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Volume 11 â&#x20AC;˘ Issue 1 â&#x20AC;˘ Summer 2016

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Resistant Hypertension: A Real Entity Requiring Special Treatment? Stefano Taddei and Rosa Maria Bruno

Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis Rocio Hinojar, Eike Nagel and Valentina O Puntmann

Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection Alessandro Pingitore, Giorgio Iervasi and Francesca Forini

Atrial Fibrillation, Cognitive Decline and Dementia Alvaro Alonso and Antonio P Arenas de Larriva

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Volume 11 • Issue 1 • Summer 2016

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

Associate Editorial Steering Committee Rao Kondapally, Aneil Malhotra, Robin Ray, Nesan Shanmugam St George’s University of London, London, UK

Luigi Paolo Badano

Eileen Handberg

Sven Plein

University of Padua, Padua, Italy

University of Florida, Florida, US

University of Leeds, Leeds, UK

Velislav Batchvarov

Koichi Kaikita

Piotr Ponikowski

Kumamoto University, Kumamoto, Japan

Wroclaw Medical University, Wroclaw, Poland

Sverre Kjeldsen

Eva Prescott

University Hospital, Oslo, Norway

Bispebjerg Hospital, København, Denmark

Wolfgang Koenig

Fausto Rigo

University of Ulm, Ulm, Germany

Ospedale dell’Angelo Hospital, Venice, Italy

Steen Dalby Kristensen

Giuseppe Rosano

Aarhus University, Aarhus, Denmark

IRCCS San Raffaele, Rome, Italy

Patrizio Lancellotti

Magdi Saba

University of Liège, Liège, Belgium

St George’s University of London, London, UK

Gaetano Antonio Lanza

Sanjay Sharma

Catholic University of the Sacred Heart, Milan, Italy

St George’s University of London, London, UK

Giuseppe Mancia

Hiroaki Shimokawa

University of Milano-Bicocca, Milan, Italy

Tohoku University, Sendai, Japan

Antoni Martínez-Rubio

Rosa Sicari

University Hospital of Sabadell, Sabadell, Spain

Italian National Research Council

Hippokration General Hospital, Athens, Greece

Mario Marzilli

Iana Simova

Kenneth Earle

University of Pisa, Pisa, Italy

National Cardiology Hospital, Sofia, Bulgaria

St George’s University of London, London, UK

Attilio Maseri

Philippe Gabriel Steg

Perry Elliott

Vita-Salute San Raffaele University, Milan, Italy

Hospital Bichat Claude Bernard, Paris, France

University College London, London

Noel Bairey Merz

Jun Takata

Albert Ferro

Cedars-Sinai Heart Institute, Los Angeles, US

Kochi University, Nankoku, Japan

King’s College London, London

Petros Nihoyannopoulos

Dimitris Tousoulis

Augusto Gallino

Imperial College London, London, UK

University of Athens Medical School, Athens, Greece

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Camici Paolo

Konstantinos Toutouzas

San Raffaele Hospital, Segrate, Italy

University of Athens, Athens, Greece

Zoltan Papp

Dimitrios Tziakas

University of Debrecen, Debrecen, Hungary

Democritus University of Thrace, Xanthi, Greece

Antonio Pelliccia

Hiroshi Watanabe

Johannes Gutenberg University Mainz, Mainz, Germany

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

Martin Halle

Joep Perk

José Luis Zamorano

Technical University of Munich, Munich, Germany

Linnaeus University, Kalmar, Sweden

University Complutense, Madrid, Spain

St George’s University of London, London, UK

Elijah Behr St George’s University of London, London, UK

John Beltrame University of Adelaide, Adelaide, Australia

Richard Conti University of Florida, Florida, US

Martin Cowie Imperial College London, London, UK

Filippo Crea Catholic University of the Sacred Heart, Milan, Italy

Alberto Cuocolo University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan Colentina University Hospital, Bucharest, Romania

Polychronis Dilaveris

Xavier Garcia-Moll Autònoma University, Barcelona, Spain

Simon Gibbs Imperial College London, London, UK

Tommaso Gori

Hamamatsu University School of Medicine, Hamamatsu, Japan

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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. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2016 All rights reserved

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Established: April 2005 Frequency: Bi-annual Current issue: Summer 2016

Aims and Scope

Submissions and Instructions to Authors

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

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

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

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

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

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

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

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

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

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

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Contents

Foreword 5

Juan Carlos Kaski

Announcement

7 ECR–ISCP Partnership

Juan Carlos Kaski

Hypertension

8 Resistant Hypertension: A Real Entity Requiring Special Treatment?

Stefano Taddei and Rosa Maria Bruno

Clinical Diagnosis and Management of Resistant Hypertension 12

Costas P Tsioufis, Alexandros Kasiakogias and Dimitrios Tousoulis

G uest Editorial: Challenges in Resistant Hypertension

Cardiac Imaging | Myocarditis | Endocarditis

Thomas Kahan

20 Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis

Rocio Hinojar, Eike Nagel and Valentina O Puntmann

25 Accuracy of Positron Emission Tomography as a Diagnostic Tool for Lead Endocarditis: Design of the Prospective Multicentre ENDOTEP Study

Sana Amraoui, Ghoufrane Tlili, Elif Hindié, Paul Perez, Olivia Peuchant, Laurence Bordenave and Pierre Bordachar

Cardiomyopathy | Cardiac Protection L eft Ventricular Remodelling: A Problem in Search of Solutions Dennis V Cokkinos and Christos Belogianneas

36 Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection

Alessandro Pingitore, Giorgio Iervasi and Francesca Forini

C ardiac Repair and Regeneration: The Value of Cell Therapies

Daniel Alejandro Lerman, Nasri Alotti, Kiddy Levente Ume and Bruno Péault

Atrial Fibrillation | Stroke Prevention | Dementia

49 Atrial Fibrillation, Cognitive Decline and Dementia

Alvaro Alonso and Antonio P Arenas de Larriva

Cardiovascular Risk Factors

U ric Acid and Cardiovascular Disease: An Update

Maria Lorenza Muiesan, Claudia Agabiti-Rosei, Anna Paini and Massimo Salvetti

Cardiology Masters

Professor Keith AA Fox

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

have great pleasure in introducing the eleventh volume of European Cardiology Review to our readers.

