parameters.50 The VASCO-angina study confirmed the efficacy and tolerability of standard and high-dose TMZ in improving effort-induced myocardial ischaemia and functional capacity in patients with chronic stable angina receiving background beta-blockers.50 Furthermore, other studies and meta-analysis have supported the use of TMZ to improve clinical manifestation (i.e. total exercise duration, time to 1-mm ST-segment depression, weekly number of angina attacks, weekly nitroglycerin use, quality of life improvement) in patients with stable IHD.51 TMZ has also been proven to be effective in patients with microvascular angina.52 In a recent study, TMZ was given for 3 months (35 mg twice a day) to patients with microvascular angina and it was associated with better control of angina symptoms and stress

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testing results compared with conventional therapy (beta-blockers/ calcium channel blockers, statins, antiplatelets, long-acting nitrates).

Moreover, there was an improvement in myocardial perfusion and endothelial function probably due to a reduction in serum endothelin-1 (ET-1) levels and an increase in total antioxidant status.53 There was a collective decrease of average number of attacks per week and silent myocardial ischaemia, a reduction of mean weekly consumption of short-acting nitrates, an improvement in quality of life, reduced severity of main clinical manifestations of chronic heart failure (CHF) and lowering of its functional class.50,54–58 Moreover, similar efficacy of TMZ has been demonstrated in both men and women and it is also suitable for people with diabetes.59–62 A single dose of 60 mg TMZ (the normal cumulative daily dose) has shown to improve exercise capacity in people with angina pectoris, as reflected by an increase in the duration of exercise, total work performed, and an improvement in ECG signs of ischaemia. All these effects occur without any detectable chronotropic or vasomotor effect.63 One ongoing large, international, randomised study – the efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by percutaneous Coronary Intervention (ATPCI) trial – could provide definitive evidence into the clinical benefits of metabolic cardioprotection for patients who have been revascularised, whether for chronic stable angina or acute coronary syndrome.

Short and long-term administration of TMZ has proven to be beneficial in improving clinical parameters and survival in patients with CHF of different aetiology and even in older people.64–70 Indeed, TMZ can improve left ventricular function, exercise capacity and New York Heart Association functional classification, and endothelium-dependent dilation in patients with CHF.50 In addition to these results, in a metaanalysis conducted by Gao et al. TMZ had a significant protective effect for all-cause mortality, cardiovascular events and hospitalisation.71 Further confirming the role metabolic disturbances plays in myocardial ischaemia, TMZ use was associated with improved myocardial perfusion and contractile response in patients with chronically dysfunctional myocardium and ischaemic cardiomyopathy.72 In addition, it has been reported that TMZ has some anti-inflammatory properties because it can attenuate neutrophil activation, thereby protecting post-ischaemic hearts from neutrophil-mediated injury, suggesting a role for this drug in pre- and post-conditioning. TMZ has shown to be cardioprotective when administered before reperfusion.

This protection appears to be mediated by activation of p38-mitogenactivated protein kinase and Akt signalling.73 In summary, in patients with IHD, the addition of TMZ has been shown to decrease the amount of angina attacks per week, as well as silent myocardial ischemia episodes; it has reduced the needs for short-acting nitrates and has been shown to improve quality of life. All these results have been accompanied by enhanced exercise tolerance. TMZ has been demonstrated to be effective both in men and women, and in patients with or without diabetes. In patients with CHF, TMZ ameliorates negative left ventricular remodelling, enhances functional capacity, reduces mortality and improves event-free survival. For these reasons as well as its anti-anginal efficacy, TMZ can be used in patients with heart failure and reduced ejection fraction and refractory angina, in addition or as an alternative to conventional medication and is safe for patients with heart failure class IIb, level A.74 Moreover, TMZ has been shown to confer cardioprotection in animal models of ischaemia-reperfusion injury, particularly relevant

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Pharmacotherapy Figure 4: Main Mechanism of Action of Ranolazine Na+ Na+ + Na+ Na+ Na Na+ Na+

Ranolazine

1Ca2+ 2+

Na /Ca exchanger

NaCh

3Na+

• Improves contraction and relaxation (positive lusitropy)

Na+ +

Na+ Na+

Decreases calcium overload

metabolism. In an animal model of CHF, RNZ significantly increased left ventricular ejection fraction, peak LV+dP/dt and stroke volume, primarily by optimising cardiac metabolism in the setting of CHF.17 At the cellular level, RNZ influenced hypertrophy, fibrosis and capillary density, as well as the expression for pathological hypertrophy and Ca2+ cycling genes.87

Na+ Na+

Improves mitochondrial function • Increases ATP production • Reduces ROS generation • Prevents mPTP channels opening

1Ca2+

Ca2+ overload

Electrical stability • Prolongs APD • Decreases afterpotentials (EADs, DADs) • Decreases abnormal automaticity (DD) • Dispersion of repolarisation (re-entry)

Ranolazine has been reclassified as a late sodium current blocker. Glycolysis is the main catabolic pathway during ischaemia, whereas fatty acid oxidation is enhanced in this period.

As a consequence, less ATP is generated at the expense of more proton production, which are ultimately responsible for myocardial acidosis and the accumulation of ions (mainly calcium).

APD = action potential duration; ATP = adenosine triphosphate; DAD = delayed afterdepolarisation; DD = decreases abnormal automaticity; EAD = early afterdepolarisation; mPTP = mitochondrial permeability transition pore; ROS = reactive oxygen species.

in patients with stable angina who experience multiple episodes of ischaemia. Generally, TMZ is well-tolerated with minor side effects, mostly comprising gastrointestinal disturbances and headache.

However, some patients experience extrapyramidal complications making this drug unsuitable for patients with Parkinson’s disease and similar disorders.75 Precautions should be taken when prescribing to the elderly and those with moderate renal impairment who will need a reduced dose. Although its clinical benefits have been documented since the early 1980s, TMZ still lacks widespread clinical use. It has been classified in European guidelines as a second choice agent for the treatment of chronic ischaemic heart disease, receiving a non-justified class IIb level of recommendation, especially when compared with traditional agents which have been less extensively studied and more largely used.76,77

In 2006, RNZ was approved for the relief of angina in patients who remained symptomatic despite taking beta-blockers, calcium channel blockers, or nitrates.88,89 RNZ, even at dosages lower than that currently prescribed, has been shown to confer significant clinical benefit in controlling angina as a monotherapy or an add-on therapy.79–81,90 Shortterm use of RNZ therapy has been showed to improve myocardial perfusion and decrease the ischaemic burden, evaluated by single photon emission CT (SPECT).91 The anti-anginal activity of RNZ was tested as a monotherapy in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial. Compared with placebo, RNZ taken twice daily significantly increased exercise duration, time to onset of angina and time to diagnostic ST-segment depression in 175 patients who were not receiving other anti-anginal medications.81 RNZ was evaluated as combination therapy in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial. It was assessed in patients with anginal symptoms and reduced exercise capacity despite taking standard doses of atenolol, amlodipine or diltiazem. Exercise duration, time to angina and time to ischaemic ECG changes increased in both RNZ groups versus placebo group (p< 0.01).79 In a post hoc analysis, RNZ 750 and 1,000 mg reduced HbA1c versus placebo; the HbA1c levels appeared to remain unchanged over time during long-term therapy.92,93 In the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial, RNZ reduced the weekly frequency of angina and sublingual nitroglycerin use in subjects with type 2 diabetes, coronary artery disease and chronic stable angina who remained symptomatic despite treatment with up to two anti-anginal agents.94 The therapeutic benefits of RNZ were shown to be greater in those with higher HbA1c values.95

Ranolazine Ranolazine (RNZ) is structurally related to piperazine and is similar to TMZ. It has proved to be effective in patients with chronic stable angina on top of or in combination with traditional antianginal drugs.78 RNZ was shown to display anti-ischaemic properties by promoting glucose oxidation at the expense of fatty acid oxidation (Figure 3).79–81 In addition to this, RNZ induces a reduction in intracellular calcium overload through inhibition of the late sodium channels, with consequent attenuation of oxidative stress (Figure 4).82,83 Randomised clinical trials have demonstrated an improvement in exercise capacity and reduction in angina episodes with ranolazine in patients with chronic stable angina. In patients undergoing elective coronary angioplasty, ranolazine demonstrated a reduction in periprocedural MI.84 Moreover, in women with evidence of MI, angina and no obstructive coronary stenosis, ranolazine improved quality of life, angina stability and myocardial perfusion reserve index.85 This therapeutic benefit occurs without the haemodynamic effects seen with conventional anti-anginal agents.86 Despite QTc-prolonging action, clinical data have not shown a predisposition to torsades de pointes, and the medication has shown a reasonable safety profile even in those with structural heart disease. RNZ may play a role in the treatment of patients with CHF as its mode of action involves the inhibition of late sodium current and it is able to modulate myocardial

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RNZ has proven to be effective not only in patients with coronary artery disease, but also in those with microvascular dysfunction.96 Compared with placebo, patients on RNZ had significantly better Seattle angina questionnaire scores, including physical functioning, angina stability and quality of life. There was a trend towards better mid-ventricular perfusion when using RNZ. Among women with coronary reactivity testing, those with coronary flow reserve (CFR) ≤3.0 had a significantly improved perfusion on RNZ versus placebo compared with women with CFR >3.0.95 This phase 2 study provided the basis to conduct a definitive large clinical trial to evaluate the role of RNZ in microvascular coronary dysfunction.85 Despite original observations, RNZ has been shown to improve non-invasive CFR in women with MI and no obstructive coronary atherosclerosis.97 When evaluated for chronic stable angina, as in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (MERLIN-TIMI 36) trial, the addition of RNZ to standard treatment was not effective in reducing major cardiovascular events.98 However, RNZ proved to be more effective in reducing recurrent ischaemia in this high-risk population, having particular efficacy in reducing recurrence of ischaemic events in women without increasing

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Trimetazidine and Other Metabolic Modifiers the risk of fatal arrhythmias, despite QT prolongation.99–101 In a post hoc analysis, in patients with BNP >80pg/ml, RNZ reduced the primary end point (a composite of cardiovascular death, myocardial infarction and recurrent ischemia).102 As with the CARISA trial, RNZ treatment improved glycaemic control, reducing fasting plasma glucose and HbA1c levels.93 Despite such promising results, in the subset of patients with stable angina that had been incompletely revascularised the Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention [RIVER-PCI] study), RNZ at the doses of 1,000 mg twice a day failed to ameliorate angina and quality of life and to reduce the composite rate of ischaemia-driven revascularisation or hospitalisation without revascularisation.103,104 In a second analysis of the RIVER-PCI trial, specifically evaluating the role of RNZ on angina frequency and quality of life in relation to diabetes, RNZ ameliorated glycaemic control (HbA1c) at 6 and 12 months compared with placebo.

In line with this result, in people with diabetes, angina frequency and quality of life was better at 6 months, but remained unchanged at 1-year follow-up. Better results were observed in patients with poor glycaemic control at enrolment (HbA1c≥58 mmol/mol).105 Larger trials are warranted to find out whether RNZ is capable of improving morbidity and mortality. In summary, RNZ appears to be an effective anti-anginal drug with great potential to fill an unmet need in the management of patients with IHD. The availability of an effective, well-tolerated, and apparently safe, anti-anginal medication such as RNZ is particularly important for patients with angina who are not candidates for revascularisation and for patients with persistent angina. This population appear to have an increased risk of developing cardiac arrhythmias and may benefit from the adjunct of RNZ on top of other medication.83,106–108 In addition to these data, new evidence suggest a possible benefit of using RNZ for CHF due to its ability to modulate myocardial metabolism and its action on late sodium current, which may suggest that this drug may offer additional benefits in patients with ischaemic and non-ischaemic cardiomyopathy due to different aetiology.87,109–115 RNZ has a good safety profile with mild gastrointestinal side-effects (constipation and nausea) and dizziness.

