ECR 12.2

European Cardiology Review Volume 12 • Issue 2 • Winter 2017

Volume 12 • Issue 2 • Winter 2017

www.ECRjournal.com

Impact on Patient Care: The 2016 European Heart Failure Guidelines Nesan Shanmugam

Role of Testosterone in the Treatment of Cardiovascular Disease Carolyn M Webb and Peter Collins

QT Prolongation and Malignant Arrhythmia: How Serious a Problem?

Christos-Konstantinos Antoniou, 1 Polychronis Dilaveris, 1 Panagiota Manolakou, 2 Spyridon Galanakos, 1 Nikolaos Magkas, 1 Konstantinos Gatzoulis, 1 and Dimitrios Tousoulis 1

Viewpoint: Recent Advances in Intracoronary Imaging for Vasa Vasorum Visualisation Kensuke Nishimiya, Yasuharu Matsumoto and Hiroaki Shimokawa

Milder LVH LVWT 15.8 vs.

19.7 mm

↑ LV cavity size 47.8 vs. 44.3 mm

Vasa vasorum Inflammatory cells/cytokines

Adventitia

↑coronary blood flow Adipose tissue

↑ TWI especially in lateral leads

Apical HCMIntima, in media over 1/3 cases ↔ CV events

Necrotic core

↓myocardial ischaemia

Intraplaque neovessel Intraplaque haemorrhage

Endothelium

Only 14 % have concentric LVH CV effects of 13–16 mm testosterone

Similar degrees of fibrosis on CMR

treatment

↔ angina

ISSN: 1758-3756

↓ prevalence of SAM and LVOTO

Characteristics of Athletes with Hypertrophic Cardiomyopathy

↑ diastolic function and GLS

Lumen ↑exercise capacity in heart failure

Cardiovascular Adventitial Vasa ↑coronary (CV) ↔ atheroma Effects ofvasomotion Testosterone Vasorum Formation in Treatment the Human Coronary Artery

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COVER ECR12.2.indd All Pages

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faster when mapping with the PENTARAY® Catheter and pattern matching filter2**

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*In a single center study, after the first ablation set **Compared to the focal ablation catheter 1. Luther. V. et al. A Prospective Study of Ripple Mapping in Atrial Tachycardias. CIRCEP. 2016 2. Body Surface Morphology Matching Pre-Clinical Evidence Report. Test report: REP9819. June 2017 3. Imanli, H. et al, A Novel CARTO® Segmentation Software for Contrast enhanced Computed Tomography guided radiofrequency ablation in patients with atrial fibrillation. HRS poster. 2016 These products can only be used by healthcare professionals in EMEA. Important information: Prior to use, refer to the instructions for use supplied with this device for indications, contra-indications, side effects, warnings and precautions.

Always verify catheter tip location using fluoroscopy or IC signals and consult the CARTO® System User Guide regarding recommendations for fluoroscopy use. Sporton S, Earley M, Nathan A, and Schilling R, Electroanatomic versus fluoroscopic mapping for catheter ablation procedures: A prospective randomized study. Journal of Cardiovascular Electrophysiology 2004;15,3:310-315.

THERMOCOOL® Navigation Catheters are indicated for the treatment of recurrent drug/device refractory sustained monomorphic ventricular tachycardia (VT) due to prior myocardial infarction (MI) in adults. These screenshots provide examples of parameters that are not intended as recommendations. All settings are user defined and must be based on clinical experience and medical judgment © Johnson & Johnson Medical NV/SA 2017

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Volume 12 • Issue 2 • Winter 2017

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

St George’s University of London, London, UK

Associate Editorial Steering Committee Pablo Avanzas

Rao Kondapally

Aneil Malhotra

Robin Ray

Gianluigi Savarese

Nesan Shanmugam

University Hospital of Oviedo, Oviedo, Spain

St George’s University of London, London, UK

St George’s University of London, London, UK

St George’s University of London, London, UK

Karolinska Institute, Stockholm, Sweden

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

Noel Bairey Merz

Michael Fisher

Amir Lerman

Giuseppe Rosano

Cedars-Sinai Heart Institute, Los Angeles, US

Royal Liverpool University Hospital, Liverpool, UK

Mayo Clinic, Minnesota, US

IRCCS San Raffaele, Rome, Italy

Augusto Gallino

José Luis López-Sendón

Magdi Saba

La Paz Hospital, Madrid, Spain

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

Vinayak Bapat Columbia University Medical Centre, New York, US

Velislav Batchvarov St George’s University of London, London, UK

John Beltrame University of Adelaide, Adelaide, Australia

Christopher Cannon

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Alberto Lorenzatti Hospital Córdoba, Cordoba, Argentina

Antoni Bayes-Genis

Angela Maas

Hospital Germans Trias i Pujol, Barcelona, Spain

Radboud University Medical Center, Nijmegen, the Netherlands

Robert Gerber

Olivia Manfrini

Conquest Hospital, Hastings, UK

University of Bologna, Bologna, Italy

Bernard Gersh

St George’s University of London, London, UK

Roxy Senior Imperial College, London, UK

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

Rosa Sicari Italian National Research Council

Iana Simova

Mayo Clinic, Minnesota, US

Felipe Martinez

David Goldsmith St George’s University of London, London, UK

National University of Cordoba, Cordoba, Argentina

Imperial College, London, UK

Tommaso Gori

Antoni Martínez-Rubio

Alberto Cuocolo

University Hospital of Sabadell, Sabadell, Spain

Konstantinos Toutouzas

University of Naples Federico II, Naples, Italy

Johannes Gutenberg University Mainz, Mainz, Germany

Gheorghe Andrei Dan

Kim Greaves

Argyrios Ntalias

Isabella Tritto

Sunshine Coast University Hospital, Sunshine Coast, Australia

University of Athens, Athens, Greece

University of Perugia, Perugia, Italy

Eileen Handberg

Denis Pellerin St Bartholomew’s Hospital, London, UK

Dimitrios Tziakas

Harvard Medical School, Boston, US

Peter Collins

Colentina University Hospital, Bucharest, Romania

Ranil de Silva

University of Florida, Florida, US

Imperial College, London, UK

Thomas Kahan

Polychronis Dilaveris

Danderyd University Hospital, Danderyd, Sweden

Hippokration General Hospital, Athens, Greece

Koichi Kaikita

Carlo Di Mario Careggi University Hospital, Florence, Italy

Kumamoto University, Kumamoto, Japan

Mike G Kirby

National Cardiology Hospital, Sofia, Bulgaria

Juan Tamargo University Complutense, Madrid, Spain University of Athens, Athens, Greece

Carl Pepine

Democritus University of Thrace, Xanthi, Greece

University of Florida, Florida, USA

Mauricio Wajngarten

Piotr Ponikowski

University of Sao Paulo, Brazil

Wroclaw Medical University, Wroclaw, Poland

Hiroshi Watanabe

Eva Prescott Bispebjerg Hospital, København, Denmark

Hamamatsu University School of Medicine, Hamamatsu, Japan

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

Axel Pries

Matthew Wright

University College, London, UK

Charité Universitätsmedizin Berlin, Germany

St Thomas’ Hospital, London, UK

Albert Ferro

Patrizio Lancellotti

Hari Raju

José Luis Zamorano

King’s College London, London, UK

University of Liège, Liège, Belgium

Macquarie University, Sydney, Australia

Hospital Ramon Y Cajal, Madrid, Spain

Perry Elliott

Managing Editor Genevieve Walton • Production Jennifer Lucy • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director David Bradbury •

Editorial Contact Genevieve Walton gen.walton@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com

Radcliffe Cardiology

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Published by Radcliffe Cardiology.

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

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Established: April 2005 Frequency: Bi-annual Current issue: Winter 2017

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.

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

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

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

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

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

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

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Associate International Member of the World Heart Federation

Join us for 23rd Annual Scientific Meeting of

the International Society of Cardiovascular Pharmacotherapy Date : May 26 (Sat.) and 27 (Sun), 2018 Venue : The Ritz-Carlton, Kyoto JAPAN for scientific exchange on current topics in evidence-based clinical management

President and Meeting Chair Koji Hasegawa (Leader, Cardiovascular Clinical Research Network, National Hospital Organization) Program Chair Masayuki Yoshida (Director, Life Science and Bioethics Research Center, Tokyo Medical and Dental University) Program Chair Masataka Sata (Professor and Chairman, Cardiovascular Medicine, University of Tokushima Graduate School) Congress Secretariat Division of Translational Research, Kyoto Medical Center Kyoto 612-8555 JAPAN FAX : 81-75-641-9252â&#x20AC;&#x192;E-mail : medical@j-iscp.com Congress website : www.iscp2018.com

Visit the website for ISCP at www.iscpcardio.org kyoto_a4.indd 1

07/12/2017 22:30

Contents

Foreword

75

Juan Carlos Kaski

Heart Failure | Cardiomyopathy

76

Highlights of the 2016 European Society of Cardiology Guidelines on Heart Failure Antoni Bayes-Genis

78

Impact on Patient Care: The 2016 European Heart Failure Guidelines Nesan Shanmugam

80

Hypertrophic Cardiomyopathy in Athletes Aneil Malhotra and Sanjay Sharma

Hormones & Ischaemic Heart Disease

83

Role of Testosterone in the Treatment of Cardiovascular Disease Carolyn M Webb and Peter Collins

Guest Editorial

88

Cardiovascular Risk Management Targeting Inflammation in Addition to Lipid-lowering Therapy Koji Hasegawa

Cardiovascular Pharmacology

89

Inflammation Revisited: Atherosclerosis in The Post-CANTOS Era Wolfgang Koenig

ISCP 2017 Best Posters

92

The Best Posters from XXII Annual Meeting of the International Society of Cardiovascular Pharmacotherapy (ISCP)

Interventions | Arrhythmias | Imaging

112

QT Prolongation and Malignant Arrhythmia: How Serious a Problem?

121

Viewpoint: Recent Advances in Intracoronary Imaging for Vasa Vasorum Visualisation

Christos-Konstantinos Antoniou, Polychronis Dilaveris, Panagiota Manolakou, Spyridon Galanakos, Nikolaos Magkas, Konstantinos Gatzoulis, and Dimitrios Tousoulis

Kensuke Nishimiya, Yasuharu Matsumoto and Hiroaki Shimokawa

Cardiology Masters

124

72

Featuring: Dr Peter Libby

Access at: www.ECRjournal.com

ECR12.2 Contents.indd 72

Š RADCLIFFE CARDIOLOGY 2017

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Lisbon, Portugal

September 22-26

CIRSE 2018 featuring

SAVE THE DATE www.cirse.org

Cardiovascular and Interventional Radiological Society of Europe

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Supporting life-long learning for cardiovascular professionals Guided by Editor-in-Chief Juan Carlos Kaski and an Editorial Board comprising of world-renowned physicians, European Cardiology Review is a peer-reviewed journal that publishes reviews, case reports and original research. Available in print and online, European Cardiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions European Cardiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality.

For further information on submitting an article, or for free access to the journal, please visit: www.ECRjournal.com

Radcliffe Cardiology European Cardiology Review is part of the Radcliffe Cardiology family. For further information, including access to thousands of educational reviews from across the speciality, visit: www.radcliffecardiology.com

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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.

W

elcome to the December 2017 issue of European Cardiology Review.

In this issue, we present a section on heart failure and cardiomyopathies featuring articles from A. Bayes-Genis and A. Malhotra and S. Sharma. Professor Bayes-Genis highlights the latest changes introduced to the European Society of Cardiology guidelines on the management of heart failure, whereas Dr Malhotra and Sharma’s manuscript focuses on findings that help differentiating athletes’ hearts from those in subjects affected by hypertrophic cardiomyopathy. Dr Shanmugan further contributes to the field with a timely critical editorial on current heart failure guidelines.

Also in this issue, in a section devoted to hormones and the heart, C. Webb and P. Collins contribute their expertise by reviewing another important topic, namely the role that testosterone may play in the pathogenesis of ischaemic heart disease and coronary artery disease progression.

I am also very pleased to report that the partnership between European Cardiology Review, Radcliffe Cardiology and the International Society of Cardiovascular Pharmacotherapy (ISCP) is going from strength to strength. Our ongoing special section on Cardiovascular Pharmacotherapy features a guest editorial by Prof Koji Hasegawa, ISCP President Elect, on the role of inflammation in ischaemic heart disease. Professor Koenig also addresses specific aspects of this important topic in an article that discusses whether and how the results of the recently published CANTOS study could change medical practice. This section also features some of the best posters presented at the ISCP Annual Scientific Sessions that took place in Barcelona in August of this year. Three of these posters have received ISCP scientific awards.

The final two review articles in this issue look at both arrhythmias and vascular imaging, with Dr Dilaveris discussing QT prolongation and malignant arrhythmias and Professor Shimokawa presenting novel data on intracoronary imaging of adventitial vasa vasorum. Both articles are likely to attract the attention of the readership given their novelty and scholarly character.

In our ongoing series — Cardiology Masters — that highlights the contributions of clinicians, academics and researchers who have become ‘legendary figures’ in the field of cardiovascular medicine, I am delighted that Dr Peter Libby has given his permission for ECR to profile him in this December issue. It is our hope that ECR’s Cardiology Masters section will stimulate younger members of the cardiovascular community worldwide to pursue excellence in the field of cardiovascular disease, guided by the quality of the work and the personality of the brilliant figures we portray in the section.

In summary, all articles in the current issue tackle extremely important topics in cardiovascular medicine and provide expert views regarding the diagnosis and practical management of important cardiovascular disease, as well as highlighting future research avenues that may lead to a better understanding of diverse cardiovascular conditions. As in previous issues, I extend my gratitude to the European Cardiology Review Editorial Board, the Steering Committee, the excellent reviewers and all the featured authors for their contributions to this issue of the journal. I hope you will enjoy reading it as much as I have enjoyed editing it.

I would like to finish by wishing you all a healthy, peaceful and productive year in 2018. n

© RADCLIFFE CARDIOLOGY 2017

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Access at: www.ECRjournal.com

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Heart Failure | Cardiomyopathy

Highlights of the 2016 European Society of Cardiology Guidelines on Heart Failure Antoni Bayes-Genis 1–3 1. University Hospital Germans Trias i Pujol, Badalona; 2. Autonomous University of Barcelona, Barcelona; 3. Carlos III Health Institute, Madrid, Spain.

Abstract The European Society of Cardiology guidelines for the diagnosis and treatment of heart failure (HF) was updated in 2016. In this article, highlights of the updates made based on new findings and practical recommendations are presented. The 2016 guidelines include definitions and criteria for diagnosing the different types of HF. In addition, a newly developed algorithm is proposed for treating particularly symptomatic HF with reduced ejection fraction, including the use of the angiotensin-converting enzyme inhibitors, betablockers, mineralocorticoid receptor antagonists and the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. Further evidence is required for some aspects of the diagnosis and treatment of HF, but these guidelines will prove useful for decision making in this setting.

Keywords heart failure, angiotensin receptor neprilysin inhibitor, angiotensin-converting enzyme inhibitors, cardiac resynchronisation therapy Disclosure: None Received: 15 May 2017 Accepted: 23 June 2017 Citation: European Cardiology Review 2017;12(2):76–7. DOI: 10.15420/ecr.2017:5:2 Correspondence: Antoni Bayes-Genis, Cardiology Service, University Hospital Germans Trias i Pujol, Carretera de Canyet s/n 08916, Badalona, Barcelona, Spain.

E: abayesgenis@gmail.com

The long-awaited 2016 European Society of Cardiology (ESC) guidelines for heart failure (HF)1 provide the large amount of novel research in HF since the previous guidelines published in 2012.2 Here, highlights of the 2016 guidelines are presented.

Definition of Heart Failure The main terminology used to describe HF is historically based on measurement of the left ventricular ejection fraction (LVEF). HF affects a wide range of patients, from those with normal LVEF (typically considered as ≥50 %; HF with preserved EF [HFpEF]) to those with reduced LVEF (typically considered as <40 %; HF with reduced EF [HFrEF]). Patients with an LVEF in the range of 40–49 % represent a ‘grey area’, which is now defined as HF with mid-range EF (HFmrEF).

The criteria for diagnosing the three types of HF are summarised in Table 3.1 in the ESC guidelines.1 It is remarkable that the new classification includes natriuretic peptides as key factors for the definition of HFmrEF and HFpEF.

Treatment of Heart Failure A newly proposed algorithm to aid in decision making for the treatment of HF is summarised in Figure 7.1 in the ESC guidelines.1 The algorithm covers the use of pills and devices, with colour-coded differentiation between classes of recommendation (class I = green, class IIa = orange).

Two major treatments for HF included in the algorithm are the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan and ivabradine.

Angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers are first-line treatments, followed by mineralocorticoid receptor antagonists (MRAs). These three therapies have received class Ia recommendations.

After this first-line treatment, there are three further options for the clinician to consider if patients remain symptomatic (New York Heart Association [NYHA] functional class II or above and LVEF ≤35 %).

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Treatment with Angiotensin Receptor Neprilysin Inhibitor If the patient is unable to tolerate ACEIs and/or angiotensin receptor blockers (ARBs), consider switching to ARNI (recommendation class Ib). In a large, prospective randomised clinical trial, sacubitril/valsartan was proven to be superior to conventional ACE inhibition (enalapril) in reducing cardiovascular deaths and HF readmissions.1 The Prospective Comparison of ARNI with ACEI to determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was the largest (N=8442) and most geographically diverse HF trial performed to date. The trial was terminated early due to overwhelming reductions in death from cardiovascular causes and the primary endpoint (cardiovascular death or first hospitalisation for worsening HF) in the group receiving sacubitril/ valsartan. After a mean treatment duration of 27 months, treatment with sacubitril/valsartan was associated with significant reductions in the primary endpoint in the sacubitril/valsartan group compared with the enalapril group (21.8 versus 26.5 %, respectively; hazard ratio [HR] 0.80; P<0.001). All-cause mortality rates were significantly reduced (17.0 versus 19.8 %; HR 0.84; P<0.001) and the average reduction in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical score reflects significantly fewer symptoms or physical limitations secondary to HF in the sacubitril/valsartan group. There was no difference in the incidence of new-onset AF or worsened renal function between treatment groups.3

Treatment with Ivabradine If the patient is in sinus rhythm, and it already receives optimally tolerated beta-blockers, the clinician should consider introducing ivabradine (class IIa recommendation). Ivabradine slows the heart rate through inhibition of the If channel in the sinus node and, therefore, should only be used for patients in sinus rhythm. Ivabradine reduced the combined endpoint of mortality or hospitalisation for HF in patients with symptomatic HFrEF or LVEF ≤35 %, in sinus rhythm and with a heart

© RADCLIFFE CARDIOLOGY 2017

08/12/2017 18:48

HF Guidelines Highlights rate ≥70 bpm who had been hospitalised for HF within the previous 12 months, receiving treatment with an evidence-based dose of betablocker (or maximum tolerated dose), an ACEI (or ARB) and an MRA.4

Cardiac Resynchronisation Therapy Recommendations for the use of cardiac resynchronisation therapy (CRT) are largely based on QRS duration: • N ot recommended (class III, level of evidence A) in patients with a QRS duration <130 ms • Indicated for patients with complete left bundle branch block and a QRS duration ≥130 ms, specifically: • Class I, level of evidence A recommendation for those with QRS >150 ms • Class I, level of evidence B recommendation for those with QRS 130–149 ms • Recommended (class IIa, level of evidence B) for patients with AF and NYHA III–IV HFrEF, despite optimal medical treatment, and a QRS duration of >130 ms, but only if it can achieve close to 100 % biventricular capture Furthermore, in patients requiring a pacemaker as a result of having heart block, implantation of a CRT device is also recommended (class I, level of evidence A). In particular, implantable cardioverter-defibrillators (ICDs) are indicated under the following circumstances: • P rimary prevention in patients with HF and reduced systolic function (LVEF <35 %) despite optimal medical treatment (class I recommendation) • Level of evidence A in patients with ischaemic cardiomyopathy • Level of evidence B in patients with non-ischaemic dilated cardiomyopathy • Secondary prevention in patients with <1 year estimated survival (class I, level of evidence A recommendation)

Further recommendations for acute HF include the following: • I n patients with normal oxygen levels avoid oxygen supplementation (class I, level of evidence C recommendation) • In patients with pulmonary oedema and chronic obstructive pulmonary disease avoid arterial blood gas testing (class IIa, level of evidence B recommendation).

• In patients with respiratory failure, consider early noninvasive ventilation (class IIa, level of evidence B recommendation) • In patients with persistent respiratory failure, intubation is recommended (class I, level of evidence C) • Systematic use of morphine or opioids is not recommended; however, they should be considered for patients with acute dyspnoea (class IIb, level of evidence B) For other acute HF drug therapies, the guidelines recommend that identification and prioritisation should be based on the patient’s initial clinical–hemodynamic profile.

Multidisciplinary Team Care Continuity of care is considered to be the key factor in ensuring that HF management programmes are suitably effective. The current guidelines outline the distinct roles for professionals involved in HF management that will enable them to empower patients to acquire the necessary skills for self-management. The benefit of correct discharge planning (i.e. incorporation of early post-discharge follow-up significantly reducing readmission rates) is also highlighted.

Palliative and End-of-life Care The guidelines include a checklist for physicians relating to palliative care of patients with HF. This list covers often overlooked aspects of such care and includes medication, and anticipated desires and emotional support for patients and their carers. However, evidence is scarce, thus development of definite recommendations for palliative care of patients with HF is not currently possible.

At the time when these guidelines were published, findings from the DANISH study5 had not yet been reported; it is likely that ICD recommendation for non-ischemic cardiomyopathy will be lowered in future guideline updates.

Although palliative therapies, such as intermittent inotropic infusion and peritoneal dialysis, can improve the quality of life of patients in this setting, these are not addressed in the guidelines.

Acute Heart Failure

Comorbidities

The 2012 guidelines characterised acute HF based on the presence or absence of signs or symptoms of congestion (fluid status: ‘wet’ versus ‘dry’) and peripheral hypoperfusion (degree of hypoperfusion: ‘cold’ versus ‘warm’).2 Combination of these characterisations results in four clinical profiles: wet–cold, wet–warm, dry–cold and dry–warm.

Determination of a patient’s clinical profile enables identification of a suitable drug therapy to initiate. The current guidelines recommend that after the initial evaluations and the patient is stabilised, clinicians should seek to identify potential causative or precipitating factors of the decompensation, keeping in mind the CHAMP (acute Coronary syndrome, Hypertension emergency, Arrhythmia, acute Mechanical cause, and Pulmonary embolism) rule.

The current guidelines include increased details pertaining to comorbidities compared with previous guidelines. Notably, in symptomatic patients with HFrEF and absolute or functional iron deficiency, intravenous ferric carboxymaltose is indicated (class IIa, level of evidence A recommendation) to improve symptoms, exercise capacity and quality of life.

1.

2.

onikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines P for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975. DOI: 10.1002/ejhf.592; PMID: 27207191.

McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart

EUROPEAN CARDIOLOGY REVIEW

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3.

Conclusion The 2016 ESC guidelines for HF were updated with new findings and detailed practical recommendations (most based on a high level [A/B] of evidence). Although gaps in the evidence for some aspects of HF diagnosis and treatment remain, these guidelines will prove immensely useful for decision making in the management and treatment of patients with HF. n

failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847.

DOI: 10.1093/eurheartj/ehs104; PMID: 22611136.

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

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wedberg K, Komajda M, Böhm M, et al. Ivabradine S and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–885. DOI: 10.1016/S0140-6736(10)61198-1; PMID: 20801500 Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016;375:1221–30. DOI: 10.1056/NEJMoa1608029; PMID: 27571011.

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Heart Failure | Cardiomyopathy

Impact on Patient Care: The 2016 European Heart Failure Guidelines Nesan Shanmugam Department of Cardiology, St George’s Healthcare, London, UK

Disclosure: NS received a travel grant and speaker fees from Servier.

Citation: European Cardiology Review 2017;12(2):78–9. DOI: 10.15420/ecr.2017.12.1.GE2 Correspondence: Nesan Shanmugam, Atkinson Morley Wing, St George’s Hospital, Blackshaw Road, London, SW17 0QT, UK. E: nesan_s@hotmail.com

I

n this issue of European Cardiology Review, Professor Bayes Genis and team give a clear and robust review of the 2016 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure (HF).1 The guidelines were last updated in 2012 and combined for the first time chronic and acute care. One year on, and in the wake of the 2017 HF Association conference in Paris, it is a good time to reflect on the impact that the guidelines have had on patient care.

There are three key components of the guidelines that will unquestionably have a major impact on patient care and outcomes. The first is in the area of therapeutics. We know that new therapies breed hope and optimism and this was certainly the case with the introduction of LCZ696, otherwise known as sacubitril/valsartan (Entresto; Novartis).

Following the pivotal PARADIGM-HF study, this was the first in the class of angiotensin receptor neprilysin inhibitors and was shown to be superior to the angiotensin-converting-enzyme inhibitor (ACEI), enalapril, reducing cardiovascular death or hospitalisation for HF by 20% and allcause mortality by 16 % to a high statistical significance (p=0.0000004).2 This effect was seen in patients with HF and reduced ejection fraction and mild-to-moderate symptoms. Consequently, there had been calls for the drug to replace existing ACEIs in all HF patients. However, the guideline committee have taken a more evidenced-based stance and have given class 1B recommendations that the requirement for previous exposure to ACEI or angiotensin receptor blocker is required prior to considering switching symptomatic (>New York Heart Association class II) patients to sacubitril/valsartan, as per the study inclusion criteria.

Despite this, 1 year on, uptake seems slow in the UK. Notwithstanding the financial impact that converting patients to sacubitril/valsartan will have, we have yet to fully understand the safety profile in ACE-inhibitor naïve patients. Moreover, sacubitril/valsartan is subject to two post-marketing surveillance studies as requested by the US Food and Drug Administration. One is to evaluate the effects of sacubitril/valsartan compared with valsartan on cognitive function, since neprilysin is a major beta amyloid-degrading enzyme in the brain; and the second study is to evaluate the incidence of angioedema in black patients treated with sacubitril/valsartan compared with a control drug. Until adequate data are available, sacubitril/valsartan cannot be recommended in a broader group of patients.

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Another notable feature of the guidelines is the prominence now given to the important issue of comorbidities and their co-management in HF patients. Comorbidities often accompany HF, with increasing prevalence as patients get older. Specific reference has been given in the guidelines to the holistic management of patients with both physical and psychological conditions. Comorbidities are known to independently predict death in patients with HF. Therefore, to focus on their management in the current guidelines will invariably have an impact on prognosis. For example, in those patients with concomitant HF with reduced ejection fraction and iron deficiency, replacement therapy with intravenous ferric carboymaltose has been shown to reduce HF hospitalization and improve exercise capacity.3 This focus on comorbidities will also likely promote collaborative thinking and engender new models of multidisciplinary care, such as joint HF–renal clinics, which can only be a positive thing.

Lastly, the acute HF section of the guidelines builds on the 2015 consensus paper from the Heart Failure Association/European Society of Emergency Medicine and the Society of Academic Emergency Medicine4 and importantly emphasise the concept of ‘time is muscle’, borrowed from patients with acute coronary syndrome. The algorithm emphasises urgent diagnosis and treatment of patients with acute HF so as to prevent organ damage. Such emphasis, at an earlier stage in the patient journey, could prevent much morbidity and mortality through timely diagnosis and coordinated disease management. The guidelines reiterate the importance of early level 2 high-dependency involvement in these highrisk patients presenting with acute pulmonary oedema. We also know HF patients treated in cardiology wards are less likely to die, either in hospital or after discharge from hospital, compared with patients treated in nonspecialist wards. The hope is that the guidelines will enable clinicians to approach policy makers at local and national levels to introduce innovative models of care in the acute setting, such as acute HF units, thus enabling close collaboration between multidisciplinary healthcare professionals. This will help ensure that every patient is cared for in the optimal manner within hospital and community settings.

The 2016 European HF guidelines have provided important evidencebased solutions; however, it is also clear that adherence to guidelines varies between settings, contributing to disparities in care and outcomes for patients. The challenge will be to overcome such inequalities and improve outcomes for all HF patients. n

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Impact on Patient Care

1.

onikowski P, Voors AA, Anker SD, et al. Authors/Task P Force Members. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819

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2.

3.

cMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF M Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. DOI: 10.1056/NEJMoa1409077; PMID: 25176015 Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.

CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.

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Eur Heart J 2015;36:657–68. DOI: 10.1093/eurheartj/ehu385; PMID: 25176939 Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on pre-hospital and early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine--short version. Eur Heart J 2015;36: 1958–66. DOI: 10.1093/eurheartj/ehv066; PMID: 25998514

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Heart Failure | Cardiomyopathy

Hypertrophic Cardiomyopathy in Athletes Aneil Malhotra and Sanjay Sharma Cardiology Clinical and Academic Group, St. George’s University of London, London, UK

Abstract Sudden cardiac death (SCD) in a young person is a rare but tragic occurrence. The impact is widespread, particularly in the modern era of media coverage and visibility of social media. Hypertrophic cardiomyopathy (HCM) is reported historically as the most common cause of SCD in athletes younger than 35 years of age. A diagnosis of HCM may be challenging in athletes as pathological hypertrophy of the left ventricle may also mimic physiological left ventricular hypertrophy (LVH) in response to exercise. Differentiation of physiological LVH from HCM requires an array of clinical tools that rely on detecting subtle features of disease in a supposedly healthy person who represents the segment of society with the highest functional capacity. Most studies are based on comparisons of clinical tests between healthy unaffected athletes and sedentary individuals with HCM. However, data are emerging that report the clinical features of athletes with HCM. This article focuses on studies that help shed further light to aid the clinical differentiation of physiological LVH from HCM. This distinction is particularly important in a young person: a diagnosis of HCM has significant ramifications on participation in competitive sport, yet an erroneous diagnosis of physiological adaptation in a young athlete with HCM may subject them to an increased risk of SCD.

Keywords Athlete’s heart, hypertrophic cardiomyopathy, left ventricular hypertrophy, sudden cardiac death Disclosure: The author has no conflicts of interest to declare.

Received: 26 July 2017 Accepted: 19 November 2017 Citation: European Cardiology Review 2017;12(2):80–2. DOI: 10.15420/ecr. 2017:12:1 Correspondence: Aneil Malhotra, Cardiology Clinical and Academic Group, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK.

Athletes who perform regular and intensive exercise regimes develop a variety of electrical and structural cardiac adaptations that manifest functionally to improve stroke volume and performance. Up to onefifth of young athletes (aged between 14–35 years) reveal greater left ventricular (LV) wall thickness compared to sedentary controls, though the majority fall under 12 mm.1,2 A small proportion of athletes, however, reveal an LV wall thickness of 13–16 mm, which overlaps with morphologically mild hypertrophic cardiomyopathy (HCM).

Hypertrophic cardiomyopathy is traditionally viewed as the most common condition responsible for sudden cardiac death (SCD) in young athletes.2–4 In a large case series of SCD in 1,866 young athletes, HCM was the causative condition identified in nearly 40 % of cases.4 Nearly two-thirds of athletes were 17 years old or younger and still at high school. Studies have also revealed a strong male preponderance for SCD, particularly in African American athletes who compete in sports with sudden movements and adrenergic surges such as football or basketball.5 Unfortunately over 80 % of affected individuals are asymptomatic before SCD, which often occurs during exercise or in its aftermath.

The incidence of SCD in young athletes (<35 years of age) varies widely according to the population studied. US data suggest an incidence ranging from anywhere between 0.5 and 13 per 100,0006,7 yet current methods of data collection have also been highlighted as underestimating the true incidence of SCD.8 Most studies have focused on HCM in sedentary individuals while few have focused on athletes. One study of over 3,000 British elite athletes revealed an HCM prevalence of 1:1500 with only morphologically mild expressions of the disease.3 The Italian screening experience also

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reports a similar prevalence among over 33,000 young athletes. This supports the theory that more severely affected individuals are likely to have been selected out due to impaired cardiorespiratory capacity.9

The Grey Zone A small proportion (2 %) of athletes who are white, male and compete in endurance sports have been reported to demonstrate LVH between 13 and 15 mm, which can also mimic morphologically mild HCM.2,3 Further studies revealed that ethnicity affects the degree of LVH, with up to 18 % of African American adult athletes exhibiting an LV wall thickness of >12 mm but never beyond 16 mm.10 The ‘grey zone’ is therefore larger in African American athletes.

Hypertrophic cardiomyopathy is characterised by asymmetric septal hypertrophy with a maximum LV wall thickness ≥15 mm in adults or >9 Z score (>2 Z score in adolescents and children).11 There is usually concomitant hyperdynamic systolic function, a relatively small LV cavity size and reduced diastolic function.12 Dynamic LV outflow tract obstruction (LVOTO) can be caused by systolic anterior motion of the mitral valve in up to one-third of patients. LVOTO can be present during exercise in up to 70 % of patients with HCM.13 Rather than relying on conventional methods to differentiate physiological LVH from HCM,14,15 recent studies have focused on direct comparisons between athletes with HCM and those with physiological LVH16,17 to provide a better understanding of the clinical features of HCM in an athlete (Figure 1). A wide array of clinical tools are available to create diagnostic algorithms to facilitate such differentiation,18 including clinical symptoms and family history, ECG, echocardiography and cardiac MRI (CMR), exercise stress testing and genetic testing.

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Hypertrophic Cardiomyopathy in Athletes Electrocardiogram Abnormal T wave inversion (TWI) is the hallmark of HCM and observed in over three-quarters of athletes with the condition according to a recent study.19 In another recent study TWI was more common among 106 athletes with HCM compared to 101 sedentary individuals with HCM (96 % versus 84 %, p=0.003)16 with the lateral leads most frequently involved. ST segment depression was observed in over half of athletes with HCM and one-quarter demonstrated pathological Q waves.

Additionally, in a subgroup of 55 healthy athletes with physiological LVH, abnormal TWI, ST segment depression or pathological Q waves were absent in everyone.

Left Ventricular Dimensions in Athletes with HCM A symmetrical increase in LV wall thickness in a homogenous pattern is seen in athletes with physiological LVH. Conversely in HCM, irregular patterns of hypertrophy occur that are localised to the septum or apex in an asymmetrical manner. Athletes with HCM exhibit less LVH than sedentary individuals with HCM (15.8 mm versus 19.7 mm, p<0.001) with a third demonstrating hypertrophy confined to the LV apex.16 The traditional ‘grey zone’ would only include 14 % of athletes with HCM who demonstrated mild concentric LVH that could also be interpreted as physiological LVH. Left ventricular cavity enlargement is also observed in most athletes with physiological LVH, which is a response to an increased cardiac workload associated with exercise, as opposed to sedentary patients with HCM where the LV dilatation indicates end-stage disease and reduced functional capacity. The LV end-diastolic dimension in healthy athletes ranges between 55 and 70 mm20 as opposed to those with HCM who generally have an LV cavity dimension of <50mm. A recent study of 28 healthy athletes and 25 patients with HCM reported that a cut-off of 54 mm for LV cavity size had a sensitivity and specificity of 100% to help distinguish physiological LV hypertrophy from HCM.21 In athletes with HCM, however, 14 % of athletes with HCM revealed an LV cavity >54 mm with an upper limit of 60 mm.16 Systolic anterior motion (SAM) of the mitral valve against the interventricular septum causing dynamic LVOTO is present in approximately 25 % of sedentary HCM individuals and up to 70 % of cases during exercise.13 Athletes with HCM do not usually reveal baseline or dynamic LVOTO.

Diastolic Dysfunction in Hypertrophic Cardiomyopathy Myofibre disarray in HCM, coupled with impaired sarcoplasmic calcium kinetics leads to reduced myocardial relaxation and diastolic dysfunction.

Most athletes with HCM, however, demonstrate normal diastolic function according to conventional parameters.17 Using E prime 9 cm/s as a cut-off for pathology according to British Society of Echocardiogram guidelines22 revealed a sensitivity of only 35 % among 56 athletes, 37 of whom were diagnosed with HCM, with the remaining 19 athletes having physiological LVH. The sensitivity fell further to 14 % when using an E/E prime ratio >12 as a marker of pathology. The highest sensitivity for identifying HCM in the athlete was found using longitudinal function as a discriminating marker (S prime <9 cm/s) albeit at 43 % with a specificity of 84 %. Assessment of global longitudinal strain (GLS) has also been shown to be useful with a measurement of more (negative) than −10 % resulting in a sensitivity of 87 % and specificity of 95 % for the diagnosis of HCM in a sedentary patient.23 A GLS of more than −15% in an athlete is deemed pathological.

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Figure 1: Characteristics of Athletes with Hypertrophic Cardiomyopathy Compared to Sedentary Patients with Hypertrophic Cardiomyopathy that Highlight the Need to Utilize an Array of Clinical Tools Available to the Clinician Milder LVH LVWT 15.8 vs.

19.7 mm

↑ LV cavity size 47.8 vs. 44.3 mm

↑ TWI especially in lateral leads

Apical HCM in over 1/3 cases

Similar degrees of fibrosis on CMR

Only 14 % have concentric LVH 13–16 mm

↓ prevalence of SAM and LVOTO

↑ diastolic function and GLS

CMR = cardiac magnetic resonance imaging; ECG = electrocardiogram; GLS = global longitudinal strain; LV = left ventricular; LVH = left ventricular hypertrophy; LVOTO = left ventricular outflow tract obstruction; SAM = systolic anterior motion; TWI = T wave inversion.

Cardiac MRI Cardiac MRI is the gold standard imaging tool for assessment of HCM in athletes and non-athletes. The ability to delineate LV hypertrophy, reveal underlying fibrosis or utilize more novel techniques such as T1 mapping give CMR a unique position in the armamentarium of imaging modalities. When comparing athletes with HCM to sedentary affected individuals, there is no discernible difference in the presence of myocardial fibrosis (33 % versus 40.6 %, p=0.258).16 Athletes with HCM, however, could have a lower ischaemic burden in the absence of mechanical LVOTO, severe LVH and microcirculatory disease.

T1 mapping and extracellular volume (ECV) content measurement may help differentiate physiological LVH from mild HCM on CMR. Patients with HCM reveal high T1 signals and increased ECV due to inflammation and fibrosis in the extra-cellular space. In contrast, physiological LVH results from an increase in myocyte size and relative reduction in the ECV. A study of 30 endurance athletes and 15 sedentary patients revealed that the ECV component of LV mass was similar between athletes and controls, yet athletes showed a significantly higher indexed cellular mass compared with controls.24 Furthermore, there was an inverse relationship between athletes demonstrating the highest functional capacity (peak oxygen consumption, VO2 max >60 mls/min per kg) and ECV on CMR using T1 mapping. Another study from the same group investigated 16 patients with HCM and 10 athletes with physiological LVH. An ECV >22.5% differentiated physiological LVH from HCM with a sensitivity of 100 % and specificity of 90 %.24

Haemodynamics with Exercise An attenuation of or drop in blood pressure response during exercise is noted in nearly one-quarter of patients with HCM. Plausible mechanisms are abnormal vascular tone, small vessel ischaemia or exertional LVOTO.25 ECG markers of pathology may also be noted during exercise and include ST segment depression, TWI or ventricular arrhythmias.

Athletes with physiological LVH, particularly those participating in endurance sports, demonstrate the greatest LV cavity size causing enhanced diastolic filling and subsequent generation of large stroke volume. A VO2 max of >50 ml/kg per min, or >120 % of age-predicted value has traditionally been used to differentiate physiological LVH from HCM.26 However, there are certain limitations regarding the widespread

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Heart Failure | Cardiomyopathy applicability of this value given that the cut-off was based primarily on white male athletes. VO2 max variations are lacking for both African American athletes who are competing in increasing numbers at every level of sport internationally and also athletes with HCM. The cessation of exercise for 6 to 8 weeks has been shown to reverse some of the structural and electrical changes associated with exercise, including normalization of TWI on the resting ECG and regression of physiological LVH.27 In contrast, an athlete with HCM will continue to demonstrate a pathological phenotype irrespective of whether they have undertaken a period of detraining or not.28

Management of Athletes with Hypertrophic Cardiomyopathy The overarching aim of managing athletes with HCM is to mitigate their risk of developing potential sequelae of the condition, including SCD. Coupled with the heterogeneous clinical course of the condition making such sequelae difficult to predict, any form of exercise prescription therefore errs on the side of caution. Both the American (AHA/ACC) and European (ESC) recommendations prohibit competitive sports with medium to high dynamic/static components.29,30 This encompasses many mainstream sports with competitive participation limited to low dynamic and low static sports such as bowling and golf.

Evolution in the field of molecular genetics has led to an increasing number of asymptomatic individuals detected through familial

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Basavarajaiah S, Wilson M, Whyte G, et al. Prevalence of hypertrophic cardiomyopathy in highly trained athletes: relevance to pre-participation screening. J Am Coll Cardiol 2008;51:1033–9. DOI: 10.1016/j.jacc.2007.10.055. PMID: 18325444.

Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 2009;199:1085–92. DOI: 10.1161/ CIRCULATIONAHA.108.804617; PMID: 19221222.

Harmon KG, Asif IM, Klossner D, Drezner JA. Incidence of sudden cardiac death in National Collegiate Athletic Association athletes. Circulation 2011;123:1594–1600. DOI: 10.1161/CIRCULATIONAHA.110.004622; PMID: 21464047.

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Harmon KG, Asif IM, Klossner D DJ. Incidence of sudden cardiac death in national collegiate athletic association athletes. Circulation 2011;123:1594–1600. DOI: 10.1161/ CIRCULATIONAHA.110.004622; PMID: 21464047.

Corrado D, Basso C, Schiavon M, Pelliccia A, Thiene G. Pre-participation screening of young competitive athletes for prevention of sudden cardiac death. J Am Coll Cardiol 2008;52:1981–9. DOI: 10.1016/j.jacc.2008.06.053; PMID: 19055989.

Sheikh N, Papadakis M, Carre F, et al. Cardiac adaptation to exercise in adolescent athletes of African ethnicity: an emergent elite athletic population. Br J Sports Med 2013;47:585– 92. DOI: 10.1136/bjsports-2012-091874; PMID: 23372065.

Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:1–55. DOI: 10.1093/eurheartj/ehu284; PMID: 25173338.

Pelliccia A, Maron BJ, Spataro A, et al. The upper limits of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med 1991;324:295–301. DOI: 10.1056/ NEJM199101313240504; PMID: 1824720.

Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation

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screening. Many do not, however, reveal any phenotypic features of HCM and in such genotype positive/phenotype negative individuals, the exercise recommendations vary between the USA and Europe.

ESC recommendations adopt a more conservative attitude on the grounds that a genetic predisposition may promote arrhythmogenesis even in the absence of LVH. This approach has been supported by imaging studies that have demonstrated mild impairment of myocardial relaxation and an increase, albeit modest, in the extracellular cardiac matrix in genotype positive/phenotype negative patients.31,32 Conversely, US studies in adolescents who were genotype positive/phenotype negative have revealed a low penetrance of disease over a 12-year follow-up period with only 2 of 36 (6 %) patients affected.33 As such, the USA permits participation in all sports for these individuals, including those with high dynamic and high static components, though it advocates regular surveillance.

Conclusion Hypertrophic cardiomyopathy reduces the functional capacity of an affected person, leading to a physical inability to participate in highintensity sports. Impaired diastolic function, small LV cavity size, dynamic left ventricular outflow tract obstruction and microcirculatory coronary disease leading to a reduction in subendocardial flow can all cause failure to augment stroke volume during exercise and low peak oxygen consumption. Differentiating physiological LVH from morphologically mild HCM in the athlete is particularly challenging with an array of clinical tools used to aid the clinician to make the correct diagnosis. n

2006;114:2232–9. DOI: 10.1161/CIRCULATIONAHA. 106.644682; PMID: 17088454.

Sharma S, Maron BJ, Whyte G, et al. Physiologic limits of left ventricular hypertrophy in elite junior athletes: relevance to differential diagnosis of athlete’s heart and hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:1431–6. PMID: 12392833.

Vinereanu D, Florescu N, Sculthorpe N, et al. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001; 88:53–8. DOI: 10.1016/S0002-9149(01)01585-5. PMID: 11423058.

Sheikh N, Papadakis M, Schnell F, et al. Clinical profile of athletes with hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 2015;8(7):e003454. DOI: 10.1161/ CIRCIMAGING.114.003454; PMID: 26198026.

Malhotra A, Sheikh N, Dhutia H, et al. Differentiating physiological left ventricular hypertrophy from hypertrophic cardiomyopathy in athletes: proposed echocardiographic protocol. Heart 2014;100(Suppl 3):A52. DOI: 10.1136/ heartjnl-2014-306118.91.

Erickson CC. Discrimination of the “athlete’s heart” from real disease by electrocardiogram and echocardiogram.

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Schnell F, Riding N, O’Hanlon R, et al. Recognition and significance of pathological T-wave inversions in athletes. Circulation 2015;131:165–73. DOI: 10.1161/ CIRCULATIONAHA.114.011038; PMID: 25583053.

Spirito P, Pelliccia A, Proschan MA, et al. Morphology of the “athlete’s heart” assessed by echocardiography in 947 elite athletes representing 27 sports. Am J Cardiol 1994;74:802–6.

Caselli S, Maron MS, Urbano-Moral J, et al. Differentiating left ventricular hypertrophy in athletes from that in patients with hypertrophic cardiomyopathy. Am J Cardiol 2014; 114:1383–9. DOI: 10.1016/j.amjcard.2014.07.070; PMID: 25217454.

Oxborough D, Zaidi A, Gati S, et al. A Guideline for the Practice of Echocardiography in the Cardiovascular Screening of Sports Participants: A Joint Policy Statement for the British Society of Echocardiography and Cardiac Risk in the Young. 2013.

Butz T, van Buuren F, Mellwig KP, et al. Two-dimensional strain analysis of the global and regional myocardial function for the differentiation of pathologic and physiologic left ventricular hypertrophy: a study in athletes and in patients with hypertrophic cardiomyopathy. Int J Cardiovasc Imaging 2011;27:91– 100. DOI: 10.1007/s10554-010-9665-5; PMID: 20623194.

Swoboda PP, McDiarmid AK, Erhayiem B, et al. Assessing myocardial extracellular volume by T1 mapping to distinguish

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Kawasaki T, Azuma A, Kuribayashi T, et al. Vagal enhancement due to subendocardial ischemia as a cause of abnormal blood pressure response in hypertrophic cardiomyopathy.

Int J Cardiol 2008;129:59–64. DOI: 10.1016/j.ijcard.2007.05.023; PMID: 17651826.

Sharma S, Elliott PM, Whyte G, et al. Utility of metabolic exercise testing in distinguishing hypertrophic cardiomyopathy from physiologic left ventricular hypertrophy in athletes. 2000;36:864–70. PMID: 10987612.

Basavarajaiah S, Wilson M, Junagde S, et al. Physiological left ventricular hypertrophy or hypertrophic cardiomyopathy in an elite adolescent athlete: role of detraining in resolving the clinical dilemma. Br J Sports Med 2006;40:727–9. DOI: 10.1136/ bjsm.2005.024596; PMID: 16864569.

Pelliccia A. Remodeling of left ventricular hypertrophy in elite athletes after long-term deconditioning. Circulation 2002;105:944–9. DOI: 10.1161/hc0802.104534; PMID: 11864923.

Maron BJ, Udelson JE, Bonow RO, et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement from the American Heart Association and American College of Cardiology. Circulation 2015;132:e273–80. DOI:10.1161/CIR.0000000000000239; PMID: 26621644.

Pelliccia A, Fagard R, Bjørnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Mycardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422–5.

DOI: 10.1093/eurheartj/ehi325; PMID: 15923204.

Ho CY, López B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552–63. DOI: 10.1056/NEJMoa1002659; PMID: 20818890.

Ho CY, Abbasi SA, Neilan TG, et al. T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. Circ Cardiovasc Imaging 2013;6:415–2. DOI: 10.1161/CIRCIMAGING.112.000333; PMID: 23549607.

Jensen MK, Havndrup O, Christiansen M, et al. Penetrance of hypertrophic cardiomyopathy in children and adolescents: a 12-year follow-up study of clinical screening and predictive genetic testing. Circulation 2013;127:48–54. DOI: 10.1161/ CIRCULATIONAHA.111.090514; PMID: 23197161.

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Hormones & Ischaemic Heart Disease

Role of Testosterone in the Treatment of Cardiovascular Disease Carolyn M Webb and Peter Collins Vascular Biology, National Heart and Lung Institute, Imperial College London and Department of Cardiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK

Abstract Cardiovascular disease (CVD) is the most prevalent non-communicable cause of death worldwide. Testosterone is a sex hormone that is predominant in males but also occurs in lower concentrations in females. It has effects directly on the blood vessels of the cardiovascular system and on the heart, as well as effects on risk factors for CVD. Serum testosterone concentrations are known to decrease with age and reduced testosterone levels are linked to premature coronary artery disease, unfavourable effects on CVD risk factors and increased risk of cardiovascular mortality independent of age. A significant number of men with heart failure demonstrate reduced serum testosterone concentrations and there is early evidence suggesting that low testosterone levels affect cardiac repolarisation. Any association between endogenous testosterone concentrations and CVD in women has yet to be established. Testosterone replacement is used to treat men with hypogonadism but also has cardiovascular effects. This review will present the current evidence, expert opinion and controversies around the role of testosterone in the pathophysiology of CVD and surrounding the use of testosterone treatment and its effects on the cardiovascular system and CVD.

Keywords Testosterone, men, cardiovascular disease, risk factors, treatment Disclosure: The authors have no conflicts of interest to declare.

Received: 17 August 2017 Accepted: 29 September 2017 Citation: European Cardiology Review 2017;12(2):83–7. DOI: 10.15420/ecr.2017:21:1 Correspondence: Carolyn Webb, Department of Cardiology, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E: c.webb@imperial.ac.uk and peter.collins@imperial.ac.uk

Cardiovascular disease (CVD) is the most prevalent non-communicable cause of death worldwide.1 The health and economic implications of caring for a growing ageing population with CVD is enormous.

Maintaining a “healthy” elderly population that is mobile and independent with a good quality of life is vital. Testosterone is a sex hormone that is predominant in males, being secreted from the testes and adrenal glands, but it also occurs in lower concentrations in females, where it produced in the ovaries. In men, testosterone is primarily involved in sex differentiation and the development of secondary sex characteristics at puberty and it also contributes to spermatogenesis. It is involved in sex drive in both men and women.

Testosterone has effects directly on the blood vessels of the cardiovascular (CV) system and on the heart, as well as having effects on risk factors for CVD, see Figure 1.2 Serum testosterone concentrations are known to decrease with age. Epidemiological studies indicate that reduced testosterone levels are linked to premature coronary artery disease (CAD),3,4 unfavourable effects on CVD risk factors5–7 and increased risk of CV mortality independent of age.8 A significant number of men with heart failure demonstrate reduced serum testosterone concentrations9,10 and there is early evidence suggesting that low testosterone levels affect cardiac repolarisation.2,11 A recent publication from the Atherosclerosis Risk in Communities observational study reported no association between endogenous testosterone and cerebrovascular disease.12 Any association between endogenous testosterone concentrations and CVD in women has yet to be established. The effects of endogenous testosterone on CVD have been well documented previously.13 Current interest has focussed

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more on the CV effects of exogenous testosterone, testosterone treatment and its effects on the CV pathophysiology. This has been driven by an increase in testosterone replacement use in men with “low” testosterone concentrations, even without other symptoms of hypogonadism, particularly in North America.14 In the following discussion we will present the current evidence and expert opinions on the CV effects of testosterone treatment, primarily in men as the evidence in women is currently less dependable.

Testosterone and Treatment of CVD The purpose of testosterone replacement is to normalise low testosterone levels to improve symptoms. Clinically this is advised in patients with symptomatic hypogonadism supported by biochemical evidence; however, many of the studies presented in the following discussion have included men with low testosterone but not necessarily other signs of hypogonadism. Research interest has focussed mainly on the effects of testosterone treatment on the CV conditions of coronary atherosclerosis, myocardial ischaemia, heart failure and, more recently, in cardiac electrophysiology, see Figure 2.

Metabolic Effects of Testosterone Treatment Endogenous testosterone concentrations are generally inversely related to CVD risk factors in men. Modifiable metabolic risk factors that are affected by testosterone concentrations include dyslipidaemia, central adiposity, insulin resistance and type 2 diabetes (T2DM).

Epidemiological and observational studies largely show that low endogenous testosterone concentrations are independently associated with an atherogenic lipid profile, the metabolic syndrome and T2DM.15

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Hormones & Ischaemic Heart Disease Figure 1: Cardiovascular (CV) effects of Low Testosterone Levels in Men

↑CV events

↓exercise capacity in heart failure

endothelial dysfunction

dyslipidaemia

↑coronary artery disease

↑atherosclerosis

Figure 2: Cardiovascular (CV) Effects of Testosterone Treatment

↑coronary blood flow

↓myocardial ischaemia

↔ CV events

CV effects of testosterone treatment

↑exercise capacity in heart failure

↔ angina

↑coronary vasomotion

↔ atheroma

Lipid Profile The evidence to date indicates that testosterone treatment reduces total and LDL-cholesterol concentrations.16–18 The evidence is less clear for HDL-cholesterol and may depend on the route of administration and resultant plasma concentrations of testosterone.15 Triglycerides are generally not changed by testosterone treatment.19 The Testosterone Replacement in Hypogonadal Men with Type 2 Diabetes and/or Metabolic Syndrome (TIMES2) study showed a reduction in lipoprotein(a) in hypogonadal men with and without T2DM or/and the metabolic syndrome treated with testosterone gel.16 In contrast, high doses of testosterone or anabolic steroids dramatically derange lipid profile.20

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The evidence consistently shows an association between low testosterone concentrations in men and insulin resistance, metabolic syndrome and T2DM.15 A number of interventional studies show an improvement in insulin resistance and glycaemic control in men with T2DM taking testosterone treatment.16,21,22 In the European TIMES2 study, testosterone gel reduced measures of insulin resistance by up 16 % after 1 year in men with the metabolic syndrome with or without T2DM.16 The BLAST study reported a decrease in HbA1c levels in men with diabetes assigned to testosterone undecanoate for 24 weeks, with a greater effect seen in men with poorly-controlled T2DM.23

Testosterone Treatment and Atherosclerosis

low endogenous testosterone in men

cardiac repolarisation

Dysglycaemia and Diabetes

Observational studies indicate that low testosterone concentrations have a detrimental effect on atherosclerosis. For example, testosterone concentrations are negatively associated with carotid artery intimamedia thickness, a measure of atheroma burden.24 The long-term consequences of testosterone supplementation on atherosclerosis in older men have been the focus of a number of recent studies. The Testosterone’s Effects on Atherosclerosis Progression in Aging Men (TEAAM) trial was designed to determine the effect of increasing circulating testosterone concentrations into a range that is midnormal for young men on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels, but not necessarily with symptoms of hypogonadism.25 The TEAAM trial enrolled just over 300 men in a randomised, placebo-controlled study of testosterone gel. This trial failed to show any benefit of testosterone compared with placebo on carotid intima-media thickness and coronary calcium, which were the co-primary endpoints, nor on the secondary outcomes of sexual function or quality of life. The authors commented that the results may have been influenced by concomitant medications such as statins and that the results of measures of sexual function may differ in men with symptomatic hypogonadism. Following on from TEAAM, the Cardiovascular Trial, one of the seven placebo-controlled Testosterone Trials,26 investigated the effects on coronary atherosclerosis of 1 year of testosterone gel treatment in 138 older, symptomatic, hypogonadal men, assessed by coronary computed tomographic angiography.27 Up to 50 % of this study population had CAD or risk factors for CAD.27 Compared with placebo, testosterone treatment was associated with a significantly greater increase in coronary artery non-calcified plaque volume and total plaque volume. Similar to the TEAAM trial, there was no significant effect on coronary calcium score. An increase in atheroma burden does not necessarily translate into an increased rate of CV events, and neither study was powered to draw conclusions on this.

These studies provide evidence for caution in the use of testosterone treatment. Larger studies are needed to understand the clinical implications of these findings.

