Page 1

European Cardiology Review Volume 13 • Issue 1 • Summer 2018

Volume 13 • Issue 1 • Summer 2018

www.ECRjournal.com

Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors Stephen J Nicholls

Familial Hypercholesterolaemia Diagnosis and Management Rodrigo Alonso, Leopoldo Perez de Isla, Ovidio Muñiz-Grijalvo, Jose Luis Diaz-Diaz and Pedro Mata

New Advances in the Management of Refractory Angina Pectoris Kevin Cheng and Ranil de Silva

Assessing the Haemodynamic Impact of Coronary Artery Stenoses: Intracoronary Flow Versus Pressure Measurements Valérie E Stegehuis, Gilbert WM Wijntjens, Tadashi Murai, Jan J Piek, Tim P van de Hoef

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ISSN: 1758-3756

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Familial hypercholesterolaemia and coronary artery calcifications

The coronary sinus reducer

OCT image of bioresorbable scaffolds; well endothelialised struts

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Volume 13 • Issue 1 • Summer 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, Cordoba, Argentina

IRCCS San Raffaele, Rome, Italy

Debasish Banerjee

Angela Maas

Augusto Gallino

St George’s University of London, London, UK

Radboud University Medical Center, Nijmegen, the Netherlands

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

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

Aneil Malhotra

Gianluigi Savarese Karolinska Institute, Stockholm, Sweden

Conquest Hospital, Hastings, UK

St George’s University of London, London, UK

Velislav Batchvarov

Bernard Gersh

Roxy Senior

Mayo Clinic, Minnesota, US

Olivia Manfrini

Imperial College, London, UK

St George’s University of London, London, UK

Antoni Bayés-Genís

St George’s University of London, London, UK

Vinayak Bapat Columbia University Medical Centre, New York, US

Robert Gerber

David Goldsmith

Hospital Germans Trias i Pujol, Barcelona, Spain

John Beltrame University of Adelaide, Adelaide, Australia

Christopher Cannon

Kim Greaves

Harvard Medical School, Boston, US

Sunshine Coast University Hospital, Sunshine Coast, Australia

Peter Collins Imperial College, London, UK

Eileen Handberg

Alberto Cuocolo

University of Florida, Florida, US

University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan

University Hospital of Sabadell, Sabadell, Spain

Noel Bairey Merz

Mike G Kirby

Imperial College, London, UK

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

Konstantinos Toutouzas University of Athens, Athens, Greece

Isabella Tritto University of Perugia, Perugia, Italy

Dimitrios Tziakas

Eva Prescott

Democritus University of Thrace, Xanthi, Greece

Mauricio Wajngarten University of São Paulo, Brazil

Axel Pries

Careggi University Hospital, Florence, Italy

Patrizio Lancellotti University of Liège, Liège, Belgium

Perry Elliott

Amir Lerman

Hari Raju

University College, London, UK

Mayo Clinic, Minnesota, US

Albert Ferro

José Luis López-Sendón

King’s College London, London, UK

La Paz Hospital, Madrid, Spain

University Complutense, Madrid, Spain

Wroclaw Medical University, Wroclaw, Poland

Charité Universitätsmedizin Berlin, Germany

Managing Editor Catherine Hyland

Juan Tamargo

Piotr Ponikowski

Bispebjerg Hospital, Copenhagen, Denmark

St George’s University of London, London, UK

Italian National Research Council National Cardiology Hospital, Sofia, Bulgaria

University of Florida, Florida, USA

Rao Kondapally

Rosa Sicari Iana Simova

Carl Pepine

Kumamoto University, Kumamoto, Japan

St George’s University of London, London, UK

Argyrios Ntalias

St Bartholomew’s Hospital, London, UK

Danderyd University Hospital, Danderyd, Sweden

Sanjay Sharma

Cedars-Sinai Heart Institute, Los Angeles, US

Denis Pellerin

Ranil de Silva

Carlo Di Mario

Antoni Martínez-Rubio

Thomas Kahan Koichi Kaikita

Hippokration General Hospital, Athens, Greece

St George’s University of London, London, UK

University of Athens, Athens, Greece

Colentina University Hospital, Bucharest, Romania

Polychronis Dilaveris

Nesan Shanmugam

Felipe Martinez National University of Cordoba, Cordoba, Argentina

Tommaso Gori Johannes Gutenberg University Mainz, Mainz, Germany

University of Bologna, Bologna, Italy

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

Production Aashni Shah

José Luis Zamorano 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 •

Editorial Contact Catherine Hyland catherine.hyland@radcliffe-group.com Circulation & Commercial Contact David Ramsey 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 that 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: Summer 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

Lifelong Learning for Cardiovascular Professionals

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Content Contents

Foreword

5

Juan Carlos Kaski

Dyslipidaemia

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Guest Editorial: Reducing Risk in Familial Hypercholesterolaemia and Severe Dyslipidaemia: Novel Drugs Targeting PCSK9 Antonio J Vallejo-Vaz

9 14

Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors Stephen J Nicholls

Familial Hypercholesterolaemia Diagnosis and Management Rodrigo Alonso,Leopoldo Perez de Isla, Ovidio Muñiz-Grijalvo, Jose Luis Diaz-Diaz and Pedro Mata

Pharmacotherapy

21

ISCP Guest Editorial: Cardiovascular Disease Prevention in Diabetes

23

Nicorandil and Long-acting Nitrates: Vasodilator Therapies for the Management of Chronic Stable Angina Pectoris

Maki Komiyama and Koji Hasegawa

Jason M Tarkin and Juan Carlos Kaski

29

Neuroendocrine System Regulatory Mechanisms: Acute Coronary Syndrome and Stress Hyperglycaemia Ricardo A Perez de la Hoz, Sandra Patricia Swieszkowski, Federico Matias Cintora, Jose Martin Aladio, Claudia Mariana Papini, Maia Matsudo and Alejandra Silvia Scazziota

35

Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator Hiroshi Watanabe

38

Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Alberto Lorenzatti and Maria Luz Servato

Basic Science

42

Cardiovascular Implications of Sphingomyelin Presence in Biological Membranes Petros Kikas, George Chalikias, and Dimitrios Tziakas

Interventions

46

Assessing the Haemodynamic Impact of Coronary Artery Stenoses: Intracoronary Flow Versus Pressure Measurements Valérie E Stegehuis, Gilbert WM Wijntjens, Tadashi Murai, Jan J Piek, Tim P van de Hoef

54

The Newest Generation of Drug-eluting Stents and Beyond

60

Effect of Percutaneous Coronary Intervention on Heart Rate Variability in Coronary Artery Disease Patients

Dae-Hyun Lee and Jose M de la Torre Hernandez

Mahmoud H Abdelnaby

Management and Comorbidities

62

Guest Editorial: Is Cardio-oncology Ready for Algorithms?

64

Cardio-oncology: A Focus on Cardiotoxicity

70

New Advances in the Management of Refractory Angina Pectoris

Steven M Ewer

Athanasios Koutsoukis, Argyrios Ntalianis, Evangelos Repasos, Efsthathios Kastritis, Meletios-Athanasios Dimopoulos and Ioannis Paraskevaidis

Kevin Cheng and Ranil de Silva

Cardiology Masters

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Featuring: Dr Patrick Serruys

© RADCLIFFE CARDIOLOGY 2018

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Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), Honorary Consultant Cardiologist at St George’s Hospital, NHS Trust, London, UK
and mmediate past Director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Prof Kaski
is Doctor of Science, University of London, immediate PastPresident of ISCP (International Society of Cardiovascular Pharmacotherapy) and editorial board member and associate editor of numerous peer review journals. He is also fellow of the ESC (FESC), the ACC (FACC), the AHA (FAHA), the Royal College of Physicians (FRCP), and over 30 other scientific societies worldwide. Prof Kaski’s research areas include mechanisms of rapid coronary artery disease progression, inflammatory and immunological mechanisms of atherosclerosis, microvascular angina and biomarkers of cardiovascular risk. Prof Kaski has published over 450 papers in peer-review journals, over 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics. DOI: https://doi.org/10.15420/aer.2018.13.1.FO

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elcome to the Summer 2018 issue of European Cardiology Review.

Major advances have taken place in relation to the pathophysiology and management of ischaemic heart disease in recent years, including pharmacological approaches as well as novel interventional tools and techniques. The diagnosis and management of co-morbidities, iatrogenic conditions and diseases refractory to conventional treatment have also captured the attention of physicians around the world. I am delighted and proud that this issue of European Cardiology Review tackles some of these major topics. Stephen Nicholls and colleagues review the use of PCSK-9 inhibitors for management of severe dyslipidaemia, and Drs Alonso and Mata discuss the diagnosis and management of familial hypercholesterolaemia. The section on dyslipidaemia has been guest edited by Dr AJ Vallejo-Vaz. The International Society of Cardiovascular Pharmacotherapy (ISCP) section on cardiovascular pharmacotherapy features an editorial by Koji Hasegawa, President of the ISCP, on current management of cardiovascular risk factors. This is an excellent introduction to the articles in this section, which review the management of pulmonary hypertension, the use of vasodilators in angina pectoris, and neuroendocrine abnormalities in the acute coronary syndrome. In addition, A. Lorenzatti and M. L. Servato highlight the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) and the role of inflammation in atherogenesis, examining selected antiinflammatory interventions and their potential use in the treatment of coronary artery disease. The Basic Science section features an article by D. Tziakas et al. on the cardiovascular implications of the presence of sphyngomyelin in biological membranes, and two important review articles are included in the section devoted to interventional cardiology. One of these addresses the problem of how to assess the haemodynamic impact of coronary artery stenoses and the other deals with the newest generation of drug-eluting stents and future developments in the field. A guest editorial by S.M. Ewer surveys recent developments in the field of cardio-oncology, including the 2016 European Society of Cardiology (ESC) position paper on cancer treatments and cardiovascular toxicity, and the 2017 American Society of Clinical Oncology (ASCO) clinical practice guideline on prevention and monitoring of cardiac dysfunction in survivors of adult cancers. Dr Ewer cautions against reliance upon detailed management algorithms that recommend specific parameters for interruption or discontinuation of cancer therapy. The management of refractory angina and new developments in cardiotoxicity associated with oncological treatment are discussed in two superb review articles also included in this issue’s management and comorbidities special section. As it is now customary, the now well-established ECR Cardiology Masters series celebrates the achievements of cardiovascular physicians and scientists that have made major contributions to help advance the field. This issue’s Cardiology Masters section highlights the brilliant career and superb contribution made by Patrick Serruys to interventional cardiology. It has been a great pleasure and an honour editing this issue of ECR, and I truly hope you will enjoy reading the excellent articles that have been included in the issue. I will attend the European Society of Cardiology’s annual meeting in Munich (August 2018) and will be delighted to meet the journal’s readers and contributors, if you happen to walk by ECR’s Radcliffe Cardiology booth at the conference. Enjoy reading ECR!

© RADCLIFFE CARDIOLOGY 2018

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Dyslipidaemia

Guest Editorial Reducing Risk in Familial Hypercholesterolaemia and Severe Dyslipidaemia: Novel Drugs Targeting PCSK9 Antonio J Vallejo-Vaz Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK

Citation: European Cardiology Review 2018;13(1):7–8. DOI: https://doi.org/10.15420/ecr.2018.13.1.GE3 Correspondence: Antonio Vallejo-Vaz, Department of Primary Care and Public Health, Imperial College London, Charing Cross Campus, Reynolds Building, St Dunstan’s Road, Hammersmith, London W6 8RP, UK. E: a.vallejo-vaz@imperial.ac.uk

E

levated LDL cholesterol (LDL-C) plays a major role in the development of atherosclerotic cardiovascular disease (ASCVD). Multiple studies and meta-analyses, including randomised controlled trials, prospective cohort studies and Mendelian randomisation studies, have consistently shown an association between LDL-C and ASCVD risk that is proportional to the magnitude and duration of exposure to elevated LDL-C levels.1

These two components – magnitude and duration – emphasise the need for early and effective LDL-C lowering in severe primary hypercholesterolaemia in order to achieve significant reductions in the risk of cardiovascular disease. However, despite the use of statins, a significant residual risk usually persists.2,3 Several factors, such as failure to reach LDL-C reduction goals and concerns with longterm adherence to medication, among others, highlight the need for additional treatment options that further reduce LDL-C levels while being well tolerated and accepted by patients. Patients with familial hypercholesterolaemia (FH) are of particular interest among people with severe dyslipidaemias. This genetic disorder, resulting from mutations in genes related to LDL-C metabolism, reflects well the notion of “LDL-C levels × time of exposure”, since FH patients are exposed to high LDL-C levels from early in life.4,5 The burden of life-long elevated LDL-C levels results in a significantly higher risk of ASCVD, particularly premature coronary artery disease.4,5 Despite compelling information supporting the risk posed by FH and recent studies suggesting FH to be far more prevalent than previously thought (around 1 in 200–300, versus previous estimates of 1 in 500 people), reports suggest that there are generally low rates of FH identification.4–6 This results partly from a lack of awareness and clinical suspicion, and also from insufficient formal programmes and support for FH detection and screening.7 In addition, a common issue that has been highlighted is the general under-treatment of FH. This is due to several factors, including lack of identification and diagnosis, delayed treatment (introduced too late) or patients not being treated with high enough levels of

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medications.4 Statins, frequently at high-intensity doses, are the first-line therapy to reduce LDL-C in people with FH.4 However, FH patients have poor rates of attainment of guidelines-recommended LDL-C levels.8 This highlights the need for additional therapies to achieve greater reductions in LDL-C, which will, in turn, further reduce adverse cardiovascular outcomes. Severe hypercholesterolaemia usually requires high-intensity statins and frequently also will involve combination therapy with additional drugs, such as ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, particularly in subgroups with elevated cardiovascular risk.9 A number of factors will influence the decision on what drug to add and when, such as the magnitude of LDL-C reduction needed (drug intensity, percentage reductions), drug availability and cost, individual risk, adherence to medication, and patient preference. The recent approval of PCSK9 inhibitors, may have a substantial positive impact on the treatment of severe dyslipidaemia. These drugs have been developed fairly quickly over the last 2 decades, with results from two large outcome clinical trials recently available. In both ODYSSEY (alirocumab) and FOURIER (evolocumab) outcomes trials in patients with cardiovascular disease, PCSK9 inhibitors (administered every 2 weeks, usually on top of statins) were shown to produce greater LDL-C reductions, while being overall safe and well-tolerated (apart from some injection site reactions).10,11 This translated into a lower risk of cardiovascular events, with some data suggesting that patients at higher risk or with higher LDL-C may benefit the most from PCSK9 therapy. Nevertheless, the cost of this therapy is still an issue, and additional data are needed on longer follow-ups, outcomes results in some subgroups (e.g. FH), and long-term daily-practice data. Thus, the identification of patients that may obtain a greater benefit has become a particular point of interest. So far, different statements have recommended that PCSK9 inhibitors should be considered in patients with substantially elevated LDL-C levels (primary elevations, including FH patients), despite maximally tolerated lipid-lowering therapy (or intolerant to therapy), with either very-high risk or established

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Dyslipidaemia ASCVD.12–14 There is an ongoing debate about whether to lower the current proposed LDL-C levels for prescribing PSCK9 inhibitors, as these cut-offs are higher than the target levels recommended in guidelines. Additionally, these recommendations were made before the results of the outcome trials were published and further updates on these recommendations are expected.

shown to produce sustained LDL-C reductions over a few months after one injection.15 This gives rise to the possibility that inclisiran might need to be administered only a few times a year, which ultimately could increase medication adherence and cost-effectiveness. Nevertheless, results from large clinical trials evaluating outcomes and long-term safety are required.

Finally, it is worth mentioning inclisiran, a promising new drug targeting PCSK9 by reducing its hepatocellular synthesis. Inclisiran has been

In this issue, R Alonso et al present an overview of FH and S Nicholls an overview of PCSK9 inhibitors for managing severe dyslipidaemias. n

1.

2.

3.

4.

5.

 erence BA, Ginsberg HN, Graham I, et al. Low-density F lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459–2472. https://doi.org/10.1093/eurheartj/ehx144; PMID: 28444290. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–35. https://doi. org/10.1056/NEJMoa050461; PMID: 15755765. Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319–35. https://doi.org/10.3132/dvdr.2008.046; PMID: 18958843. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478–90a. https://doi.org/10.1093/eurheartj/eht273; PMID: 23956253. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial

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Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146–57. https://doi.org/10.1093/ eurheartj/ehu274; PMID: 25053660. 6. Vallejo-Vaz AJ, Ray KK. Epidemiology of familial hypercholesterolaemia: Community and clinical. Atherosclerosis 2018; doi:10.1016/j.atherosclerosis.2018.06.855; In Press. 7. Vallejo-Vaz AJ, Kondapally Seshasai SR, Cole D, et al. Familial hypercholesterolaemia: A global call to arms. Atherosclerosis 2015;243:257–9. https://doi.org/10.1016/j. atherosclerosis.2015.09.021; PMID: 26408930. 8. Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-Year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278–85. https://doi.org/10.1016/j. jacc.2016.01.008; PMID 26988947. 9. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281–344. https://doi.org/10.1016/j.atherosclerosis.2016.08.018; PMID: 27594540. 10. Steg PG. Evaluation of cardiovascular outcomes after anacute coronary syndrome during treatment with alirocumab – ODYSSEY OUTCOMES. American College of Cardiology, 10

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14.

15.

March 2018. Available at: http://www.acc.org/latest-incardiology/clinical-trials/2018/03/09/08/02/odyssey-outcomes (accessed 23 July 2018). Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi.org/10.1056/ NEJMoa1615664; PMID: 28304224. Landmesser U, Chapman MJ, Stock JK, et al. 2017 update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2018;39:1131–43. https://doi.org/10.1093/eurheartj/ehx549; PMID: 29045644. National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. London: National Institute for Health and Care Excellence, 2016. Available at: https://www.nice.org.uk/guidance/ta394/ chapter/1-Recommendations (accessed 23 July 2018). National Institute for Health and Care Excellence. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. London: National Institute for Health and Care Excellence, 2016. Available at: https://www.nice.org.uk/guidance/ta393/ chapter/1-Recommendations (accessed 23 July 2018). Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430–40. https://doi.org/10.1056/ NEJMoa1615758; PMID: 28306389.

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Dyslipidaemia

Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors Stephen J Nicholls South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, Australia

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulation of LDL receptors on the hepatocyte surface and therefore is essential for effective removal of LDL particles from circulation. Genetic and biochemical studies have established that altered PCSK9 functionality influences both LDL cholesterol levels and cardiovascular risk. This has prompted development of inhibitory strategies targeting PCSK9. Study of monoclonal PCSK9 antibodies has progressed to the clinic, where they have been found to lower LDL cholesterol levels and reduce cardiovascular event rates in large, clinical outcome trials. The use of PCSK9 inhibitors in the setting of dyslipidaemia is reviewed.

Keywords Atherosclerosis, cardiovascular risk, clinical trials, lipids, risk factors Disclosure: Stephen J. Nicholls has received research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience and is a consultant for AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion and Boehringer Ingelheim. Received: 29 January 2018 Accepted: 15 May 2018 Citation: European Cardiology Review 2018;13(1):9–13. DOI: https://doi.org/10.15420/ecr.2018.3.2 Correspondence: Stephen Nicholls, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA 5001, Australia. E: stephen.nicholls@sahmri.com

Therapeutic targeting of dyslipidaemia has been one of the major successes in cardiovascular medicine over the last three decades. On the basis of unequivocal evidence from animal models through to both population and genetic studies in humans, there is a clear association between increasing levels of LDL cholesterol (LDL-C) and incident cardiovascular risk.1 This has prompted efforts to develop a range of therapeutic strategies that lower LDL-C levels. Seminal clinical trials have demonstrated that lowering LDL-C levels with statins reduces cardiovascular event rates in the setting of primary and secondary prevention.2 More recently, addition of the cholesterol absorption inhibitor ezetimibe to a statin results in further reduction in cardiovascular risk.3 These studies contribute to large meta-analyses that have consistently demonstrated that each 1 mmol/l lowering of LDL-C is associated with an approximately 21 % reduction in the rate of cardiovascular events.2 While these findings have been translated to clinical practice, with statins becoming a cornerstone of cardiovascular prevention strategies, there remains an ongoing need to develop additional lipid-lowering approaches.

associations with adverse effects such as new-onset diabetes and impaired cognitive function. While many patients do experience myalgia that prevents use of effective statin doses, the clinical implications of new-onset diabetes are uncertain and there is no evidence to clearly establish that statins have any objective impact on cognitive function.6 The additional challenge for statins is the inability of some patients to achieve guideline-mandated treatment goals.5 This is particularly problematic in patients with familial hypercholesterolaemia, in which the combination of very high baseline LDL-C levels and genetically altered lipid metabolism continues to expose many of these patients to unacceptably high LDL-C levels.7 This is likely to underscore a considerable high risk of cardiovascular events. Even when patients do achieve treatment targets with statin therapy, many cardiovascular events will continue to occur.8 This residual risk continues to support the need to develop additional lipid lowering strategies and to ask whether reducing LDL-C to very low levels will result in even greater cardiovascular protection.

Challenges with Statins The findings of the statin cardiovascular outcome trials have supported the widespread use of statins in clinical practice as the first therapeutic option in prevention strategies. Recently, studies highlighting the importance of more intensive lipid lowering have led to calls for greater use of more potent statins in patients deemed to be at high cardiovascular risk.4 While these data are irrefutable, particularly for the very high-risk patient, many patients are either not treated, do not undergo appropriate dose escalation or stop taking this treatment.5 While clinical inertia contributes to the suboptimal prescription of statins, particularly at more potent doses, high discontinuation rates are driven by a range of factors, including inability to comply with longterm therapy, symptomatic myalgia and concerns regarding potential

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PCSK9 and Lipid Homeostasis Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and plays an important role in the regulation of lipid metabolism.9 PCSK9 is a factor, synthesised within the hepatocyte and secreted into the circulation, where it binds to the complex between LDL particles and the LDL receptor. Within the hepatocyte, the presence of PCSK9 prevents dissociation of the LDL particle from the receptor, which directs both to lysosomal degradation. This process prevents ongoing shuttling of the free LDL receptor back to the hepatocyte surface, where it continues to remove LDL particles and their cholesterol content from circulation. Gain-of-function PCSK9 mutations have been identified as the third autosomal dominant locus underlying familial

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Dyslipidaemia hypercholesterolaemia.10 In addition, a number of polymorphisms have been identified that result in reduced PCSK9 and are associated with both lower LDL-C levels and lower rates of cardiovascular events.11,12 Mendelian randomisation studies have provided further evidence linking low levels of PCSK9 activity with both lower lipid levels and cardiovascular risk.13 These data have supported the rapid expansion of efforts to develop inhibitory approaches to PCSK9 inhibition as a potential cardioprotective agent.

PCSK9 Monoclonal Antibodies and Lipid Levels Advances in monoclonal antibody technology permit development of fully human antibodies targeting PCSK9. A large number of lipid studies have demonstrated that the agents evolocumab and alirocumab produce dose-dependent lowering of LDL-C by up to 60 %. In addition, PCSK9 inhibitors have been demonstrated to lower triglyceride levels by up to 20 % and lipoprotein(a) by 25–30 % and to modestly raise HDL cholesterol (HDL-C) levels. These findings are observed when these agents are administered either as monotherapy14–16 or in combination with statins.17–19 Given their ability to produce robust LDL-C lowering, these agents have been extensively evaluated in patients with familial hypercholesterolaemia, with evidence of substantial lipid lowering in both heterozygous (−60 %) and homozygous (−30 %) patients.20–22 The finding of LDL-C lowering in homozygous familial hypercholesterolaemia suggests that some of these patients have some level of functioning LDL receptor activity. In fact, further analyses demonstrated LDL-C lowering in those patients with functional LDL receptors, while there was no activity in patients with no functioning LDL receptors.22 The ability to achieve effective lipid lowering as monotherapy has permitted the evaluation of PCSK9 inhibitors in patients with statin intolerance. The lipid efficacy is balanced by the finding of no excess in myalgia rates compared with ezetimibe treatment in these patients.16 The observation of similar lipid lowering in statin-treated patients would be anticipated, given that statins are associated with an increase in PCSK9 levels.23 In general, these agents were well tolerated, with no concerning signs of adverse events.

PCSK9 Monoclonal Antibodies and Clinical Outcomes Clinical trials have transitioned queries regarding the impact of PCSK9 inhibitors on circulating lipid levels to atherosclerotic plaque within the artery wall and subsequently cardiovascular events.

Evolocumab The GLobal Assessment of plaque reGression with a PCSK9 antibOdy as measured by intraVascular ultrasound (GLAGOV) study employed serial intravascular ultrasound imaging to determine the impact of the PCSK9 inhibitor evolocumab on progression of coronary atherosclerosis in patients already treated with a statin, who had presented for a clinically indicated coronary angiogram.24 The combination of evolocumab and statin produced a lower LDL-C than statin monotherapy (0.95 mmol/l versus 2.4 mmol/l). This translated to a beneficial impact on the change in percentage total atheroma volume (−0.95 % versus 0.05 %) and a greater percentage of patients demonstrating any degree of disease regression (64 % versus 47 %). A direct relationship was observed between achieved LDL-C levels and the rate of disease progression, demonstrating no loss of incremental benefit at lower LDL-C levels. Patients with baseline LDL-C levels less than 1.8 mmol/l demonstrated even greater

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reductions in percentage atheroma volume (−1.97 %) and a greater percentage of patients with regression (81  %). This may reflect the need for additional risk factors for study entry in these patients and the fact that their lower LDL-C did not protect them from the need for coronary angiography, thus potentially identifying patients with more modifiable disease. Subsequent analyses have revealed that ongoing progression, despite treatment with evolocumab, was observed in patients with additional risk factors and that regression was accompanied by an increase in plaque calcium, further supporting a role in plaque stabilisation. The Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) study was the first large clinical outcomes trial to evaluate the impact of adding evolocumab to existing statin therapy in patients with a prior history of MI, stroke or peripheral arterial disease and LDL-C ≥1.8 mmol/l.25 Similar to GLAGOV, patients had generally been on optimised regimens prior to study entry, with more than 60 % receiving the highest intensity statin therapy prior to the study. Mean LDL-C reduced in the evolocumab/statin group by 2.4 mmol/l versus 0.78 mmol/l in the placebo group. This was associated with a reduction in the risk of cardiovascular events for patients in the evolocumab/statin group, with a 15 % reduction in the risk for the primary composite end point (cardiovascular mortality, non-fatal MI, non-fatal stroke, coronary revascularisation and hospitalisation for unstable angina, and a 20  % reduction in the risk of secondary end point events (cardiovascular death, non-fatal MI and non-fatal stroke). While this study was large (27,654 patients), the median treatment exposure was only 26 months, with many taking the study drug for only 12 months. Given that the event curves did not begin to separate for at least 6 months, the limited treatment exposure in many patients may have led to a potential underestimate of event reduction with evolocumab. Prespecified landmark analyses revealed a greater proportional reduction in cardiovascular events with evolocumab in patients treated in the second year and beyond. Subsequent analyses demonstrated a direct association between achieved LDL cholesterol levels and cardiovascular event rates, further extending the lower-isbetter concept. Evolocumab was well tolerated, with no excess in the rate of adverse events compared with placebo. In particular, there was no excess in the rate of injection-site reactions or adverse events that are often raised in relation to statins (new-onset diabetes, myalgia, cataracts, cognitive decline).25 While a prior pooled analysis of evolocumab-treated patients in longer-term lipid studies signalled a potential excess rate of investigator-reported neurocognitive adverse events,26 this was not observed in FOURIER.25 Furthermore, a large substudy that evaluated executive cognitive function using well-validated assays failed to demonstrate any impairment with either evolocumab treatment or achievement of very low LDL-C levels.27 A number of subgroup analyses have been subsequently reported providing further insight into the efficacy and safety profile of evolocumab therapy. These findings included: • S imilar event reductions in patients with a baseline LDL-C <1.8 mmol/l.28 • Similar event reductions in patients with and without diabetes, with no worsening of glycaemic control or in the incidence of new-onset diabetes.29 • Similar event reductions in patients with and without prior stroke.30

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PCSK9 Inhibitors • G  reater event reductions in patients with prior MI and high-risk features (<2 years from index MI, at least two prior MIs, multivessel coronary artery disease).31 • Greater proportional reductions with evolocumab were observed in patients with an established history of peripheral arterial disease, compared to those without. In addition to the reduction in coronary and cerebrovascular events, evolocumab administration resulted in a significant reduction in the incidence of major adverse limb events (acute limb ischaemia, major amputation or urgent peripheral revascularisation for ischaemia) in both patients with and without established peripheral arterial disease.32

Bococizumab Bococizumab is a humanised monoclonal antibody targeting PCSK9. While preliminary lipid studies were favourable with similar findings to that observed with both evolocumab and alirocumab, two large clinical outcome trials were stopped prematurely due to the incidence of neutralising antibodies, resulting in a loss of LDL-C lowering in many patients. The presence of neutralising antibodies with the humanised agent bococizumab, but not the fully human antibodies evolocumab and alirocumab, seems most likely to explain the loss of LDL-C lowering in patients treated with this agent alone. However, the Studies of PCSK9 Inhibition and the Reduction of vascular Events 2 (SPIRE-2) study of bococizumab in patients with higher baseline lipid levels at entry (LDL-C ≥2.59 mmol/l or non-HDL-C >3.36 mmol/l) demonstrated a significant reduction in event rates, despite accruing a relatively small number of clinical events.33,34 This supports the benefits of novel lipid lowering agents in patients with higher baseline LDL-C levels.

Alirocumab The primary results of the ODYSSEY Outcomes trial were reported at the 2018 Scientific Sessions of the American College of Cardiology.35 This study evaluated the impact of addition of alirocumab to background statin therapy in patients who have experienced an acute coronary syndrome in the preceding 4–52 weeks.36 This study differed from FOURIER from the perspective that it aimed for a target LDL-C of 0.65–1.3 mmol/l. This required backtitration of alirocumab dose for patients with LDL-C <0.39 mmol/l. From an intention-to-treat perspective, alirocumab produced lower LDL-C levels than placebo (1.72 mmol/l versus 2.67 mmol/l), which was associated with a 15 % reduction in the primary composite endpoint of coronary heart disease death, non-fatal MI, ischaemic stroke or unstable angina requiring hospitalisation. On nominal, non-hierarchical testing, a reduction in all-cause mortality was observed in alirocumab-treated patients (3.5 % versus 4.1  %). While the benefit appeared to be largely observed in those patients with a baseline LDL-C greater than 2.59 mmol/l, further supporting findings from SPIRE and FOURIER, patients at lower baseline levels were more likely to undergo backtitration of alirocumab dose. Reassuring data were observed for safety and tolerability, providing additional information that intensive lowering of LDL-C can be beneficial for high-risk patients.

Use of PCSK9 Monoclonal Antibodies in Clinical Practice These trials have now translated the benefits of PCSK9 monoclonal antibodies from their effects on circulating lipid parameters in the blood to plaque within the artery wall and ultimately cardiovascular events. As predicted, incremental lowering of LDL-C produces clinical benefit, extending prior observations of a direct association between these parameters. In fact, the early studies with evolocumab now

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demonstrate both cardiovascular efficacy and overall safety in patients achieving very low LDL-C levels. The question will now involve how to translate these findings to clinical practice. It would appear that there are a number of groups in whom use of a PCSK9 inhibitor should be considered. Familial hypercholesterolaemia is common and, left untreated, is a major driver of premature atherosclerotic cardiovascular disease. Many patients with this genetic disorder continue to demonstrate unacceptably high LDL-C levels, despite use of maximally tolerated lipid-lowering agents.7 Accordingly, there is a need to develop novel approaches to achieve more effective lipid lowering. Clinical studies performed in these patients have demonstrated that administration of a PCSK9 inhibitor can provide a useful adjunctive therapy in both heterozygous and homozygous states.20–22 The clinical utility of this benefit is further evidenced by a reduction in need for LDL apheresis in those patients with the most refractory forms of dyslipidaemia.37 The evolution of PCSK9 inhibitors has provided an important stimulus to increase awareness of familial hypercholesterolaemia, which should result in greater use of cascade screening of relatives and early initiation of effective lipid lowering. Statin intolerance is increasingly recognised in clinical This results in poor adherence and discontinuation of with consequent higher lipid levels. Clinical studies in with documented statin intolerance have demonstrated lipid lowering, without reproducing symptomatic myalgia patients.14–16 While clinical outcome trials of PCSK9 inhibitors

practice. therapy, patients effective in these

have not been directly performed in this patient cohort, the ability to achieve more effective lipid lowering is likely to result in cardiovascular protection worth considering in the patient at very high risk of cardiovascular events. The fundamental importance of very high LDL-C levels in driving cardiovascular risk highlights that these individuals should be considered for therapy, regardless of the presence of either familial hypercholesterolaemia or statin intolerance. A patient with very high LDL-C levels, despite use of maximal statin doses and ezetimibe, might derive a potentially greater clinical benefit with PCSK9 inhibition. This is further supported by the findings of SPIRE-2.33,34

Patients with the highest cardiovascular risk, regardless of LDL-C levels, should also be considered for therapy. Subgroup analyses of FOURIER provide some insight into groups with elevated levels of modifiable risk, with an apparent association with lower numbers needed to treat.28–32 A take-home message from each of these studies has been the tolerability of achieving lower LDL-C levels than currently advocated by treatment guidelines. In the large outcomes trials, no adverse effect was observed in relation to achieving low lipid levels. This should give clinicians increasing reassurance of the importance of targeting lower LDL-C levels in patients deemed to be at a high risk of having a cardiovascular event. As these agents are increasingly used in clinical trials, particularly in older patients than typically enrolled in the outcome trials, it will be important to continue to evaluate their safety in a real world setting. An important factor underscoring how to optimally integrate these agents into clinical practice will be their cost effectiveness. A high

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Dyslipidaemia cost of production, combined with more modest event reductions than originally predicted and a lack of mortality benefit all suggest that PCSK9 inhibitors are unlikely to be used empirically.38 In fact, modelling performed to date suggests that a more convincing case would be made for broader use if the annual cost per patient were to be reduced to approximately US$2,500, well below current prices.39 As a result, identification of groups that are at particularly high risk, as outlined above, in addition to demonstration of cost effectiveness in these groups are urgently required in order to determine how to most effectively use these agents in clinical practice. This appears to be the position of contemporary clinical statements, including the European Society of Cardiology/European Atherosclerosis Society and the UK’s National Institute for Health and Care Excellence, which advocate for the use of these agents in very high-risk patients whose LDL-C remains unacceptably high despite use of maximally tolerated statin therapy, with or without concomitant ezetimibe.40–42 Such information will be pivotal in terms of the ability to inform updates to treatment guidelines with regard to effective lipid lowering interventions in cardiovascular prevention.

is slightly less than that observed with monoclonal antibodies, the durability of these effects is considerably longer.43 In general, this agent appears to be well tolerated. This provides the potential for administration three or four times a year. This may present a more cost-effective approach to PCSK9 inhibition, although the longterm efficacy and safety will require thorough investigation in larger clinical trials. The role of PCSK9 inhibition in other atherogenic lipid parameters remains uncertain. While these agents have been demonstrated to lower levels of lipoprotein(a), the relative contribution of this effect to clinical benefit has not been fully elucidated. This may be particularly important in patients with familial hypercholesterolaemia, in whom elevated levels of both LDL-C and lipoprotein(a) often coexist.44 The modest impact on triglyceride-rich lipoprotein levels suggests that alternative strategies are more likely to be of benefit in targeting patients whose heightened cardiovascular risk is driven by hypertriglyceridaemia.

Conclusion Future Steps ODYSSEY outcomes and further subgroup analyses, in combination with appropriate cost effectiveness data, are essential in further determining the optimal clinical use of these agents. Alternative approaches to targeting PCSK9 are receiving attention in clinical development. RNA inhibition using inclisiran aims to impair hepatocellular synthesis of PCSK9. While the degree of PCSK9 inhibition and LDL-C lowering

1.

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In a relatively short period, the science of PCSK9 and its fundamental role in lipid metabolism has been elucidated, in parallel with the development of effective inhibitory agents. This has translated to predictable benefits on cardiovascular risk. Considerable work continues to define how to most cost effectively triage the right patient to treatment with those agents in order to prevent the ongoing pandemic of cardiovascular disease. n

frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161–5. https://doi.org/10.1038/ng1509; PMID: 15654334. 12. C  ohen JC, Boerwinkle E, Mosley THJ, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72. https://doi. org/10.1056/NEJMoa054013; PMID: 16554528. 13. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144–53. https://doi.org/10.1056/ NEJMoa1604304; PMID: 27959767. 14. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8. https://doi.org/10.1016/j.jacc.2014.03.019; PMID: 24694531. 15. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol 2015;9:758–69. https://doi. org/10.1016/j.jacl.2015.08.006; PMID: 26687696. 16. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA 2016;315:1580–90. https://doi.org/10.1001/ jama.2016.3608; PMID: 27039291. 17. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108–18. https://doi.org/10.1056/NEJMoa1105803; PMID: 22435370. 18. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or highintensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311: 1870–82. https://doi.org/10.1001/ jama.2014.4030; PMID: 24825642. 19. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebocontrolled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809–19. https://doi.org/10.1056/NEJMoa1316222; PMID: 24678979. 20. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2014;385:331–40. https://doi.org/10.1016/S0140-6736(14)61399-4; PMID: 25282519 21. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996–3003. https://doi.org/10.1093/ eurheartj/ehv370; PMID: 26330422. 22. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia

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(TESLA Part B): a randomised, double-blind, placebocontrolled trial. Lancet 2015;385:341–50. https://doi. org/10.1016/S0140-6736(14)61374-X; PMID: 25282520 Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004;24:1454–9. https://doi.org/10.1161/01. ATV.0000134621.14315.43; PMID: 15178557. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV randomized clinical trial. JAMA 2016;316:2373–84. https://doi.org/10.1001/jama.2016.16951; PMID: 27846344. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi.org/10.1056/ NEJMoa1615664; PMID: 28304224 Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9. https://doi.org/10.1056/ NEJMoa1500858; PMID: 25773607. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633–43. https://doi.org/10.1056/NEJMoa1701131; PMID: 28813214. Giugliano RP, Keech A, Murphy SA, et al. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial. JAMA Cardiol 2017;2:1385– 91. https://doi.org/10.1001/jamacardio.2017.3944; PMID: 29117276. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:941–50. https://doi.org/10.1016/ S2213-8587(17)30313-3. PMID: 28927706. AMGEN. New analysis shows Repatha® (evolocumab) reduces cardiovascular events in patients with history of stroke. 29 August 2017. Available at: www.amgen.com/ media/news-releases/2017/08/new-analysis-shows-repathaevolocumab-reduces-cardiovascular-events-in-patients-withhistory-of-stroke (accessed 16 June 2018). Maxwell YL. Two FOURIER subgroup analyses show added benefit of evolocumab in those with PAD, prior MI. tctMD 3 November 2017. Available at: www.tctmd.com/news/twofourier-subgroup-analyses-show-added-benefit-evolocumabthose-pad-prior-mi (accessed 16 June 2018). Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights

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PCSK9 Inhibitors

from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018;137:338–50. https://doi.org/10.1161/ CIRCULATIONAHA.117.032235; PMID: 29133605. 33. Ridker PM, Amarenco P, Brunell R, et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes trials. Am Heart J 2016;178:135–44. https://doi. org/10.1016/j.ahj.2016.05.010; PMID: 27502861. 34. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527–39. https://doi.org/10.1056/NEJMoa1701488; PMID: 28304242. 35. Steg PG. Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab – ODYSSEY OUTCOMES. American College of Cardiology 10 March 2018. Available at: http://www.acc.org/latest-in-cardiology/

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clinical-trials/2018/03/09/08/02/odyssey-outcomes (accessed 16 June 2018). 36. S  chwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682–9.e1. https://doi.org/10.1016/j.ahj.2014.07.028; PMID: 25440796. 37. Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J 2016;37:3588–95. https://doi.org/10.1093/eurheartj/ ehw388; PMID: 27572070. 38. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 2016;316:743–53. https://doi.org/10.1001/ jama.2016.11004; PMID: 27533159. 39. Hlatky MA, Kazi DS. PCSK9 inhibitors: economics and policy. J Am Coll Cardiol 2017;70:2677–87. https://doi.org/10.1016/j. jacc.2017.10.001; PMID: 29169476.

40. L andmesser U, Chapman MJ, Stock JK, et al. New prospects for PCSK9 inhibition? Eur Heart J 2018. https://doi. org/10.1093/eurheartj/ehy147; PMID: 29579192; epub ahead of press. 41. National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. London: NICE; 2016. Available at: www.nice.org.uk/ta394 (accessed 16 June 2018). 42. National Institute for Health and Care Excellence. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. London: NICE; 2016. Available at: www.nice.org.uk/ta393 (accessed 16 June 2018). 43. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430–40. https://doi.org/10.1056/ NEJMoa1615758; PMID: 28306389. 44. Vuorio A, Watts GF, Kovanen PT. Depicting new pharmacological strategies for familial hypercholesterolaemia involving lipoprotein (a). Eur Heart J 2017;38:3555–9. https://doi. org/10.1093/eurheartj/ehx546; PMID: 29029165.

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Dyslipidaemia

Familial Hypercholesterolaemia Diagnosis and Management Rodrigo Alonso, 1 Leopoldo Perez de Isla, 2 Ovidio Muñiz-Grijalvo, 3 Jose Luis Diaz-Diaz 4 and Pedro Mata 5 1. Department of Nutrition, Clínica Las Condes, Santiago, Chile; 2. Cardiology Department, Clinical Hospital San Carlos, IDISSC, Complutense University, Madrid, Spain; 3. Department of Internal Medicine, Virgen del Rocío Hospital, Seville, Spain; 4. Department of Internal Medicine, University A Coruña Hospital, A Coruña, Spain; 5. Spanish Familial Hypercholesterolemia Foundation, Madrid, Spain

Abstract Familial hypercholesterolaemia is the most common monogenic disorder associated with premature coronary artery disease. Mutations are most frequently found in the LDL receptor gene. Clinical criteria can be used to make the diagnosis; however, genetic testing will confirm the disorder and is very useful for cascade screening. Early identification and adequate treatment can improve prognosis, reducing negative clinical cardiovascular outcomes. Patients with familial hypercholesterolaemia are considered at high cardiovascular risk and the treatment target is LDL cholesterol <2.6 mmol/l or at least a 50 % reduction in LDL cholesterol. Patients require intensive treatment with statins and ezetimibe and/or colesevelam. Recently, proprotein convertase subtilisin/kexin type 9 inhibitors have been approved for the management of familial hypercholesterolaemia on top of statins.