This issue of the journal coincides with the 2016 European Society of Cardiology Conference in Rome. I hope to meet as many of our readers and contributors as possible at the conference, and I also look forward to getting acquainted with the results of the large studies that will be presented at the ESC meeting and which may have a huge impact on patient management. European Cardiology Review will have a presence at the conference and I hope that you will visit us at our publisher’s, Radcliffe Cardiology’s, booth during the event. This issue of the journal also marks the beginning of an exciting partnership between European Cardiology Review, Radcliffe Cardiology and the International Society of Cardiovascular Pharmacotherapy (ISCP). I am delighted that the ISCP has chosen to partner with the journal to share their research and guidelines directly with our readers henceforth in every issue. I provide further details on this partnership in an editorial on page 7, and I am looking forward to the incumbent ISCP President, Professor Antoni Martinez Rubio, providing an editorial article in every issue, from the next issue onward. This will allow our readers to gain insight into the rapidly evolving world of cardiovascular pharmacotherapy and the valuable educational work of the ISCP in this area. In another new development for European Cardiology Review, we are happy to present a new series that reflects on the contributions of iconic clinicians and researchers in cardiology. We have dubbed the section ‘Cardiology Masters’ and are honoured that Professor Keith AA Fox allowed us to profile him for the first instalment (page 60). We are looking forward to bringing you inspiring articles in this section that chart the many routes to excellence in the field. In this issue we have leading experts review a crucial list of subjects of relevance to the practising cardiologist. I call the readers’ attention especially to the section on resistant hypertension, which comprises excellent articles by Taddei and Bruno (page 8) and Tsioufis et al. (page 12), as well as a guest editorial on the topic by Professor Thomas Kahan (page 18). The work presented in this section will shed light on defining resistant hypertension, as well as the implementation of suitable treatment strategies. All articles presented in the current issue deal with extremely important topics in cardiovascular medicine and provide expert views regarding diagnosis, prevention and management of diverse cardiovascular conditions. I extend my thanks to the European Cardiology Review Editorial Board 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. n

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Radcliffe Cardiology

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www.radcliffecardiology.com A free-to-access community supporting best practice in cardiovascular care

www.ECRjournal.com

Resistant Hypertension: A Real Entity Requiring Special Treatment? Stefano Taddei and Rosa Maria Bruno

Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis Rocio Hinojar, Eike Nagel and Valentina O Puntmann

US Cardiology Review

European Cardiology Review Volume 11 • Issue 1 • Summer 2016

Volume 11 • Issue 1 • Summer 2016

Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection Alessandro Pingitore, Giorgio Iervasi and Francesca Forini

Alvaro Alonso and Antonio P Arenas de Larriva

Artery

Vein Arterioles

Venules Capillaries

Volume 10 • Issue 1 • Spring 2016 • RELAUNCH ISSUE

Atrial Fibrillation, Cognitive Decline and Dementia

Collagen Adventitial progenitor Smooth muscle cell

www.USCjournal.com

Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors Michelle Kittleson, MD, PhD

Ischemic Complications of Pregnancy: Who is at Risk?

LIVE FROM THE HAMMERSMITH

Sara C Martinez, MD, PhD and Sharonne N Hayes, MD

Optimizing Heart Rate and Controlling Symptoms in Atrial Fibrillation Pragnesh Parikh, MD and KL Venkatachalam, MD

Pericyte

Public Reporting of Cardiovascular Data: Benefits, Pitfalls, and Vision for the Future

Endothelial cell

T1 mapping using the modified look-locker sequence

Gregory J Dehmer, MD, MACC, MSCAI, FAHA, FACP

Adventitia-derived MSC

Sagittal fused PET/ CT showing increased FDG uptake

Origin of potential stem cells

SNS

NPS

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ECR–ISCP Partnership Announcement

European Cardiology Review partners with the International Society of Cardiovascular Pharmacotherapy

am delighted to announce that European Cardiology Review (ECR) has now started a partnership with the International Society of Cardiovascular Pharmacotherapy (ISCP), a leading non-for-profit organisation devoted to

medical education in the field of cardiovascular therapy. The mission of the ISCP – an associate member of the World Heart Federation – is to foster research initiatives and develop educational programmes on topics related to cardiovascular pharmacology and pharmacotherapy. With representatives from over 35 countries worldwide in its ranks, the ISCP represents an important forum for vital discussions on cardiovascular pharmacotherapy. Among many educational activities, the ISCP supports two major initiatives, namely the Cardiovascular Pharmacotherapy Book Series, with the publication of an average of six volumes on the treatment of cardiovascular conditions per year, and the ISCP Annual Scientific Sessions, which attract a large audience of medical practitioners and healthcare professionals from the world over. The ISCP holds approximately 12 regional meetings annually, aimed at discussing novel issues in the field of cardiovascular and pharmacology and therapy. Starting with the December issue this year, each volume of ECR will contain a Cardiovascular Pharmacotherapy section that will be jointly edited by the president of the ISCP and myself. This section will publish review articles as well as original systematic reviews and meta-analyses on the most important developments in cardiovascular pharmacotherapy. Recent outstanding clinical trials, with the potential to change clinical practice, will be presented and discussed by international experts in the field. We also plan to include editorial articles written by the president of the ISCP that will highlight important developments in the field and their potential impact on clinical practice. In addition, we will publish ‘expert opinion’ articles, which will be accompanied by brief scholarly comments by other experts and online interviews with key scientists and opinion leaders. This is an exciting project that both ECR and ISCP are embracing with optimism, determination and great enthusiasm. We hope that our readers will find this new initiative valuable for their day-to-day practice as well as a means to gain insight into the new developments in the field of cardiovascular pharmacotherapy. n