Coronary Blood Flow, Myocardial Ischaemia and Angina in Men with CAD Testosterone has direct effects on arteries independent of the reproductive system. Evidence for this has come from both basic scientific28–30 and clinical studies.31–36 Clinical studies show the favourable effects of shortor longer-term exposure to testosterone treatment on coronary and peripheral vasomotion and peripheral arterial stiffness.31–36 Physiological concentrations of intracoronary testosterone cause epicardial coronary artery dilatation and increases in volume blood flow in men with CAD.31 To investigate the effects of longer-term testosterone treatment on coronary blood flow, cardiac magnetic resonance myocardial perfusion

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Testosterone in Cardiovascular Disease scans were performed in men with CAD before and 8 weeks following oral testosterone treatment in a placebo-controlled, cross-over study.32 Myocardial perfusion was enhanced in myocardium supplied by unobstructed coronary arteries but not in areas supplied by coronary arteries with significant atherosclerosis, concurring with previous findings.31,32 The lack of effect of testosterone on myocardium supplied by significantly diseased coronary arteries may explain the results of studies of oral, transdermal and intramuscular testosterone treatment that failed to demonstrate an improvement in the frequency of anginal symptoms of men with CAD.32,37,38 However, these results do not explain the favourable effects of short- and longer-term testosterone treatment on signs of myocardial ischaemia in men with chronic stable angina.37,39,40 The number of studies that have investigated this is small, each enrolling a relatively small number of patients and using varying preparations of testosterone. The conclusions that can be drawn from these data and used to direct clinical practice are therefore limited.

The largest study to date included 46 men with stable angina and baseline testosterone concentrations at the lower end of the normal range who were treated with a transdermal testosterone patch or placebo for 12 weeks in a parallel designed study.37 Time to exerciseinduced myocardial ischaemia was prolonged by testosterone treatment compared with placebo, with the effect being more pronounced in men with lower baseline testosterone concentrations.37 The study of longest duration thus far is a 12-month parallel, placebo-controlled trial using a testosterone undecanoate injection administered four times per year.40 Thirteen men with angina, signs of myocardial ischaemia on treadmill exercise testing and plasma testosterone concentrations <12 nmol/l completed the study, with the results showing a significant delay in time to myocardial ischaemia in men taking testosterone versus placebo.40 Larger studies are needed to clarify any clinical application of testosterone treatment in men with myocardial ischaemia, anginal symptoms and low testosterone concentrations.

Testosterone and Heart Failure Testosterone deficiency is estimated to affect approximately a third of men with chronic heart failure. Low circulating levels of testosterone independently correlate with exercise intolerance in men with heart failure41 and relate to the muscle-wasting characteristic of the condition.42 The excess of catabolic hormones and a relative deficiency of anabolic hormones in heart failure have been well documented,42,43 and in the past decade testosterone has been investigated as a potential therapy to correct the anabolic balance.

The first study was a small randomised, double-blind, placebocontrolled, cross-over trial that included men with chronic heart failure.44 Compared with placebo, a single dose of buccal testosterone increased cardiac output and reduced systemic vascular resistance, with the maximal effect coinciding with maximal free testosterone concentrations at 180 minutes.44 Since then, the same group and others have shown the beneficial effects of a variety of testosterone preparations on exercise capacity, oxygen consumption and functional class, with treatment periods lasting from 12 weeks to 12 months.45–47 There has been one study of testosterone treatment undertaken in elderly women with heart failure.48 Given via a transdermal patch for 6 months, testosterone significantly increased the distance walked in a 6-minute walk test and improved peak oxygen consumption, despite the women having pre-treatment testosterone concentrations in the normal range.48 The authors speculated that a peripheral mechanism of action might explain this effect.

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A meta-analysis published in 2012 reinforced the beneficial effect of testosterone treatment on exercise capacity and oxygen consumption in patients with heart failure.49 However, reports of the effects of testosterone treatment on muscle strength in men with heart failure are not consistent, with some showing a null effect45 and others finding a benefit.46 This may be because none of these studies included patients with cachexia or muscle wasting. Apart from the testosterone patch,45 generally testosterone was well tolerated in heart failure studies to date. However, on average these studies only lasted a few months and the numbers included were small. Future studies with a longer duration of treatment, a larger study population and including patients with muscle wasting should produce valuable evidence with which to guide clinical practice.

Testosterone and Cardiovascular Events Controversy surrounds the conflicting evidence on the effects of testosterone on CV events. Prospective population studies, such as the Health in Men Study, found that low testosterone concentrations were associated with an increased risk of incident stroke, but other studies reported no association between testosterone levels and CV events. 50–53 Data from a more recent study in Sweden show an inverse association between both serum testosterone and sex hormone binding globulin concentrations and the risk of CV events, with high testosterone (≥550 ng/dl) predicting reduced fatal and nonfatal CV events.54 Whether testosterone treatment has a favourable effect on CV events in men is a contentious issue. Two large observational studies reported an increased risk of adverse outcomes (death, myocardial infarction and stroke) in testosterone-treated men, particularly in men aged >75 years.55,56 However, the results of these studies have been criticised and must be considered in view of the fact that there was no check of testosterone levels or drug compliance following testosterone initiation.9,57 Contrary to these studies, others have shown a decreased risk of CV events and mortality in testosterone users versus non-users.58,59 An interesting approach was used in an observational study that grouped a large cohort of men with low testosterone concentrations, newly treated with testosterone and then followed for 6 years, into those that achieved a normalised testosterone concentration and those that did not.60 Compared with those not achieving normal testosterone concentrations and with never-users of testosterone treatment, men achieving normalised testosterone concentrations had a lower relative risk of all-cause mortality, myocardial infarction and stroke.60 The discrepancies in the findings of these observational studies may be explained by differences in the age of the study cohorts, co-existing disease (Vigen et al. included men referred for coronary angiography;46 the population studied by Sharma et al. was healthy with no known CVD50) and knowledge of compliance with testosterone therapy after initiation.56,60 Randomised controlled trials of testosterone treatment in men with low testosterone levels also report conflicting results. The Testosterone Treatment in Older Men with Mobility Limitations (TOM) trial of men aged ≥65 years was stopped early due to CV events in the testosteronetreated group;61 however, the study was not designed to report on safety and whether the events were hard endpoints has been a subject of contention.9 Other randomised trials have been too small to draw conclusions about the risks of testosterone treatment, although the reported adverse event rates were similar in the testosteronetreated group versus placebo.25,27,62 There are obvious parallels with hormone-replacement treatment in women in past decades, where

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Hormones & Ischaemic Heart Disease observational studies indicated a benefit of postmenopausal hormone therapy on CVD risk but the results of randomised trials did not support this. Unequivocal trials of testosterone treatment in a clinically-relevant population are needed to inform users and prescribers of the safety of testosterone treatment; however, we must acknowledge that this would be an enormous undertaking.63

Risks of Testosterone Treatment Testosterone administration in hypogonadal men can cause sideeffects such as erythrocytosis (more so with oral preparations), fluid retention, benign prostatic hyperplasia, hepatotoxic and neoplastic effects (mostly with oral preparations but not testosterone undecanoate), gynaecomastia and acne and skin reactions (mostly with patches).64 Increased haematocrit and haemoglobin levels and small detrimental effects on lipids have also been documented.

There is much controversy over the association of testosterone treatment with an increased incidence of prostate cancer, which is discussed in detail elsewhere.64,65 In brief, there is no evidence for an increased risk of prostate-cancer-specific death related to testosterone treatment in either direction; however, there is evidence implying that testosterone treatment may adversely affect the progression of prostate cancer.66 Large-scale, long-term trials are needed to clarify the safety of testosterone treatment. The current recommendation from the Endocrine Society is to make “a careful diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels”, then to treat men with confirmed symptomatic androgen deficiency with testosterone therapy.67 Once testosterone treatment is initiated, it is suggested that mid-normal range testosterone levels are aimed for and that therapy is monitored using a standardised plan.67

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Conclusions Low endogenous testosterone concentrations can affect risk factors for CVD, atheroma development and vasomotion beyond the blood vessels of the reproductive system. They are associated with coronary atherosclerosis and heart failure in approximately a third of men. The discrepant results of clinical studies of testosterone replacement in older men with hypogonadism have resulted in controversy over its clinical use, largely concerning variances in CV event rate and the ability of these studies to generate reliable data on this endpoint. Testosterone treatment is not without sideeffects and risks. The Endocrine Society 2010 clinical practice guideline and the European Menopause and Andropause Society give detailed recommendations on the use of testosterone therapy in men with androgen deficiency, supporting such treatment in men with symptomatic androgen deficiency (repeated early morning low serum testosterone levels) followed by scheduled testing for efficacy and adverse events.67,68 Testosterone treatment is not recommended in men with breast or prostate cancer, suspected or increased risk of prostate cancer, haematocrit >50 % or uncontrolled heart failure.67,68 Individualised management of patients is recommended, including the evaluation of comorbidities and careful risk–benefit assessment, and not general prescription of testosterone therapy to all ageing men with low testosterone.67,68 A number of professional organisations agree that there is no consistent evidence that testosterone treatment either increases or decreases CV risk.68 Large studies with hard CV endpoints in older symptomatic hypogonadal men are needed encompassing longer-term treatment periods and investigating the differing types of testosterone replacement available in order to provide strong evidence on which to base clinical decisions in this population. n

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51. Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur J Endocrinol 2009;161:435–42. DOI: 10.1530/EJE-090284; PMID: 19542243.

52. Yeap BB, Hyde Z, Almeida OP, et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab 2009;94:2353–9. DOI: 10.1210/ jc.2008-2416; PMID: 19351733.

53. Maggi M, Wu FC, Jones TH, et al. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Int J Clin Pract 2016;70:843–52. DOI: 10.1111/ ijcp.12876; PMID: 27774779.

54. Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol 2011;58:1674–81. DOI: 10.1016/j.jacc.2011.07.019; PMID: 21982312.

55. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9:e85805. DOI: 10.1371/ journal.pone.0085805; PMID: 24489673.

56. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction,

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and stroke in men with low testosterone levels. JAMA 2013; 310:1829–36. DOI: 10.1001/jama.2013.280386; PMID: 24193080.

Morgentaler A, Kacker R. Andrology: Testosterone and cardiovascular risk–deciphering the statistics. Nat Rev Urol 2014;11:131–2. DOI: 10.1038/nrurol.2014.24; PMID: 24535586.

Wallis CJ, Lo K, Lee Y, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol 2016;4:498–506. DOI: 10.1016/S2213-8587(16)00112-1.

Cheetham TC, An J, Jacobsen SJ, et al. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med 2017;177:491–9. DOI: 10.1001/jamainternmed.2016.9546; PMID: 28241244.

Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015;36:2706–15. DOI: 10.1093/eurheartj/ehv346; PMID: 26248567.

Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363:109–22. DOI: 10.1056/NEJMoa1000485; PMID: 20592293.

Snyder PJ, Ellenberg SS, Farrar JT; Testosterone Trials Investigators. Testosterone Treatment in Older Men. N Engl J Med 2016;375:90. DOI: 10.1056/NEJMoa1506119; PMID: 27406354 Onasanya O, Iyer G, Lucas E, et al. Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews. Lancet Diabetes Endocrinol 2016;4:943–6. DOI: 10.1016/S2213-8587(16)30215-7; PMID: 27669646.

Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482–92. DOI: 10.1056/NEJMra022251; PMID: 14749457.

Morales A. Androgen replacement therapy and prostate safety. Eur Urol 2002;41:113–20. DOI: 10.1016/S03022838(01)00039-2; PMID: 12074396.

Klotz L. Testosterone therapy and prostate cancer–safety concerns are well founded. Nat Rev Urol 2015;12:48–54. DOI: 10.1038/nrurol.2014.338; PMID: 25563848.

Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59. DOI: 10.1210/jcem.95.6.9999; PMID: 20525905.

Dimopoulou C, Ceausu I, Depypere H, et al. EMAS position statement: Testosterone replacement therapy in the aging male. Maturitas 2016;84:94–9. DOI: 10.1016/​ j.maturitas.2015.11.003; PMID: 26614257.

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Guest Editorial

Cardiovascular Risk Management Targeting Inflammation in Addition to Lipid-lowering Therapy Koji Hasegawa National Hospital Organization Kyoto Medical Center President-elect, International Society of Cardiovascular Pharmacotherapy

Citation: European Cardiology Review 2017;12(2):88. DOI: 10.15420/ecr.2017:25:1 Correspondence: Prof. Koji Hasegawa, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan. E: koj@kuhp.kyoto-u.ac.jp

M

yocardial infarction is often caused by the rupture of unstable plaque in atherosclerosis with mild-to-moderate stenosis.

Research has revealed that local tissue inflammation is closely involved in the rupture of atherosclerotic plaque.1 Stabilization of atherosclerotic plaque by strictly managing the risk factors for coronary artery disease is a crucial strategy to prevent the recurrence of myocardial infarction. Among the risk factors for coronary artery disease, high LDL cholesterol (LDL-C) level contributes most to the development of atherosclerosis. The incidence of cardiovascular events decreases in conjunction with decreasing LDL-C levels by statins (the incidence decreases by 28 % for every 38.7 mg/dL drop in LDL-C level).2 Lipid-lowering drugs besides statins include ezetimibe, which is a cholesterol absorption inhibitor, and monoclonal antibodies against PCSK9 (i.e., PCSK9 inhibitors; PCSK9 is an enzyme that clears the LDL-C receptor from the liver). Research has revealed that administering ezetimibe or a PCSK9 inhibitor along with a statin more potently lowers LDL-C level than administering statin alone, thereby further reducing the incidence of cardiovascular events.3,4 If an individual is at a risk of developing cardiovascular disease, the predominant theory on LDL-C is “the lower the better,” i.e., the LDL-C level should be lowered to its fetal level (approximately 40 mg/dL). At present, no studies have indicated that mortality increases at LDL-C level <40 mg/dL. Potent lowering of LDL-C level reduces the risk of cardiovascular events by approximately 40 %. In other words, the risk of such events remains at approximately 60 % despite potent lowering of LDL-C level. Therefore, what is this residual risk?

The results of the CANTOS trial were announced at a recent European Society of Cardiology Congress (ESC2017, Barcelona, Spain).5 Remarkably, it was found that a drug with only anti-inflammatory action and no lipid-lowering action inhibited the development of

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ansson GK. Inflammation, atherosclerosis, and coronary H artery disease. N Engl J Med 2005;352:1685–1695. DOI: 10.1056/ NEJMra043430; PMID: 15843671 Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.

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cardiovascular disease. Subjects in the trial were patients with a history of myocardial infarction and a high-sensitivity CRP level of ≥2 mg/L. In the trial, the efficacy of canakinumab, a selective IL-1beta inhibitor, was examined. Canakinumab provides an anti-inflammatory action by blocking the IL-1beta–CRP pathway and is used to treat rheumatic arthritis-related diseases. In patients with persistently elevated CRP level after non-fatal myocardial infarction, inhibiting IL-1beta caused CRP level to decrease in a dose-dependent manner. Because IL-1beta is an inflammatory regulator, inhibiting IL-1beta caused CRP level to decrease, which is not surprising, but the key point is that CRP level decreased even though LDL-C level remained unchanged. Patients who were administered canakinumab at a dose of 150 mg every 3 months had a reduced risk of myocardial infarction, stroke, and cardiovascular mortality after 4 years. IL-1beta is a cytokine that plays an essential role in regulating inflammation; therefore, inhibiting its action can lead to complications such as exacerbating infection.

Nonetheless, no differences in the incidence of serious infections between groups were noted in the trial.

In the JUPITER trial, patients with high-sensitivity CRP levels above 2 mg/L but with LDL-C levels below 130 mg/dl were administered a statin for primary prevention.6 It was found that decreased LDL-C and CRP levels reduced the risk of cardiovascular events. Accordingly, observers stated that statins might reduce the risk of cardiovascular events through lipid-lowering action “coupled with” anti-inflammatory action. Unlike the results of the JUPITER trial, the results of the CANTOS trial were unaffected by lipids, and anti-inflammatory action alone reduced the recurrence of atherosclerosis. Inflammation is a key component of residual cardiovascular risk despite potent lipid-lowering therapy, and drugs such as canakinumab could be used to potentially target that inflammation. n

pinar J, Spinarova L, Vitovec J (2014): IMProved reduction S of outcomes: Vytorin efficacy international trial (studie IMPROVE-IT). Vnitr Lek 2014;60:1095–1101. PMID: 25692840 Sabatine MS, et al. for the FOURIER steering committee and investigators: Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. DOI: 10.1056/NEJMoa1615664; PMID: 28304224

5.

6.

idker PM, et al. for the CANTOS trial group: Antiinflammatory R therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. DOI: 10.1056/NEJMoa1707914; PMID: 28845751 Ridker PM, et al. for the JUPITER Study Group: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008;359:2195–2207. DOI: 10.1056/NEJMoa0807646; PMID: 18997196

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Cardiovascular Pharmacology

Inflammation Revisited: Atherosclerosis in The Post-CANTOS Era Wolfgang Koenig 1,2 1. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; 2. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich Germany

Abstract It is fairly well accepted in the scientific community that atherosclerosis carries features of a local and low-grade systemic inflammation.

However, it was unclear thus far whether this is simply an epiphenomenon or if it plays a causal role in atherosclerosis and its clinical complications. After several failed attempts, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence of interleukin-1 beta as a target whose neutralisation by a selective antibody reduces major cardiovascular events without affecting LDL-cholesterol. This provides strong evidence in support of the inflammation hypothesis and will certainly stimulate research in this area and open the way for novel therapy in high-risk patients following MI.

Keywords Inflammation, atherosclerosis, biomarkers, outcome studies, canakinumab Disclosure: The author is a member of the Executive Steering Committee of the CANTOS trial.

Received: 18 September 2017 Accepted: 4 October 2017 Citation: European Cardiology Review 2017;12(2):89–91. DOI: 10.15420/ecr.2017:18:1 Correspondence: Professor Wolfgang Koenig, MD, FRCP, FACC, FAHA, FESC, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636 München, Germany. E: Koenig@dhm.mhn.de

The notion that atherosclerosis carries features of an inflammatory disease has existed for quite some time. As early as 1856, Rudolf Virchow in his Textbook on Pathology mentioned the term “coronaritis”.

Almost 150 years later, following the elucidation of major cardiovascular risk factors in the 1950s Framingham Study, Russell Ross entitled his 1999 review on mechanisms of atherosclerosis “Atherosclerosis – an inflammatory disease”.1 An abundance of data, including experimental studies in vascular biology and extensive observational research in the general population and clinical cohorts, have demonstrated a strong association between elevated markers of inflammation and short- and long-term cardiovascular outcomes. These include various acute phase reactants, in particular C-reactive protein (CRP), and various cytokines.

Nevertheless, inflammation has continued to be considered as an epiphenomenon and not suitable as a target for intervention.2 Substantial progress in the treatment of atherosclerotic complications – in particular in secondary prevention – has led to a significant reduction of recurrent cardiovascular events. This has been through the use of polypharmacotherapeutic strategies including potent lipidlowering drugs such as statins, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, along with the introduction of early percutaneous coronary intervention in acute coronary syndrome (ACS) with consecutive application of dual antiplatelet therapy. Despite such progress, several registries over the last 10 years have clearly demonstrated that there is still considerable risk in patients after MI. For example, data from the Global Registry of Acute Coronary Events (GRACE)3 have shown that approximately 20 % of patients following an ACS have died after 5 years. Further evidence from the large Swedish National Registry in more than 100,000 patients has suggested that after 1-year post-ACS, approximately 15–20 % of patients have experienced an event, in particular cardiovascular death, MI or stroke.4 Finally, the most recent Second Manifestations Of Arterial

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Disease (SMART) registry of more than 6,000 patients with manifest vascular disease showed that approximately 40 % of patients had a 10–20 % risk for recurrent events over 10 years, which was highest in those with multi-vessel disease, even after optimised treatment of all known risk factors.5 This raises the question of the existence of other pathophysiological pathways, and inflammation may be considered one of them.

With the introduction of proprotein convertase subtilisin-kexin type 9 (PCSK9) antibodies, unprecedented low LDL-cholesterol levels have been shown to be achievable. For example, the Further Cardiovascular Outcomes Research With PCSK9 Inhibition In Subjects With Elevated Risk (FOURIER)6 study reported levels of 30 mg/dL and the Global Assessment Of Plaque Regression With A PCSK9 Antibody As Measured

By Intravascular Ultrasound (GLAGOV)7 study reported levels in the region of 36 mg/dL. Despite this, a significant number of patients continue to go on to have a recurrent event or show progression in intravascular ultrasound studies.

During recent years we have seen the failure of a number of clinical trials that aimed, at least in part, to target inflammation. For example the Stabilization of Atherosclerotic Plaque By Initiation Of Darapladib Therapy (STABILITY)8 and Stabilization Of Plaques Using DarapladibThrombolysis In Myocardial Infarction 52 (SOLID-TIMI-52)9 trials investigated the effect of the lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor darapladib. While they showed no signal of harm, they were neutral in their effect regarding main cardiovascular outcomes. Lp-PLA2 is a molecule that generates free fatty acids and phosphatidylcholine from oxidised LDL in the vessel wall. Its selective inhibitor, darapladib, has been shown to both decrease systemic levels of Lp-PLA2 and to decrease Lp-PLA2 expression in plaque.

A further phospholipase inhibitor targeting secretary phospholipase

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Cardiovascular Pharmacology A2, varespladib, was tested in the Evaluation Of Safety And Efficacy Of Short-Term A-002 Treatment In Subjects With Acute Coronary Syndrome (VISTA-16)10 study, which even showed increased morbidity and mortality in the intervention group. Furthermore, losmapimod, a drug that has been suggested to decrease oxidative stress in the vascular wall, has failed in the Phase 3 Clinical Outcomes Study To Compare The Incidence Of Major Adverse Cardiovascular Events In Subjects Presenting With Acute Coronary Syndrome Treated With Losmapimod Compared To Placebo (LATITUDE-TIMI 60)11 trial. What all these targets have in common is that they are not on the interleukin (IL)-6 signaling pathway. This may be important, because inflammation is a complex and fairly redundant system that on the one hand is needed for reparative processes and on the other hand may exert negative effects through its prolonged activation. It has been shown convincingly in several Mendelian randomisation studies that IL-6 most likely is on the causal pathway in atherogenesis, and variants associated with impaired function of the IL-6 receptor have been associated not only with decreased surrogate parameters like CRP but also with decreased incidence of CHD events.12,13 Thus, similar to lowering of LDL cholesterol for which the LDL receptor is crucial, it may be that interfering with inflammation is not always beneficial but has to rely on specific pathways.

A few years ago the Low-Dose Colchicine (LoDoCo) trial,14 a small study comprising only 532 patients, reported dramatic reductions of recurrent cardiovascular events in stable CHD patients receiving 0.5 mg colchicine/day over 3 years. Colchicine has been known in clinical medicine for many years and is mainly used to treat acute gout, but more recently has also been introduced in cardiovascular medicine to reduce inflammatory reactions of pericarditis and Dressler’s syndrome. Colchicine has been known to act, at least in part, via inhibition of IL-6.

Based on convincing experimental studies in vascular biology along with clinical data,15 IL-1 beta has been suggested to play a central role in the inflammation cascade. Therefore, a few years ago, the protocol of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) study was conceived.

The highlight of this year’s European Society of Cardiology congress in Barcelona was indeed the presentation of the eagerly awaited results from the CANTOS trial.16 CANTOS was a randomised double-blind trial of canakinumab, a fully human monoclonal antibody that selectively inhibits IL-1 beta and leaves the IL-1 alpha pathway intact. The trial included 10,061 patients with a previous MI and elevated CRP (≥2 mg/L) measured by a high-sensitivity (hs) assay as the major entry criteria.

This intervention was compared with placebo on top of standard of care, which included among others adequate treatment of blood pressure and high-dose statin therapy resulting in a baseline LDLcholesterol of 82 mg/dL. Randomised patients represented a high-risk group particularly characterised by a median hs CRP of 4.1 mg/L. The

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Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115–26. DOI: 10.1056/NEJM199901143400207; PMID: 9887164.

Koenig W. High-sensitivity C-reactive protein and atherosclerotic disease: from improved risk prediction to riskguided therapy. Int J Cardiol 2013;168:5126–34. DOI: 10.1016/ j.ijcard.2013.07.113; PMID: 23978367.

Fox KA, Carruthers KF, Dunbar DR, et al. Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study). Eur Heart J 2010;31:2755–64. DOI: 10.1093/eurheartj/ehq326; PMID: 20805110.

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incidence rate for cardiovascular disease outcomes in the placebo group was 2 times higher compared with all-comers after MI in contemporary studies. Furthermore, approximately 40 % of patients had diabetes, 25 % were ongoing smokers and the majority (4/5) had already undergone prior revascularisation. Canakinumab administered at 50, 150 or 300 mg subcutaneously every 3 months resulted in dosedependent reduction in surrogate inflammatory endpoints such as (hs) CRP and IL-6. There was no interference with lipid metabolism: LDL cholesterol was not affected at all, whereas only a slight increase in triglycerides was observed. The main clinical outcome was a primary endpoint consisting of non-fatal MI and non-fatal stroke or cardiovascular death, which was reduced by 15 % with the 150-mg dose and equally so with the 300-mg dose. The secondary endpoint, which additionally included urgent revascularisation, showed an even stronger effect – a 17 % relative risk reduction over a median follow-up of 3.7 years. Most importantly, the effect on cardiovascular endpoints was strongest in those who were identified as responders based on the fact that their achieved CRP during the study would be below the median hs CRP in the overall population. In this group the relative risk reduction amounted to 27 %. In addition to these clinically relevant reductions in cardiovascular outcomes, incidence rates of other proinflammatory diseases such as arthritis, osteoarthritis, and gout were also significantly reduced. Further analyses of CANTOS in the future will reveal whether or not other diseases associated with an inflammatory response, such as diabetes, supraventricular arrhythmias, deep vein thrombosis, pulmonary embolism or incident heart failure after the index event can also be reduced. A further interesting observation in CANTOS, based on exploratory analyses, showed a marked reduction in cancer mortality, in incident lung cancers and in particular in fatal lung cancers.17 For example, the 300-mg dose of canakinumab led to a 51 % reduction in cancer mortality, with regard to incident lung cancer there was a 67 % reduction and, finally, a 70 % reduction in fatal lung cancers was observed. These findings are not surprising based on the pathophysiology of IL-1 beta, whereby convincing data also demonstrate that it is intimately involved in tumourigenesis, tumour invasiveness, and metastasis formation of various cancers, in particular lung cancers, but also for example colon cancer.18 This clearly represents an important additional clinical benefit of canakinumab and is also theoretically important since it demonstrates that, despite an intervention in the immune system by application of canakinumab over 3.7 years, the immune system does not seem to be compromised. Otherwise one would have expected an opposite effect, namely increased morbidity and mortality from malignancies.

Overall, CANTOS has changed the clinical landscape in cardiovascular medicine and it has now become quite clear that inflammation can no longer be considered simply as an epiphenomenon but that it represents a new treatment strategy to further reduce residual risk in patients after a cardiovascular event. After many years of extremely controversial debate, this trial demonstrates a paradigm shift in our understanding of the pathophysiology of atherosclerosis. n

J ernberg T, Hasvold P, Henriksson M, et al. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective.

Eur Heart J 2015;36:1163–70. DOI: 10.1093/eurheartj/ehu505; PMID: 25586123.

5. Kaasenbrood L, Boekholdt SM, van der Graaf Y, et al.

Distribution of estimated 10-year risk of recurrent vascular events and residual risk in a secondary prevention population. Circulation 2016;134:1419–29. DOI: 10.1161/ CIRCULATIONAHA.116.021314; PMID: 27682883.

6. 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. DOI:10.1056/NEJMoa1615664; PMID: 28304224.

7. 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.

DOI: 10.1001/jama.2016.16951; PMID: 27846344.

8. STABILITY Investigators, White HD, Held C, et al. Darapladib for preventing ischemic events in stable coronary heart disease.

N Engl J Med 2014;370:1702–11. DOI: 10.1056/NEJMoa1315878; PMID: 24678955.

9. O’Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary

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Atherosclerosis in The Post-CANTOS Era

syndrome: the SOLID-TIMI 52 randomized clinical trial.

JAMA 2014;312:1006–15. DOI: 10.1001/jama.2014.11061; PMID: 25173516.

10. Nicholls SJ, Kastelein JJ, Schwartz GG, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA 2014;311:252–62. DOI: 10.1001/jama.2013.282836; PMID: 24247616.

11. O‘Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: A randomized clinical trial. JAMA 2016;315:1591–9. DOI: 10.1001/ jama.2016.3609; PMID: 27043082.

12. IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, et al. Interleukin-6

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receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012;379:1205–13.