Keywords Familial hypercholesterolaemia, genetic testing, cascade screening, statins Disclosure: The authors have no conflicts of interest to declare. Acknowledgments: The authors thank the Spanish Familial Hypercholesterolemia Foundation, especially Maria Teresa Pariente for the development of cascade screening and the SAFEHEART Registry. Received: 7 March 2018 Accepted: 23 April 2018 Citation: European Cardiology Review 2018;13(1):14–20. DOI: https://doi.org/10.15420/ecr.2018:10:2 Correspondence: Pedro Mata, Spanish Familial Hypercholesterolemia Foundation, General Alvarez de Castro 14, 1ºE, 28010-Madrid, Spain; E: pmata@colesterolfamiliar.org

Familial hypercholesterolaemia (FH) is the genetic disorder most commonly associated with elevated LDL cholesterol (LDL-C) levels from birth and with premature atherosclerotic cardiovascular disease (ASCVD).1 It is caused by mutations in genes related to the clearance of LDLs such as LDL receptor (LDLR), apolipoprotein B-100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9).2 The prognosis for patients with FH has improved in the past 30 years, with statins improving clinical outcomes and reducing total mortality.3,4

In patients with genetically confirmed acute coronary syndromes, the prevalence of FH is up to 8.7 %.10,11

Different strategies have been proposed to improve early detection of the disorder and ensure adequate treatment to prevent the development of ASCVD. The detection of index cases (IC; the first individual diagnosed in the family) through different case-finding strategies and cascade screening in relatives using LDL-C levels and/or genetic testing is feasible and cost-effective, especially for identifying cases in young people.5–7

Molecular Defects

This comprehensive review focuses on epidemiology, diagnosis and screening programmes, the goals of treatment and current lipidlowering therapy in FH.

Prevalence Traditionally, the prevalence of heterozygous FH has been estimated to be one case in 500 in the general population (0.2 %).2 However, a recent systematic review and meta-analysis has shown a prevalence of one in 250 individuals – higher than initially thought.8 Due to a founder effect, the prevalence of the disorder can be higher– up to one in 50–67 of the general population – in specific populations.9

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The prevalence of homozygous FH (HoFH) has been estimated to be one in 1 million, based on the frequency of heterozygous FH among relatives’ survivors of MI.12 However, a recent analysis established the prevalence of molecularly defined HoFH as being one in 300,000 individuals.13

FH is autosomal-dominantly inherited and >80 % of cases are caused by functional mutations in the LDLR gene. As of October 2017, >1,700 different functional mutations in the LDLR gene had been described worldwide.14,15 Five to 10  % of FH cases are caused by mutations in the APOB gene16,17 and <1  % are caused by some specific ‘gain-offunction’ mutations in the PCSK9 gene.14,18 These later mutations enhance the binding of PCSK9 to LDLR, increasing degradation of the receptor in the endosome, resulting in high cholesterol levels.19 There is emerging evidence that some patients with FH phenotype in whom a mutation in these three genes has not been detected may have a polygenic hypercholesterolaemia. These individuals have significantly higher number of LDL-C-increasing variations and LDL-C levels than controls.20 A very rare recessive form of FH that is clinically similar to HoFH is caused by mutations in low-density lipoprotein receptor adaptor protein 1 (LDLRAP1). The remaining FH cases are driven by monogenic mutations in other genes related to high cholesterol levels, such as APOE, SREBP2, STAP1 and LIPA.21

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Familial Hypercholesterolaemia Figure 1: Coronary Artery Calcifications (Red Arrows) in a 37-year-old Man with Familial Hypercholesterolaemia

Cardiac CT allows us to establish the presence of coronary atherosclerotic plaques in asymptomatic subjects with familiar hypercholesterolaemia.

Cardiovascular Disease in Familial Hypercholesterolaemia ASCVD in FH results from prolonged exposure to very high levels of LDL-C from birth.2 Vascular imaging studies in children have confirmed that carotid intima-media thickness is greater than in unaffected siblings by 8 years of age.22 Other studies using coronary angiography or electron beam tomography have shown that coronary atherosclerosis is evident from age 17 in males and 25 in females, and that 25 % of adolescents with FH have detectable coronary calcium.23,24 The first manifestation of the disorder is usually MI, which occurs as early as the third decade of life, and on average 20 years earlier than in individuals without FH.25,26 In the pre-statin era, a cumulative risk of fatal and non-fatal coronary events was observed in around 50  % of men and 30 % of women by the age of 60.27 The first UK Simon Broome Register analysis in 1991 showed that younger FH patients had a 100fold increase in coronary mortality and nearly 10-fold increase in total mortality compared to the general normolipidaemic population.28 A recent analysis of the Copenhagen General Population Study showed a multifactorial adjusted odds ratio for coronary artery disease of 3.3 in carriers of a FH mutation.29 Data from the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART) showed a prevalence of ASCVD in molecularly-defined FH subjects of 13  %, which is threefold higher than their unaffected relatives.30 Cardiovascular manifestations are highly variable depending on the molecular basis of the FH, LDL-C levels and the presence of other risk factors including lipoprotein(a).30–35 Patients with severe mutations are at higher risk than those patients with milder mutations.32,33 Lipoprotein(a) >1.8 µmol/l has been established as a cardiovascular risk factor in FH and its interaction with the type of mutation has been observed in molecularly-defined FH patients.34,35 HoFH is characterised by accelerated atherosclerosis that mainly affects the aortic root and coronary ostium. Absolute LDL-C levels are

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related to the severity of cardiovascular disease. The first cardiovascular event often occurs during early adolescence, especially in those cases with severe mutations (LDLR-negative). LDLR-defective patients usually develop clinical cardiovascular disease by the age of 30.36,37

Subclinical Atherosclerosis The atherosclerotic burden of FH can be demonstrated using non-invasive imaging techniques.38–40 In recent years, coronary CT angiography has emerged as a safe and non-invasive method of assessing coronary atherosclerosis.41 Cross-sectional studies have shown that FH patients have higher coronary artery calcium scores than non-FH individuals (Figure 1).42,43 However, it is still necessary to determine whether imaging studies improve risk stratification, intensity of treatment and clinical outcomes if they are incorporated as part of FH management.

Clinical Diagnosis of Heterozygous FH A clinical diagnosis of FH is made based on high plasma levels of LDL-C, family history of hypercholesterolaemia, a history of premature ASCVD and the presence of tendon xanthomas.1,2 In general, LDL-C levels in adult patients are >4.9 mmol/l; however, lower cholesterol levels may be observed in some FH patients and their relatives, especially younger individuals, and an overlap in the distribution of LDL-C levels can be observed.44,45 Triglyceride levels are usually normal; however, high levels do not exclude the diagnosis if other criteria strongly suggest FH. Tendon xanthomas are pathognomonic for the disorder and are associated with higher cardiovascular risk.46,47 Xanthomas are present in <20 % of FH patients with a functional mutation;30,48 therefore, the absence of xanthomas does not exclude the diagnosis of FH. In the past 30 years, three different clinical criteria have been developed for the diagnosis of FH. The MEDical PEDigrees with FH to Make Early Diagnosis and Prevent Early Deaths (MedPed) programme focuses on lipid levels, and does not incorporate clinical characteristics or

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Dyslipidaemia Table 1: Clinical Criteria for the Diagnosis of Heterozygous Familial Hypercholesterolaemia from the Dutch Lipid Clinic Network Family history

Score

1. First-degree relative with premature coronary heart disease or 2. First-degree relative with LDL cholesterol >95th percentile by age and gender for country 3. First-degree relative with xanthoma and/or arcus cornealis or 4. Children <18 years with LDL cholesterol >95th percentile by age and gender for country

1 1 2 2

Clinical history 1. Premature coronary heart disease 2. Premature cerebral or peripheral vascular disease

2 1

Physical examination 1. Tendon xanthoma 2. Arcus cornealis <45 years

6 4

LDL cholesterol 1. >8.5 mmol/l 2. 6.5–8.4 mmol/l 3. 5.0–6.4 mmol/l 4. 4.0–4.9 mmol/l

8 5 3 1

DNA analysis 1. Causative mutation in LDLR, APOB or PCSK9

8

Clinical diagnosis Definite Probable Possible Unlikely

>8 6­–8 3–5 <3

Source: Nordestgaard et al., 2018.7 Published with permission from Oxford University Press.

genetic testing.49 The Simon Broome Register criteria for IC include lipid levels, tendon xanthomas, family history of hypercholesterolaemia, premature ASCVD and the presence of a functional mutation on genetic testing.6 Relatives should be diagnosed using gender- and age-specific LDL-C levels.50

lipid-lowering treatment) and the presence of cutaneous and tendon xanthomas in the first decade of life. Both parents must be heterozygous FH and should have elevated LDL-C levels.36 Phenotypic expression of this condition is highly variable depending on the type of mutation.37

Genetic Testing The most accepted and commonly used FH diagnosis criteria are the Dutch Lipid Clinic Network criteria (Table 1). These criteria calculate a score based on LDL-C levels, the presence of arcus cornealis and tendon xanthomas, hypercholesterolaemia and premature CVD in relatives, and positive genetic testing. A total score ≥8 makes the diagnosis definite.51 These criteria should only be used for the identification of ICs.

Diagnosis in Children and Adolescents FH should be suspected in children and adolescents where LDL-C >4.9 mmol/l after the exclusion of secondary causes of hypercholesterolaemia, or where LDL-C >3.9 mmol/l and one parent has confirmed FH.5–7,49 In the Netherlands, LDL-C >3.5 mmol/l can predict the presence of a LDLR mutation with a post-test probability of 0.98.52 Lipid levels vary with age, especially during puberty, and some overlap in LDL-C levels might be observed. Total cholesterol and LDL-C discriminate better among children with and without FH at 1–9 years of age.53 The affected parent should undergo genetic testing and, once the diagnosis has been confirmed, the implications of genetic testing in children should be discussed with them.5,54,55

Diagnosis of Homozygous Familial Hypercholesterolaemia The diagnosis of HoFH is typically based on very high levels of LDL-C (untreated LDL-C >13 mmol/l or treated LDL-C >7.8 mmol/l on maximum

16

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Genetic testing is the gold standard for the diagnosis of the disorder and facilitates cascade screening. A pathogenic mutation in one of the LDLR, APOB and PCSK9 genes is identified in 70–80 % of definite FH cases and in 20–40 % in those with a milder phenotype.14,56 The Dutch Lipid Clinic Network criteria have better sensitivity and specificity than genetic testing.57 The absence of a known mutation does not exclude a diagnosis of FH, especially in those cases with a strong phenotype. Different studies have shown that using only cholesterol levels in ICs or relatives leads to the misdiagnosis of approximately 18 % of carriers and non-carriers of a mutation.58,59 In addition to the importance of confirming the diagnosis, a positive result from genetic testing is associated with prognosis. For any LDL-C level, individuals carrying a mutation are at higher risk for ASCVD than those who do not have a mutation.60 The type of mutation is also related to LDL-C levels and ASCVD risk, as shown in several studies.32,61

Screening Strategies Early identification of FH is important for the prevention of coronary artery disease. At diagnosis, most patients are unaware of their condition and are receiving inadequate lipid-lowering therapy.62–65 ICs should be identified among individuals with total cholesterol >8 mmol/l, with cardiovascular disease <60 years of age and/or with tendon xanthomas or premature arcus cornealis (Table 2).6,7 When

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Familial Hypercholesterolaemia Table 2: Criteria for Suspected Familial Hypercholesterolaemia According to Guidelines and Consensus Panels Spanish Familial

European Atherosclerosis

National Institute for

National Lipid

Hypercholesterolaemia

Society7

Health and Care

Association49

Foundation5 Adults

Excellence6

>18 years

>18 years

>16 years

>20 years

LDL-C >5.7 mmol/l plus one of the following:

Total cholesterol >8.0 mmol/l

Total cholesterol >7.8 mmol/l

LDL-C >4.9 mmol/l

Premature coronary heart disease in case or family member

LDL-C >4.9 mmol/l

Non-HDL-C >5.7 mmol/l

• Children LDL-C >3.9 mmol/l • Adult relative LDL-C >4.9 mmol/l

Xanthoma in case or family •P  remature cardiovascular disease in member index case or relative Sudden cardiac death in family member • Xanthoma in index case or relative Children

<18 years

<18 years

<16 years

<20 years

LDL-C >4.9 mmol/l

LDL-C >4.9 mmol/l on two occasions after 3-month diet

LDL-C >4.1 mmol/l

LDL-C >4.1 mmol/l

LDL >3.9 mmol/l plus high cholesterol and/or premature cardiovascular disease in one parent or DNA-positive in one parent Exclusion of secondary causes

Non-HDL-C >4.9 mmol/l

LDL-C >4.1 mmol/l plus premature coronary heart disease and/or high cholesterol in one parent Exclusion of secondary causes

Exclusion of secondary causes

Exclusion of secondary causes

HDL-C = HDL cholesterol; LDL-C = LDL cholesterol.

an IC is identified, the individual should be referred to a specialist for genetic testing, if available. Cascade screening using LDL-C measurement should be conducted in their relatives. If the mutation is known in the IC, consenting family members should also be offered a genetic test.6,7,49 Molecular testing avoids misclassification and is included as part of the screening algorithm in countries like Spain, the Netherlands and Norway.66,67 Different analyses have demonstrated that the identification of an adult IC through different case-finding strategies and cascade screening in relatives using lipid and/or genetic testing is the most efficient and cost-effective method of identifying new FH cases.64,68,69 Analysis of the SAFEHEART Registry predicted that identifying 9,000 cases of FH in 10 years could prevent 847 coronary events and 203 coronary deaths and add 767 quality-adjusted life years.69 Universal screening has the potential to detect more affected people in the community; for this, LDL-C levels should be measured in adults by the age of 20.49 Screening in children is still controversial, especially in relation to the age at which testing should be carried out and lipid-lowering therapy started.70,71 The US National Lipid Association recommends universal lipid screening of all children aged 9–11, and as early as 2 years of age if there is a family history of hypercholesterolaemia or premature ASCVD.49 In some countries, children are screened between 2 and 5 years of age as part of cascade screening in families with a known diagnosis of the disorder.5,53,55 In the UK, the National Institute for Health and Care Excellence guidelines recommend a genetic test is performed by the age of 10 in children who are at risk because they have one parent with FH.6

LDL-C Targets and Treatment of FH Observational data have shown that statins significantly reduce the risk of coronary and total mortality in FH.3,4,72 Intensive LDL-C reduction with statins or LDL apheresis also has beneficial effects on surrogate endpoints for ASCVD.73–75 Despite aggressive lipid-lowering therapy, FH patients still experience cardiovascular events, partly due to uncontrolled risk factors.76 Many studies have found that patients with FH are undertreated.77,78 A recent analysis of the SAFEHEART Registry showed that although most patients were on the maximum lipidlowering therapy after 5 years of follow-up, only 11 % had reached

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the target of LDL-C <2.6 mmol/l.78 Despite the elevated lifetime risk for cardiovascular disease associated with FH, individuals’ risk profiles are heterogeneous. A cardiovascular risk equation including some classic risk factors and lipoprotein(a) and able to accurately predict incident ASCVD in molecularly-defined FH has recently been developed (Figure 2). Although recalibration with other populations is needed, this tool will improve risk stratification and treatment in FH patients.79 International guidelines consider LDL-C <2.6 mmol/l as the optimal target in adults with FH; <1.8 mmol/l in adults with FH and cardiovascular disease or type 2 diabetes; and at least a 50 % reduction in LDL-C levels if these goals cannot be achieved with maximally tolerated lipid-lowering therapy.5–7,49 Adults with FH should be treated from the moment of diagnosis. There is no evidence to support a target LDL-C level in children. Expert consensus-recommended targets are <4.1 mmol/l,5,55 <3.5 mmol/l,5,70 <2.6 mmol/l80 and a reduction of 50  % from pre-treatment levels in children aged 8–10 years.70 The recommended age at which to start lipid-lowering therapy varies between 881 and 10 years,5,6,49,70,80 with5 or without70 differences between boys and girls. Analysis of 217 children <18 years old with FH in the SAFEHEART Registry found that the percentage achieving LDL-C <3.4 mmol/l increased from 20 % to 42 % after 4.7 years of follow-up. This result was principally explained by the use of statins.82 When pharmacological treatment is offered, the adult or child/ adolescent or their parents or carer should be informed that treatment is lifelong.

Statins All statins have been used in FH; however, most adult patients will require high-intensity statin therapy, such as atorvastatin 40–80 mg or rosuvastatin 20–40 mg. In children with FH, treatment should be started at the lowest recommended dose and titrated up according to response and tolerability.5,70,82 In HoFH, statins can be started at age 2 and can

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Dyslipidaemia Figure 2: Five- Versus 10-year Risk of Developing Incident Atherosclerotic Cardiovascular Disease for 66-year-old Men with Familial Hypercholesterolaemia Estimated % risk of developing incident ASCVD

of both these PCSK9 inhibitors have been demonstrated in FH patients with LCL-C inadequately controlled by statins and/or other lipidlowering therapy. A significant 50–60 % reduction in LDL-C over the reduction achieved by statins was obtained compared to placebo and they were well tolerated. Furthermore, >60 % of patients achieved LDL-C <1.8 mmol/l with PCSK9 inhibitors.86,87

70 60 50 5-year risk

The efficacy and tolerance of evolocumab have also been demonstrated in HoFH. A significant reduction in LDL-C levels of 20 % maintained after 48 weeks of treatment was observed in patients with and without apheresis.88 This reduction is modest compared with its effect in heterozygous FH. The reduced efficacy is because PCSK9 inhibition requires some LDLR activity, which is almost absent in HoFH.

40

10-year risk 30 20 10 0 Overweight

+

Obesity

+

+

+

+

+

+

+

High blood pressure –

+

+

+

+

+

+

Active smoking

+

+

+

+

+

Lp(a) >1.8 µmol/l

+

+

+

+

LDL-C 2.6–4.0 µmol/l –

+

LDL-C ≥ 4.1 mmol/l

+

+

History of ASCVD

+

Changes in risk profile can be estimated according the modification of cardiovascular risk factors. ASCVD = atherosclerotic cardiovascular disease; LDL-C = LDL cholesterol; Lp(a) = lipoprotein(a). Source: Pérez de Isla et al., 2017,30 with permission from Wolters Kluwer.

produce a modest and variable effect on LDL-C, depending on the type of mutation.36 Women with FH should receive pre-pregnancy counselling. They should be given instructions to stop any lipid-lowering treatment at least 4 weeks before discontinuing contraception and should not use statins during pregnancy and lactation.

Ezetimibe In patients with primary hypercholesterolaemia, ezetimibe monotherapy reduced LDL-C levels by about 18 %. It can be safely co-administered with statins, resulting in up to a 23 % incremental decrease in LDC-C in FH patients.83

Bile Acid Sequestrants Bile acid sequestrants are rarely used due to their adverse gastrointestinal side-effects and poor patient compliance. Colesevelam has a greater potency to bind bile acids, providing a much better tolerability profile than the other sequestrants. Colesevelam reduces LDL-C by 13–19 % when administered as monotherapy and by an additional 18 % when prescribed in combination with statins.84

Recent results from long-term outcome trials of PCSK9 inhibitors in patients with ASCVD have shown a significant 15 % relative risk reduction for major cardiovascular events, supporting their cardiovascular benefit.89,90 Although these trials were not carried out specifically in a FH cohort, they may also support the benefit of this class of drugs in this high-risk population.

Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide inhibits microsomal triglyceride transfer protein at the hepatocytes and enterocytes, preventing the assembly of triglycerides into very-low-density lipoprotein and chylomicrons. Lomitapide has been approved for the treatment of HoFH in people >18 years of age. LDL-C reductions of 50 % and 40  % at week 26 and 78, respectively, have been described.91 Due to its mechanism of action, gastrointestinal side-effects (mild transaminase elevations and diarrhoea) are the most common adverse events. These effects are managed by gradual titration of the dose and adherence to the recommended low-fat diet. Hepatic fat was found to be increased by up to 8 % at week 26 in patients taking lomitapide, but no further increase was reported for the 18-month duration of the study.91

LDL Apheresis LDL apheresis is safe and is the only long-term treatment with the potential to slow early atherosclerosis and prolong survival in HoFH patients.92 LDL apheresis is also an option for patients with severe heterozygous FH, especially if pharmacological treatment insufficiently controls their LDL-C and their cardiovascular risk is still high. Practical considerations have to be taken into account with this treatment. The cost, problems with insurance, venous access and the biweekly apheresis sessions are important issues that must be considered for each patient before proceeding.

PCSK9 Inhibitors

Conclusion

Evidence that loss-of-function mutations in the PCSK9 gene produce low levels of LDL-C and lower the incidence of cardiovascular disease85 has further substantiated the role of PCSK9 as a potential target for the new generation of cholesterol-lowering drugs.

FH is a common and treatable disorder. Early diagnosis and treatment will improve clinical cardiovascular outcomes. Identification of ICs and cascade screening using lipids and genetic testing in their relatives is cost-effective. Screening programmes are necessary to increase the number of cases identified and treated. Patients require high-intensity statin therapy and ezetimibe. For those not achieving target LDL-C, the new iPCSK9 are a good option for reducing LDL-C and cardiovascular risk. For severe HoFH, lomitapide and LDL apheresis are indicated. n

In 2015, the US Food and Drug Administration and European Medicines Agency approved evolocumab and alirocumab for the treatment of FH in patients who do not achieve LDL-C targets with maximum tolerated doses of conventional lipid-lowering therapy. The efficacy and safety

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9.

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17.

18.

19.

20.

21.

22.

23.

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Atherosclerosis 2011;12:s221–63. https://doi.org/10.1016/j. atherosclerosissup.2011.06.001; PMID: 21917530.  Descamps O, Tenoutasse S, Stephenne X, et al. Management of familial hypercholesterolemia in children and young adults: Consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis 2011;218:272–80. https://doi.org/10.1016/j. atherosclerosis.2011.06.016; PMID: 21762914.  Humphries SE, Norbury G, Leigh S, et al. What is the utility of DNA testing in patients with familial hypercholesterolemia. Curr Opinion Lipidol 2008;19:362–8. https://doi.org/10.1097/ MOL.0b013e32830636e5; PMID: 18607183.  Civeira F, Ros E, Jarauta E, et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. 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Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29365 individuals tested for 64 specific lowdensity lipoprotein-receptor sequence variants. Eur Heart J 2012;33:2325–30. https://doi.org/10.1093/eurheartj/ehs038; PMID: 22390909.  Mata N, Alonso R, Badimon L, et al. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids Health Dis 2011;10:94. https://doi. org/10.1186/1476-511X-10-94; PMID: 21663647. Neil HA, Hammond T, Huxley R, et al. Extent of underdiagnosed of familial hypercholesterolemia in routine practice: prospective registry study: BMJ 2000;321:148. PMID: 10894692. Leren T, Finbourd T, Manshaus T, et al. Diagnosis of familial

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6736(00)04053-8; PID: 11558482. 75. A  lonso R, Mata P, De Andres R, et al. Sustained longterm improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin. Atherosclerosis 2001;157:423–9. https://doi. org/10.1016/S0021-9150(00)00733-4; PMID: 11472743. 76. Galema-Boers AM, Lenzen MJ, Engelkes SR, et al. Cardiovascular risk in patients with familial hypercholesterolemia using optimal lipid-lowering therapy. J Clin Lipidol 2018;12:409–16. https://doi.org/10.1016/j. jacl.2017.12.014; PMID: 29398430. 77. Pijlman AH, Huijgen R, Verhagen SN, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: A large cross-sectional study in the Netherlands. Atherosclerosis 2010;209:189–94. https://doi. org/10.1016/j.atherosclerosis.2009.09.014; PMID: 19818960. 78. Perez de Isla L, Alonso R, Watts G, et al. Attainment of LDL-cholesterol treatments goals in patients with familial hypercholesterolemia. 5-year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278–85. https://doi.org/10.1016/j. jacc.2016.01.008; PMID: 26988947.  79. Pérez de Isla L, Alonso R, Mata N, et al. SAFEHEART investigators. Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART Registry. Circulation 2017;135:2133–44. https://doi.org/10.1161/ CIRCULATIONAHA.116.024541; PMID: 28275165.  80. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease – executive summary. Endocr Pract 2017;23:479–97. https://doi.org/10.4158/ EP171764.APPGL; PMID: 28437620. 81. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. Int J Cardiol 2014;171:309–25. https://doi.org/10.1016/j.ijcard.2013.11.025; PMID: 24418289.  82. Saltijeral A, Pérez de Isla L, Alonso R, et al. Attainment of LDL cholesterol treatment coals in children and adolescents with familial hypercholesterolemia. The SAFEHEART Followup Registry. Rev Esp Cardiol 2017;70:444–50. https://doi. org/10.1016/j.recesp.2016.10.012; PMID: 27913073.  83. van der Graaf A, Cuffie-Jackson C, Vissers MN, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol 2008;52:1421–9. https:// doi.org/10.1016/j.jacc.2008.09.002; PMID: 18940534. 

84. H  uijgen R, Abbink EJ, Bruckert E, et al. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther 2010;32:615–25. https://doi.org/10.1016/j. clinthera.2010.04.014; PMID: 20435231. 85. Cohen JC, Boerwinkle E, Mosley TH, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72. https://doi. org/10.1056/NEJMoa054013; PMID: 16554528.  86. Raal F, Stein E, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331–40. https://doi.org/10.1016/S0140-6736(14)61399-4; PMID: 25282519. 87. Kastelein JJ, Ginsberg H, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996–3003. https://doi.org/10.1093/ eurheartj/ehv370; PMID: 26330422. 88. Raal F, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol 2017;5:280–90. https://doi.org/10.1016/S22138587(17)30044-X. 89. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi.org/10.1056/ NEJMoa1615664; PMID: 28304224. 90. Steg G, Schwartz GG, Szarek M, et al. The ODYSSEY OUTCOMES Trial: Topline results Alirocumab in patients after acute coronary syndrome. Presented at 67th Scientific Sessions, American College of Cardiology, Orlando, Florida, US, 10 March 2018. 91. Cuchel M, Mehageer EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013;381:40–6. https://doi.org/10.1016/S0140-6736(12)61731-0; PMID: 23122768. 92. Thompson GR, Catapano A, Saheb S, et al. Severe hypercholesterolaemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol 2010;21:492–8. https://doi.org/10.1097/ MOL.0b013e3283402f53; PMID: 20935563.

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Pharmacotherapy ISCP Guest Editorial

ISCP Guest Editorial Cardiovascular Disease Prevention in Diabetes

Maki Komiyama National Hospital Organisation, Kyoto Medical Centre, Kyoto, Japan

Koji Hasegawa National Hospital Organisation, Kyoto Medical Centre, Kyoto, Japan

Citation: European Cardiology Review 2018;13(1):21–2. DOI: https://doi.org/10.15420/ecr.13.1.1.GE1 Correspondence: Koji Hasegawa, 1-1 Fukakusa Mukaihatacho, Fushimi-ku, Kyoto, Kyoto Prefecture 612-8555, Japan. E: koj@kuhp.kyoto-u.ac.jp

T

ype 2 diabetes is a major risk factor for the development of cardiovascular disease (CVD) such as MI, and cerebrovascular incidents such as stroke. A substantial body of evidence has indicated that the proper management of blood glucose in people with diabetes can inhibit the progression of microvascular disease such as retinopathy and nephropathy.

Nevertheless, whether strict blood glucose control is effective at reducing the risk of CVD in people with diabetes has long been debated. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the overall mortality significantly increased by strict control of blood glucose (target HbA1c < 6.0 %) compared with a less stringent control (target HbA1c of approximately 7  %).1 Strict glucose control resulted in a significantly higher likelihood of developing severe hypoglycaemia, leading to adverse events. Severe hypoglycaemia itself was associated with death due to CVD.2 The important point is that the risk of developing CVD increases from the early stages of an impairment in glucose tolerance. Previous epidemiological data have revealed that the risk of CVD or death begins to increase at an HbA1c level of approximately 5 %.3 The risk of developing coronary artery disease in European and American men with an HbA1c 5–5.4  % is 1.56 times higher than the risk in those with an HbA1c < 5.0 %.4 In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOPNIDDM) trial, the administration of acarbose (an alpha-glucosidase inhibitor) to patients with impaired glucose tolerance prevented the progression to type 2 diabetes and significantly reduced the onset of CVD and hypertension.5

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Sodium glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by reducing glucose reabsorption in the kidneys and eliminating glucose in the blood via urine. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial involved approximately 7,000 patients with type 2 diabetes and a history of CVD.6 The primary endpoint in this trial was a composite cardiovascular endpoint (cardiovascular death, MI or stroke), the incidence of which was significantly reduced by empagliflozin, an SGLT2 inhibitor. In particular, the incidence of cardiovascular death decreased by approximately 40 %. Among the trials involving patients with type 2 diabetes, the EMPA-REG OUTCOME trial was the first to find such a substantial reduction in cardiovascular events. The detailed mechanism by which SGLT2 inhibitors effectively inhibit a composite cardiovascular endpoint is unclear. In addition to reducing plasma volume, improving haemodynamics and lowering blood glucose levels, SGLT2 inhibitors promote weight loss, reduce visceral fat, lower blood pressure, increase HDL cholesterol and decrease triglycerides and uric acid levels. As an overall consequence, SGLT2 inhibitors probably reduce oxidative stress and the hyperactivity of the sympathetic nervous system. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study is an international largescale observational study that retrospectively verified the efficacy of SGLT2 inhibitors in patients with type 2 diabetes.7 In that trial, hospitalisation due to heart failure decreased by 31  % in patients receiving SGLT2 inhibitors compared with patients treated with a hypoglycaemic drug other than SGLT2 inhibitors. This inhibition is

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Pharmacotherapy ISCP Guest Editorial presumably related largely to the antihypertensive and diuretic actions of SGLT2 inhibitors. The trial also found that the overall mortality rate of patients decreased by 51 %. In that study, 87 % of the overall study population possessed no prior history of CVD. The mechanisms by which SGLT2 inhibitors reduce total mortality in patients both with and without CVD requires further study.

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 ction to Control Cardiovascular Risk in Diabetes A Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59. https://doi.org/10.1056/NEJMoa0802743; PMID: 18539917. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010;340:b4909. https://doi.org/10.1136/bmj.b4909; PMID: 20061358. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of

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The results of epidemiological studies demonstrate that CVD risk increases before the onset of type 2 diabetes.3,4 Instead of blood glucose control in advanced diabetes, active intervention in patients in the early stages of impaired glucose tolerance may therefore be crucial for the inhibition of cardiovascular events. Thus, a more effective use of alpha-glucosidase inhibitors and SGLT2 inhibitors in such patients should be considered. n

Cancer and nutrition (EPIC-Norfolk). BMJ 2001;322:15–8. https://doi.org/10.1136/bmj.322.7277.15; PMID: 11141143. Khaw KT, Wareham N, Bingham S, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004;141:413–20. https://doi.org/10.7326/0003-4819-141-6-200409210-00006; PMID: 15381514. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003;290:486–94. https://doi.org/10.1001/jama.290.4.486; PMID: 12876091.

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Z inman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/NEJMoa1504720; PMID: 26378978. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017;136:249–59. https://doi.org/10.1161/ CIRCULATIONAHA.117.029190; PMID: 28522450.

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Vasodilator Therapies

Nicorandil and Long-acting Nitrates: Vasodilator Therapies for the Management of Chronic Stable Angina Pectoris Jason M Tarkin 1,2 and Juan Carlos Kaski 3 1. National Heart and Lung Institute, Imperial College London; 2. Division of Cardiovascular Medicine, University of Cambridge; 3. Cardiovascular and Cell Sciences Research Institute, St George’s, University of London

Abstract Nicorandil and long-acting nitrates are vasodilatory drugs used commonly in the management of chronic stable angina pectoris. Both nicorandil and long-acting nitrates exert anti-angina properties via activation of nitric oxide (NO) signalling pathways, triggering vascular smooth muscle cell relaxation. Nicorandil has additional actions as an arterial K+ATP channel agonist, resulting in more “balanced” arterial and venous vasodilatation than nitrates. Ultimately, these drugs prevent angina symptoms through reductions in preload and diastolic wall tension and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. While there is some evidence to suggest a modest reduction in cardiovascular events among patients with stable angina treated with nicorandil compared to placebo, this prognostic benefit has yet to be proven conclusively. In contrast, there is emerging evidence to suggest that chronic use of long-acting nitrates might cause endothelial dysfunction and increased cardiovascular risk in some patients.

Keywords Nicorandil, long-acting nitrates, vasodilators, stable angina, coronary artery disease Disclosure: JM Tarkin is supported by the NIHR and the Wellcome Trust. The authors have no others conflict of interests to declare. Received: 17 April 2018 Accepted: 6 July 2018 Citation: European Cardiology Review 2018;13(1):23–8. DOI: https://doi.org/10.15420/ecr.2018.9.2 Correspondence: Dr Jason Tarkin, ICTEM Building, Fifth Floor, Hammersmith Campus, Du Cane Road, London W12 0NN. E: jt545@cam.ac.uk

Stable angina pectoris is the most prevalent clinical manifestation of coronary heart disease. While the overall prognosis in patients with stable angina is good, with a low yearly event rate of ~1–2 %,1 for many, adequate symptom control can be difficult to achieve, leading to significantly impaired quality of life.

blockers and other rate-limiting anti-angina drugs for patients with effort-induced angina and a low resting heart rate or atrioventricular conduction defects, and are avoided in patients with low systemic blood pressure who are most susceptible to the haemodynamic sideeffects of these medications.

The traditional approach to the pharmacological management of stable angina, as advocated by European Society of Cardiology (ESC), American Heart Association/ American College of Cardiology (AHA/ ACC), and National Institute for Health and Care Excellence (NICE) guidelines, follows a stepwise algorithm based on categories of firstand second-line anti-angina drugs for all patients.1–3 However, none of the first- or second-line drugs used to treat stable angina symptoms have been shown to reduce cardiovascular mortality or the rate of myocardial infarction (MI) when evaluated in clinical trials. Clinical trial data showing the superiority of any one anti-anginal drug over another is, similarly, lacking.

Although calcium-channel antagonists are the drugs of choice for the treatment of angina resulting from coronary artery spasm, vasospastic angina can also be successfully treated with both nicorandil and nitrates.5,6 These vasodilator drugs are also useful for some patients with mixed angina (who experience symptoms of both typical effortinduced angina and coronary vasospasm), as well as those with microvascular angina.7 However, long-acting nitrates are effective in only ~50 % of patients with microvascular angina8 as, unlike nicorandil, they have little effect on small resistance vessels.9

Therefore, because all available anti-angina drugs are equally effective, an alternative mechanistic-based approach to drug selection based on individual patient factors has been proposed (Figure 1).4 Importantly, this new approach recognises the multifactorial aetiology of stable angina, which includes not only typical effort-induced angina arising from obstructive epicardial artery disease, but also microvascular angina (where coronary blood flow abnormalities occur in the absence of epicardial artery stenoses), and vasospastic angina due to episodic vasoconstriction of both atherosclerotic and unobstructed coronary arteries. In this proposed scheme based on expert consensus, vasodilatory drugs – including nicorandil and nitrates – are preferred over beta-

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This article provides a focused update on the use of nicorandil and long-acting nitrates for the treatment of stable angina.

Nicorandil Nicorandil is a balanced vasodilator, with dual mechanisms of action as both a nitric oxide (NO) donor and K+ATP channel agonist. Its chemical structure – N-[2-(Nitro-oxy) ethyl]-3-pyridine carboxamide – consists of a nicotinamide derivative combined with nitrate moiety. Nicorandil undergoes denitration and bioactivation via the nicotinamide/nicotinic acid pathway.10 The nitrate-like action of nicorandil possibly accounts for the majority of its clinical efficacy in angina, which is mediated via NO activation of cyclic guanosine-3’,-5’-monophosphate (cGMP) signaling pathways within vascular smooth muscle cells, causing peripheral venous and coronary arterial vasodilatation.11,12

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Pharmacotherapy Figure 1: Possible Combinations of Classes of Antianginal Drugs According to Different Comorbidities.

BB VER • DILT IVAB

TRIM • RAN

DHP NITR • NIC

R IT N • N IC A N •R • P IM DH TR

DHP NITR • NIC IVAB

TRIM • RAN High HR ≥70 BPM BB VER • DILT

BB VER • DILT IVAB

Atrial fibrillation

Bradycardia

BB DHP • VER DILT • NITR NIC

DHP VER • DILT NIC Myocardial ischaemia Heart failure

Hypertension

TRIM • RAN IVAB

TRIM • NITR RAN

Left ventricular dysfunction

BB • IVAB

DHP VER • DILT NIC

N•

TRIM IVAB • RAN NITR

IM

TR BB

Preferred

All possible

None

Hypotension

A •R

B

IVA

BB• VER DILT • DHP NITR • NIC

Co-administered

Contraindicated or caution needed

BB, beta-blockers; DHP, dihydropyridine calcium-channel blockers; DILT, diltiazem; HR, heart rate; IVAB, ivabradine; NIC, nicorandil; NITR, nitrates; RAN, ranolazine; TRIM, trimetazidine; VER, verapamil. Source: Ferrari R, et al. Nat Rev Cardiol 20184

On average, a single dose of nicorandil 20 mg results in a 10–15 % increase in mean luminal diameter of the epicardial coronary arteries.13 In addition, nicorandil causes significant vasodilatation of the coronary microvasculature and peripheral resistance arteries.14,15 These haemodynamic changes offload the ventricles through reductions in both preload and afterload, and improve coronary blood flow.16 In some patients, a mild baroreceptor reflex tachycardia occurs in response to vasodilatation. However, unlike several other anti-angina drugs, nicorandil does not affect cardiac conduction or contractility. Although nicorandil is used as a treatment for stable angina in many countries, it is not currently licensed in the US.

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Dosage and Pharmacokinetics The usual starting dose of nicorandil is 10 mg twice daily (5 mg for patients susceptible to headache). While this dosage can be uptitrated to 20 mg or a maximum of 30 mg twice daily, the lowest effective dose is recommended to avoid potential side-effects, particularly in the elderly. Nicorandil is rapidly absorbed via the gastrointestinal tract, with >75 % oral bioavailability as it does not undergo first-pass metabolism. Nicorandil exhibits a linear dose-to-plasma concentration, and reaches a maximal plasma concentration after 30–60 minutes, and steady-state levels after 4–5 days. Gastric absorption is delayed by food, but its pharmacokinetic properties are not significantly

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Vasodilator Therapies affected by age, chronic liver disease or chronic kidney disease. The desired clinical effects of nicorandil persist for ~12 hours, hence the need for twice-daily dosing.10,17 Nicorandil is eliminated mainly in the urine as metabolites N-(2-hydroxyethyl)-nicotinamide, nicotinuric acid, nicotinamide, N-methyl-nicotinamide and nicotinic acid, with a half-life of ~2 hours for the main phase of elimination.

Clinical Efficacy Data Nicorandil was shown to significantly reduce the frequency of angina episodes and improve exercise capacity in several small placebocontrolled studies performed in the late 1980s.18-22 Subsequent shortterm studies demonstrated that the nicorandil was similarly effective for angina prophylaxis as other conventional anti-anginal drugs, including beta-blockers,23-25 calcium-channel antagonists26,27 and longacting nitrates.28,29 The Study of Nicorandil in Angina Pectoris in the Elderly (SNAPE) study found that there were similar improvements in both the time to angina and ST-segment depression during symptom-limited bicycle exercise testing after 4 weeks of treatment with nicorandil and isosorbide mononitrate compared to placebo.30 Similarly, the Comparison of the Antiischaemic and Antianginal Effects of Nicorandil and Amlodipine in Patients with Symptomatic Stable Angina Pectoris (SWAN) study showed comparable increases in time to angina and exercise capacity, and a reduction in the magnitude of ST-depression for nicorandil and amlodipine.31

Does Nicorandil Improve Prognosis? Data from two trials suggest that nicorandil might confer modest improvements in clinical outcomes for patients with stable angina; however, this prognostic benefit has yet to be proven conclusively. The Impact Of Nicorandil in Angina (IONA) study was a randomised placebo-controlled trial of 5,126 patients with stable angina followed up for an average of 1.6 years, which showed a reduction in the composite endpoint of death caused by coronary heart disease, nonfatal MI or unplanned hospital admission with chest pain in patients treated with nicorandil compared to placebo (HR 0.83, p=0.014).32 While there was no evidence of heterogeneity of benefit from nicorandil across subgroup status in the IONA study,33 there was also no difference in the secondary outcome of coronary heart disease death or non-fatal MI, and the individual components of the composite endpoint did not differ significantly between the two treatment groups.34 Nicorandil also had no effect on the distribution of functional Canadian Cardiovascular Society grading of angina at the end of the study, and a similar number of patients in both the treatment and placebo groups experienced a deterioration in their angina symptoms during the study. Multi-centre observational data from a total of 2,558 patients treated with nicorandil and controls subjected to propensity score matching from the Japanese Coronary Artery Disease (JCAD) study provide additional evidence that nicorandil might confer a degree of longterm cardioprotection for patients with stable angina; this study demonstrated a 35 % reduction in all-cause mortality (HR: 0.65; p=0.0008) and 56 % reduction in cardiac death (HR: 0.44; p<0.0001) in patients treated with nicorandil over an average 2.7 years. Among the proposed cardioprotective mechanisms for nicorandil include K+ATP channel activation of myocardial mitochondrial ischaemic preconditioning,35,36 protection against long-term endothelial dysfunction,37,38 stabilisation of atherosclerotic plaques39 and other ancillary properties, including antiplatelet effects.40

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Several studies have indicated that nicorandil confers possible beneficial effects after an MI, including the prevention of ischaemic reperfusion injury and microvascular dysfunction during percutaneous intervention,41,42 as well as improvement of myocardial salvage and reduction in mortality following hospital discharge.43,44 There is also some evidence that nicorandil reduces the arrhythmic burden in patients with unstable angina. In the Clinical European Studies in Angina and Revascularisation (CESAR) 2 trial, which included 188 patients with unstable angina, a lower incidence of transient myocardial ischaemia (12.4 % versus 21.2 % p=0.0028), non-sustained ventricular tachycardia (three runs versus 31 runs, p<0.0001), and supraventricular tachycardia (four runs versus 15 runs, p=0.017) was observed during continuous 48 hours ECG monitoring in patients randomised to nicorandil compared to placebo.45

Side-Effects and Drug Cautions Nicorandil is well tolerated by most patients, with a satisfactory safety profile confirmed by real-world data from 13,260 patients in the Nicorandil Prescription Event Monitoring (PEM) study.46 Other studies have shown that fewer than 10 % of patients report side-effects after treatment with nicorandil for 30 days47 and around 70 % of patients continue to take the medication after 1 year.48 Headache is the most common side-effect of nicorandil, occurring in about 30 % of patients. Other common side-effects include dizziness, flushing, malaise and gastrointestinal upset. Unlike nitrates, the longterm use of nicorandil does not appear to cause significant drug tolerance or rebound angina.49 However, in one study, attenuation of the anti-ischaemic effect of nicorandil was observed after 2 weeks of therapy in terms of time-to-1 mm ST segment depression on exercise testing.50 Nicorandil is avoided in patients with low systemic blood pressure, e.g. due to decompensated heart failure or cardiogenic shock, and contraindicated by concomitant use of phosphodiesterase (PDE)-5 inhibitors (e.g. sildenafil) because of a risk of severe hypotension resulting from this dangerous drug combination. Additional contraindications to nicorandil are detailed in the SPC (https:// www.medicines.org.uk/emc/product/652/smpc). Rarely, nicorandil can cause gastrointestinal, skin, mucosal or eye ulceration.51,52 Nicorandil should be stopped immediately if ulceration occurs. Because of the risk of gastrointestinal ulceration, caution is advised when prescribing nicorandil for patients who are also taking corticosteroids. The manufacturer states that gastrointestinal ulcers can progress to perforation, haemorrhage, fistula or abscess; patients with diverticular disease might be at higher risk of these severe complications. Ulcers caused by nicorandil are refractory to conventional ulcer treatment, including surgery, and most only respond to withdrawal of nicorandil therapy. The effects of nicorandil during pregnancy, breastfeeding and on fertility have not been studied in humans. Nicorandil should be avoided in pregnancy and is not recommended during breastfeeding..