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Hypertension

Resistant Hypertension: A Real Entity Requiring Special Treatment? Stefa n o Ta d d e i 1 a n d R o s a M a r i a B r u n o 1 ,2 1. University of Pisa, Pisa, Italy; 2. Institute of Clinical Physiology – CNR, Pisa, Italy

Abstract Resistant hypertension (RH) was defined many years ago as a clinical situation in which blood pressure remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses. This operative definition was aimed at identifying a subset of hypertensive patients requiring a more extensive clinical workup in order to achieve an adequate blood pressure control. An oversimplification of this picture led to consider RH as a separate clinical entity requiring special, expensive treatments, such as renal denervation and baroreceptor activating therapy. In this review we will discuss the utility and the shortcomings of the definition of RH and the possible consequences for treatment.

Keywords Resistant hypertension, definition, ambulatory blood pressure Disclosure: Stefano Taddei has received honoraria for lectures from Pfizer, Recordati and Servier. Received: 9 November 2015 Accepted: 23 February 2016 Citation: European Cardiology Review, 2016;11(1):8–11 DOI: 10.15420/ecr. 2016.11.1 Correspondence: Stefano Taddei, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67 56126, Pisa, Italy. E: stefano.taddei@med.unipi.it

The concept of resistant hypertension (RH) has received great attention in the past years, mainly as a possible target population for innovative therapeutic strategies. An increasing number of original articles and commentaries have focused on the clinical significance, prognosis and treatment of this condition. Thus it is not surprising than even its definition is still a matter of debate, though the diagnosis of RH has important clinical implications, as patients with RH have an increased prevalence of secondary causes of hypertension,1 more severe target organ damage2 and increased cardiovascular morbidity and mortality risk of cardiovascular complications and death.3,4 According to the 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of arterial hypertension, RH is a clinical situation in which blood pressure (BP) remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses.5 According to the 2008 American Heart Association (AHA) scientific statement, patients who require four drugs or more to have their BP controlled are also considered as resistant:6 this definition is probably the most used nowadays, but has several shortcomings, which will be discussed below. First, it should be noted that definition of RH is substantially different from the one of uncontrolled BP. A recent cross-sectional cohort study compared the clinical characteristics of RH patients with uncontrolled BP and with controlled BP (those that are considered RH by AHA but not by ESC/ESH guidelines) and found many similarities.7 However, RH patients with uncontrolled BP showed higher prevalence of diabetes and increased low-density lipoprotein (LDL) cholesterol levels.7 An increased prevalence of associated risk factors might thus be associated with a worse prognosis. However, the main caveat in current definitions of RH is probably the fact that is still based on office rather than out-of-office BP pressure

Access at: www.ECRjournal.com

Taddei_FINAL.indd 8

measurement. For that reason, it has been recently proposed that a new, stricter definition of RH based on ambulatory BP measurement might be more useful in risk stratification and in patients selection for device-based therapies.8 Indeed, white-coat resistant hypertension might be responsible for about one-third of the classically defined RH patients, as highlighted by de la Sierra and co-authors in a cohort consisting of 8,295 RH patients from the Spanish Ambulatory Blood Pressure Monitoring Registry. True RH patients were younger, more frequently men, with a longer duration of hypertension and a worse cardiovascular risk profile, including a greater prevalence of associated risk factors, of cardiac and renal target organ damage and of established cardiovascular disease, compared with white-coat RH patients.2 Interestingly, in the same study the prevalence of masked RH (uncontrolled ambulatory BP but controlled office BP) was 31.0 % among hypertensive patients taking three antihypertensive drugs, confirming that the use of office or 24-h BP for the definition of RH identifies two populations that only partially overlap. A higher cardiovascular risk in true RH patients was confirmed by a prospective study recruiting 742 treated hypertensive patients followed up for about 5 years.9 In this study, the rate of cardiovascular fatal and nonfatal events was twofold in masked RH patients and almost threefold in true RH patients compared with responders to treatment, while it was not increased in white-coat RH patients. Furthermore, Salles et al. demonstrated that ambulatory BP, especially nighttime BP, but not office BP, predicts cardiovascular events and overall death in a cohort of 556 apparently RH patients.10

Resistant Hypertension: Which Prevalence? Given the discrepancies among definitions of RH and the ongoing debate within the scientific community, it is not surprising that several uncertainties about the prevalence of RH exist. In the general outpatient population with newly diagnosed hypertension,

31/07/2016 19:15

Resistant Hypertension: A Real Entity Requiring Special Treatment?