Caution should be applied when RNZ is used in patients who already take medication to prolong QT and have liver cirrhosis. However,

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RNZ-induced QT prolongation has not been associated with torsades de pointes. RNZ may be used as an alternative when beta-blockers are not tolerated in patients with heart failure with reduced ejection fraction and ischaemic heart disease. RNZ can also inhibit late Na(+) current, suggesting a clinical role for this drug in patients with long QT syndrome type 3.116–118 RNZ has been a major success and has gained a class IIa level B recommendation for angina relief in both European and American guidelines on management of stable IHD.1,10

Conclusions Metabolic agents can be recommended in conjunction with or as an alternative when classic anti-anginal agents are not tolerated or they are contraindicated. Their efficacy has been proven in clinical trials in patients with refractory angina, chronic IHD and in patients exposed to ischaemia-reperfusion injury. Moreover, in patients with heart failure, metabolic agents slow the progression of the disease and improve prognosis. The failing and the ischaemic heart are energy-starved organs dependent on inefficient fatty acid oxidation.

Metabolic agents induce a switch in substrate use, rendering the heart more oxygen efficient. Through this and other mechanisms, modulation of cellular energetics has the potential to improve cardiac performance and reduce symptoms in patients with chronic stable angina without relying on alteration of haemodynamics or further neuro-hormonal modulation. As such, agents acting with this approach are likely to complement or substitute, rather than mimic, established therapy and hold a possibility for clinical benefit in a wide range of cardiovascular disorders.

Cardiac metabolic modulators open the way to a better understanding of ischaemic heart disease and its common clinical manifestations, where myocardial ischaemia is no longer considered as a mere imbalance in oxygen and metabolites demand/supply but as an energetic disorder. A better understanding of the mechanisms underlying IHD and chronic stable angina helps in the selection of the most appropriate agents, to properly design clinical trials, to improve symptoms and to improve patient prognosis.

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Rich MW, Crager M, McKay CR. Safety and efficacy of extended-release ranolazine in patients aged 70 years or older with chronic stable angina pectoris. Am J Geriatr Cardiol 2007;16:216–21. https://doi.org/10.1111/j.10767460.2007.07119.x; PMID: 17617747.

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Trimetazidine and Other Metabolic Modifiers 90. C occo G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol 1992;20:131–8. PMID: 1383622.

91. Venkataraman R, Belardinelli L, Blackburn B, et al. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc Imaging 2009;2:1301–9. https://doi.org/10.1016/j. jcmg.2009.09.006; PMID: 19909934.

92. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006;27:42–8. https://doi.org/10.1093/ eurheartj/ehi495; PMID: 16176940.

93. Chisholm JW, Goldfine AB, Dhalla AK, et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care 2010;33:1163–8. https://doi.org/10.2337/dc09-2334; PMID: 20357382.

94. Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol 2013;61:2038–45. https://doi.org/10.1016/j.jacc.2013.02.011; PMID: 23500237.

95. Arnold SV, McGuire DK, Spertus JA, et al. Effectiveness of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina according to baseline hemoglobin A1c. Am Heart J 2014;168:457–65.https://doi.org/10.1016/j. ahj.2014.06.020; PMID: 25262254.

96. Mehta PK, Goykhman P, Thomson LE, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging 2011;4:514–22. https://doi.org/10.1016/j. jcmg.2011.03.007; PMID: 21565740.

97. Tagliamonte E, Rigo F, Cirillo T, et al. Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease.

Echocardiography 2015;32:516–21. https://doi.org/10.1111/ echo.12674; PMID: 25041234.

98. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al.

Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297:1775–83. https://doi.org/10.1001/jama.297.16.1775; PMID: 17456819.

99. Melloni C, Newby LK. Metabolic efficiency with ranolazine for less ischemia in non-ST elevation acute coronary syndromes (MERLIN TIMI-36) study. Expert Rev Cardiovasc Ther 2008;6:9–16. https://doi.org/10.1586/14779072.6.1.9;

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100. Mega JL, Hochman JS, Scirica BM, et al. Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromesthrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation 2010;121:1809–17. https://doi.org/10.1161/ CIRCULATIONAHA.109.897231; PMID: 20385930.

101. Karwatowska-Prokopczuk E, Wang W, Cheng ML, et al. The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: effect of ranolazine. Europace 2013;15:429–36. https://doi. org/10.1093/europace/eus400; PMID: 23258816.

102. Morrow DA, Scirica BM, Sabatine MS, et al. B-type natriuretic peptide and the effect of ranolazine in patients with non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial.

J Am Coll Cardiol 2010;55:1189–96. https://doi.org/10.1016/j. jacc.2009.09.068; PMID: 20298924.

103. Alexander KP, Weisz G, Prather K, et al. Effects of ranolazine on angina and quality of life after percutaneous coronary intervention with incomplete revascularization: results from the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) Trial. Circulation 2016;133:39–47. https://doi. org/10.1161/CIRCULATIONAHA.115.019768; PMID: 26555329.

104. Weisz G, Genereux P, Iniguez A, et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:136–45. https://doi.org/10.1016/S0140-6736(15)00459-6; PMID: 26474810.

105. Fanaroff AC, James SK, Weisz G, et al. Ranolazine after incomplete percutaneous coronary revascularization in patients with versus without diabetes mellitus: RIVER-PCI Trial.

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106. Antzelevitch C, Burashnikov A, Sicouri S, et al.

Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm 2011;8:1281–90. https://doi. org/10.1016/j.hrthm.2011.03.045; PMID: 21421082.

107. Bunch TJ, Mahapatra S, Murdock D, et al. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol 34:1600–6. https://doi.org/10.1111/j.1540-8159.2011.03208.x; PMID: 21895727.

108. Frommeyer G, Rajamani S, Grundmann F, et al. New insights into the beneficial electrophysiologic profile of ranolazine in heart failure: prevention of ventricular fibrillation with

increased postrepolarization refractoriness and without drug-induced proarrhythmia. J Card Fail 2012;18:939–49. https://doi.org/10.1016/j.cardfail.2012.10.017; PMID: 23207083.

109. Sabbah HN, Chandler MP, Mishima T, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002;8:416–22. https://doi.org/10.1054/jcaf.2002.129232; PMID: 12528095.

110. Chandler MP, Stanley WC, Morita H, et al. Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. Circ Res 2002;91:278–80. https://doi.org/10.1161/01.RES.0000031151.21145.59; PMID: 12193459.

111. Aaker A, McCormack JG, Hirai T, et al. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol 1996;28:353–62. https://doi.org/10.1097/00005344199609000-00002; PMID: 8877580.

112. Randle PJ, Garland PB, Hales CN, et al. The glucose fattyacid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785–9. https:// doi.org/10.1016/S0140-6736(63)91500-9; PMID: 13990765.

113. Sossalla S, Wagner S, Rasenack EC, et al. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts – role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol 2008;45:32–43. https://doi. org/10.1016/j.yjmcc.2008.03.006; PMID: 18439620.

114. Wu Y, Song Y, Belardinelli L, et al. The late Na+ current (INa) inhibitor ranolazine attenuates effects of palmitoyl-Lcarnitine to increase late INa and cause ventricular diastolic dysfunction. J Pharmacol Exp Ther 2009;330: 550–7. https://doi. org/10.1124/jpet.109.151936; PMID: 19403851.

115. Fragasso G, Spoladore R, Cuko A, et al. Modulation of fatty acids oxidation in heart failure by selective pharmacological inhibition of 3-ketoacyl coenzyme-A thiolase. Curr Clin Pharmacol 2007;2:190–196. https://doi. org/10.2174/157488407781668776; PMID:18690865.

116. Singh BN, Wadhani N. Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs. J Cardiovasc Pharmacol Ther 2004;9:S85–97. https://doi.org/10.1177/ 107424840400900107; PMID: 15378133.

117. Moss AJ, Zareba W, Schwarz KQ, et al. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol 2008;19:1289–93. https://doi.org/10.1111/j.15408167.2008.01246.x; PMID: 18662191.

118. Kaufman ES. Use of ranolazine in long-QT syndrome type 3. J Cardiovasc Electrophysiol 2008;19:1294–5. https://doi. org/10.1111/j.1540-8167.2008.01255.x; PMID: 18662183.

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Pharmacotherapy

Using Pharmacogenetic Testing or Platelet Reactivity Testing to Tailor Antiplatelet Therapy: Are Asians different from Caucasians?

Doreen Tan Su-Yin Pharmacy Department, PGY2 Cardiology Pharmacy Residency Programme and Pharmacogenomics, Clinical Adoption Workgroup, Precision Medicine Initiatives, Ministry of Health, Singapore

Abstract All studies to date involving platelet reactivity and gene testing document singular interventions and their associations with outcomes. The East Asian paradox has been well documented – Asians who have had a percutaneous coronary intervention (PCI) are at a lower risk of ischaemic events even though they have a higher platelet reactivity. Asians who have had a PCI also have a higher risk of bleeding. This article covers the differences in outcomes between Caucasians and Asians, and explores the impact of outcomes, highlighting differences between the two patient populations. Given the high prevalence of loss-of-function alleles in Asia, treatment strategies will differ for different populations. It is plausible that both platelet reactivity and gene testing should be used to inform holistic decision-making for all patients – Caucasian or Asian – with acute coronary syndrome who are undergoing PCI.

Keywords Clopidogrel, de-escalation, CYP2C19 gene testing, platelet reactivity testing, Asian Disclosure: The author has no conflict of interest to declare.

Received: 29 October 2018 Accepted: 30 October 2018 Citation: European Cardiology Review 2018;13(2):112–4. DOI: https://doi.org/10.15420/ecr.2018.13.2.EO2 Correspondence: Doreen Tan Su-Yin, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828. E: tan.doreen.sy@ktph.com.sg

Ischaemic heart diseases (IHD) – mainly MI – represent a large disease burden all over the world. Almost 18 million people die each year from cardiovascular diseases, accounting for 31 % of deaths globally.1 Ticagrelor, the more potent cousin of antiplatelet therapy clopidogrel, has been shown to reduce the composite endpoint of death from vascular causes, MI or stroke by an additional 16 % compared with clopidogrel when used with aspirin.2 Controversially, a meta-analysis of similar patient groups in Asia demonstrated that these ticagrelor benefits did not seem to be replicated in Asians, and Asian patients treated with ticagrelor experienced more bleeding. Even less is known about a third P2Y12 inhibitor, prasugrel.3,4 While international guidelines promote the use of ticagrelor and prasugrel over clopidogrel for patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI), the World Heart Federation issued a consensus statement in 2014 on antiplatelet use in East Asians with ACS or requiring PCI, clearly stating that there is insufficient data to suggest that ticagrelor or prasugrel are superior to clopidogrel for this patient group.5 Notably, East Asian patients have a similar or an even lower rate of ischaemic events after PCI compared with Caucasian patients, despite a higher level of platelet reactivity during dual antiplatelet therapy (DAPT). Asians have also been found to have a higher risk of bleeding. This has been dubbed the ‘East Asian Paradox’, and it has been suggested that there should be a different approaches to treatment for Caucasian patients and Asian patients who have undergone PCI.5,6 The clinical benefits of ticagrelor and prasugrel come at a price – not only do they cost more than clopidogrel, but they also increase the risk of bleeding. In the Trial to Assess Improvement in