DOI: 10.1016/S0140-6736(11)61931-4; PMID: 22421339.

13. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Swerdlow DI, Holmes MV, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214–24. DOI: 10.1016/S0140-6736(12)60110-X; PMID: 22421340.

14. Nidorf SM, Eikelboom JW, Budgeon CA, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10. DOI: 10.1016/ j.jacc.2012.10.027; PMID: 23265346.

15. Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving upstream to identify novel targets for

atheroprotection. Circ Res 2016;118:145–56. DOI: 10.1161/ CIRCRESAHA.115.306656; PMID: 26837745.

16. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017. DOI: 10.1056/NEJMoa1707914; PMID: 28845751; epub ahead of press.

17. Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017 pii: S0140-6736(17)32247-X. DOI: 10.1016/S0140-6736 (17)32247-X; PMID: 28855077; epub ahead of press.

18. Dinarello CA. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev 2010;29:317–29. DOI: 10.1007/ s10555-010-9229-0; PMID: 20422276.

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ISCP 2017 Best Posters

The Best Posters from XXII Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy (ISCP) Barcelona, Spain 24–25 August 2017 Citation: European Cardiology Review 2017;12(2):92–111. DOI: 10.15420/ecr.2017:23:1

Young Investigator Award Topic: 3. Heart Failure and Cardiomyopathy

Nobiletin a Citrus Flavonoid, Exerts Additional Effects with Angiotensin II Receptor Blocker on Systolic Function in Salt-sensitive Dahl Rats Haruka Ebi, 1 Masafumi Funamoto, 1 Yoichi Sunagawa, 1 Anna Suzuki, 1 Kana Shimizu, 1 Yasufumi Katanasaka, 1 Yusuke Miyazaki, 1 Hiromishi Wada, 2 Akira Shimatsu, 2 Koji Hasegawa, 1 Tatsuya Morimoto 1 1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Japan, 2. Division of Translational Research, 3. Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan, 3. Shizuoka General Hospital, Shizuoka, Japan

Keywords: Nobiletin, Candesartan, salt-sensitive Dahl rats, Heart failure, systolic dysfunction

Introduction and Objectives Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. We screened natural compounds purified from fruits library and found that Nobiletin, contained in the peel of Citrus depressa, represses phenylephrine-induced hypertrophic responses in cardiomyocytes. Nobiletin has various useful effects such as anti-cancer, anti-inflammation, and anti-oxidant. In previous study, we demonstrated that Nobiletin suppresses phenylephrine-induced hypertrophic responses in cardiomyocytes in a dose-dependent manner in cultured cardiomyocytes and oral administration of Nobiletin prevented systolic dysfunction and development of heart failure after myocardial infarction in rats. Thus, Nobiletin is expected as an effective agent for heart failure. To clinically apply this novel therapy to humans, it should be clarified whether or not Nobiletin exhibits additional effects on conventional heart failure therapy, such as Candesartan, an angiotensin II receptor antagonist (ARB). Thus, we examined the effects of Nobiletin / Candesartan combination therapy on heart failure in vivo.

Materials and Methods Six week-old salt-sensitive Dahl (DS) rats and salt-resistant Dahl (DR) rats were fed with a high salt diet for 5 weeks. Eleven week-old DS rats were randomly assigned to 4 groups. Group I: DR rats with vehicle treatment (1 % gum Arabic, n=5) as control. Groups II: DS rats with vehicle (n=8). Group III: Nobiletin (20 mg/kg/day, n=9). Group IV: Candesartan (1 mg/kg/day, n=8). Group V: Nobiletin and Candesartan combination (n=8). This dose of Candesartan has therapeutic potency

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for heart failure without affecting blood pressure. Oral administrations were repeated everyday for 7 weeks. At 18 week-old, echocardiography were performed. The mRNA were extracted from left ventricle of these rats and the expression levels of the hypertrophic markers, such as ANF and BNP, were measured with quantified RT-PCR. Finally, left ventricle of these rats were stained with hematoxylin-eosin and myocardial cell diameter was measured.

Results There were no differences among the 4 groups of DS rats in any LV geometric and functional parameters at 11 weeks-old. At 18 weeks-old, both Nobiletin and Candesartan did not affect increases in systolic and diastolic blood pressures. Left ventricular fractional shortening (LVFS) was significantly higher in Nobiletin (50.1 %; p < 0.05) and Candesartan (49.7 %; p < 0.05) groups than in the DS vehicle group (38.9 %). Notably, LVFS additionally increased in Nobiletin / Candesartan combination treatment (58.3 %; p < 0.05) compared to Nobiletin or Candesartan alone. The DS vehicle group had increased hypertrophy-response gene activation, and this increase was significantly inhibited by all of treatments. Finally, the results of the quantitative analyses were that DS vehicle group had increased myocardial cell diameter, and that this increase was significantly inhibited by all the treatments.

Conclusions A polymethoxy flavonoid, Nobiletin prevents hypertension-induced systolic dysfunction addition to ARB in vivo. This compound might be applicable for heart failure patients in clinical setting. n

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ISCP 2017 Best Posters Young Investigator Award Topic: 3. Heart Failure and Cardiomyopathy

Cardiac Resynchronization is Associated with Reduction in the Rate of ICD Therapies, While Improves Ventricular Function Gerard Oristrell, Enrique Galve, Juan Gabriel Acosta, Aida Rivera, Angel Moya, Ignacio Ferreira, Jordi Perez-Rodon, David Garcia-Dorado Hospital de la Vall d’Hebron – Cardiology

Keywords: ICD CRT-D

Background

Rate of ICD therapies

Once ICD has been implanted, device therapies worsen prognosis.

1.00

Hypothesis

0.80

CRT-D may reduce number of first appropriate ICD therapy, and independent factors can be identified.

0.60

Methods

0.40

175 consecutive patients (age 64.6±10.4 years, 23 [13.1 %] women), left ventricular ejection fraction (LVEF) 27.9 ± 7.6 % (range 10-50 %), 97 of ischemic origin, were treated, according to standard indications, with an ICD (in 80 cases the device was CRT-D) and followed-up during 2.5±1.5 years. Devices were placed for either primary (n=95) or secondary prevention (n=80).

0.20

0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Follow-up (months) ICD

CRT-D

Results 44 (25.1 %) patients received at least one appropriate therapy, 11.55 (8.57-15.57) per 100 patient-years. In the multivariable analysis, indication for secondary prevention was associated with a higher risk of first appropriate therapy (HR 3.42 [1.36-8.57] p=0.009), and CRT-D was associated to a lower risk of first therapy (0.31 [0.11-0.88] p=0.027). This reduction was present across all subgroups, even in patients in primary prevention (p=0.05), and although patients treated with CRT-D had significant lower ejection fraction and poorer NYHA class that their counterparts. In the follow-up, LVEF in

1.

2.

patients with CRT-D improved from 25.3 % (5.6) to 37.0 % (5.6) (p=0.001).

There were no differences in mortality in patients with and without CRT.

Conclusion Although patients receiving CRT-D have a worse clinical profile, they receive less device therapies in comparison to those receiving an ICD; this reduction is associated with significant improvement in LV function. n

rmis C, Seutter R, Zhu AX, Benditt LC, VanHeel L, Sakaguchi S, Lurie KG, Lu F, Benditt DG. Impact of upgrade cardiac resynchronization therapy on ventricular arrhythmia frecuency in patients with E implantable cardioverter-defibrillators. J Am Coll Cardiol 2005;46:2258–63.

Manfredi JA, Al-khatib SM, Shaw LK, Thomas L, Fogel RI, Padanilam B, Rardon D, Vatthyam R, Gemma LW, Golden K, Prystowsky EN. Association between left ventricular ejection fraction post-cardiac resyncronization treatment and subsequent implantable cardioverter defibrillator therapy for sustained ventricular tachyarrhythmias. Circ Arrhythm Electrophysiol. 2013 Apr;6(2):257-64.

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ISCP 2017 Best Posters Young Investigator Award Topic: 4. Arrhythmias

Prevalence of Appropriate Non-Antiarrhythmic Pharmacotherapy in Atrial Fibrillation Patients with Rhythm Control Strategy Anna E. Platek, 1 Anna Hrynkiewicz-Szymanska, 2 Anna Rys, 1 Karolina Semczuk, 1 Filip M. Szymanski, 1 Krzysztof J. Filipiak 1 1. 1st Department of Cardiology - Medical University of Warsaw, Poland, 2. Department of Cardiology, Hypertension and Internal Diseases - Medical University of Warsaw, Poland

Keywords: atrial fibrillation; non-antiarrhythmic pharmacotherapy

Introduction and Objectives Guidelines of the European Society of Cardiology (ESC) from 2016 recommend pre-treatment with non- antiarrhythmic drugs (namely ACE-Is or ARBs) in patients with recurrent atrial fibrillation (AF), in whom rhythm control strategy is considered.1 This recommendation is based on possible antiarrhythmic effects of these drugs. Little is known of the prevalence of this guideline-based treatment in the clinical practice.

Materials and Methods The study included AF patients hospitalized in a tertiary cardiology department, in whom an invasive rhythm control strategy (ablation or electrical cardioversion) was taken. All patients included in the study hospitalized with a primary diagnosis of AF between 2011 and 2014.

Prospective data on the drugs prescribed on discharge was collected in all patients.

Results The study population consisted of 267 patients with primary diagnosis of AF in whom rhythm control strategy was considered. The mean age

1.

of the study population was 57.6±10.1 years, and 174 (65.2 %) patients were male. Out of the study population, 194 (72.7 %) patients had arterial hypertension, and 22 (8.2 %) had a history of myocardial infarction.

According to the discharge records, 164 (61.4 %) patients were prescribed renin-angiotensin-aldosterone system blocking medication. Out of this group, 127 (47.6 %) patients were prescribed ACE-I and 37 (13.9 %) received ARB. When we compared patients with and without arterial hypertension, we saw that patients with arterial hypertension were more likely to receive renin-angiotensin-aldosterone system blocking medication (76.8 % vs. 20.5 %; p < 0.0001), ACE-I (59.8 % vs. 15.1 %; p < 0.0001), and ARB (17.0 % vs. 5.5 %; p = 0.009).

Conclusions Non-antiarrhythmic drugs (ACE-Is or ARBs) possible antiarrhythmic effects are largely underutilized in patients with recurrent atrial fibrillation (AF), in whom rhythm control strategy is considered. Main reason for ACE-I/ARB prescription in this group is probably arterial hypertension. More effort should be put on informing physicians on possible benefits from ACE-I/ARB in non-hypertensive patients with AF. n

Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893-2962.

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ISCP 2017 Best Posters Best Poster Award Topic: 5. Secondary Prevention of Cardiovascular Disease.

Oral Anticoagulation and Prognosis of Patients with Atrial Fibrillation After Ischemic Stroke: A Real-world Data Analysis Mario Diaznuila-Alcázar, Daniel Valcárcel-Paz, Pablo Del Castillo-Vásquez, Marcel Santaló-Corcoy, Walter Bragagnini, Joan Carles Oliva-Morera, Eduard Bosch-Peligero, Antoni Martínez-Rubio Hospital Parc Tauli de Sabadell - Universidad Autonoma de Barcelona

Keywords: Atrial Fibrillation, Secondary prevention

Introduction Atrial fibrillation (AF) is one of the most common arrhythmias and a recognized source of embolic ischemic stroke which has critical prognostic implications.

Objetives To prospectively analyze the clinical characteristics of hospitalized patients with atrial fibrillation presenting with an ischemic stroke, the subsequent preventive strategies, the quality of dicumarinic therapy (if used) and the posterior outcomes (cardiovascular events and mortality).

Materials and Methods Between January of 2006 and June 2013, 370 patients (Pts) (Age: 81 + 7 years, 66 % female, CHA2DS2-VASC: 5,1 + 1,7, arterial hypertension: 80 %, chronic kidney disease (CKD): 40 %, diabetics: 28 %, dyslipemics: 34 %, any prior bleeding: 19 %, previous ischemic stroke: 9 %, chronic obstructive pulmonary disease: 7 %) were admitted to the hospital because of stroke and AF and form the basis of analysis.

Results From those 370 pts, 72 pts (19 %) already died in- hospital during the index event. Based on the decision of the attending physicians (who considered the clinical status and characteristics of those individuals who survived the index event (n=298)) and the chosen

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treatment, four subgroups of strategies were identified: Dicoumarin therapy (DIC), direct oral anticoagulation (DOAC), antiplatelet therapy (APT), finally without APT and without anticoagulant therapy (NO-T).

The DIC subgroup was composed of 129/298 pts (43 %). Furthermore, during a follow-up of 22+18 months, 4270 INR level determinations were performed (mean number of INR determinations per patient was 30±18). A total of 1879 INR determinations (44 %) showed an inappropriate level (<2 or >3). Thus, overall patients were during 7.9±6 months at risk of thromboembolic or bleeding events in relationship to INR out of therapeutic range. The DOAC, APT and NO-T groups included 25 (8 %), 112 (37 %) and 32 (11 %) pts, respectively.

The follow-up of survivors lasted until June 2016. At this date, only 90 (24 %) pts were alive (total death rate of 76 %). Cardiovascular mortality occurred in 162/280 (58 %) of deceased patients.

Conclusions A population with AF suffering ischemic stroke, advanced age and a high-risk profile showed a very poor outcome (reflected by a very high mortality). Even in an identified very high-risk population, the DIC therapy shows an inappropriate INR in 44 % of the determinations. Therefore, modern therapies (e.g. DOAC) should be more often used. n

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ISCP 2017 Best Posters Best Poster Award Topic: 1. Clinical Cardiology

Effects of Pharmacotherapy for Smoking Cessation on LOX Index, a Cardiovascular Risk Marker Maki Komiyama, 1 Hiromichi Wada, 1 Hajime Yamakage, 1 Noriko Asahara, 1 Sayaka Shimada, 1 Masaharu Akao, 1 Tatsuya Morimoto, 2 Yuko Takahashi, 1 Tatsuya Sawamura, 3 Koji Hasegawa 1 1. National Hospital Organization, Kyoto Medical Center, Japan, 2. School of Pharmaceutical Sciences, University of Shizuoka, Japan, 3. Department of Physiology, Shinshu University, Nagano, Japan

Keywords: Smoking Cessation; LOX Index; Inflammation; Atherosclerosis

Introduction and Objectives Vessel wall Inflammation promotes the destabilization of atherosclerotic plaques. The lectin-like oxidized low- density lipoprotein (LDL) receptor-1 (LOX-1) expressed by vascular cells and monocytes. LOX index is calculated by multiplying LOX-1 ligand containing apolipoprotein B level with the soluble LOX-1. A high LOX index reflects an increased risk for stroke and myocardial infarction. However, the change in LOX index after smoking cessation and the relationship between smoking-related variables and LOX index is unknown. Additionally, epidemiologic studies report that there is a possibility that the risk of cardiovascular events may increase during treatment with varenicline, and some alarm bells for smoking cessation using varenicline as a smoking cessation aid in patients with cardiovascular disease. However, the exact details are unknown. The present study investigated the change of cardiovascular risk marker, LOX index, after smoking cessation and the relationship between smoking-related factors and LOX index. In addition, the present study investigated the impact of smoking cessation as well as the effects of a smoking cessation aid on the LOX index.

the influence of BMI increase on a cardiovascular risk marker. The effects of a smoking cessation aid on the LOX index were also determined.

Results Sex-adjusted regression analysis and multivariate analysis identified three independent determinants of the LOX index, namely lowdensity lipoprotein-cholesterol (LDL-C; β = 0.273, p = 0.002), highsensitivity C-reactive protein (β = 0.324, p < 0.001), and expired carbon monoxide concentration reflecting smoking heaviness (β = 0.225, p = 0.008). Body mass index (BMI) significantly increased 3 months after the onset of smoking cessation (p < 0.001).

However, the LOX index significantly decreased from baseline to 3 months (from 3.31 to 2.57; p < 0.001), regardless of the rate of increase in BMI post-cessation. There was no significant difference in the degree of change in the LOX index between patients who were prescribed varenicline and those were prescribed nicotine patch.

Materials and Methods

Conclusions

A prospective study was conducted on patients who consulted the Smoking Cessation Clinic. Varenicline or nicotine patch were used as a smoking cessation aid. Relation of the clinical parameters to the LOX index was examined on 207 subjects (155 males and 52 females) at the first visit to our outpatient clinic for smoking cessation. Various parameters including LOX index were evaluated at 12 weeks after beginning a smoking cessation therapy in the 94 subjects (62 males and 32 females) who successfully stopped smoking. The subjects who successfully quit smoking were divided into two groups based on the rate of BMI increase to investigate

The findings suggest that the LOX index is closely related to smoking heaviness, a marker of dyslipidemia (LDL-C), and a marker of inflammation (hsCRP). A significant decrease in LOX index was detected within 3 months after smoking cessation, which might reflect a reduction in cardiovascular risk at an early stage. In addition, a significant decrease in LOX index was noted even in subjects exhibiting larger weight gain after smoking cessation, regardless of the type of prescription drugs. Thus, the LOX index may constitute a sensitive marker of smoking status, rather than just a marker of weight gain. n

1.

Sawamura T, Wakabayashi I, Okamura T (2015) LOX-1 in atherosclerotic disease. Clin Chim Acta 440: 157-163.

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ISCP 2017 Best Posters Best Poster Award Topic: 1. Clinical Cardiology

Impact of an Integral Assistance on the Management of Patients with Chronic Heart Diseases Román Freixa-Pamias, 1 Pere Blanch Gràcia, 1 Lluïsa Rodriguez Latre, 2 Antoni Oliva Vicedo, 1 Carmen Alonso Permanyer, 2 Pilar Sánchez Chamero, 1 Elisabet Mena Sebastià, 1 Miriam García Bermúdez, 1 Alberto Cabestrero de Diego, 1 Angels González Guardia, 1 Elena Salas González, 1 Carolina Bosch Carabante, 1 José Manuel Depares López, 2 Mireia Sans Corrales, 3 Juan Francisco Pajares Díaz-Meco, 1 Jordi Vericat Garcia, 1 Maria Jesús Megido Badía, 2 Jordi Vilarasau Farre, 1 Maria Rotllan Terradellas, 1 Angel Jover Blanca 2 1. Hospital Moisès Broggi (L’Hospitalet de Llobregat/ Sant Joan Despí). - Consorci Sanitari Integral., 2. Servei d’Atenció Primària (SAP) Baix Llobregat Centre - Institut Català de la Salut (ICS), 3. Servei d’Atenció Primària (SAP) Delta del Llobregat. - Institut Català de la Salut (ICS)

Keywords: anticoagulation; atrial fibrillation; heath care levels; integration; LDL cholesterol

Introduction and Objectives

Results

Conventional care model between cardiology and primary care has many limitations (i.e. inadequate communication and coordination between healthcare levels). A change in healthcare model is mandatory. The objective of this study is to analyze the impact of implementing a program integrating cardiology and primary care in clinical practice.

The implementation of the new care model was associated with a significant reduction of 31.2 % (p<0.05) in the request of the first visits.

In addition, the delay to the cardiologist consultation significantly decreased in 55 days (54.5 %) for the first visits, and 112 days (57.1 %) for the follow-up visits (p<0.05). Between 2013 and 2016 the proportion of patients that achieved recommended LDL-cholesterol goals significantly increased from 20.8 % to 29.6 %, respectively (OR 1.61; 95 % CI 1.471.75). The proportion of anticoagulated patients significantly increased from 62.2 % to 72.8 % (p<0.05), respectively. Among anticoagulated patients, the proportion of patients taking direct oral anticoagulants significantly increased from 7.7 % in 2013 to 27.2 % in 2016 (p<0.05).

Materials and Methods In the integrated care model, every cardiologist was integrated in each specific primary care center, attending patients weekly, participating in the discussion of clinical cases, virtual visits and ongoing medical education. In this observational study, number of visits and delay to cardiologist consultation were determined. LDLcholesterol control rates in patients with ischemic heart disease and antithrombotic therapy in patients with atrial fibrillation (AF) were also studied. The new model was progressively implemented since December 2013.

Conclusions Implementing an integrated care model is feasible, reduces the number of visits, the delay to cardiologist consultation and improves surrogate variables, such as LDL cholesterol control rates and the proportion of AF patients receiving anticoagulation. n

Falces C, Andrea R, Heras M, Vehí C, Sorribes M, Sanchis L, et al. Integration between cardiology and primary care: impact on clinical practice. Rev Esp Cardiol. 2011;64:564-71. ook RI, Render M, Woods DD. Gaps in the continuity of care and progress on patient safety. BMJ. 2000;320:791-4.

C Haggerty JL, Reid RJ, Freeman GK, Starfield BH, Adair CE, McKendry R. Continuity of care: a multidisciplinary review. BMJ. 2003;327:1219-21.

Comín-Colet J, Verdú-Rotellar JM, Vela E, Clèries M, Bustins M, Mendoza L, et al. Efficacy of an integrated hospital-primary care program for heart failure: a population-based analysis of 56,742 patients.

Rev Esp Cardiol (Engl Ed). 2014;67:283-93.

5. Díaz Sánchez S, Lobos Bejarano JM, Gonzalez-Juanatey JR. Atrial fibrillation: from detection to treatment. Role of the family physician, cardiologist and other specialists. New models of clinical management. Aten Primaria. 2013;45Suppl 1:18-29.

6. Penm J, MacKinnon NJ, Strakowski SM, Ying J, Doty MM. Minding the Gap: Factors Associated With Primary Care Coordination of Adults in 11 Countries. Ann Fam Med. 2017;15:113-119.

7. Hernández-Afonso J, Facenda-Lorenzo M, Rodríguez-Esteban M, Hernández-García C, Núñez-Chicharro L, Viñas-Pérez AD. New Model of Integration Between Primary Health Care and Specialized Cardiology Care. Rev Esp Cardiol (Engl Ed). 2017 Feb 28. [Epub ahead of print] 8. Barrios V, Escobar C, Calderón A, Rodríguez Roca GC, Llisterri JL, Polo García J. Use of antithrombotic therapy according to CHA2DS2-VASc score in patients with atrial fibrillation in primary care. Rev Esp Cardiol (Engl Ed). 2014;67:150-1.

9. Barrios V, Escobar C, Prieto L, Osorio G, Polo J, Lobos JM, et al.Anticoagulation Control in Patients With Nonvalvular Atrial Fibrillation Attended at Primary Care Centers in Spain: The PAULA Study. Rev Esp Cardiol (Engl Ed). 2015;68:769-76.

10. Martínez-Rubio A, Dan GA. Are low doses of direct-acting oral anticoagulants justified and appropriate in patients with nonvalvular atrial fibrillation?. European Cardiology Review, 2016;11(2):115–7.

DOI: 10.15420/ecr.2016:11.2:ED2.

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2.

3.

4.

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ISCP 2017 Best Posters Topic: 5. Secondary Prevention of Cardiovascular Disease.

5-Year Outcomes After Implementation of Optimal Medical Therapy in General Practice Using Liaison Critical Pathway for Secondary Prevention of Coronary Artery Disease: An Observational Study Morihiro Matsuda, Kanako Yuasa, Toshiharu Kawamoto, Toshiharu Oka, Hiroshi Sugino National Hospital Organization Kure Medical Center - Department of Cardiology

Keywords: liaison critical pathway, coronary artery disease, optimal medical therapy

Introduction and Objectives

Results

Liaison critical pathways (LCPs) for coronary artery disease (CAD) were developed to support collaborative care for CAD patients between cardiologists in emergency hospitals and referring physicians through sharing of medical information, including cardio protective medications and cardiovascular risk factors.1 LCPs for CAD may be effective for facilitating implementation of optimal medical therapy (OMT) in general practice.

However, little is known about the outcomes of the patients managed using LCPs. The objective of this study was to investigate the outcomes after the implementation of OMT in general practice using the LCP.

Implementation rate of hospital visits was elevated from 50.7 % to 89.3 % after establishing the LCP. High prescription rate for anti-platelet drugs and statins was maintained for 5 years (92.7 % and 86.4 %, respectively, at the 5th year survey). Target achievement rates for low-density lipoprotein cholesterol < 100 mg/dL and high-density lipoprotein cholesterol ≥40 mg/dL were significantly elevated from 48.4 % to 78.7 % and 61.7 % to 83.9 %, respectively, after establishing the LCP, which remained high during the follow-up period. The revascularization rate of non-target lesion was relatively low (23 % in 5 years), although that of target lesion did not decrease. The 5-year cumulative event rate of nonfatal myocardial infarction was 2.5 %, which was low in comparison with the data reported in previous studies.2 28 patients

Materials and Methods We conducted an observational study of 314 CAD patients (age, 69.2 ± 9.9 years old; male, 74 %) undergoing percutaneous coronary intervention for stable CAD (67.8 %) or acute coronary syndrome (32.2 %) in our hospital between September 2007 and June 2010; these patients were managed with an LCP by referring physicians after discharge for two years. We surveyed implementation of scheduled hospital visits, prescription of cardio protective medicines, target achievement of risk factors and the outcome, including revascularization, nonfatal myocardial infarction and death from any cause, during a follow-up period of 5 years.

1.

2.

died from any causes; main causes were cancers (n=10) and infectious disease (n=9) and only 2 patients died from myocardial infarction.

Conclusions Implementation of OMT in general practice using LCPs may contribute to decreasing non-target lesion revascularization, and nonfatal and fatal myocardial infarction, but may not be effective for reducing target lesion revascularization and death from any causes. n

atsuda M, Akizuki M, Nishimoto O, Nakamoto K, Nishiyama H, Tamura R, Kawamoto T. Cardiovascular risk management with liaison critical path in Japan: its effects on implementation of evidenceM based prevention in practice. J Clin Med Res. 2012 Apr;4(2):102-9.

Kimura T, Morimoto T, Nakagawa Y, Kawai K, Miyazaki S, Muramatsu T, Shiode N, Namura M, Sone T, Oshima S, Nishikawa H, Hiasa Y, Hayashi Y, Nobuyoshi M, Mitudo K; j-Cypher Registry Investigators. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. Circulation. 2012 Jan 31;125(4):584-91.

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ISCP 2017 Best Posters Topic: 3. Heart Failure and Cardiomyopathy

A Risk Score to Predict the Absence of Left Ventricular Reverse Remodelling: Implications for the Timing of ICD Implantation in Primary Prevention Jordi Pérez-Rodon, 1 Enrique Galve, 1 Carmen Pérez-Bocanegra, 2 Teresa Soriano-Sánchez, 1 Jesús Recio-Iglesias, 2 Eva Domingo-Baldrich, 1 Mila Alzola-Guevara, 1 Ignacio Ferreira-Gonzalez, 3 Josep Ramon Marsal, 3 Aida Ribera-Solé, 3 Laura Gutierrez García-Moreno, 1 Luz María Cruz-Carlos, 4 Nuria Rivas-Gandara, 1 Ivo Roca-Luque, 1 Jaume Francisco-Pascual, 1 Artur Evangelista-Masip, 1 Àngel Moya-Mitjans, 1 David Garcia-Dorado 1 1. Hospital Universitari Vall d’Hebrón, Department of Cardiology - Universitat Autònoma de Barcelona, Vall d’Hebrón Institut de Recerca, CIBER-CV, Spain, 2. Hospital Universitari Vall d’Hebrón, Department of Internal Medicine - Universitat Autònoma de Barcelona, Vall d’Hebrón Institut de Recerca, Spain, 3. Hospital Universitari Vall d’Hebrón, Department of Cardiology - Universitat Autònoma de Barcelona, Vall d’Hebrón Institut de Recerca, CIBER de Epidemiología y Salud Púbilica, CIBERESP, Spain, 4. Hospital Universitari Vall d’Hebrón, Department of Clinical Laboratory Universitat Autònoma de Barcelona, Vall d’Hebrón Institut de Recerca, Spain

Keywords: Heart failure; implantable cardioverter defibrillator; left ventricular reverse remodelling; pharmacological treatment optimization; risk score

Introduction and Objectives

Materials and Methods Consecutive outpatients with left ventricular ejection fraction (LVEF) ≥ 35 % were included in this observational prospective study. Up-titration of angiotensin-converting enzyme inhibitors (ACE inhibitors) / angiotensin II receptor blockers (ARBs), beta-blockers, aldosterone antagonists and ivabradine was performed in our Heart Failure (HF) Unit. The absence of LVRR was defined as the persistence of an LVEF 35 % at the 6-month follow-up.