the incidence of RH is very low, ranging from 1 % to 2 % over a median 1.5 years.4 The prevalence of RH is expected to increase in the next years, due to increased life expectancy and increased prevalence of obesity, diabetes and chronic kidney disease, all factors associated with difficult-to-control hypertension. In the National Health and Nutrition Examination Survey (NHANES) study, the prevalence of apparent RH increased from 15.9 % (1998–2004) to 28.0 % (2005–2008) of treated hypertensive patients, confirming this trend.11 RH can be even more common in selected populations at high cardiovascular risk or in clinical trials where forced up-titration of antihypertensive drugs occurs. For example, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled about 33,000 hypertensive participants with associated cardiovascular risk factors, 27 % required at least three BP medications.12 Similarly, in a subanalysis of the International Verapamil-Trandolapril Study (INVEST), which included 17,190 patients with established coronary artery disease, the prevalence of RH was 38 %.13 In hypertension specialty clinics, where up-titration of antihypertensive medications occurs regularly and more severe cases are referred to, the prevalence of RH may range between 12 and 40 % (see Figure 1).14,15 Among the 10,700 participants of the Reasons for Geographic and Racial Differences in Stroke study on treatment for hypertension, the prevalence of RH was double in the presence of an estimated glomerular filtration rate (GFR) lower than 45 ml/min/1.73 m2, in comparison to individuals with GFR greater than 60 ml/min/1.73 m2.16 A recent systematic review and meta-analysis exploring the prevalence of RH in treated hypertensive populations included 20 observational studies and four randomised control trials (RCTs) with a total population of 961,035 individuals. The random-effect method for observational studies and RCTs yielded RH prevalence ratios of 13.72 % and 16.32 %, respectively. However the authors noted that most studies were incapable of ruling out pseudoresistance caused by white-coat effect, poor medication adherence and suboptimal dosing.17

Hypertension: Which Treatment? One of the main reasons for the lack of efficacy of antihypertensive pharmacological treatment, and for pseudoresistant hypertension, is that very often drugs are not administered at the correct dosage and in rational combinations.18 This is especially the case for angiotensinconverting enzyme (ACE) inhibitors, compounds characterised by a flat dose-response curve. The significance of this flat doseresponse curve is that a low dose of an ACE inhibitor has the same antihypertensive potency as a high dose but a shorter duration of action.19 Since the prescription of inadequate drug dosages and/ or inadequate drug combinations are probably among the main and overlooked causes of pseudoresistance to antihypertensive treatment, it is therefore important to be aware of the clinical pharmacology of antihypertensive drugs in order to choose not only the class or the molecule best suited to the clinical characteristics of the patient, but also the correct dosages and combinations, in order to ensure effective and homogeneous 24-h BP reduction.19 Garg and coauthors demonstrated that 58 % of the patients referred to a tertiary care hypertension clinic for uncontrolled BP by three or more BP-lowering drugs had incorrect drug dosage and/or combination.18 More recently, this aspect has been elegantly taken into account in the design of the Renal Denervation for Hypertension (DENERHTN) study, a nationwide, multicentre, open-label, Q3 RCT testing the effect of a standardised stepped-care antihypertensive treatment alone or plus renal denervation in RH patients.20 Of 121 eligible patients

EUROPEAN CARDIOLOGY REVIEW

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Figure 1: Prevalence of Resistant Hypertension According to the ESC/ESH Definition in a Hypertension Outpatient Clinic (Pisa, Italy)

17.4 %

10.4 %

Untreated hypertension Controlled hypertension, no criteria for resistant hypertension

33.5 %

Uncontrolled hypertension, no criteria for resistant hypertension Resistant hypertension

38.7 %

Unpublished data referring to 586 hypertensive patients accessing for the first time to a hypertension outpatient clinic in Pisa, Italy.

(in which secondary hypertension had been excluded), 12 had their ambulatory BP controlled after switching to a standardised triple therapy (indapamide 1.5 mg, ramipril 10 mg or irbesartan 300 mg and amlodipine 10 mg daily), and thus were not randomised to treatment.20 Furthermore, there is evidence to suggest that monotherapy with renin-angiotensin system (RAS) blockers in low-renin individuals might induce a pressor response in a not negligible proportion of individuals.21 The impact of this poorly studied phenomenon on individuals in combination therapy such as RH is still unknown. Improving treatment compliance is another crucial therapeutic target in RH patients. Non-adherence to BP-lowering therapy, detected by high performance liquid chromatography-tandem mass spectrometry urine analysis, is common, particularly in patients with suboptimal BP control and those referred for renal denervation to a tertiary hypertension clinic.22 Ambulatory BP monitoring after witnessed drug intake might also be a more-feasible and less-expensive option.23 An increasing body of evidence suggests that the use of drug monitoring in RH might be useful not only for diagnostic purposes, in order to assess actual compliance to antihypertensive treatment, but also for therapeutic purposes, as recently supported by preliminary observations.24 There is still a paucity of data about how to improve compliance to non-pharmacological and pharmacological treatment in resistant hypertensive patients. In this view, hypertension specialists should be careful not to negatively label the non-compliant patient, whereas the use of therapeutic drug monitoring results should always be accompanied by counselling of methods to overcome barriers to adherence. An adequate clinical workup in RH patients must include a thorough screening for secondary causes of hypertension, which are conceivably more frequent in this subgroup of individuals in comparison to the general hypertensive population.25 Obstructive sleep apnoea syndrome (OSAS) and primary aldosteronism are particularly common in RH patients.1,26 A large retrospective study analysed a group of 1,616 patients with RH over 20 years and demonstrated that 20 % resulted to have a positive aldosterone–renin ratio, and after three confirmatory tests the diagnosis of primary aldosteronism was confirmed in 11.3 %.1,26 By contrast, the ‘spontaneous hypokalemia/no antihypertensive drug’ diagnostic approach resulted in predicted primary aldosteronism prevalence rates of less than 0.5 % of hypertensive patients,26 thus hyperaldosteronism should be actively searched for in RH