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Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON TIMI) 38, the medical community was warned about the use of prasugrel in patients with a past history of stroke, age >75 years and a body weight <60 kg.7 Consequently in Japan, the dose labelled for use was one-third of the dose used in Caucasians.8 Additionally, the Asian counterpart, Phase the International Study of Ticagrelor and Clinical Outcomes in Asian ACS Patients (PHILO) study, was not able to replicate the ischaemic benefits seen in US patients in the PLATelet Inhibition and Patient Outcomes (PLATO) trial; and the bleeding rate was twice that seen in PLATO.2,9 In the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS) trial, ticagrelor was used for an extended period at a reduced dose of 60 mg twice daily beyond the first year, and the number needed to treat (NNT) and number needed to harm (NNH) was similar at three years (79 versus 81, respectively).10 More recently, there have been a series of guided strategies for de-escalation of antiplatelet therapy.11 The strategy to de-escalate could be driven by the risk of bleeding (unguided), or platelet reactivity testing (guided). This could be particularly important for Asians, as illustrated in a large registry study of patients with ST-elevation MI (STEMI) that identified Asian ethnicity as an independent predictor of major in-hospital bleeding compared with Caucasians (3.6 % versus 2.2 %, p<0.001; OR 1.32, p<0.001).12 In our single-centre observational study of 349 Asian STEMI subjects started on ticagrelor, there were 8.5 % clinically significant bleeds for

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Platelets and the Coagulation System Table 1: Average P2Y12 Reactivity Units by Phenotype Group Phenotype

n

Mean P2Y12 reactivity units

SD

SE

95% CI for Mean Lower Bound

Upper Bound

Minimum

Maximum

Poor

36

211.17*

77.612

12.935

184.91

237.43

97

394

Intermediate

117

176.30†

79.805

7.378

161.69

190.91

4

422

Extensive

82

140.06*

64.421

7.114

125.91

154.22

4

360

Ultrarapid

12

127.92*

63.662

18.378

87.47

168.37

8

224

Total

247

167.00

77.788

4.950

157.25

176.75

4

422

†

*Poor metaboliser compared with extensive metaboliser and ultrarapid metaboliser, p<0.001 and p=0.005 respectively; †Intermediate metaboliser compared with extensive metaboliser, p=0.005, Bonferroni correction applied.

CYP2C19 genotype mutations and its associations with greater major adverse cardiovascular event (MACE) risk is well documented. Numerous meta-analyses have demonstrated that CYP2C19 loss-of-function (LoF) alleles is associated with significantly worse ischaemic outcomes if clopidogrel is used in ACS patients undergoing PCI. While it is known that CYP2C19 genotype variations influence the antiplatelet activity of clopidogrel, neither ticagrelor nor prasugrel appear to be affected by the same mutations. This has led to international drug label approval bodies to acknowledge of the clinical significance of poor metaboliser (PM) and intermediate metaboliser (IM) phenotypes compared with extensive metaboliser (EM) and ultrarapid metaboliser (UM) phenotype groups, following the Clinical Pharmacogenetics Implementation Consortium guidelines.16 The American and Dutch guidelines recommend that ticagrelor or prasugrel should be used for PM and IM.16,17 Sorich’s metaanalysis revealed that Asian populations who had PCI and at least one LoF allele have worse ischaemic outcomes than with Caucasians with at least one LoF allele and PCI. The authors state that this is particularly worrying since the incidence of at least one LoF allele in Asians is 53.9 %, compared with 28.4 % in Caucasian patients.18 Our local data corroborates these authors’ findings, with LoF alleles present in at least 60 % of subjects studied.19,20 Furthermore, our own CLOpidogrel – PRAsugrel Switch study (CLOPRA) population comprising 247 patients with ACS found that those with PM are at 10-fold increased risk of developing an ischaemic event compared with those with EM (30.8 % versus 13.7 %, OR 10.2, p=0.042).16 Cohort studies based in America have shown that using alternatives to clopidogrel is associated with reduced ischaemic outcomes, while high dose clopidogrel did not seem to mitigate ischaemic risk of LoF subjects.21–23 The ongoing prospective randomised controlled trial, Tailored Antiplatelet Therapy Following PCI (TAILOR-PCI) which assigns

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Figure 1: Clopidogrel or Prasugrel Use by CYP2C19 Phenotype Group 100 Kept on clopidogrel Switched to prasugrel/HOTR 80 Number of subjects

those receiving ticagrelor for a full 12 months duration, compared with 7.8 % in the de-escalated group (HR 3.36; p=0.047). In the de-escalated group, 5.9 % of bleeds occurred while on ticagrelor and only 1.8 % while on clopidogrel (unpublished data). Notably, the net clinical benefit study Timing of Platelet Inhibition After Acute Coronary syndrome (TOPIC) demonstrated that the strategy of unguided de-escalation of ticagrelor to clopidogrel at 1 month does not result in increased risk of ischaemic events but significantly reduces bleeding at 1 year.13 Its platelet function sub-study TOPIC Vasodilator-Stimulated Phosphoprotein (TOPIC-VASP) elucidated that while de-escalation was superior regardless of initial platelet reactivity, the benefit was greater in low on-treatment platelet reactivity patients.14 The European Society of Cardiology 2018 guidelines for myocardial revascularisation now alludes to the potential use of platelet reactivity testing to consider de-escalation of antiplatelet therapy.15

60

40

20

0

PM

IM

EM

UM

CYP2C19 phenotype

HOTR/ Prasugrel use (%)

PM

IM

EM

UM

Total

11 (31.4 %)

23 (20.5 %)

5 (6.3 %)

0 (0 %)

39

EM = extensive metaboliser; HOTR = high on-treatment reactivity; IM = intermediate metaboliser; PM = poor metaboliser; UM = ultra metaboliser.

LoF subjects to alternative treatments to clopidogrel, will give us firmer answers in regard to the effectiveness of alternatives in this group.24 How is platelet reactivity related to genotype mutation? An East Asian group undertook a prospective registry study comprising more than 4,000 subjects, looking at the genetic effects on platelet reactivity and 1-year outcomes. CYP2C19 was significantly associated with high on-treatment platelet reactivity (OPR), and the number of CYP2C19*R (*2 or *3) alleles was proportional to the increased risk of high OPR. The other single-nucleotide polymorphisms – CYP2C9, ABCB1, PON1 and P2Y12 – were not significantly associated with high OPR.25 We present a similar relationship with our Southeast Asian CLOPRA subjects. Table 1 shows that the average OPR significantly differed when comparing PM with EM and UM (p<0.001 and p=0.005, respectively) and IM compared with EM (p=0.005). However, we also found that platelet reactivity testing, with P2Y12 reactivity units (PRU) cut-off at 230 only picked up 31.4 % and 20.5 % of PM and IM as high OPR (Figure 1). As PRU was used as the strategy to switch therapies, the majority of patients with IM and PM were kept on clopidogrel.

We thus had the opportunity to observe MACE and bleeding rates for the patients who were left on clopidogrel for the full duration of

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Pharmacotherapy follow-up. We observed that the non-LoF clopidogrel patients experienced 1.1 % incidence of MACE while the event rate of LoF patients taking clopidogrel and LoF who were prescribed prasugrel were 8.8 % and 5.9 % respectively. LoF subjects who stayed on clopidogrel had a statistically significant 8.7-fold increased risk of MACE compared with non-LoF left on clopidogrel (p=0.041).

The clinical community has now been thrown into a conundrum in respect to how best to decide which P2Y12 inhibitor to use, for what duration, and if we should be using platelet reactivity, CYP2C19 phenotype or both to guide our choice of antiplatelet therapy. The most attractive, logical solution would be to use both platelet reactivity testing and CYP2C19 phenotype in decision-making algorithms, alongside traditional cardiovascular risk factors.26 Since the high OPR cut-off in Asians was suggested to be higher than that in Caucasian people, coupled with our findings, CYP2C19 genotype testing might be the more effective test to use.25 However, it is attractive to consider the use of rapid point-of-care platelet reactivity testing for two reasons: it offers the pharmacodynamics of how the antiplatelet is working, akin to how we use international normalised ratio for warfarin, and genotyping may take up to 3 days to run and discharge decisions have to be rapid, especially for escalation strategies.

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While we patiently await TAILOR-PCI findings based predominantly in countries with a mainly Caucasian population, now would be a great time to carry out large-scale, well-designed studies using either one or both gene and platelet reactivity assays to determine the best means to use both for an Asian population , especially in a real-world setting. However, platelet reactivity cut-offs must first be defined for Asians. For this to succeed, research, governmental and administration bodies and pharmaceutical industries must support the need for such large-scale, Asian studies. For now, it is certainly permissible to use pharmacogenomic testing to escalate antiplatelet therapy, and potentially de-escalate antiplatelet therapy in patients who have a high risk of bleeding.

Lastly, since Asian ethnicity is independently associated with major bleeding with ticagrelor and prasugrel, coupled with a higher incidence of CYP2C19 LOF, studying this issue is more pressing for Asians than for Caucasians.3,6 Biomarkers such as gene testing and platelet reactivity testing assist us in the holistic assessment of the risks of therapy and treatment. Therefore, there is certainly a strong case for routine gene testing for escalation or de-escalation, particularly in Asians, after there has been a holistic consideration of procedural or anatomical risk factors for MACE and factors associated with bleeding.20

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14. Deharo P, Quilici J, Camoin-Jau L, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome according to on-treatment platelet reactivity: the TOPIC-VASP pre-specified analysis of the TOPIC randomized study. JACC Cardiovasc Interv 2017;10:2560–70. https://doi.org/10.1016/j. jcin.2017.08.044; PMID: 29268886.

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Zhang L, Yang J, Zhu X, et al. Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention – a systematic review and meta-analysis. Thromb Res 2015;135:449–58. https://doi. org/10.1016/j.thromres.2014.12.007; PMID: 25511576.

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Baber U. Defining PCI complexity in the contemporary DES era: Clarity or confusion? Int J Cardiol 2018;268:94–5. https://doi.org/10.1016/j.ijcard.2018.05.044; PMID: 30041807.

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Anticoagulation in Patients with Ischaemic Heart Disease and Peripheral Arterial Disease: Clinical Implications of COMPASS Study Josep Gradolí, 1 Verónica Vidal, 1 Adrian JB Brady 2 and Lorenzo Facila 1 1. Department of Cardiology, Hospital General Universitario, University of Valencia, Valencia, Spain; 2. Department of Cardiology, Glasgow Royal Infirmary, Glasgow, UK

Abstract Patients with established cardiovascular disease may suffer further cardiovascular events, despite receiving optimal medical treatment.

Although platelet inhibition plays a central role in the prevention of new events, the use of anticoagulant therapies to reduce events in atheromatous disease has, until recently, been overlooked. The recent Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) study showed an important reduction in cardiovascular events without increasing the risk of fatal and intracranial bleeding when using rivaroxaban, a novel oral anticoagulant, combined with aspirin. This article reviews the available evidence regarding the use of anticoagulant therapies for prevention of cardiovascular events, the results of the COMPASS study and how these results may affect patient management in everyday clinical practice.

Keywords Cardiovascular disease, cardiovascular events, clinical practice, COMPASS, novel oral anticoagulants, rivaroxaban, secondary prevention, thrombosis Disclosure: Adrian Brady and Lorenzo Facila have received speaker fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Daiichi-Sankyo.

The other authors have no other conflicts of interest to declare.

Received: 20 April 2018 Accepted: 21 September 2018 Citation: European Cardiology Review 2018;13(2):115–8. DOI: https://doi.org/10.15420/ecr.2018.12.2 Correspondence: Lorenzo Fácila Rubio, Department of Cardiology, Consorcio Hospital General Universitario de Valencia, Avda Tres Cruces 2, 46014 Valencia, Spain.