100 90.0 % 90.8 %

Probability of absence of LVRR

Although treatment optimization in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) may result in left ventricular reverse remodelling (LVRR) in some cases, predictors of this phenomenon are scarce. This study aimed to: 1) determine the incidence and predictors of absence of LVRR after treatment optimization in patients with HFrEF and its potential effects on indications of prophylactic implantable cardioverter defibrillator (ICD) implantation, 2) create a risk score of absence of LVRR.

80

63.4 % 62.6 %

60

40

23.3 % 24.4 %

20

0 Risk score group Patients at risk

Results One hundred and seven patients were included, age 66 ± 12 years, 79 (74 %) male, 48 (45 %) with ischaemic cardiomyopathy (ICM) and 59 (55 %) with non-ischaemic cardiomyopathy (non-ICM). At the 6-month follow-up, 64 %, 76 %, 72 % and 7 % of patients were taking 100 % of the target dose of ACE inhibitors/ARBs, beta-blockers, aldosterone antagonists and ivabradine, respectively. LVRR was observed in 48 % of the overall population and in 33 % and 60 % of patients with ICM and non-ICM, respectively, p< 0.005. Consequently, we observed a marked reduction (52 %) in potential ICD indications after the optimization of HF pharmacological therapy [99 (95 %) at baseline to 45 (43 %) at the 6-month follow-up, p< 0.001], that was more pronounced in nonICM than in ICM patients: 65 % vs 35 %, p = 0.003. ICM, prolonged HF duration and larger left ventricular end-diastolic diameter index (LVEDDI) were independent predictors of the absence of LVRR. A risk score of absence of LVRR was created based on these predictors.

Patients were divided into three groups according to the risk of the absence of LVRR: low risk (≤ 4 points), intermediate risk (5-9 points)

1.

2.

Low

Intermediate

High

43 (41.4 %)

41 (39.4 %)

20 (19.2 %)

Observed probability

Probability predicted by the scoring system

and high risk (≥ 10 points). The probability of the absence of LVRR increased as the score increased according to each risk group. The observed probabilities and those predicted by the scoring system differed by < 2 % (Figure 1). The risk score based on these predictors showed a c-statistic value of 0.81. Three patients died during the study period (2.8 %).

Conclusions In patients with HFrEF, target doses of disease-modifying drugs can be reached in most patients and are associated with LVRR in approximately half of cases, reducing potential ICD indications in parallel. Ischaemic cardiomyopathy, prolonged HF duration and larger LVEDDI predict the absence of LVRR and favour ICD implantation without delay. The risk score based on these variables identifies the absence of LVRR with a high discriminatory capacity. n

Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996; 94: 2807-16.

Lupón J, Gaggin HK, De Antonio M, et al. Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score. Int J Cardiol 2015; 184: 337-43.

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ISCP 2017 Best Posters Topic: 3. Heart Failure and Cardiomyopathy

Does Angiotensin Receptor Neprilysin Inhibitor (ARNI) Improve Functional Capacity Assessed by 6 Minutes Walking Test?

Merce Faraudo, Paola Beltran, Roman Freixa, Elisabet Mena, Olga Guri, Anna Contra, Luís Miguel Ceresuela, Josep Masip Hospital de Sant Joan Despí Moises Broggi - Consorci Sanitari Integral

Keywords: angiotensin receptor neprilysin inhibitor 6 minutes walking test

Introduction and Objectives LCZ696 has been considered class I B in the recent ESC Guidelines of heart failure (HF) for stable HF patients with left ventricular ejection fraction (LVEF) < 35 %, who remain symptomatic after the standard therapy, based on the results of the PARADIGM trial. This study showed a significant reduction in the risk of cardiovascular death and hospitalization for HF in patients treated with LCZ696 compared to those treated with enalapril. Although the study reported to improve the quality of life and NYHA functional class, it was not tested the functional capacity with any functional test. The 6-minute walk test (6MWT) is an easy method to objectively measure patients’ submaximal functional capacity because of its reproducibilty, simplicity, and cost-effectiveness.

To analyse the impact of Sacubitril/Valsartan on functional capacity in patients with chronic HF.

Table 1

Basal

6MWT (m)

274±96 335±100

After 3 months

0.05

< 300 m

52 %

0.045

NTproBNP (pg/ml)

3470 1965

0.04

K+ (mEq/L)

4,3

4,4

n.s.

TAS (mmHg)

128±13

119±17

n.s.

% pacientes con TAS < 100 mmHg

0 %

7 %

n.s.

FG (ml/min/1.73m2)

62±17

60±17

n.s.

%pacientes con FG < 60 ml/min/1.73m2

53 %

43 %

n.s.

30 %

p

males, mean LVEF was 30 %, isquemic etiology of HF 37 %, mean maximal tolerated dose 98mg/day. The results of the 6MWT, physiological parameters and blood samples are presented in Table 1.

Materials and Methods Since October 2016, when the drug was marketed, all the patients referred to our HF-Unit who accomplished the 2016 HF ESC guidelines criteria for entresto were included in the study. A 6MWT was performed before starting the treatment and after three months of having optimized the dose. Physiological parameters and blood analysis were also measured at these time points.

Results are mean or percentage. 6MWT: 6 minute walk test; M= meters; SBP: systolic blood pressure; GFR: glomerular filtration rate

Conclusions Patients treated with Sacubitril/Valsartan improved their submaximal functional capacity at three months of treatment. Safety criteria such as hypotension or impaired renal function were not observed. n

Results 41 patients were screened and 30 of them entered in the study. These patients had the following characteristics: mean age 70, 80 % were

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4.

Myers J, Zaheer N, Quaglietti S, Madhavan R, Froelicher V, Heidenreich P. Association of functional and health status measures in heart failure. J Card Fail. 2006;12:439-45. uyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132:919-23.

G Yap J, Lim FY, Gao F, Teo LL, Lam CS, Yeo KK. Correlation of the New York Heart Association Classification and the 6-Minute Walk Distance: A Systematic Review. Clin Cardiol. 2015;38:621-8.

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.

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ISCP 2017 Best Posters Topic: 4. Arrhythmias

External 30 Days Holter Usefulness in Unexplained Syncope, Palpitations and Cardioembolic Suspected Cryptogenic Stroke Study Míriam Garcia Bermúdez, Antonia Ortega Diaz, Ana Bonet Basiero, Antoni Carol Ruiz, Pilar Sánchez Chamero, Pere Blanch, Alberto Cabestrero, Manuel Gomez Choco, Román Freixa Pamias Hospital moises broggi. - sant joan despí

Keywords: external holter, syncope, palpitations, atrial fibrillation, cryptogenic stroke

Introduction and Objectives The more time the heart rhythm is evaluated, the more rhythm disturbances are diagnosed in patients with syncope, palpitations or cryptogenic stroke. Increasing from 24-48h to 30 days with external holter allows further registering cardiac rhythm without invasive and expensive techniques such as ILR (implantable loop recorder). Moreover, it allows evaluating the whole continuous electrocardiographic register.

Our aim is to evaluate the cost- effectiveness of the external 30 days Holter Nuubo nECG PLATFORM (H30D) in palpitations, syncope and cardioembolic suspected cryptogenic stroke study in diagnose of bradiarrhythmias and taquiarrhythmias.

Materials and Methods A retrospective analysis of H30D dispositives from september 2016 to may 2017 is performed. Indication, demographic variables, complementary studies, time to event, diagnostic, therapeutic management, follow-up and nurse support to resolve doubts were collected.

Results 28 patients were enrolled, 40 % women, median age 77 years (Interquartile range (IQR) 70-83). The most frequent indication was syncope (82 %), followed by palpitations. Since April 2017, the indication was widen to cryptogenic stroke study therefore, 2 patients with this indication were enrolled as well. In 100 %, an echocardiography and, at least, 24h monitoring rhythm were performed. In syncope indication patients, basal rhythm was sinus rhythm in 82 %. 18 % of the patients had bifascicular block and 4 % left bundle branch block. In syncope patients, carotid sinus massage and orthostatic test were performed in 17 % and 22 % of cases , respectively, all of them negative. Tilt test was performed in 18 % (50 % positives and 50 % negatives).

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In cardioembolic suspected stroke patients indication (2 patients), supra-aortic trunks ultrasound was performed and transoesophageal echocardiography was performed in one of them.

Cardiac rhythm register was obtained in 92 % (IQR 88-97 %) of the days and allowed to analyze 91 % (84-95 %) of the time. A conclusive diagnostic (electrocardiographic register and study event presence) was obtained in 36 % of the patients: 2 patients with palpitations (atrial tachycardia and supraventricular taquiarrhythmia), 7 patients with syncope (5 bradyarrythmias, 2 vasovagal syncopes) and one patient with asymptomatic atrial fibrillation in one cardioembolic suspected stroke. A probable diagnose was considered in two more patients (rising to 43 % the total success). This avoided the ILR implantation and one pacemaker replacement. The median time to study event appearance was early: 10 days (IQR 4-18) and the median follow-up time was 40 days (IQR 11-123). There was not any complication.

According to the early time event appearance (10 days) and 60 % of nurse telephone support requirement in first 20 patients, a weekly telephone call by nurse was implemented. 78 % of doubts were resolved by nurse. The dispositive was well tolerated, without any complication.

Conclusions External 30 days holter monitoring is a useful and cost-effective dispositive in syncope and palpitation study due to its non-invasive collocation and patient\’s comfort. It\’s useful to diagnose the cardiac etiology of the symptoms, and non cardiac as well. It may be useful in cryptogenic stroke study but this must be validated in a huge number of patients. According to the early detection of events, 30 day monitoring should be considered before ILR implantation. n

L ocati ET, Vecchi AM, Vargiu S, Cattafi G, Lunati M. Role of extended external loop recorders for the diagnosis of unexplained syncope, pre-syncope, and sustained palpitations. Europace. 2014 Jun;16:914-22.

Locati ET, Moya A, Oliveira M, Tanner H, Willems R, Lunati M, et al.External prolonged electrocardiogram monitoring in unexplained syncope and palpitations: results of the SYNARR-Flash study. Europace.

2016;18:1265-72.

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ISCP 2017 Best Posters Topic: 2. Ischemic Heart Disease

Differences in Clinical Characteristics, Results and Management of Patients Referred for Pharmacologic Cardiac Stress SPECT Depending on the Protocol Used Pablo Del Castillo, 1 Núria Casanovas, 1 Marcel Santaló, 1 Fernando Narro, 1 Ana Paula Caresia, 2 Ana Barradas, 1 Walter Bragagnini, 1 Joan Carles Martin, 2 Laura Guillamon, 1 Lluís Bernà, 2 Antoni Martínez-Rubio 1 1. Hospital Universitari Parc Taulí - Cardiology, 2. Hospital Universitari Parc Taulí - Nuclear Medicine

Keywords: Radionuclide imaging, Stress, Vasodilator agents, Ischemia, Prognosis

Introduction and Objectives Pharmacologic cardiac stress SPECT (PS-SPECT) is recommended for non-invasive evaluation of ischemic heart disease (IHD) in patients unable to exercise. Drugs used for stress in our centre are Dipyridamole (DIP) and Dobutamine (DBT). DIP can be associated to exercise (ex-DIP).

The objective of the study is to evaluate the diagnostic capacity of the different strategies.

Materials and Methods Retrospective study of 838 patients referred for PS-SPECT between 2010 and 2016.

chronic IHD. Complications of the test were similar for DIP and DBT (19,8 % vs 18,6 %) and lower for ex-DIP (10,3 %). Hypotension was the main complication for DIP and arrhythmias and hypotension for DBT. Gammagraphic ischemia was detected in similar percentages with the different protocols (39 % with DIP, 44.4 % with ex-DIP and 44.9 % with DBT). However, number of invasive angiography was lower for DBT group (10.6 % vs 14.6 % DIP and 16.1 % ex-DIP) and revascularization higher for ex-DIP (10.3 %) compared to DIP and DBT groups (7.2 % and 6.7 %). Mortality after a mean follow-up of 20 months, was higher for DBT (24,5 %), followed by DIP (16,6 %) and ex-DIP (9,4 %).

Conclusions Results DIP was the main agent used for stress (730 tests), followed by DBT (63 tests) and combined ex-DIP (45 tests). DIP is preferred to DBT for its best security profile, reserving DBT to patients with contraindications for DIP administration. Basal characteristics of the patients were similar except for younger age in ex-DIP (69 vs 74 years- old) and lower proportion of women in the DBT group (36,5 % DBT vs 57,5 % DIP).

Overall, they had high prevalence of cardiovascular risk factors and

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PS-SPECT is currently reserved to older and sicker patients. Different protocols of study found similar rates of gammagraphic ischemia.

Patients unable to exercise, especially those with contraindications for DIP administration, represent a high-risk profile of patients that are infrequently referred for invasive strategy independently of the result of the study and have high mortality risk. We should rethink about indication of this kind of tests in that kind of patients, tests that can be harmful, expensive and sometimes useless. n

Comparison of long-term mortality risk following normal exercise vs adenosine myocardial perfusion SPECT. Rozanski et al. Journal of Nuclear Cardiology 2010,17(6);999–1008.

Symptom-limited exercise combined with dipyridamole stress: Prognostic value in assessment of known or suspected coronary artery disease by use of gated SPECT imaging. Ahlberg A et al. Journal of Nuclear Cardiology 2008,15(1);42-56.

Survival by Stress Modality in Patients With a Normal Myocardial Perfusion Study. Johnson N et al. Am J Cardiol 2011;107:986 –989.

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ISCP 2017 Best Posters Topic: 5. Secondary Prevention of Cardiovascular Disease.

Secondary Prevention in Patients with Non Valvular Atrial Fibrillation and Previous Stroke. Is It Possible to Have an Appropriate INR Control?

Mario Diaznuila Alcazar, Daniel Valcárcel-Paz, Marcel Santaló-Corcoy, Pablo Del Castillo-Vasquez, Walter Bragagnini, Fadwa Taibi, Carlos Roca-Gutiérrez, Joan Carles Oliva-Morera, Eduardo Bosch-Peligero, Josep Guindo-Soldevila, Antoni Martínez-Rubio Hospital Universitario Parc Taulí de Sadell - Universidad Autonoma de Barcelona

Keywords: atrial fibrillation, secondary prevention, stroke

Introduction

Results

Coumadin therapy has been the best oral anticoagulation strategy available since several decades and is considered obligatory in some countries as the first strategy to be attempted because of economical reasons/arguments.

A total of 4416 INR level determinations from 125 consecutive patients (age: 76.6 + 9 years, females: 62. %, CHA2DS2-VASC: 5.2 + 1.7) were included in the analysis during a follow-up period of 23±20 months. The mean number of INR determinations per patient was 34±25. It was found that 1946 INR determinations (44 %) showed an inappropriate level (<2 or >3). Thus, a mean of 14±11 determinations/person were out of the therapeutic range and overall patients were during 7.9±8 months at risk of thromboembolic or bleeding events in relationship to INR out of therapeutic range.

Objectives To evaluate if patients already identified at highest-risk of stroke receive appropriate anticoagulation with dicumarinics and this strategy can be subsequently recommended in the actual days.

Methods We analyzed the quality of anticoagulation with coumadin in our area and its clinical consequences. For that purpose, we selected a very high-risk population (previously diagnosed of a possible cardioembolic stroke and concomitant Atrial Fibrillation (AF)) in whom is mandatory to have an excellent anticoagulant level. All consecutive INR measurement were considered for all patients as well as their outcomes.

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Furthermore, during the follow-up period, cardiovascular events (any ischemic or hemorrhagic event) occurred in 66 patients (53 %) with INR at the time of the event being inappropriate in 66 % of the cases.

Conclusions Even in a very high risk population with AF treated with coumadin because of secondary stroke prevention, the INR control is poor and is related to cardiovascular new events. n

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ISCP 2017 Best Posters Topic: 1. Clinical Cardiology

Consensus is Possible: Initiation and Exchange of Oral Anticoagulants in Non-valvular Atrial Fibrillation, According to a Territorial Protocol in a Period of Time Kristian Rivera, Cristina Marzo, Nuria Sans, Ainara Ferrero, Albina Aldomà, Joan Antoni Schoenenberger, Leonardo Galván, Fernando Worner Hospital Universitari Arnau de vilanova. IRBLLEIDA - Lleida. Spain

Keywords: Oran anticoagulation, atrial fribrillation, new oral anticoagulants

Introduction

Results

Universal use of Direct Oral Anticoagulants (DOACs) in non-valvular atrial fibrillation (nVAF) is not possible for economic reasons. It is necessary to prescribe them to those patients with greater potential benefit. The best way to achieve this objective is the application of a territorial protocol, designed and accepted by all professionals involved in nVAF.

In a period of 13.5 months (03/01/16 to 04/14/17), a total of 1142 events related to anticoagulation were performed in 1063 patients. Of the prescribed treatments, 96.8 % were adjusted to the protocol. Nine hundred and fourteen patients were on initiation therapy. According to protocol, 717 patients started acenocoumarol and 197 (21.6 %) DOACs (mainly in peri-cardioversion and CHADS 4 patients without chronic ACO indication).

In addition, in 228 cases already treated, the anticoagulant treatment was changed one or more times (187 treated with acenocoumarol started DOACs due to poor INR control, intolerance or complications; 11 patients receiving DOACs switched to acenocoumarol, and finally 30 patients already treated with DOACs exchanged drug or dose). In the set of this population and time, 373 patients (35.1 %) are under treatment with DOACs.

Objective To review the degree of compliance with a territorial, prospective and controlled protocol on anticoagulation in nVAF over a period of time, according to the indications of DOACs and acenocoumarol.

Materials and Methods A multidisciplinary team of 12 professionals involved in the nVAF process (family medicine, cardiology, neurology, internal medicine, hematology, emergency medicine, hospital and community pharmacy) developed a territorial protocol for a population of 400,000, which is reviewed each 6 months. Prescriptions and follow-ups were centralized in the hemostasis consultation. An ACCES database was designed ad hoc for the introduction of all data.

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Conclusions A rigorous compliance of a territorial protocol can be achieved when it is duly agreed by all the professionals involved and centralized its followup. We are convinced that it is the way to achieve maximum efficiency in addition to having the knowledge of the reality itself. Although a third of the patients are being treated with DOACs, their prescription due to poor INR control should still be improved. n

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ISCP 2017 Best Posters Topic: 3. Heart Failure and Cardiomyopathy

A Novel Target Molecule of Nobiletin Derived from Citrus Peels has a Therapeutic Potency Against the Development of Heart Failure Yoichi Sunagawa, 1 Masafumi Funamoto, 1 Anna Suzuki, 1 Kana Shimizu, 1 Ryoga Sakurai, 1 Yasufumi Katanasaka, 1 Yusuke Miyazaki, 1 Tomohiro Asakawa, 2 Toshiyuki Kan, 2 Junya Inagaki, 3 Hiromichi Wada, 4 Koji Hasegawa, 4 Tatsuya Morimoto 1 1. Division of Molecular Medicine, School of Pharmaceutical Sciences - University of Shizuoka, 2. Synthetic Organic & Medicinal Chemistry, School of Pharmaceutical Sciences - University of Shizuoka, 3. Department of Diabetes and Clinical Nutrition, Graduate School of Medicine - Kyoto University, 4. Division of Translational Research, Clinical Research Institute - Kyoto Medical Center

Keywords: Hypertrophy, heart failure, natural product

Introduction and Objectives Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. In a previous study, we demonstrated that a natural compound, curcumin, prevented cardiomyocyte hypertrophy and the development of heart failure in two different model animals.1–4 Recently, we screened a natural compound library and found that nobiletin, a poly-methoxy flavonoid derived from Citrus unshu, repressed phenylephrine (PE)-induced hypertrophic responses in cardiomyocytes and prevented the deterioration of systolic function and LV pathological hypertrophy in animals with myocardial infarction and pressure-overload.

Thus, nobiletin is expected as an attractive pharmacological agent for the treatment of heart failure. However, the target molecule of nobiletin in cardiomyocytes is still unclear. To solve this problem, we attempted to identify novel nobiletin-binding proteins by a proteomics approach and investigate its functional mechanism in mice.

Materials and Methods To purify NBPs, biotin-conjugated nobiletin (Bio-nobiletin) was synthesized. Protein extracts form rat hearts were incubated with Bio-nobiletin or biotin alone. Nobiletin binding proteins (NBP) were precipitated with streptavidin beads and analyzed by LC/ LC-MS/MS. In vitro binding assay and enzyme activity assay were performed using recombinant NBP1. Neonatal rat cardiomyocyte expressing NBP1 or transducing siRNA-NBP1 were treated with nobiletin and then stimulated with PE for 48 hours. These cells were stained with β-MHC antibody and cell size were measured.

TG mice carrying NBP1 gene under the CAG promoter (NBP1-TG)

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and WT mice were subjected to sham or transarotic constriction (TAC). After 8 weeks, echocardiography, histological analysis, and quantification of hypertrophic responses gene transcription were performed.

Results 162 NBPs were identified by LC-LC/MS-MS. One of them, nobiletinbinding protein 1 (NBP1) which related to cellular metabolic pathway, physically bound to biotin-conjugated nobiletin. Nobiletin also activated enzyme activity of NBP1 in vitro. In cardiomyocyte, knockdown of NBP1 failed to nobiletin-mediated anti-hypertrophic effect, and overexpression of NBP1 inhibited phenylephrine-induced cardiomyocyte hypertrophy. The results of echocardiography showed that NBP1-TG mice resisted TAC induced cardiac hypertrophy and systolic dysfunction compared with WT mice. NBP1 overexpression prevented TAC-induced myocardial cell hypertrophy and perivascular fibrosis, and hypertrophy-responses genes activation such as ANF and BNP.

Conclusions Proteomics analysis on molecular targets of nobiletin is useful to delineate nobiletin-mediated signaling pathways and anti-hypertrophic effect in cardiomyocytes. These finding suggest that nobiletin inhibits cardiomyocyte hypertrophy and the development of heart failure through the functional regulation of NBP1 activity. A natural compound, nobiletin, might be a candidate for heart failure agent in human. n

Sunagawa Y, Sono S, Katanasaka Y, et al. Optimal dose-setting study of curcumin for improvement of left ventricular systolic function after myocardial infarction in rats. J Pharmacol Sci 2014;126(4):329–36.

DOI: 10.1254/jphs.14151FP. PMID: 25409899 Sunagawa Y, Wada H, Suzuki H, et al. A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats. Biol Pharm Bull 2012;35(2):139–44. PMID: 22293342 Sunagawa Y, Morimoto T, Wada H, et al. A natural p300-specific histone acetyltransferase inhibitor, curcumin, in addition to angiotensin-converting enzyme inhibitor, exerts beneficial effects on left ventricular systolic function after myocardial infarction in rats. Circ J 2011;75(9):2151–9. PMID: 21737953 Morimoto T1, Sunagawa Y, Kawamura T, et al. The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 2008;118(3):868–78.

DOI: 10.1172/JCI33160. PMID: 18292809

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ISCP 2017 Best Posters Topic: 3. Heart Failure and Cardiomyopathy

Curcumin Analogue GO-Y030 Significantly Improves Pressure Overload-induced Heart Failure in Vivo Kana Shimizu, 1 Masafumi Funamoto, 1 Mai Genpei, 1 Yoichi Sunagawa, 1 Yasufumi Katanasaka, 1 Yusuke Miyazaki, 1 Hiroyuki Shibata, 2 Hiromichi Wada, 3 Koji Hasegawa, 3 Tatsuya Morimoto 3 1. University of Shizuoka - Division of Molecular Medicine, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, 2. Akita University - Department of Clinical Oncology, Graduate School of Medicine, 3. Kyoto Medical Center - Clinical Research Institute, National Hospital Organization

Keywords: Curcumin, Analogue, p300, Acetylation, Heart failure

Introduction and Objectives Signals activated by increased hemodynamic overload to the heart finally reach the nuclei of cardiac myocytes and induce maladaptive hypertrophy in them. Nuclear acetylation, which is controlled by histone deacetylases and the intrinsic histone acetyltransferase p300, is a critical event in this process. We previously found that a natural p300 HAT inhibitor, curcumin, can inhibit cardiomyocyte hypertrophy and the development of heart failure in vivo. However, curcumin is insoluble in water, and its bioavailability is low. Therefore, a more efficient system for heart failure therapy is desirable for actual clinical practice. To overcome this limitation, we recently synthesized a curcumin analog, GO-Y030, which possesses stronger anti-cancer activity than curcumin. However, the effect of GO-Y030 on heart failure is still unclear. The purpose of this study was to determine whether GO-Y030 inhibits p300-HAT activity and can be used as a therapeutic agent for heart failure.

Materials and Methods First, to investigate whether GO-Y030 inhibits p300-HAT activity, an in vitro HAT assay was performed using a recombinant p300-HAT domain and histone H3. The histones were processed for western blotting with anti-histone H3K9 antibody. The 50% inhibitory concentrations (IC50) for p300-HAT activity were estimated from dose-response curves.

Second, primary cardiomyocytes from neonatal rats were stimulated with saline or phenylephrine (PE) in the presence of curcumin or GO-Y030 for 48 hours. Proteins isolated from these cells by acid extraction were subjected to western blotting for acetylated histone H3K9 or total histone 3. Measurement of hypertrophic response gene transcription was performed by RT-PCR. Cardiomyocytes were stained with anti-γ-MHC antibody, and the surface area of these cells was measured. Third, C57BL/6j male mice (8 weeks old) were

subjected to sham or transverse aortic constriction (TAC). One day after TAC, the mice were randomly assigned to daily oral treatment with curcumin (1 or 50 mg/kg), GO-Y030 (0.1, 0.5 or 1 mg/kg), and vehicle (1% gum Arabic) as a control, for 6 weeks. After treatment, the effects of Y030 on TAC-induced cardiac hypertrophy and systolic dysfunction were investigated by echocardiography.

The mRNA levels of hypertrophic genes were measured by real-time RT-PCR.

Results The results of the in vitro HAT assay revealed that GO-Y030 inhibited p300-HAT activity more strongly than curcumin: The IC50 value of Y030 was 1.1 μM, while curcumin was 9.4 μM. In cardiomyocytes, 1 μM of GO-Y030 suppressed the following effects to the same extent as 10 μM of curcumin: PE-induced histone H3K9 acetylation, activation of hypertrophic response genes such as ANF and BNP, and increase in the surface area of cardiomyocytes. Echocardiographic analysis showed that 0.5 and 1 mg/kg of GO-Y030 and 50 mg/kg of curcumin suppressed TAC-induced increase in left ventricular posterior wall thickness and decrease in fractional shortening. Low doses of GO-Y030 (0.5 and 1 mg/kg) significantly suppressed TAC-induced increases in HW/BW ratio and hypertrophic response gene transcription to the same extent as 50 mg/kg of curcumin. One mg/kg of curcumin did not suppress these four effects.

Conclusions These results indicate that, compared to curcumin, the curcumin analogue GO-Y030 strongly inhibits p300-HAT activity, hypertrophic responses, and pressure overload-induced development of heart failure. These findings suggest that GO-Y030 may be effective for heart failure therapy. n

1. Yanazume T, Hasegawa K, Morimoto T, et al. Cardiac p300 is involved in myocyte growth with decompensated heart failure. Mol Cell Biol 2003 May;23(10):3593–606. PMID: 12724418 2. Morimoto T, Sunagawa Y, Kawamura T, et al. The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats.

3. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm 2007 Nov-Dec;4(6):807–18. PMID: 17999464; DOI: 10.1021/mp700113r 4. Ohori H, Yamakoshi H, Tomizawa M, et al. Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer. Mol Cancer Ther 2006;5(10):2563–71. PMID: 17041101; DOI: 10.1158/1535-7163.MCT-06-0174

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ISCP 2017 Best Posters Topic: 3. Heart Failure and Cardiomyopathy

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

Keywords: Curcumin, Glucuronide, p300

Introduction and Objectives Hemodynamic stimuli such as hypertension and myocardial infarction activate an intracellular signaling pathway, finally reach the nuclei of cardiomyocytes, change the pattern of hypertrophic response gene expressions, and induced cardiac hypertrophy and systolic dysfunction.