Long-acting Nitrates Nitrates have been used to treat symptoms of chronic stable angina for more than 135 years. Long-acting nitrate vasodilators, including isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN), belong to a group of organic nitrate esters with a nitrooxy (-O-NO2) moiety, which act as NO donors.53 Pentaerythrityl tetranitrate is a highpotency long-acting nitrate, which is not currently recommended due to lack of clinical efficacy data.54 Unlike high-potency short-acting glyceryltrinitrate (GTN), bioactivation of ISDN and ISMN appears to

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Pharmacotherapy be independent of mitochondrial aldehyde-dehydrogenase (ALDH)-2 activity, and remains incompletely understood.55 The clinical effects of nitrates are mediated via activation of endogenous NO-cGMP signaling pathways, including cGMP-dependent kinases and cyclic nucleotide-gated ion channels that reduce intracellular free Ca2+ and desensitise vascular smooth muscle cell contractile elements to Ca2+, causing vasorelaxation.56-58 The action of nitrates in some patients with stable angina may compensate for deranged endothelial function.59 At therapeutic doses, nitrates affect venous capacitance vessels predominately, but also dilate large and medium-sized coronary arteries and arterioles of >100 μm.60 Peripheral venous dilatation decreases venous return, lowering left ventricular end-diastolic filling pressure (preload) and volume, thereby decreasing myocardial work and oxygen demands, and indirectly increasing sub-endocardial blood flow. At higher doses, nitrates result in arterial vasodilatation, reducing systemic vascular resistance (afterload) and blood pressure.

Dosage and Pharmacokinetics The use of extended-release nitrate formulations with an eccentric dosing regimen, which incorporates a nitrate-free interval of at least 8–10 hours, is recommended to prevent the problem of nitrate tolerance.61 A typical starting dose of extended release ISMN is 30–60 mg once daily, which can be uptitrated to 120 mg or a maximum 240 mg, once daily if required. A single dose of extended-release ISMN provides cover for up to 12–14 hours. While ISDN undergoes extensive first-pass metabolism by the liver resulting in low bioavailability, oral ISMN is completely absorbed and has 100 % bioavailability, leading to a more predictable dose response with less variation in plasma levels than other nitrates.62 When transdermal GTN is used, tolerance can be avoided by interrupting patches with regular nitrate-free breaks.63,64 However, this approach can be associated with “rebound” angina due to nitrate withdrawal, and the “zero-hour” effect resulting in worsened exercise tolerance in the morning before patch application.65 Rebound angina does not occur with long-acting oral nitrates. Pseudo-tolerance can be problematic in patients treated with nitrates owing to neurohormonal activation and increased levels of circulating catecholamines, sodium retention, and intravascular volume expansion.66

Clinical Efficacy Data Like other anti-anginal drugs, long-acting nitrates have been shown in clinical trials to improve exercise tolerance, time to symptom onset and time to ST-segment depression during exercise testing in patients with stable effort-induced angina. In a meta-analysis of 51 clinical trials including a total of 3,595 patients, nitrate therapy reduced the number of angina episodes by an average 2.45 episodes per week.67 In another double-blind, placebo-controlled study of 313 patients with stable effort-induced angina, exercise tolerance was significantly increased at four and 12 hours after administration of extended release ISMN, with an incremental dose response observed, and without tolerance or rebound angina developing.68

Do Long-term Nitrates Increase Cardiovascular Risk? Although historically nitrates have been considered to have a neutral effect on prognosis, emerging evidence suggests that long-term nitrate therapy might have a detrimental influence on clinical outcomes

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because of the development of endothelial dysfunction in some patients who experience nitrate tolerance. Nitrate tolerance occurs after 12–24 hours of continuous therapy, and has been linked to excess free radical formation, among other mechanisms.69,70 Accumulation of free radicals during nitrate therapy is associated with endothelial dysfunction,71 and increased vasoconstrictor sensitivity underlying rebound angina.72,73,74 In an unblinded study of 1,002 patients with healed MI randomised to treatment with nitrates or non-treatment for an average of 18 months, the rate of recurrent coronary events was higher among those treated with nitrates.75 A deleterious effect of long-term nitrate therapy in patients who have had an MI was also observed from an analysis of data from two large observational studies; however, it is unclear whether patients in these cohorts who were prescribed nitrates had more severe angina symptoms (and greater atherosclerotic burden) than the patients who did not receive nitrates.76 Data from studies in patients with chronic vasospastic angina have also demonstrated higher rates of major adverse cardiac events in those treated with long-term nitrates77 and combined therapy with nitrates and nicorandil.78 In contrast, an analysis of the Global Registry of Acute Coronary Events (GRACE), which included 52,693 patients, found that those receiving long-term nitrates who presented with an acute coronary syndrome tended to have less ST-segment elevation and lower cardiac enzyme release than those who were nitrate naïve.79 Among the potential beneficial actions of nitrates that might contribute to the likelihood of more favourable acute clinical outcomes here include inhibition of platelet aggregation and other antithrombotic and anti-inflammatory effects, as well as protection against ischaemic reperfusion injury mediated in part by impaired opening of the mitochondrial permeability transition pore.80,81 However, the observation of divergent patterns of clinical presentation between patients with an acute coronary syndrome who are prescribed long-term nitrates for antecedent stable angina, and those with acute coronary syndrome who were nitrate-naive, might instead reflect differences in underlying atherosclerotic disease processes in these two patient groups. Further clinical studies are needed to determine the effects of nitrate therapy on long-term prognosis.

Side-effects and Contraindications Headache is the most common side-effect of nitrates. When occurring within the first hour of nitrate administration, headache is usually due to vasodilation and can often be avoided by starting with a low dosage.82 Occurrence of headache usually dissipates after several weeks of therapy, and co-administration of nitrates with aspirin, prescribed for secondary prevention, can also help to reduce this side-effect. However, in some patients, nitrates can also trigger migraine and other more complex types of headache.83 Approximately 10 % of patients are unable to tolerate nitrates due to headache.84 Other common side-effects of nitrates are light-headedness, flushing, orthostatic hypotension and syncope. The risk of orthostatic hypotension and syncope is greater in the elderly because of agerelated autonomic dysfunction. Nitrates are contraindicated in patients with hypertrophic cardiomyopathy, and used with caution in those with aortic stenosis because this could worsen the outflow tract gradient. Other absolute contraindications to nitrates are coadministration with PDE-5 inhibitors because of a risk of profound hypotension, and closed-angle glaucoma. Methemoglobinemia is a rare adverse

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Vasodilator Therapies effect that can occur with large nitrate doses. The safety of nitrates in pregnancy and breastfeeding has not been evaluated, so they should be avoided in these circumstances.

Conclusion Nicorandil and long-acting nitrates are effective drugs for the treatment of chronic stable angina in patients with effort-induced symptoms arising from epicardial coronary artery stenoses, as well as coronary vasospasm and microvascular angina.

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The success of any pharmacological angina therapy hinges on selecting the appropriate drug regimen tailored to individual patient factors and the prevailing underlying angina mechanism(s). Vasodilator drugs, such as nicorandil and long-acting nitrates, are most useful in patients who are unaffected by the haemodynamic side effects of these medications, and in those who have contraindications to rate-limiting anti-angina drugs. Further work is needed to better understand the long-term implications of these drugs on cardiovascular risk. n

2945420. 19. Hayata N, Araki H, Nakamura M. Effects of nicorandil on exercise tolerance in patients with stable effort angina: a double-blind study. Am Heart J 1986;112:1245–50. https://doi. org/10.1016/0002-8703(86)90355-8; PMID: 2947447. 20. Camm AJ, Maltz MB. A controlled single-dose study of the efficacy, dose response and duration of action of nicorandil in angina pectoris. Am J Cardiol 1989;63:J61–5. https://doi. org/10.1016/0002-9149(89)90207-5; PMID: 2525328. 21. Meany TB, Richardson P, Camm AJ, et al. Exercise capacity after single and twice-daily doses of nicorandil in chronic stable angina pectoris. Am J Cardiol 1989;63:J66–J70. https://doi. org/10.1016/0002-9149(89)90208-7; PMID: 2525329. 22. Why HJ, Richardson PJ. A potassium channel opener as monotherapy in chronic stable angina pectoris: comparison with placebo. Eur Heart J 1993;14(Suppl B):25–9. https://doi.org/10.1093/eurheartj/14.suppl_B.25; PMID: 8370369. 23. Hughes LO, Rose EL, Lahiri A, Raftery EB. Comparison of nicorandil and atenolol in stable angina pectoris. Am J Cardiol 1990;66:679–82. https://doi.org/10.1016/00029149(90)91129-T; PMID: 2144705. 24. Meeter K, Kelder JC, Tijssen JG, et al. Efficacy of nicorandil versus propranolol in mild stable angina pectoris of effort: a long-term, double-blind, randomized study. J Cardiovasc Pharmacol 1992;20(Suppl 3):S59–66. PMID: 1282178. 25. Di Somma S, Liguori V, Petitto M, et al. A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris. Cardiovasc Drugs Ther 1993;7:119–23. https:// doi.org/10.1007/BF00878320; PMID: 8485067. 26. Ulvenstam G, Diderholm E, Frithz G, et al. Antianginal and anti-ischemic efficacy of nicorandil compared with nifedipine in patients with angina pectoris and coronary heart disease: a double-blind, randomized, multicenter study. J Cardiovasc Pharmacol 1992;20(Suppl 3):S67–73. https://doi. org/10.1097/00005344-199206203-00012; PMID: 1282179. 27. Guermonprez JL, Blin P, Peterlongo F. A double-blind comparison of the long-term efficacy of a potassium channel opener and a calcium antagonist in stable angina pectoris. Eur Heart J 1993;14(Suppl B):30–4. https://doi.org/10.1093/ eurheartj/14.suppl_B.30; PMID: 8370370. 28. Döring G. Antianginal and anti-ischemic efficacy of nicorandil in comparison with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multicenter, double-blind, randomized studies with stable coronary heart disease patients. J Cardiovasc Pharmacol 1992;20 Suppl 3:S74–81. https:// doi.org/10.1097/00005344-199206203-00013; PMID: 1282180. 29. Lai C, Onnis E, Solinas R, et al. A new anti-ischemic drug for the treatment of stable effort angina pectoris: nicorandil. Comparison with placebo and isosorbide-5-mononitrate. Cardiologia 1991;36:703–11 [in Italian]. PMID: 1839369. 30. Ciampricotti R, Schotborgh CE, de Kam PJ, van Herwaarden RH. A comparison of nicorandil with isosorbide mononitrate in elderly patients with stable coronary heart disease: the SNAPE study. Am Heart J 2000;139:e1–9. 31. SWAN Study Group. Comparison of the antiischaemic and antianginal effects of nicorandil and amlodipine in patients with symptomatic stable angina pectoris: the SWAN study. J Clin Basic Cardiol 1999;2:213–7. 32. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 2002;359:1269–75. https://doi.org/10.1016/S0140-6736(02)08265-X; PMID: 11965271. 33. IONA Study Group. Impact of nicorandil in angina: subgroup analyses. Heart 2004;90:1427–30. https://doi.org/10.1136/ hrt.2003.026310; PMID: 15547020. 34. Henderson RA, O’Flynn N, on behalf of the Guideline Development Group. Management of stable angina: summary of NICE guidance. Heart 2012;98:500–7. https://doi. org/10.1136/heartjnl-2011-301436.PMID: 22275526. 35. Matsubara T, Minatoguchi S, Matsuo H. Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease. J Am Coll Cardiol 2000;35:345–51. https://doi.org/10.1016/S07351097(99)00539-2; PMID: 10676679. 36. Sato T, Sasaki N, O’Rourke B, Marbán E. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATPdependent potassium channels. J Am Coll Cardiol 2000;35:514–8. https://doi.org/10.1016/S0735-1097(99)00552-5; PMID: 10676702. 37. Sekiya M, Sato M, Funada J, et al. Effects of the long-

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Neuroendocrine System Regulatory Mechanisms: Acute Coronary Syndrome and Stress Hyperglycaemia Ricardo A Perez de la Hoz, Sandra Patricia Swieszkowski, Federico Matias Cintora, Jose Martin Aladio, Claudia Mariana Papini, Maia Matsudo and Alejandra Silvia Scazziota School of Medicine, Buenos Aires University, Buenos Aires, Argentina

Abstract Neurohormonal systems are activated in the early phase of acute coronary syndromes to preserve circulatory homeostasis, but prolonged action of these stress hormones might be deleterious. Cortisol reaches its peak at 8 hours after the onset of symptoms, and individuals who have continued elevated levels present a worse prognosis. Catecholamines reach 100–1,000-fold their normal plasma concentration within 30 minutes of ischaemia, therefore inducing the propagation of myocardial damage. Stress hyperglycaemia induces inflammation and endothelial dysfunction, and also has procoagulant and prothrombotic effects. Patients with hyperglycaemia and no diabetes elevated in-hospital and 12-month mortality rates. Hyperglycaemia in patients without diabetes has been shown to be an appropriate independent mortality prognostic factor in this type of patient.

Keywords Acute coronary syndrome, prognosis, hyperglycaemia, catecholamines, cortisol, insulin, neurosecretory systems, coronary thrombosis Disclosure: The authors have no conflicts of interest to declare. Received: 22 September 2017 Accepted: 11 May 2018 Citation: European Cardiology Review 2018;13(1):29–34. DOI: https://doi.org/10.15420/ecr.2017:19:3 Correspondence: Prof Ricardo Perez de la Hoz, Institute of Cardiology, Hospital de Clínicas, School of Medicine, Buenos Aires University, Buenos Aires, Argentina. E: rphoz2010@gmail.com.

The aim of reviewing the neuroendocrine–humoral response in acute coronary syndrome (ACS) is based on the fact that beyond the distinctive thrombotic event that defines acute occlusion of a coronary artery, generically referred to as a plaque accident, it is not an isolated event. It is clear that a series of physiological and physiopathological mechanisms related to stress – before, during and after the thrombotic occlusion of a coronary artery – mediate together with the plaque accident both in the genesis of the same and in its consequences. Stress is, according to Walter Cannon, a physiological reaction provoked by the perception of situations or stimuli – aversive or pleasurable – and should be the first concept to bring us closer to evaluating the physiological response.1 Recently, publications focusing on neuroendocrine system regulatory mechanisms have increased, in an attempt to determine the importance of psychological and physical stress,2 as well as determining what kind of influence catecholamines, cortisol, growth hormone, and thyroid hormones have on the pathophysiology of plaque. How do lipids interact in these events? How are inflammation mediators related to these effects? What is the role of all these circumstances regarding the activation of the thrombotic mechanism? How should we interpret elements called “acute phase reactants”, such as leukocytosis, hyperglycaemia, or increased erythrocyte sedimentation rate? Are they causes or consequences? Should they be considered prognostic measures or just temporary situational phenomena?

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Hans Seyle proposed the general adaptive syndrome, and defined it as the body’s stereotyped physiological response to a stressful stimulus, which helps an organism to adapt, independent of the type of stimulus involved – either aversive or pleasurable.3 Physical stressors are stimuli that alter the physiological state affecting homeostatic mechanisms, and initiate a rapid adaptive response that is necessary to survive. Psychological stressors are stimuli that threaten the current state of an individual and provoke a state of anticipation – even if they do not represent an immediate threat to physiological conditions, being that these stimuli largely depend on previous experiences.

Role of Cortisol in Acute Coronary Syndrome Cortisol is the final product of the hypothalamic–pituitary–adrenal axis, and acts as a ligand of both intracellular receptors – present in almost all tissues – and mineralocorticoid receptors in sodium transporter epithelia (for example, nephrons, colon, sweat glands, and salivary glands), vascular endothelium, and non-epithelial cells, such as vascular smooth muscle, myocardium, and the brain.4 ACS triggers a stress response that involves activation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, which causes cortisol and catecholamines release, with cardiovascular, metabolic, cerebral, and immunomodulatory effects tending to maintain homeostasis.5–7 Cortisol may exert negative effects on the cardiovascular system – for example, increasing sensitivity to catecholamines and stimulating mineralocorticoid receptors present in the myocardium.6,8

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Pharmacotherapy In patients with ACS, cortisol increases at an early stage, reaches a peak around 8 hours after the onset of symptoms, and then progressively decreases to reach normal or almost normal levels within 30–72 hours.6,9,10 Half of the patients hospitalised for MI show total cortisol levels above the maximum normal range (25 mg/dl) on the first day of admission, and the duration of cortisol increase is higher in patients with poor evolution, as well as those with left ventricle ejection fraction <50 %.10 Several authors have observed an association between disease severity and cortisol levels. Patients with ST segment elevation MI have higher cortisol levels than those without ST elevation, and there is a positive correlation between cortisol and peak creatine phosphokinase muscle/brain (CPK-MB) levels.5,9,11 Morbidity and mortality of ST segment elevation MI increase with higher cortisol levels on admission.4–6,9 Stress hyperglycaemia in patients with ACS is associated with increased morbidity and mortality. In agreement with other authors, we have reported that cortisol is one of the main determinants of hyperglycaemia in these patients and correlates independently with glycaemia.5,11–13

Catecholamine in Neuroendocrine Activity in Acute Coronary Syndrome Neurohormonal systems are activated at early stages of ACS to preserve circulatory homeostasis. The sympathetic nervous system is mainly an efferent system whose neurotransmitters are norepinephrine (NE) and epinephrine (EPI). The main site of synthesis of NE is the locus coeruleus, located on the floor of the fourth ventricle, and receives afferents from the hypothalamus, the cingulate cortex, and the amygdala. Nerve impulses descend along the neuroaxis to the preganglionic neurons located at T1 to L2–L3 levels and activate the postganglionic neurons. The axon travels with epicardial vascular structures to the myocardium, where NE is released and acts directly on the post-synaptic alpha and beta receptors. NE also stimulates the hypothalamic–pituitary–adrenal axis, which is involved in the release of EPI from the adrenal medulla.14 There is also a local release of catecholamines in various blood vessels of the peripheral sympathetic nervous system, and in cardiac myocytes that can synthesise and release NE and EPI in an autocrine/paracrine manner.15 In the early stages of acute MI (AMI), the concentrations of NE and EPI are only fivefold the normal levels at rest, and these mildly increased levels of catecholamines do not induce a major deterioration of myocardial function during ischaemia. Accumulation of neurotransmitter is prevented by three mechanisms: NE exocytosis is an active adenosine triphosphate-dependent process, and during ischaemia adenosine triphosphate levels are not sufficient; NE-specific uptake-1 transporter that reuptakes NE from the synaptic cleft; and adenosine accumulating in the ischaemic myocardium stimulates presynaptic A1-adenosine receptors and suppresses NE exocytosis. If ischaemia progresses for >10 minutes, the myocardium loses the protection against the excessive adrenergic stimulation. The catecholamines are released from the storage vesicles of the neuronal cytoplasm and normal transportation from the cytoplasm to the synaptic cleft through the axolemma is reversed. This results in extracellular levels that reach 100–1,000-fold the normal plasma concentrations within 30 minutes of ischaemia.16 There is also a 20–30 % increase of the adrenergic receptors secondary to adenylyl cyclase sensitisation spreading the myocardial damage.17

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Ischaemia sets up a context of excessive increase of catecholamines with sensitised adrenergic receptors that lead to intracellular calcium overload, formation of free radicals, functional hypoxia, decoupling of oxidative phosphorylation, electrolytic disorders, cell membrane increased permeability, and formation of aminolutins (that are the product of the pathological auto-oxidation of catecholamine catabolism), finally leading to irreversible myocardial injury.18,19 Catecholaminergic activation is reduced during the first post-infarction days, mainly NE, as levels of EPI only remain high during the first 24 hours of hospitalization. However, in patients with anterior localization or stable coronary artery disease associated with various dysrhythmias, high levels of plasma NE at admission and during follow up were observed.20 In addition, patients who develop heart failure (HF) with reduced ejection fraction after AMI have elevated levels of NE for 1 month.21 In conclusion, catecholamines in myocardial ischaemia are involved at different levels and its genesis has different origins. This determines a complex approach due to the multiple factors to consider and also that catecholamines play a physiological role in the response to ischaemia. In addition, the evaluation of neurohormonal activity can be difficult because of the overlap with other systems (such as the cortical adrenal system) and the multiple mechanisms of catecholamine’s reuptake and metabolism. This could be the reason that neither plasmatic nor urinary concentration of catecholamines could precisely reflect the neuroendocrine activity in post-infarction patients.

Glucose, Insulin and Fatty Acids in Acute Coronary Syndrome In response to the stress that represents ACS, cortisol, catecholamines, glucagon, growth hormone, and some cytokines (tumour necrosis factor-alpha; TNF-alpha), which stimulate glycogenolysis and hepatic glyconeogenesis, are released. In addition, insulin resistance is generated due to defects at the glucose transporter type 4 and postreceptor signalling pathways. This configures ‘stress hyperglycaemia’.22,23 In this context, hyperglycaemia induces glycotoxicity at the systemic and cardiac levels, as it is able to prolong and generate dispersion of the QTc interval, which may predispose to arrhythmias,24 generates oxidative stress that stimulates inflammation (interleukin-6, TNF and interleukin-18), and alters endothelium-dependent vasodilatation.25–28 It also decreases the collateral coronary flow dependent on nitric oxide and may increase infarction size.29,30 Hyperglycaemia attenuates the protective effect of ischaemic preconditioning and perconditioning, and exacerbates the non-reflow phenomenon.30–34 Hyperglycaemia has procoagulant and prothrombotic effects by stimulating thrombin formation, increasing factor VIII levels and procoagulant activity of tissue factor.35,36 It induces adenosine diphosphate-mediated platelet activation and attenuates the inhibitory effect of aspirin on glycoprotein IIb–IIIa and P-selectin expression, and may attenuate the anti-aggregant response to nitric oxide, which reverts with glycaemic control.37–39 Hypoglycaemia also has deleterious effects, as it prolongs the QTc interval, stimulates inflammation, and favours platelet aggregation and coagulation. It has also been shown that insulin-induced hypoglycaemia decreases coronary flow reserve in healthy individuals and patients with diabetes.40,41 Fatty acids, together with glucose, are one of the major energy sources of the myocardium, but during ACS, catecholamines generate an excessive increase in the concentration of free fatty acids that are

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Stress Hyperglycaemia capable of generating lipotoxicity on the myocardium, as they induce membrane peroxidation, inhibition of mitochondrial beta-oxidation, inhibition of the Na+, K+-adenosine triphosphatase pump with Ca++ and Na+ intracellular accumulation, and favour the occurrence of ventricular arrhythmias.42

6 months have been shown in ACS patients with elevated levels within the first 36 hours of symptom onset and at 5 days after the event. This trial was compared with the Global Registry of Acute Coronary Events score, revealing that preproadrenomedullin is a better predictor of mortality at 6 months.49,50

As identified by other authors, it is important to remember that insulin has other important effects for the ischaemic myocardium besides metabolic modulation.43

Chromogranin A (CgA) is a 49-kDA polypeptide with 439 amino acids identified throughout the nervous and endocrine system. Significant high plasma levels are recorded in patients with neuroendocrine tumours. The increased concentration of CgA correlates with augmented sympathetic activity in both the adrenal medulla and nerve terminals, suggesting that CgA could involve neuroendocrine signals from several sources, thus representing an overall index of neuroendocrine activity.

Insulin is a vasodilator at the systemic and coronary level, and this effect seems to be largely dependent on the endothelium and on the action of nitric oxide. Improvement in coronary blood flow (in a dose-dependent manner) has been seen in healthy people, and in patients with diabetes, in ischaemic and non-ischaemic areas.44,45 It also has proangiogenic effects mediated by vascular endothelial growth factor that could be involved in vascular regeneration at the peri-infarct areas.46 Therefore, it appears that beyond its determinant condition on the evolution of patients with myocardial ischaemia, hyperglycaemia should not be the only factor to be considered when an analysis focusing on the metabolic control of patients with ACS is posed.

Other Serum Markers in Neuroendocrine Activity in Acute Coronary Syndrome Regarding ACS, parallel with the advancement of medical treatment, attention has focused on early patient stratification and, particularly, on the prognostic potential of serum markers. (In the following section, some of these are listed together with the implications of their dosage for ACS prognosis). B-type natriuretic peptide is the part of the natriuretic peptide family that is released by the ventricle in response to increased parietal stress; it exerts its biological effect by acting on the receptor of the guanylate cyclase system, increasing the concentration of cyclic guanosine monophosphate, generating vasodilatation and natriuresis, and inhibiting the renin–angiotensin–aldosterone system, decreasing the sympathetic activity and the synthesis of endothelin 1. Therefore, it has emerged as a serum marker that assists in the diagnosis of HF. B-type natriuretic peptide has been evaluated in multiple trials as an independent predictor of prognosis in patients with ACS, showing that high concentrations of B-type natriuretic peptide, both within the first hours and at 7 days of evolution, are associated with higher mortality and worse prognosis. When compared with troponin I and C-reactive protein, it works as a stronger prognostic marker – predicting death at 30 days.47,48 Adrenomedullin (AM) is a 52-amino acid peptide related to the calcitonin gene. First isolated from pheochromocytoma cells, it could be detected in other tissues later, such as the adrenal medulla, heart, brain, lung, kidneys, and endothelial cells. It exerts a vasodilatatory action, increasing the levels of cyclic adenosine monophosphate, thus inducing diuresis and natriuresis. Increased levels in both HF and ACS predict an unfavourable evolution. Preproadrenomedullin, a precursor of AM, was dosed in a clinical trial – secreted in equal proportion – revealing itself more stable than AM. Higher mortality and recurrent acute MI (AMI) at 30 days and

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The production of CgA was demonstrated among individuals with dilated and hypertrophic cardiomyopathy, and the plasma levels of CgA correlate with the disease severity. This association has a prognostic value in patients with HF and post-AMI HF. Another study also revealed that CgA is independently associated with all-cause mortality, and through univariate analysis it was determined that basal CgA concentration was strongly associated with the incidence of hospitalization for HF and recurrent AMI.51 Osteoprotegerin – a member of the TNF receptor superfamily – is identified as a bone resorption regulator. Binding to the receptor activator of nuclear factor-kappa B ligand, it competitively inhibits the receptor activator of nuclear factor-kappa B ligand interaction with consequent inhibition of osteoclastogenesis. Osteoprotegerin is expressed in the vascular system, smooth muscle cells, atherosclerotic plaques, and early atherosclerotic lesions. In patients with ACS, early high dosage was associated with greater all-cause mortality and HF at 30 days and 1 year.52 All these serum markers have proven independent prognostic values. However, an integrated multivariate approach is required among patients with ACS within heterogeneous populations.

Neuroendocrine Activity and Thrombosis in Acute Coronary Syndrome Progressive endothelial dysfunction is the initial event in the development of atheroma plaques within the coronary arteries, which can interrupt blood flow and cause ischaemic injury in the myocardium, triggering an ACS. In response to an abnormal glycometabolic state, an oxidative stress and an inflammatory environment are generated; meanwhile, the endothelium acquires a prothrombotic phenotype.53–56 The acute inflammatory response is initiated by t-cells and mast cells, which synthesise pro-inflammatory cytokines and foster the expression of adhesion molecules, which ease the migration of monocytes and t-cells into the arterial intima. Interleukin-6 and TNF contribute to the local and systemic inflammatory process, and increase the expression of tissue factor in macrophages, endothelial cells, and smooth muscle vascular cells. The latter secrete collagen that expands the extracellular matrix and forms the atheromatous plaque surrounded by a covering of fibrous tissue and cellular infiltrates in the arterial intima, while a proliferation of smooth muscle cells occur.

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Pharmacotherapy Eventually, interferon gamma released by t-cells and mast cell proteases induces an overexpression of metalloproteases that downgrade the components of the interstitial matrix and slim down the plaque, which becomes vulnerable and breakable at the most exposed areas to turbulent blood flow.57

Prognosis Value of Hyperglycaemia According to Neuroendocrine Activity in Acute Coronary Syndrome

The rupture of the plaque releases tissue factor that, in contact with blood, locally triggers the coagulation cascade that generates thrombin, which acts on protease-activated receptors (proteaseactivated receptor 1 and 4) of the platelet and cardiomyocyte.58

This fact has been observed for several decades. In 1931, Cruikshank reported on the high prevalence of glycosuria in patients without diabetes with infarction.68

Collagen is exposed from the plaque and surrounding subendothelium, platelets attach to it, activate, and expose alpha IIb beta 3 integrin, which binds to fibrinogen and to von Willebrand Factor (VWF), and platelet aggregation occurs. Activated platelets also release VWF, thromboxane A2, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, fibronectin, and factor XIII, which stabilise the fibrin clot by cross-linking fibrin monomers and culminates with the formation of a thrombus within the vessel lumen, which may partially or totally obstruct the coronary artery.59 With this process in progress, tissue plasminogen activator and urokinase activator are released from the endothelium to digest the thrombus in situ, and at the same time the inhibitor PAI-1 is released, which forms an inactive complex with both activators. The increase of PAI-1 is related to adverse cardiovascular events; paradoxically, the same happens with tissue plasminogen activator increase, but this is due to the fact that tissue plasminogen activator antigen concentration mostly evaluates the inactive complex that it forms with PAI-1. Local fibrinolytic capacity would depend on the balance between activators and inhibitors, which would determine a greater or lesser generation of plasmin. This enzyme downgrades the fibrin network – whose lysing product is D-dimer (DD) – plasmin also participates in plaque rupture, activating the metalloproteases.60 Meanwhile, factor XIII cross-links alpha 2 antiplasmin in the fibrin mesh to inactivate plasmin in situ. Fibrinolysis is a dynamic process; plasmin smoothes the fibrin mesh and increases DD, but if the fibrinolytic reserve is depleted, the possibility of thrombus lysis decreases, and DD does not increase.61 Prospective studies show that the specificity of DD for the early detection and prognosis of ACS is questionable,62 as it is a variable marker that depends on the moment when this system in continuous change is studied.63,64 In the early stages of plaque development, VWF and P-selectin are mediators of platelet–endothelial cell interactions. VWF is secreted from the endothelial cells as very high molecular weight multimers, and is highly adhesive.65 ADAMTS13 is the enzyme responsible for cleaving the multimers in smaller and less adhesive forms, but oxidative stress inhibits it, forming highly thrombogenic platelet aggregates that promote plaque progression.66 Platelet thrombus is more resistant to lysis because of its high PAI-1 content and because platelet microparticles contribute to thrombin generation, which activates thrombin-activatable fibrinolysis inhibitor, a fibrinolytic inhibitor, which promotes thrombolysis resistance. Platelets – the source of growth factors and mitogens – play a major role in thrombus formation and propagation67 and are the main target of antithrombotic therapy in arterial disease.

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Hyperglycaemia is a common finding at admission in patients with MI in both people with and without diabetes.

Numerous studies have been published confirming not only that hyperglycaemia is common in these patients, but also that it is an independent predictor of mortality in the short, medium, and long term. In 2000, Capes published a meta-analysis of 15 studies focusing on the mortality or HF rate after MI in relation to blood glucose levels.69 The proportion of patients with hyperglycaemia was 3–71 % in people without diabetes and 46–84  % in people with diabetes. Patients with no history of diabetes and with glycaemia ranging from 6.1 mmol/l to 8 mmol/l had a 3.9-fold (95  % CI [2.9–5.4]) higher mortality rate than patients without a history of diabetes and with lower blood glucose levels. Also, patients without diabetes with higher blood glucose levels of 8–10 mmol/l had an increased risk of HF or cardiogenic shock. In contrast, among patients with diabetes, death risk was moderately augmented (RR 1.7 [1.2–2.4]) from glycaemia between 10 and 11 mmol/l. Similar findings were observed in Canada among 1,664 patients hospitalised for MI who were stratified according to the presence or absence of a history of diabetes and glycaemia at admission lower or higher than 11 mmol/l. The group with the worst prognosis in terms of in-hospital mortality and along 1 year (among the four groups analysed) was the patients without diabetes with hyperglycaemia on admission group.70 In a large cohort of elderly patients with MI (n=141,680), glycaemia on admission was analysed as a continuous and categorical variable (≤6.1, >6.1–7.8, >7.8 9.4, >9.4–13.3, >13.3 mmol/l), and its association with 30-day and annual mortality rates in patients with and without diabetes.71 It was found that the 30-day mortality rate increased from 10  % in patients without diabetes with glycaemia at admission <6.1 mmol/l to 39  % in patients without diabetes with glycaemia >13.3 mmol/l, and from 22  % to 55  % in mortality per year. Among the patients with diabetes, 30-day mortality was 16  % in patients with glycaemia ≤6.1 mmol/l and 24 % in those with glycaemia >13.3 mmol/l. Mortality per year was 35–41  %. Higher blood glucose levels were associated with an increased risk of mortality in patients without a history of diabetes (p for interaction <0.001). These findings imply that hyperglycaemia in patients with MI has a worse prognostic significance in patients without diabetes than in patients with diabetes. One possible explanation is that among patients considered to not have diabetes, one group would be undiagnosed diabetics who are often treated less with insulin. Only 26 % of patients without a history of diabetes and with glycaemia <13.3 mmol/l received insulin, whereas 73 % of patients with diabetes were treated with insulin.71 In both patients with or without diabetes, hyperglycaemia could reflect the seriousness of the disease as a result of increased catecholamines and other stress hormones, such as cortisol. Several studies have

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Stress Hyperglycaemia shown the relationship. In 1986, Yudkin et al. showed a correlation between the EPI concentration at the early stages of infarct and the size of the infarct.72 Also, hyperglycaemia on admission in people without diabetes was determined both by the extent of the MI, mainly through the secretion of EPI, and the secretion of other hormones that were independent of the extent of the infarct. Patients with a high glycaemic index on admission showed a high concentration of NE and cortisol, with no relationship between these hormones and the extent of MI. A substudy of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) determined that NE is elevated in all patients and normalised within the first 2 days, remaining high in patients with HF during the first month after infarction.21 This difference was not found in EPI, which also increased in the early stage of infarction. The authors concluded that sustained neurohormonal activation following infarction occurs primarily in patients with HF and at the same time is related to the size of the MI. This activation would initially be an early compensatory response mechanism to preserve circulatory homeostasis, but the extension of its activation could be deleterious. This activation, therefore, could be a marker of myocardial damage, but also a detrimental mechanism itself. In this sense, several groups explored the value of persistent hyperglycaemia after MI. Aronson et al. studied fasting glucose after admission in 735 MI patients without diabetes.73 Mortality in patients

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with blood glucose in a fasted state <5.6 mmol/l was 2 % at 30 days of MI, and 10 %, 13 %, and 29 % at the first, second, and third tertile of high fasting blood glucose was found. Fasting blood glucose was a better predictor than glycaemic control at admission. Greater risk was found in those who entered with hyperglycaemia and remained hyperglycaemic, followed by the group that entered without hyperglycaemia, but presented hyperglycaemia during the hospitalisation. Likewise, with a larger number of patients (n=16,871), Kosiborod et al. observed that persistent hyperglycaemia is a better predictor of mortality than hyperglycaemia at admission.74 They also showed that there is a gradual increase in the in-hospital mortality rate for every 0.6 mmol/l increase of glycaemia, when mean glucose is >6.7 mmol/l. In contrast, they observed a higher mortality at <3.9 mmol/l, determining a J-curve relationship between mortality and mean blood glucose during hospitalisation. The curves are different in people with diabetes than in people without diabetes, being more abrupt and with an increased rate of mortality in relation to blood glucose in people without diabetes. Finally, and to emphasise the prognostic importance of the value of glycaemia in patients with MI, Timóteo et al. published a study where they proposed to include the glycaemia value at admission to the Global Registry of Acute Coronary Events score in patients with ACS. This incorporation increases the predictive value of the score, albeit with a modest magnitude.75 n

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org/10.1136/heartjnl-2011-301260; PMID: 22373720. 53. S  hah B, Amoroso NS, Sedlis SP. Hyperglycemia in nondiabetic patients presenting with acute myocardial infarction. Am J Med Sci 2012;343:321–6. https://doi.org/10.1097/ MAJ.0b013e31822fb423; PMID: 21946827. 54. Carter AM. Inflammation, thrombosis and acute coronary syndromes. Diab Vasc Dis Res 2005;2:113–21. https://doi. org/10.3132/dvdr.2005.018; PMID: 16334592. 55. Hansen CH, Ritschel V, Halvorsen S et al. Markers of thrombin generation are associated with myocardial necrosis and left ventricular impairment in patients with ST-elevation myocardial infarction. Thromb J 2015;13:31. https://doi. org/10.1186/s12959-015-0061-1; PMID: 26396552. 56. Fujino M, Ishihara M, Honda S, et al. Impact of acute and chronic hyperglycemia on in-hospital outcomes of patients with acute myocardial infarction. Am J Cardiol 2014;114:1789– 93. https://doi.org/10.1016/j.amjcard.2014.09.015; PMID: 25438903. 57. Abbate R, Cioni G, Ricci I, et al. Thrombosis and acute coronary syndrome. Thromb Res 2012;129:235–40. https://doi. org/10.1016/j.thromres.2011.12.026; PMID: 22281070. 58. Zannad F, Stough WG, Regnault V, et al. Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges. Int J Cardiol 2013;167:1772–82. https://doi.org/10.1016/j.ijcard.2012.12.018; PMID: 23298559. 59. Loeffen R, van Oerle R, Leers MP, et al. Factor XIa and thrombin generation are elevated in patients with acute coronary syndrome and predict recurrent cardiovascular events. PloS ONE 2016;11:e158355. https://doi.org/10.1371/ journal.pone.0158355; PMID: 27419389. 60. Gorog DA. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol 2010;55:2701–9. https://doi.org/10.1016/j.jacc.2009.11.095; PMID: 20538163. 61. Tokita Y, Kusama Y, Kodani E, et al. Utility of rapid D-dimer measurement for screening of acute cardiovascular disease in the emergency setting. J Cardiol 2009;53:334–40. https://doi.org/10.1016/j.jjcc.2008.12.001; PMID: 19477373. 62. Itakura H, Sobel BE, Boothroyd D, et al. Atherosclerotic Disease, Vascular Function and Genetic Epidemiology Advance (ADVANCE) study. Do plasma biomarkers of coagulation and fibrinolysis differ between patients who have experienced an acute myocardial infarction versus stable exertional angina? Am Heart J 2007;154:1059–64. https://doi.org/10.1016/j.ahj.2007.09.015; PMID: 18035075. 63. van der Krabben MD, Rosendaal FR, van der Bom JG, Doggen CJ. Polymorphisms in coagulation factors and the risk of recurrent cardiovascular events in men after a first myocardial infarction. J Thromb Haemost 2008;6:720–5. https://doi.org/10.1111/j.1538-7836.2008.02930.x; PMID: 18284606. 64. Shim CY, Liu YN, Atkinson T, et al. Molecular imaging of platelet-endothelial interactions and endothelial von Willebrand factor in early and mid-stage atherosclerosis. Circ

Cardiovasc Imaging 2015;8:e002765. https://doi.org/10.1161/ CIRCIMAGING.114.002765; PMID: 26156014. 65. Y  an B, Xu M, Zhao Y, et al. Development of a novel flow cytometric immunobead array to quantify VWF: Ag and VWF: GPIbR and its application in acute myocardial infarction. Eur J Haematol 2017;99:207–15. https://doi.org/10.1111/ejh.12905; PMID: 28523822. 66. Maino A, Rosendaal FR, Algra A, et al. Hypercoagulability is a stronger risk factor for ischaemic stroke than for myocardial infarction: a systematic review. PLoS ONE 2015;10:e0133523. https://doi.org/10.1371/journal. pone.0133523; PMID: 26252207. 67. Okafor ON, Gorog DA. Endogenous fibrinolysis: an important mediator of thrombus formation and cardiovascular risk. J Am Coll Cardiol 2015;65:1683–99. https://doi.org/10.1016/j. jacc.2015.02.040; PMID: 25908074. 68. Cruikshank N. Coronary thrombosis and myocardial infarction, with glycosuria. BMJ 1931;1:618–9. https://doi.org/10.1136/ bmj.1.3666.618; PMID: 20776111. 69. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000;355:773–8. https://doi.org/10.1016/S01406736(99)08415-9; PMID: 10711923. 70. Wahab NN, Cowden EA, Pearce NJ, et al. ICONS Investigators. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol 2002;40:1748–54. https://doi.org/10.1016/S07351097(02)02483-X; PMID: 12446057 71. Kosiborod M, Rathore SS, Inzucchi SE, et al. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation 2005;111:3078–86. https://doi.org/10.1161/CIRCULATIONAHA.104.517839; PMID: 15939812. 72. Oswald GA, Smith CC, Betteridge DJ, et al. Determinants and importance of stress hyperglycaemia in non-diabetic patients with myocardial infarction. Br Med J (Clin Res Ed) 1986;293:917–22. https://doi.org/10.1136/bmj.293.6552.917; PMID: 3094714. 73. Suleiman M, Hammerman H, Boulos M, et al. Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: a prospective study. Circulation 2005;111:754–60. https://doi.org/10.1161/01. CIR.0000155235.48601.2A; PMID: 15699267. 74. Kosiborod M, Inzucchi SE, Krumholz HM, et al. Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk. Circulation 2008;117:1018–27. https://doi.org/10.1161/ CIRCULATIONAHA.107.740498; PMID: 18268145. 75. Timóteo AT, Papoila AL, Rio P, et al. Prognostic impact of admission blood glucose for all-cause mortality in patients with acute coronary syndromes: added value on top of GRACE risk score. Eur Heart J Acute Cardiovasc Care 2014;3:257–63. https://doi.org/10.1177/2048872614528858; PMID: 24687188.