E: lfacila@gmail.com

Atherosclerotic cardiovascular disease (CVD) comprises a large number of related pathologies, including ischaemic heart disease and peripheral arterial disease (PAD).1 This group of illnesses is the main cause of global morbidity and mortality and its prevalence increases remorselessly.2 Despite implementation of guideline-based therapy and optimal medical treatment, patients with established CVD may suffer further cardiovascular events (CVE). This is known as residual risk and research into therapeutic strategies to reduce this has intensified in recent years.3 Along with control of classic cardiovascular (CV) risk factors, platelet inhibition plays a central role in the prevention of new events.4,5 However, this inhibition only achieves a partial risk reduction, even when two antiplatelet drugs are combined.6–8 Antithrombotic therapies that affect the synthesis or action of fibrin – typically heparin and warfarin – have been in widespread use as anticoagulants for many decades but their prolonged use to reduce events in atheromatous disease has, until recently, been largely overlooked.

Initial studies evaluating the use of warfarin in secondary prevention of MI showed a significant benefit, although this came at the cost of a substantial risk of bleeding.9–11 However, the emergence of the novel oral anticoagulant (NOAC) drugs, with a better safety profile,has resulted in the re-emergence of interest into the role of anticoagulation in the prevention of CVE.12–15

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The recent Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) study evaluated the use of rivaroxaban, an oral anticoagulant that is a selective inhibitor of factor Xa.16 Patients with established CVD in sinus rhythm were randomised to low-dose rivaroxaban plus aspirin, versus aspirin alone.

There was an important reduction in CVE without increasing the risk of fatal and intracranial bleeding. However, the impact of the COMPASS study results for standard clinical practice remains to be defined.

Atherosclerotic Cardiovascular Disease The atherosclerotic process of coronary artery disease (CAD) starts with the formation of lipid streaks in the wall of blood vessels, between the endothelium and the internal elastic lamina. These lipid streaks contain atherogenic lipoproteins and macrophage foam cells.

Over time, a necrotic centre of lipids and an extracellular matrix are wrapped in a fibrous covering of smooth muscle cells, establishing the atheromatous plaque.17 The instability and rupture of the plaque has an essential role in the development of acute coronary syndrome (ACS). Rupture of the plaque exposes the highly thrombogenic core, producing platelet adhesion and aggregation.17,18 Furthermore, with the rupture of the plaque, cholesterol crystals are released as well as multiple proteins that activate the coagulation cascade, leading to the formation of an occlusive thrombus.18 Patients with CAD may present either with stable chronic angina, as an atheromatous plaque gradually develops with a low lipid content and thick fibrous covering, or with ACS, when a fissure appears in a plaque

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Pharmacotherapy with a high lipid content (vulnerable or unstable) with the consequent thrombus formation on its surface.18,19 Risk stratification will identify those who may benefit from revascularisation. Lifestyle modification and control of CV risk factors should be promoted for all.20 Clinical practice guidelines recommend aspirin as the standard antiplatelet treatment,21–23 clopidogrel as an alternative in cases of intolerance or contraindication to aspirin, and a combination of antiplatelet agents in selected patients with high risk of ischaemic events.24,25 Dual antiplatelet therapy (DAPT) is usually prescribed for 3–12 months.21,24,25 In the context of ACS, there is only one study showing long-term benefit up to three years following the index ACS event.

The recent Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS) trial showed that DAPT up to 36 months with ticagrelor and aspirin decreased the primary endpoint (cerebrovascular accident and MI) with a modest increase in bleeding risk.

However, the thrombotic process involves fibrin as well as platelets and for decades cardiologists have considered trying to modulate the coagulation cascade as well as platelet action. NOACs have only recently arrived to make such combination therapy a real possibility.

use of NOACs had previously been studied in patients with unstable CVD, mainly in the context of ACS. Initial studies carried out years ago using VKAs showed a reduction in CVE but with a substantial increase in bleeding risk. This benefit was observed with the use of moderate and high warfarin doses and an international normalised ratio (INR) greater than 2.0, but low-intensity treatment (INR less than 2.0) showed no benefit. For example, the Warfarin-Aspirin Reinfarction Study II (WARIS-II) compared the use of aspirin (160 mg daily), aspirin (75 mg) associated with warfarin (target INR 2.0–2.5) and warfarin alone (target INR 2.8–4.2). A significant reduction in CVE was observed (combined endpoint: CV death, nonfatal reinfarction, thromboembolic stroke) in the groups treated with VKA drugs as monotherapy (HR 0.81; 95 % CI [0.69–0.95], p=0.03) or combined with aspirin (HR 0.71; 95 % CI [0.60–0.83], p=0.001) compared with aspirin alone.31 In both groups treated with warfarin, an increase in the annual rate of non-fatal major bleeding was observed in comparison with aspirin monotherapy (0.67 % versus 0.17 %, p<0.001). Similar data on comparable characteristics were obtained in studies such as Combination Hemotherapy And Mortality Prevention (CHAMP),32 Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2)33 and Organization to Assess Strategies for Ischemic Syndromes (OASIS),34 among others.

Rivaroxaban Rivaroxaban, an oral anticoagulant with no vitamin K antagonist (VKA) activity, is a drug capable of directly and selectively inhibiting free factor Xa, as well as factor Xa linked to prothrombinase or associated with thrombi. It has an oral bioavailability close to 100 %, is not affected by food intake and its anticoagulant action has proven to be predictable – having a dose-dependent potency so it can be used in fixed doses – without the need for routine anticoagulation controls.

Rivaroxaban’s use is currently approved in the prevention of venous thromboembolism in adult patients who are going to undergo a knee or hip prosthesis implantation and in the prevention of embolic events in patients with non-valvular AF. Further studies have also recently shown the potential usefulness of rivaroxaban in the prevention of atherothrombotic CVE; it is not only capable of inhibiting the thrombin formation but it can also interfere with platelet activation.26 Following these observations, different mechanisms have been proposed to explain the vascular protection associated with this drug. Firstly, it significantly reduces the formation, progression and destabilisation of cholesterol plaques through an anti-inflammatory mechanism, blocking macrophage activation and it inhibits thrombotic formation over unstable plaques.27 Secondly, it promotes viability, growth and migration of endothelial cells, protects them from the proinflammatory effects of factor Xa, improving endothelial function28 and it facilitates vascular neoformation.29 In addition, rivaroxaban’s use is associated with an enhancement of bone formation and resorption parameters and an improvement of pulse wave velocities when compared with VKAs, as vitamin K is an essential cofactor in the correct functioning of phosphocalcium metabolism and its variations can precipitate the appearance of osteoporosis and, even more importantly, vascular calcification.30

Anticoagulation and Cardiovascular Prevention: Pre-COMPASS Evidence The COMPASS study provides the only available data supporting anticoagulant therapy in the prevention of events in stable CVD.16 The

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The substantial advantages of NOACs compared with well-managed warfarin have been demonstrated in large randomised clinical trials – Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation –Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) with edoxaban, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban, Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF) with rivaroxaban and Randomized Evaluation of LongTerm Anticoagulation Therapy (RE-LY) with dabigatran.35–38 Following these trials, several studies have been carried out recently to evaluate the potential role of this pharmacological group in secondary prevention of atherothrombotic CVE. In the RandomizEd Dabigatran Etexilate Dose Finding (RE-DEEM) study, patients who had suffered an ACS (ST-elevation MI or non-STelevation MI) were randomly assigned to receive dabigatran (50, 75, 110 or 150 mg) plus conventional therapy consisting of a thienopyridine (e.g., clopidogrel) and aspirin, or placebo plus conventional therapy.39 The use of dabigatran was associated with up to a fourfold increase in risk of clinically relevant minor bleeding and major bleeding, and showed a dose-dependent relationship. CVE were less common in patients treated with higher doses of dabigatran (110 and 150 mg).

The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) study that tested the use of apixaban in a similar clinical trial had to be stopped early because of a considerable increase in the risk of bleeding in patients receiving this new anticoagulant.40 Rivaroxaban is the best studied of the NOACs; as well as the COMPASS study other trials have evaluated its efficacy and safety in the prevention of CVE. In patients with ACS, the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2–Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2 - TIMI 51) study showed a significant reduction in the risk of CV death,

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Anticoagulation in Patients with IHD and PAD acute MI (AMI) and stroke (HR 0.84; 95 % CI [0.74–0.96], p=0.008) with both tested dosages of rivaroxaban (2.5 mg or 5.0 mg twice daily), compared with placebo.41 Only the 2.5 mg dose reduced all-cause mortality (2.9 % versus 4.5 %, p=0.002). Compared with placebo, rivaroxaban led to an increase in the rates of major and intracranial bleeding and a non-significant increase in fatal bleeding. On the other hand, the Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI-ACS-1) compared the use of aspirin 100.0 mg and rivaroxaban 2.5 mg twice daily added to clopidogrel or ticagrelor after ACS.42 The bleeding rate at the end of follow-up was similar in both groups (HR 1.09; 95 % CI [0.80–1.50], p=0.584), as well as CV morbimortality (HR 1.06; 95 % CI [0.77–1.46], p = 0.731) and all-cause mortality.

The Study Exploring Two Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) of patients with non-valvular AF who underwent percutaneous coronary intervention, compared the use of low dosages of rivaroxaban (15.0 mg daily or 10.0 mg daily in a single dose) with very low dosages of rivaroxaban (2.5 mg twice daily) together with DAPT versus triple standard therapy of aspirin/clopidogrel/warfarin, for one, six or 12 months. At 12 months the rate of significant bleeding was lower in the two groups receiving rivaroxaban, with similar rates of CV death, AMI or stroke. In addition, treatment with rivaroxaban was associated with a significant reduction in the risk of hospitalisation compared with conventional triple therapy.

The COMPASS Study Study Design and Results The COMPASS clinical trial was based on the existing evidence that anticoagulation with VKA drugs with or without aspirin is superior to aspirin monotherapy in secondary prevention of AMI, although with an increased risk of bleeding, including intracranial haemorrhage.

The authors of the COMPASS study hypothesised that there is benefit in administering rivaroxaban in patients with coronary or vascular events, at doses lower than those used in the anticoagulation of non-valvular AF. The study took 27,395 patients with stable CVD (CAD, PAD or both) and randomised them to three arms: rivaroxaban 2.5 mg twice daily plus aspirin 100 mg, rivaroxaban 5 mg twice daily monotherapy, and aspirin 100 mg monotherapy. Patients with recent surgical coronary revascularisation were also included. The primary outcome was the composite of CV death, AMI and stroke. The main safety outcome was major bleeding according to the modified International Society on Thrombosis and Haemostasis criteria, including fatal bleeding, symptomatic haemorrhage in critical organs (including intracranial bleeding), haemorrhage at a surgical site that required reoperation, or any haemorrhage requiring hospitalisation. The secondary efficacy outcomes were the composite of major thrombotic events (death caused by ischaemic stroke, AMI, acute ischaemia of the limbs and death caused by CHD), the composite of ischaemic stroke, MI, acute ischaemia of the limbs and CV death, and death from any cause.

After a mean follow-up of 23 months, it was shown that rivaroxaban plus aspirin, compared with aspirin alone, significantly improved the composite of CV death, AMI and stroke in patients with stable CVD. Specifically, it was found that the primary outcome occurred in

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4.1 % of the rivaroxaban plus aspirin group versus 4.9 % in the rivaroxaban monotherapy group and in 5.4 % of patients who only received aspirin (p<0.001 for rivaroxaban plus aspirin versus aspirin monotherapy; there were no significant differences for rivaroxaban alone versus aspirin).

With regard to secondary outcomes, a benefit of rivaroxaban plus aspirin versus aspirin was also observed. This difference in favour of the rivaroxaban plus aspirin group was seen in total mortality (3.4 % versus 4.1 % in aspirin, p=0.01) and stroke (0.9 % rivaroxaban plus aspirin versus 1.6 % in aspirin treated patients, p<0.001). However, no significant differences in incidence of AMI or heart failure were observed between the groups.