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Hypertension patients. It should also be noted that aldosterone-antagonists, such as spironolactone, are the most effective BP-lowering drugs that can be used in RH patients on top of three drugs (usually a RAS-blocker, a simil-thiazide diuretic and a calcium-channel blocker). This was suggested first from the non-randomised post hoc analysis of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, in which the addition of spironolactone to a triple-drug treatment led to a significant decrease of systolic BP of 21.9 mmHg and diastolic BP of 9.5 mmHg.27 The beneficial effect of add-on therapy with spironolactone 25 mg against placebo in RH patients was then confirmed in the Addition of Spironolactone in Patients with Resistant Arterial Hypertension (ASPIRANT) study, an investigator-led, prospective, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial,28 demonstrating a significant difference in mean fall of systolic BP on daytime ambulatory BP monitoring of 5.4 mmHg between the two arms. Finally, the Prevention And Treatment of Hypertension With Algorithm-based therapy number 2 (PATHWAY-2) study was a double-blind, placebo-controlled, crossover trial, enrolling 335 patients with office and home BP uncontrolled despite treatment for at least 3 months with maximally tolerated doses of three drugs. Patients rotated, in a pre-assigned, randomised order, through 12 weeks of once-daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin-modified release (4–8 mg) and placebo, in addition to their baseline antihypertensive drugs. Spironolactone was the most effective drug in lowering home systolic BP compared with placebo (–8.70 mmHg), but also compared with the other two active treatments.29 Spironolactone was more effective in the presence of low plasma renin levels, suggesting that among underlying pathophysiological causes of RH, sodium retention and undetected aldosterone producing adenomas play a significant role. Based on the results of the PATHWAY-2 study, the authors claim that truly RH should now be considered rare and redefined as BP not controlled by three drugs at full doses (a RAS-blocker, a simil-thiazide diuretic and a calcium-channel blocker), plus spironolactone. The role of sodium retention in pathogenesis of RH is also reinforced by the striking effect of dietary sodium restriction in this population. In a small 4-week, randomised, crossover trial, 12 RH patients were randomised to the low- (50 mmol of sodium per day) or high-salt diet (250 mmol of sodium per day) for 1 week. The difference in mean BP between the two treatments was –20.1 mmHg for systolic BP and –9.8 mmHg for diastolic BP.30 OSAS is commonly associated with hypertension31–33 and with RH, with a prevalence reaching up to 60 % in the latter group.1 Normotensive individuals with OSAS and increased daily sleepiness have an increased risk of developing hypertension, while continuous positive airway pressure (CPAP) is able to reduce its incidence.33 Based on this evidence, some authors claim that OSAS should be considered among secondary causes of hypertension.1,25 This point of view is reinforced by the fact that the treatment of OSAS by CPAP is able to effectively reduce ambulatory BP valueseven in RH patients.34 Furthermore, it is likely that any cause of sleep loss and fragmentation may be

Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension 2011;58 :811–7. DOI: 10.1161/HYPERTENSIONAHA.111.179788; PMID: 21968750 de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure

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associated with increased BP values and RH,35,36 though the actual prevalence of other sleep disorders in RH and the impact of their presence and treatment on BP control have not been investigated yet. In the past years, device-based therapies targeting sympathetic activation, namely renal denervation and baroreceptor activating therapy, have been tested in RH patients.37 After brilliant results in proof-of-concept, small studies, both the techniques failed to demonstrate sustained efficacy in large randomised trials.34,35,38,39 As demonstrated by the results of the DENERHTN trial,20 which showed a significant (and realistic) drop in ambulatory BP (mean adjusted difference in daytime systolic BP −5.9 mm Hg) in resistant hypertensive patients after renal denervation on top of a rational, standardised titration and add-on therapeutic scheme, an accurate definition of RH is crucial in order to select patients for invasive and expensive therapies. In conclusion, the debate on definition and treatment of RH is still open. The first, broader definitions of RH still retain an utility in identifying the subset of individuals requiring special attention by the clinician: in this subset of individuals, the hypertension specialist should be involved in order to exclude spurious forms of RH, including whitecoat RH, inappropriate therapeutic schemes and lack of adherence to treatment. Only the remaining individuals, those with true RH, should then undergo an extensive diagnostic workup for secondary causes of hypertension and other conditions whose removal might represent a benefit for BP control and then offered with innovative therapies if appropriate. In this view, RH can be still considered a special entity requiring special treatment.

Conclusion RH was defined many years ago as a clinical situation in which BP remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses. The broader, original definition should be used as a temporary label, useful for the identification of a subset of hypertensive patients requiring a more extensive clinical workup in order to achieve an adequate BP control, but does not represent per se a separate clinical entity requiring special treatment. This definition allowed a substantial proportion of patients with white-coat RH or suboptimal medical treatment to undergo, for example, renal denervation, while pseudoresistance to treatment might be responsible for about 95 % of cases of apparent RH.18 Conversely, a more stringent definition would require, as a minimum set of additive criteria the confirmation of uncontrolled BP by means of ambulatory BP monitoring, the verification of a rational combination therapy and the failure of add-on therapy with spironolactone; objective assessment of treatment compliance and a thorough screening for secondary causes of hypertension, followed by tailored treatment, should be implemented too. This approach will reduce the number of residual uncontrolled patients and will help improve BP control in the hypertensive population, possibly reducing also healthcare costs. n

monitoring. Hypertension 2011;57 :898–902. DOI: 10.1161/ HYPERTENSIONAHA.110.168948; PMID: 21444835 Kumbhani DJ, Steg PG, Cannon CP, et al. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis. Eur Heart J 2013;34 :1204–14. DOI: 10.1093/eurheartj/ehs368; PMID: 23144048 Daugherty SL, Powers JD, Magid DJ, et al. Incidence and

prognosis of resistant hypertension in hypertensive patients. Circulation 2012;125 :1635–42. DOI: 10.1093/eurheartj/ehs368; PMID: 23144048 Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens

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(PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015;386 :2059–68. DOI: 10.1016/S01406736(15)00257-3; PMID: 26414968 Pimenta E, Gaddam KK, Oparil S, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 2009;54 :475–81. DOI: 10.1161/ HYPERTENSIONAHA.109.131235; PMID: 19620517; PMCID: PMC2771382 Parati G, Lombardi C, Hedner J, et al. Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea. J Hypertens 2012;30 :633–46. DOI: 10.1097/HJH.0b013e328350e53b; PMID: 22406463. Thomopoulos C, Skalis G, Makris T. Resistant Hypertension: A Real Entity or a Phantom Diagnosis? J Clin Hypertens (Greenwich) 2015;17 :578–9. DOI: 10.1111/jch.12565; PMID: 25891442. Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;23 ;307:2161–8. DOI: 10.1001/ jama.2012.4366; PMID: 22618923. Hu X, Fan J, Chen S, et al. The role of continuous positive airway pressure in blood pressure control for patients with obstructive sleep apnea and hypertension: a metaanalysis of randomized controlled trials. J Clin Hypertens (Greenwich) 2015;17 :215–22. DOI: 10.1111/jch.12472; PMID: 25582849 Palagini L, Bruno RM, Gemignani A, et al. Sleep loss and hypertension: a systematic review. Curr Pharm Des 2013;19 :2409–19. PMID: 23173590 Bruno RM, Palagini L, Gemignani A, et al. Poor sleep quality and resistant hypertension. Sleep Med 2013;14 :1157–63. DOI: 10.1016/j.sleep.2013.04.020; PMID: 23993872 Bruno RM, Di Giulio A, Bernini G, et al. Device-based therapies for resistant hypertension. Curr Pharm Des 2013;19 :2401–8. PMID: 23173589 Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370 :1393–401. DOI: 10.1056/NEJMoa140267; PMID: 24678939 Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011;58 :765–73. DOI: 10.1016/j.jacc.2011.06.008; PMID: 21816315

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Hypertension

Clinical Diagnosis and Management of Resistant Hypertension C osta s P T sioufis , A l e x a n d r o s Ka s i a k o g i a s a n d D i m i t r i o s To u s o u l i s First Cardiology Clinic, University of Athens, Hippokration Hospital, Athens, Greece

Abstract Resistant hypertension (RHT) is variably defined as insufficient blood pressure (BP) response to multiple drug treatment. Prevalence of RHT has been thoroughly studied in the recent years, ranging from about 5 to 30 % in various cohorts. Initial management of patients with apparent RHT requires identification of true treatment resistance by out-of-office BP measurements, assessment of adherence and screening for treatable causes of uncontrolled BP. Endorsement of lifestyle modifications and maximisation of the doses of a suitable regimen, preferably with the further addition of an aldosterone antagonist, are the mainstay of treatment. An invasive approach to RHT, mainly represented by renal nerve ablation, should be kept for persistently severe cases managed in a specialised hypertension centre.

Keywords Resistant hypertension, uncontrolled blood pressure, hypertension, clinical management, diagnosis Disclosure: CPT has received a research grant, honoraria and travel expenses from St. Jude Medical, and honoraria and travel expenses from Medtronic. AK and DT have no conflicts of interest to declare. Received: 6 January 2016 Accepted: 5 May 2016 Citation: European Cardiology Review, 2016;11(1):12–7 DOI: 10.15420/ecr.2016:1:2 Correspondence: Costas Tsioufis, 108 Vas. Sofias Ave, 11527 Athens, Greece. E: ktsioufis@hippocratio.gr

Recent guidelines have defined resistant hypertension (RHT) as blood pressure (BP) that does not fall below 140/90 mmHg, despite a therapeutic strategy that includes appropriate lifestyle measures, plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses.1 The definition of RHT has been quite arbitrary, a fact reflected on various definitions of ideal drug dosing (e.g. optimal, appropriate, maximal tolerated), the still officebased BP approach and the inclusion of patients controlled with four drugs (irrespective of dose).1,2 Better understanding of the disease in the recent years has led to different reported prevalences of RHT compared to earlier reports. Data from earlier trials documented a prevalence of 15–30 %,3 but with a more thorough evaluation of treatment resistance, especially with the use of ambulatory BP monitoring, a prevalence of less than 10 % is more realistic, though higher numbers in specialised HT centres may apply.4,5 In clinical practice, causes of HT that is difficult to control may be classified into: a) incorrect characterisation as uncontrolled HT due to e.g. white-coat effect; b) inappropriate drug treatment or insufficient adherence to therapy and lifestyle measures; c) secondary forms of HT; d) true drug RHT. RHT has been associated with increased target organ damage and increased cardiovascular risk among hypertensives and high-risk patients.6,7 Patients with persistent RHT through time have been shown to have a more than twofold risk of cardiovascular morbidity compared to patients never having RHT.8 This review will focus on the clinical management of this high-risk population; a stepwise approach that may still require rolling back to previous steps is advised (see Figure 1).

Confirming the Diagnosis A patient with RHT represents one of the most complex cases in the field of HT, and referral and management in a specialised HT clinic is

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considered wise. Accordingly, a thorough clinical history and physical examination can provide significant information, while a proposed set of further tests is presented in Table 1. A number of clinical correlates of RHT have been variably documented in post-hoc analysis of clinical trials and large registries. These include older age, obesity, black race, diabetes mellitus, a volume overload state, left ventricular hypertrophy, albuminuria and chronic kidney disease (CKD).2,4,7–9 A long history of HT and isolated systolic HT are often identified. Proper diagnosis of the condition needs a series of careful checkpoints.