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Pharmacotherapy

Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator Hiroshi Watanabe Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan and Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan

Abstract Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the similarities and differences between phosphodiesterase type 5 inhibitors and sGC stimulator based on pharmacological action and clinical trials, and considers which is better for the treatment of pulmonary arterial hypertension.

Keywords Pulmonary arterial hypertension, phosphodiesterase type 5 inhibitor, soluble guanylate cyclase stimulator, nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate axis Disclosure: The author has no conflicts of interest to declare. Received: 1 November 2017 Accepted: 9 March 2018 Citation: European Cardiology Review 2018;13(1):35–7. DOI: https://doi.org/10.15420/ecr.2017:22:2 Correspondence: Hiroshi Watanabe, Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan. E: hwat@hama-med.ac.jp

Pulmonary arterial hypertension (PAH) is a chronic and lifethreatening disease characterised by progressive vascular remodelling that leads to increased pulmonary vascular resistance, right ventricular heart failure and death. PAH is defined by >25 mmHg increase in pulmonary arterial blood pressure and a pulmonary capillary wedge pressure of 15 mmHg.1 If left untreated PAH is fatal; it has a survival rate of just 34 % after 5 years.2 Current therapies for PAH include stimulating the nitric oxide (NO)– soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) axis, improving the prostacyclin pathway or inhibiting the endothelin pathway.3,4 Although the causal relationship remains unproven, the NO–sGC– cGMP axis is ultimately a critical factor in the development of PAH because the condition is associated with endothelial dysfunction, impaired NO synthesis and insufficient stimulation of the NO–sGC– cGMP pathway.5 NO activates sGC, resulting in the synthesis of cGMP, which is a key mediator of pulmonary arterial vasodilatation that may also inhibit vascular smooth muscle proliferation and platelet aggregation. Dysregulation of the NO–sGC–cGMP axis results in pulmonary vascular inflammation, thrombosis and constriction, and ultimately leads to PAH. Therapeutic options targeting the NO–sGC–cGMP axis include phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil and tadalafil, and the sGC stimulator riociguat.6 This review discusses the similarities and differences between PDE5 inhibitors and sGC stimulator and considers which is better for the treatment of PAH (Table 1).

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Similarities in Pharmacological Action Both classes of drug modify the cGMP-mediated signalling cascade. Increased levels of cGMP lead to vasodilatation and the inhibition of vascular smooth muscle proliferation and fibrosis. The presence of this nucleotide also exerts antithrombotic and anti-inflammatory effects. These effects are controlled by cGMP-dependent protein kinases, cGMP-dependent ion channels and phosphodiesterases.7,8 Activation of cGMP-dependent protein kinase isotype I (cGKI) decreases cytosolic Ca2+ concentration indirectly via the activation of membrane K+ channels, leading to the hyperpolarisation of vascular smooth muscle cell membrane. Additionally, cGKI phosphorylates vasodilator-stimulated phosphoprotein, an actin-binding protein whose phosphorylation status is related to the proliferation of vascular smooth muscle cells.9 These effects lead to the relaxation of smooth muscle cells.10 The cGKI also enhances canonical bone morphogenetic protein signalling via Smad1/5 and keeps pulmonary artery smooth muscle cells in a differentiated state with low proliferation. These effects are lost if there is a mutation in the bone morphogenetic protein type II receptor, as there is a reduction in downstream Smad1/5 phosphorylation.11,12 Increasing the amount of cGMP present through the use of PDE5 inhibitors or a sGC stimulator could lead to inhibition of the phosphodiesterase type 3 subtype, in turn leading to increased levels of cyclic adenosine monophosphate resulting in a positive inotropic effect.4 In addition to this effect, protein kinase G activation following the rise in cGMP level causes the mitochondrial KATP channels in cardiac cells to open,13,14 resulting in cardioprotective effects.15,16 These effects may improve right heart function in PAH.

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Pharmacotherapy Table 1: Comparison of Phosphodiesterase Type 5 Inhibitors and Soluble Guanylate Cyclase Stimulator for the Treatment of Pulmonary Arterial Hypertension PDE5 Inhibitor

sGC Stimulator Riociguat

Available agents

Sildenafil, tadalafil

Mode of action

Potent selective inhibitor of PDE5

Stimulates sGC

Mechanism of action

Releases nitric oxide, which activates the enzyme guanylate cyclase resulting in increased levels of cyclic guanosine monophosphate, leading to smooth muscle relaxation and increased blood flow

Directly stimulates sGC independent of nitric oxide; indirectly stimulates the NO–sGC–cGMP pathway via sensitisation of sGC to endogenous nitric oxide

Type of action

Specific: lungs and corpus cavernosum

Systemic: pulmonary and systemic vasculature

Adverse effects

Rare

Hypotension

Contraindications

Sildenafil: Recent history of stroke or myocardial infarction; sickle-cell anaemia; hereditary degenerative retinal disorders; history of nonarteritic anterior ischaemic optic neuropathy

History of serious haemoptysis; previous bronchial artery embolisation; pulmonary hypertension associated with idiopathic interstitial pneumonias; pulmonary veno-occlusive disease

Tadalafil: recent acute myocardial infarction; history of non-arteritic anterior ischaemic optic neuropathy

Co-administration with nitrates and PDE5 inhibitors

cGMP = cyclic guanosine monophosphate; NO = nitric oxide; PDE5 = phosphodiesterase type 5; sGC = soluble guanylate cyclase. BNF, 2018.40–42

Differences in Pharmacological Action PDE5 Inhibitors The enzyme PDE5 is found in high concentrations in the pulmonary arteries and specifically degrades cGMP. It is important in the regulation of cGMP-specific signalling pathways, which effect smooth muscle contraction and relaxation, and is therefore a key target of PAH treatment. PDE5 inactivates cGMP by catabolising it to 5’GMP. In PAH, the expression and activity of PDE5 are enhanced in the smooth muscle cells of the pulmonary arteries.17–19 Enhancement of PDE5 activity and reduction in NO bioavailability both lower cGMP concentration, resulting in vasoconstriction, enhanced smooth muscle cell proliferation and the promotion of resistance to apoptosis.20 The PDE5 inhibitors sildenafil and tadalafil block the breakdown of cGMP. The resultant increase in cGMP concentration leads to relaxation of the smooth muscle and vasodilation. These effects are dependent on NO availability and sGC activity.21,22 PDE5 is distributed in the smooth muscles of the corpus cavernosum in penile tissue and in blood vessels in the lungs, which are the main sites of action of PDE5 inhibitors. The selectivity of these agents for lung tissue is maintained even when they are administered systemically.23,24

and tadalafil are selective and potent inhibitors of PDE5 and increase intracellular cGMP levels. As PDE5 is expressed at high levels in the pulmonary circulation compared with systemic vessels, PDE5 inhibitors induce pulmonary vasodilation without decreasing systemic artery pressure. Sildenafil Use in Pulmonary Arterial Hypertension (SUPER), a double-blind, placebo-controlled, randomised study, demonstrated that sildenafil improved exercise capacity, World Health Organization functional class and haemodynamics in patients with symptomatic PAH.30 PDE5 inhibitors are widely used as an effective treatment for clinical PAH and their long-term safety and tolerability have been demonstrated by several randomised clinical trials.31 It is also strongly suggested that earlier treatment with sildenafil could bring better outcome in the treatment for PAH.31 Tadalafil has a longer half-life than sildenafil;32 however, a recent analysis designed to estimate the costs and quality-adjusted life years associated with bosentan, ambrisentan, riociguat, tadalafil, sildenafil and supportive care for PAH in treatmentnaive patients suggested that sildenafil was the most cost-effective therapy in patients with functional class II or III PAH.33 Despite this, tadalafil was found to be less costly and more effective than supportive care in these patients.

sGC Stimulator sGC Stimulator The conversion of guanosine triphosphate to cGMP is catalysed by the enzyme sGC. This enzyme exists as a heterodimer, consisting of a larger α subunit and a smaller haem-binding subunit. In the resting state, the subunit contains a ferrous haem iron (Fe2+) that binds NO with picomolar affinity, enhancing sGC activity by several hundredfold.25,26 Other circulating peptides, such as natriuretic peptide, can activate particulate guanylate cyclase to convert guanosine triphosphate to cGMP. The sGC stimulator riociguat has a dual mode of action, sensitising sGC to endogenous NO by stabilising NO–sGC binding and directly stimulating sGC via a different binding site. This drug has been shown to produce cGMP independent of the presence of NO.27,28 As sGC is expressed in the pulmonary and systemic vasculature, the effect of riociguat is not limited to the pulmonary arteries and hypotension is often the dose-limiting adverse effect.

Supportive Evidence PDE5 Inhibitors Decreased endothelial NO production and increased PDE5 expression and activity are two important pathological features of PAH. Sildenafil

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Endothelial NO synthase expression, NO production and NO availability are substantially reduced in patients with PAH,5,10 so the sGC stimulator may be effective in patients who have not sufficiently responded to a PDE5 inhibitor.34–36 The recent open-label, uncontrolled, phase IIIb Riociguat Clinical Effects Studied in Patients with Insufficient Treatment Response to PDE5 Inhibitor (RESPITE) study suggested that switching from PDE5 inhibitors to riociguat improved a range of clinical and haemodynamic endpoints in patients with PAH who have had an inadequate response to PDE5 inhibition.34 Patients with PAH-systemic sclerosis (SSc) tend to have a worse prognosis than patients with idiopathic PAH, and have poorer responses to treatment and worse outcomes than those whose PAH is associated with other connective tissue diseases (CTDs). However, the long-term extension of the Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT-2) demonstrated the same survival at 2 years (93 %) for those with PAHCTD and those with idiopathic or familial PAH who were receiving treatment with riociguat, despite more than half of the PAH-CTD patients having PAH-SSc.37 Since SSc is characterised by systemic vascular disorder, the action of a non-selective vasodilator such as a sGC stimulator may be more favourable than a pulmonary artery-

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Pulmonary Arterial Hypertension selective vasodilator. A randomised, double blind, placebo-controlled phase II study to investigate the efficacy and safety of riociguat in patients with diffuse cutaneous SSc is underway.38

safety signs with sildenafil plus riociguat and no evidence of a positive benefit–risk ratio. Therefore, concomitant use of riociguat with PDE5 inhibitors is contraindicated.

Combination Treatment

Conclusion

Upstream NO–sGC activity and downstream PDE5 activity affect the level of cGMP. Even if the degradation of cGMP is completely blocked by a PDE5 inhibitor, there will not be sufficient cGMP produced if there is insufficient NO produced upstream. In the same way, even if sGC stimulator enhances the production of cGMP, the cGMP level cannot be maintained if its degradation has been enhanced by excessive PDE5 activity. The combination of sGC stimulator and a PDE5 inhibitor would therefore appear to be an attractive therapeutic option. However, combination therapy with riociguat and sildenafil had no favourable effects on exploratory clinical parameters, including haemodynamics and exercise capacity, in patients with PAH in the PATENT PLUS study.39 There were high rates of discontinuation due to hypotension and three deaths – one due to cardiac arrest, one from right heart failure and one from cerebral bleeding due to a fall – occurred during the study. The possibility that the combination of medications contributed to the fall could not be excluded. There were potentially unfavourable

Based on recent cost-utility analysis, sildenafil may be recommended as the first choice and tadalafil as second choice in patients with functional class II and III PAH. However, some patients may gain more benefit taking tadalafil, with its once-daily administration, rather than sildenafil, which needs to be taken a three times per day. Patients with insufficient response to PDE5 inhibitors should be switched to the sGC stimulator riociguat. Patients with PAH-SSc may gain further benefit from riociguat due to its systemic vascular action.

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While there are clear pharmacokinetic and pharmacodynamic differences between these agents, it is still difficult to determine which agent is most appropriate for a specific PAH patient. Some patients respond better to sGC stimulator than a PDE5 inhibitor and vice versa. Additional data from clinical trials are needed to clarify which treatment is best; a randomised controlled trial to further investigate switching from PDE5 inhibitors to riociguat is underway (REPLACE: NCT02891850). n

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bi9519718; PMID: 8573563. 27. S  tasch JP, Hobbs AJ. NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol 2009;191:277–308. https://doi.org/10.1007/978-3-540-689645_13; PMID: 19089334. 28. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123:2263–73. https://doi.org/10.1161/ CIRCULATIONAHA.110.981738; PMID: 21606405. 29. Dumitrascu R, Weissmann N, Ghofrani HA, et al. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 2006;113:286–95. https://doi.org/10.1161/ CIRCULATIONAHA.105.581405; PMID: 16391154. 30. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148– 57. https://doi.org/10.1056/NEJMoa050010; PMID: 16291984. 31. Rubin LJ, Badesch DB, Fleming TR, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 2011;140:1274–83. https://doi.org/10.1378/chest.10-0969; PMID: 21546436. 32. Galiè N, Brundage BH, Ghofrani HA, et al. Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894–903. https://doi.org/10.1161/CIRCULATIONAHA.108.839274; PMID: 19470885. 33. Coyle K, Coyle D, Blouin J, et al. Cost effectiveness of firstline oral therapies for pulmonary arterial hypertension: a modelling study. ParmacoEconomics 2016;34:509–20. https://doi.org/10.1007/s40273-015-0366-8; PMID: 26739957. 34. Hoeper MM, Corris PA, Klinger JR, et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase type 5 inhibitors. Eur Respir J 2017;50:1602425. https://doi. org/10.1183/13993003.02425-2016; PMID: 28889107. 35. Andersen A, Korsholm K, Mellemkjaer S, Nielsen-Kudsk JE. Switching from sildenafil to riociguat for the treatment of PAH and inoperable CTEPH: Real-life experiences. Respir Med Case Rep 2017;22:39–43. https://doi.org/10.1016/j. rmcr.2017.06.005; PMID: 28652963. 36. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330–40. https://doi.org/10.1056/NEJMoa1209657; PMID: 23883378. 37. Ghofrani HA, Grimminger F, Grunig E, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016;4:361–71. https:// doi.org/10.1016/S2213-2600(16)30019-4; PMID: 27067479. 38. Distler O, Pope J, Denton C, et al. RISE-SSc: Riociguat in diffuse cutaneous systemic sclerosis. Respir Med 2017;122(Suppl 1): S14–S17. https://doi.org/10.1016/j.rmed.2016.09.011; PMID: 27746061. 39. Galiè N, Muller K, Scalise AV, et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in PAH. Eur Respir J 2015;45:1314–22. https://doi. org/10.1183/09031936.00105914; PMID: 25657022. 40. Sildenafil. BNF. https://bnf.nice.org.uk/drug/sildenafil.html (accessed 28 March 2018). 41. Tadalafil. BNF. https://bnf.nice.org.uk/drug/tadalafil.html (accessed 28 March 2018). 42. Riocigaut. BNF. https://bnf.nice.org.uk/drug/riociguat.html (accessed 28 March 2018)

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Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Alberto Lorenzatti 1,2 and Maria Luz Servato 3 1. Docencia, Asistencia Médica e Investigación Clínica (DAMIC) Medical Institute, Rusculleda Foundation for Research, Córdoba, Argentina; 2. Cardiology Department, Córdoba Hospital, Córdoba, Argentina; 3. Clinical Research Section, DAMIC Medical Institute, Rusculleda Foundation for Research, Córdoba, Argentina

Abstract Coronary artery disease (CAD) is the leading cause of death worldwide. Despite notable advances in understanding the nature of atherosclerotic processes and the use of effective medications such as statins, there remains a significant residual risk. Even after optimal medical treatments and precise revascularisations, the recurrence of MI remains at approximately one-third for 5 years after an acute coronary syndrome (ACS). Over the past two decades, compelling data from animal and human studies has clearly identified atherosclerosis as an inflammatory disease of the arterial wall, but clinical applications related to this accumulated knowledge are still scarce. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence that an anti-inflammatory intervention with the monoclonal antibody canakinumab reduces cardiovascular events in well-treated CAD patients without affecting LDL cholesterol levels. This article presents a brief description of the role of inflammation in atherogenesis and examines selected anti-inflammatory interventions and their potential use in CAD-affected individuals.

Keywords Atherosclerosis, canakinumab, cholesterol, coronary artery disease, cytokine, inflammasome, inflammation, revascularisation, statin Disclosure: Dr. Lorenzatti served as a Country Coordinator and Member of the CANTOS Steering Committee and received research grant support from its sponsor, Novartis. Dr Servato has no conflicts of interest to declare. Received: 10 April 2018 Accepted: 23 June 2018 Citation: European Cardiology Review 2018;13(1):38–41. DOI: https://doi.org/10.15420/ecr.2018.11.1 Correspondence: Alberto Lorenzatti, DAMIC Medical Institute, Av. Colon 2057, Cordoba, Argentina. E: alorenzatti@damic.com.ar

Coronary artery disease (CAD) is the leading cause of death in most countries. Compelling evidence from epidemiological, genetic and clinical studies as well as experiments in animal models has unquestionably established that elevated concentrations of cholesterol (mainly transported by LDL particles) promote atherosclerotic lesions.1 Although statin-based lipid-lowering therapies have been shown to reduce major CV events, even after a strong reduction in LDL cholesterol levels there is still a significant residual risk that cannot be ignored. Despite continuous advances in the treatment of acute and chronic coronary syndromes with catheter- and pharmacotherapybased interventions, additional therapies are needed to reduce the rate of recurrent CV events, which remains too high.2,3

Inflammation and Atherosclerosis: New Insights into an Old Story Classically, atherosclerosis was considered to be a degenerative disease caused by the continuous accumulation of cholesterol in the arterial intima. Furthermore, the idea that atherosclerosis is a predominantly lipid-driven disease has dominated the field of CV diseases for many years. However, over the last few decades, the concept of atherogenesis has changed as a result of new evidence that atherosclerosis is linked to a chronic low-grade inflammation of the vessel wall. In fact, the notion that atherosclerosis carries features of an inflammatory disease has been suspected since the 19th century, based on pathological observations made by Rudolf Virchow, Karl Rokitansky and others.4 The concept that inflammation may play an

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important role in atherosclerosis is one that has grown in parallel with the pathology itself for more than a century. Nevertheless, it is only in recent years that chronic inflammation has become recognised as a pivotal factor in the development of CAD. Dr Russell Ross, in a classic review on mechanisms of atherosclerosis in 1999, stated: “Atherosclerosis, an inflammatory disease”.5 It is recognised that in atherosclerosis, inflammation starts and evolves in response to cholesterol accumulation in the arterial intima of the large and medium arteries. However, new insights into innate immunity have shifted the understanding of the events that initiate and drive the inflammation. This has changed several concepts regarding the pathogenesis of the inflammatory disorders and made it clear that innate and adaptive immune responses play a pivotal role throughout the initiation, progression, and clinical consequences of atherosclerotic diseases. It is now known that one of the initial stages involves endothelial cell activation and the recruitment of inflammatory cells to the vessel wall, leading to a wide array of monocyte-derived macrophages, among other cells and proinflammatory cytokines.6–8 Recently, another factor within atherosclerotic plaques, the cholesterol crystal, has been identified as the predominant endogenous danger signal that initiates an inflammatory response via stimulation of the caspase-1-activating NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome.9 As a result of retention of lipoproteins in the

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Anti-inflammatory Interventions in Coronary Artery Disease vessel wall, cholesterol accumulation may result in the formation of cholesterol crystals, which are taken up by macrophages and elicit an inflammatory reaction through the activation of the NLRP3 inflammasome, leading to an amplifying cascade of immune responses. Therefore, cholesterol crystals may be an initiating and/or an exacerbating factor in atherosclerosis by inducing cell injury and apoptosis.9 The major function of NLRP3 is to sense phagocytosed material and relay the signal to caspase-1, resulting in proteolytic cleavage and secretion of interleukin (IL)-1beta (pro-interleukin) as bioactive IL-1beta and IL-18, ultimately leading to increased production of other downstream inflammatory cytokines.10 IL-1beta and IL-6, among other systemic inflammatory mediators such as TNF-alpha, are then released into the circulation, leading to hepatic production of C-reactive protein (CRP).11 Consequently, the NLRP3 inflammasome has now been identified as a cross-link between inflammation and cholesterol metabolism in atherosclerosis (Figure 1).12

Targeting Inflammation in CAD Despite compelling data from studies in animals and humans, the final confirmation of the inflammatory hypothesis of atherosclerosis has remained elusive. Serum biomarkers of inflammation, such as high-sensitivity CRP (hs-CRP), were independently shown to predict the risk of CV disease in observational studies.13,14 In addition, as treatment with statins reduces the levels of both LDL cholesterol and CRP, with a concurrent reduction in the number of CV events, the idea of targeting inflammation as a way of reducing CAD mortality and morbidity has received strong support. Indeed, the role of hs-CRP in CV disease prevention became clearer after the publication of the results of the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study in 2008.15 In the JUPITER study, the degree of CRP lowering following statin therapy was significant and the therapeutic benefit of this intervention independent of the lipid-lowering effect was also predicted.16 In addition, a pre-specified analysis showed that a lower number of CV events were observed in patients who achieved both very low LDL cholesterol (<1.81 mmol/l) and low hs-CRP (<1 mg/l) levels. Recently, in secondary prevention IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), this relationship between CV events (CV death, major coronary event, or stroke) and LDL cholesterol and hs-CRP levels was analysed in patients randomly assigned to simvastatin monotherapy or a combination of simvastatin and ezetimibe. In the 15,179 individuals studied, simvastatin plus ezetimibe significantly increased the likelihood of reaching the prespecified dual target of LDL cholesterol <1.81 mmol/l and hs-CRP <2 mg/l one month after randomisation. Those achieving both targets (39 %)had lower primary endpoint rates than those meeting neither target (14 %) (38.9 % versus 28.0 %; adjusted HR 0.73; 95 % CI [0.66– 0.81]; p<0.001).17 Although the addition of ezetimibe increased the likelihood of target achievement, the specific choice of agent used to reach the target did not have any influence on the outcome.17 Interestingly, this approach (lower values for both LDL cholesterol and hs-CRP being desirable) seemed to work even at low LDL cholesterol levels. In IMPROVE-IT, where a significant number of patients had an on-treatment LDL cholesterol level of <1.3 mmol/l, the rates of the primary endpoint were decreased in all subgroups when a

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Figure 1: Inflammation and Cholesterol Metabolism in Atherosclerosis Cholesterol crystals Monocyte/ macrophage

NLRP3 inflammasome

IL-1beta

Vessel wall Atherosclerotic lesion

TNF-alpha

IL - 6

CRP

Liver

Canakinumab (CANTOS) (+) Low-dose methotrexate (CIRT) (?)

? Cardiovascular events

hs-CRP

The NLRP3 inflammasome has now been identified as a cross-link between inflammation and cholesterol metabolism in atherosclerosis. In CANTOS, canakinumab targeted IL-1beta with positive results, whereas in CIRT, low-dose methotrexate was used to explore IL-6 blockage, and the results will be published later this year. CANTOS = Canakinumab Antiinflammatory Thrombosis Outcomes Study; CIRT = Cardiovascular Inflammation Reduction Trial, hs-CRP = high-sensitivity C-reactive protein; IL = interleukin, TNF = tumour necrosis factor.

lower exploratory target of LDL cholesterol <1.3 mmol/l and hs-CRP <1 mg/l were applied. Therefore, a fundamental question remains about whether or not inflammation can still play a significant role in patients who achieve ‘ultra low’ LDL cholesterol levels such as ≤0.78 mmol/l when, for example, treated with proprotein convertase subtilisin/kexin type 9 inhibitors, which have been shown to be unable to modify hs-CRP levels.18 Independent of their LDL-lowering capacity, statins have also been shown to attenuate inflammation.19 However, despite their success in reducing inflammation, LDL cholesterol levels and CV events, the major issue of targeting inflammation remained unresolved. Statins did not provide a proof of inflammation causality in atherosclerosis. The only way of resolving this issue by was testing the inflammatory hypothesis of atherosclerosis, without reducing LDL cholesterol levels and directly randomising patients to be targeted for anti-inflammatory therapies.

CANTOS: the Eagerly Awaited Proof of Concept Of the various pathways and inflammatory mediators that have been implicated in atherogenesis, cytokine IL-1 of the innate inflammatory response is considered to be a ‘master cytokine’ in local and systemic inflammations. It also seems to play a central role in the atherosclerotic process.20 Furthermore, blocking IL-1 activity has revealed a pathological role of this cytokine in a broad spectrum of diseases, including heart failure and diabetes.21,22 Other related polypeptides IL-1alpha, IL-1beta, and the IL-1 receptor antagonist (IL-1Ra) are constituents of the IL-1 family, and are predominantly synthesised by mononuclear phagocytes and endothelial cells in response to microbial or endogenous stimulus triggers such as cholesterol crystals.23 Classical risk factors, such as dyslipidemia, diabetes, smoking or hypertension, and circulating levels of IL-1beta have been associated with CAD, along with higher concentrations of IL-1beta and IL-1Ra in atherosclerotic coronary arteries compared with normal arteries.24 Similarly, NLRP3 inflammasome and downstream cytokine (IL-1beta and IL-18) levels were linked with the severity of CAD, and variations in their levels were seen in patients with acute MI. In addition, an increase in the plasma levels of IL-1beta and IL-18 was associated with

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Pharmacotherapy CAD severity. These results revealed that the increased expression of NLRP3 and downstream cytokines might be reflected in CAD severity.25 This pathophysiology background reinforced by a number of studies supported the rationale for specifically targeting IL-1beta, because IL-1alpha may participate in the host defence.22 Neutralising IL-1beta antibodies has been shown to prolong drug efficacy by several weeks after the cessation of therapy. This implies that only a low dose is required to treat an IL-1beta-mediated disease, which is an emerging and optimal strategy for chronic diseases such as CAD.23 CANTOS was the first large randomised controlled clinical study to examine the use of canakinumab, a fully human anti-IL-1beta monoclonal antibody, in the prevention of CV events in subjects with prior MI and elevated levels of hs-CRP, despite undergoing the usual therapy including high statin doses, and a baseline LDL cholesterol level of 2.12 mmol/l. The study included 10,061 subjects and was shown to reduce the primary endpoint of MI, stroke, or CV death by 15 % with a dosage of either 150 mg or 300 mg every three months. No change in LDL cholesterol was seen, whereas large concomitant reductions in hs-CRP and IL-6 were produced.26 The secondary endpoint, which included urgent revascularisation, revealed an even more significant result, with a 17  % relative risk reduction over a median follow up of 3.7 years.26 In addition, demonstrating the importance of inflammation in multiple systemic disorders, the inhibition of IL-1beta in the CANTOS also reduced incident lung cancer and lung cancer mortality by more than half in a dose-dependent manner.27 It is important to note that in CANTOS, among the included patients who represent a high-risk group characterised by a median hs-CRP of 4.1 mg/l, 40 % had diabetes, there was a significant number of smokers, and four out of five had already undergone revascularisation. Thus, the incidence rate for CV events in the placebo group was roughly two times higher than contemporary secondary prevention studies. Most importantly, the effect on CV endpoints was strongest in those who were identified as ‘responders’ based on the fact that their achieved hs-CRP levels during the study were below the median hs-CRP in the overall population, and in this group the relative risk reduction amounted to 27  % (p<0.001). Among these robust responders, CV mortality and all-cause mortality were reduced. In addition to these clinically relevant reductions in CV outcomes, other pro-inflammatory diseases, such as arthritis, osteoarthritis, and gout, were significantly reduced. Nevertheless, there was no significant difference in all-cause mortality (HR for all canakinumab doses versus placebo 0.94; 95 % CI [0.83–1.06]; p=0.310). The fact that may limit the use of this drug in ischaemic heart disease is that canakinumab was associated with a higher incidence of fatal infection, small in proportion but significant.

hs-CRP concentrations ≥2 mg/l (HR 0.90; 95 % CI [0.79–1.02]; p=0.11). Similarly, canakinumab treated patients who achieved on-treatment hs-CRP concentrations <2 mg/l, showed a significant reduction in both CV mortality (HR 0.69; 95  % CI [0.56–0.85]; p=0.0004) and all-cause mortality (HR 0.69, 95 % CI [0.58–0.81], p<0.0001), whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hs-CRP concentrations of ≥2 mg/l.28 By confirming the inflammatory hypothesis of atherosclerosis, CANTOS is a possible game changer. However, whether canakinumab can be included among the drugs to be used in CAD patients will depend on additional studies. In the meantime, secondary prevention patients with elevated CRP who clearly respond to a single dose of canakinumab by significantly reducing their hs-CRP levels, seem to be candidates for receiving the treatment.28 Related to this, observational studies in patients with rheumatoid arthritis (RA) support the idea that the immune modulator drug methotrexate has a favourable impact by attenuating the systemic inflammation and decreasing CV events.29 Moreover, a systematic review of the effect of methotrexate on CV disease in patients with RA concluded that its use was associated with a reduced risk of CV events, suggesting that methotrexate improves concomitant atherosclerosis in such patients.30 This favourable effect has been corroborated in a recent meta-analysis, where methotrexate was associated with a 21 % (95  % CI [0.73–0.87]; p<0.001) lower risk for total CV disease and an 18 % (95 % CI [0.71–0.96]; p=0.01) lower risk for MI.31 The Cardiovascular Inflammation Reduction Trial (CIRT) used methotrexate in patients with chronic atherosclerosis and either diabetes or metabolic syndrome, who were being randomised to low-dosage methotrexate, 15–20 mg/week or placebo. The trial was recently stopped after 4,786 patients of the planned 7,000 patients had been enrolled.32 The sponsor of the study, the National Heart, Lung, and Blood Institute, stated that there were no substantive safety concerns but the trial had accrued enough data to answer the main question of the study, and these results will be presented at the American Heart Association meeting in November 2018.

In conclusion, the anti-inflammatory therapy of targeting the IL-1beta innate immunity pathway with canakinumab at a dosage of 150 mg every three months significantly reduced the recurrence of CV events in patients with elevated hs-CRP, compared with placebo. This beneficial effect was independent of any lowering effects on cholesterol levels.

Colchicine, a classic anti-inflammatory drug used to treat gout, is also being tested for CV protection and represents a potentially useful agent for inflammation in atherosclerosis. Colchicine reduces the downstream production of hs-CRP, and recently a newly discovered mechanism has been described. Colchicine appears to block the crystal-induced activation of the NLRP3 inflammasome, thereby decreasing secretion of the pro-inflammatory cytokines IL-1beta and IL-18.33 In a preliminary open-label trial of 532 patients, low-dose colchicine showed promise for secondary prevention and, interestingly, the active intervention significantly reduced the primary endpoint of recurrent ACS, cardiac arrest or non-embolic stroke (HR 0.33; 95 % CI [0.18–0.59] p=0.001). Following on from CIRT, two double-blind, placebo-controlled trials are on-going; Low Dose Colchicine for secondary prevention in table Coronary Heart Disease (LoDoCo2) and Colchicine Cardiovascular Outcomes Trial (COLCOT) in patients after ACS.

Interestingly, in a recently published secondary analysis, individuals allocated to canakinumab who achieved hs-CRP concentrations <2 mg/l had a 25 % reduction in major adverse cardiac events (multivariable adjusted HR 0.75; 95 % CI [0.66–0.85]; p<0.0001), whereas no significant benefit was observed among those with on-treatment

Canakinumab is currently the only anti-inflammatory agent that has been proven to reduce CV events in patients with elevated markers of inflammation. At the time of writing, we are awaiting the results of other trials with alternative agents, including low dose methotrexate and colchicine.

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Anti-inflammatory Interventions in Coronary Artery Disease Among these, individuals who respond with a robust reduction in hs-CRP level -reaching <2 mg/L after an initial canakinumab dose-, would be the ideal candidates for this anti-inflammatory

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approach since a significant risk reduction in both total and cardiovascular mortality was observed in this specific group of patients in CANTOS study.28 n

14. E  merging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010;375:132–40. https://doi.org/10.1016/S0140-6736(09)61717-7; PMID: 20031199. 15. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. https://doi.org/10.1056/NEJMoa0807646; PMID: 18997196. 16. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Am J Cardiol 2010;106:204–9. https://doi.org/10.1016/j.amjcard.2010.03.018; PMID: 20599004. 17. Bohula EA, Giuliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 2015;132:1224–33. https://doi.org/10.1161/CIRCULATIONAHA.115.018381; PMID: 26330412. 18. Sabatine MS, Giuliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017, 376:1713–22. https://doi.org/10.1056/NEJMoa1615664; PMID: 28304224. 19. Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005;46:1855–62. https://doi.org/10.1016/j.jacc.2005.05.085; PMID: 16286171. 20. Lorenzatti A, Retzlaff B. Unmet needs in the management of atherosclerotic cardiovascular disease: Is there a role for emerging anti-inflammatory interventions? Int J Cardiol 2016;221:581–6. https://doi.org/10.1016/j.ijcard.2016.07.061; PMID: 27420583. 21. Dinarello CA. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J Immunol 2011;41:1203–17. https://doi.org/10.1002/eji.201141550; PMID: 21523780. 22. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11:633–52. https://doi.org/10.1038/nrd3800; PMID: 22850787. 23. Qamar A, Rader DJ. Effect of interleukin 1β inhibition in cardiovascular disease. Curr Opin Lipidol 2012;23:548–53. https://doi.org/10.1097/MOL.0b013e328359b0a6; PMID: 23069985. 24. Galea J, Armstrong J, Gadsdon P, et al. Interleukin-1 beta in coronary arteries of patients with ischemic

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Cardiovascular Implications of Sphingomyelin Presence in Biological Membranes Petros Kikas, George Chalikias, and Dimitrios Tziakas Democritus University of Thrace, Alexandroupolis, Greece

Abstract Sphingomyelin (SM) is a type of sphingolipid found within plasma, cellular membranes and plasma lipoproteins. Here we highlight the basic biochemical features of SMs and their role in biological membranes. We further discuss evidence of the association between SM and cardiovascular diseases such as atherosclerosis, valvular disease, heart failure and diabetes mellitus.

Keywords Sphingomyelin, sphingolipids, cardiovascular implications Disclosure: The authors have no conflicts of interest to declare. Received: 07 Sept 2017 Accepted: 07 March 2018 Citation: European Cardiology Review 2018;13(1):42–5. DOI: https://doi.org/10.15420/ecr.2017:20:3 Correspondence: Professor Dimitrios Tziakas, Cardiology Department, University Hospital of Alexandroupolis, Dragana, Alexandroupolis 68100, Greece. E: dtziakas@med.duth.gr

Sphingolipids are one of the major categories of lipids and beyond their role as structural membrane components they have important functions as signalling molecules in a wide array of biological processes. They are composed of two key lipid building blocks – long-chain bases (usually sphingosine or 1,3-dihydroxy-2-amino-4octadecene) and fatty acids – and use a glycerol-based backbone to which acyl chains are attached.1,2 Sphingomyelins (SMs) are among the most common sphingolipids in many mammalian cells and tissues, especially in the membranous myelin sheath that surrounds nerve cell axons.3 SMs have significant structural and functional roles in the cell such as creating unique lateral structures (lipid rafts and ordered domains) in membranes, binding to and functional regulation of membrane-spanning proteins and involvement in cell signalling events.3 They play an important role in the regulation of plasma membrane and cell cholesterol homeostasis.3 SM was first isolated from brain tissue by German chemist Johann LW Thudicum in the 1880s.4 In 1927 the structure of SM was first reported by Pick and Bielschowsky; SM is an N-acyl-sphingosine-1phosphorylcholine, consisting of a phosphocholine head group, a sphingosine and a fatty acid.5 The most common long-chain base in SM is 1,3-dihydroxy-2-amino-4-octadecene (sphingosine or d18:1). The most common N-linked acyl chain of SMs in mammalian peripheral cells is palmitic acid (16:0), whereas stearic acid (18:0) is more common in neural tissue SMs. Long-chain fatty acids (e.g. 24:0 and 24:1) are also common constituents of the SMs found in most tissues.3 SMs are synthesised in the endoplasmic reticulum, where they can be found in low levels, and in the trans Golgi.6 The first step in SM synthesis is the condensation of L-serine and palmitoyl-coenzyme A. This reaction is catalysed by serine palmitoyltransferase and yields 3-keto-dihydrosphingosine, which is reduced to dihydrosphingosine. Dihydrosphingosine undergoes N-acylation followed by desaturation

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to generate ceramide, which has a central role in sphingolipid metabolism.3,7 These reactions occur on the cytosolic surface of the endoplasmic reticulum. Subsequently, ceramide is delivered to the Golgi apparatus where it is converted to SM or glucosylceramide. In most mammalian cell types the majority of ceramide is converted to SM in the lumen of the trans Golgi by an SM synthase (SMS) enzyme named SMS1, which catalyses the transfer of phosphocholine from phosphatidylcholine to ceramide, yielding a diacylglycerol side product.3,7 A second enzyme, SMS2, resides at the plasma membrane and may convert locally produced ceramide to SM.3,7 An alternative pathway of SM synthesis has been postulated in which ceramide is first converted to ethanolamine phosphorylceramide via transfer of the head group from phosphatidylethanolamine.7 Ethanolamine phosphorylceramide is then converted to SM by stepwise methylation. Although this pathway has been demonstrated in isolated membrane fractions from rat brain and liver, its precise contribution to the de novo synthesis of SM remains to be established.7 Since major SMS activity is found in the luminal trans Golgi and the plasma membranes, it is not surprising that SM is enriched in membranes derived from trans Golgi and in the plasma membrane (including the endosomal recycling compartment). The asymmetric location of SMS activity (luminal trans Golgi and outer leaflet of plasma membranes) may explain why SMs are enriched at the plasma membrane with a greater concentration on the outer than the inner leaflet.3,6,8 In humans, SMs comprise nearly 85 % of all sphingolipids and 10–20 mol % of the total plasma membrane lipids. SMs comprise 4–18  % of all sarcolemma membrane lipids with 93  % present in the outer leaflet.8

The Role of Sphingomyelin in Biological Membranes The presence of SM in biological membranes is associated with various critical functions. SMs accumulate in the exoplasmic leaflet of the

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Sphingomyelin and Cardiovascular Implications plasma membrane where their high packing density and affinity for sterols help create a rigid barrier to the extracellular environment.7 Under this notion, the membranous myelin sheath that surrounds nerve cell axons is particularly rich in SMs, which may suggest a role as an insulator of nerve fibres.9,10 SM presence in the plasma membrane directly affects cholesterol homeostasis.11,12 The addition of SM to cells has been shown to increase cholesterol biosynthesis and affect LDL binding to cell surface receptors and subsequent internalisation.13 Together they form SM/ sterol-rich domains that often are more ordered than the surrounding phase in biological membranes.14 The growing body of evidence regarding their favourable interaction with sterols indicates that SM may be a key a regulator of cholesterol distribution within cellular membranes and cholesterol homeostasis in cells.14 In addition, excess levels of SM in the red blood cell membrane (i.e. abetalipoproteinemia) cause increased lipid accumulation in the outer leaflet of the red blood cell plasma membrane, which results in abnormally shaped red cells called acanthocytes.15 The SM pool in the plasma membrane acts as a reservoir of lipid signalling molecules, the liberation of which is catalysed by acidic or neutral SMSs in response to a variety of biological stimuli. SM metabolites such as ceramide,16 sphingosine17,18 and sphingosine 1-phosphate17,18 are emerging as critical regulators of cell proliferation, differentiation and apoptosis. 7 The ability of SM to function as a precursor of signalling molecules in a wide array of biological processes is extensively reviewed elsewhere.19 As SMs have a strong, inherent capacity to form microdomains, their production in the trans Golgi may affect the lateral organisation of other membrane molecules and are thus associated with the formation of lipid rafts, caveoles and other micro-membrane structures involved in various cellular processes (including endocytosis, intracellular trafficking, and signal transduction by membrane receptors, cell–cell communication and host–pathogen interactions).7,10,20-23 SM synthesis in the trans Golgi may create a local pool of diacylglycerol, which leads to protein kinase D recruitment and the formation of secretory vesicles.7,10,24

sphingolipids were correlated with histological markers of plaque instability and also induced an inflammatory response in human coronary artery smooth muscle cells. SM and ceramide were also found to be positively correlated with lipid plaque burden.27 A study of hypercholesterolaemic rabbits found that SMs were relatively abundant within atherosclerotic lesions compared with other lipids.28 Furthermore, strikingly elevated intra-platelet levels of triglycerides and SM were found in patients with ST-elevation MI in comparison with matched controls.29 Several studies have assessed the association between circulating plasma SM levels and incidence of cardiovascular disease, with conflicting results. Fernandez et al. showed that SM (38:2) levels was the only lipid species of its class to be associated with increased risk of future cardiovascular disease.30 In another study, patients with stable angina, unstable angina or acute MI showed higher plasma SM and ceramide levels as well as higher SMS activity compared with healthy individuals.31 However, in the population-based Multi-Ethnic Study of Atherosclerosis, a high plasma SM level was not associated with an increased risk of incident coronary heart disease in adults free of clinical cardiovascular disease at baseline.32 Recently, erythrocytes have received considerable attention as significant players in accelerating plaque progression, with observations of erythrocytes being ‘driven’ to the plaque lipid core via intraplaque haemorrhages.33 Assessing the sphingolipid content of erythrocyte membranes, Zhang et al. demonstrated that SM levels were elevated in patients with an acute coronary syndrome compared with patients with stable angina.34 However, no differences were found between patients with stable coronary artery disease and healthy individuals regarding SM content in erythrocyte membranes. In the same study, a significant correlation between plasma SM levels, erythrocyte membrane SM content and lipoprotein alpha(a) levels were shown. These observations suggest a link between SM content of erythrocyte membrane and clinical instability in coronary artery disease, which may reflect another potential source of atheromatous plaque instability via intraplaque haemorrhages. Therefore, the SM content of erythrocyte membranes could serve as a marker for coronary artery disease activity independent of other risk factors and clinical features.34

Diabetes The proportion of SM within a membrane as well as SM structural configuration contribute to membrane thickness and recruitment of specific integral proteins, thereby modulating membrane structural integrity and function.25,10 Furthermore, published evidence suggests that SM interacts with these integral membrane proteins, modulating their functional role.10 Interdigitation occurs when a long acyl chain in SM located in one leaflet penetrates through the bilayer into the opposite leaflet. Such interdigitation has been shown to affect the diffusion rates in opposing glycerophospholipid leaflets, suggesting interleaflet coupling with possible biological significance.26,10

Cardiovascular Implications Associated with Sphingomyelin

As part of the Finnish Diabetic Nephropathy Study, 326 patients with type 1 diabetes were studied for presence of diabetic renal disease.35 Serum levels of SM and large HDL particles were the strongest predictors after adjustment of established kidney injury biomarkers. In addition, SM levels assessed in serum was correlated significantly with 24 hour albumin excretion rate. In contrast, another study demonstrated that compared with healthy controls, patients with impaired fasting glucose levels or type 2 diabetes had significantly reduced serum concentrations of glycerophospholipids and SMs, even after adjusting for age, gender and BMI or even when separately analysed for those not receiving lipid-modifying medications.36 The authors suggested that the decrease in the SM pool in diabetes could potentially contribute to increased oxidative stress and reduced insulin secretion, resulting in hyperglycaemia secondary to an inability to compensate for reduced insulin sensitivity.36

Atherosclerosis/Thrombosis A study of human carotid plaques showed that levels of several sphingolipids (including SM) were increased in plaques associated with symptoms and correlated with inflammatory cytokines.27 All

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Lipoproteins SM is the most abundant sphingolipid in lipoproteins. Very low density liopoprotein/LDL and HDL comprise approximately 63–75 % and

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Basic Science 25–35 % of SMs, respectively.37 SM is slightly more abundant (13  %) in large light HDL2 particles than in small dense HDL3 particles per millilitre of plasma.38 The decrease in SM content in HDL particles associated with smaller and more dense HDL molecules was shown to correlate with the atheroprotective functionality of HDL, such as cholesterol efflux capacity, antioxidative activity toward LDL oxidation, antithrombotic activity in human platelets, anti-inflammatory activity and anti-apoptotic activity.38 In another study, anti-apoptotic and antioxidative activities of small dense HDL particles were associated with depletion in SM within the same molecules.39 This association between structural reformation of HDL molecules and their anti-atherogenic properties (mainly their capacity for cholesterol efflux) was explained by the negative impact that SM had on molecular surface fluidity and lecithin:cholesterol acyltransferase activity. LDL present in atherosclerotic plaques has higher SM levels than plasma LDL; this is mainly due to de novo synthesis in the aorta.37,40 Furthermore, early studies have shown that advanced aortic wall atherosclerosis is characterised by increased SM proportion.41 Schissel et al. have shown that in rabbit aorta and human atherosclerotic lesions, arterial-wall SMS activity hydrolyses the SM of retained LDL leading to LDL aggregation, an important event regarding the initiation and progression of atherosclerosis.37,42

mitral valve regurgitation. Furthermore, several published cases of patients with Niemman–Pick disease report severe mitral regurgitation as a clinical manifestation of the disease, thus suggesting an association between progressive accumulation of SM in lysosomes and degeneration of cardiac valves.46

Cardiomyopathies Ceramides are produced by either de novo synthesis or hydrolysis of SM catalysed by acid and/or neutral SMS.47 Accumulation of cardiac ceramides in the post-ischaemic heart is mediated by acid SMS and not by de novo sphingolipid synthesis.48 Therefore, the presence of ceramides in the post-ischaemic myocardium is most likely due to SM degradation by SMS, thus suggesting a detrimental role of SM in a wide variety of cardiomyopathies, especially in ischaemic cardiomyopathy. However, a recent study in mice showed that inhibition of acid SMS does not result in improved heart function or survival after an induced MI despite reducing ischaemia-induced ceramide accumulation.49 In a rodent model of lipotoxic cardiomyopathy, mice exhibited increased lipid uptake and oxidation, ceramide accumulation and a dilated cardiomyopathy, with decreased functional cardiomyocyte shortening.49 In contrast, we must emphasise that within this cardiolipotoxic model, ceramides were de novo synthesised within the myocardium and that the mechanism of this cardiac dysfunction was not clear.