Concerning the primary outcome of safety, there were more haemorrhagic events in the rivaroxaban plus aspirin group than in the control arm of aspirin (3.1 % versus 1.9 %, p<0.001), primarily bleeding that required medical assistance or hospitalisation, mostly gastrointestinal bleeding. Encouragingly, there was no difference in fatal, intracranial or symptomatic bleeding in a critical organ. When comparing rivaroxaban alone with aspirin, a significantly higher number of bleeding events were observed in the rivaroxaban group (2.8 % versus 1.9 %, p<0.001), including symptomatic bleeding in a critical organ. There were no differences in the rate of other adverse events reported in any of the three trial arms.

Analysis of net benefit that included death, infarction, stroke, fatal bleeding or bleeding in a critical organ, showed a benefit for rivaroxaban plus aspirin (4.7 % versus 5.9 % in aspirin, p<0.001). There was no significant difference between rivaroxaban monotherapy and aspirin monotherapy. These differences persisted in the subgroup analysis.

Because of the major mortality benefit, COMPASS was stopped early at 23 months. The authors showed that the rivaroxaban plus aspirin combination is beneficial for secondary prevention of CVE, with a small risk of major bleeding, predominantly non-fatal bleeding. It is noteworthy that isolated rivaroxaban did not show superiority to aspirin.

COMPASS Results in Absolute Terms The primary event rate of the COMPASS study was reduced by 24 % in the group that received rivaroxaban plus aspirin (4.1 % versus 5.4 %).

This means that 154 patients would be needed to treat to prevent one major CVE. The rate of major bleeding with aspirin was 1.9 %, while the rate of major bleeding with 2.5 mg of rivaroxaban plus aspirin was 3.1 %, an absolute annualised difference of 0.6 %. These results indicate that the number needed to harm would be 166; nine additional haemorrhagic events would occur for every 10 CVE prevented.

Clinical Implications of the COMPASS Study There is general agreement on prescribing DAPT in the context of ACS, as well as single antiplatelet therapy in patients with stable CAD.21–24 In the last decade, the use of anticoagulation in both scenarios has begun to play an important part and many studies testing combinations of antithrombotic drugs have been conducted.

NOACs are established as the anticoagulants of choice for patients with AF or venous thromboembolism and the role of NOACs in patients with CVD and sinus rhythm is now much clearer. Several trials

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Pharmacotherapy have been published with NOACs in patients post-ACS (ATLAS ACS 2–TIMI 51, RE-DEEM, APPRAISE-2). The COMPASS study provides data strongly supporting anticoagulant therapy in the prevention of CVE in stable CVD. COMPASS was stopped early because of overwhelming efficacy, demonstrating the evident benefit of the combination of lowdose aspirin plus rivaroxaban 2.5 mg twice daily for the secondary prevention of CVE. Future questions of novel combination therapies remain, for example, about the addition of a second antiplatelet drug to aspirin versus a very low dose of a factor Xa inhibitor, or a platelet P2Y inhibitor or thrombin-receptor antagonist plus low dose factor Xa inhibitor, which could possibly offer greater efficacy by reducing AMI, but with more bleeding risk.44 It must not be forgotten that the COMPASS study included different subgroups of patients with stable CVD, such as those with a history

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of ACS in the past 20 years, patients with multivessel coronary disease who underwent percutaneous coronary intervention or coronary artery bypass graft surgery, or those with PAD. These diverse subgroups may have different responses to the different therapies, so a more personalised approach might be needed. However, despite these limitations, the COMPASS trial shows encouraging results and represents a turning point in the management of patients with established CVD.

Conclusion The COMPASS trial showed that rivaroxaban 2.5 mg twice daily given with low dose aspirin reduces the incidence of the composite endpoint of stroke, heart attack and death in patients with stable CAD. Although there are some limitations to the study, COMPASS offers promising conclusions and may change secondary prevention in patients with stable CVD. Of course, this is a complex field and further investigation is needed in this fascinating and fast evolving topic.

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35. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013;369:2093–104. https://doi.org/10.1056/NEJMoa1310907; PMID: 24251359.

36. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J 2013;34:2464–71. https://doi.org/10.1093/eurheartj/eht135; PMID: 23594592.

37. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91. https://doi.org/10.1056/NEJMoa1009638. PMID: 21830957.

38. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. https://doi.org/10.1056/NEJMoa0905561; PMID: 19717844.

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ISCP 2018 Best Posters

23rd Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy Koji Hasegawa President, International Society of Cardiovascular Pharmacotherapy (ISCP) Chair, 23rd Annual Scientific Meeting of the ISCP in Kyoto, Japan

Citation: European Cardiology Review 2018;13(2):119 DOI: https://doi.org/10.15420/ecr.2018.13.2.GE2 Correspondence: Koji Hasegawa, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan. E: koj@kuhp.kyoto-u.ac.jp

C

ardiovascular pharmacotherapy has drastically advanced in the past 30 years and made a major contribution to health and welfare worldwide. This advancement is attributable to the accumulation of evidence from clinical trials. Blood pressure and lipid management is the most important first-line therapy for arteriosclerotic cardiovascular disease. The medical treatment of systolic heart failure has drastically improved the 5-year survival rate. Prevention of cerebral embolism in AF has been achieved by the wide distribution of novel oral anticoagulants.

The development of pharmacotherapy has greatly benefited patients with heart and vessel diseases. However, cardiovascular diseases remain the most serious cause of death worldwide, with some 18 million lives lost annually because of them. Educating medical workers on risk management by pharmacotherapy, based on guidelines, is an important social contribution. In addition, recent advances in basic science have elucidated pathophysiology and signal transduction mechanisms for the onset of heart and vessel diseases. Further benefits could be achieved for patients with cardiovascular disease if we applied information obtained from basic research to clinical situations.

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The International Society of Cardiovascular Pharmacotherapy (ISCP) promotes research on pharmacotherapy for cardiovascular diseases. The ISCP introduced cardiovascular pharmacotherapy reviews, international clinical trials results and pharmaceutical safety information. We disseminate this knowledge through our website and scientific meetings.

The 23rd Annual Scientific Meeting of the ISCP was held in Kyoto, Japan, on 26 and 27 May 2018. Medical workers, including physicians and pharmacists, attended educational seminars and received training about appropriate cardiovascular pharmacotherapy. An active discussion was conducted for optimal cardiovascular pharmacotherapy based on evidence. In poster sessions of general abstracts, young investigators presented results of basic and translational research for future cardiovascular pharmacotherapy. In the following section, we present some of the excellent abstracts.

We are eagerly seeking more improvement in prognosis for patients with heart and vessel diseases through future development of cardiovascular pharmacotherapy.

Access at: www.ECRjournal.com

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The Best Posters from the 23rd Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy (ISCP) Kyoto, Japan 26–27 May 2018 A total of 64 general abstracts were submitted, with 14 abstracts selected by the judges as candidates for the Best Abstract Awards, which are presented here. Of these 14 abstracts, three were recipients of an award.

Best Abstract Award – First prize Topic: Heart Failure (Basic), Molecular Cardiology

Cavin-2 Deficiency Attenuates Cardiac Fibrosis and Dysfunction in Pressure-overloaded Hearts Yusuke Higuchi, 1 Takehiro Ogata, 2 Masahiro Nishi 1 and Satoaki Matoba 1 1. Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine; 2. Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan

Keywords: Heart failure, Cavin-2 deficiency, cardiac fibrosis, systolic dysfunction, fibroblasts, myofibroblasts Citation: European Cardiology Review 2018;13(2):120. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO1

Introduction Heart failure (HF) is a debilitating disease associated with high morbidity and mortality. The high mortality rate reflects inadequacy of modern therapy and calls for new mechanistic treatments. A major cause of HF is the adverse tissue remodelling with fibrosis. Excessive extracellular matrix (ECM) turnover is involved in poor outcome. Transdifferentiation of fibroblasts into activated myofibroblasts is a defining feature of fibrosis. Myofibroblasts express alpha-smooth muscle actin and secrete ECM proteins. Previous report showed that the cavin family gene is involved in cardiac function. However, the role of Cavin-2 in cardiac fibrosis and cardiac function remains unknown.

shortening was significantly preserved in Cavin-2-/- mice. In addition, the fibrosis area was significantly attenuated in Cavin-2-/- mice.

Moreover, mRNA expression of fibrosis genes was attenuated in the hearts of Cavin-2-/- mice four weeks after TAC. In in vitro study, we isolated mouse embryonic fibroblasts (MEFs) from Cavin2-/- mice and WT mice. Western blotting showed that alphasmooth muscle actin protein level was decreased in TGF-alpha-1 stimulated MEFs derived from Cavin-2-/- mice. Furthermore, mRNA expression of fibrosis genes was attenuated in MEFs derived from Cavin-2-/- mice.

Conclusions Methods and Results To examine the role of Cavin-2 in cardiac function, transverse aortic constriction (TAC) was performed on wild type (WT) mice and Cavin2-/- mice. Four weeks after TAC procedure, left ventricular fractional

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Our observations suggest that Cavin-2 contributes to the development of cardiac fibrosis and systolic dysfunction with the differentiation of fibroblasts into myofibroblasts. Cavin-2 may be a novel therapeutic target for cardiac fibrosis. n

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ISCP 2018 Best Posters Best Abstract Award – Second prize Topic: Heart Failure (Basic), Molecular Cardiology

Analysis of the Effects of EPA and DHA on Cardiomyocyte hypertrophy Ayumi Katayama, 1 Masafumi Funamoto, 1,2 Kana Shimizu, 1,2 Mai Gempei, 1 Yoichi Sunagawa, 1,2,3 Hiromichi Wada, 2 Koji Hasegawa 1,2,3 and Tatsuya Morimoto 1,2,3 1.Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2. Kyoto Medical Center, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Keywords: Eicosapentaenoic acid, docosahexaenoic acid, cardiomyocyte, phenylephrine, hypertrophic responses, histone acetyltransferase activity Citation: European Cardiology Review 2018;13(2):121. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO2

Introduction A major morphogenic change in heart failure is the hypertrophy of individual cardiomyocytes. Suppressing cardiomyocytes hypertrophy enables the prevention and treatment of heart failure. Although many experimental studies and clinical intervention trials have shown the cardioprotective effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), little is known about the effects of these acids on cardiomyocyte hypertrophy. This study investigated whether DHA and EPA inhibit cardiac hypertrophy, and compared the effects of EPA and DHA on cultured cardiomyocytes.

hypertrophic response gene transcription, and the ratio of acetylated histone H3 were measured. Next, an in vitro HAT assay was performed to determine the direct effect of EPA and DHA on p300-HAT activity.

Results Treatment with either DHA or EPA significantly inhibited PE-induced hypertrophic response including myofibrillar organisation, increase in cell size, and mRNA expression of ANF and BNP. Moreover, DHA and EPA repressed the PE-induced acetylation of histone-3 in cardiomyocytes to the same extent. The in vitro HAT assay revealed that EPA and DHA significantly inhibited p300-HAT activity.

Methods First, to compare the effects on hypertrophic responses, neonatal rat cultured cardiomyocytes were stimulated with 30 µM phenylephrine (PE) in the presence or absence of EPA or DHA. Palmitic acid and stearic acid were used as controls. After 48 hours, cardiomyocyte surface area,

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Conclusions These findings suggest that EPA and DHA repress PE-induced hypertrophic responses in cardiomyocytes to the same extent, through the direct inhibition of histone acetyltransferase activity. n

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ISCP 2018 Best Posters Best Abstract Award – Third Prize Topic: Arrhythmia (Basic), Electrophysiology

3D Ultrastructure of the “Arrhythmogenic” Purkinje Fibre-ventricular Junction in Rabbit Hearts Shu Nakao, 1,3 Il-Young Oh, 1,4 Luke Stuart, 1 Hiren Sitpura, 1 Joseph Yanni, 1 Sunil JSR Logantha, 1 Xue Cai, 1 Tobias Starborg, 2 Halina Dobrzynski, 1 Ashraf Kitmitto 1 and Mark R Boyett 1 1. Division of Cardiovascular Sciences, Department of Biology, Medicine and Health, University of Manchester, Manchester, UK; 2. Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester, UK; 3. Department of Biomedical Sciences, Ritsumeikan University, Shiga, Japan; 4. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, South Korea

Keywords: Ventricular arrhythmias, ultrastructure, Purkinje fibre-ventricular junction Citation: European Cardiology Review 2018;13(2):122. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO3

Introduction Ventricular arrhythmias are often associated with advanced heart failure and cardiomyopathies, and potentially originated from the Purkinje-ventricular (PV) junction where fast electric conduction is transferred to functional working myocardium. Despite its well-known electrophysiological property, in situ ultrastructure of the PV junction has not yet been studied. Here we analyse 3D nano-architecture of the PV junction in rabbit hearts using Gatan 3View, a serial block face-scanning electron microscopy (SEM).