These eventually lead to the development of heart failure. In our study, we demonstrated that an intrinsic histone acetyltransferase, p300, is a critical role on hypertrophic response in cardiomyocytes and may be a pharmacological target for heart failure therapy. It has been reported that several compounds inhibit HAT activity in vitro and in culture. One of them, a natural compound curcumin (CUR) isolated from Curcuma longa has a p300-specific HAT inhibitory activity and cell permeability. Previous study showed that we demonstrated that CUR significantly prevented the development of heart failure by inhibiting p300-HAT activity in two different heart failure model rats.

In an oral administration, CUR almost undergoes rapid metabolism by glucuronidation and exists in blood as curcumin glucuronide (CUR-G).

So we hypothesized that CUR-G itself could exhibit beneficial biological activities as well as CUR. The purpose of this study was to investigate whether CUR-G inhibited p300-HAT activity in vitro and hypertrophic responses in cardiomyocytes.

Materials and Methods First, to compare the inhibitory effects of CUR and CUR-G against p300HAT activity, we performed an in vitro HAT assay using a recombinant p300-HAT domain and core histones. The activity of p300-HAT was quantified by immunoblotting and the ratio of acetylated histone-H3K9 to total histone-H3 was calculated. Next, primary cardiomyocytes from

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neonatal rats in culture were stimulated with 30 μM phenylephrine (PE), an ?1-adrenergic agonist, in the presence or absence of CUR or CUR-G for 48 hours. Protein extracts from these cell were subjected to immunoblotting. The mRNA levels of hypertrophic response genes, such as atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) were quantified by RT-PCR. Cardiomyocytes were stained with anti-cardiac MHC antibody and cell surface area was measured.

Results The results of in vitro HAT assay showed that the half maximal inhibitory concentration (IC50) value of CUR-G on p300-HAT activity was 37.3 μM, while that of CUR was 9.4 μM. In cardiomyocytes, 30, 100 μM of CUR- G, but not 10 μM of CUR-G, significantly inhibited PE-induced histone-H3K9 acetylation whereas 10 μM of CUR suppressed this acetylation. Moreover, in cultured cardiomyocytes, 100 μM, but not 10 μM of CUR-G, significantly repressed PE-induced hypertrophic response gene activations such as ANF and BNP and increases in cardiomyocyte size and myofibrillar organization.

Conclusions These results indicate that CUR-G has p300-HAT inhibitory activity and prevente PE-induced hypertrophic responses that effects are lower than those of CUR. The reduction of these effects may be due to the depression of the inhibitory activity against p300-HAT by the structure of glucuronic acid conjugated to CUR. These findings may help to elucidate the therapeutic potency of CUR. Further studies, especially in vivo studies, are needed to better understand the pharmacokinetics of CUR and CUR-G. n

Yanazume T, et al. Mol Cell Biol 2003;23:3593-606.

Balasubramanyam K, et al. J. Biol. Chem. 2004;279:51163-51171.

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ISCP 2017 Best Posters Topic: 1. Clinical Cardiology

Prospective and Centralized Follow-Up of a Territorial Protocol of Use of Direct Oral Anticoagulants in Non Valvular Atrial Fibrillation Fernando Worner, Cristina Marzo, Kristian Rivera, Nuria Sans, Ainara Ferrero, Joan Antoni Schoenenberger, Leonardo Galván, Albina Aldomà Hospital Universitari Arnau de Vilanova. - Gerència Territorial de Lleida i Pirineus

Keywords: non Valvular Atrial fibrillation, Direct Oral Anticoagulants, Territorial Protocol

Introduction Universal use of Directs Oral Anticoagulants (DOACs) in non valvular atrial fibrillation (nVAF) is not possible for economic reasons. Therefore, it is mandatory to guarantee their prescription of these drugs in patients theoretically most benefited.

Objectives To review indications and results of one territorial, prospective and centralized controlled protocol about the use of DOACs in nVAF.

Methods In November 2010 a multidisciplinary group of 13 professionals evolved in the atrial fibrillation process (primary assistance, internal medicine, cardiology, neurology, hemostasis, hospitality and community pharmacy and administration) elaborated one territorial protocol for an area of 400.000 inhabitants, which is updated every six months. Prescriptions and follow-up are centralized in the Hemostasis clinics, collecting all data in an ACCES data base ad hoc constructed.

Results Between 2011 and august 2016, 887 patients have been prescribed DOACs with a mean exposition time of 1,55 years. Mean age was 74 ± 12 years, CHADS2 2,3 ± 1,7 and CHA2DS2VASC 3,5 ± 1,9.

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According to our protocol indications, dabigatran was prescribed in 52,4 % of patients (mean follow up 1,29 years / patient), apixaban in 45,7 % (mean follow up 1,41 years / patient) and rivaroxaban in 1,9 % (mean follow up 2,09 years / patient). The reason for prescriptions were: peri electric cardioversion in patients without indication of chronic anticoagulation (27,3 %), CHADS2 > 4 (27,0 %), poor control of INR in antivitamin K treated patients (22,8 %), embolic/hemorrhagic complications under antivitamin K treatment (15,9 %), miscellany (7,0 %). Complications per 100 patients/year were: ictus + peripheral emboli 1,53, total mortality 4,43, cardiovascular mortality 1,24, major digestive bleeding 0,44, intracranial bleeding 0,87.

Conclusions Our series shows: 1.- A still a very low index of DOACs prescription

by INR control. 2.- It is constituted by very high embolic risk patients (especially if peri electric cardioversion patients were excluded). 3.The sample and follow up time do not allow to compare our efficacy and security results with clinical trials.

Anticoagulation in atrial fibrillation process is complex and applied many different professionals. We are convinced that a common territorial protocol and an centralized follow up is the best way to reach the maximum efficiency. n

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ISCP 2017 Best Posters Topic: 4. Arrhythmias

Choice of Anticoagulation Therapy in Atrial Patients with Rate Control and Rhythm Control Strategy - Data from a Multicenter Real-life Registry Anna E. Platek, 1 Anna Hrynkiewicz-Szymanska, 2 Anna Rys, 1 Karolina Semczuk, 1 Filip M. Szymanski, 1 Krzysztof J. Filipiak 1 1. 1st Department of Cardiology - Medical University of Warsaw, Poland., 2. Department of Cardiology, Hypertension and Internal Diseases - Medical University of Warsaw, Poland

Keywords: atrial fibrillation; anticoagulation

Introduction and Objectives

We analyzed data from a registry of continuous AF patients hospitalized with a primary diagnosis of AF between 2011 and 2014. In all cases, we collected prospective data on medical history, cardiovascular and thromboembolic risk factors and on discharge anticoagulation treatment.

strategy group. Compared to the rate control group, patients in whom the rhythm control strategy was chosen were younger (71.9±12.1 vs.

75.3±10.4; p = 0.005). There were no differences in terms of sex, and hypertension or diabetes mellitus prevalence. When we analyzed use of anticoagulation treatment, it was shown that in the general population 325 (72.7 %) were prescribed oral anticoagulant on discharge, out of which 287 (64.2 %) were prescribed vitamin K antagonist (VKA), 38 (8.5 %) were prescribed non-vitamin K oral anticoagulant (NOAC). 128 (28.6 %) patients were prescribed aspirin. When we compared patients with rhythm control vs. rate control strategy, we showed that OAC were used in 67.5 % vs. 82.3 % patients (p < 0.0001), VKA in 57.8 % vs. 75.9 % (p = < 0.0001), NOAC in 9.7 % vs. 6.3 % (p = 0.15) and aspirin in 33.2 % vs. 20.3 % (p = 0.002).

Results

Conclusions

The registry included 1205 records of hospitalization with AF. Out of this group 447 patients with primary diagnosis of AF were hospitalized at least one time in the given period. Baseline characteristics showed that the mean age of the population was 73.1±13.2 years, and their mean body mass index (BMI) was 29.2±6.4 kg/m2. 211 (47.2 %) patients were male. 289 (64.6 %) patients were in the rhythm control

In AF patients in whom the rhythm control strategy OAC are used less often than in patients with rate control strategy. These differences are probably related to a different distribution of comorbidities and therefore other profile of thromboembolic risk. Moreover, underutilization of NOACs may be related to a period in which the study was conducted. n

Atrial fibrillation (AF) patients can be managed with rate control and rhythm control strategies. Both seem to be equally safe and effective, and the decision should be made depending on patients and doctors’ preferences.1 The aim of the study was to compare patients with persistent AF in whom rhythm control strategy is chosen to those with rate control, in terms of the choice of anticoagulation therapy.

Materials and Methods

1.

Knecht S, O\’Neill MD, Verbeet T. Rhythm control versus rate control for atrial fibrillation. N Engl J Med. 2008;359(14):1522.

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ISCP 2017 Best Posters Topic: 3. Heart Failure and Cardiomyopathy

A Transcriptional Co-activator, p300 is Involved in the Epigenetic Gene Activation on Hypertrophic Response Gene Promoters in Heart Failure Funamoto Masafumi, 1 Yoichi Sunagawa, 1 Yasufumi Katanasaka, 1 Yusuke Miyazaki, 1 Hiromichi Wada, 2 Koji Hasagawa, 2 Tatsuya Morimoto 1 1. University of Shizuoka - Division of Molecular Medicine, Graduate School of Pharmaceutical Science, 2. National Hospital Organization Kyoto Medical Center - Clinical Research Institute

Keywords: Heart Failure, Histone

Introduction and Objectivesâ&#x20AC;¨ An intrinsic histone acetyltransferase (HAT), p300, is required for acetylation and the transcriptional activity of GATA4, as well as for pathological left ventricular hypertrophy (LVH) and the development of heart failure (HF) in vivo. Many studies of histone modification have been performed within the flexible tails of these histones, such as on the lysines H3K9 and H3K14. Although most previously studied histone modifications have been carried out within these flexible tails, it has been reported recently that the lysine H3K122 is a novel site of the histone globular domain acetylated by p300, and that its acetylation activates gene transcriptions by destabilizing histone-DNA binding and increasing the accessibility of transactional factors to DNA. However, little is known about the extent to which histone modifications directly affect LVH and HF. We hypothesized that p300 induces epigenetic changes through the acetylation of both the globular domain and the tail domain of histone during the LVH and HF.

Materials and Methodsâ&#x20AC;¨ First, to investigate whether the acetylation of H3K122 in the globular domain and H3K9 and H3K14 in the tail domain increased in cardiomyocyte hypertrophy, western blotting and chromatinimmunoprecipitation (ChIP) assays were performed using neonatal rat cultured cardiomyocytes with phenylephrine (PE). Second, neonatal rat cultured cardiomyocytes were treated by using siRNA of p300 or curcumin, a p300-specific HAT inhibitor. Third, to investigate the role of p300 HAT activity in histone acetylation in vivo, we utilized mice overexpressing p300 in the heart, which induces LVH.

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Finally, to investigate whether these acetylation changes occurred during the development of LVH and HF, an in vivo ChIP assay was performed using the hypertensive heart disease model of Dahl saltsensitive rats.

Results Western blotting indicated that treatment with PE increased the acetylation of H3K122, H3K9, and H3K14 in cardiomyocyte hypertrophy.

The ChIP assay demonstrated that PE increased the recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters containing the GATA element. Time course analyses of the acetylated levels by western blotting indicated that acetylated H3K9 increased after PE stimulation but acetylated H3K122 increased slowly after PE stimulation compare with acetylated H3K9. These acetylations were significantly inhibited by both p300 knockdown using siRNA and treatment with curcumin. Conversely, in vivo ChIP assays in mice overexpressing p300 indicated that p300 overexpression increased the recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters containing the GATA element. Next, in the hypertensive heart disease model of Dahl salt-sensitive rats, in vivo ChIP assays revealed that acetylation of H3K9 was increased around the ANF and BNP promoters containing the GATA element at the LVH stage, but that of H3K122 was increased at the HF stage.

Conclusions These results indicate that the acetylation of H3K122 in the globular domain of histones by p300 is a key event of the transition from LVH to HF. n

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ISCP 2017 Best Posters Topic: 5. Secondary Prevention of Cardiovascular Disease.

Analysis of Factors Associated with Smoking Relapse Sayaka Shimada, Maki Komiyama, Hiromichi Wada, Hajime Yamakage, Akira Shimatsu, Yuko Takahashi, Koji Hasegawa Clinical Research Institute - National Hospital Organization Kyoto Medical Center

Keywords: smoking cessation BMI HbA1c

Introduction and Objectives

Results

It is reported that 3 months of professional smoking cessation treatment achieves an initial smoking cessation rate of 80Â %. However, a 1 year cessation rate decreases to approximately 50Â %. The most common causes of relapse are weight gain, stress, and nicotine withdrawal symptoms. Relapse prevention is important in smoking cessation treatment. The aim of the present study was to investigate the differences between those who continued smoking cessation (group A) and those who resumed (group B) at 1 year after smoking cessation.

There were no significant differences in nicotine dependence, daily cigarette consumption, age, body mass index (BMI) and metabolic parameters between group A (N = 135) and group B (N = 8) before smoking cessation and at 3 months after smoking cessation. However, regarding the changes in values before and after 3 months smoking cessation, the degree of change in HbA1c was significantly larger (p = 0.009) and that in BMI tended to be larger (p = 0.083) in group A than in group B.

Materials and Methods We evaluated 143 outpatients who had continued smoking cessation for 3 months and revisit our outpatient clinic at 1 year after smoking cessation. We measured various parameters before smoking cessation, and at 3 months and 1 year after smoking cessation.

1.

Conclusions The increase in BMI and HbA1c after 3 months smoking cessation was larger in those who successfully maintained abstinence at 1 year after smoking cessation. Therefore, focusing on continuation of smoking cessation instead of worrying weight gain may lead to better outcomes in relapse prevention in the early period after quitting smoking. The small sample size is a limitation of this study, thus further studies are required. n

Central Social Insurance Medical Council.

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Interventions | Arrhythmias | Imaging

QT Prolongation and Malignant Arrhythmia: How Serious a Problem?

Christos-Konstantinos Antoniou, 1 Polychronis Dilaveris, 1 Panagiota Manolakou, 2 Spyridon Galanakos, 1 Nikolaos Magkas, 1 Konstantinos Gatzoulis, 1 and Dimitrios Tousoulis 1 1. First University Department of Cardiology, Hippokration Hospital, Athens, Greece; 2. First Department of Cardiology, Korgialenion–Benakion/Hellenic Red Cross Hospital, Athens, Greece

Abstract QT prolongation constitutes one of the most frequently encountered electrical disorders of the myocardium. This is due not only to the presence of several associated congenital syndrome but also, and mainly, due to the QT-prolonging effects of several acquired conditions, such as ischaemia and heart failure, as well as multiple medications from widely different categories. Propensity of repolarization disturbances to arrhythmia appears to be inherent in the function of and electrophysiology of the myocardium. In the present review the issue of QT prolongation will be addressed in terms of pathophysiology, arrhythmogenesis, treatment and risk stratification approaches.

Although already discussed in literature, it is hoped that the mechanistic approach of the present review will assist in improved understanding of the underlying changes in electrophysiology, as well as the rationale for current diagnostic and therapeutic approaches.

Keywords QT prolongation, action potential duration, restitution curve, long QT syndromes, sudden cardiac death Disclosure: The authors have no conflicts of interest to declare.

Received: 24 August 2017 Accepted: 16 October 2017 Citation: European Cardiology Review 2017;12(2):112–20. DOI: 10.15420/ecr.2017:16:1 Correspondence: Polychronis Dilaveris, First University Department of Cardiology, Hippokration Hospital, 22, Miltiadou street, 15561, Athens, Greece. E: hrodil1@yahoo.com

Ventricular repolarization, as opposed to depolarization, is not a triggered phenomenon following an orderly sequence, hence the dissimilarity between their inscribed electrocardiographic waves; rather, ventricular myocytes repolarize at a time and rate determined by their intrinsic electrophysiological properties (relative concentration of ion channel types and isoforms), as well as by the preceding electrical and mechanical events that affect the former. Given that different segments and layers of the myocardium have divergent baseline properties and consequently respond differently to stimuli, it is not surprising that several arrhythmic disorders of the myocardium, both congenital and acquired, are related to derangements in precisely this repolarization process.

More specifically, disorders may involve abnormal initial repolarization rate (phase 1 of the action potential – Brugada syndrome) or abnormally shortened/prolonged late repolarization (phase 3 – short and long QT syndromes, respectively). In the following short review, focused on QT prolongation, it will be attempted to summarise the underlying (patho)physiology of this entity and the extent to which it constitutes a problem with regard to both prevention and management of malignant, potentially lethal arrhythmic events in various substrates.

(Patho)Physiology of QT Prolongation and Related Arrhythmias The surface ECG represents a time and space integral to the individual cells’ action potentials, with the ‘time’ parameter also incorporating the delay in activation between myocardial areas, as opposed to solely the time course of the phenomenon in each cell. Thus, the QRS complex reflects the summed depolarization (phase 0), the ST segment the transient current equilibrium leading to a brief electrical quiescence (phase 2) and the T wave the summed repolarization (phase 3) of the

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action potential (Figure 1). The TQ interval corresponds to phase 4 of the action potential.

The QT interval is a more or less easily identifiable segment in the ECG and thought to visualise the full cycle of ventricular depolarization and repolarization. It follows that even changes in the velocity of depolarization propagation (i.e. bundle/fascicle block) are prone to cause increases in the overall QT interval, not only by delaying cycle initiation for certain areas but also through a direct effect on ion movement (by affecting stretch-activated channels).

The normal sequence of repolarization1,2 begins at the epicardial layer, moving (not propagating, except for the small contribution of gap junctions) towards the endocardium, based on the intrinsic action potential duration (APD) of the respective cells.3 However, a defined population of cells, mainly located in the intermediate layers of myocardium (M cells), but also found in islets nearer the epi- and endocardium,4,5 exhibits a more protracted action potential because of their unique ion channel properties, as explained later on. Thus, they form a layer, or area, more susceptible to causing unidirectional block (larger possibility for an extrasystole to fall into the absolute refractory period), all the more so if baseline APD prolongation exists.

They may also potentially affect APD of neighbouring endo/epicardial cells though gap junction coupling.4 Of crucial importance, APD in these cells is more susceptible to changes leading to its prolongation as compared to cells in the other myocardial layers.4 Regarding the ionic substrate, the plateau of action potential (phase 2) is due to antagonism between positive inward and outward (Figure 2) currents. More specifically, those generated by the sustained opening of long (L)-type calcium channels (then triggering sarcoplasmic reticulum

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QT Prolongation and Arrhythmias calcium release through ryanodine-sensitive calcium channels leading to excitation – contraction coupling), as well as a late sodium current (through the Nav1.5 channel also responsible for phase 0) on one hand and potassium currents on the other. The latter can be categorised as rapid ( IK r ) and slow ( IK s ) delayed currents, mediated by the HERG (new nomenclature Kv11.1) and KCNQ1 (new nomenclature Kv7.1) channels, respectively.2 M cells mainly depend on IK r and not on IK s and therein lies their propensity for pronounced APD prolongation when conditions favour it, especially in cases where depolarizing currents (INa, ICa – late sodium current has also been found inherently more potent in these cells, thus constituting a second mechanism accounting for the more prolonged baseline APD)6,7 increase.2 Crucially, IK s inhibition per se does not lead to significantly larger effects on M cells.8 Thus, although prolonging the QT interval, it does not cause increased dispersion of repolarization in the absence of increased adrenergic stimulation.

Indeed, when adrenergic stimulation is combined with Kv7.1 mutations there is a blunted response and consequently disproportionately long QT for the given heart rate.9 The term ‘delayed’ refers to their timing in comparison to the transient outwards potassium currents ( Ito1 and Ito2 ) that are active during phase 1 (initial repolarization) of the action potential. Given that the latter are of interest in the pathophysiology of Brugada, rather than long QT, syndrome, we will not further discuss them.

Repolarization (phase 3 of the action potential) occurs as the result of a net outward-directed positive current, i.e. net loss of positive ions. Eventually, the continued inactivation of sodium channels at high positive intracellular voltages and activation of potassium ones leads to a decrease in membrane voltage and movement towards the Nernst potential for K+ (given that permeability is at this phase practically

Figure 1: Correlation Between Ventricular Cellular Action Potential and Surface ECG

PHASE 2

PHASE 3

B

PHASE 0

The duration of repolarization is substantially affected by the preceding diastolic interval (DI), as already mentioned, exhibiting restitution properties.10 Their interdependence can be visualised by the APD = f(DI) curve (restitution curve). This curve, according to most, but not all,11 authors has a rather simple, reverse exponential, and thus monotonic, form:12 b

APD = a +

1+ e

−( DI − c ) d

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PHASE 4 QRS

P

T

ST Normal Long QT Adapted from Dilaveris, 20055

Figure 2: Outward (Repolarizing) Potassium Currents Throughout the Cardiac Cycle

limited to that ion alone). Inward rectifier ( IK ir ) current through Kir voltage- and ligand-gated channels stabilises membrane potential (phase 4). Finally, cellular interdependence by means of connexin presence (allowing for current flow, and thus voltage equalisation – functional syncytium) and stretch-activated channels (nonspecific cationic channels leading to inward depolarizing currents) may lead to action potential changes secondary to extrinsic events.

1 2

0 mV–

Voltage Time

3

0 4

lK1

Repolarizing

Prolongation of the action potential can be appreciated in all cases where an increase in an inward positive or a decrease in an outward positive current occur. These are either the result of genetic mutations (gain/loss of function, abnormal intracellular trafficking), or the effects of acquired conditions. Tables 1 and 2 present the congenital genetic syndromes and acquired clinical conditions associated with QT prolongation, along with remarks concerning their underlying mechanisms. As evident from them, in addition to the well-established three major congenital long QT syndromes, there is a host of other ion currents and channels/transporters (such as adenosine triphosphategated K+ channels and Na+/Ca2+ antiporter) that become relevant in APD and QT prolongation in different nosological entities.

D

lto, 1 lto, 2 lKr lKs

Adapted from Koeppen and Stanton, 2010104

The significance of studying its properties13 lies in the fact that extrasystoles occurring early (i.e. with a short DI) lead to self-promoting instability regarding both APD and DI of subsequent cycles, eventually reaching a DI falling within the absolute refractory period, and thus causing conduction block. This can either initiate re-entry, should the refractory tissue be excited later on by the stimulus following a different pathway, or lead to degeneration of existing ventricular tachycardia into VF if it occurs along the tail of the spiral wave emanating from the central rotor. In terms of the restitution curve this translates into occurring at the steeper initial part of the curve, where the gradient

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Interventions | Arrhythmias | Imaging Table 1: Genetic Causes of QT Prolongation and Associated Syndromes Syndrome Gene/Protein

Function/Comments

LQTS1

KCNQ1/Kv7.1 (alpha* subunit of IKs channel) Reduced repolarization potential causes QT prolongation. T waves are broad and start close to QRS end ( IKr still functional).8 Mainly associated with arrhythmias during prolonged sympathetic activation.

Frequency 30–35 % of LQTS, penetrance 62 %

LQTS2

KCNH2/Kv11.1 (alpha subunit of IKr channel) Similar to LQTS1; however, T wave is farther off the QRS complex (only the slow rectifying current is active) and usually biphid.8 Associated with arrhythmias following abrupt stimuli. Frequency 25–30 %, penetrance 75 %

LQTS3

SCN5A/Nav1.5 (alpha subunit of sodium channels) Gain of function mutations lead to APD. Associated with arrhythmias during bradycardia. A long ST interval (long plateau of action potential) along with a delayed, mostly normal, yet peaked, T wave (potassium currents normal) appreciated.8 Frequency 5–10 % and penetrance 90 %

Patients with type 3 long QT syndrome tend to experience fewer, albeit more serious, arrhythmic events. This could be explained by the sensitivity of M cells to sodium currents during repolarization leading to pronounced prolongation of APD. Thus, it is more likely that upon return, the re-entrant wave will encounter refractory tissue, and thus stop propagating. However, if it does propagate, the steeper APD restitution curve18,77,78 – as noted its initial part mainly depends on sodium currents11 – renders wave break more probable, and thus favours degeneration into fibrillation.

Given that the following syndromes are each estimated to occur in <1 % of congenital LQTS cases, a 25–40 % of these syndromes remains without established molecular cause LQTS4

ANKB/Ankyrin beta Ankyrin mediates the attachment of integral membrane proteins (including channels) to the spectrin-actin based membrane cytoskeleton.79 Mutations increases calcium (and sodium) currents (affects sodium/calcium exchanger and the sodium/potassium pump

LQTS5

KCNE1/minK (beta – regulatory – subunit of IKs)

A variation essentially of LQTS1

When LQTS1 and LQTS5 are associated with deafness (inner ear hair cells’ action potential is, unusually, mediated by potassium influx), they constitute the Jervell and Lange-Nielsen syndromes, their more severe (in terms of prognosis) counterparts. Their mode of inheritance is autosomal recessive (since it requires either homozygosity for the mutation or compound heterozygosity), as opposed to autosomal dominant of all the other mentioned LQTS (collectively termed Romano– Ward syndrome) LQTS6

KCNE2/MiRP1 (beta – regulatory – subunit of IKr )

LQTS7

KCNJ2/Kir2.1 (alpha subunit of inward rectifier Known as Andersen–Tawil syndrome, it is characterised by the triad of hypokalaemic potassium ion channel) periodic paralysis, potentially fatal cardiac ventricular ectopy and characteristic physical features (clinodactyly, micrognathia, low-set ears). Mutations either disrupt protein function, its trafficking to cell membrane or its association with phosphatidylinositol 4,5-bisphosphate (the channel is both voltage- and ligandgated), thus prolonging the terminal phase of repolarization

LQTS8

CACNA1/Cav1.2 (alpha subunit of the long-type Timothy syndrome.80 In addition to arrhythmias (gain of function), there is also calcium channels) immunological deficiency and cognitive disorders, such as autism. Highly malignant, associated with early occurrence of arrhythmias47

A variation essentially of LQTS1

Both LQTS7 and LQTS8 syndrome-associated genes have also been found inversely (in terms of function) mutated in Brugada syndrome forms.81 LQTS9

CAV3/Caveolin 3 Caveolins are scaffolding proteins for membrane invaginations (caveolae) involved in endocytosis and assembly of membrane proteins in specific membrane areas.82– 84 Mutations lead to altered Nav1.5 function (increase), and thus a variant of the LQTS3

LQTS10

SCN4B/(beta subunit of sodium channels)

LQTS11

AKAP9/A-kinase anchor protein 9 This protein binds to the regulatory subunit of protein kinase A, involved itself in adrenergic receptor signal transduction. A direct interaction with Kv7.1 (LQTS1) has also been described85

LQTS12

SNTA1/Alpha-1-syntrophin Cytoskeletal protein found at the inner surface of muscle fibres. Has been shown to interact and affect Nav1.586 (thus a variant of both LQTS3 and LQTS4)

Increased inwards sodium current, another variant of LQTS3

Various other mutations leading to LQTS >12 have been reported. Several genes implicated in congenital long QT syndrome exhibit incomplete penetrance, and thus may both mask the syndrome and lead to sudden prolongation and arrhythmic events in the presence of even minor, normally harmless, precipitators.87 Thus, it could be argued that myocardial repolarization is subject to Murphy’s Law, where everything that could go wrong does, at least in different scenarios. *alpha subunits are pore-forming subunits. APD = action potential prolongation; LQTS = congenital long QT syndrome.

of its tangent is >1.10 Prolongation of the action potential, as in long QT syndromes, leads to steepening of the curve, thus increasing its first derivative (i.e. slope), rendering the condition f‘(DI) > 1 valid for a broader area of DIs, and thus increasing the risk of an extrasystole inducing electrical instability. Individuals with known structural heart disease (ischaemic and dilated nonischaemic cardiomyopathy) have been found to exhibit an altered restitution curve, with a wider area where (more pronounced) alternans occurs.14 Restitution function slightly differs in form between isolated cells and tissue samples, given the dampening/dispersing effect of gap junctions on cellular

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membrane voltage. Interestingly, it has been postulated that current methods for plotting the APD restitution curve are inherently flawed inasmuch as the rapid ventricular pacing involved leads to alteration in calcium cycling, in turn distorting measurements (thus the process itself affects the outcome, reminiscent of the Heisenberg principle).15 Given the absence of overall control and the deleterious effects of increased intracellular calcium, there is a tight regulation of repolarization on the cellular level. The cellular mechanisms involved in the restitution properties of the APD are thought to include all

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QT Prolongation and Arrhythmias Table 2. Acquired Long QT Causes Cause Comments Drugs Drugs that prolong the QT interval mainly do so by inhibiting IKr , thus mimicking a long QT syndrome type 2 phenotype.33,88,89 This is attributable to the structure of this ionic channel, inasmuch as its wider pore allows for easier access of drug molecules to that critical part, and its content in aromatic amino acids favours interactions with aromatic moieties in exogenous molecules.2 Although a host of medications may lead to QT prolongation,90 and QT prolongation induction is the first cause of drug withdrawal by the Federal Drug Administration,91 their actual torsadogenic potential differs widely inasmuch as: not all increase dispersion of repolarization, and several also inhibit ionic channels responsible for afterdepolarizations, thus preventing the triggering stimulus of the arrhythmia (amiodarone and ranolazine being prime examples of this). Thiopental prolongs QT, yet does so while reducing dispersion of repolarization via more pronounced effects on endo/epicardial cells (normally having shorter APD than M cells).92 Several targeted anticancer drugs do prolong the QT interval93 (histone deacetylase inhibitors, tyrosine kinase inhibitors, antiangiogenic factors, farnesylation inhibitors), again through effects on the Kv11.1 channel (but not related to direct pore blockade).