Valvular Disease Recently, the presence of intra-leaflet haemorrhages and the associated increase in intra-leaflet lipid accumulation has been recognised as a novel mechanism for valve tissue degeneration. In a study by Lehti et al., higher SM:phosphatidylcholine ratio as well as higher proportions of lysophosphatidylcholine and unesterified cholesterol were found in lipid particles isolated from patients with stenotic aortic valves compared with non-stenotic counterparts.43 Under the same notion, using a metabolomics approach in aortic tissue, Doppler et al. showed that levels of SM were significantly increased in patients with bicuspid aortic valve disease undergoing ascending thoracic aorta surgery and with tricuspid aortic valve associated aortic dissection compared with controls.44 Niemann–Pick disease is a rare lysosomal storage disease caused by deficient activity of acid SMS and the accumulation of SM within cells; these abnormalities occur especially in the monocyte–macrophage system. In a prospective, cross-sectional survey study, McGovern et al. demonstrated that most patients with Niemann–Pick disease had low HDL cholesterol, high total cholesterol, high triglyceride and high LDL levels compared with control subjects.45 Two-dimensional echocardiograms performed during the study, showed abnormalities in the majority of patients with Niemann–Pick disease, most commonly

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As part of the Alberta Heart Failure Etiology and Analysis Research Team (HEART) project, ambulatory patients with clinical diagnosis of heart failure (HF; with preserved or reduced ejection fraction) and agematched non-HF controls were selected for metabolomic analysis.50 Compared with non-HF control subjects, patients with HF with preserved ejection fraction had lower levels of phosphatidylcholines and SMs. Furthermore, in a recent study enrolling patients with either ischaemic or non-ischaemic cardiomyopathy, healthy controls and patients with pulmonary diseases, three specific metabolomic features belonging to the lipid classes of SMs, triglycerides and phosphatidylcholines together with N-terminal pro-B-type natriuretic peptide (NT-proBNP) distinguished patients with HF from healthy controls.51 In addition, the diagnostic accuracy of this combination was significantly superior compared with the diagnostic accuracy of NT-proBNP alone.51

Conclusion Dysregulation of sphingolipid synthesis and transport is associated with cardiovascular disease, diabetes and other metabolic disorders. However, further studies are needed to identify the molecular and pathophysiological pathways by which certain sphingolipids species are associated with different pathologies. n

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Artery Dis 2014;25:230–5. https://doi.org/10.1097/ MCA.0000000000000079; PMID: 24589572. 32. Y  eboah J, McNamara C, Jiang XC, et al. Association of plasma sphingomyelin levels and incident coronary heart disease events in an adult population: MultiEthnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:628–33. https://doi.org/10.1161/ ATVBAHA.109.199281; PMID: 20032291. 33. Michel JB, Martin-Ventura JL, Nicoletti A, Ho-Tin-Noé B. Pathology of human plaque vulnerability: mechanisms and consequences of intraplaque haemorrhages. Atherosclerosis 2014;234:311–9. https://doi.org/10.1016/j. atherosclerosis.2014.03.020; PMID: 24726899. 34. Zhang J, Tu K, Xu Y, et al. Sphingomyelin in erythrocyte membranes increases the total cholesterol content of erythrocyte membranes in patients with acute coronary syndrome. Coron Artery Dis 2013;24:361–7. https://doi. org/10.1097/MCA.0b013e328362228f; PMID: 23652364. 35. Makinen VP, Tynkkynen T, Soininen P, et al. Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study). Metabolomics 2012;8:369–75. https://doi. org/10.1007/s11306-011-0343-y; PMID: 22661917. 36. Xu F, Tavintharan S, Sum CF, et al. Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics. J Clin Endocrinol Metab 2013;98:E1060–5. https://doi.org/10.1210/jc.2012-4132; PMID: 23633210. 37. Iqbal J, Walsh MT, Hammad SM, et al. sphingolipids and lipoproteins in health and metabolic disorders. Trends Endocrinol Metab 2017;28:506–18. https://doi.org/10.1016/j. tem.2017.03.005; PMID: 28462811. 38. Camont L, Lhomme M, Rached F, et al. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, antiinflammatory, and antiapoptotic functionalities. Arterioscler Thromb Vasc Biol 2013;33:2715–23. https://doi.org/10.1161/ ATVBAHA.113.301468; PMID: 24092747. 39. Kontush A, Therond P, Zerrad A, et al. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities. Arterioscler Thromb Vasc Biol 2007;27:1843–9. https://doi. org/10.1161/ATVBAHA.107.145672; PMID: 17569880. 40. Guyton JR, Klemp KF. Development of the lipid-rich core in human atherosclerosis Arterioscler Thromb Vasc Biol 1996;16:4–11. https://doi.org/10.1161/01.ATV.16.1.4; PMID: 8548424.

41. B  ottcher CJ, Vangent CM. Changes in the composition of phospholipids and of phospholipid fatty acids associated with atherosclerosis in the human aortic wall. J Atheroscler Res 1961;1:36–46. https://doi.org/10.1016/S0368-1319(61)80052-5. 42. Schissel SL, Tweedie-Hardman J, Rapp JH, et al. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. J Clin Invest 1996;98:1455–64. https://doi.org/10.1172/JCI118934; PMID: 8823312. 43. Lehti S, Käkelä R, Hörkkö S, et al. Modified lipoprotein-derived lipid particles accumulate in human stenotic aortic valves. PLoS One 2013;8:e65810. https://doi.org/10.1371/journal. pone.0065810; PMID: 23762432. 44. Doppler C, Arnhard K, Dumfarth J, et al. Metabolomic profiling of ascending thoracic aortic aneurysms and dissections Implications for pathophysiology and biomarker discovery. PLoS One 2017;12:e0176727. https://doi.org/10.1371/journal. pone.0176727; PMID: 28467501. 45. McGovern MM, Wasserstein MP, Giugliani R, et al. A prospective, cross-sectional survey study of the natural history of NiemannPick disease type B. Pediatrics 2008;122:e341–9. https://doi. org/10.1542/peds.2007-3016; PMID: 18625664. 46. Fotoulaki M, Schuchman EH, Simonaro CM, et al. Acid sphingomyelinase-deficient Niemann-Pick disease: novel findings in a Greek child. J Inherit Metab Dis 2007;30:986. https://doi.org/10.1007/s10545-007-0557-3; PMID: 17876723. 47. Nilsson A, Duan RD. Absorption and lipoprotein transport of sphingomyelin. J Lipid Res 2006;47:154–71. https://doi. org/10.1194/jlr.M500357-JLR200; PMID: 16251722. 48. Klevstig M, Ståhlman M, Lundqvist A, et al. Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart. J Mol Cell Cardiol 2016;93:69–72. https://doi.org/10.1016/j.yjmcc.2016.02.019; PMID: 26930027. 49. Park TS, Hu Y, Noh HL, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 2008;49:2101–12. https://doi.org/10.1194/jlr.M800147-JLR200; PMID: 18515784. 50. Zordoky BN, Sung MM, Ezekowitz J, et al. Metabolomic fingerprint of heart failure with preserved ejection fraction. PLoS One 2015;10:e0124844. https://doi.org/10.1371/journal. pone.0124844; PMID: 26010610. 51. Mueller-Hennessen M, Düngen HD, Lutz M, et al. A novel lipid biomarker panel for the detection of heart failure with reduced ejection fraction. Clin Chem 2017;63:267–77. https://doi.org/10.1373/clinchem.2016.257279; PMID: 28062623.

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Assessing the Haemodynamic Impact of Coronary Artery Stenoses: Intracoronary Flow Versus Pressure Measurements Valérie E Stegehuis, Gilbert WM Wijntjens, Tadashi Murai, Jan J Piek, Tim P van de Hoef AMC Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

Abstract Fractional flow reserve (FFR)-guided percutaneous coronary intervention results in better long-term clinical outcomes compared with coronary angiography alone in intermediate stenoses in stable coronary artery disease (CAD). Coronary physiology measurements have emerged for clinical decision making in interventional cardiology, but the focus lies mainly on epicardial vessels rather than the impact of these stenoses on the myocardial microcirculation. The latter can be quantified by measuring the coronary flow reserve (CFR), a combined pressure and flow index with a strong ability to predict clinical outcomes in CAD. However, combined pressure-flow measurements show 30–40 % discordance despite similar diagnostic accuracy between FFR and CFR, which is explained by the effect of microvascular resistance on both indices. Both epicardial and microcirculatory involvement has been acknowledged in ischaemic heart disease, but clinical implementation remains difficult as it requires individual proficiency. The recent introduced pressure-only index instantaneous wave-free ratio, a resting adenosine-free stenosis assessment, led to a revival of interest in coronary physiology measurements. This review focuses on elaborating the coronary physiological parameters and potential of combined pressure-flow measurements in daily clinical practice.

Keywords Coronary artery stenoses, fractional flow reserve, coronary flow velocity reserve, flow measurements, pressure measurements, microvascular resistance Disclosure: JJP and TPH have served as speaker at educational events organised by Philips-Volcano, St Jude Medical, and/or Boston Scientific, manufacturers of sensorequipped guide wires. GWMW and TM are partially supported by a research grant by Philips-Volcano Corporation. VES has no conflicts of interest to declare. Received: 9 February 2018 Accepted: 18 March 2018 Citation: European Cardiology Review 2018;13(1):46–53. DOI: https://doi.org/10.15420/ecr.2018:7:2 Correspondence: Tim P van de Hoef, Academic Medical Center, University of Amsterdam, AMC Heart Center, Room B2-250, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. E: t.p.vandehoef@amc.nl

The emphasis in ischaemic heart disease (IHD) diagnosis has historically been directed towards the identification of epicardial coronary stenosis by selective coronary angiography, and its management by percutaneous coronary intervention (PCI) or coronary bypass graft surgery. Over the past two decades, the application of coronary physiology techniques to identify the haemodynamic severity of epicardial coronary stenoses to guide decision-making regarding revascularisation has evolved into an indispensable part of IHD management.1 This is mainly attributable to the finding that routine PCI of stenoses deemed significant by coronary angiography (>50 % diameter stenosis) does not lead to improved patient outcomes beyond swift alleviation of angina pectoris.2 The introduction of fractional flow reserve (FFR), a coronary pressure-derived estimate of the impact of the coronary stenosis on coronary flow, has played a pivotal role in this regard.3–5 FFR-guided coronary intervention has been documented to provide equivalent functional and long-term clinical outcomes of IHD management compared with an angiography-guided approach, while reducing the number of revascularisation procedures.6 The results of the pivotal Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME I) and FFR-guided Percutaneous Coronary Intervention plus Medical Treatment versus Medical Treatment Alone in Patients with Stable Coronary Artery Disease (FAME II) studies have led FFR to be endorsed by revascularisation guidelines with a class I level of evidence A recommendation in the setting of stable IHD with angiographically equivocal disease severity and absence

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of noninvasive documentation of myocardial ischaemia.1 However, the results of the FAME II study, evaluating the benefit of PCI over guideline-directed medical therapy in vessels with an abnormal FFRvalue, indicate that over 80 % of patients with abnormal FFR do not suffer from adverse events, while 60 % of these patients did not require PCI during a two years follow-up period.7,8 The finding that a dominant proportion of FFR-positive vessels may not require revascularisation to improve clinical or functional outcomes is confusing in an era when strict adherence to obtained FFR-values is advocated in clinical practice guidelines. The origin of these findings is, at least, partially explained by the difference between coronary pressure-derived estimation of coronary flow impairment due to a stenosis and direct measurement of coronary flow for this purpose.9 This review details the fundamental basis of clinical coronary physiology, and how this relates to the evaluation of coronary stenosis using coronary pressure or coronary flow.

Coronary Pressure-flow Relations: Autoregulation and Metabolic Adaptation Figure 1 illustrates the fundamental coronary pressure-flow relationship. At a given level of myocardial demand, coronary flow remains relatively stable within a physiological range of perfusion pressures. This phenomenon is illustrated by the flow plateau in Figure 1, and is termed coronary autoregulation.10,11 An increase or decrease in myocardial demand leads to a parallel shift of the pressure-flow relationship, which is

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Haemodynamics of Coronary Artery Stenoses

Stenosis Physiology as the Basis for Stenosis Assessment Figure 2 and Figure 3A illustrate the basic physiological behaviour of epicardial coronary stenosis. The pressure loss across a coronary stenosis not only depends on the severity of coronary narrowing, but to a large extent on the magnitude of flow that goes through the coronary artery.17,18 This pressure loss is due to viscous friction losses across the throat of the lesion, and separation losses that occur through acceleration of flow through the stenosis and the formation of eddies at the stenosis exit. Due to the combination of these effects, the pressure loss incurred by a stenosis increases quadratically with an increase in coronary flow (Figure 2A). For the application of coronary physiology in clinical practice, it is important to realise this implies that distal coronary pressure (thus, FFR) decreases (does become more abnormal) when coronary flow through the coronary artery increases (Figure 3B). As such, a severe decrease in coronary pressure can occur with low FFR-values merely due to the presence of high coronary flow. The clinical relevance of decreased coronary pressure in the presence of maintained coronary flow is debated, with studies documenting a relative high prevalence of this phenomenon and suggesting a benign character with favourable clinical outcomes.19,20 This agrees with early experimental findings documenting that decreased coronary pressure of the coronary circulation does not lead to evidence of myocardial ischaemia as long as coronary flow remains stable.21 The opposite of this phenomenon also occurs frequently, where a stenosis is associated with only limited decreased coronary pressure, merely due to the fact that coronary flow does not increase upon pharmacological vasodilation.19,20,22 This may occur in the setting of microvascular disease, or in the setting of focal stenosis superimposed on diffuse epicardial and/or microvascular disease. This phenomenon has been linked to impaired clinical outcomes, which suggests that the sole use of coronary pressure in practice may underestimate the clinical relevance of these stenoses.20,22

Coronary Flow for Stenosis Evaluation Since the myocardium thrives on coronary flow to exert its contractile function,9,21 and coronary flow is the critical determinant of myocardial

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Figure 1: The Coronary Pressure-flow Relationship (2) Hyperaemia

Coronary blood flow

a process termed metabolic adaptation.10,11 Autoregulation and metabolic adaptation together maintain stable coronary flow at a level that meets myocardial demand. Put simply, these processes occur through compensatory adaptation of the coronary resistance vessels, which may vasodilate or vasoconstrict to adapt to perfusion pressure changes or changes in myocardial demand.12 The ability of the coronary resistance vessels to accommodate to such changes can be abolished by the use of potent coronary vasodilators, such as adenosine, papaverine or regadenoson, which override autoregulation by inducing pharmacological vasodilation of the coronary resistance vessels.10,11 Therefore, at maximal vasodilation, the coronary circulation cannot adapt to pressure or metabolic changes, and is perfusion pressure-dependent: an incrementallinear relationship between coronary pressure and flow occurs.13 Note that the relationship is linear, as the relationship is represented by a straight line, but this relationship is not proportional: the relationship does not pass through the zero-pressure intercept. The course of this pressure-flow relationship at maximal vasodilation is variable both within and between patients.14 The zero-pressure intercept is, among others, influenced by changes in heart rate, left ventricular filling pressures and myocardial hypertrophy.10 Similarly, the slope of the pressure-flow relationship in the individual patient changes, among other conditions, in the presence of small vessel disease or abnormal left ventricular function.15,16

Increased myocardial demand Resting conditions (1) Decreased myocardial demand

Pv Pzf

(3) Coronary perfusion pressure

Pw Coronary blood flow at rest (solid lines) is controlled to match myocardial oxygen demand and to counteract variations in perfusion pressure by parallel changes in microvascular resistance, resulting in an autoregulatory plateau. During coronary vasodilatation, control is exhausted and blood flow depends on perfusion pressure (dotted line). The coronary pressure-flow relationship is concave at low perfusion pressures. The zero-flow intercept on the pressure axis (Pzf) slightly exceeds venous pressure (Pv). Straight extrapolation of the hyperaemic pressure-flow relationship results in an incrementalâ&#x20AC;&#x201C;linear relationship that intercepts the pressure axis at the coronary wedge pressure (Pw), which incorporates collateral flow, heart rate and ventricular wall tension. Small vessel disease or abnormal left ventricular function decreases the slope of the pressure-flow relationship (curved arrow). Elevated left ventricular end-diastolic pressure or left ventricular hypertrophy cause a parallel shift to the right (straight arrow). Adapted from van de Hoef, et al., 2013.13

ischaemia,23,24 it seems self-evident that the evaluation coronary flow provides an important tool to identify haemodynamically relevant stenoses. The most widely studied flow-based index for this purpose is the maximal increase in coronary flow that is available upon an increase in myocardial demand: the coronary flow reserve (CFR).17,25 CFR is defined as the ratio of flow during maximal vasodilation to flow during resting conditions, and thereby reflects the reserve vasodilator capacity of the coronary resistance vessels. CFR can be assessed by either the Doppler flow velocity or coronary thermodilution technique.26,27 Doppler flow velocity can be assessed using a Doppler sensor-equipped guide wire and provides the operator with both average flow velocity values as well as the coronary flow velocity profile. Such assessment of Doppler flow velocity has the advantage that its magnitude is intrinsically corrected for the amount of perfused myocardial mass in the arterial distribution by the laws of normalised shear stress, and is therefore relatively independent of perfused myocardial mass.28,29 Coronary thermodilution can be assessed with a temperature-sensitive guide wire using rapid injections of room-temperature saline to obtain mean transit times of the saline boluses. These transit times are inversely relative to absolute coronary flow and allow to calculate CFR. Although CFR is not impacted by myocardial mass-dependence of coronary thermodilution, it is important to realise that absolute mean transit time values are influenced by the amount of subtended myocardial mass.30 Moreover, coronary thermodilution measurements require forced quick injection of room-temperature saline, which may affect coronary haemodynamics and may therefore affect flow values particularly during non-vasodilated conditions.31 Finally, coronary thermodilution requires a hyperaemic plateau phase to provide sufficient time for the repeated saline boluses, which is usually obtained using intravenous adenosine infusion. However, intravenous adenosine infusion frequently leads to a decrease in blood pressure. Since maximal coronary flow at coronary vasodilation depends on coronary perfusion pressure, such decreases in blood pressure due to intravenous adenosine infusion

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Interventions Figure 2: Diagram of Stenosis Flow Field Flow separation

Viscous friction and flow acceleration

Coronary blood flow (v)

vn

Dn

Ds

vs

Pa

vd

Microcirculation

Pd

∆P

P

v

The pressure gradient across a stenosis is determined by the sum of viscous and separation losses. Pressure is lost owing to viscous friction along the entrance and throat of the narrowed section (Poiseuille’s law). In addition, the area reduction leads to convective acceleration along the stenosis, whereby pressure is converted to kinetic energy (Bernoulli’s law). Flow separation and the formation of eddies prevent complete pressure recovery at the exit. Measurement of intracoronary haemodynamics includes proximal perfusion pressure (Pa), coronary pressure and flow velocity distal to the stenosis (Pd and Vd, respectively), and the venous pressure (Pv), which is usually assumed to be negligible. Delta-P is the difference between Pd and Pa. Normal diameter (Dn), stenosis diameter (Ds), proximal velocity (Vn) and stenosis velocity (Vs) are indicated. Adapted from van de Hoef, et al., 2013.13

Figure 3: Relationship Between Coronary Flow Through a Stenosis and the Stenosis Pressure Drop and Fractional Flow Reserve

A

Baseline

40

ΔP = Av+Bv2

Coronary blood flow velocity (cm/s)

B 0

Hyperaemia

20

40

60

80

1 Stenosis C 0.9 Stenosis B 0.8 20 Pd/Pa

Pressure gradient (mmHg)

30

0.7 Diameter stenosis

Stenosis A

10

0.6

13 % 49 %

Reference vessel

60 % 0.5

68 %

0 0

10

30 40 20 Coronary flow velocity (cm/s)

50 0.4

(A) The relationship between stenosis pressure drop and flow velocity. This relationship describes the haemodynamic characteristics for a given stenosis geometry, and becomes steeper with increasing stenosis severity (from stenosis A to C). The pressure drop (delta-P) at rest (blue squares) and at maximal hyperaemia (red circles) is determined by baseline microvascular resistance and the vasodilatory capacity of the downstream resistance vessels. The relationship between delta-P and flow velocity (v) is described by delta-P = Av + Bv2, where the first and second terms represent the losses caused by viscous friction and flow separation at the exit, respectively. The coefficients A and B are a function of stenosis geometry and the rheological properties of blood. The flow-limiting behaviour of a coronary stenosis is largely caused by the inertial exit losses that scale with the square of the flow. Without a stenosis, the second term is zero, and delta-P = Av. (B) Relationship between coronary flow velocity and the distal:aortic pressure ratio during the vasodilatory response to adenosine. Fractional flow reserve (FFR), expressed as distal to aortic pressure ratio (Pd/Pa), decreases when microvascular resistance is reduced by administration of adenosine. Conversely, coronary flow velocity reserve (CFVR; hyperaemic velocity/basal velocity) increases with decreasing microvascular resistance. For a mild stenosis, dilatation of resistance vessels has little effect on FFR, but a large effect on CFVR. By contrast, for a severe stenosis, the decrease in microvascular resistance has a large effect on FFR, whereas the effect on CFVR is small. Figures A and B adapted from van de Hoef, et al., 2013.13

lead to lower maximal flow values and underestimation of CFR if not accounted for. Doppler velocity measurements can, in contrast, also be performed using intracoronary adenosine administration, which circumvents this issue. Nonetheless, despite its potential advantages, Doppler flow velocity measurements are considered more technically challenging than coronary thermodilution measurements. With increasing stenosis severity, the coronary circulation compensates by progressive vasodilation of the coronary resistance vessels to maintain coronary flow at a level that meets myocardial demand. Hence, with increasing stenosis severity the resistance vessels progressively dilate, leading to a reduction in reserve

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vasodilator capacity, and therefore to a reduction in CFR. This concept of CFR has been applied to both invasive and noninvasive methods that allow to measure coronary flow or myocardial perfusion, which have consistently shown important prognostic value for this index.32–40 A theoretical issue with CFR, however, is the fact that it is sensitive towards physiological alterations in coronary flow, either during resting or hyperaemic conditions, that are not related to stenosis severity.41 Moreover, it is important to note that CFR incorporates impairment in vasodilator capacity originating from both the epicardial coronary stenosis, as well as potential microcirculatory dysfunction. Therefore, not all reductions in CFR can be attributed to the presence and severity of the epicardial stenosis, and not all

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Haemodynamics of Coronary Artery Stenoses impairment of CFR may, therefore, be relieved by PCI. Nonetheless, regardless of the methodology applied, a strong association between CFR and clinical outcomes has repeatedly been observed.22,32,33,35–40 Moreover, CFR has been evaluated against noninvasive standards for myocardial ischaemia, which documented an overall diagnostic accuracy for CFR values ≤2.0 of 81 % to identify stenosis associated with evidence of myocardial ischaemia on noninvasive stress testing.34 Randomised clinical trial data for the use of CFR to guide coronary intervention are, however, not available. All large studies on CFR have either investigated its use to guide the optimisation of coronary angioplasty,42,43 or as part of (large) clinical registries. Together with its relative technical difficulty, especially for ad-hoc evaluation in the catheterisation laboratory, this means that CFR is not widely used as a clinical decision-making tool at this moment. Nonetheless, as will be discussed below, renewed interest into the complex multilevel involvement of the coronary circulation in the setting of IHD has reinvigorated an interest in CFR, leading to the design of large clinical trials to reintroduce CFR in clinical practice.

Coronary Pressure for Stenosis Evaluation The Basis of Fractional Flow Reserve Young et al. first introduced the theoretical concept of estimating the impairment of coronary flow due to a coronary stenosis by relating the flow in the coronary artery with the stenosis to that in the same coronary artery without the stenosis.18 This method, however, includes the measurement of coronary flow before and after alleviation of the stenosis and, therefore, unfeasible as a tool to identify haemodynamic stenosis severity before revascularisation. This concept was later expanded upon by Pijls et al., introducing the FFR.5 FFR applies the measurement of proximal and distal coronary pressure during maximal coronary vasodilation to estimate flow impairment due to the stenosis. The FFR framework is therefore based on the assumption that during maximal vasodilation, a proportional linear relationship occurs between coronary perfusion pressure and coronary flow, and that this relationship is the same in the presence and in the absence of a stenosis.11,13 By this assumption, the proximal coronary pressure, or aortic pressure, can be used as an estimate of coronary flow in the absence of a stenosis, and distal coronary perfusion pressure, measured by a pressure-sensing guide wire, can be used to estimate coronary flow in the presence of the stenosis. By expressing the ratio of distal to proximal coronary pressures, FFR reflects the estimated fraction of coronary flow in the presence of the stenosis relative to the situation when the stenosis would be fully relieved (Figure 2).

Clinical Validation of Fractional Flow Reserve FFR has been evaluated against a multitude of noninvasive tests for myocardial perfusion deficits, which has yielded an overall accuracy of FFR to identify such perfusion impairment of around 81 %.34,44 Moreover, ample randomised clinical outcome data supports the benefit of FFRguided coronary intervention over the use of the coronary angiogram alone. FFR-guided intervention is associated with equivalent functional and clinical outcomes compared with angiographic guidance, while requiring significantly less revascularisation procedures. 6 These findings have led FFR to be incorporated as a dominant diagnostic test in the management of IHD,1 and even has (inappropriately) led several investigators to use FFR as a gold standard reference test for the evaluation of novel tools for IHD management, including advanced noninvasive tests.45 The recent FAME II study results have, however, shed new light on the diagnostic and prognostic characteristics of FFR. This study evaluated routine PCI of FFR-positive stenosis on

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top of guideline-directed medical therapy versus an approach using guideline-directed medical therapy alone.7,8 Among stenoses with an average FFR of 0.68 ± 0.15, 80 % of medically managed FFR-positive stenosis did not suffer major adverse cardiac events up to two years of follow up, and over 60 % of patients did not require PCI at all during this period. This means that the majority of stenoses that should actually undergo revascularisation according to contemporary clinical guidelines, do not require revascularisation to prevent adverse cardiac events.46,47 Hence, although there is a distinct benefit of FFR-guided revascularisation over PCI-guided by the coronary angiogram, it is not a perfect tool and substantial room for improvement seems to exist.

Theory Versus Reality: Accuracy of Fractional Flow Reserve to Identify Flow Impairment Comparing the theoretical pressure-flow relationship that forms the basis of FFR with the actual pressure-flow relationship in humans illustrates why FFR only provides an estimate of – and is not the same as – stenosis-induced flow impairment in the individual patient (Figure 4).5,10,48,49 First and foremost, in reality the relationship between perfusion pressure and coronary flow is not proportional linear (Figure 4A), but is incremental linear and varies in slope with variation in clinical and haemodynamic conditions (Figure 4B).10,13,49 The variability of the pressure-flow relationship both between patients, as well as within patients between adjacent perfusion territories, means that the deviation of the proportional linear pressure-flow relationship assumed by FFR from the actual relationship in the individual patient is variable as well. Moreover, the FFR-theory assumes that such relationship is the same for unobstructed and stenosed coronaries, which can only occur when coronaries would be rigid pipes that do not change in diameter with a change in perfusion pressure: after all, resistance in the coronary arteries can only be the same in these situations when coronary diameter is independent of perfusion pressure.50,51 However, it is well-known that coronary arteries are pressure-distensible, which precludes the aforementioned assumption and induces another uncertainty regarding the accuracy of FFR to identify actual stenosisinduced flow impairment.52 With such detailed analysis of the assumed and actual pressure-flow relationship, it becomes clear that many factors influence the accuracy with which FFR estimates stenosisinduced flow impairment in the individual patient: it may be very close in some patients, but can be ill-estimated in others. Finally, beyond the conceptual issues with FFR as an estimate of coronary flow impairment, it is important to recall that FFR becomes more abnormal as flow through the coronary artery becomes more normal: an abnormal FFR may therefore coincide with highly normal coronary flow, and vice versa.19,20 Since the myocardium thrives on coronary flow, not on coronary perfusion pressure,21 and coronary flow is the critical determinant of myocardial ischaemia,23,24 such can be interpreted as inaccuracy of FFR to estimate stenotic flow impairment. Clearly, coronary pressure can theoretically be used to estimate coronary flow impairment induced by a stenosis, but it should be realised that many factors interfere with its reliability. Reconciling that the aim of FFR is to identify stenosis-induced flow impairment, which it may misestimate on the basis of basic physiological principles, it becomes clear the limited prognostic value of positive FFR in FAME II may well be explained by misestimated stenosis-induced flow impairment.

The Basis of Instantaneous Wave-free Ratio The instantaneous wave-free ratio (iFR) is a pressure-derived index of stenosis severity that can be calculated during resting conditions and therefore does not require the use of potent vasodilators in the

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Interventions Figure 4: Theoretical and Actual Pressure-flow Relationships A

Assumed relationship for FFR

B

Actual relationship in patients

QMax no stenosis

QMax no stenosis

QMax stenosis

QMax stenosis

Pd

Pa

Pd

Pa

(A) The theoretical framework of fractional flow reserve (FFR) assumes a proportional linear relationship between coronary pressure and flow, since only then a change in pressure can be directly related to a proportional change in flow. Such a relationship is illustrated by a straight line with a zero-pressure intercept. (B) Actual pressure-flow relationship in patients. The is an incremental–linear relationship between coronary pressure and flow: the relationship is illustrated by a straight line but a non-zero pressure intercept. A change in pressure is not proportional to a change in coronary flow. The relationship is variable, as both the slope (red arrow, red dotted line) and the zero-pressure intercept (green arrow, green dotted line) are influenced by concomitant pathological changes in the coronary circulation (see Figure 1).

catheterisation laboratory. iFR is defined as the ratio of distal to proximal coronary pressure during a restricted part of cardiac diastole, termed the wave-free period. This approach means the stenosis pressure gradient is assessed during that portion of the cardiac cycle where coronary flow is intrinsically highest. Thereby, iFR aims to maximise the information on stenosis severity that can be derived during resting conditions. The fact that iFR can be assessed in resting conditions overcomes several ambiguities associated with the use of coronary vasodilators in clinical practice, and simplifies physiological assessment of coronary stenosis severity.

Diagnostic Value of Instantaneous Wave-free Ratio Compared with Fractional Flow Reserve The diagnostic value of iFR has been evaluated against FFR as the reference standard, as well as against independent reference standards. Overall, iFR agrees with FFR in approximately 80 % of cases.53 When independent reference tests were used to compare the diagnostic efficiency of iFR and FFR, such as CFR assessed with intracoronary Doppler velocity measurements and with PET or invasively assessed hyperaemic stenosis resistance index, no benefit of FFR over iFR could be identified.54–56 Actually, iFR showed better agreement with direct assessment of coronary flow than FFR.57 Hence, both techniques can be considered equivalent alternatives in terms of their diagnostic efficiency to detect haemodynamically relevant coronary stenosis. To date, two large-scale randomised clinical outcome trials comparing iFRguided versus FFR-guided coronary intervention have been performed: the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization (DEFINE-FLAIR) and the Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome (iFR-SWEDEHEART) studies. Combining approximately 4,500 patients, these studies documented no difference in the occurrence of major adverse cardiac events between an iFR-guided or FFR-guided revascularisation strategy. Hence iFR and FFR can be considered alternatives for stenosis assessment with respect to clinical outcomes as well. In both the DEFINE-FLAIR and iFR-SWEDEHEART studies, significantly fewer coronary stenoses were identified as haemodynamically significant in the iFR-guided arm compared with the FFR-guided arm, and significantly fewer coronary interventions were performed in the iFR-guided arms.58 Yet, patients deferred from coronary intervention on the basis of iFR had equivalent

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clinical outcomes compared with patients deferred on the basis of FFR. Moreover, patients with an acute coronary syndrome (ACS) had significantly worse outcomes than the stable coronary artery disease patients (SCAD) in the FFR-guided arm, but not in the iFR-guided arm where outcomes between ACS and SCAD were similar.59 Aside from its proven non-inferiority, iFR induces less patient discomfort since it obviates the use of vasodilators, can be assessed quickly compared with FFR and has the ability to assess serial lesions by performing an iFR-pullback. The latter may be the largest benefit of iFR-guided intervention. In hyperaemic conditions, serial coronary stenoses show interplay as soon as they reach >50 % diameter stenosis: in sequential stenosis, the proximal stenosis will lower blood flow across the distal stenosis and vice versa. When treating either of the stenosis with PCI, coronary flow across the second stenosis will increase, increasing the residual pressure gradient across the residual stenosis. Due to this phenomenon, hyperaemic pressure-wire assessment with FFR does not allow identification of the individual impact of coronary stenosis on the overall FFR-value. In resting conditions, such stenosis interplay does not occur until stenosis severity exceeds >85 % diameter stenosis. Therefore, since PCI does not influence resting flow across the residual stenosis, pre-intervention pressure gradients can be assessed for each individual stenosis. An iFR-pullback, therefore, allows to identify the individual contribution of each stenosis to the overall iFR value, and to optimise planning of the PCI procedure in serial stenoses. Moreover, this iFR scout calculates stenosis severity according to the pressure gradient obtained during the iFR-pullback and predicts real-time potential haemodynamic gain in iFR post-PCI according to stent size.60–62

Improving Identification of True Stenosis Haemodynamic Significance: Combining Fractional Flow Reserve and Coronary Flow Reserve FFR and CFR were long considered alternatives for the physiological assessment of coronary artery disease, and discrepancies between the two have historically been linked to the technical difficulty of obtaining accurate CFR values and the limitations of CFR defined above. Conversely, it has now become evident that FFR and CFR comprise complementary tools, and that discrepancies between the two are the result of basic coronary (patho)physiology.19,20,22,63 Accordingly, the combined interpretation of FFR and CFR allows more accurate discrimination of the pathophysiological substrate in the setting of IHD. The relationship between FFR and CFR is illustrated in Figure 5. On the basis of their clinical cut-off values, four main quadrants can be defined in this relationship. When FFR and CFR are in agreement they are easily interpreted in combination: either no haemodynamically relevant coronary artery disease is present – illustrated by the combination of normal FFR and normal CFR – or there is coronary artery disease that severely impairs coronary flow – illustrated by the combination of abnormal FFR and abnormal CFR. Disagreement between FFR and CFR may arise from distinct (patho)physiological mechanisms. In the presence of a coronary stenosis, the combination of abnormal FFR and normal CFR illustrates the presence of non-flow limiting coronary artery disease. In this situation, the (highly) normal coronary flow through the coronary artery induces a significant pressure drop across the stenosis, leading to an abnormal FFR value. Since the myocardium thrives on coronary flow, not on perfusion pressure, and coronary flow is the critical determinant of myocardial ischaemia, it is the high coronary flow that determines the benign clinical follow up in these patients.20,64 The combination of normal FFR with abnormal CFR illustrates the presence of focal epicardial coronary

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Combining Pressure and Flow Signals: Calculation of Coronary Resistances Beyond the combined interpretation of FFR and CFR, the combined assessment of coronary pressure and flow allows for calculation of indices that relate to resistance to coronary flow in the coronary circulation. The resistance in a vascular compartment is defined as the pressure drop across the compartment divided by the flow that goes through it. Accordingly, the maximal resistance to coronary flow induced by an epicardial stenosis can be calculated as the pressure drop across the stenosis divided by distal coronary flow (velocity) during coronary vasodilation. This hyperaemic stenosis resistance index (HSR) was noted to provide significantly higher accuracy to identify stenosis associated with perfusion deficits on nuclear stress imaging than FFR.67 Moreover, it was shown to provide high prognostic value, particularly in those cases where FFR and CFR disagree.68 Together with its strong physiological fundament, these findings have led several investigators to use HSR as a diagnostic reference standard in studies evaluating novel tools for stenosis assessment.69,70 Notably, when calculated during resting conditions, the basal stenosis resistance index also provided very high diagnostic accuracy of at least equivalent magnitude to that of FFR, especially when contemporary guide wires were used that allow measurement of coronary pressure and flow velocity simultaneously.69,71

Clinical Implications and Future Outlook Above all, the use of FFR has importantly improved the selection of patients that benefit from coronary revascularisation over the use of the coronary angiogram alone. Yet, the robust clinical data documents that further improvement in patient selection should be possible. The complex multilevel involvement of the coronary circulation in IHD means that multimodality physiological evaluation will be required to achieve this goal. As with FFR, it can be assumed that more advanced physiological testing will lead to

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The combined interpretation of FFR and CFR to optimise decision making is until now only supported by retrospective clinical data. The ongoing Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses (DEFINE-FLOW) study (NCT02328820) aims to evaluate this diagnostic approach in a multicentre prospective observational setting. This study tests the hypothesis that deferral of PCI in stenosis with abnormal FFR and normal CFR leads to equivalent clinical outcome compared with deferral of PCI in stenosis where both FFR and CFR are normal. Such prospective clinical data are needed to ultimately define the role of this approach in clinical practice. This study will similarly provide insight into the clinical relevance of FFR–CFR discordance and its relationship with clinical outcomes.