Methods and Results Small pieces of the PV junctions were dissected from rabbit hearts in oxygenised Tyrode solution and processed with a modified method for standard SEM preparations. Up to 4,000 consecutive images per resin block were acquired in 3View. IMOD software

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was used for segmentation and image processing. Free running Purkinje fibres were spindle-shaped, longitudinally arranged, and formed a bundle enveloped with connective tissue. Mitochondria and myofilaments were not packed but longitudinally aligned. The PV junction was made up of thin layers containing two different cell types. Type I junctional cells were characterised by thick and long column-shaped, whereas type II cells were wide and flat-shaped.

PV cells in the both types were exhibited t-tubules, more organised mitochondria and myofilaments, and greater cell volume compared with Purkinje fibres. The junctional cells contacted some ventricular myocytes situated in the deeper layer.

Conclusion These findings correspond with unique functional features to trigger contraction of large mass of the ventricular myocytes. n

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ISCP 2018 Best Posters Featured Abstracts The following abstracts were also accepted for display at the meeting

Topic: Atherosclerosis (Clinical), Cardiac Catheterisation

Relationship Between VEGF-C Levels and Mortality in Patients with Peripheral Artery Disease Nobutoyo Masunaga, 1,2 Shuichi Ura, 1 Mitsuru Ishi, 1,2 Takashi Unoki, 1 Daisuke Takagi, 2 Moritake Iguchi, 1,2 Kensuke Takabayash, 2 Yugo Yamashita, 2 Yasuhiro Hamatani, 2 Hisashi Ogawa, 1,2 Noriko Satoh-Asahara, 3 Akira Shimatsu, 3 Mitsuru Abe, 1,2 Masaharu Akao, 1,2 Koji Hasegawa 1 and Hiromichi Wada 1 1. Division of Translational Research, Kyoto Medical Center, Kyoto, Japan; 2. Department of Cardiology, Kyoto Medical Center, Kyoto, Japan; 3. Department of Endocrinology, Metabolism and Hypertension, Kyoto Medical Center, Kyoto, Japan; 4. Division of Diabetes Research, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan

Keywords: VEGF-C levels, peripheral artery disease, atherosclerotic disease, all-cause mortality Citation: European Cardiology Review 2018;13(2):123. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO4

The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular disease.

Vascular endothelial growth factor-C (VEGF-C) plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidaemia and atherosclerosis. However, the relationship between VEGF-C levels and mortality in patients with atherosclerotic disease is unknown.

We performed a prospective cohort study involving a total of 204 patients with peripheral artery disease. Patients were followed up over 4 years. The outcome was all-cause death. Serum levels of VEGF-C were measured at baseline. Patients were divided into two

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groups based on median VEGF-C levels. During the follow-up, a total of 53 patients (26.0 %) died from any cause. In Kaplan-Meier analysis, the low-VEGF-C group had a significantly higher risk of all-cause death compared with the high-VEGF-C group (p<0.001 by log-rank test). Furthermore, multivariate Cox proportional hazard analysis revealed that the VEGF-C level was significantly and inversely associated with the risk of all-cause death after adjustment for age, sex, traditional risk factors, chronic kidney disease, and the Fontaine stages (adjusted hazard ratio 0.70 for 1-SD increase; 95 % CI [0.52– 0.95]; p=0.02). In conclusion, a low VEGF-C value was independently associated with the risk of all-cause mortality in patients with peripheral artery disease. n

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ISCP 2018 Best Posters Topic: Atherosclerosis (Clinical), Cardiac Catheterisation

VEGF-C and Cardiovascular Mortality in Patients Undergoing Drug-eluting Stent Implantation Takashi Unoki, 1 Shuichi Ura, 1 Daisuke Takagi, 2 Nobutoyo Masunaga, 2 Mitsuru Ishii, 2 Moritake Iguchi, 2 Kensuke Takabayashi, 2 Yugo Yamashita, 2 Yasuhiro Hamatani, 2 Hisashi Ogawa, 1,2 Noriko Satoh-Asahara, 3 Akira Shimatsu, 3 Mitsuru Abe, 2 Masaharu Akao, 1,2 Koji Hasegawa 1 and Hiromichi Wada 1 1. Division of Translational Research, Kyoto Medical Center, Kyoto, Japan; 2. Department of Cardiology, Kyoto Medical Center, Kyoto, Japan; 3. Department of Endocrinology, Metabolism and Hypertension, Kyoto Medical Center, Kyoto, Japan; 4. Division of Diabetes Research, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan

Keywords: VEGF-C, cardiovascular mortality, drug-eluting stent implantation, lymphatic system, vascular endothelial growth factor-C, lymphangiogenesis, dyslipidaemia, atherosclerosis, coronary artery disease Citation: European Cardiology Review 2018;13(2):124. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO5

The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular disease.

Vascular endothelial growth factor-C (VEGF-C) plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidemia and atherosclerosis. However, the relationship between VEGF-C levels and cardiovascular mortality in patients with established coronary artery disease is unknown.

We performed a prospective cohort study involving a total of 433 patients who underwent successful drug-eluting stent implantation.

The prescription rate of statin was 100% at the baseline.

Patients were followed up over 4 years. The outcome was cardiovascular death. Pre-procedural serum levels of VEGF-C were

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measured. Patients were divided into two groups based on the median of VEGF-C levels. During the follow-up, a total of 23 patients (5.3 %) died from cardiovascular disease. In Kaplan-Meier analysis, the lowVEGF-C group had a significantly higher risk of cardiovascular death compared with the high-VEGF-C group (p<0.001 by log-rank test).

Furthermore, multivariate Cox proportional hazard analysis revealed that VEGF-C levels were significantly and inversely associated with the risk of cardiovascular death after adjustment for traditional risk factors and chronic kidney disease (adjusted hazard ratio, 0.55 for 1-SD increase; 95 % CI [0.34–0.87]; p=0.011).

In conclusion, a low VEGF-C value was independently associated with cardiovascular mortality in patients after drug-eluting stent implantation. n

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ISCP 2018 Best Posters Topic: Heart Failure (Basic), Molecular Cardiology

The GATA4 Acetylation Site Plays a Key Role in the Development of Cardiomyocyte Hypertrophy Satoshi Shimizu, 1 Yoichi Sunagawa, 1,2,3 Kodai Hara, 1 Asami Hishiki, 1 Masafumi Funamoto, 1,2 Sari Nurmila, 1 Kana Shimizu, 1 Yusuke Miyazaki, 1,2,3 Yasufumi Katanasaka, 1,2,3 Hiromichi Wada, 2 Koji Hasegawa, 1,2 Hiroshi Hashimoto 1 and Tatsuya Morimoto 1,2,3 1. Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2. Clinical Research Institute, Kyoto Medical Center, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Keywords: GATA4 acetylation, cardiomyocyte hypertrophy, heart failure Citation: European Cardiology Review 2018;13(2):125. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO6

Introduction The zinc finger protein GATA4 is a transcription factor that associates with the intrinsic histone acetyltransferase p300 and regulates myocardial transcriptional activity in response to hypertrophic stimuli.

It is known that GATA1, another member of the GATA transcription family, forms a homo-dimer and regulates transcriptional activity.

However, whether GATA4 forms a homo-dimer, and what its relationship is to hypertrophic responses, are still unknown.

Methods and Results GST pull-down assay demonstrated that GATA4 dimerisation required the GATA4 acetylation site from residues 308-326. Overexpression of a mutant containing a 3xGATA4 acetylation site (3xG4D) both prevented p300-induced GATA4 dimerisation and inhibited p300/ GATA4-induced ANF and ET-1 promoter activity without inhibiting

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GATA4 acetylation. In cardiomyocytes, the overexpression of 3xG4D inhibited phenylephrine-induced cardiomyocyte hypertrophy. To perform a crystal structure analysis, a recombinant GATA4 fragment, including an acetylation site with a GST tag, was purified with GS4B beads. The GST tag was cleaved using HRV3C protease and applied to an anion-exchange column followed by a size-exclusion column. Crystallisation was performed using a commercial kit to screen crystallisation conditions and then optimise them.

X-ray diffraction data was collected with the BL-17A beamline at Photon Factory.

Conclusions These results suggest that the dimerisation of GATA4 is involved in hypertrophic responses in cardiomyocytes. This finding may contribute to the development of new heart failure drugs. n

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ISCP 2018 Best Posters Topic: Heart Failure (Basic), Molecular Cardiology

TBL1 Suppresses Cardiomyocyte Hypertrophy by Regulating the Interaction Between HDAC3 and GATA4 Yasufumi Katanasaka, 1,2,3 Masatoshi Namiki, 1 Yoichi Sunagawa, 1,2,3 Yusuke Miyazaki, 1,2,3 Hiromichi Wada, 2 Koji Hasegawa 2 and Tatsuya Morimoto 1,2,3 1. Division of Molecular Medicine, Graduate School of Pharmaceutical Science, University of Shizuoka, Shizuoka, Japan; 2 Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Keywords: Cardiac hypertrophy, heart failure, HDAC3, novel pharmacological therapy, p300 acetylation of GATA4, transducin beta like protein 1, GATA4-binding protein, cardiomyocytes, atrial natriuretic peptide, endothelin-1, HEK293T cells Citation: European Cardiology Review 2018;13(2):126. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO7

Cardiac hypertrophy is a risk factor for the development of heart failure. To elucidate underlying molecular mechanism is necessary for the development of novel pharmacological therapy targeting to pathological cardiac hypertrophy. We have previously reported that the acetylation of GATA4 by p300 is essential for cardiomyocyte hypertrophy and heart failure.

In the present study, we have identified transducin beta like protein 1 (TBL1) as a novel GATA4-binding protein by tandem affinity purification and mass spectrometry analyses. Overexpression of TBL1 significantly repressed p300/GATA4-induced activations of atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) promoters in HEK293T cells. Furthermore, overexpression of TBL1 significantly inhibited phenylephrine- (PE) induced hypertrophic responses,

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including an increase in the cell size and the transcriptional activation of ANP and ET-1 promoters in primary cultured cardiomyocyte.

Conversely, knockdown of TBL1 by RNAi increased PE-induced mRNA expression of ANP and BNP. TBL1 repressed p300-induced acetylation of GATA4 and enhanced the binding between HDAC3 and GATA4.

The treatment with RGFP966, a specific inhibitor of HDAC3, rescued the TBL1- mediated inhibition of hypertrophic responses in cultured cardiomyocytes.