Identify Pseudoresistance Identification of pseudoresistance is a crucial step in the clinical diagnosis of RHT (see Table 2). It is defined as persistently uncontrolled HT at the clinic, for reasons other than true resistance to drug treatment; simple clinical tips can unmask many of these. Blood pressure should be measured according to current guidelines. A mismatch between the arm perimeter and the cuff bladder width (the latter wrongly being less than 80 % of the former) is a usual cause of spurious HT, as it can lead to recorded BP higher by 10–20 mmHg than true values. Falsely high BP may be recorded in older patients that have stiff, sclerotic arteries that remain palpable when the cuff exceeds systolic BP levels (Osler manoeuvre). A look at previous prescriptions indicating suboptimal drug combinations lacking a clear rationale, or insufficient dosing can help identify physician inertia. This may result from clinical inexperience, fear of side effects, guideline ignorance and ever-changing evidence of the optimal BP target.10,11 The most common cause of pseudoresistance, however, is the whitecoat effect that also extends to RHT. Therefore, performing ambulatory BP monitoring (or home BP recordings if the latter is unavailable) is a sine qua non in these patients. Analysis of 68,045 treated hypertensives in Spain showed that 12.2 % of patients had apparent RHT, but of those

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Resistant Hypertension

Figure 1: A Clinical Management Algorithm for the Patient with Apparent Resistant Hypertension

Evaluate Exclude pseudoresistance (out-ofoffice blood pressure measurements; adherence evaluation)

Optimise three-drug regimen (appropriate doses; appropriate combination)

Assess and manage secondary causes (comorbidities; concurrent medications)

Continued uncontrolled blood pressure Patient with true treatment-resistant hypertension

Manage Endorse lifestyle measures: weight loss and salt intake reduction

Optimise regimen (agents, doses, intervals) and add fourth drug (preferably spironolactone)

only one-third also had true RHT confirmed with ambulatory monitoring.5 Accordingly, risk of patients with white-coat RHT is expected to be significantly lower than in true RHT but higher than controlled HT.6 Whitecoat RHT may be clinically suspected when symptoms of overtreatment or lack of target organ damage are identified. Hypertension is a chronic asymptomatic condition that is often in need of multiple pills per day, usually for all lifetime. Adherence is traditionally defined as the extent to which a patient acts in accordance with the prescribed interval and dosing of a regimen, while persistence is the accumulation of time from initiation to discontinuation of therapy. In hypertensive patients, adherence measured by prescription refill frequency falls to less than 60 % in two years.12 It is thus imperative that issues concerning these patientrelated parameters are considered in apparent RHT as regimen complexity and drug intolerance are often. An inverse relationship exists between the number of drugs and daily doses and adherence.13 A series of methods to assess and manage adherence to treatment have been proposed in both research and clinical setting that include the BP response per se, regular follow-up visits, patient interview and diaries, pill counting, chemical markers of drugs, prescription refill records and electronic pill dispensers. Witnessed drug intake and further confirmation with ambulatory BP monitoring is the only method that ensures complete adherence but would not be practical outside a clinical study setting. Therapeutic drug monitoring by repeatedly measuring serum or urine drug concentrations (mostly by means of liquid chromatography-mass spectrometry) is a promising method that has been shown to be cost effective.14,15 Subsequently, confronting patients with low drug levels and providing further counselling has been reported to significantly improve BP control without drug intensification.16 Still, no optimal method exists, while even white-coat adherence has been reported as patients tend to improve their adherence before and after clinic visits. Fixed-dose combinations are endorsed in order to improve adherence, and highdose, three-drug combination pills are now widely available.17

Diagnose and Treat Causes of Insufficient BP Control Causes of secondary HT – affecting about 5–10 % of the general hypertensive population – may remain undiagnosed and potentially

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Consider interventional treatments if persistent true drug-resistant hypertension after 6 months

Table 1: Basic Testing in the Patient with Resistant Hypertension • Ambulatory blood pressure monitoring • 12-lead electrocardiogram • Transthoracic echocardiogram • Complete blood count • Serum glucose, urea, creatinine, electrolytes, lipids • Urine analysis (protein, erythrocytes, leukocytes) • 24-hour urine assessment for aldosterone, sodium and albumin • Plasma aldosterone concentration and renin • Thyroid stimulating hormone • Renal echocardiogram • Renal artery duplex

contribute to treatment resistance. Previously controlled HT or inexplicably high BP levels should raise suspicion. Primary hyperaldosteronism is the most common secondary cause, with a prevalence reaching 21 % in a cohort of true RHT patients.18 It is mostly found in patients 30–60 years old with increasing BP levels. Only about 40 % of patients have hypokalaemia. The plasma aldosterone-renin ratio (ARR) is considered to have higher sensitivity compared to other markers (aldosterone concentration or renin alone) for screening; yet age, concurrent drugs and method of collection affect the test results. It should be thoroughly performed according to current guidelines.19 The direct renin concentration assay, rather than plasma renin activity, is increasingly used. A low ratio of morning plasma aldosterone concentration in ng/dl to plasma renin activity in ng/ml/h (usual cut-off being 20–40) is a detection test that has a high negative predictive value.20 Its accuracy, however, is affected by salt intake, concurrent drugs and time of sampling. Preparation for the measurement includes: a) correction of hyperaemia and unrestricted sodium intake; b) discontinuation of drugs affecting ARR (aldosterone antagonists should be stopped for up to 6 weeks before testing) and switching to drugs with limited effects on ARR if needed (e.g. slow release verapamil, hydralazine and a1-antagonists); c) collection of blood in the morning after patient has been out of bed for at least 2 hours and seated for 5–15 minutes.19 A positive result should be confirmed with further tests