Figure 5: Conceptual Plot of the Fractional Flow Reserve– Coronary Flow Reserve Relationship

Coronary flow reserve

artery disease superimposed on a background of either microvascular disease and/or diffuse epicardial coronary artery disease. This pattern has been associated with impaired long-term clinical outcomes.20,22 Although it is generally assumed that the normal FFR in this setting reflects that PCI is not applicable in this setting to improve coronary flow, impaired microvascular function may mask haemodynamically relevant coronary stenosis.65 On the basis of this phenomenon, recent case-based clinical data suggests that in select cases, PCI might be a last resort option in an attempt to alleviate the epicardial contribution to coronary flow impairment.66

1.0

Fractional flow reserve Four main quadrants can be identified by applying the clinically applicable cut-off values for fractional flow reserve (FFR) and coronary flow reserve (CFR), indicated by the dotted lines. Patients in the upper-right blue area are characterised by concordantly normal FFR and CFR, and patients in the red lower-left area are characterised by concordantly abnormal FFR and CFR. Patients in the upper-left orange area and lower-right light-green area are characterised by discordant results between FFR and CFR, where the combination of an abnormal FFR and a normal CFR indicates predominant focal epicardial, but non-flow limiting, coronary artery disease, and the combination of a normal FFR and an abnormal CFR indicates predominant microvascular involvement or diffuse epicardial disease. The small dark-green region in the lower-right is characterised by a FFR near 1 and a normal CFR, indicating sole involvement of the coronary microvasculature. The FFR grey zone indicates the equivocal 0.75–0.80 FFR range. Adapted from Johnson, et al., 2012.19

stricter selection of patients eligible for PCI, reducing unnecessary patient exposure to mechanical revascularisation and improving the benefit of PCI in the individual patient. Yet, this requires the routine measurement of coronary flow in clinical practice, which remains technically challenging. Improvements in the available armamentarium of wire technology are required to make coronary flow measurements feasible, and thereby to provide the opportunity for more complex physiology uptake in clinical practice. Moreover, prospectively gathered (randomised) clinical trial data are needed to further substantiate the relevance of these endeavours for patient outcomes in stable ischaemic heart disease.

Conclusion In the evaluation of coronary stenosis, coronary pressure and flow both have advantages and disadvantages. Ultimately, both parameters are complementary, and together optimally define the pathophysiological basis of IHD. Although coronary pressure represents the cornerstone of contemporary clinical coronary physiology, evidence is emerging on the clinical relevance of the complex multilevel involvement of the coronary circulation in IHD. More complex physiological testing may well enhance our ability to direct the risk and benefit of mechanical revascularisation to those patients and stenosis that are most likely to benefit. For this purpose, both technical advancement in wire technology and prospective clinical data are needed. n

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stenosis resistance index derived from simultaneous pressure and flow velocity measurements. EuroIntervention 2016;12: e199–207. https://doi.org/10.4244/EIJV12I2A33; PMID: 27290679. 70. Sen S, Asrress K, Nijjer S, et al. Diagnostic classification of the instantaneous wave-free ratio is equivalent to fractional flow reserve and is not improved with adenosine administration. Results of CLARIFY (the classification accuracy of pressureonly ratios 3 against indices using flow study). J Am Coll Cardiol 2013;61:1409–20. https://doi.org/10.1016/j.jacc.2013.01.034; PMID: 23500218. 71. van de Hoef TP, Nolte F, Damman P et al. Diagnostic accuracy of combined intracoronary pressure and flow velocity information during baseline conditions: adenosine-free assessment of functional coronary lesion severity. Circ Cardiovasc Interv 2012;5:508–14. https://doi.org/10.1161/ CIRCINTERVENTIONS.111.965707; PMID: 22787017.

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Interventions

The Newest Generation of Drug-eluting Stents and Beyond Dae-Hyun Lee and Jose M de la Torre Hernandez Cardiology Service, Interventional Cardiology Unit, University Hospital Marques de Valdecilla, Santander, Spain

Abstract There has been a great evolution in the development of coronary stents in order to avoid both restenosis and thrombosis. Improvements have led to improvements in the design and conformation of metallic or resorbable structures, with an adequate balance between trackability and radial force, the development of antiproliferative drugs and the polymers to control release and allow adequate endothelialisation and an optimal duration of the antiplatelet regimen. Some suggestions are provided about the ideal characteristics of future coronary stents.

Keywords Drug-eluting stent, -limus drugs, biodegradable polymers, bioresorbable stent, stent thrombosis, double antiplatelet therapy) Disclosure: JTH is in receipt of an unrestricted grant from Boston Scientific and has received payments from Medtronic and Boston Scientific for sitting on advisory panels. DHL has no conflicts of interest to declare. Received: 21 February 2018 Accepted: 8 May 2018 Citation: European Cardiology Review 2018;13(1):54–9. DOI: https://doi.org/10.15420/ecr.2018:8:2 Correspondence: Jose M de la Torre Hernandez, Haemodynamics and Interventional Cardiology Unit, University Hospital Marques de Valdecilla, South Valdecilla, 39008 Santander, Spain. E: josemariadela.torre@scsalud.es

When Andreas Grüntzig introduced balloon coronary angioplasty in 1977 it represented the first alternative to coronary artery bypass graft surgery. However, balloon dilatation had inherent limitations – including elastic recoil and vessel closure in the acute phase, as well as negative remodelling and restenosis in the late phase – which limited its applicability and further expansion. In the 1980s, bare metal stents (BMS) rapidly demonstrated superiority over balloon angioplasty, improving angiographic results and clinical outcomes. Despite these improvements, neointimal hyperplasia and restenosis continued to be major limitations of BMS technology. Drug-eluting stents (DES) were designed to minimise neointimal hyperplasia and reduce repeat revascularisation, but an increased risk of late stent thrombosis (ST) was observed with the first generation of devices. New DES have been developed to ensure good acute and long-term results while minimising stent thrombosis rate. Continuous innovation and research to improve all aspects of DES technology, such as platform material and structure, polymers, coating distribution, additional coating and antiproliferative drugs, have led to newer, improved generations of DES (Figure 1).1 In this article, we review the diverse features of current and future developments in DES.

stent strut thickness has been identified as an independent predictor of in-stent restenosis.4 Current stent designs are based on a sequential-ring construction method consisting of a series of expandable Z-shaped structural elements (known as struts) joined by connecting elements (known as bridges, hinges or nodes). In closed cell designs, the adjacent ring segments are connected at every possible junction. This provides greater radial force and scaffolding uniformity but reduces flexibility and conformability – even with flexible bridge connectors – compared to an open-cell design where some of the internal inflection points are joined by bridging connectors.5,6 An open-cell configuration provides greater flexibility, adaptability and access to side-branches and has a higher resistance to fracture. All of the currently available stents are made by laser-cutting metallic tubes. Continuous sinusoid technology is a manufacturing method that folds a single strand of cobalt alloy wire into a sinusoidal wave, enabling greater deliverability and conformability to the vessel wall. It remains to be seen whether nanotechnology will make the design of stents with ultrathin struts feasible in future.

Metallic Drug-eluting Stents Platform

Drug

The first DES were made of stainless steel and were coarse (up to 140 μm strut). New-generation DES are made of different kinds of alloys, such as cobalt chromium or platinum chromium, that are thinner (up to 60 μm strut), have high radial strength and radiopacity, and enhance biocompatibility as well as corrosion resistance.2

First-generation DES used paclitaxel and sirolimus. Paclitaxel interferes with microtubule dynamics during mitosis by binding to the beta-tubulin subunit of the microtubules. The drug is cytostatic at the low doses used for coronary stents. It has a very high level of lipophilicity, which means that it can be linked to the stent without the use of a polymer. Sirolimus is a sophisticated natural antibiotic that was developed for its powerful immunosuppressive activity. It blocks protein synthesis, cell cycle progression and migration by inhibiting mammalian target of rapamycin.7 Its better kinetics and wider therapeutic index are the reasons why the antirestenotic

Thicker struts delay full neointimal coverage and increase the risk of subacute thrombosis. Research has shown that the thinner the strut, the better the endothelialisation.3 Stents with thinner struts are more flexible, which enhances their trackability and crossability. In addition,

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Drug-eluting Stents efficacy of sirolimus-eluting stents are higher than paclitaxel-eluting stents.8,9 The antirestenotic efficacy of these drugs is the reason newgeneration DES use the -limus family of drugs, which also includes everolimus, zotarolimus, umirolimus, novolimus and amphilimus. These drugs differ in terms of structure, molecular weight, potency and lipophilicity. Zotarolimus is a highly lipophilic analogue of sirolimus. It was designed to have a shorter in vivo half-life than sirolimus but the same high-affinity binding to the immunophilin FKBP12 along with comparable inhibition of t-cell proliferation in vitro.10 Everolimus has a much higher interaction with mechanistic target of rapamycin complex 2, higher bioavailability and shorter half-life than sirolimus. Everolimus also reduces vascular inflammation.11 The everolimuseluting stent has shown more rapid endothelialisation.12 Umirolimus has been specifically developed for local delivery to the coronary arteries. It is the most lipophilic of the common -limus drugs (around 10 times greater than sirolimus), which is why a low dose is used in free-polymer stents.13 Novolimus is an active metabolite of sirolimus and has been shown to be a potent inhibitor of smooth muscle cells in in vitro studies.14 In the near future, the use of different drugs or combinations of drugs with different actions may address not only intimal proliferation but also thrombosis and, in the long term, in-stent neoatherosclerosis (Figure 2).

Coating and Polymers Great advances have been made in the field of coating and polymers. Drug release and availability are determined not only by the properties of the drug but also by the characteristics and architecture of the polymer that contains it. Depending on its composition, the polymer can cause undesirable inflammatory phenomena. The characteristics of an ideal polymer for use in a stent are given in Box 1.17 The durable polymers used in first-generation DES led to persistent arterial wall inflammation and delayed vascular healing, which contributed to stent thrombosis and delayed in-stent restenosis.15 Although the durable polymers currently used in DES are less thrombogenic than those used in first-generation DES, doubts remain about their safety in the long term. This is why a huge effort has been made to develop both biodegradable-polymer and no-polymer stents. Polymer coating can be conformal, inhibiting smooth cell proliferation over the entire surface of the stent, or abluminal, i.e. the release of the drug only has an effect on the surface in contact with the vessel wall. Abluminal coating reduces drug dose and polymer exposure, so it could theoretically reduce thrombogenicity while having a minimal affect on endothelial cell strut coverage.16 Of the new generation of biocompatible durable polymer coatings, two stand out: vinylidene-fluoride hexafluoropropylene copolymer and C10–C19–polyvinylpyrrolidone polymer.18 Fluorinated copolymers such as vinylidene-fluoride hexafluoropropylene copolymer reduce protein adsorption, platelet adhesion and thrombus formation.19 The blend of three different polymers – C10, C19 and polyvinylpyrrolidone – acts as an amphiphilic molecule. Its hydrophilic components face the stent surface, which is in contact with the cells, so it does not induce activated monocyte adhesion. This improves the biocompatibility of the polymer blend.

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Figure 1: Drug-eluting Stent Evolution

↓ Restenosis ↓↓ Late thrombosis Mechanical performance ↓↓↓ Restenosis ↑ Late thrombosis ≅ Mechanical performance

≅ Restenosis ↑ Early and late thrombosis Mechanical performance

2nd G.DES BRS

1st G.DES

BMS BMS = bare-metal stent; BRS = bioresorbable stent; G.DES = generation drug-eluting stent.

Biodegradable Polymers It was hypothesised that durable polymers used in the first generation DES would trigger the inflammatory process and induce stent thrombosis.16,20 Biodegradable polymer coatings, which are composed of lactic or glycolic acids, facilitate drug delivery to the vessel wall and are fully resorbed by hydrolysis after drug release without causing any long-term sequelae.21 Polylactic (PLLA, PDLLA), polyglycolic (PGA) and polylactic-co-glycolic (PLGA) copolymers are widely used for drug delivery. They differ not only in how they release the drug but also how long they take to degrade. A copolymer’s total degradation period may vary from 3 to 15 months. Future research is needed to optimise the composition and pharmacokinetics of copolymers. Although the use of biodegradable polymers in newer-generation DES platforms looks promising, there are some issues that need to be resolved before their widespread clinical application.22 Biodegradable polymers have a lower risk of late thrombosis than first-generation DES but not compared to the new generation of durable polymer DES.23 Whether stents with biodegradable polymers require shorter double antiplatelet therapy (DAPT) than stents with durable polymers has yet to be properly assessed in randomised studies.24

Polymer-free Drug Eluting Stent Inflammatory issues caused by the polymers used in stents can be avoided by eliminating the polymer coating completely and releasing the antiproliferative drug directly from the stent surface. Without a polymer coating, it would be expected that the elution rate would increase, which might affect the stent’s therapeutic efficacy.25 To address this issue, stent manufacturers have adopted different approaches to decrease the elution rate. These approaches can be roughly separated into five categories: smooth surface, macroporous, microporous, nanoporous and drug-filled stents.26 Perhaps the simplest polymer-free design is where the drug is coated directly onto the relatively unmodified smooth surface of the metal stent. With no polymer or pores to control drug release, the release rate is determined solely by the solubility and diffusion coefficient of the drug in the release medium and by the thickness of the coating. In macro-, micro- and nanoporous techniques, the surface of the stent is roughened. The drug is put into holes or slits in the body of macroporous stents. Pits and holes (in the order of microns) are made on the surface of microporous stents by a sandblasting or microabrasion process. The rough surface is then coated with the drug,

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Interventions Figure 2: Optical Coherence Tomography Images of New-generation Drug-eluting Stents

A: Well endothelialised struts. B: Restenosis. C: Uncovered struts.

Figure 3: Optical Coherence Tomography Images of Bioresorbable Scaffolds

A: Well endothelialised struts. B: Restenosis. C: Covered but malappositioned struts.

Box 1: Minimum Characteristics of an Ideal Polymer

• Biocompatible and inert as well as compatible with the vessel. The polymer should not to produce inflammatory reactions or increase the risk of thrombosis but behave in a benign manner when implanted in a blood vessel. • Drug release from the polymer to the arterial wall should be predictable and capable of being modulated in time and dose in order to inhibit excess smooth muscle cell growth. Drug release should not affect the normal arterial endothelisation process. • Be highly elastic. The polymer particles should not be fractured, broken or detached on stent deployment. • Does not alter the activity of the drug or modify the structural and mechanical characteristics of the stent.

resulting in the micropores being filled and a nominal layer covering the stent surface. The micropores act as a reservoir for the drug and aid adhesion to the stent surface. The nanopores of nanoporous stents are created by electrochemical treatments or sputter-coating techniques. These stents allow for a higher drug-loading capacity. Finally, drug-filled stents are a new and promising technology that allows the drug to be eluted from inside the stent through holes laserdrilled on the abluminal side.27

Carbofilm™ is a high-density, ultra-thin (≤0.5 µm) turbostratic carbon film. It has a structure similar to diamond, giving it exceptional bio- and haemocompatibility and allowing extremely fast endothelialisation.29

Additional Coating Technologies

Stents can also be coated with biological agents. CD34 antibodies are immobilised on the luminal surface of the stent from where they capture the circulating endothelial progenitor cells. The sheer stress triggered by the circulating blood and other cell signals leads the endothelial progenitor cells to differentiate and mature into endothelial cells, enhancing the vessel healing.30

PROBIO® is a passive amorphous silicon carbide coating that was developed to reduce the thrombogenic properties of metal stents. By providing a barrier against ion release, the silicon carbide coating creates a surface that reduces the deposition of fibrin, platelets and leucocytes, as well as enhancing the growth of endothelial cells. When a platelet comes into contact with the PROBIO coating, it remains in a resting state.28

Titanium nitride oxide can be used to coat all of the surfaces of a stent, resulting in the presence of nitric oxide particles. This nitric oxide coating is specifically active against restenosis and thrombosis, as well as being an accelerator of endothelialisation.31 This, and other nanotextured ceramic coatings, could be advantageous but the benefits remain to be proved.32 Some coronary stents characteristics are summed up in Table 1.

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Drug-eluting Stents Table 1: Characteristics of Some Coronary Stents Stent

Stent

Strut

Material

Thickness

Polymer

Polymer

Coating

Polymer

Type

Distribution

Thickness Time

(µm)

Absorption

Drug

Additional

Drug Elution

Coating

Time

(µm)

Cypher

Stainless steel

140

PEVA/PBMA

Durable

Conformal

13

Permanent

Sirolimus

No

90 days

Taxus Express

Stainless steel

132

SIBS

Durable

Conformal

22

Permanent

Paclitaxel

No

Lineal >180 days

Xience Alpine

CoCr

81

PVDF-HFP

Durable

Conformal

7–8

Permanent

Everolimus

No

120 days

Xience Sierra L-605 CoCr

81

PVDF-HFP

Durable

Conformal

7–8

Permanent

Everolimus

No

120 days

Resolute Integrity

CoNi

91

BioLinx

Durable

Conformal

6

Permanent

Zotarolimus

No

180 days

Resolute Onyx

CoNi with Pt-Ir

81–91

BioLinx

Durable

Conformal

4.8

Permanent

Zotarolimus

No

180 days

Orsiro

CoCr

60–80

PLLA

Biodegradable

Conformal

7

15 months

Sirolimus

Silicon carbide; conformal

100–120 days

Ultimaster

CoCr

80

PDLLA-PCL

Biodegradable

Abluminal

15

3–4 months

Sirolimus

No

3–4 months

Synergy

PtCr

79–81

PLGA

Biodegradable

Abluminal

4

3–4 months

Everolimus

No

3 months

BioMatrix Nobori

Stainless steel

120

PDLLA

Biodegradable

Abluminal

10

6–9 months

Biolimus

No

6–9 months

Combo

Stainless steel

100

PDLLA-PLGA

Biodegradable

Abluminal

5

90 days

Sirolimus

Anti CD-34 antibodies; comformal

30–45 days

BioMatrix Flex

316L Stainless steel

112

PDLLA

Biodegradable

Abluminal

16.6

6–9 months

Biolimus

No

180 days

BioFredoom

316L Stainless steel

119

Polymer free Polymer free

Abluminal

Polymer free

Polymer free

Biolimus

No

30 days

Drug-filled stents

CoNi with Tantalum

81

Polymer free Polymer free

Abluminal

Polymer free

Polymer free

Sirolimus

No

180 days

CoCr = cobalt–chromium; CoNi = cobalt–nickel; PBMA = poly n-butyl methacrylate; PCL = poly(e-caprolactone); PDLLA = poly-D, L-lactic acid; PEVA = poly-ethylene-co-vinyl acetate; PLGA = poly-lactic co-glycolic acid; PLLA = poly-L-lactic acid; PtCr = platinum–chromium; Pt-Ir = platinum–iridium; PVDF-HFP = co-polymer of vinylidene fluoride and hexafluoropropylene; SIBS = poly(styrene-b-isobutylene-b-styrene)

Table 2: Characteristics of Some Bioresorbable Scaffolds Bioresorbable

Strut material

Scaffold

Strut Thickness Polymer Type

Coating

Resorption

Eluting

(µm)

Distribution

Time (months)

Polymer

Drug

Drug Elution Time (months)

Absorb

PLLA, Pt markers

157

Bioresorbable

Conformal

>24

PDLLA

Everolimus

3

Absorb-GT1

PLLA, Pt markers

157

Bioresorbable

Conformal

>24

PDLLA

Everolimus

3

DESolve 100

PLLA, Pt-Ir markers

100

Bioresorbable

Conformal

24

PLLA

Novolimus

3

MeRes

PLLA, Pt-Ir markers

100

Bioresorbable

Conformal

24-36

PDLLA

Sirolimus

3

Magmaris

Mg backbone, Ta markers

150

Bioresorbable

Conformal

12

PLLA

Sirolimus

3

Ir = Iridium; Mg = magnesium; PDLLA = poly-D, L-lactic acid; PLLA = poly-L-lactic acid. Pt = platinum; Ta = tantalum;

Bioresorbable Stent Technology Bioresorbable stent (BRS) technology has been called the fourth revolution in interventional cardiology due to its potential advantages.33 Apart from preventing acute vessel closure or recoil by transiently scaffolding the vessel, these fully-biodegradable scaffolds elute antiproliferative drugs that inhibit constrictive remodelling and neointimal hyperplasia. Complete resorption of the scaffold liberates the vessel from its cage and potentially restores vessel anatomy as well as vasomotor response, pulsatility, cyclical strain, physiological shear stress and mechanotransduction. In-stent

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restenosis secondary to low-grade inflammatory response to the polymer or device is mitigated. The risk of late or very late thrombosis is eliminated as the foreign material (platform plus coating) is replaced by connective tissue and the scaffolded segment healed with matured endothelium. The use of BRS could shorten the DAPT administration period and reduce complications due to secondary bleeding. Currently, there are many materials used as the backbone for scaffolding (Table 2). Magnesium alloys, PLLA and tyrosine polycarbonate are the most common. The bioresorbable vascular

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Interventions scaffold system (based on polylactic polymers) was the first to become commercially available and is by far the most widely used and tested (Figure 3). There are still many issues that lead the interventional cardiologist to be cautious about BRS. There are practical concerns about strut thickness (up to 170 μm), which may lead to vessel injury, rheological disturbances, platelet deposition and poor deliverability. Thus, mechanical considerations are more challenging, especially when calcification or tortuosity are present. To address this issue, new bioresorbable designs with thinner struts (about 100 µm) will become available soon.34 Regardless of lesion anatomy, due to lack of radial strength and poor deliverability in BRS, pre-dilatation is mandatory to facilitate lesion crossing and attain adequate expansion. Post-dilatation is also mandatory to ensure correct expansion and apposition. Defective healing and late adverse reactions may therefore not be completely avoided with the use of BRS. These technical particularities mean that the total cost and duration of percutaneous coronary intervention with BRS may be higher than with conventional DES. There are other drawbacks to BRS. The most challenging issue is the process of resorption and scaffold disintegration in human coronary arteries with atherosclerosis. There is an increased scaffold fracture risk with over-dilatation of BRS; thus, significant upsizing is impossible. Recently, scaffold collapse has been described in subacute and late coronary thrombosis.35,36 In addition to this, greater shear stress from the thick struts of current BRS may cause platelet activation. Observational findings from cases with very late thrombosis show the presence of largely dismantled scaffold remnants 2–3 years after implantation. These concerns have been confirmed clinically in trials. For example, there is a significantly higher risk of subacute and very late thrombosis with BRS compared to metallic everolimus-eluting stents.37 Although resorption is achieved after a relatively short period of time in some devices, others take over 24 months (Table 2), and so the optimal duration of DAPT in conjunction with BRS application is unclear. Having highlighted these issues, we think this technology is worth pursuing and hope that research will overcome most, if not all, of its limitations.

Looking to the Future Although considerable advances have been made, the ideal DES system has yet to be developed. The occurrence of stent thrombosis has accelerated technological evolution in interventional cardiology and the eradication of this fatal outcome should be the focus of new DES. Since the advent of DES, restenosis figures have dropped to a single digit, even for the most complex lesions. The most recent generation of DES are associated with a greater reduction in the risk of early

1.

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 tefanini GG, Byrne RA, Windecker S, Kastrati A. S State of the art: coronary artery stents – past, present and future. EuroIntervention 2017;13:706–16. https://doi.org/10.4244/EIJ-D-17-00557; PMID: 28844032. Karjalainen PP, Nammas W, Airaksinen J. Optimal stent design: past, present and future. Interv Cardiol 2014;6:29–44. Simon C, Palmaz JC, Sprague EA. Influence of topography on endothelization of stents: clues for new designs. J Long Term Eff Med Implant 2000;10:143–51. https://doi.org/10.1615/.v10.i12.120; PMID: 10947627. Kastrati A, Mehilli J, Dirschinger J, et al. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation 2001;103:2816–21. https://doi.org/10.1161/01.CIR.103.23.2816; PMID: 11401938. Stoeckel D, Bonsignore C, Duda S. A survey of stent designs. Min Invas Ther Allied Technol 2002;11:137–47. https://doi.org/10.1080/136457002760273340; PMID: 16754063. Wholey M, Finol E. Designing the ideal stent. Endovascular Today

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and late thrombosis than BMS. However, target lesion-related events are still observed years after implantation due to neoatherosclerosis. Future DES designs will have to address this issue. The ideal DES should incorporate a number of newer and improved materials and delivery systems to enhance safety, efficacy and cost-efficiency. The ideal system should include:38 • • • • • • • • • • • •

A very low-profile stent delivery system High flexibility and conformability due to a hybrid open-cell design Thinner struts Adequate radiopacity and radial strength A high-pressure balloon that is suitable for direct stenting Minimal late loss (≤0.2 mm) A -limus drug. Drug-elution for 60–90 days, followed by complete absence of drug release Stimulation of early re-endothelialisation A thrombus-resistant luminal surface A very thin surface of durable or biodegradable polymer coating A minimal duration of DAPT

The duration of DAPT for new DES could safely be shortened by up to 3 months in stable patients and 6 months in acute coronary syndrome patients who have a higher bleeding risk.39 For specific models, such as BioFreedom, the duration of DAPT could be shortened to 1 month with better results than a BMS.40 Other new DES are being evaluated in trials of 1 month of DAPT in patients with high bleeding risk. The safety and efficacy of contemporary stents are supported by evidence from clinical trials and registries; however, larger trials and longer follow-up are necessary to assess the effectiveness of novel devices. The risk of late thrombosis with first-generation metallic DES and the risk of early and very late thrombosis with BRS were not properly identified in the preclinical stages of research. Animal models’ ability to reveal the significant long-term limitations of devices implanted in diseased coronary arteries of humans is limited. The more complex the interplay between a device and arterial wall-plaque, the harder it is to predict the long-term effects in humans. From BMS to DES, and particularly to BRS, stents are increasing in complexity. Computational models based on finite element analysis could complement the animal data but new advances in animal models will be crucial. In summary, a validated and standardised set of preclinical studies is warranted before clinical studies of new stent models are conducted. Once a device is approved for use in humans, a well-designed programme of clinical studies is warranted before it is widely introduced on the market. n

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controlled trials. Curr Probl Cardiol 2017;42:404–17. https://doi.org/10.1016/j.cpcardiol.2017.04.001; PMID: 29110813. Costa RA, Abizaid A, Mehran R, et al. Polymer-free biolimus A9-coated stents in the treatment of de novo coronary lesions: 4- and 12-month angiographic follow-up and final 5-year clinical outcomes of the prospective, multicenter BioFreedom FIM clinical trial. JACC Cardiovasc Interv 2016;9: 51–64. https://doi.org/10.1016/j.jcin.2015.09.008; PMID: 26762911.  McGinty S, Vo TT, Meere M, et al. Some design considerations for polymer-free drug-eluting stents: a mathematical approach. Acta Biomater 2015;18:213–25. https://doi.org/10.1016/j.actbio.2015.02.006; PMID: 25712386. Worthley SG, Abizaid A, Kirtane AJ, et al. First-in-human evaluation of a novel polymer-free drug-filled stent: angiographic, IVUS, OCT, and clinical outcomes from the RevElution study. JACC Cardiovasc Interv 2017;10:147–56. https://doi.org/10.1016/j.jcin.2016.10.020; PMID: 28104208.  Dahm JB1, Willems T, Wolpers HG, et al. Clinical investigation into the observation that silicon carbide coating on cobalt chromium stents leads to early differentiating functional endothelial layer, increased safety and DES-like recurrent stenosis rates: results of the PRO-Heal Registry (PRO-Kinetic enhancing rapid in-stent endothelialisation). EuroIntervention 2009;4:502–8. https://doi.org/10.4244/EIJV4I4A85; PMID: 19284073. Visconti G, Focaccio A, Tavano D, et al. The CID Chrono cobalt-chromium alloy carbofilm-coated coronary stent system. Int J Cardiol 2011;149:199–204. https://doi.org/10.1016/j.ijcard.2010.01.009; PMID: 20138377.  Nakazawa G, Granada JF, Alviar CL, et al. Anti-CD34 antibodies immobilized on the surface of sirolimus-eluting stents enhance stent endothelialization. JACC Cardiovasc Interv 2010;3:68–75. https://doi.org/10.1016/j.jcin.2009.09.015; PMID: 20129572.  Karjalainen PP, Nammas W. Titanium-nitrideoxide-coated coronary stents: insights from the available evidence. Ann Med 2017;49:299–309. https://doi.org/10.1080/07853890.2016.1244353;

PMID: 27690662. 32. K  arimi M, Zare H, Bakhshian Nik A, et al. Nanotechnology in diagnosis and treatment of coronary artery disease. Nanomedicine (Lond) 2016;11:513–30. https://doi.org/10.2217/nnm.16.3; PMID: 26906471. 33. Wykrzykowska JJ, Onuma Y, Serruys PW. Vascular restoration therapy: the fourth revolution in interventional cardiology and the ultimate “rosy” prophecy. EuroIntervention 2009;5:F7–8. https://doi.org/10.4244/EIJV5IFA1; PMID: 22100680. 34. Boeder NF, Dörr O, Bauer T, et al. Impact of strut thickness on acute mechanical performance: A comparison study using optical coherence tomography between DESolve 150 and DESolve 100. Int J Cardiol 2017;246:74–9. https://doi.org/10.1016/j.ijcard.2017.05.087; PMID: 28579164.  35. Braun D, Baquet M, Massberg S, et al. Collapse of a bioresorbable novolimus-eluting coronary scaffold. JACC Cardiovasc Interv 2016;9:13–4. https://doi.org/10.1016/j. jcin.2015.10.019; PMID: 26685077. 36. Ruiz-Salmerón RJ, Pereira S, de Araujo D. Bioresorbable vascular scaffold collapse causes subacute thrombosis. J Invasive Cardiol 2014;26:98–9. PMID: 24993999. 37. Sorrentino S, Giustino G, Mehran R, et al. Everolimuseluting bioresorbable scaffolds versus everolimuseluting metallic stents. J Am Coll Cardiol 2017;69:3055–66. https://doi.org/10.1016/j.jacc.2017.04.011; PMID: 28412389. 38. Thakkar AS, Dave BA. Revolution of drug-eluting coronary stents: an analysis of market leaders. Eur Med J 2016; 4:114–25. 39. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622. 40. Garot P, Morice MC, Tresukosol D, et al. 2-year outcomes of high bleeding risk patients after polymer-free drug-coated stents. J Am Coll Cardiol 2017;69:162–71. https://doi.org/1 0.1016/j.jacc.2016.10.009; PMID: 27806919.

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Interventions

Effect of Percutaneous Coronary Intervention on Heart Rate Variability in Coronary Artery Disease Patients Mahmoud H Abdelnaby Medical Research Institute, Alexandria University, Alexandria, Egypt

Abstract Patients with coronary artery disease (CAD) have a state of autonomic imbalance with a sympathetic predominance. Autonomic dysfunction has been linked to an increased risk of cardiovascular morbidity and mortality. Heart rate variability (HRV) analysis is one of the most encouraging non-invasive diagnostic models and is increasingly used for the assessment of autonomic dysfunction. Percutaneous coronary intervention (PCI) is considered the gold standard in CAD treatment. Revascularisation through PCI eliminates the state of sympathetic hyperactivity, restores the normal cardiac autonomic modulation that can be assessed by HRV measurement.

Keywords Coronary artery disease, percutaneous coronary intervention, heart rate variability Disclosure: The author has no conflict of interest to declare. Acknowledgements: The author would like to thank Prof Dr Moustafa Nawar, Prof Dr Mohammed Ahmed Sadaka, Faculty of Medicine, Alexandria University, Alexandria, Egypt; and Dr Moataz Ahmed Zaki, Medical Research Institute, Alexandria University, Alexandria, Egypt. Received: 25 April 2018 Accepted: 13 July 2018 Citation: European Cardiology Review 2018;13(1):60–1. DOI: https://doi.org/10.15420/ecr.2018.13.2 Correspondence: Mahmoud Hassan Abdelnaby, Cardiology and Angiology Unit, Clinical and Experimental Internal Medicine Department, Medical Research Institute, Alexandria University, 165 El-Horeya Rd, Al Ibrahimeyah Qebli WA Al Hadrah Bahri, Qesm Bab Sharqi, Alexandria, Egypt. E: mahmoud.hassan.abdelnabi@outlook.com

Coronary artery disease (CAD) is the most common cause of morbidity and premature mortality globally,1 and cardiac autonomic dysfunction is one of the risk factors for CAD.2 Heart rate variability (HRV) is the physiological phenomenon of variation in the time interval between heartbeats and is one of the most promising non-invasive diagnostic methods for assessing autonomic dysfunction. HRV measurement can efficiently reflect the activity of both sympathetic and vagal components of the autonomic nervous system on the sinus node of the heart.3 It is well established that reduced HRV is an independent predictor of sudden cardiac death in congestive heart failure, poorer outcomes for survivors of acute MI (AMI), and increased cardiovascular risk in people with diabetes.4–7

Effect of Coronary Revascularisation in the Restoration of Normal Autonomic Balance Patients with CAD and exercise-induced angina have a state of autonomic dysfunction in the form of sympathetic overstimulation, which is considered to be triggered by myocardial ischaemia.8 Many studies have linked CAD to reduced HRV even in the absence of heart failure or previous MI.2,9 Theoretically, coronary revascularisation in CAD patients by percutaneous coronary intervention (PCI) could restore the normal autonomic balance, which can be proved and quantified by HRV measurement. This theory has been proved in several trials. Bonnemeier et al. assessed the effect of successful reperfusion by primary PCI on HRV after AMI.10 The principal conclusion of the study was that early reperfusion in AMI resulted in a significant recovery of HRV parameters, which indicates vagal activation and sympathetic withdrawal. HRV was significantly lower in patients undergoing late perfusion compared with

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those with early reperfusion. Early reperfusion has a beneficial effect by normalisation of HRV, reflecting attenuation of cardiac autonomic impairment that yields a better outcome after AMI. Sedziwy et al. studied HRV time domains in patients before PCI and during a 1-year follow-up after PCI using serial 24-hour Holter monitoring.11 They concluded that successful revascularisation using PCI led to a significant improvement in HRV autonomic balance. Aydinlar et al. investigated the effect of PCI on QT dispersion and HRV in patients with single-vessel CAD who underwent elective PCI.12 They concluded that HRV parameters significantly improved after PCI. Abrootan et al. studied changes in HRV parameters after elective PCI in patients with stable angina pectoris showing that short-term HRV parameters improved 24 hours after PCI.8 Thes two studies show that PCI is associated with an improved autonomic modulation and overall survival in CAD patients.

Current Limitations of Using Heart Rate Variability in Clinical Practice Despite several published experimental and clinical trials of HRV measurement, the use of HRV is limited to research and not routinely used in daily clinical practice.9 This can be explained by several factors. The clinical application of HRV assessment is limited by the lack of standard methods and the variability of parameters such as gender, age, drug interferences and concomitant diseases. There is still no consensus about the most accurate HRV parameter for clinical usage. The sensitivity, specificity and positive predictive accuracy of HRV in risk stratification are still limited. Notably, its positive predictive accuracy is modest, ranging from 14 % to 40 %. However, it has a higher negative

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Effect of PCI on HRV in CAD patients predictive value, ranging from 77 % to 98 %.9 Conflicting data suggest that it may be insufficient by itself for adequate risk stratification in high-risk patients. The combination of HRV with other risk stratification methods, including left ventricular ejection fraction, non-sustained ventricular tachycardia, and baroreceptor sensitivity may increase the overall predictive accuracy.13,14

1.

2.

3.

4. 5.

6.

 ichols M, Townsend N, Scarborough P, Rayner M. N Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 2014;35:2950–9. https://doi.org/10.1093/ eurheartj/ehu299; PMID: 25139896. Feng J, Wang A, Gao C, Zet al. Altered heart rate variability depend on the characteristics of coronary lesions in stable angina pectoris. Anatol J Cardiol 2015;15:496–501. https://doi. org/10.5152/akd.2014.5642; PMID: 25550177. Sztajzel J. Heart rate variability: a noninvasive electrocardiographic method to measure the autonomic nervous system. Swiss Med Wkly 2004;134:514–22. PMID: 15517504. Musialik-Łydka A, Sredniawa B, Pasyk S. Heart rate variability in heart failure. Kardiol Pol 2003;58:14–6. PMID: 14502297. Buccelletti E, Gilardi E, Scaini E, et al. Heart rate variability and myocardial infarction: systematic literature review and metanalysis. Eur Rev Med Pharmacol Sci 2009;13:299–307. PMID: 19694345. Futterman L, Lemberg L. Heart rate variability: prognostic

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Conclusion HRV is one of the most promising methods for detection and quantification of autonomic dysfunction. Further research is required for further validation of its effectiveness in clinical usage and its usefulness in risk stratification and as an independent prognostic factor for CAD. n

implications. Am J Crit Care 1994;3:476–80. PMID: 7834011. Markuszewski L, Bissinger A. Application of heart rate variability in prognosis of patients with diabetes mellitus. Pol Merkur Lekarski 2005;19:548–52 [in Polish]. PMID: 16379323. 8. Abrootan S, Yazdankhah S, Payami B, Alasti M. Changes in heart rate variability parameters after elective percutaneous coronary intervention. J Tehran Heart Cent 2015;10:80–4. PMID: 26110006. 9. Pivatelli FC, Dos Santos MA, Fernandes GB, et al. Sensitivity, specificity and predictive values of linear and nonlinear indices of heart rate variability in stable angina patients. Int Arch Med 2012;5:31. https://doi.org/10.1186/1755-7682-5-31; PMID: 23110977. 10. Bonnemeier H, Hartmann F, Wiegand UK, et al. Heart rate variability in patients with acute myocardial infarction undergoing primary coronary angioplasty. Am J Cardiol 2000;85:815–20. https://doi.org/10.1016/S00029149(99)00873-5; PMID: 10758919. 11. Sedziwy E, Olszowska M, Tracz W, Pieniazek P. Heart rate 7.

variability in patients treated with percutaneous transluminal coronary angioplasty. Przegl Lek 2002;59:695–8 [in Polish]. PMID: 12632888. 12. Aydinlar A, Sentürk T, Ozdemïr B, et al. Effect of percutaneous transluminal coronary angioplasty on QT dispersion and heart rate variability parameters: cardiovascular topics. Cardiovasc J Africa 2009;20:240–4. PMID: 19701536. 13. Odemuyiwa O, Farrell TG, Malik M, et al. Influence of age on the relation between heart rate variability, left ventricular ejection fraction, frequency of ventricular extrasystoles, and sudden death after myocardial infarction. Br Heart J 1992;67:387–91. https://doi.org/10.1136/hrt.67.5.387; PMID: 1382505. 14. Farrell TG, Bashir Y, Cripps T, et al. Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram. J Am Coll Cardiol 1991;18:687–97. https://doi.org/10.1016/0735-1097(91)90791-7; PMID: 1822090.

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Management and Comorbidities

Guest Editorial Is Cardio-oncology Ready for Algorithms? Steven M Ewer Associate Professor of Medicine, University of Wisconsin School of Medicine and Public Health

Citation: European Cardiology Review 2018;13(1):62–3. DOI: https://doi.org/10.15420/ecr.2018.13.1.GE2 Correspondence: Associate Prof Steven M Ewer, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. E: smewer@medicine.wisc.edu

C

ardio-oncology can be defined as a cross-disciplinary, collaborative sub-specialty focused on the prevention, management and mitigation of cardiovascular disease in cancer patients in order to achieve optimal patient outcomes.1 As such, this sub-specialty has been in existence for approximately 40 years, if not in name, then certainly in its goals of clinical practice and lines of scientific inquiry. Interest in cardio-oncology has blossomed over the past 15 years, as many newer targeted agents have been recognised for their potential to cause cardiotoxicity. The increasing complexity arising from cardiotoxicity of anti-cancer treatment has left clinicians hungry for advice on how to approach this unique patient population. Two recent publications have sought to provide some authoritative guidance regarding the management of patients undergoing potentially cardiotoxic treatments: the 2016 European Society of Cardiology (ESC) position paper on cancer treatments and cardiovascular toxicity and the 2017 American Society of Clinical Oncology (ASCO) clinical practice guideline on prevention and monitoring of cardiac dysfunction in survivors of adult cancers.2,3 The ESC position paper is not a formal clinical practice guideline, but rather a document reflecting expert consensus. The ASCO guideline is more limited in scope, addressing five specific clinical questions for which we have more mature evidence to support recommendations. They both acknowledge the limitations of and gaps in our current scientific evidence.

For patients receiving potentially cardiotoxic therapy, both documents agree on the following recommendations: • O  btain a baseline clinical assessment of risk for cardiotoxicity based on established risk factors, anticipated cancer treatments and assessment of left ventricular ejection fraction. • Identify and manage modifiable cardiovascular risk factors, such as hypertension and smoking, prior to cancer therapies. • Consider cardioprotective strategies for patients at high risk for cardiotoxity. •  Monitor for signs and symptoms of cardiac dysfunction during treatment. •  Follow-up assessment of ejection fraction after completion of treatment. Both documents are also in agreement that there is no evidence to support withholding or interrupting cancer treatment based on biomarkers or global longitudinal strain echocardiography. Koutsoukis et al. present a nice overview of the spectrum of cardiotoxcity, with particular emphasis on myocardial dysfunction.4 The authors then go on to provide guidance regarding evaluation and monitoring for patients receiving potentially cardiotoxic therapy. The authors’ proposed algorithm for baseline evaluation (Figure 1) aligns nicely with the above evidence-based recommendations endorsed by the ESC and ASCO.

Specifically regarding surveillance, the ESC document states: “The timing of cardiotoxicity surveillance using echocardiography and biomarkers needs to be personalized to the patient in the context of their baseline cardiovascular risk and the specific cancer treatment protocol prescribed.”

It should be mentioned that routine measurement of cardiac biomarkers is not necessarily part of a pre-treatment cardiovascular assessment. Baseline biomarker values may be reasonable if additional monitoring of biomarkers during treatment is anticipated. Biomarkers can certainly be of use in assessment if signs and symptoms of cardiac dysfunction develop during treatment.

Likewise, the ASCO guidelines remain intentionally vague for asymptomatic patients with increased risk for cardiotoxicity: “Frequency of surveillance should be determined by health care providers based on clinical judgement and patient circumstances.”

The measurement of global longitudinal strain is a tool we have to identify higher risk patients, but it is not yet clear how to integrate this data into our current management algorithms, and thus, firm recommendations on its routine use may not be justified.

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Cardio-oncology We should be even more cautious, however, regarding algorithms that recommend specific parameters for interruption or discontinuation of cancer therapy. An algorithm for patients receiving anthracyclines (Figure 2) is adapted from a review article by Herrmann, et al.5 The proposed algorithm for trastuzumab (Figure 3) is based on recommendations of the UK National Cancer Research Institute,6 which are referenced and discussed in the ESC document, but not formally endorsed by the ESC or ASCO. The proposed monitoring and treatment algorithms presented in Figures 2 and 3 may represent reasonable starting points for some patients, but cannot be applied uniformly to large groups of patients

1.