Event risk is highest during the first days of initiation of the QT prolonging agent (cohort effect? myocardial adaptation?)94 Inflammatory conditions

Thought to exert a negative effect on repolarization dispersion, mainly through production of radical oxygen species and activation of the sphingosine-1 pathway that downregulates Kv11.1, thus similar to drug effects (drugs may also act through the sphingosine pathway)95

Obesity Obesity is linked to QT prolongation,96 possibly through the effects of hyperinsulinemia either direct97 or mediated by hypokalaemia.98 Clinical significance of this association remains unknown Heart failure Reduced IKr and increased late INa.24 These changes may represent adaptation attempts inasmuch as prolonged APD leads to prolonged increased intracellular calcium concentration, and thus potentiate actin-myosin interaction. Late sodium current may itself be a result of increased intracellular calcium given that it will cause the Na+/Ca2+ to operate in reverse, excreting 1 calcium ion for every three sodium ones entering the cell Female sex

Effects of estradiol on potassium currents.18 See female sex related paragraph in pathophysiology section

Hypokalaemia

Mimics effects of potassium channel mutations

Hypocalcaemia Reduced negative feedback of intracellular calcium on long-type calcium channels that prolongs their open state. QT morphology will resemble that of LQTS3 Hypomagnesemia Magnesium is also known as ‘nature’s calcium inhibitor’, since release of calcium from the sarcoplasmic reticulum is inhibited by magnesium. Furthermore, it acts as a cofactor of sodium/potassium ATPase and at the same time increases potassium efflux by IK1 channels.25 Moreover, it prevents potassium loss in nephrons, ameliorating hypokalaemia. These actions justify its use in the emergency treatment of LQTS, with the obvious exception of hypocalcaemia being the underlying cause Bradycardia Based on the normal APD restitution curve. Relevant especially if concomitant use of torsadogenic medication or congenital bradycardiaassociated LQTS (such as LQTS3) Ischaemia Relative ischaemia (borders of scar) induces QT prolongation by activating sodium/hydrogen exchangers (to prevent intracellular acidosis.

Moreover, it may induce increased dispersion of repolarization inasmuch as other mechanisms (opening of ATP-gated potassium channels) may induce shortening of APD.99 On the contrary, complete ischaemia induces shortening of action potential until its eventual abolition.

Thus acute/relative, but not chronic/complete, ischaemia has a high torsadogenic potential, a feature well-known in clinical cardiology practice Hypothermia

Calcium ion channel aberrations

Hypothyroidism Thyroid hormone positively controls the expression of calcium ATPase and phospholamban.100,101 These proteins are involved in intracellular calcium level homeostasis by regulating its sequestration into the sarcoplasmic reticulum. Hypothyroidism leads, thus to decreased activity of these proteins, increasing calcium concentration during the repolarization phase of the cardiac cycle A recent meta-analysis including almost 90,000 patients102 found that hypokalaemia, use of diuretics, antiarrhythmic medications and QT prolonging medications of list 1 by CredibleMeds90 were the factors most strongly associated with QT prolongation. On the contrary, weak evidence was found for history of a prolonged QT interval of even torsades, point either to the extrinsic, and thus modifiable, factors associated with QT prolongation or to the significant variability of the QT interval in the same individual APD = action potential prolongation; ATP = antitachycardia pacing; LQTS = congenital long QT syndrome.

three main ions:11 sodium for very short preceding DIs (the cycle in question will alter and be affected by Na+ kinetics since it will occur before complete inactivation of relevant channels – moreover it will decrease conduction velocity, further promoting potential for re-entry),10,16 calcium for the intermediate part of the curve (with an effect depending on the onset timing of negative feedback mechanism linking intracellular calcium and calcium channel permeability) and potassium for longer DIs of the extrasystole. Thus, a simplified threecurrent model for the restitution curve as a function of the preceding DI can be constructed. (See figure 9 in Franz.11 Note that curves do not represent temporally successive currents, rather they present the extent of each ion’s contribution to the alteration of the action potential form with regard to the prematurity of the extrasystole.)

Female sex appears to be associated with prolonged baseline QT interval17 as well as increased risk for further QT prolongation and subsequent arrhythmogenesis, especially after adolescence.18 Indeed, in a population with congenital QT prolongation (long QT syndromes

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1–3) event rates were equal among sexes in the early and later years with a female predilection in the 20–50 age range.19 This has been attributed to the effects of estradiol and testosterone on ionic currents given that the former inhibited all potassium currents while the latter enhanced IK s and inhibited ICaL .20,21 However, androgen effects appear to be more significant inasmuch as virilised women and castrated men that regressed (regarding repolarization) to the phenotype of their reassigned gonadal sex.22 To complicate matters, aromatase (converting testosterone to estradiol) is expressed in human ventricular myocytes, thus it is potentially the balance between sex hormones, rather than their separate effects that ultimately determine APD behaviour.23 What is the mechanistic sequence of events leading from QT prolongation to (polymorphic) ventricular tachycardia (‘torsade des pointes’) and potentially to degeneration into lethal fibrillation? Prolongation of APD leads to increased probability of L-type calcium channels reopening (as opposed to Nav1.5 these channels do not assume an inactive configuration, and thus may reopen if transmembrane voltage is still

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Interventions | Arrhythmias | Imaging Figure 3: Relationship Between QT Prolongation and Polymorphic Ventricular Tachycardia

Manifest QT prolongation

Concealed QT prolongation, either discoverable through prolonged monitoring or expressed under favourable conditions*

Polymorphic VT occurrence

*refers to concomitant presence of a second QT prolongator. VT = ventricular tachycardia

favourable). This could lead to an early afterdepolarization, either by itself or by the added contribution of the electrogenic sodium/calcium exchanger. This is facilitated by the triangulation of the action potential curve (increased duration of repolarization from between 30 % and 90 % of total process) observed during its prolongation, allowing for the relative refractory period to commence.24 If timing is suitable, locating it to the steeper portion of the restitution curve, conduction block may occur, especially in the more affected M cells in either the initial or in subsequent cycles.16 This is facilitated if the preceding action potential (n-1 where n is the action potential inducing the tachycardia) has been already prolonged following a previous (n-2) extrasystole (short-long-short phenomenon).25 This block, in conjunction with the reduced conduction velocity though the tissue (due to less steep phase 0 upstroke since not all Nav1.5 channels have recovered) favours re-entry. Of note, it is APD dispersion, not prolongation per se, that renders the tissue prone to sustaining re-entry. (If the extend of APD prolongation was similar in the endo/epicardial layers, the re-entry circuit would likely be interrupted upon reaching them, arriving during refractoriness.)8,24 Moreover, the short wavelength at the rotor leading edge, combined with the more prolonged APD of the M cells (area of unidirectional block) leads to rotor instability (local restitution curve derivative >1) and thus meandering and changes in its spatial orientation, yielding the well-described ECG feature of polymorphic tachycardia. 10 Should the curve shift to unstable areas in the arms of the rotor, this will lead to wave break, potential secondary rotor formation and, eventually, VF. Interestingly, abolishing both calcium and sodium mechanisms of restitution (but keeping conduction velocity stable) theoretically may prevent degeneration into VF (achievable with concomitant use of class IV and III antiarrhythmics – pharmacological defibrillation).10 Alternatively, a triggered activity-related mechanism for polymorphic ventricular tachycardia (VT) has been postulated (i.e. afterdepolarization in one area triggering afterdepolarization in a different myocardial segment, accounting for the ever-changing QRS morphology and reminiscent of bidirectional VT substrate), although substantial controversy exists regarding its contribution to arrhythmogenesis.26–28

Diagnosis of QT Prolongation and Risk Stratification The estimated prevalence of congenital long QT syndrome is approximately 1 × 10−4 to 2 × 10−4 individuals1,25 with a predilection for Caucasian subjects and reproductive-age females. On the other

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hand, incidence of mutation carriers is approximately 2 × 10−4 to 3.3 × 10−4, supporting the notion of incomplete penetrance.29 The syndrome may be responsible for 3,000–4,000 sudden deaths annually in the US alone.30 One might think that QT prolongation diagnosis would be straightforward; however, neither diagnostic criteria, nor even correct measurement of the QT interval, or alternative indices are generally agreed upon and consistently performed, at least in daily clinical practice.

To begin with, QT interval should be measured in certain leads where it was thought to be most prolonged31 and averaged over several cycles.

These leads generally are DII or V5, and should their tracing be difficult to interpret, leads V3 and V4 can be substituted for them. AF represents an even more ambiguous condition, whereupon the longest and shortest measured QT intervals should be averaged.2 Older approaches stipulated that prominent U waves (thought to represent repolarization of Purkinje fibres or M cells)32 should be included in the measurement only if merging with the final part of the T wave;33 however, newer recommendations define QT as the interval from the earliest onset of QRS complex to the intersect of the tangent to the steepest descending part of T wave and the baseline in DII or V5 leads.34 Despite historical preference of manual QT interval measurement, manufacturers of electrocardiographic equipment have developed powerful automated algorithms, such as the MarquetteTM 12SLTM ECG analytical software (GE Healthcare), partly due to the necessity of cost reduction in studies assessing torsadogenic potential of medications under development, allowing for accurate QT interval assessment (as compared to the gold standard of manual measurement) in the overwhelming majority of cases (divergence in approximately 7 out of 10,000 cases).35 Linear regression of the QT on the RR interval, reminiscent of the APD restitution curve, allowing a more thorough and individualised36 visualisation of ventricular repolarization under differing conditions, has been introduced (although linearity may be an issue).37,38 More specifically, the ‘individualised corrected QT interval’39 is defined as the QT interval corresponding to an RR of 1,000 msec, with the regression line acting as the connecting function. This approach may even allow for identification of long QT syndrome-associated mutation carriers with concealed prolongation. Alternatively, the QT/TQ ratio could be plotted against the RR interval to yield a variation of the ECG restitution curve.40 It assumes values <1 at lower heart rates and >1 at higher rates (despite the adaptation of APD it does not suffice to fully negate the relative QT prolongation). Stress renders the curve both steeper and displaces it to the right, so that there is increased relative QT prolongation at lower rates. Whether this approach could be used to assess long QT patients and estimate their arrhythmogenetic potential remains to be seen.

Measured QT interval should always be corrected (QTc) by the underlying heart rate. The most widely used formulae are that of Bazzet ( QTRR , QT in msec, RR in seconds) and Fridericia ( QTRR , QT in msec, RR in seconds), although several other approaches have been proposed (i.e. Framingham and Hodges).41 Evidently, accuracy of those depends on the degree of approximation of the actual APD = f(DI) function, which explains, for instance, the limitation of Bazzet’s formula to rates in the 60–100 range (where the square root approximates the actual relationship). Normal corrected QT values are depicted in Table 3.

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QT Prolongation and Arrhythmias The 1993 modified Schwarz criteria42 have been used for long QT syndrome diagnosis; however, recently the European Heart Rhythm Association43 included the following as criteria for long QT syndrome diagnosis: a Schwarz score ≥3.5; or presence of unequivocal pathogenic mutation; or Bazzet-corrected QT interval >500 msec or QTc 480–499 with presence of unexplained syncope.

Sugrue et al. attempted to address the issue of diagnosing concealed QT prolongation by pursuing a different approach44 based on alterations of the T wave per se45 (corresponding to phase 3 of ventricular cell action potential) due to pathogenic mutations. They reported that, in a population of 290 patients without manifest prolongation but carrying an established pathogenic mutation (based on long QT syndrome presence in close relatives), certain features of the T wave could correctly classify those without overt prolongation with an accuracy of 83 %. Interestingly, lead V6 appeared to be the most technically amenable to assessment.

These were: reduced upslope of the wave, prolonged peak-to-end time and temporally displaced wave (further apart from peak R).

Provocative manoeuvres, such as transition from supine to erect position, adrenaline infusion and QT measurement during exercise recovery may be used to unmask inappropriate QT interval behaviour (i.e. failure to proportionally shorten),46 and thus ‘conditional’ long QT syndrome in case of diagnostic dilemmas.47 Following a different conceptual framework, vectorcardiography (VCG) may allow for non-invasive assessment of repolarization dispersion.

More specifically, proof of concept studies48 have reported that in healthy individuals VCG indices of repolarization homogeneity, such as normality of T wave loop area and total QRS-T angle are strongly affected by body position and provocative manoeuvres, similar to those used in the unmasking of long QT syndrome.

Finally, a novel approach in congenital long QT syndrome diagnosis and also arrhythmic risk stratification (but theoretically applicable to acquired forms as well) is based on the application of ECG imaging.49 This technique fuses anatomical data from ECG-gated chest CT with a 256-lead surface ECG (whereupon an electrode-loaded chest plate is used) to produce >500 unipolar epicardial ECGs,50 reminiscent of invasive electroanatomical mapping, yet having the added feature of assessing repolarization as well. Consequently, regional differences in recovery time (defined as the time to maximum first temporal derivative of voltage at the ascending part of the T wave) and activation-recovery time (a surrogate for action potential duration)51 can be appreciated. As expected, long QT patients do not exhibit alterations in activation time, yet they do present varying degrees of recovery and activation-recovery time prolongation.50 Given its unipolar nature, each one of these ‘leads’ does assess the behaviour of all regional myocardial wall layers, including M cells. Thus, when abrupt changes are noted in temporal values of adjacent areas in the reconstructed 3D map, it could suggest an increased propensity to arrhythmogenesis (in the form of a figure of 8 re-entry), and indeed exploratory findings appear to support this notion.50

Table 3: Normal QTc Values by Age and Gender (Bazzet formula) QTc value (msec)

1–15 years

Males

Normal

<440

<430 <450

Females

Borderline

441–460

431–450 451–470

Prolonged

>460

>450 >470

QTc = corrected QT. Note absence of gender difference until early adolescence. Bazzet formula adapted from Goldenberg, et al., 2006103

congenital long QT syndrome type 1 and 2, beta-blockers constitute the recommended initial approach to all patients in the absence of contraindications, such as asthma.6,52,53 They have been shown to reduce event rates by as much as 81 % and 59 %, respectively,54 and most of residual events are often due to non-adherence to the regimens.55 Beta-blockers do not themselves shorten the QT interval, rather, they abrogate the prolonging effects of increased heart rate on it. However, they should be judiciously, if not carefully used in type 3 long QT syndrome, given that this form is most often associated with bradycardia-induced arrhythmias.56 On the contrary, INa blockers, such as mexiletine or flecainide, have been shown in experimental models to potently reverse QT interval prolongation in type 3 long QT syndrome, consistent with their more pronounced effects on the electrophysiological properties of M cells.6 Care should be taken so as not to overtreat and elicit a Brugada phenotype (Ito currents remain unaffected while sodium current decreases, mimicking the SCN5A loss of function mutation).57 Moreover, they have also been found effective in types 1 and 2 of the syndrome (reducing depolarizing currents, thus restoring equilibrium with the affected potassium ones). Finally, the most potent late INa inhibitor, ranolazine, is thought to be of value in all long QT syndrome forms.6 Evidence regarding potassium current enhancers, such as nicorandil is at present based only on experimental data, and thus these drugs do not constitute an established choice in clinical practice.5 On the contrary, and given the role of calcium not only in shaping the action potential but also in determining the form of the restitution curve for a given DI,10,15 it is not surprising that verapamil has been found beneficial in all three major forms of congenital long QT syndrome, as well as in type 8 of the syndrome (etiological therapy since it is caused by increased L-type calcium channel activation) both at the bench- and bedside.58,59 Ryanodine receptor inhibitors may prevent calcium-induced calcium release from the sarcoplasmic reticulum, and thus abrogate afterdepolarizations, removing the triggering stimulus for potential re-entry initiation.16 More advanced pharmacological therapies involve restoration of protein localisation to the cellular membrane, especially useful in the case of (intracellular) trafficking affecting mutations,6,16 and both up- and downregulation of gap junction opening, aiming to increase conduction velocity and reduce the transmural gradient of repolarization (the former) and increase refractoriness (the latter). Ultimately, these changes will increase the functional wavelength of the tachycardia, potentially ‘short-circuiting’ the re-entry by creating a discordance between it and the actual anatomical pathway available.

Treatment of Long QT Syndrome The uncovering of molecular mechanisms responsible for QT prolongation (Tables 1 and 2) has led to a more rationalised approach to its treatment, i.e. pharmacological, device-based and interventional.

Recently, consensus has been reached regarding management of congenital long QT syndrome.47 More specifically, in the case of

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Device therapy in long QT syndrome includes both pacemakers and ICDs. A pacemaker may be used in those with acquired, pause-dependent forms of the syndrome, or in those with type 3 congenital long QT that exhibit similar susceptibility to arrhythmia during bradycardia.52 Obviously, both pacemakers and isoproterenol infusion

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Interventions | Arrhythmias | Imaging (in cases of acute management) are contraindicated in syndromes with tachycardia-induced polymorphic ventricular tachycardia, such as types 1 and 2 of congenital long QT. Defibrillators on the other hand, are clearly indicated in those long QT patients that have survived a cardiac arrest (class I) and should be considered for those remaining symptomatic while on optimal pharmacotherapy (IIa).43 Factors generally associated with increased arrhythmogenic potential in long QT syndromes include:60 presence of deafness (homozygosity/ double heterozygosity [see Table 1 for Jervell and Lange-Nielsen syndrome]), recurrent syncope/family history of sudden death, conduction disturbances, QTc >500 msec and T wave alternans (i.e. repolarization is unstable enough to differ on a beat-by-beat basis). Indeed,53 presence of either QTc >500 msec or prior syncope is associated with a cumulative 5-year rate of aborted or suffered sudden cardiac death of 3 % (thus rendering them appropriate candidates for primary prevention), while in their absence the risk falls down to 0.5 %. According to a 2012 study61 of 233 long QT patients, defibrillator appropriate therapy may be predicted by age at presentation <20 years, QTc >500 msec, prior cardiac arrest and symptoms while on medications. Although no events occurred in those without any of these factors, 70 % of those with at least one of them experienced an appropriate shocks during a 7-year follow up.61 Despite any potential future advances in stratification (e.g. though use of ECG imaging as described earlier), currently the decision to implant a device should reasonably lead to defibrillator implantation given its built-in pacing capability.

Cardiac sympathetic denervation is generally reserved for those remaining symptomatic despite use of all indicated, as per syndrome category, therapies,6 including syncope or multiple appropriate therapies by an implantable defibrillator. It has been shown62 to be very efficacious (event reduction ~91 %) especially in type 1 and, unexpectedly, type 3 congenital long QT syndrome.

Arrhythmogenic Potential of QT Prolongation QT prolongation, an umbrella term for both congenital and acquired forms of the syndrome, constitutes the most well-known form of repolarization-related arrhythmogenic disorders. It forms one of the syndromes accounting for the majority of sudden deaths amongst those without structural heart disease (10–20 % of sudden deaths).63 Although its course used to be thought of as relatively benign, with a 30-year event rate of 4 %,64 several subpopulations exist with significantly higher risk for arrhythmic events and a consistent correlation exists between QT duration and mortality (hazard ratio 1.35 for total mortality, 1.51 for cardiovascular mortality and 1.44 for sudden cardiac death, with every 50 msec increment conferring a 20 % additional risk for total mortality and a 24 % additional risk for sudden death).65 A mathematical formula correlating risk of torsade QTc – 300 with QT duration has been proposed:66 Risk = 1.052x, where X X== 10 , QTc being the corrected QT duration in msec. Moreover, in 30–40 % of patients the first manifestation of the syndrome is sudden cardiac death, while morality rates of untreated patients are as high as 50 % at the first decade.67 However, QT prolongation is not always evident on the ECG, it may vary in a diurnal fashion (90 ± 20 msec),68 a large overlap is noted between healthy outliers and the three major congenital QT prolongation syndromes60 and, ultimately, neither is it necessary nor sufficient for the occurrence of arrhythmia (i.e. events may occur if dispersion is

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sufficient [≈12 msec/mm in canine heart tissue4] regardless of QT duration, 5 % of long QT patients had suffered cardiac arrest with an interval <440 msec69). Indeed, there is no identifiable QT prolongation value cutoff70 associated with polymorphic VT occurrence. Furthermore, the congenital long QT syndromes may be characterised by ‘formes frustes’ (generally when mutations are not in the pore-forming region or involve intracellular trafficking rather than functional defects and lead to a <50 % reduction in function1) requiring a second precipitator to manifest the phenotype. This could account for the finding that the dose of a precipitating medication has not been found to correlate with torsade risk.71 Approach considerations are even more complicated in the case of young athletes; however, newer US guidelines72 are considerably more liberal, allowing phenotype-negative individuals to partake in competitive sports provided all secondary QT prolongating factors are meticulously addressed and an external defibrillator is available.47 Obviously, this excludes activities that are directly associated with arrhythmogenesis, such as swimming in diagnosed type 1 long QT syndrome.

Evidently this raises the issue of whether QT prolongation should be a valid definite diagnosis, especially in conditions without established arrhythmia propensity, or further assays (and which ones) assessing the underlying electrophysiological implications of each condition should be pursued. This stems from the relationship between QT prolongation and torsadogenic potential exposed earlier and illustrated by the Venn diagrams in Figure 1. However, techniques combining imaging and function have started to yield interesting results.73 More specifically, strain echocardiography has revealed that type 1 and 2 congenital long QT syndrome patients exhibit reduced global longitudinal strain, as well as increased mechanical dispersion.74 Furthermore, there is increased temporal discrepancy between the duration of mechanical diastole and that of electrical recovery, as evidenced by increased electromechanical time (delta t between Q-Aortic valve closure and QT duration). Increased mechanical dispersion has previously been correlated with increased arrhythmogenicity in the long QT,75,76 potentially though its link with APD dispersion, inasmuch as prolonged depolarization will delay relaxation (maintaining high intracellular calcium concentrations) of those cells most affected by the disorder.

Other techniques, such as MRI tagging, potentially the gold standard in 3D strain assessment may, in this conceptual framework, also prove invaluable in arrhythmic risk stratification of long QT patients.

Conclusion It appears that repolarization propensity to instability, and thus arrhythmogenesis, sometimes evidenced by prolongation of the QT interval on surface ECG, stems from its inherent non-coordinated and active nature (as opposed to the triggered, coordinated and passive [i.e. depending on electrochemical gradients established during repolarization – nature of depolarization]). The reason behind this apparent design flaw may be explainable by the following fundamental aspect of cardiovascular physiology: contraction is coupled with depolarization, thus coordination, speed and effectiveness of the former is entirely dependent on coordination, speed and effectiveness of the latter, achievable through its triggered and passive nature (ion channels are orders of magnitude faster ion transporters than pumps that, on the other hand can actively modify ionic concentrations). To achieve this, repolarization has to restore electrochemical gradients via active, energy-consuming ion

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QT Prolongation and Arrhythmias movement and cannot itself be effectively coordinated, inasmuch as there are no gradients that can be harvested for a trigger to activate.

Thus, in clinical practice, when evaluating long QT patients, every

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Interventions | Arrhythmias | Imaging

Viewpoint: Recent Advances in Intracoronary Imaging for Vasa Vasorum Visualisation Kensuke Nishimiya, Yasuharu Matsumoto and Hiroaki Shimokawa Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

Abstract The coronary adventitia harbours the vasa vasorum (VV), which has a diameter of 50–300 µm and plays an important role as a network of nutrient blood vessels to the arterial wall. The VV is thought to be involved in the development of coronary atherosclerosis. Recent advances in the field of intracoronary imaging, including optical coherence tomography, have enabled us to visualise coronary VV in humans in vivo and increased the clinical relevance of the VV in patients with coronary artery disease.

Keywords Vasa vasorum, adventitia, intravascular ultrasound, optical coherence, tomography Disclosure: The authors declare not conflicts of interest.

Submitted: 17 August 2017 Accepted: 20 September 2017 Citation: European Cardiology Review 2017;12(2):121–3. DOI: 10.15420/ecr.2017:13:1 Correspondence: Dr Hiroaki Shimokawa MD, PhD, Professor and Chairman, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba, Sendai, 980-8574, Japan. E: shimo@cardio.med.tohoku.ac.jp

Vasa Vasorum The coronary arterial wall generally consists of the tunica intima, tunica media and tunica adventitia. In particular, the coronary adventitia harbours the vasa vasorum (VV),which has a diameter of 50–300 µm and plays an important role as a network of nutrient blood vessels to the arterial wall (Figure 1).1–3 The VV is enhanced in association with arterial wall thickening when the wall exceeds 29 lamellar units in mammals.4 Intraplaque neovessels arising from adventitial VV leads to intraplaque haemorrhage,5,6 resulting in coronary plaque disruption (Figure 1).7,8 Thus, efforts have been made to identify the coronary VV in experimental animals and humans.9 Indeed, recent advances in the field of intracoronary imaging have enabled us to visualise the coronary VV in humans in vivo, and have shed light on the clinical relevance of the VV in patients with coronary artery disease (CAD).10 In this brief review, we provide an overview of the recent progresses in intracoronary imaging for VV visualisation.

which was obtained using porcine coronary arteries in vivo (Figure 2B).13 The VV area on the IVUS showed a strong correlation with the VV volume measured with micro-computed tomography (MCT) using the same porcine tissue ex vivo.

Clinical Relevance Based on their histological validation study, Kume et al. demonstrated with a commercially-available IVUS that the prevalence of the VV at the proximal and distal reference segments adjacent to culprit lesions was significantly increased in patients with acute coronary syndrome compared with those with stable angina pectoris.12,14 Using commercially-available echogenic microbubbles composed of albumin microspheres filled with octafluoropropane gas, Vavuranakis et al. demonstrated the feasibility of the IVUS contrast-enhancement detection techniques for the VV in both the adventitia and the plaque of human coronary arteries in vivo.15

Limitations of Intravascular Ultrasound Intravascular Ultrasound Intravascular ultrasound (IVUS) has been a most widely-used intracoronary imaging technique that offers a spatial resolution of 100 µm,11 with the potential for VV visualisation and the detection of volume of blood flow in the VV. On cross-sectional IVUS imaging, the VV can be seen as a small, tubular, low-echoic structure (Figure 2A).12

A fundamental limitation of IVUS is that it does not possess sufficient resolution for visualising the VV <100 µm, while the penetration depth of 8–10 mm seems to be sufficient for reaching the adventitia. A highdefinition, 60-MHz IVUS with superior spatial resolution <100 µm might have the potential to resolve this.16 Another limitation of IVUS is that serial studies are needed to verify the accuracy of VV visualisation and measurements unequivocally.

Validation Studies In a human autopsy study by Kume et al., a 40-MHz IVUS (Boston Scientific) was used to detect adventitial VV, which was validated with histology.12 For the measurement of VV distribution, Moritz et al. developed the special IVUS system (ChromaFlo®, Volcano Corporation), which was used for blood flow detection within the arterial wall.13 In the Moritz et al. study, blood flow in the VV was colourised within the encompassed arterial wall on the IVUS image,

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Intravascular Optical Coherence Tomography Optical coherence tomography (OCT) is another commerciallyavailable intracoronary imaging technique that offers a spatial resolution of 10 µm, using backscattering of near-infrared light.11,17 The resolution of 10 µm is high enough for detecting the VV of any size in humans in vivo. On cross-sectional OCT images, the VV can be visualised clearly as signal-voiding tubular or layer structures (Figure 3).