Finally, the interaction of TBL1 with HDAC3 decreased by treatment with PE in cardiomyocytes. These findings have demonstrated that TBL1 suppresses p300/GATA4-dependent gene transcription and cardiomyocyte hypertrophy by regulating the interaction between HDAC3 and GATA4. n

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ISCP 2018 Best Posters Topic: Heart Failure (Basic), Molecular Cardiology

The Role of p53 Localised in Cytosol and Mitochondria During Reprogramming to iPS Cells Tomomi Akama, 1 Araya Tenghattakorn, 1 Motoharu Yamasaki, 1 Yukihiro Harada, 1 Dai Ihara, 1 Tomoe Ueyama, 1 Takahiro Sogo, 2 Shu Nakao 1 and Teruhisa Kawamura 1 1. Department of Biomedical Science, Ritsumeikan University, Kyoto, Japan; 2. Global Innovation Research Organization, Ritsumeikan University, Kyoto, Japan

Keywords: Cytosolic and mitochondrial p53, somatic cell reprogramming, induced pluripotent stem cell formation, apoptosis, cell cycle arrest Citation: European Cardiology Review 2018;13(2):127. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO8

Previous studies, including ours, suggest that tumour repressor p53 is activated during somatic cell reprogramming, and efficiency of induced pluripotent stem cell (iPSC) formation is limited through transactivation of p53 target genes leading to apoptosis and cell cycle arrest. Recent studies revealed non-transcriptional effects of p53 on mitochondria that directly trigger apoptosis. Thus, we attempted to examine the role of cytosolic and mitochondrial p53 in iPSCs. We constructed plasmids to express EGFP fused with either p53 wild-type (WT) and its mutant K27R which is expected abundantly to localise to mitochondria. Then, we performed live cell imaging using mouse embryonic fibroblasts (MEFs) infected with retroviruses encoding p53 WT-EGFP or p53 K27R-EGFP. While EGFP-fused with K27R as well as WT was observed in both cytosol and nucleus at the

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basal condition, nuclear expression was significantly enhanced after irradiation, suggesting nuclear translocation of p53 by DNA damage.

Localisation of p53 K27R seemed similar to that of p53 WT under fluorescence microscopy. Inhibitory effects of p53 on cell proliferation were, however, not observed in K27R-expressing cells.

Since the results suggest the role of K27R except nucleus, we further tested whether K27R affects the efficiency of iPSC colony formation.

We introduced combinations of the reprogramming factors, Oct4, Sox2, and Klf4 with or without c-Myc into MEFs, together with either p53 WT or p53 K27R. Interestingly, K27R mutant repressed iPSC formation to similar extent as p53 WT. These results above suggest that cytosolic p53 would a potential negative regulator for somatic cell reprogramming in a transcription-independent manner. n

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ISCP 2018 Best Posters Topic: Heart Failure (Basic), Molecular Cardiology

The Mechanism of Hey2 Expression in Cardiac Development Dai Ihara, 1,2 Yusuke Watanabe, 2 Daily Seya, 2 Yukihiro Harada, 1,2 Osamu Nakagawa 2 and Teruhisa Kawamura 1 1. Department of Life Science, Ritsumeikan University, Kyoto, Japan; 2. Department of Molecular Physiology, National Cerebral and Cardiovascular Center, Osaka, Japan

Keywords: Hey2 expression, cardiac development, YRPW motif proteins Citation: European Cardiology Review 2018;13(2):128. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO9

Hairy/enhancer-of-split related with YRPW motif proteins, known as Hey family, were reported to encode a downstream transcription factor of Notch and ALK1 signalling pathways. Among the three Hey family members (Hey1, Hey2, HeyL), Hey2 null mice show postnatal lethality with various cardiac malformations, ventricular septum defect, right ventricular hypoplasia, and tricuspid atresia. Hence, it is clear that Hey2 is crucial during heart formation. Hey1 and Hey2 are expressed in the atrium and ventricle, respectively, throughout the cardiac development. Thus, we focused on the ventricular specific expression of Hey2 to reveal the molecular transcription mechanism.

Enhancer activity was investigated by multistep analysis. First, Hey2 enhancer regions were predicted by in silico ChIP-seq

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analysis including cardiac transcription factor bindings and histone modification. Second, the response of the enhancers were examined by Lusicerase assay against cardiac transcription factors; involvement Gata4, Nkx2.5 and Tbx5. Finally, enhancer activity was confirmed with transgenic (Tg) mice LacZ reporter system using the minimal promoter. The analysis of Tg mouse embryo heart showed that two enhancers had region specific activity respectively.

In this study, we found Hey2 ventricular specific expression was not only regulated by one enhancer, but by multiple enhancers specific to each region. This novel finding on Hey2 expression regulation is significant to understand cardiac development. n

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ISCP 2018 Best Posters Topic: Heart Failure (Clinical), Cardiomyopathy, Myocarditis

Relationship Between VEGF-C Levels and All-cause Mortality in Patients with Chronic Heart Failure Moritake Iguchi, 1,2 Shuichi Ura, 1 Nobutoyo Masunaga, 1,2 Mitsuru Ishii, 1,2 Takashi Unoki, 1,2 Hisashi Ogawa, 1,2 Daisuke Takagi, 2 Noriko Satoh-Asahara, 3 Akira Shimatsu, 4 Mitsuru Abe, 1,2 Masaharu Akao, 1,2 Koji Hasegawa 1 and Hiromichi Wada 1 1. Division of Translational Research, Kyoto Medical Center, Kyoto, Japan; 2. Department of Cardiology, Kyoto Medical Center, Kyoto, Japan; 3. Department of Endocrinology, Metabolism and Hypertension, Kyoto Medical Center, Kyoto, Japan; 4. Division of Diabetes Research, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan

Keywords: Lymphatic system, chronic heart failure, vascular endothelial growth factor-C, lymphangiogenesis Citation: European Cardiology Review 2018;13(2):129. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO10

The lymphatic system has been suggested to play an important role in cardiovascular disease. Vascular endothelial growth factor-C (VEGF-C) plays a key role in lymphangiogenesis. However, the relationship between VEGF-C levels and mortality in patients with chronic heart failure is unknown.

We performed a prospective cohort study involving a total of 220 symptomatic patients with chronic heart failure. Patients were followed up over 4 years. The outcome was all-cause death. Serum levels of VEGF-C were measured at the baseline. Patients were divided into two groups based on the median of VEGF-C levels.

During the follow-up, a total of 59 patients (26.8%) died from any cause. In Kaplan-Meier analysis, the low-VEGF-C group had a

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significantly higher risk of all-cause death compared with the highVEGF-C group (p=0.003 by log-rank test). Furthermore, multivariate Cox proportional hazard analysis revealed that the VEGF-C level was significantly and inversely associated with the risk of all-cause death after adjustment for established risk factors (i.e. age, sex, the body mass index, hypertension, diabetes, previous heart failure hospitalisation, coronary artery disease, persistent/permanent atrial fibrillation, chronic kidney disease, anaemia, and a reduced left ventricular ejection fraction [<50 %]) (adjusted hazard ratio, 0.72 for 1-SD increase; 95 % CI [0.52–0.99]; p=0.04).

In conclusion, a low VEGF-C value was independently associated with the risk of all-cause mortality in patients with chronic heart failure. n

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ISCP 2018 Best Posters Topic: Heart Failure (Clinical), Cardiomyopathy, Myocarditis

A PRMT5 Selective Inhibitor EPZ015666 Suppressed TAC-induced Left Ventricular Dysfunction Kazuma Hanajima, 1 Yusuke Miyazaki, 1,2,3 Yasufumi Katanasaka, 1,2,3 Hiroki Honda, 1 Hunamoto Masafumi, 1,2 Nurmila Sari, 1 Sunagawa Yoichi, 1,2,3 Koji Hasegawa 1,2 and Tatsuya Morimoto 1,2,3 1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2. Division of Translational Research, Kyoto Medical Center, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Keywords: Cardiac hypertrophy, heart failure, cardiomyocyte hypertrophy, arginine methyltransferase 5, EPZ015666, transverse aortic constriction (TAC)-induced cardiac hypertrophy Citation: European Cardiology Review 2018;13(2):130. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO11

Background The mortality of heart disease has been increasing in all over the world.

Cardiac hypertrophy is an important risk factor for heart failure. We have previously reported that protein arginine methyltransferase 5 (PRMT5) specific inhibitor EPZ015666 (EPZ) suppressed cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. However, it is unclear whether EPZ can suppress transverse aortic constriction (TAC)induced cardiac hypertrophy and systolic dysfunction in vivo.

Fractional shortening (FS) and ejection fraction (EF) was significantly decreased in TAC+vehicle group and EPZ significantly improved in them. Following the echocardiography, mice were killed and body weight (BW), tibia length (TL), and heart weight (HW) were measured. HE staining and qRT-PCR were performed. There were no significant difference in BW between TAC+EPZ group and TAC+vehicle group. HW/TL ratio, cardiomyocyte diameter, and hypertrophic gene expression were significantly suppressed in TAC+EPZ group compared with TAC+vehicle group.

Methods and Results TAC or sham operation was performed on male C57BL/6J mice at 8â&#x20AC;&#x201C;10 weeks old. EPZ or vehicle was administrated to mice every morning for 8 weeks beginning on the next day of operation.

Echocardiography was performed at 8 weeks after surgery.

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Conclusion These results indicated that EPZ suppressed TAC-induced cardiac hypertrophy and systolic dysfunction. EPZ may be a new therapeutic agent for heart failure. n

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ISCP 2018 Best Posters Topic: Arrhythmia (Basic), Electrophysiology

Cell-specific Mathematical Modelling of hiPSC-CMs and Its Potential for Prediction of Drug Testing Hirohiko Kohjitani, 1 Shigeya Koda, 2 Yukiko Himeno, 2 Takeru Makiyama, 1 Yimin Wuriyanghai, 1 Yuta Yamamoto, 1 Takeshi Kimura, 1 Akinori Noma 2 and Akira Amano 1 1. Cardiovascular Medicine, Kyoto University Hospital, Kyoto, Japan; 2. College of Life Sciences, Ritsumeikan University, Kyoto, Japan

Keywords: Human-induced pluripotent stem cells, cardiomyocytes, cell-specific computer simulation Citation: European Cardiology Review 2018;13(2):131. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO12

Background Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) are expected tool for preclinical evaluation of the safety and efficacy of compounds on the heart. Its action potential (AP) parameters were measured in order to estimate pro-arrhythmic effects of new drugs, mutation of ion-channels, and so on. But, hiPSCCMs exhibit varying AP morphologies, and even exhibit paradoxical reaction for some compounds.

Hypothesis Variations of APs of hiPSC-CMs express their total balance of ion-currents, and might affect the result of drug-testing. So, in order to interpret the results of drug-testing using hiPSC-CMs platform accurately, cell-specific precise mathematical modelling of hiPSC-CMs may be useful.

Methods We developed novel hiPSC-CMs mathematical models based on HuVEC model (Asakura et al, 2014), adopting experimental data of

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ionic channels. We recorded APs from 40 hiPSC-CMs, and reproduced all AP morphologies simulationally by changing conductance of each ion current. After that, in silico IKr-blocking test was performed.

Results All 40 AP morphologies were successfully recapitulated within 5 % error range. In simulational IKr-blocking test, AP duration (APD) prolongation was observed in 15 cells (37.5%). In 21 cells, APD prolongation and rising of maximum diastolic potential (MDP) was observed. In 4 cells, APD shortening and rising of MDP was observed. All APD shortening cell has morphological character of MDP >−68.0 mV.

Conclusion Our new mathematical models can reproduce experimental AP morphology precisely. To interpret the results of hiPSC-CMs drug testing appropriately, cell-specific computer simulation is very useful. n

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ISCP 2018 Best Posters Topic: Hypertension, Diabetes, Lipid Metabolism

Characteristics of Lipid Profile of LPL Deficiency in Japan – Comparison with Non-LPL Deficiency Junji Kobayashi Department of General Medicine, Kanazawa Medical University, Kanazawa, Japan

Keywords: Lipoprotein lipase deficiency, autosomal recessive lipid disorder, severe hypertriglyceridaemia Citation: European Cardiology Review 2018;13(2):132. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO13

Objective Lipoprotein lipase deficiency is a rare autosomal recessive lipid disorder caused by a mutation in the gene which codes lipoprotein lipase and is characterised by severe hypertriglyceridaemia. On the other hand, we encounter subjects with very severe hypertriglyceridaemia, but they are not LPL deficient (non-LPL deficiency). In this study, we clarify the differences in lipid profiles between LPL deficiency and non-LPL deficiency.