2.

3.

Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol 2015;12:547–58. https://doi.org/10.1038/ nrcardio.2015.65; PMID: 25962976. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J 2016;37:2768–801. https:// doi.org/10.1093/eurheartj/ehw211; PMID: 27567406. Armenian SH, Lacchetti C, Barac A, et al. Prevention and

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4.

5.

without further validation. Decisions on withholding cancer treatment must always be individualised after careful consideration of risk and benefit by both the oncologist and the cardiologist. Our goal is not to minimise cardiotoxicity at any cost, but rather to weigh the cardiac risks against the oncologic benefits of our treatments in order to maximise the overall health of our patients. Until more scientific evidence becomes available to support their use, we are not yet ready for detailed management algorithms. Until then, we are left with our best clinical judgement and nuanced collaborative discussions that currently make the practice of clinical cardio-oncology rich and rewarding. n

monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2017;35:893–911. https://doi. org/10.1200/JOP.2016.018770; PMID: 27922796. Koutsoukis A, Ntalianis A, Repasos E, et al. Cardio-oncology: a focus on cardiotoxicity. European Cardiology Review 2018;13(1):64–9. https://doi.org/10.15420/ecr.2017:17:2 Herrmann J, Lerman A, Sandhu NP, et al. Evaluation and management of patients with heart disease and cancer:

6.

cardio-oncology. Mayo Clin Proc 2014;89:1287–306. https://doi.org/10.1016/j.mayocp.2014.05.013; PMID: 25192616. Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer 2009;100:684–92. https://doi.org/10.1038/sj.bjc.6604909; PMID: 19259090.

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Management and Comorbidities

Cardio-oncology: A Focus on Cardiotoxicity Athanasios Koutsoukis, Argyrios Ntalianis, Evangelos Repasos, Efsthathios Kastritis, Meletios-Athanasios Dimopoulos and Ioannis Paraskevaidis Department of Clinical Therapeutics, National and Kapodistrian University of Athens Alexandra Hospital, Athens, Greece

Abstract Cardio-oncology is a recently developed field in cardiology aimed at significantly reducing cardiovascular morbidity and mortality and improving quality of life in cancer survivors. Cancer survival rates have been constantly increasing, mainly because of the advent of new, more potent and targeted therapies. However, many of the new therapies – along with some of the older chemotherapeutic regimens such as anthracyclines – are potentially cardiotoxic, which is reflected increasingly frequently in the published literature. Cardiotoxicity adversely affects prognosis in cancer patients, thus its prevention and treatment are crucial to improve quality and standards of care. This review aims to explore the existing literature relating to chemotherapy- and radiotherapy-induced cardiotoxicity. An overview of the imaging modalities for the identification of cardiotoxicity and therapies for its prevention and management is also provided.

Keywords Adverse effects, cancer, cardio-oncology, chemotherapy, chemotherapy-associated cardiotoxicity Disclosure: The authors have no conflicts of interest to declare. AK and AN contributed equally to this work. Received: 1 September 2017 Accepted: 21 March 2018 Citation: European Cardiology Review 2018;13(1):64–9. DOI: https://doi.org/10.15420/ecr.2017:17:2 Correspondence: Argyrios Ntalianis ,Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital,11528 Athens, Greece. E: arg_nt@yahoo.gr

Cardio-oncology is an emerging field of cardiology that focuses on cardiovascular diseases in patients with cancer. The classic cardio-oncology paradigm is the prevention, diagnosis and treatment of cardiotoxicity resulting from chemotherapy and/or radiotherapy. Diagnosis and treatment of primary and metastatic cardiac tumours as well as cardiac amyloidosis can be considered ‘less classical’ cardiooncology objectives. Anthracycline-induced cardiotoxicity was first reported in early 1970s.1 Since then, there has been increasing recognition of its association with poor prognosis and survival.2 More recently, while new targeted and more effective molecules have been introduced in clinical oncology, cardiotoxic effects – which are not uncommon – may potentially outweigh theoretical clinical benefit. The incidence of cardiotoxicity varies with the type of the treatment. Doxorubicin is associated with cardiotoxicity in 3–26 % of treated patients, trastuzumab in 2–28 % and sunitinib in 2.7–11 %.3 In a recent retrospective study, 6.6  % of patients with breast or haematological cancer who received chemotherapy went on to develop heart failure.4 Furthermore, patients with cancer are also at a higher risk for coronary artery disease, arrhythmias and thromboembolism. 5 Interestingly, cancer and coronary artery disease share common cellular and genetic pathways as well as risk factor profiles.6 Overall, the management of patients with cancer is complex and requires a multidisciplinary team approach involving oncologists, surgeons, radiologists and clinical cardiologists. The aim of this review is to provide an overview of chemotherapy and radiotherapyrelated cardiotoxicity, with a special focus on diagnosis, prevention and management.

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Cardiovascular Complications Anti-cancer treatment is associated with serious cardiovascular adverse events, including arterial and pulmonary hypertension, supraventricular and ventricular arrhythmias, systolic and diastolic cardiac dysfunction and coronary artery disease. It has been postulated that chemotherapy- and radiotherapy-related endothelial dysfunction, thrombogenesis and myocardial injury may partly explain these cardiovascular complications.

Myocardial Dysfunction According to recent cardio-oncology expert consensus, significant cardiotoxicity after chemotherapy is considered when the following heart echocardiographic criteria are fulfilled: (i) an absolute decrease of ≥10 % in left ventricular ejection fraction (EF), and (ii) an EF of <50  %. Additionally, left ventricular global longitudinal strain (GLS) is proposed as an early marker of imminent cardiotoxicity because a reduction in GLS of >15  % during chemotherapy is associated with a higher probability of significant left ventricular systolic dysfunction in the near future.7 Two pathophysiological mechanisms have been described for chemotherapy-induced cardiotoxicity. First is direct toxicity and destruction of myocardial cells, which results in permanent and possibly irreversible myocardial dysfunction (type I cardiotoxicity). The second is inhibition of the physiological function of myocardial cells, which results in ‘stunned’ myocardium and significant but eventually reversible myocardial dysfunction (type II cardiotoxicity).8 These two mechanisms frequently overlap. The classic example of type I cardiotoxicity is anthracycline cardiotoxicity, which is usually dose dependent. Trastuzumab cardiotoxicity is an example of type II cardiotoxicity but it is not dose-dependent.9

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Chemotherapy-associated Cardiotoxicity Myocardial Ischaemia Some chemotherapeutic agents (i.e. 5-fluorouracil and gemcitabine) increase the risk of coronary atherosclerosis and acute coronary syndromes. Continuous intravenous infusion of 5-fluorouracil can induce myocardial ischaemia that manifests as chest pain and ischaemic ECG changes, usually between the second and fifth day of treatment. This effect is not dose dependent.10 The pathophysiological mechanisms implicated are vasculitis, spasm and thrombosis. VEGF inhibitors such as bevacizumab and cisplatin have also been associated with myocardial ischaemia through endothelial dysfunction, hypercoagulability and thrombosis.28 The incidence of cisplatin-associated acute coronary syndrome is approximately 2 %.7 Radiotherapy is associated with coronary atherosclerosis – especially in the coronary ostia – and a higher risk for acute coronary syndromes. Following radiotherapy for Hodgkin lymphoma, the cumulative incidence of coronary artery disease is high (approximately 20 %), even 40 after years.38 Therefore, long-term follow-up and close monitoring for several years after radiotherapy is reasonable. Interestingly, coronary artery disease and cancer share similar risk factors and pathophysiological pathways (i.e. chronic inflammation). Modification of risk factors has been shown to prevent the development of both coronary artery disease and cancer but little is known about its effect on chemotherapy and/or radiotherapyinduced coronary cardiotoxicity.6

Arterial Hypertension Arterial hypertension is frequently reported in patients receiving VEGF inhibitors (11–45 %). Bevacizumab and sunitinib increase the risk of arterial hypertension or aggravation of pre-existing hypertension – possibly via inhibition of angiogenesis, reduction in nitric oxide and increase in endothelin-1 levels along with glomerular injury and renal microangiopathy.11 Furthermore, the inhibition of beta-type plateletderived growth factor receptor by sunitinib has been associated with microcirculatory dysfunction. Consequently an acute rise in arterial blood pressure – even in normotensive patients – can be expected following the introduction of VEGF inhibitors, and regular blood pressure recordings and blood pressure adjustment with antihypertensive medications are generally recommended. A significant increase in arterial blood pressure is normally observed in the first year after treatment. Angiotensinconverting-enzyme (ACE) inhibitors and calcium channel blockers are usually prescribed in these cases.12

Arrhythmias and Anticoagulation in Atrial Fibrillation/Flutter Arrhythmias – either supraventricular or ventricular – can frequently occur during chemotherapy. It has been shown recently that a nonnegligible number of patients with chronic lymphocytic leukaemia treated with ibrutinib developed AF (approximately 3 %).13 In contrast, thalidomide is associated with an increased risk of bradyarrhythmias and therefore beta-blockers and calcium channel blockers should be used with caution in these cases. Arsenic trioxide, a very effective drug for relapsing acute promyelocytic leukaemia, may prolong the QT interval and induce torsades de pointes.14 Thus, QT interval should be carefully monitored in patients receiving arsenic trioxide before every new cycle of therapy. Less frequently, tyrosine kinase inhibitors, proteasome inhibitors and histone deacetylase inhibitors may prolong QT.14

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Anticoagulation in patients with cancer and AF can be difficult to manage. Cancer is often associated with a higher risk for thrombosis, but at the same time cancer therapies may predispose to a higher risk for bleeding. The scores commonly used to evaluate embolic (CHADS-VASC) and bleeding risk (HAS-BLED) in patients with AF are possibly not applicable in patients with coexistent AF and malignancy.7 Furthermore, there are no robust data on the safety and efficacy of both vitamin K antagonists and the new oral anticoagulants during or after chemotherapy – especially in patients with imminent thrombocytopaenia. For this reason, decision making for anticoagulation in patients with malignancy and AF should be individualised. Low molecular weight or classical heparin might be an alternative short-term anticoagulation option.15

Pulmonary Hypertension Dyspnoea secondary to pulmonary hypertension is a relatively frequent adverse effect of dasatinib, a chimeric oncogene BCR-ABL tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia. The underlying pathophysiological mechanism is not clear, although toxicity is usually reversible after dasatinib discontinuation.16 Pulmonary arterial hypertension has also been sporadically reported with thalidomide and carfilzomib.17,18

Thromboembolic Disease Malignancy is known to be associated with a prothrombotic milieu, which may be exacerbated by chemotherapy. Immunomodulatory imide drugs such as thalidomide, lenalidomide and pomalidomide commonly used in the treatment of multiple myeloma are associated with a risk for thromboembolism, ranging from 10 to 40 %. Both patient- and drug-related factors have been implicated in this variability.19 The prophylactic use of aspirin for low-risk patients and anticoagulation with either low molecular weight heparin or warfarin for high-risk patients is generally recommended.15,20 Cisplatin, erlotinib and bevacizumab have also been reported to increase the risk for thrombotic events but there are no special recommendations for thrombosis prophylaxis.15

Valvular Heart Disease Autopsy studies have suggested that mediastinal irradiation for a wide range of cancers may potentially adversely affect the heart valves.21 Diffuse or focal fibrosis, thickening and calcification of the valves as a result of upregulation of fibrogenic growth factors, and increased formation of osteogenic factors have been described. Interestingly, in contrast to rheumatic valve disease, radiation does not usually affect the tips of the valves. The prevalence of radiation-induced valve disease ranges from 2 to 37 % for Hodgkin lymphoma and from 0.5 to 4.2  % for breast cancer.21 A long latent interval between radiation exposure and valve disease (usually >10 years) has been reported.21 It is important to note that in immunocompromised patients a high level of awareness of infective endocarditis is particularly warranted, especially when valve regurgitation is discovered during or after chemotherapy. Finally, chemotherapy-induced cardiotoxicity may associate with severe functional mitral valve regurgitation, which should be promptly diagnosed and treated.

Pericarditis and Pericardial Effusion Both radiotherapy and chemotherapy (i.e. anthracyclines, bleomycin, cyclophosphamide) can be associated with a chronic inflammatory process of the pericardium. Radiation-induced pericardial effusion has been reported as late as 15 years following radiotherapy.22 Another

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Management and Comorbidities manifestation of pericardial disease is constrictive pericarditis, which might develop after exposure to high radiation doses.23

is via myocardial capillary rarefaction, which induces hypoxia and activation of hypoxia-related genes and apoptosis.20

Peripheral Artery Disease

Proteasome Inhibitors

Tyrosine kinase inhibitors (nilotinib and ponatinib) may adversely affect the peripheral arterial circulation and increase the risk of peripheral artery disease even in the absence of traditional cardiovascular risk factors.12 Previous neck irradiation increases the chance of acceleration of carotid artery atherosclerosis and ischaemic stroke.21

Proteasome inhibitors inhibit different catalytic sites of proteasome and through caspase 3/7 signalling result in apoptosis and left ventricular systolic dysfunction.35 Bortezomib is the first proteasome inhibitor clinically tested in haematological malignancies, and acts via reversible inhibition the 26S site of proteasome. It has been estimated that it might double the risk for all-grade cardiotoxicity in multiple myeloma patients.35 Carfilzomib is a novel proteasome inhibitor approved by the Food and Drug Administration for multiple myeloma resistant to bortezomib. It irreversibly inhibits the beta 5 subunit of the 20S proteasome complex and is considered more cardiotoxic than bortezomib. Carfilzomib has also been associated with a higher incidence of cardiac arrhythmias. Ixazomib is the first oral proteasome inhibitor that reversibly inhibits the beta 5 subunit of the 20S proteasome complex, and only sporadic cases of cardiotoxicity have been reported.35

Cancer Treatments Associated with Cardiotoxicity Anthracyclines Anthracycline-associated cardiotoxicity is traditionally divided into early-onset acute toxicity and late-onset chronic evolving toxicity. Early-onset cardiotoxicity usually occurs within hours to weeks but definitely during the first year after anthracycline administration, and can be reversible with early detection and treatment.24 Late-onset cardiotoxicity can present in a period of 10–20 years after treatment. The clinical presentation of acute toxicity is variable, ranging from arrhythmias and myocarditis to acute coronary syndromes and acute heart failure.25 The molecular mechanism of anthracycline-induced cardiotoxicity involves the inhibition of topoisomerase IIb in myocardial cells, which induces DNA double-strand breaks and activation of the apoptotic programme of the heart via mitochondriopathy and increase in radical oxygen species.26 The most commonly used anthracyclines are doxorubicin, epirubicin and idarubicin. The highest doxorubicin cumulative dose recommended is 400–550 mg/m2.27 Higher doses significantly increase the risk of cardiotoxicity, which can range from 18 to 48 % for a cumulative dose of 700 mg/m2.7 However, even low doses (<300 mg/m2) are associated with a non-negligible risk for cardiotoxicity (1.6  %). Liposomal anthracyclines such as pegylated liposomal doxorubicin are significantly less cardiotoxic and have comparable effectiveness, and can be an alternative choice for patients at high risk for cardiotoxicity.28

HER2 Inhibitors The human epidermal growth factor receptor (HER) 2 inhibitor trastuzumab has proven to be very effective in metastatic HER2-positive breast cancer. However, HER2 is also expressed on cardiomyocytes and its inhibition by trastuzumab can possibly lead to the development of cardiotoxicity.29 Trastuzumab cardiotoxicity is often reversible with cessation of therapy and initiation of heart failure medications. However, some degree of persistent myocardial dysfunction is documented in nearly one third of these patients.30 Re-introduction of the medication should be always balanced against cardiotoxicity risk.30 Concomitant use of trastuzumab and anthracyclines is associated with a higher risk of cardiotoxicity compared with anthracycline monotherapy.31 Other approved anti-HER2 agents, such as pertuzumab and trastuzumab emtansine, are also considered cardiotoxic.31

VEGF Inhibitors It is difficult to make an accurate estimate of vascular endothelial growth factor (VEGF) inhibitor-related cardiotoxicity as large clinical trials are lacking. In general, sunitinib has been found to cause systolic dysfunction in 3–15 % of patients and bevacizumab-associated heart failure is observed in 2 % of patients.7,32 A recent meta-analysis showed a higher risk for congestive heart failure with anti-VEGF molecules, although severe heart failure was rare.33 In murine models, one possible mechanism explaining VEGF inhibitor-related cardiotoxicity

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Other Commonly used and Potentially Cardiotoxic Treatments Cyclophosphamide- and ifosfamide-induced cardiotoxicity is dose dependent and usually presents few days after treatment. High doses (>140 mg/kg) are considered very cardiotoxic. Although platinum-based therapies have been associated with decompensated heart failure, pre-existing myocardial dysfunction and volume overload during platinum administration are probably responsible for heart failure decompensation rather than platinum per se.36 New immunotherapy agents such as ipilimumab (an anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody) and nivolumab (an anti-programmed death 1 monoclonal antibody) are usually co-administered for the treatment of melanoma and have been estimated to induce resistant myocarditis in approximately 1 % of patients.37 Interestingly, several chemotherapeutic agents have been linked with left ventricular diastolic dysfunction, with a benign prognosis in the majority of cases.

Radiotherapy The relative risk for the development of heart failure in the context of radiotherapy is difficult to estimate with accuracy because the co-administration of cardiotoxic chemotherapy is a confounding factor. However, it should be emphasised that patients with breast cancer treated with both chemotherapy and radiotherapy are at increased risk for developing cardiotoxicity compared with chemotherapy alone. There is often a long delay between exposure to radiation and clinically apparent heart dysfunction. The development of significant fibrosis post radiotherapy that can potentially affect all cardiac structures (myocardium, pericardium, coronary arteries or heart valves) has been described widely in the literature.38 Of note, radiotherapy-induced coronary or valvular heart disease may also progress after years to congestive heart failure.39,40

Diagnosis and Treatment Initial Evaluation A baseline work-up including medical history, clinical examination, laboratory tests, an electrocardiogram and an echocardiogram with speckle tracking should precede a potentially cardiotoxic chemotherapy (Figure 1).6,41 Predictive models can be used to assess the risk of cardiotoxicity on the basis of the baseline patient characteristics.

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Chemotherapy-associated Cardiotoxicity Factors that may predispose to cardiac adverse events include a previous diagnosis of structural heart disease, the presence of traditional cardiovascular risk factors, previous or future exposure to cardiotoxic therapy and older age (Table 3). Other baseline tests, such as 24–hour ECG and 24-hour blood pressure monitoring, functional ischaemia testing, magnetic resonance imaging and right heart catheterisation, can also be considered for diagnosis and/or risk stratification. Cardiac biomarkers such as high sensitivity troponin I, brain natriuretic peptide (BNP) and NT-proBNP may be helpful in identifying patients at risk for cardiotoxicity. However, limited data exist on the timing for these tests and their clinical impact on further patient management.42

Imaging and Monitoring for Systolic Dysfunction At present, the most commonly used parameter for the evaluation of the systolic function is the EF. However, intra-observer and interobserver variability for 2D EF measurements using the Simpson’s biplane method is not negligible. In addition, small but significant EF changes (≤10 %) might be missed by 2D but usually not by 3D echo.43 Obstacles such as poor image quality resulting from rapid heart rate, increased cardiac translocation, and respiratory interference might be overcome with intravenous contrast infusion. Radionuclide ventriculography or multigate acquisition scan (MUGA) is another relatively accurate and alternative to heart echo imaging modality to detect even asymptomatic left ventricular dysfunction in patients receiving chemotherapy. MUGA has been previously used to evaluate left ventricular function after anthracycline administration, and many of the recommendations for the monitoring and management of anthracycline-induced cardiotoxicity are based on MUGA findings.44 Cardiac MRI is another imaging modality that can precisely identify early signs of cardiotoxicity (i.e. inflammation and oedema) and assess ventricular volumes and function. The extent of late gadolinium enhancement may identify patients with worse prognosis, whereas diffuse fibrosis in T1 mapping can predict late anthracycline cardiotoxicity.45 Furthermore, cardiac MRI is probably the best technique for the diagnosis of cardiac tumours and radiotherapy-related pericardial disease.

Follow-up and Treatment of Myocardial Dysfunction For patients receiving anthracyclines and/or trastuzumab after baseline clinical evaluation and heart echo, routine clinical followups and heart echos are recommended every 3 months for the first year of therapy. 41 For anthracyclines in particular, a repeat echo is also advisable at a cumulative dose of 240 mg/m 2 or even earlier if clinical symptoms and/or an increase in cardiac enzymes is observed (Figure 2). For higher anthracycline doses, routine echocardiograms are recommended before each anthracycline cycle. For less cardiotoxic chemotherapy, follow-up assessments should be individualised. Troponin levels at the beginning of the treatment and after each cycle might be helpful in the early identification of patients at high risk for cardiotoxicity.46 Any troponin increase should be discussed in a multidisciplinary team meeting with oncologists and cardiologists to set the onward treatment plan for the patient. In patients with breast cancer, troponin and GLS measurements are the best predictors of cardiotoxicity with a specificity of 93 % and a negative predictive value of 91 %.47

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Figure 1: Proposed Algorithm for the Baseline Evaluation of a Patient Planned to Receive Cardiotoxic Treatment Cardiotoxic treatment to be initiated

• Cardiovascular risk evaluation/pre-existing cardiac disease • Cancer history/previous cardiotoxic treatment

• Clinical examination • Laboratory work-up (consider baseline BNP and troponin levels) • ECG • Baseline cardiac ultrasound (consider baseline global longitudinal strain measurements) • Alternative imaging modalities: 3D echo, MUGA scan, MRI

• No previous heart disease history • Low risk for cardiotoxicity • ECG and cardiac ultrasound without evidence of heart disease

• Previous heart disease history and/or cardiac symptoms • Medium/high risk for cardiotoxicity • Abnormal ECG or cardiac ultrasound

Start chemotherapy +/- radiotherapy and re-evaluate

• Further investigations • Start/optimise cardioprotective treatment before chemotherapy +/- radiotherapy

BNP = brain natriuretic peptide; MUGA = multigate acquisition scan.

Long-term clinical follow-up is mandatory for anthracyclines. Routine heart echos are recommended at 6, 24 and 36 months after the last anthracycline cycle. In particular, for patients who received anthracyclines before adolescence (<15 years old) or those exposed to high doses (>240 mg/m2), follow-up monitoring should extend to 4 and probably 10 years after therapy.13 Anthracyclines are contraindicated in patients with baseline severe systolic dysfunction (EF <30 %). A strong indication for temporary cessation of anthracyclines is an absolute EF decline of >10 %.43 In patients receiving trastuzumab, the detection of a mildly decreased EF (45–50  %) after therapy advocates both the introduction of heart failure treatment and re-assessment after 3 weeks without modification of trastuzumab dose (Figure 3). However, trastuzumab should be discontinued when EF drops below 45%, or to 45–50 % with an absolute decrease of at least ≥10 % compared with baseline.48 In patients receiving VEGF inhibitors, the optimal follow-up strategy remains unclear. However, it is reasonable to schedule a routine clinical examination and heart echo after 2–4 weeks of treatment, especially in patients with high risk criteria for developing cardiotoxicity.7 The prophylactic prescription of beta-blockers and ACE inhibitors before chemotherapy is generally reserved for high-risk patients (i.e. previous administration of anthracyclines/trastuzumab, baseline EF <50  %) although data are still controversial.46 In contrast, the prophylactic use of dexrazoxane is strongly supported for the prevention of cardiotoxicity in breast cancer patients treated with high doses of doxorubicin (>300 mg/m2).27

Treating Myocardial Ischaemia in Patients with Cancer The management of acute coronary syndromes in patients with cancer is challenging. A recent study from the Mayo Clinic has shown that

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Management and Comorbidities Figure 2: Proposed Follow-up Algorithm for Patients Receiving Anthracyclines BASELINE ASSESSMENT History, clinical exam, ECG, echocardiogram with strain

EF <50 %*

EF >50 % Anthracycline initiation

Re-evaluation before each cycle

Re-evaluation at doxorubicin dose: 250–300 mg/kg2

therapy should be the shortest time possible. In patients with severe thrombocytopaenia (platelet count <50.000/μL) the bleeding risk increases exponentially. According to current guidelines, dual antiplatelet therapy can be considered with caution when platelet count is higher than 30.000/μL, whereas aspirin as monotherapy is recommended when platelet count is between 10.000 and 30.000/μL.50 Radial access is associated with less bleeding and better clinical outcomes in patients with acute coronary syndromes. Extrapolating these findings in patients with cancer, a radial approach must be the preferred route for these patients too, because their bleeding risk is much higher than in the general population.

Prevention and Follow-up Re-evaluation at 400–450 mg/kg2 and after each cycle

• Interrupt if EF reduction >10 % , or EF < 30 % or symptoms of heart failure • Heart failure treatment • Re-evaluation in 3 weeks *Do not administer anthracyclines if EF <30 %. EF = ejection fraction.

Figure 3: Proposed Follow-up Algorithm for Patients Receiving Trastuzumab BASELINE ASSESSMENT History, clinical exam, ECG, echocardiogram

EF > 50 %: trastuzumab initiation

Re-evaluate at 12-week intervals • EF reduction >10 % or EF <40 % or • Symptoms of heart failure

Oncology patients at high risk for cardiotoxicity should be referred and assessed by cardiologists before chemotherapy. Less cardiotoxic chemotherapeutic agents and anti-remodelling drugs such as a beta-blockers, ACE inhibitors or angiotensin receptor blockers before chemotherapy may theoretically prevent cardiotoxicity in high risk patients. Of the beta-blockers, both nebivolol and carvedilol have been studied for the prevention and treatment of cardiotoxicity.46 However, there is equivocal evidence for the prophylactic use of some beta-blockers, ACE inhibitors and angiotensin receptor blockers in the recent literature. Pituskin et al. showed that perindopril and bisoprolol attenuated cardiotoxicity in patients treated with trastuzumab, but not left ventricular remodelling.51 In contrast, enalapril prevented cardiotoxicity in patients receiving anthracyclines as evidenced by the extent of myocardial injury measured with troponin.52 In the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial, candesartan but not metoprolol prevented the development of systolic dysfunction in breast cancer patients receiving anthracyclines.53 Conversely, Boekhout et al. showed that candesartan was not superior to placebo in preventing cardiotoxicity in breast cancer patients treated with anthracyclines and trastuzumab.54

EF >50 %

EF 45–50 % Re-evaluate at 12-week intervals

• Interrupt treatment • Introduce HF treatment

• Re-evaluate EF and symptoms in 3 weeks

Continue trastuzumab and introduce ACE inhibitors

EF >50 %: consider re-introducing trastuzumab

• Re-evaluate EF and symptoms in 3 weeks • Continue if EF stable and no symptoms

Data from retrospective studies suggest that statins may prevent the development of heart failure, but prospective data are warranted to confirm this. 55 As already discussed, dexrazoxane may attenuate the cardiotoxic effect of anthracyclines, possibly via a significant reduction of superoxide radicals produced by anthracyclines. Interestingly, it has been suggested that the modification of traditional risk factors together with regular aerobic exercise may prevent cardiotoxicity. 56

Conclusion

ACE = angiotensin-converting-enzyme; EF = ejection fraction.

10 % of patients presenting with ST-elevation MI (STEMI) are patients with cancer. Interestingly, primary percutaneous coronary intervention results in similar survival benefit in those patients compared with the general population with STEMI.49 The administration and duration of dual antiplatelet therapy must be individualised after balancing ischaemic and bleeding risk. The type of cancer and its prognosis and management should also be taken into account before dual antiplatelet therapy is given. In general, the duration of dual antiplatelet

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Cardio-oncology is increasingly becoming part of routine clinical practice. Alongside oncologists and cardiologists it requires the collaboration of several medical specialties, with this multidisciplinary approach contributing to improved outcomes in cancer patients in the contemporary era. The goal of cardio-oncology is to accomplish the prevention, early recognition and management of cardiotoxicity, but there are still a number of questions to be answered to improve patient prognosis and quality of life. On-going and future research is expected to elucidate the exact mechanisms involved in chemotherapy-induced cardiotoxicity and to accurately identify the genetic and molecular profiles underlying those mechanisms and making the heart more vulnerable to chemotherapy. n

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Management and Comorbidities

New Advances in the Management of Refractory Angina Pectoris Kevin Cheng 1,2 and Ranil de Silva 1,3 1. Specialist Angina Service, Royal Brompton and Harefield NHS Foundation Trust, London, UK; 2. Imperial College Healthcare NHS Trust, London, UK; 3. Vascular Science Department, National Heart and Lung Institute, London, UK

Abstract Refractory angina is a significant clinical problem and its successful management is often extremely challenging. Defined as chronic angina-type chest pain in the presence of myocardial ischaemia that persists despite optimal medical, interventional and surgical treatment, current therapies are limited and new approaches to treatment are needed. With an ageing population and increased survival from coronary artery disease, clinicians will increasingly encounter this complex condition in routine clinical practice. Novel therapies to target myocardial ischaemia in patients with refractory angina are at the forefront of research and in this review we discuss those in clinical translation and assess the evidence behind their efficacy.

Keywords Chest pain, angina pectoris, refractory angina pectoris, myocardial ischaemia, coronary sinus reducer, external enhanced counterpulsation, extracorporeal shockwave therapy, stem cells, cell therapy, clinical trials, innovation Disclosure: The authors have no conflicts of interest to declare. Received: 4 January 2018 Accepted: 27 March 2018 Citation: European Cardiology Review 2018;13(1):70–9. DOI: https://doi.org/10.15420/ecr.2018:1:2 Correspondence: Dr Ranil de Silva, Senior Lecturer in Clinical Cardiology, National Heart and Lung Institute, Brompton Campus, Sydney Street, London SW3 6NP, UK. E: r.desilva@imperial.ac.uk

Refractory angina (RA) is defined as chronic angina-type chest pain (duration ≥ 3 months) associated with reversible ischaemia that persists despite optimal medical, interventional and surgical management.1 The clinical burden of RA is growing due to an ageing population and improved survival from coronary artery disease (CAD). Estimates suggest that in the US between 600,000 and 1.8 million patients suffer from RA, with 75,000 new patients diagnosed each year. In Canada, approximately half a million patients live with RA, while in Europe, 30,000–50,000 new cases are diagnosed per year.2,3 Data on the epidemiology of RA in the UK are lacking and further work to define the disease burden is needed. The successful management of RA is often extremely challenging. Povsic et al. showed that patients with RA were more frequently hospitalised, often undergoing angiographic investigation without revascularisation and consequently incurring US$10,108 greater healthcare costs per patient over a 3-year period compared to a matched control group.4 Coupled with evidence that RA is not associated with worse long-term mortality, novel treatment approaches targeted at improving symptoms and quality of life in this challenging patient population are needed.5 Patients with RA may be more appropriately considered as having a chronic chest pain syndrome with both physical and psychological components that may require the implementation of pharmacological and psychological approaches as well as interventional strategies. 6–9 In this review, we focus on advances in the interventional management of RA, specifically coronary sinus reducer (CSR) implantation, external enhanced counterpulsation (EECP), extracorporeal shockwave therapy (ECSWT) and cell therapy.

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Coronary Sinus Reducer The CSR is a balloon catheter-mounted hourglass-shaped stent that has been shown to improve symptoms and quality of life in patients with RA (Figure 1). Stenting of the coronary sinus to produce a stenosis and increase venous backpressure has gained traction recently as a means of improving perfusion by diverting blood to ischaemic myocardium. It follows from studies originating from 1955 by Beck and colleagues at the Cleveland Clinic whereby experimental narrowing of the coronary sinus was able to reduce myocardial infarct size by increasing retrograde perfusion.10 Early translation into 185 patients with severe CAD who underwent surgical narrowing of the coronary sinus (through an open chest approach to produce a 60–70 % narrowing and achieve a 3 mm residual lumen diameter of the coronary sinus) demonstrated significant improvements in anginal symptoms, medication use and mortality.11,12 However, interest in this concept waned as interventions to improve arterial inflow, i.e. coronary bypass grafting and percutaneous coronary interventions, gained prominence in the latter half of the 20th century. More recent preclinical studies have shown that occlusion of the coronary sinus can preserve the endocardial-to-epicardial perfusion ratio, improving subendocardial perfusion by redistributing blood flow from non-ischaemic to ischaemic areas.11 To achieve this via a minimally invasive percutaneous approach, the CSR was developed as a catheter-mounted balloon-inflatable stent that can be implanted via a trans-jugular approach. In normal physiology, exercise-induced sympathetic-mediated vasoconstriction of epicardial arteries promotes blood flow to the subendocardium (subendocardial:subepicardial perfusion ratio: ~1.2).13 In the presence of epicardial CAD this is dysfunctional and, together with regional wall motion abnormalities with consequent raised left ventricular end-diastolic pressure and compression of

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Refractory Angina Pectoris the subendocardial capillaries, perfusion falls (perfusion ratio: 0.8). By raising venous backpressure through coronary sinus occlusion, venules are dilated and resistance to subendocardial perfusion is reduced, with collaterals recruited between the subepicardium and subendocardium. First-in-man studies by Banai et al. demonstrated the safety of device implantation and reported improvements in angina score in 12 out of 14 patients. Canadian Cardiovascular Society (CCS) class was significantly improved (from 3.07 to 1.64, p<0.0001), together with stress-induced ST-segment depression and myocardial ischaemia on dobutamine echocardiography and single-photon emission computed tomography (SPECT).14 Endothelialisation of the CSR takes about 6 weeks. In our centre, patients are counselled that they should not gauge success immediately after implantation but should await a more accurate assessment of treatment response at several months follow-up. Anecdotal evidence exists as to immediate symptomatic benefit after implantation. Possible reasons for this include a significant placebo effect and device implantation over a valve in the coronary sinus leading to early endothelialisation. Questions have been raised as to the feasibility of using the coronary sinus for cardiac resynchronisation therapy.15 CSR implantation is unlikely to improve symptoms of exertional dyspnoea in severe left ventricular systolic dysfunction and although the stent can be further dilated for cardiac resynchronisation therapy, CSR implantation in these patients is not advisable.12 Furthermore, given that optimal CSR implantation is approximately 2 cm distal to the ostium of the coronary sinus, where the middle cardiac vein drains the right coronary territory, any backpressure generated is unlikely to affect this territory. CSR implantation is only suitable for left-sided ischaemia. The largest study to date was the Phase II randomised, blinded, sham-controlled Coronary Sinus Reducer for Treatment of Refractory Angina (COSIRA) trial.16 Of 104 patients with CCS III–IV RA, 35 % of treated patients compared to 15  % of controls met the primary endpoint a reduction of ≥2 CCS classes at 6-month follow-up (p=0.02). Encouragingly, improvements in ≥1 CCS were significant (71 % versus 42  %, p=0.003) as were improvements in quality of life (p=0.03) as assessed with the Seattle Angina Questionnaire (SAQ). Interestingly, no changes were seen in exercise time or mean change in wallmotion index on dobutamine echocardiography, although it should be noted that the study was not powered to meet these endpoints. The CSR may also improve psychosocial outcomes such as anxiety and depression.17 Moreover, high rates of procedural success have been demonstrated (91 and 96 %), with unsuitable coronary sinus anatomy and the presence of venous valves accounting for the small proportion of failures.16,18 CSR implantation also has low rates of adverse events – the COSIRA trial reported only one case of periprocedural serious adverse event in the CSR cohort (n=50) and the rates of other serious adverse events were similar to the sham control group. There was no evidence of device migration in patients followed-up with CT angiography (n=36). Given the success of the COSIRA trial, which predominantly included centres in Canada and Europe, a Phase III multicentre, randomised, double-blind sham-controlled trial (COSIRA II) is planned in the US and Canada.12 A European registry (REDUCER-I, NCT02710435) is currently recruiting patients to a long-term study of the Neovasc Reducer™ system in patients with refractory angina pectoris. This registry encompasses 40 international centres and almost 100 of the planned 400 participants

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Figure 1: The Coronary Sinus Reducer A

D

E B

C

LPVC *

LA

DA

LV CSR (A) Fluoroscopic coronary sinus venogram. (B) Implantation of the hourglass-shaped reducer stent (arrow). (C) CT image showing the position of the coronary sinus reducer (CSR) in relation to the left ventricle (LV), left atrium (LA), left pulmonary venous confluence (LPVC) and descending aorta (DA). *Calcified plaque in the left circumflex artery. (D) CSR stent in relation to 10 pence coin. (E) Three-dimensional reconstruction of a cardiac CT showing the correct positioning of the reducer in the coronary sinus. Adapted from Cheng et al., 2016.6

have been recruited to date. Preliminary data suggest improvement in CCS class and 6-minute walk test.12 Interestingly, 15–20 % of patients show no improvement with CSR (non-responders) and work is underway to identify potential mechanisms for this, with a recent study suggesting that non-responders have better-developed alternative venous drainage systems and achieve lower pressure rises in the coronary sinus during occlusion.19 While the CSR procedure is still in its relative infancy, its adoption into routine clinical practice is likely due to further positive clinical evidence and dissemination of specialist interventional expertise. The frequency of implantation currently varies between centres: an Italian centre reported five cases over 9 months, whereas a single-centre retrospective Dutch registry found 23 patients implanted with the CSR in a single year (2014).20,21 Furthermore, it has been suggested that the CSR may be used for a range of indications beyond RA. These include conditions with chronic chest pain, such as syndrome X and hypertrophic cardiomyopathy, as well as microvascular dysfunction. Studies to investigate this device in these patients are needed. A recent series of eight patients with microvascular dysfunction demonstrated significant improvements in CCS class (p=0.014), quality of life on SAQ (p=0.018) and 6-minute walk test (p=0.018) following CSR, with a subgroup (n=3) demonstrating improved myocardial perfusion reserve index.22 However, this was a small open-label case series with no control group and was non-randomised in design. In chronic angina, patients can be revascularised by intervention of chronic total occlusions (CTOs). This method of improving arterial blood flow is often-lengthy, technically challenging and requires skilled operators. It is not without complications, although these have significantly reduced over time to rates comparable to nonCTO percutaneous coronary intervention.23 Nevertheless, there is still

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Management and Comorbidities Figure 2: Principles of External Enhanced Counterpulsation A

B

Step 1

Step 2

Step 3

Diastolic inflation

ECG Normal pulse ECP

Step 4

Pre-systolic deflation

ECG Normal pulse ECP

(A) A series of cuffs sequentially inflate from distal to proximal followed by rapid deflation. (B) External counterpulsation and its relation to the electrocardiogram and pulse waveform. Adapted from Sinvhal et al., 2003107 and Yati Mediquip.108

debate regarding the clinical efficacy of CTO at improving patientrelated outcomes such as angina frequency, physical limitation and quality of life, given the conflicting results of recent CTO studies.24,25 Furthermore, CTO interventions do not offer any prognostic benefit but improve symptoms, which the CSR is also able to achieve. Consequently, an alternative for patients with occluded left coronary arteries – or those who have failed CTO procedures – may be the CSR, which is implanted in a shorter (~45-minute), easier procedure. Further studies to compare CSR against CTO are warranted.

External Enhanced Counterpulsation This non-invasive therapy involves placing external compressive cuffs on the calves, lower and upper thighs and then sequentially inflating them from distal to proximal in time with the cardiac cycle. Producing an effect similar to that of an intra-aortic balloon pump, the cuffs are inflated in early diastole to improve coronary perfusion and venous return, and deflated in systole to reduce systemic vascular resistance, improving cardiac workload and systemic perfusion (Figure 2). Treatment is performed in 1–2 hour sessions over a number of weeks, totalling approximately 35 hours in total. The mechanism of action through which counterpulsation improves coronary perfusion has been examined in a number of small studies that have also reported improved clinical outcomes.26 EECP has been shown to improve endothelial function,27 collateral flow and fractional flow reserve,28,29 to reduce arterial stiffness30,31 and to promote peripheral flow-mediated dilatation, as well as affecting endothelial-derived vasoactive agents by increasing nitric oxide turnover and reducing pro-inflammatory cytokines.31–33 It has also been shown that EECP up-regulates circulating CD34+ and CD133+ stem cell populations.34

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The International EECP Patient Registry investigated patients with heart failure (ejection fraction of ≤35 %) with RA and found significant improvements in angina class (p<0.001), nitroglycerin use and quality of life after completion of treatment. These effects were maintained in a substantial proportion of patients at 3-year follow-up.35,36 However, the majority of studies of EECP have investigated its use in stable angina rather than exclusively in RA and, due to the nature of the intervention, blinding and control are difficult. Notably, the MUlticenter STudy of Enhanced External Counterpulsation (MUST-EECP), which included 139 participants, showed that time to ≥1 mm ST-segment depression improved significantly (~15  %, p=0.01) and angina frequency was reduced by 25 % compared to control (p<0.05).37 While meta-analyses have been encouraging, suggesting that about 85  % of patients with either refractory or chronic stable angina improve by ≥1 CCS class after EECP,38,39 a 2009 health technology assessment and 2010 Cochrane systematic review were unable to conclude clinical or costeffectiveness, mainly due to poor trial design, lack of long-term followup, limited improvements in clinically-significant outcomes and an increased rate of adverse events.40,41 Consequently, the 2013 European Society of Cardiology guidelines for the management of chronic stable angina give EECP a Class IIa, Level of Evidence B recommendation for RA.42 The updated 2014 American Heart Association guideline for stable ischaemic heart disease made no change to the 2012 recommendation, which remains Class IIb, Level of Evidence B.43 EECP is limited by a number of contraindications, such as coagulopathy with an international normal ratio of >2.5, arrhythmias, severe peripheral arterial disease, venous disease and severe chronic obstructive pulmonary disease.26 In the UK, EECP is still in its infancy. There are currently only three active treatment centres and in 10 years fewer than 800 patients have been treated.44 However, EECP has been shown to reduce hospital costs.45 Growing interest, robust randomised clinical trials and evidence of cost-effectiveness will serve to encourage EECP adoption going forward.