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Interventions | Arrhythmias | Imaging Figure 1: Adventitial Vasa Vasorum Formation in the Human Coronary Artery Vasa vasorum Inflammatory cells/cytokines

Adventitia Adipose tissue Intima, media

Intraplaque neovessel Intraplaque haemorrhage

Necrotic core Endothelium

Lumen

Coronary adventitia harbors the VV, inflammatory cells/cytokines and adipose tissue. The VV plays an important role as a conduit that diffuses inflammatory cells/cytokines derived from adipose tissue in the pathogenesis of coronary artery disease. Intraplaque neovessels arising from adventitial VV can be a trigger of intraplaque haemorrhage in the lesion with a necrotic core, resulting in coronary plaque disruption. VV = vasa vasorum.

Figure 2: Intravascular Ultrasound images of coronary adventitial Vasa Vasorum Formation in Pigs and Humans A

B

Validation Studies In a post-mortem study, Vorpahl et al. first reported the possibility that small black holes on cross-sectional OCT images correspond to intraplaque neovessels arising from the VV in the histology of a patient with ruptured plaque ex vivo.1 We were able to demonstrate for the first time that a second-generation OCT (Terumo) is capable of visualising the adventitial VV in porcine and human coronary arteries ex vivo and in vivo (Figure 3).18,19 We also showed the accuracy of manual measurements for adventitial VV on cross-sectional OCT images.19 In order to develop the measurement method, we defined adventitial area as ‘area outside the external elastic lamina within a distance of the thickness of intima plus media – vessel area’ and adventitial VV area as ‘adventitial VV area / adventitial area’.20,21 Another human autopsy study by Aoki et al. demonstrated the usefulness of 3D volume-rendering OCT reconstructed with the ANALIZE software (Biomedical Imaging Resource) for the volumetric analysis of adventitial VV, which was validated with the number of VV counted on MCT.22 In the Aoki et al. study, adventitial the VV was defined as signal-voiding tubular or layer structures with diameters from 50 to 300 µm, which were consistently noted in at least two consecutive slices and located within 1 mm from the lumen–intima border.22

Clinical Relevance Choi et al. demonstrated that OCT-derived intraplaque neovessels are associated with the early manifestation of coronary atherosclerosis in humans in vivo.23 However, Taruya et al. examined the structural

Small, tubular, low-echoic structures (red arrows) on the IVUS image represent adventitial VV in a patient with acute coronary syndrome (A). Blood flow in the VV is in red within the encompassed arterial wall (yellow concentric circles) on the special IVUS system (ChromaFlo®) and porcine coronary artery in vivo (B). IVUS = intravascular ultrasound; VV = vasa vasorum. Adapted with permission from Kume et al.14 and Moritz et al.13

Figure 3: Optical Coherence Tomography Images of Coronary Adventitial Vaso Vasorum Formation in Pigs and Humans

Porcine coronary artery

A

Ex-vivo OCT

B

Human coronary artery

Histology

C

In-vivo OCT

OCT light core

500 µm

500 µm Factor VIII

200 µm

200 µm

1.0 mm

Signal-voiding structures on the ex-vivo OCT image (A) can accurately detect adventitial VV, which was validated in histology, (B) and in the porcine coronary artery. The in-vivo OCT image shows the signal-voiding tubular or layer structures (red arrows) as adventitial VV in the human coronary artery in vivo (C). OCT = optical coherence tomography. Adapted with permission from Nishimiya et al.18,19

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pattern of the VV on 3D OCT images of human coronary atherosclerotic lesions and demonstrated that there are two different roles of the VV in the pathogenesis of coronary atherosclerosis.24 Adventitial VV was associated with plaque volume, while the increased internal running VV was correlated with plaque vulnerability.24 Tsujita et al. recently reported that intraplaque neovessels can be seen on OCT at the site of a repeatedly-provoked coronary spasm, indicating that such coronary spasms could be a trigger of coronary thrombosis.25 Kitabata et al. demonstrated that patients with intraplaque neovessels on OCT have a greater frequency of plaque rapture compared with those without intraplaque neovessels.26 Uemura et al. examined the morphological features of non-significant stenotic lesions in patients with CAD and demonstrated that complex characteristics of thin-capped fibroatheroma and intraplaque neovessels could be potential predictors of subsequent plaque progression after coronary intervention.27 Similarly, Amano et al. found that intraplaque neovessels are an independent predictor of a slow-flow phenomenon after stent implantation. 28 Allograft vasculopathy after heart transplantation is generally characterised by intimal hyperplasia and diffuse progressive luminal narrowing, where the OCT-derived adventitial VV volume is one of the major determinant factors of intimal plaque progression.29 Coronary vasomotion abnormalities, such as coronary spasm and coronary microvascular disorders (CMD), play key roles in the pathogenesis of CAD. We were able to demonstrate for the first time that the OCT-proven adventitial VV is markedly enhanced along with the spastic coronary segments in patients with vasospastic angina.20,21 In our study, the extent of the VV formation was highly correlated with that of acetylcholine-induced coronary vasoconstricting responses and activity of Rho-kinase, a key molecule of coronary spasm.30 Coronary blood flow assessment combined with OCT observation resulted in adventitial VV density being negatively correlated with endothelium-dependent microvascular function, and positively correlated with endothelium-

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Viewpoint independent microvascular function, suggesting that adventitial VV has relevance to CMD in the early stage of coronary atherosclerosis.31 Notably, we recently demonstrated that coronary segments under a myocardial bridge (MB) lack adventitial VV compared with proximal or distal reference segments.32 Because the VV carries inflammatory cells and cytokines derived from pericoronary adipose tissue (PCAT) to atherosclerotic lesions, this result could explain, at least in part, the fact that coronary segments under an MB have less atherosclerotic lesions. Sudden coronary artery dissection (SCAD) has emerged as a cause of heart attacks among young women, especially during the peripartum period. An OCT study by Kwon et al. found evidence that adventitial VV is augmented at the coronary segment of intramural haematoma in patients with SCAD.33

Limitations of Optical Coherence Tomography First, the penetration depth of OCT light is limited in few millimetres, and is prone to higher absorption in the advanced coronary lesions (e.g. lipid-pooling and necrotic core), which limit the visualisation of adventitial VV behind such lesions. Second, it remains to be elucidated whether or not OCT-derived VV arises from arteries or veins. Third, the current OCT system is not equipped with the facility for blood flow measurements in VV. Interestingly, Cheng et al. reported an intensity kurtosis detection method on OCT that may enable us to examine blood flow dynamics in VV.34

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ATV.0000178991.71605.18; PMID: 16037567 Barger AC, Beeuwkes R 3rd. Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction. Am J Cardiol 1990;66(16):41G–3G. PMID: 2239713 Laine P, Kaartinen M, Penttilä A, et al. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation 1999;99(3):361–9.

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DOI:10.1155/2014/285058. PMID: 24790560 Alfonso F, De la Torre Hernández JM. Vasa vasorum and coronary artery disease progression: optical coherence tomography findings. Eur Heart J Cardiovasc Imaging 2016;17(3):280–2. DOI: 10.1093/ehjci/jev318; PMID: 26764420 Koskinas KC, Ugni GJ, Windecker S, et al. Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment. Eur Heart J 2016;37(6):524–35. DOI: 10.1093/eurheartj/ehv642; PMID: 26655874 Kume T, Okura H, Fukuhara K, et al. Visualization of coronary plaque vasa vasorum by intravascular ultrasound. JACC Cardiovasc Img 2013;6(9):985. DOI: 10.1016/j.jcin.2013.04.021; PMID: 24050867 Moritz R, Eaker DR, Anderson JL, et al. IVUS detection of vasa vasorum blood flow distribution in coronary artery vessel wall. JACC Cardiovasc Img 2012;5(9):935–40. DOI: 10.1016/ j.jcmg.2011.12.027; PMID: 22974807 Kume T, Okura H, Yamada R, et al. In vivo assessment of vasa vasorum neovascularization using intravascular ultrasound: A comparison between acute coronary syndrome and stable angina pectoris. J Cardiol 2017;69(4):601–5. DOI: 10.1016/ j.jjcc.2016.09.013; PMID: 27793409

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Future Perspectives The formation of VV has been suggested to initiate the development of coronary atherosclerosis. 35 We recently demonstrated that 18 F-fluorodeoxyglucose (FDG) PET can accurately detect PCAT inflammation in pigs ex vivo and in vivo.36 Further studies with multimodalities (e.g. OCT combined with FDG PET) are needed to elucidate the causal relationship between adventitial inflammatory changes and the manifestation of coronary atherosclerosis. Moreover, there is a pressing unmet need for direct and/or indirect therapeutic approaches to mitigate adventitial VV angiogenesis. Importantly, we recently demonstrated that after drug-eluting stent implantation in pigs in vivo, adventitial sympathetic nerve fibres (SNF) can be enhanced and associated with adventitial VV growth. Catheter-based renal denervation also significantly upregulates the expression of α2-adrenergic receptor-binding sites in the nucleus tractus solitaries and attenuates adventitial VV enhancement associated with a decrease in SNF.37 Thus, intracoronary imaging could also be useful when testing these novel approaches in practice.

Conclusions Recent advances in intracoronary imaging have begun to uncover the roles of the VV in the pathogenesis of CAD. We consider intracoronary imaging to have important potential in elucidating the pathogenesis of CAD in general and pathophysiological roles of the coronary adventitia in particular. n

15. V avuranakis M, Kakadiaris IA, O’Malley SM, et al. A new method for assessment of plaque vulnerability based on vasa vasorum imaging, by using contrast-enhanced intravascular ultrasound and differential image analysis. Int J Cardiol 2008;130(1):23–9. DOI: 10.1016/j.ijcard.2007.07.170; PMID: 18068834 16. Chin CY, Maehara A, Fall K, et al. Imaging comparisons of coregistered native and stented coronary segments by high-definition 60-MHz intravascular ultrasound and optical coherence tomography. JACC Cardiovasc Interv 2016;9(12):1305– 6. DOI: 10.1016/j.jcin.2016.04.011; PMID: 27262862 17. Tearney GJ, Regar E, Akasaka T, et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies. A report from the international working group for intravascular optical coherence tomography standardization and validation.

J Am Coll Cardiol 2012;59(12):1058–72. DOI: 10.1016/ j.jacc.2011.09.079; PMID: 22421299 18. Nishimiya K, Matsumoto Y, Takahashi J, et al. In vivo visualization of adventitial vasa vasorum of the human coronary artery on optical frequency domain imaging.

Validation study. Circ J 2014;78(10):2516–18. PMID: 24976390 19. Nishimiya K, Matsumoto Y, Uzuka H, et al. Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans. A validation study. Circ J 2015;79(6):1323–31.

DOI: 10.1253/circj.CJ-15-0078; PMID: 25843557 20. Nishimiya K, Matsumoto Y, Uzuka H, et al. Focal vasa vasorum formation in patients with focal coronary vasospasm. An optical frequency domain imaging study. Circ J 2016;80(10): 2252–4. DOI: 10.1253/circj.CJ-16-0580; PMID: 27557851 21. Nishimiya K, Matsumoto Y, Takahashi J, et al. Enhanced adventitial vasa vasorum formation in patients with vasospastic angina. J Am Coll Cardiol 2016;67(5):598–600.

DOI: 10.1016/j.jacc.2015.11.031; PMID: 26846957 22. Aoki T, Rodeuguez-Porcel M, Matsuo Y, et al. Evaluation of coronary adventitial vasa vasorum using 3D optical coherence tomography – Animal and human studies.

Atherosclerosis 2015;67(1):598–600. DOI: 10.1016/ j.atherosclerosis.2015.01.016; PMID: 25618027 23. Choi BJ, Matsuo Y, Aoki T, et al. Coronary endothelial dysfunction is associated with inflammation and vasa vasorum proliferation in patients with early atherosclerosis.

Arterioscler Thromb Vasc Biol 2014;34(11):2473–7. DOI: 10.1161/ ATVBAHA.114.304445; PMID: 25234815 24. Taruya A, Tanaka A, Nishiguchi T, et al. Vasa vasorum restructuring in human atherosclerotic plaque vulnerability. A clinical optical coherence tomography study. J Am Coll Cardiol 2015;65(23):2469–77. DOI: 10.1016/j.jacc.2015.04.020; PMID: 26065984 25. Tsujita K, Kaikita K, Araki S, et al. In vivo optical coherence tomography visualization of intraplaque neovascularization at the site of coronary vasospasm: a case report. BMC Cardiovasc Disord 2016;16(1):235. DOI: 10.1186/s12872-016-0408-y; PMID: 27884129

26. K itabata H, Tanaka A, Kubo T, et al. Relation of microchannel structure identified by optical coherence tomography to plaque vulnerability in patients with coronary artery disease. Am J Cardiol 2010;105(12):1673–8. DOI: 10.1016/ j.amjcard.2010.01.346; PMID: 20538113 27. Uemura S, Ishigami K, Soeda T, et al. Thin-cap fibroatheroma and microchannel findings in optical coherence tomography correlate with subsequent progression of coronary atheromatous plaques. Eur Heart J 2012;33(1):78–85. DOI: 10.1093/eurheartj/ehr284; PMID: 21831910 28. Amano H, Koizumi M, Okubo R, et al. Comparison of coronary intimal plaques by optical coherence tomography in arteries with versus without internal running vasa vasorum. Am J Cardiol 2017;119(10):1512–7. DOI: 10.1016/ j.amjcard.2017.02.025; PMID: 28347486 29. Park KH, Kwon TG, Matsuzawa Y, et al. Association between the vasa vasorum and the atherosclerotic changes in cardiac allograft vasculopathy: volumetric analysis. Eur Heart J 2016; 17(3):272–9. DOI: 10.1093/ehjci/jev285; PMID: 26657475 30. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-kinase in the cardiovascular system. Circ Res 2016;118(2):352-66. DOI: 10.1161/CIRCRESAHA.115.306532; PMID: 26838319 31. Park KH, Sun T, Diez-Delhoyo F, et al. Association between coronary microvascular function and the vasa vasorum in patients with early coronary artery disease. Atherosclerosis 2016;253:144–9. DOI: 10.1016/j.atherosclerosis.2016.08.031; PMID: 27626971 32. Nishimiya K, Matsumoto Y, Wang H, et al. Absence of adventitial vasa vasorum formation at the coronary segment with myocardial bridge - An optical coherence tomography study. Int J Cardiol 2017. DOI: 10.1016/j.ijcard.2017.09.211.

[Epub ahead of print]; PMID: 28993001 33. Kwon TG, Gulati R, Matsuzawa Y, et al. Proliferation of coronary adventitial vasa vasorum in patients with spontaneous coronary artery dissection. JACC Cardiovasc Img 2016;9(7):891–2. DOI: 10.1016/ j.jcmg.2015.11.030; PMID: 27388667 34. Cheng KHY, Sun C, Vuong B, et al. Endovascular optical coherence tomography intensity kurtosis: visualization of vasa vasorum in porcine carotid artery. Bio Opt Express 2012;3(3):388–99. DOI: 10.1364/BOE.3.000388; PMID: 22435088 35. Herrman J, Lerman LO, Rodriguez-Porcel M, et al.

Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 2001;51(4):762–6. PMID: 11530109 36. Ohyama K, Matsumoto Y, Amamizu H, et al. Association of coronary perivascular adipose tissue inflammation and DESinduced coronary hyperconstricting responses in pigs – 18F-FDG PET imaging study. Arterior Thromb Vasc Biol 2017;37:1757-64.

DOI: 10.1161/ATVBAHA.117.309843; PMID: 28751570 37. Uzuka H, Matsumoto Y, Nishimiya K, et al. Renal denervation suppresses coronary hyperconstricting responses after drugeluting stent implantation in pigs in vivo through the kidney– brain–heart axis. Arterior Thromb Vasc Biol 2017;37(10):1869–80 DOI:10.1161/ATVBAHA.117.309777; PMID: 28818859

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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 Peter Libby, Mallinckrodt Professor of Medicine, Harvard Medical School; and Cardiovascular Specialist, Brigham and Women’s Hospital.

On the first day of medical school at University of California (UC), San Diego, I met Professor Eugene Braunwald, and that pretty much set the course of the rest of my professional career. He presided over and presented in a course called Introduction to the Clinic which, in that year, highlighted a case of rheumatic heart disease that grabbed my imagination because it united infection, physiology, pathology, socioeconomic considerations, medical management and surgical treatment all in one package. The combination sold me on the potential of cardiovascular medicine, and then I went to work in Prof Braunwald’s group, and started to work on experimental myocardial infarction.

I never looked backwards.

From Berkeley to Boston

A

s the founding chairman of the department of medicine UC, San Diego’s new medical school, Prof Braunwald put a very strong stamp on the value of research excellence, emphasising cardiovascular and pulmonary considerations. We students understood that, before us lay a great opportunity not just to master facts, but to add to knowledge in a way that would improve understanding of disease and improve patient care.

This environment was exciting, particularly because I am, by nature, a bit of a contrarian. I was born and bred in Berkeley, California, steeped in the world of not accepting the status quo unexamined. In the US, we complete general studies before beginning professional school. I earned my bachelor’s degree in biochemistry and French literature in 1969 at the University of California, Berkeley. The ‘people’s republic of Berkeley’ fostered an anti-authority streak and was in the vanguard of shaking off the student torpor of the 1950s. I think being part of that experience is one of the reasons I’ve never been content to jump on the bandwagon, but have always sought my own path — including in my research career.

As a medical student and then as a postdoctoral trainee, I worked on experimental myocardial infarction (MI) in Prof Braunwald’s lab. But I soon grew unsatisfied because we were dealing with the end stage of a disease that had its inception usually decades before we would meet a patient with acute coronary syndrome (ACS). Instead of putting my finger in the dyke at the ultimate stage of the disease, I wanted to understand more about the

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pathogenesis of the root cause of atherosclerosis. At that time, the research on atherosclerosis was dominated by lipids and, although I have turned back to lipidology a great deal since, I was not satisfied that the association with cholesterol alone explained how atherosclerosis develops.

I needed to understand more about the connection between traditional risk factors and heart disease that had emerged from observational epidemiology. I felt the need to develop a deeper scientific background which, at the time, meant delving further into cell biology and biochemistry. I was also a bit of a rebel and so, after several years, I rather brashly told Prof Braunwald that I wanted to reach beyond work in his group. And Prof Braunwald, to his eternal credit, arched only one eyebrow, and then arranged for me to meet some of the fundamental scientists at the Harvard Medical School — which led me to a three-year postdoctoral fellowship in a basic science laboratory.

Breaking new ground I had strayed from the traditional pathway, and then after I did my clinical speciality training in cardiovascular medicine, I set out to establish my own independent research group. The tools had become available to culture the endothelial cells of blood vessels in the mid-1970s, which led to the development of vascular biology. So when I started my own laboratory in 1980, I decided to devote myself to this new field, ultimately with the aim of learning more about the root causes of atherosclerosis — well before the current strong links that now exist between the traditional lipid community and vascular biology.

© RADCLIFFE CARDIOLOGY 2016

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Cardiology Masters: Dr Peter Libby Figure 1: Finishing in the Rain

Figure 2: Libby and Wife

Dr Libby credits the ‘unstinting support’ of his wife, Professor Beryl Benacerraf (of Harvard Medical School) with the ability to take the early risks that led to his successes in the field.

He adds that she ‘is much smarter and more accomplished than I am’. This photo shows Profs Benacerraf and Libby in Davos after the Cardiology Update meeting in February 2017 In the personal and professional spheres alike, Dr Libby relishes the challenge of persevering and mastering a new field, shown here finishing a half marathon in the rain in October 2017

It was a perhaps foolhardy ambition; it was certainly risky and careless. But I was young and had a certain degree of confidence — not necessarily in myself — that, if I failed, I could always earn a living as a cardiologist, a practice that I enjoy immensely. That attitude allowed me to take the risks. I also had the unstinting support through thick and thin of my wife, Professor Beryl Benacerraf (of Harvard Medical School), who is much smarter, talented and more accomplished than I (see Figure 1 and 2).1 I then began to encounter early failures with trying to obtain grants, being told that I had no background in atherosclerosis. But I wanted to grasp the golden ring, to follow my curiosity and motivation to learn more. I became quite used to having scepticism about where I was going, and the doubts and the difficulties I encountered initially in getting funded only strengthened my resolve to persevere, and that trait continues to this very day. It’s part of my success, and probably also has gained me reputation for being perhaps a contrarian in some circles.

But that’s skipping ahead. At that time (among other work), based on some emerging science, I hypothesised that the newly discovered pro-inflammatory cytokine, interleukin-1, had a role in inflammation and immunity in atherosclerosis.2 My laboratory published that hypothesis based on laboratory experiments in 1986,3 and largescale clinical trial published in August 2017 has now validated that

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conjecture.4 This success reflects a measure of good luck, being in the right place at the right time, but also doing the right things for the right reason, along with some hard work, patience and persistence.

It also requires considerable fortitude and willingness to accept risk to subject one’s cherished laboratory hypothesis to the acid test of a clinical trial.

I’ve continued to tackle the questions that I considered at the forefront of clinical challenge at various junctures of my career where I thought that my toolkit, both intellectual and technical, could have a chance at cracking them. For example, there was a time when transplantation atherosclerosis was a key problem, and so my lab started work towards understanding its pathogenesis. As a matter of fact, few remember that I did that work, because it’s in the textbooks as accepted knowledge now, but over about 10 years we produced a body of work to gain insight into the adaptive immune mechanisms that contribute to this problem.2 When balloon angioplasty was introduced, re-stenosis presented a huge challenge, and many considered re-stenosis a matter of thrombosis. There was a great deal of interest in platelets and smooth muscle cell proliferation. My lab was perhaps among the first to determine the link between arterial injury and inflammatory activation.5 I certainly can’t take credit for developing the concepts that led to our current generation of drug-eluting stents, but these devices deliver immunosuppressive agents, and some of the basic

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Cardiology Masters work that we did when we attacked the problem of re-stenosis bolstered that approach.

We also focused on plaque rupture as a cause of ACS for some 20 years, and I think we helped to solve its mechanisms. Although it wasn’t just my laboratory, we did a lot of work that showed that inflammation and inflammatory pathways make an atherosclerotic plaque susceptible to rupture, and determined the cellular and molecular mechanisms in detail. When statins came onboard, our work provided insight into how lipid lowering could calm inflammation, and render plaques less likely to rupture.6 Yet when on hospital duty, I commonly see patients who have taken statins for years and have well-controlled low-density lipoprotein (LDL) yet still present with ACS. So we’re not done yet, and that’s why, about four years ago, I told my lab we should move on from studying plaque rupture. It was a conscious change in direction in my laboratory to study another mechanism that I think is becoming more important in the statin era: superficial erosion.7,8 I’m constantly pushing myself to look around the bend to deal with today’s and tomorrow’s disease, not yesterday’s.

Lessons from the past, looking to the future The world has gone through the epidemiologic transition.

Cardiovascular disease (CVD) and atherosclerosis no longer affects primarily Caucasian males in developed countries, people of higher socioeconomic status. Many factors contribute to this shift: use of tobacco, consumption of fast food, increase in leisure time, decrease in physical activity due to mechanisation, and longevity due to the conquering of many communicable diseases. People in the developing world now live longer, and CVD has spread worldwide, driven by obesity and diabetes. I think we’re sowing the seeds of a two-pronged epidemic and will start seeing younger people pay the price of these epidemic cardiovascular risk factors on one end, while CVD increases in the accumulating elderly population on the other, as ageing potently promotes atherosclerosis.

For patients who have well-controlled low-density lipoprotein (LDL) using statins, we have to address the other risks. The recently published, large-scale clinical trial has provided proof of principle that some people may be helped by an anti-inflammatory agent,4 but what about those people who have elevated triglycerides? We started a new trial in the last year investigating pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, which lowers triglycerides and reduces triglyceride-rich lipoproteins — risks not necessarily addressed by anti-inflammatory or lipid-lowering agents. In five years, we hope to be able to tell you whether we’re making inroads against this triglyceride-rich lipoprotein risk.

The next step is making connections between immunology, infectious disease, oncology and haematology within cardiology. Patients who have clonal proliferation of white blood cells most often die of cardiovascular events, providing an exciting new avenue to pursue that seemingly has nothing to do with lipids, but with inflammation.9 This connection was completely unknown a few years ago, and now I’m working with a really wonderful haematology/oncology group to

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understand the cardiovascular risk associated with clonal proliferation of white blood cells. Making these connections forces me to master a new field, a challenge I relish, and that has enabled innovative science.

Committing to your own path Younger people with research interests should pursue such connections — scientifically, personally and professionally. It’s the recipe that worked for me and my career, but then I have a bit of a restless curiosity and bore easily. Shaping a career requires courage to leave your comfort zone so that you can innovate. If you’re comfortable, you’re probably not doing something important. I have learned to thrive on being uncomfortable and to embrace intellectual insecurity. When I think I have a hypothesis, an insight that could enrich the field, I tend to pursue it. This trait requires willingness to be wrong, to learn from mistakes, and to regroup. After doing this for 40 years, I’ve begun to gain the confidence that, perhaps, my contrarian concepts might actually bear fruit. I’ve become very used to putting my foot in a field, encountering resistance, yet persevering; eventually, this path usually pays off.

The cross-fertilisation between practising cardiology and working in the lab keeps me from becoming bored. When I’m caring directly for patients, I realise how little we know and how far we have to go to answer questions and meet their needs. Then I return to the laboratory, where I can be a ‘big-picture’ person and try to enrich the field with my clinical perspective. I like to go into an area and make some early observations and then, as other people are mining the details of that topic, I’m off looking to the next thing. Some have said that, when you find the secret of life, it will be a matter of a few ångströms — a tiny shift in some molecule that you can perceive only with structural biology. That’s not my kind of science.

It’s very important. It’s beautiful, it’s elegant. It’s necessary, but it’s not me.

It has been very nice to receive recognitions over the course of my career, but such awards actually drive me to delve deeper and strive harder. They stimulate me to ask myself, ‘What have I done lately?’ rather than rest on the laurels. Receiving the Gold Medal of the European Society for Cardiology was a particularly meaningful honour, especially because I consider myself a globalist. But the real reward is not the plaques or medals, it’s what you accomplish. My motto is two little words: “change medicine.” The ultimate reward is seeing many people whom I have trained and mentored over the years have a multiplier effect through their own contributions. That’s the really enduring satisfaction.

I’ve had the immense privilege of embarking on a path that started in a basic science laboratory and have persevered to see it pay off clinically. It’s been quite an adventure for me — starting out very lonely, not even able to publish in the cardiology literature — and now able to reap the harvest of some of the concepts we helped to establish. I can’t see not continuing to bash away at the problems with which I grapple. If Prof Braunwald is still going strong and starting studies that are slated to last five years, so can I. The opportunities have never been greater, and the need is commensurate.

So long as I am able, I’m going to be combatting the enemy. n

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1.

2.

3.

4.

Watts G. Beryl Benacerraf: new AIUM President gets the picture. Lancet 2015;385(9973):1065.

Libby P. History of discovery: inflammation in atherosclerosis.

Arterioscler Thromb Vasc Biol 2012;32(9):2045–51.

Libby P, Ordovàs JM, Auger KR, et al. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol 1986;124(2):179–86.

Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab

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5.

6.

7.

for atherosclerotic disease. N Engl J Med 2017;377(12): 1119–31.

Tanaka H, Sukhova GK, Swanson SJ, et al. Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Circulation 1993;88(4 Pt 1):1788–803.

Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;369(21):2004–13.

Quillard T, Araújo HA, Franck G, et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis

8.

9.

and detachment – implications for superficial erosion.

Eur Heart J 2015; 36(22):1394-1404. PMC4458287.

Franck G, Mawson T, Sausen G et al. Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice – Implications for Superficial Erosion.

Circ Res 2017;121:31-42.

Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017;377(2):111–21.

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Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

European Cardiology Review Volume 12 • Issue 1 • Summer 2017

Radcliffe Cardiology

Volume 12 • Issue 1 • Summer 2017

www.ECRjournal.com

Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors Tracey Keteepe-Arachi and Sanjay Sharma

Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis Marie Mide Michelsen, Naja Dam Mygind, Daria Frestad and Eva Prescott

Cardiac Disease after Pregnancy: A Growing Problem Christina Y Aye, Henry Boardman and Paul Leeson

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care Konstantinos N Aronis, Brittany Edgar, Wendy Lin, Maria Auxiliadora Parreiras Martins, Michael K Paasche-Orlow and Jared W Magnani

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