Methods We analysed 16 patients in 13 articles on LPL deficiency published

by Japanese researchers since 1990 and 11 non-LPL deficiency as controls. The differences in lipid values between the two groups were analysed using Mann-Whitney U test.

Results In LPL deficiency (n=16, F/M 5/11) versus non-LPL deficiency (n=11, F/M

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5/6), TC (mg/dl) were 267 ± 214 and 328 ± 52 (p=0002), respectively; TG (mg/dl) were 2,446 ± 2,234 and 1,477 ± 670 (p=0.29), respectively and HDL-C (mg/dl) were 14.2 ± 5.1 and 31.8 ± 6.01 (p<0.0001), respectively.

To assess the usefulness of TG and HDL-C values to discriminate LPL deficiency from non-LPL deficiency, we conducted ROC analysis.

In the case of TG, the area under the ROC curve (AUC) was 0.693, whereas in the case of HDL-C, the AUC was 0.991. These results indicate that HDL-C may be an excellent value for discriminating LPL deficiency from non-LPL deficiency. When we used HDL-C of 26.5 mg/dl as cut value, the detection sensitivity and specificity of the non-LPL deficient case were 0.82 and 1.00, respectively.

Conclusion It was suggested that the HDL-C value may be extremely useful for discriminating the presence or absence of LPL deficiency in severe hypertriglyceridaemia. n

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ISCP 2018 Best Posters Topic: Preventive Medicine

Omega-6 Polyunsaturated Fatty Acid Levels and Delirium in Patients With Acute Cardiovascular Disease Yurina Sugita, Tetsuro Miyazaki, Kazunori Shimada, Megumi Shimizu, Mitsuhiro Kunimoto, Tatsuro Aikawa, Shohei Ouchi, Tomoyasu Kadoguchi, Yuko Kawaguchi, Tomoyuki Shiozawa, Masaru Hiki, Syuhei Takahashi, Miho Yokoyama, Hiroshi Iwata and Hiroyuki Daida Department of Cardiology, Juntendo Graduate School of Medicine, Tokyo, Japan

Keywords: Delirium, omega-6 polyunsaturated fatty acids, acute cardiovascular disease, dihomo-gamma-linolenic acid Citation: European Cardiology Review 2018;13(2):133. DOI: https://doi.org/10.15420/ecr.2018.13.2.PO14

Background Delirium frequently occurs in patients admitted to the intensive care unit and is associated with mortality and morbidity. Although several studies reported associations between polyunsaturated fatty acids (PUFAs) and cognitive disorders, the association between PUFAs and delirium in patients with acute cardiovascular disease remains unknown.

as patients with a delirium score ≥4 using the Intensive Care Delirium Screening Checklist. Delirium was present in 54 patients. The levels of dihomo-gamma-linolenic acid (DGLA) was significantly lower in patients with delirium than in those without delirium (DGLA: 23.1 ± 10.3 versus 31.4 ± 12.6 μg/ml, p<0.0001), whereas AA and omega-3 PUFAs did not differ between the two groups. In addition, DGLA and AA, but not omega-3 PUFA, were negatively associated with the delirium score (DGLA: p<0.0001; AA: p=0.002).

Methods and Results We enrolled 589 consecutive patients (mean age: 70 ± 14 years) admitted to the coronary care unit of Juntendo University Hospital from January 2015 to December 2016. Fasting serum PUFA levels were measured within 24 hours of admission. Delirium was defined

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Conclusion Low omega-6 PUFA levels on admission were significantly associated with delirium in the coronary care unit, indicating that low omega-6 PUFA levels may identify patients at high risk of developing delirium. n

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Cardiology Masters

Dr Renu Virmani

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 edition, we feature Dr Renu Virmani, Founder and President of CVPath Institute.

DOI: https://doi.org/10.15420/ecr.13.2.CM2

Dr Renu Virmani is a cardiovascular pathologist who is recognised as a leading researcher in the field of cardiovascular disease treatments. She is a clinical professor in the Department of Pathology at Georgetown University, University of Maryland-Baltimore, George Washington University and Vanderbilt University. She served as chairperson of the Department of Cardiovascular Pathology of the Armed Forces Institute of Pathology from 1984 until 2004. Dr Virmani is a member of the American Heart Association, the US and Canadian Academy of Pathology and is a Fellow of the American College of Cardiology. Dr Virmani serves as the President of CVPath Institute, which she founded in 2005. She lectures at international scientific meetings and has delivered more than 800 presentations globally. She has authored or co-authored more than 600 publications in peer-reviewed journals, covering atherosclerosis, vulnerable plaque, stents and other cardiovascular diseases. Dr Virmani has edited seven books, written more than 100 book chapters and is a manuscript reviewer for many scientific journals. Dr Virmani was awarded the TCT Career Achievement Award by the Cardiovascular Research Foundation. She has been recognised by the Council on Clinical Cardiology of the AHA and delivered the Laennec Clinician Educator Lecture. She was awarded an honorary degree from the University of Antwerp, Belgium and received honorary awards from European Society of Cardiology and EuroPCR. Dr Virmani received her MD from Lady Hardinge Medical College, Delhi University, New Delhi, India.

Luck or circumstance?

Standing on the shoulders of giants

It was 1974 when I met my husband in India and we decided to move to the US. I had already completed my MD Pathology in India, so I set out looking for a job. Two months passed and still I had found nothing.

However, a chance conversation with my parents-in-law connected me to Professor Sylvan Weinburg – an incredibly influential cardiologist and past president of the American College of Cardiology – who subsequently introduced me to Dr William (Bill) Roberts.

Bill was a very exciting person – I couldn’t have asked for a better mentor. He had a charming way of teaching you, making everything a learning opportunity. I remember, he would always look at a case and ask me: “What is unique about it?” Bill influenced me, and my career path, much more than the research itself.

Bill himself is a renowned cardiologist and was ‘the man’ of cardiac pathology at the time. I supported him for 8 months in an unpaid internship, writing my first research papers with him while I continued my residency. Bill taught me everything I know; I never set out to become a cardiac pathologist, but Bill inspired me, motivated me and made me who I am today. He had faith in me and gave me the opportunity to flourish. I was incredibly lucky to meet and learn from one of the best cardiac pathologists in the world. Our meeting was circumstantial and subsequently my career seemingly fell into my lap.

Or, perhaps, did things fall the way they were supposed to? For me, it was both luck and hard work that determined my direction.

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Mentors are everything. If your mentor excites you, you follow in their footsteps – and I wanted to emulate Bill. This was so influential for me that I have tried to do the same for my fellows over the years. The future lies in training and helping them to access opportunities that will help them to flourish. I’ve been lucky to support some young researchers and inspire them to achieve their own successes; to instil the belief that if you work hard and apply yourself, you can achieve anything you want. It’s something I’m very proud of.

Mentors can come from both your personal and professional life.

I grew up in a very large family – I am the youngest of 10 girls! That really drove me to be someone amongst the crowd, a trait that I think

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Cardiology Masters: Dr Renu Virmani

Figure 1: The CVPath Institute Team, 2017

I have carried throughout my career. My aunty was instrumental in seeing I got an MD. Having trained as a neurologist in the later stages of her life, she had the foresight to push me from a young age.

I admired her, and she showed me that women can do whatever they want. Of course, there are hurdles, but we can go around them. It’s not always a straight path so don’t be afraid to take a zigzag one!

Driving research and new technologies The first paper I worked on was with Bill and focused on rheumatic heart disease. This really excited me as, coming from India, rheumatic heart disease was a really big problem and I wanted to contribute. Bill had certain views on atherosclerosis and I didn’t always agree with him! Nevertheless, working alongside him gave me more and more exposure to the field and the experts in it. From this, I built a greater understanding and that’s been my main area of interest ever since.

Technology and devices have driven my interests too – and that’s largely thanks to Marty Leon. We were fellows at the same time and he first came to me with a stent; I’d never seen one before and he asked me: “How do I evaluate this? How do I determine if this is a good thing, or not?”

I think he came to me because I always try and speak the truth – I always try and remain honest to myself and my patients; so, if you see something wrong, you must speak up. For me, it’s important to always describe things as they are, rather than painting a good picture. This is because no matter how good something is, there can always be room for improvement. By acknowledging this, we as physicians and the industry can correct ourselves and continually drive improvements.

The motto that I live by is: “The patients are the first thing that matter.”

That’s how I got into devices! More and more people started to come to me to critically appraise new technology, so I took the opportunity to

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be the honest voice on behalf of the patient. That was a major driving force for my career that again steered me because of who I knew.

Taking an unexpected path was the best thing I ever did My biggest achievement has to be setting up CVPath Institute. It was never an ambition of mine to start up myself, but I’d been working in the Armed Forces’ Institute of Pathology for 20 years and when I learned that our base was closing, I just couldn’t let that happen!

I took what we had and worked solidly over the next 5 months to turn the Institute into a non-profit organisation. We started with 10 people in 2005; within 2 years we reached 26 people, and now, after 14 years, we’re close to 50 people strong (Figure 1).

Sometimes you need the courage to do something different – you find yourself in situations or meet people who give you the courage to take a path that is unusual to you. That was the Institute for me, and it’s the best thing I ever did.

Visions of advances in prosthetic valves I’m interested now in the area of valves and how we can improve the longevity of prosthetic valves in patients. Can we get them to stay in patients for longer without deteriorating, avoiding the need for re-surgery in large numbers of patients? Can we further improve coronary stenting? These areas still very much excite me.

I think the future is not just in bioprosthetic valves, but also in bioabsorbable scaffold/stents. Unfortunately, the first iterations didn’t work, but I hope to see it one day. The technology is not here yet – reiterations are required first. It takes honesty to see and realise that.

For example, when the first drug-eluting stents became available, I highlighted the flaws and discussed how they could be improved. This, in part, led to the development of the bioabsorbable stents and I hope I played a small role in driving that.

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Erratum

Erratum to: The Inhibitory Effects of Crucumin Glucuronide on p300-HAT Activity and Hypertrophic PhenylephrineInduced Responses in Cardiomyocytes Mai Genpei,1 Yoichi Sunagawa,1 Masafumi Funamoto,1 Kana Shimizu,1 Yusuke Miyazaki,1 Yasufumi Katanasaka,1 Nobuaki Takahashi,2 Hideaki Kakeya,2 Hiromichi Wada,3 Koji Hasegawa3 and Tatsuya Morimoto1 1. University of Shizuoka - Division of Molecular Medicine, Graduate School of Pharmaceutical Science, 2. Kyoto University - Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, 3. Kyoto Medical Center, National Hospital Organization - Clinical Research Institute

Citation: European Cardiology Review 2018;13(2):136. DOI: https://doi.org/10.15420/ecr.2018.13.2.ER1

In the abstract by Mai Genpei, Yoichi Sunagawa, Masafumi Funamoto, Kana Shimizu, Yusuke Miyazaki, Yasufumi Katanasaka, Nobuaki Takahashi, Hideaki Kakeya, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto entitled ‘The Inhibitory Effects of Crucumin Glucuronide on p300-HAT Activity and Hypertrophic Phenylephrine- Induced Responses in Cardiomyocytes’ (Citation: European Cardiology Review 2017;12(2):107), the following corrections should be made: The abstract’s title should be corrected to ‘The Inhibitory Effects of Curcumin Glucuronide on p300-HAT Activity and Hypertrophic PhenylephrineInduced Responses in Cardiomyocytes’.

The editors would like to sincerely apologise for any inconvenience or confusion this may have caused our readers.

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