Extracorporeal Shockwave Therapy Another potential non-invasive therapy is ECSWT, which delivers lowenergy shockwaves to the border zones of ischaemic myocardium and is guided by echocardiography (Figure 3). With the energy of such shockwaves typically being about 10 % of that delivered in urolithiasis, ECSWT is given in a series of sessions – typically over 4–9 weeks. It is a targetable treatment, unlike EECP, although both are able to treat right- and left-sided ischaemia. ECSWT is thought to induce neovascularisation. Animal studies have shown that ECSWT induces the development of collaterals and improves capillary density; recent data from clinical studies have reported improvements in myocardial perfusion.46–51 Pre-conditioning of chronic ischaemic tissue with ECSWT up-regulates chemoattractants such as stromal cell-derived factor 1 and vascular endothelial growth factor, improving the recruitment of endothelial precursor cells. In a clinical study, together with bone marrow-derived mononuclear cells (BMC), this recruitment results in modest but significant improvements in left ventricular ejection fraction (ECSWT + BMC: 3.2  %, 95  % CI [2.0–4.4  %] versus ECSWT + placebo infusion: 1.0 %; 95 % CI [−0.3–2.2 %]; p=0.02) and regional wall thickening (ECSWT + BMC: 3.6 %, 95 % CI [2.0–5.2 %] versus ECSWT + placebo infusion: 0.5 %, 95 % CI [−1.2–2.1 %]; p=0.01).50,52,53 To date, several randomised controlled studies in stable angina have demonstrated promising clinical outcomes without serious adverse effects.54 The largest study (n=45) to date showed that CCS class,

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Refractory Angina Pectoris NYHA class, myocardial perfusion, nitroglycerin usage, SAQ score, 6-minute walk test and left ventricular ejection fraction were all significantly improved at 3 months compared to controls as well as baseline (0 months). In the control group, none the above parameters had changed significantly from baseline at 3 months.55 A recent metaanalysis of ECSWT for angina was able to demonstrate significant improvements in angina class, SAQ score, nitrate consumption and exercise capacity. However, it should be noted that this study included single-arm, non-randomised and randomised trials and considered studies of chronic stable angina (the majority) as well as RA. Most trials were also small – the largest randomised, placebo-controlled study had a treatment arm consisting of 45 individuals – and they had varying durations of follow-up (range 1–72 months).54 ECSWT has been investigated specifically for RA in several studies, all of which suggest its efficacy and safety. A single-arm multicentre prospective study (n=111) of patients with RA undergoing ECSWT demonstrated improved summed difference score on stress SPECT (baseline 9.53±17.87; follow-up 7.77±11.83; p=0.0086), significantly improved SAQ score and nitroglycerin use.47 Recent data from the longest published follow-up (2.88±1.65 years) showed sustained reductions in CCS class (from 2.78±0.67 to 1.44±0.6; p=0.0002), nitroglycerin consumption (67  % versus 21.  %; p<0.001) and also – importantly – reduced hospitalisation rate (40  % versus 18  %; p<0.03).56 Although progress has been made, ECSWT remains an experimental treatment. Its mechanism of action is uncertain and randomised controlled studies specific to RA are required. Indeed, the 2013 ESC guidelines on stable angina make little note of ECSWT, claiming that “more data are needed before establishing a potential recommendation”.57

Figure 3: Extracorporeal Shockwave Therapy Ultrasound shockwaves

Improved myocardial perfusion

Shear stress

Neovascularisation

Increase in chemokines e.g. SDF-1, VEGF

Recruitment of endothelial precursor cells Physiological principles that may underpin how extracorporeal shockwave therapy improves myocardial perfusion. SDF-1 = stromal cell-derived factor 1; VEGF = vascular endothelial growth factor.

The potential of stem cells to protect, repair and regenerate the heart has been the subject of immense research over the past few decades. Researchers have investigated numerous cell populations, including unselected/selected bone marrow mononuclear cells,58–61 mesenchymal stromal cells,62 embryonic stem cells,63,64 induced pluripotent stem cells65 (pre-clinical studies only) and different populations of resident cardiac progenitor cells66-72 (see Table 2 in Madonna et al.73). It is increasingly recognised that these cell populations act through paracrine mechanisms to promote cardiac protection, repair and neovascularisation. While most reports have studied patients with acute myocardial infarction, as well as ischaemic and non-ischaemic heart failure, several studies have investigated the effects of cellular therapies for the treatment of patients with RA (Table 1).74–92

events (MACE) (p=0.08 for both).88 On the basis of these promising results, the Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects with Refractory Angina (RENEW) trial was undertaken. This Phase III randomised, double-blinded, active-controlled standard of care trial included patients with RA, with CCS III or IV angina and ischaemia on stress testing. Randomisation was to three arms: cell therapy (granulocyte colony stimulating factor-mediated stem cell mobilisation, apheresis and intramyocardial injection of CD34+ cells); active control (granulocyte colony stimulating factor-mediated mobilisation, apheresis and intramyocardial placebo injection); or open-label standard of care.95 Primary efficacy was a change in exercise treadmill time. After recruitment of 112 out of the 444 planned patients, the study was terminated early due to strategic considerations. Although incomplete, the authors state that the results were consistent with earlier phase studies, demonstrating trends towards improved exercise time (improvement of 61 seconds with cell therapy at 3 months (p=0.06); 46.2 seconds at 6 months (p=0.22); and 36.6 seconds at 12 months (p=0.43)) and angina frequency at 6 months (p=0.05).95

Bone marrow-derived CD34+ cells, which are considered to have haematopoietic and endothelial potential, have been shown to promote neovascularisation in ischaemic myocardium.93,94 Initial studies by Losordo et al. in a Phase I/IIa double-blind, randomised controlled trial demonstrated that intramyocardial injection of autologous CD34+ stem cells in patients with RA was feasible, safe and showed potential bioactivity with improvement in CCS class.84 The larger Phase II Adult Autologous CD34+ Stem Cells (ACT34-CMI) trial showed that intramyocardial injection of CD34+ cells into ischaemic but viable myocardium significantly lowered weekly angina frequency and improved exercise tolerance.86 Interestingly, the administration of high-dose CD34+ cells did not achieve a significantly greater therapeutic effect. At 2-year follow-up, both low- and high-dose groups had a significant reduction in angina frequency (p=0.03) and there was a trend towards improved mortality and major adverse cardiac

Favourable outcomes have been demonstrated in studies with unselected and CD133+ bone marrow-derived stem cells. 78,81,82 A long-term safety and efficacy study has demonstrated significant improvements in exercise time, CCS class, nitroglycerin use and SAQ score. Treatment also resulted in reduced hospital admissions and was demonstrated to have a good safety profile over a 3-year period.76 Small studies have investigated bone marrow-derived CD133+ cells. The recently-reported Intracardiac CD133+ Cells in Patients with No-option Resistant Angina (RegentVsel) trial (n=31) did not meet its primary endpoint of absolute change in myocardial ischaemia by SPECT compared to placebo; however, A Trial with Dronedarone to Prevent Hospitalization or Death in Patients with Atrial Fibrillation (ATHENA) recently suggested that the use of adipose-derived regenerative cells via intramyocardial delivery was feasible and should be investigated further for the treatment of RA (Table 1).91,92,96,97

Cell Therapy

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Open-label, non-controlled; Phase I

Open-label, noncontrolled

Percutaneous retrograde coronary sinus perfusion; autologous BMMNC

Repeated intramyocardial injection (4.6±2.5 years after first injection); autologous BMMNC

Tuma et al. 201179 (Peru)

Mann et al. 201580 (Netherlands, Reinject Trial)

Refractory angina (improved perfusion after first cell injection but residual angina and ischaemia)

Refractory angina

Open label, non- Refractory angina controlled; Phase I/IIa

Surgical intramyocardial delivery (ReACT protocol); autologous BMMNC

Hossne et al. 200978 (Brazil)

Refractory angina

Prospective, randomised, double-blind, placebocontrolled

Autologous BMMNC

Prospective, Refractory angina randomised, blinded, placebocontrolled

Van Ramshorst et al. 200977 (Netherlands)

Tse et al. 200776 Autologous (Hong Kong BMMNC and Australia, PROTECT-CAD Trial)

Ischaemic HF ± refractory angina

No

No

No

Yes

Yes

Yes

23

14

8

50

28

92

Prospective randomised, double-blind, placebocontrolled

Autologous BMMNC

Perin et al. 201260 (USA, FOCUSCCTRN Trial)

Yes

30

Ischaemic HF with refractory angina

Prospective, randomised, single-blind

Perin et al. 2011 (USA, FOCUS-HF Trial)

Autologous BMMNC

Population

75

Control (n)

Patient cohort

type

trial)

Study design

Route and cell

Study (country,

Table 1: Trials of Cell Therapy for Refractory Angina Primary outcome

12 months

2 years

18 months

6 months

6 months

6 months

6 months

ReACT protocol safe and effective; correlation between number of BMMNC and improvement supports cell-related effect

Significant but modest improvement in myocardial perfusion compared with placebo

Direct endomyocardial implantation of autologous BMMNC improved exercise time, LVEF and NYHA in patients with severe CAD who failed conventional therapy

Transendocardial injection of BMMNC compared to placebo did not improve LVESV, MVO2 or reversibility on SPECT

Autologous BMMNC are safe and improves symptoms, quality of life and possibly perfusion in chronic HF

Conclusion

Repeated cell injection in previously responding patients associated with improved perfusion, angina and quality of life

All but one patient improved PRCSP should be considered by ≥ 1 CCS class compared to baseline alternative method of delivery (p<0.001); area of ischaemia improved from 38.2 % (baseline) to 23.5 % (2 years; p=0.001) and LVEF from 31.2 % to 35.5 % (p=0.019)

Positive correlation between BMMNC concentration and CCS class improvement (r=–0.759; p<0.05) but not improvement in ischaemic myocardium; no change in LVEF

Significant improvements in LVEF (3 % absolute increase at 3 months), CCS class (p=0.03) and quality of life (p=0.05)

Significant increase in LVEF (+5.4%, 95% CI [0.4–10.3], p=0.044) and lower NYHA class (OR: 0.12, p=0.021); no significant difference in CCS class or SSS or SDS between groups

No significant difference in percent total myocardial defect on SPECT, RWM on echocardiography, clinical outcomes (CCS class, NYHA, medication) or MACE

Efficacy – significantly improved CCS class; no change in NYHA; improved quality of life; trend towards improved perfusion in cell-treated patients and no increase in fixed defects compared to controls

Secondary outcome

Significantly improved perfusion No significant change in exercise sustained at 12 months (SSS capacity; significantly improved CCS baseline versus 12 months, class and quality of life on SAQ score p=0.002); no significant change in LV function or volume

Cell delivery successful in all patients

Significant improvement in CCS class at 18 months (p=0.008) and reduction in myocardial ischaemia at 12 months (84.4 % reduction; p<0.004)

SSS significantly improved with treatment (from 23.5 to 20.1, p<0.001) compared to placebo (24.8 to 23.7, p=0.004); Treatment effect: –2.44; 95 % CI [−3.58 to –1.30] p<0.001

Exercise treadmill time significantly improved (treatment effect +0.43 log seconds (+53 %), 95 % CI: [0.11– 0.74] p=0.014)

3 co-primary endpoints – changes in (1) LVESV by echocardiography, (2) MVO2, and (3) reversibility on SPECT; all not statistically significant

Safety – no major adverse events at cell injection; averse events similar in both groups; no deaths or myocardial infarctions during follow up

Autologous BMMNC

Follow up

Management and Comorbidities

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Refractory Angina Pectoris trial)

Study (country, type

Route and cell

Table 1: Cont.

Hossne et al. 201581 (Brazil) Surgical intramyocardial delivery (ReACT protocol); autologous BMMNC

Open-label, noncontrolled

Study design

Haack-Sørensen et al. 201382 (Denmark)

Intramyocardial injection; autologous bone marrow MSCs Open-label, non-controlled; Phase I–II

Patient cohort

Refractory angina

Refractory angina

Open label, non- Refractory angina controlled; Phase IIa/b

Mathiasen et al. 201383 (Denmark)

Intramyocardial injection; autologous bone marrow MSCs

Prospective, double-blind, randomised, placebocontrolled

Losordo et al. 200784 (USA)

Intracoronary delivery; autologous CD34+ cells

Refractory angina

Refractory angina

Double-blind, Refractory angina randomised, placebocontrolled; Phase I/IIa

Wang et al. 201085 (China)

Intramyocardial delivery; autologous CD34+ cells

Intramyocardial delivery; autologous CD34+ cells

Losordo et al. 201186 (USA, ACT34-CMI Trial)

Prospective, double-blind, randomised, placebocontrolled; Phase II

Control No

No

No

Yes

Yes

Yes

12 months

Follow up

Significant improvement in CCS class (p=0.002) and reduction in myocardial ischaemia at 12 months (100 % decrease; p<0.004)

Primary outcome

Significantly improved MET during exercise, CCS class, angina frequency, GTN use and SAQ (all p<0.001)

Positive correlation between BMMNC concentration and CCS improvement; quality of life improved with reduction in angina-related direct costs

Secondary outcome

Safe in the intermediate/long term to treat patients with autologous culture expanded MSCs

Long-term follow-up and strong improvement in quality of life reinforce effectiveness; direct costs reduced

Conclusion

6 months

12 months

3 years

12 months

Safety – no serious adverse events

Safety – no incidence of MI induced by mobilisation or injection; injection did not result in enzyme elevation, perforation or pericardial effusion; similar serious adverse events between groups

Trends in improvement in angina frequency, GTN usage, exercise time and CCS class with treatment

Safety – no procedural Significant improvements in exercise complications or serious cardiac time, CCS class, weekly angina arrhythmias; significantly frequency, GTN use and SAQ scores reduced hospitalisation for stable angina revascularisation and overall cardiovascular disease with treatment; no deaths during follow up

Safe to culture and expand MSCs and use for clinical treatment

Significantly improved angina Demonstrated safety and feasibility frequency (p<0.01), GTN use (p<0.001), of intracoronary CD34+ therapy ETTs (p<0.01) and CCS class (p<0.01) and evidence for efficacy

Feasibility, safety and bioactivity with intramyocardial injection of autologous CD34+ cells

Sustained clinical effects, reduced hospital admissions for cardiovascular disease and long-term safety at 3 years; improvement of symptoms and potential of slowing disease progression Autologous CD34+ cells

12 months

Autologous bone marrow MSCs

Population 14

(n)

41

31

24

112

167

Significantly improved exercise tolerance at 6 & 12 months with lowdose treatment than placebo; exercise tolerance not significantly improved compared to placebo; significantly improved SPECT perfusion with low-dose treatment (p=0.002); no significant MACE with treatment

Significant improvements in angina frequency and exercise tolerance with intramyocardial injections of autologous CD34+ cells

Significantly lower weekly angina frequency with low-dose treatment than placebo at 6 and 12 months (p=0.020 and 0.035 respectively); angina frequency was not significantly improved with high-dose treatment compared to placebo

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76

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Prospective, randomised, double-blinded, placebocontrolled

2 parallel, prospective, randomised, placebocontrolled double-blind

Transendocardial delivery; autologous CD133+ cells

Intramyocardial delivery; ADRCs

Wojakowski et al. 201791 (Poland, REGENTVSEL Trial)

Refractory angina and left ventricular dysfunction

Refractory angina

Refractory angina

Refractory angina

Yes

Yes

Yes

No

31

31

28

5

No significant difference in inducible ischaemia between groups on SPECT at 4 months (p=0.52)

Similar adverse events between groups; 1 patient had a cardiac tamponade during procedure in treatment group

Injection was safe; over average of 3.8 weeks, significant improvement in CCS class and serial SPECT (rest and stress) perfusion at 6 months

12 months

58.1 % of patients had at least one serious adverse event (ADRC: 52.9 %; placebo 64.3 %) and MACE occurred in 35.3 % (ADRC) and 21.4 % (placebo); 2 patients with TIA/stroke after IM injection leading to suspension of enrollment

Adipose-derived regenerative cells

12 months

6 months

1 year

Autologous CD133+ cells

Significant reduction in angina frequency with low- and highdose treatment (p=0.03)

No significant difference in total exercise time at 3, 6 or 12 months

Primary outcome

No significant difference in VO2max, LVEF, LVESV or perfusion. Significant improvement in MLHFQ.

Significant reduction in left ventricular volumes but not LVEF in treatment group; no significant benefit in CCS class or GTN use

No significant efficacy difference between groups; significant improvement in monthly angina episodes (–8.5; 95 % CI: –15.0 to –4.0) and CCS class within treatment group; summed score on SPECT at rest and stress significantly improved in treatment group

Sustained clinical improvements in 4 of 5 cases (at mean 36.5 months postoperatively)

7 deaths in control group; 1 death in low-dose and 2 in high-dose groups; MACE: 33.9 % (control), 21.8 % (lowdose) and 16.2 % (high-dose)

Improved angina frequency at 6 months (p=0.05); safe compared to standard of care and controls

Secondary outcome

Intramyocardial delivery of autologous ARDCs is feasible with suggestion of benefit

CD133+ therapy safe; study underpowered to validate efficacy

CD133+ injection is feasible and safe

Long-term clinical and perfusion improvements in absence of adverse events

Persistent improvement in angina at 2 years and trend for reduction in mortality

Incomplete experiment due to early termination – results consistent with earlier studies

Conclusion

ADRC = adipose-derived regenerative cells; BMMNC = bone marrow mononuclear cells; CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; ETT = exercise tolerance tests; GTN = glyceryl trinitrate; HF = heart failure; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; MACE = major adverse cardiac events; MET = metabolic equivalent of task; MI = myocardial infarction; MLHFQ = Minnesota Living with Heart Failure Questionnaire; MSC = mesenchymal stem cells; MVO2 = maximal oxygen consumption; NYHA = New York Heart Association; RWM = regional wall motion; SAQ = Seattle Angina Questionnaire; SDS = sum of difference scores; SPECT = single-photon emission computed tomography; SSS = sum of stress scores; VO2max = maximum oxygen consumption.

Henry et al. 2017 (USA, ATHENA Trials)

Prospective, randomised, double-blind

Transendocardial injection; autologous CD133+ cells

Jimenez-Quevedo et al. 201490 (Spain)

92

Open label, noncontrolled

Surgical intramyocardial delivery; autologous CD133+ cells

Yes

2 year follow-up

Pompilio et al. 200889 (Italy)

Refractory angina

167

Prospective, double-blind, randomised, placebocontrolled; Phase II

Intramyocardial delivery; autologous CD34+ cells

Henry et al. 201688 (USA, ACT34-CMI Trial)

Yes

112 (proposed 12 months enrollment of n=444; sponsor terminated early)

Refractory angina

Prospective, randomised, double-blind, placebocontrolled; Phase III

Follow up

Intramyocardial delivery; autologous CD34+ cells

Population

Povsic et al. 2016 (USA, RENEW Trial)87

Control (n)

Patient cohort

type

trial)

Study design

Route and cell

Study (country,

Table 1: Cont.

Management and Comorbidities

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Refractory Angina Pectoris Several meta-analyses have been performed on cell therapy to date.98-100 Collating data from five randomised controlled trials (n=381), Li et al. found that, compared to controls, cell therapy improved exercise tolerance by 61.3 seconds (p=0.005) reduced angina frequency by 7.3 episodes per week (p=0.02) and lowered the risk of myocardial infarction (OR 0.37, 95 % CI [0.14–0.95], p=0.04) with no difference in risk of death (OR 0.33, 95 % CI [0.08–1.39], p=0.13).98 The largest meta-analysis to date identified six randomised controlled trials (n=353) and concluded that cell therapies were safe but that they also improved angina frequency, use of anti-anginal medications, CCS class, exercise tolerance and myocardial perfusion and reduced MACE and arrhythmias compared to patients on maximal medical therapy.100 However, such publication-based meta-analyses should be interpreted with caution. Meta-analysis should ideally be performed using individual patient data, which although more arduous will reduce bias, e.g. from data analysis and reporting.101,102 By performing a metaanalysis on individual patient data from 1,275 people, Gyöngyösi et al. showed that effect sizes were much smaller than previously reported publication-based meta-analyses.103,104 We may now be seeing a move towards patient-level meta-analyses. A recent study by Henry et al. that pooled several studies of autologous CD34+ cells was encouraging, demonstrating meaningful improvements in total exercise time at 3, 6 and 12 months, and significantly reduced mortality at 24 months (12.1 % versus 2.5 %; p=0.0025).105 Limitations still exist and cell therapy remains an experimental treatment. Randomised controlled trials have been small and varied in design, with short follow-up periods. Questions remain, including

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 annheimer C, Camici P, Chester MR, et al. The problem of M chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 2002;23:355–70. https://doi.org/10.1053/euhj.2001.2706; PMID: 11846493. Statistics Canada. Canadian Community Health Survey (CCHS). 2002. Available at: www23.statcan.gc.ca/imdb/p2SV. pl?Function=getSurvey&Id=3359 (accessed 8 June 2018) McGillion M, Arthur HM, Cook A, et al. Management of patients with refractory angina: Canadian Cardiovascular Society/Canadian Pain Society joint guidelines. Can J Cardiol 2012;28(2 Suppl):S20–41. https://doi.org/10.1016/j. cjca.2011.07.007; PMID: 22424281 Povsic TJ, Broderick S, Anstrom KJ, et al. Predictors of longterm clinical endpoints in patients with refractory angina. J Am Heart Assoc 2015;e001287. https://doi.org/10.1161/ JAHA.114.001287; PMID: 25637344. Henry TD, Satran D, Hodges JS, et al. Long-term survival in patients with refractory angina. Eur Heart J 2013;34:2683–8. https://doi.org/10.1093/eurheartj/eht165; PMID: 23671156. Cheng K, Sainsbury P, Fisher M, et al. Management of refractory angina pectoris. Eur Cardiol Rev 2016;11:69. https://doi.org/10.15420/ecr.2016:26:1. Sainsbury PA, Fisher M, de Silva R. Alternative interventions for refractory angina. Heart 2017;103:1911–22. https://doi. org/10.1136/heartjnl-2015-308564; PMID: 28954830. Wright C, de Silva R. Management of refractory angina: the importance of winning over both hearts and minds. Br J Cardiol 2016;23:45–6. https://doi.org/10.5837/bjc.2016.018. Cheng K, Wright C, de Silva, R. The effect of a multidisciplinary care pathway for refractory angina on psychological outcomes, quality of life and medication use. European Society of Cardiology Congress 2017, Barcelona, Spain, 1 August 2017. Abstract 2237. https://doi.org/10.1093/eurheartj/ehx502.2237. Beck CS, Leighninger DS. Scientific basis for the surgical treatment of coronary artery disease. J Am Med Assoc 1955;159:1264–71. https://doi.org/10.1001/ jama.1955.02960300008003; PMID: 13271060. Beck CS, Leighninger DS. Operations for coronary artery disease. J Am Med Assoc 1954;156:1226–33. https://doi.org/10.1001/jama.1954.02950130006002; PMID: 13211223. Konigstein M, Giannini F, Banai S. The Reducer device in patients with angina pectoris: mechanisms, indications, and perspectives. Eur Heart J 2017;39:925–33. https://doi.org/10.1093/eurheartj/ehx486; PMID: 29020417. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830–40. https://doi.org/10.1056/NEJMra061889; PMID: 17314342.

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optimal cell type, dosage, isolation and delivery methods. The duration of efficacy has also been questioned and researchers have suggested that repeated administration may be needed.80,106 The mechanism by which cell therapy is thought to improve clinical outcomes is also unclear. Suggestions that it promotes neovascularisation and improves microvascular and collateral perfusion are supported by an increase in myocardial perfusion on SPECT, although it must be noted that its reliability is limited in this population due to the common presence of multivessel disease. Consequently, larger Phase III studies are needed and should build on lessons learnt from previous studies. Clinicallyrelevant outcomes should be studied including quality of life, costeffectiveness and MACE, and quantitative assessment of myocardial perfusion should consider the use of PET and cardiovascular magnetic resonance to overcome the limitations of SPECT, such as poor spatial resolution, long acquisition times and balanced flow reduction seen in multivessel disease.108

Conclusion Significant progress has been made in developing novel treatments for patients with RA. Given the growing clinical burden that this condition represents, the need for such interventions is greater than ever. This paper discusses four major advances and considers the evidence supporting their use. While some remain experimental, the CSR and EECP are currently being used in clinical practice. Further robust clinical data and assessment of cost-effectiveness must be sought to aid their incorporation into guidelines. Nevertheless, with growing experience of their use and evidence from larger randomised controlled studies, these therapies hold much promise in treating patients with RA. n

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JAMA 2009;301:1997-2004. https:// doi.org/10.1001/jama.2009.685; PMID: 19454638. 78. Hossne NA, Invitti AL, Buffolo E, et al. Refractory angina cell therapy (ReACT) involving autologous bone marrow cells in patients without left ventricular dysfunction: a possible role for monocytes. Cell Transplant 2009;18:1299–310. https://doi.org/10.3727/096368909X484671; PMID: 20149298. 79. Tuma J, Fernández-Viña R, Carrasco A, et al. Safety and feasibility of percutaneous retrograde coronary sinus delivery of autologous bone marrow mononuclear cell transplantation in patients with chronic refractory angina. J Transl Med 2011;9:183. https://doi.org/10.1186/1479-5876-9-183; PMID: 22029669. 80. Mann I, Rodrigo SF, van Ramshorst J, et al. Repeated intramyocardial bone marrow cell injection in previously responding patients with refractory angina again improves myocardial perfusion, anginal complaints, and quality of life. Circ Cardiovasc Interv 2015;8:e002740. https://doi.org/10.1161/CIRCINTERVENTIONS.115.002740; PMID: 26259770. 81. Hossne NA, Cruz E, Buffolo E, et al. Long-term and sustained therapeutic results of a specific promonocyte cell formulation in refractory angina: ReACT® (Refractory Angina Cell Therapy) clinical update and cost-effective analysis. Cell Transplant 2015;24:955–70. https://doi.org/10.3727/096368914X681595; PMID: 24819720. 82. Haack-Sørensen M, Friis T, Mathiasen AB, et al. Direct intramyocardial mesenchymal stromal cell injections in patients with severe refractory angina: one-year follow-up. Cell Transplant 2013;22:521–8. https://doi. org/10.3727/096368912X636830; PMID: 22472086. 83. Mathiasen AB, Haack-Sørensen M, Jørgensen E, Kastrup J. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina – final 3-year followup. Int J Cardiol 2013;170:246–51. https://doi.org/10.1016/j. ijcard.2013.10.079; PMID: 24211066. 84. Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation 2007;115:3165–72. https://doi. org/10.1161/CIRCULATIONAHA.106.687376; PMID: 17562958. 85. Wang S, Cui J, Peng W, et al. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology 2010;117:140-7. https://doi.org/10.1159/000320217; PMID: 20975266. 86. Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res 2011;109:428–36. https://doi.org/10.1161/ CIRCRESAHA.111.245993; PMID: 21737787. 87. Povsic TJ, Henry TD, Traverse JH et al. The RENEW Trial: efficacy and safety of intramyocardial autologous CD34(+) cell administration in patients with refractory angina. JACC Cardiovasc Interv 2016;9:1576-85. https://doi.org/10.1016/j. jcin.2016.05.003; PMID: 27491607 88. Henry TD, Schaer GL, Traverse JH, et al. Autologous CD34(+) cell therapy for refractory angina: 2-year outcomes from the ACT34-CMI study. Cell Transplant 2016;25:1701–11. https://doi.org/10.3727/096368916X691484; PMID: 27151378. 89. Pompilio G, Steinhoff G, Liebold A, et al. Direct minimally invasive intramyocardial injection of bone marrow-derived AC133+ stem cells in patients with refractory ischemia: preliminary results. Thorac Cardiovasc Surg 2008;56:71–6. PMID: 18278680. 90. Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabate M, et al. Selected CD133+ progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial. Circ Res 2014;115:950–60. https://doi.org/10.1161/CIRCRESAHA.115.303463; PMID: 25231095. 91. Wojakowski W, Jadczyk T, Michalewska-Włudarczyk A, et al. Effects of transendocardial delivery of bone marrowderived CD133(+) cells on left ventricle perfusion and function in patients with refractory angina: final results of randomized, double-blinded, placebo-controlled REGENTVSEL trial. Circ Res 2017;120:670–80. https://doi.org/10.1161/ CIRCRESAHA.116.309009; PMID: 27903568. 92. Henry TD, Pepine CJ, Lambert CR, et al. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv 2017;89:169–77. https://doi.org/10.1002/ccd.26601; PMID: 27148802. 93. Iwasaki H. Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and

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cardiomyogenesis for functional regenerative recovery after myocardial infarction. Circulation 2006;113:1311–25. https://doi.org/10.1161/CIRCULATIONAHA.105.541268; PMID: 16534028. Psaltis PJ, Harbuzariu A, Delacroix S, et al. Resident vascular progenitor cells—diverse origins, phenotype, and function. J Cardiovasc Transl Res 2011;4:161–76. https://doi.org/10.1007/s12265-010-9248-9; PMID: 21116882. Povsic TJ, Junge C, Nada A, et al. A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study. Am Heart J 2013;165:854–61.e2. https://doi.org/10.1016/j.ahj.2013.03.003; PMID: 23708155. Pompilio G, Steinhoff G, Liebold A, et al. Direct minimally invasive intramyocardial injection of bone marrow-derived AC133+ stem cells in patients with refractory ischemia: preliminary results. Thorac Cardiovasc Surg 2008;56:71–6. https://doi.org/10.1055/s-2007-989351; PMID: 18278680. Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabate M, et al. Selected CD133+ progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial. Circ Res 2014;115:950–60. https://doi.org/10.1161/CIRCRESAHA.115.303463; PMID: 25231095.

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98. L i N, Yang Y-J, Zhang Q, et al. Stem cell therapy is a promising tool for refractory angina: a meta-analysis of randomized controlled trials. Can J Cardiol 2013;29:908–14. https://doi.org/10.1016/j.cjca.2012.12.003; PMID: 23465346. 99. Fisher SA, Dorée C, Brunskill SJ, et al. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systematic review and meta-analysis. PloS One 2013;8:e64669. https://doi.org/10.1371/journal.pone.0064669; PMID: 23840302. 100. Khan AR, Farid TA, Pathan A, et al. Impact of cell therapy on myocardial perfusion and cardiovascular outcomes in patients with angina refractory to medical therapy: a systematic review and meta-analysis. Circ Res 2016;118: 984–93. https://doi.org/10.1161/CIRCRESAHA.115.308056; PMID: 26838794. 101. Martin-Rendon E. Meta-analyses of human cell-based cardiac regeneration therapies: What can systematic reviews tell us about cell therapies for ischemic heart disease? Circ Res 2016;118:1264–72. https://doi.org/10.1161/ CIRCRESAHA.115.307540; PMID: 27081109. 102. Gyöngyösi, M. ACCRUE and cell-based therapy meta-analysis. European Society of Cardiology Congress 2017, Barcelona, Spain, 1 August 2017. Abstract 988 [Oral Presentation]. 103. Gyöngyösi M, Wojakowski W, Lemarchand P, et al. Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE)

in patients with acute myocardial infarction based on individual patient data. Circ Res 2015;116:1346–60. https://doi.org/10.1161/CIRCRESAHA.116.304346; PMID: 25700037. 104. Gyöngyösi M, Wojakowski W, Navarese EP, et al. Metaanalyses of human cell-based cardiac regeneration therapies: Controversies in meta-analyses results on cardiac cell-based regenerative studies. Circ Res 2016;118:1254–63. https://doi. org/10.1161/CIRCRESAHA.115.307347; PMID: 27081108. 105. Henry TD, Losordo DW, Traverse JH, et al. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. Eur Heart J 2018. https://doi.org/10.1093/eurheartj/ ehx764/4791398; PMID: 29315376; epub ahead of press. 106. Henry TD, Povsic TJ. Repeat cell therapy for refractory angina: Déjà vu all over again? Circ Cardiovasc Interv 2015;8:e003049. https://doi.org/10.1161/CIRCINTERVENTIONS.115.003049; PMID: 26259771. 107. Sinvhal RM, Gowda RM, Khan IA. Enhanced external counterpulsation for refractory angina pectoris. Heart 2003;89:830–3. https://doi.org/10.1136/heart.89.8.830 PMID: 12860848. 108. ECP Machine (External CounterPulsation). Yati Mediquip. 2018. Available at: www.yatimediquip.com/what-is-ecp.html (accessed 10 April 2018).

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Cardiology Masters

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 Patrick Serruys, professor of cardiology at the National Heart and Lung Institute at Imperial College, London, UK. DOI: https://doi.org/10.15420/ecr.13:2:CM1

Prof Patrick Serruys is an expert in interventional cardiology, He and a colleague developed drug-eluting stents, which drastically reduced restenosis after procedures. He later devised a fully biodegradable drug-eluting scaffold so a permanent metallic stent would not need to be implanted in patients. He previously led on establishing the methodology of quantitative coronary angiography. Along with having an office “full of diplomas and medals”, he has won career achievement awards from TCT and the American College of Cardiology, as well as the gold medal of the European Society of Cardiology. He acknowledges that introducing something new has immense ethical issues and advises practitioners to remain curious and open to novelty.

The hippopotamus and left ventricular contractility In 1947, shortly after my birth, my family arrived in Zaire, now the Democratic Republic of Congo (DRC), in Africa. It was in the postwar period, and my parents had no choice other than to emigrate. So, my youth (until my return to Belgium) was in Africa – an experience of living in wide open space under the African sun, with wild animals all around. There were no seasons; it was a great feeling of liberty in an unbelievable continent with unlimited space and extraordinary wildlife.

contractility. At the time, the concept was described as a ‘white elephant’, because it was very difficult to catch and to comprehend. There were multiple diseases that could contribute, and a lot of debate on a definition. One day, I was in a debate with Sonnenblick. I was still a very young man, and that’s how my mentor, Prof Paul Hugenholtz, presented me to the audience: he said this young fellow was not afraid to debate with a great expert. He quipped that, instead of chasing the white elephant, I was able to master the black hippopotamus.

Leaving Socrates behind It has been published in Circulation that my favourite pet was an alcoholic hippopotamus – there are pictures of it (Figure 1).1 We lived in a house that had gardens that ran down to the Congo River and, when we moved in, the previous resident told my father that a potentially dangerous hippopotamus would come up from the water into the garden, but we should not worry. The solution – in an age when animal welfare was little developed and it was politically correct to give alcohol to animals – was to provide liberal quantities of alcohol. Vermouth was the preferred alcohol and, because the animal has no lactate dehydrogenase to metabolise the alcohol, he would fall asleep, not to say that he was in a coma. Then, with my friends, I used to climb on his back, open his eyes, open his mouth, look in his ears. That hippopotamus became famous when my mentor showed those pictures to Edmund Sonnenblick, a great expert on left ventricular

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I spent six years studying Greek and Latin – at the end of high school, I was more fluent in these languages than I was in French, German, English or Flemish. When the time came to make a decision about future studies, I wrote a letter to my father saying that I wanted to study pure philosophy. My father wrote back to me from the DRC, saying: “Boy, this is fine, but it will be difficult being Socrates in the 20th century. You are a good student, so why don’t you do something like engineering, medicine or law, as well as philosophy?” So I entered the University of Leuven to study philosophy in parallel with medicine. My plan at the time was to combine philosophy with psychiatry but, after one year, I gave up on the philosophy. The course was boring, with a lot to memorise and it was all about old stuff. I was 17 and very existential at the time. Then, in the second year of studying medicine, I joined the department of physiology run by Xavier Auber. I became fascinated by the

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Cardiology Masters: Dr Patrick Serruys physiology of the vascular system – in particular, the contraction of smooth muscle and the contraction of mammalian and amphibian muscles. In Prof Auber’s laboratory, I studied contraction of the sartorius muscle of the frog, and spent a lot of time on the force– velocity relationship.

Figure 1: The Famous Hippo

Then I joined Prof Alan Hodgkin, later Sir Alan; he won the Nobel Prize in 1963 with Andrew Huxley and John Eccles for their discoveries concerning the ionic mechanism involved in excitation and inhibition of the peripheral and central portion of the nerve-cell membrane. I was based at the Marine Institute, Marine Biological Association in Plymouth, England, which was a wonderful experience, studying the voltage clamp technique. During the day, we would fish for squid, which have giant axons and nerve-cell membranes and, at night, we were using the Hodgkin’s voltage-clamp technique to investigate nerve transmission in the squid’s huge nerve fibre. However, I soon realised that physiologists were exceptional individuals, with knowledge of biochemistry, physiology, statistics and engineering; Aubert had made his own strain gauge. For me, I wanted to focus on being just one thing, and that was why I decided to join the clinical field.

Setting out on the path In my final year of cardiology training at the University of Leuven, I happened to attend a meeting on the use of computers in cardiology and met Prof Paul Hugenholtz, who asked me to visit the thoracic centre, and I fell in love with the place immediately. He was an extraordinary mentor, the father of the European Society of Cardiology, and gave me full confidence, which really shaped my personality, with the classic motto “Nothing is impossible”. When I graduated summa cum laude in internal medicine in 1972, I continued to work on muscle physiology using a creatine phosphokinase block. During my first years in cardiology, 1973–7, we were basically making diagnoses for the surgeon – providing fresh flesh to them, as Hugenholz put it. In our institution, we were the great provider of coronary bypass and valve replacement surgery. I had just got married and my wife suggested I should spend more time at home so, in 1974, I started working in the cath lab in Leuven, as it was a more elective, planned way of life, and I fell in love with this sort of working environment. This was before the advent of interventional cardiology as we know it. When the angioplasty era came, we jumped on the opportunity to become a treating physician independent of the surgeon.

Developing the field of interventional cardiology Very soon, I became aware of restenosis occurring after balloon angioplasty. For many years, I investigated multiple pharmacological treatments – ketanserin, angiotensin-converting-enzyme inhibitors, anti-sense therapy – and all studies were published in the New England Journal of Medicine and The Lancet. There were 13 unsuccessful trials in total; I felt like the champion of the negative trial. But during this period, through to the early 1980s, I established the methodology of quantitative coronary angiography with the bioengineering group at the Thoraxcenter in Rotterdam. In those days, I also developed my worldwide network with experts to unravel the issue of restenosis. After the unsuccessful pharmacological trials, I shifted my focus to mechanical device engineering such as stenting and, in 1986, introduced the technique in the Netherlands.

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Prof Serruys, aged 10, on the back of his favourite pet. His parents moved the family to the Democratic Republic of Congo in 1947 after they “lost everything” in World War II. When they moved into their home, the previous resident warned them that potentially dangerous hippopotamuses would come up from the water into the garden, but they should not worry. The solution was to provide liberal quantities of alcohol. Prof Serruys explains: “Hippopotamuses have no lactate dehydrogenase, so they can’t metabolise alcohol.”

The advent of the drug-eluting stent The bare-metal stent was creating even more new intimal hyperplasia than balloon angioplasty, and then I discovered – albeit by chance – the concept of the drug-eluting stent. At the Cordis Corporation facilities in New Jersey, I jumped on the concept, using the latest scientific and experimental knowledge in the field of molecular biology of neointimal inhibition. Eduardo Sousa, in São Paolo, Brazil, and I introduced the drug-eluting stent for the first time to the world in 1999. This was a revolution for interventional cardiology, as it drastically reduced the restenosis rate after an intervention; however, implantation of a permanent metallic prosthesis was viewed as a major drawback in the treatment of coronary artery stenosis. Therefore, in 2006, I introduced with John Ormiston, of Mercy Hospital, Auckland, New Zealand, the worldwide use of fully biodegradable, drug-eluting scaffolds that eliminated the presence of a permanent metallic foreign body in the coronary circulation. I am proud that, in the implementation design of quantitative coronary angiography, the initial algorithm I developed with Hans Reiber at the Thoraxcenter in Rotterdam remains unchanged and the gold standard 40 years after its inception. And, of course, of the value demonstrated by the bare-metal stent, the drug-eluting stent, and the introduction of the PLLA bio-resorbable scaffold.

Reaping the rewards I have received many awards; my office is full of diplomas and medals, but the TCT Career Achievement Award in 1996 has a special place in my heart and in my memories, because TCT director Dr Marty Leon flew my entire family – my parents, wife and the three kids – to Washington for the event. When I went to stage to thank him for

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Cardiology Masters bestowing this honour on me, I suddenly realised in a kind of extraordinary emotional shock that my entire family was in the main arena watching the whole ceremony. The second moment that stands out was a standing ovation at the American Heart Association in November 2001, two months after the terrible events of September 2001. There was a gloomy atmosphere and a metal gate at the entrance of the main arena, but my speech was full of enthusiasm, optimism and novelty in the field of cardiology, which is probably what triggered a standing ovation. First, I thought that it was a manifestation of some individual action – but then I thought perhaps that if only the people on my right were standing up, it was because there was a leak in the plumbing and they’d just realised their feet were in water. It was only when I saw the Dutch attendees standing up that I realised it was a standing ovation. Finally, I received a career achievement award from the American College of Cardiology, as well as the gold medal of the European Society of Cardiology. I received the latter jointly with Dr Pedro Brugada – we both became professors of cardiology in 1988 – and it was a huge ceremony in a big cathedral. There were no slides; from behind the lectern it felt rather like talking as a priest. In terms of my work, I have good memories of the first streptokinase intracoronary, the first bare metal stent, the first drug-eluting stent and the first valve implantation. Those are things that you cannot forget.

1.

Reflecting on the future I think future of cardiology will turn out to be, as usual, unexpected. Over my career, I’ve constantly been surprised by the direction it has taken. There has been tremendous competition between device and pharma over the past 50 years and I am sure that nanotechnology, gene therapies and artificial intelligence will play a major role in the future. By 2025, computers will have the capacity of the human brain; big data is coming very quickly, and advances in imaging and holograms will quickly appear and lead to a rapid pace of change in our practice. I would tell others that the first step when you try to introduce something new is to be aware that medicine is terribly difficult and has immense ethical issues. I will never forget the extraordinary dialogue with the patient that precedes the first in man. The patient must trust you. It is a frightening moral responsibility for you, when you treat the first patient, the first 10, the first 1,000 – before finally you have millions of people benefiting from something that you have introduced, such as a stent, a drug-eluting stent or a valve. It is important to be curious. Don’t look at the past – try to guess the future. Be open to novelty. Keep thinking that, at the very end, whatever the discovery is, it has to be potentially beneficial to your father, your brother, your mother and your sister, and to basically every patient around the world. n

Shurlock B. Special feature: Patrick W. Serruys, MD, PhD, FACC, FESC, and the Thoraxcenter, Rotterdam, the Netherlands. Circulation 2010;121 :F1–6. https://doi.org/10.1161/CIR.0b013e3181cbbf05

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ECR 13.1  

European Cardiology Review Volume 13 Issue 1 Summer 2018

ECR 13.1  

European Cardiology Review Volume 13 Issue 1 Summer 2018