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Hypertension Table 2: Factors to be Considered in a Patient with Apparent Treatment Resistant Hypertension White-coat Effect Patient Management Issues Incorrect blood pressure measurement Physician inertia Inappropriate drug regimen Insufficient drug doses Adherence Issues Complicated regimen and dosing Financial issues Drug side effects Lack of disease perception Insufficient patient education Secondary Hypertension Renal parenchymal disease Renal artery stenosis Primary hyperaldosteronism Thyroid disease Cushingâ&#x20AC;&#x2122;s syndrome

gathered with a simple renal ultrasound that can image small or asymmetrical kidneys. Sodium and fluid retention, sympathetic and renin-angiotensin system (RAS) activation and functional vascular changes contribute to treatment resistance. Renal artery stenosis is by 90 % due to atherosclerotic lesions and should be suspected in patients of an older age, especially when atherosclerotic disease in other sites is present, reaching a prevalence of 70 % among patients undergoing cardiac catheterisation.24 Flash pulmonary oedemas and deteriorating renal function, especially shortly after application of RAS blockers, should pose suspicion. Imaging with duplex ultrasonography or computed tomography/ magnetic resonance will set the diagnosis. The uncommon form of fibromuscular dysplasia of the renal arteries may be effectively treated with balloon angioplasty with or without stent placement. Regarding atherosclerotic stenosis, as a series of randomised controlled trials failed to show a clear benefit of renal artery stenting,25,26 management requires a close follow-up of renal function and classic drug treatment. Drugs that block the RAS are not contraindicated unless there are bilateral lesions or a unilateral lesion in a solitary kidney.

Pheocromocytoma Aortic coarctation Conditions Affecting Blood Pressure Control Obstructive sleep apnoea Chronic kidney disease Significant obesity High salt intake High alcohol consumption Drug-induced Resistant Hypertension Nonsteroidal anti-inflammatory drugs Oral contraceptives Corticosteroids Sympathomimetics (e.g. decongestants) Erythropoetin Cancer drugs (e.g. bevacizumab) Cyclosporin Cocaine Licorice Ephedra

such as a captopril challenge or saline infusion test. An easy method is measurement of plasma aldosterone before and after intravenous administration of 2l 0.9 % saline in 4 hours (aldosterone levels <5 ng/dl indicating an unlikely diagnosis and >10 ng/dl a very likely diagnosis). Adrenal imaging with computed tomography is recommended for subtype testing and exclusion of a cancerous form. Bilateral adrenal vein sampling is needed to identify lateralisation of aldosterone secretion in cases of an adrenal adenoma. If this is the case, laparoscopic adrenalectomy is indicated in unilateral disease. Surgery is more likely to lead to a cure in milder forms and a shorter history of hypertension.21 In bilateral disease, such as adrenal hyperplasia, treatment is conservative with the application of mineralocorticoid receptor antagonists. Dosing of spironolactone starts low and can reach up to more than 200 mg daily with a close follow-up for side effects. The less potent eplerenone is mostly free of antiandrogen side-effects, yet requires multiple daily doses.22 Prevalence of RHT is very high in patients with CKD,23 which is easily diagnosed with estimation of glomerular filtration rate and urine analysis (protein, erythrocytes, leukocytes). Further data may be

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Obstructive sleep apnoea (OSA) has been extensively studied with respect to its association with HT.27 The pathophysiological triad of intermittent hypoxia, ever-sustained sympathetic activation and intrathoracic pressure swings has served as a solid background for numerous studies reporting a close link between OSA and HT. Accordingly, in the setting of OSA, a close association between fluid overload, aldosterone excess and development of RHT has been proposed.28 Simple clinical tests, such as measurement of neck circumference (cut-off being >40 cm) and inspection of the uvula, as well as the use of widely accepted questionnaires (the Epworth, which assesses daytime sleepiness, and the Berlin, which assesses the clinical probability of OSA) can set suspicion in order to ask for a diagnostic polysomnographic study.29 Continuous positive airway pressure (CPAP), albeit mildly efficient in reducing BP in normotensive or mildly hypertensive patients,30 is unequivocally suggested in RHT patients with at least moderate OSA.31 However, unlike previous data, a recent randomised controlled trial failed to show a solid benefit in RHT patients.32 A long list of drugs may induce raises in BP or blunt the effects of antihypertensives mostly by promoting vasoconstriction, salt and water retention and improper neurohormonal activation. Oral contraceptives, nonsteroidal anti-inflammatory drugs and aspirin, as well as sympathomimetics, such as some anorectics and locally applied drugs for nasal congestion, should be recorded in the patientsâ&#x20AC;&#x2122; history. In younger ages, recreational drugs such as cocaine and methamphetamines should also be considered. Herbal supplements that contain stimulants, such as ephedra, are often not reported by the patients. The BP response is largely idiosyncratic and these drugs should be withdrawn if possible to record the BP effect. Increased salt intake is a worldwide epidemic and salt intake affects the efficacy of RAS blockers and diuretics. Patients that are traditionally more salt-sensitive are diabetics, the elderly and those with CKD. A total sodium consumption of 2400 mg or 100 mmol/day (6 g or one teaspoon of salt) is advised in current guidelines.1 In a randomised cross-over study in patients with RHT, extremely low salt intake (2.8 g) compared to high salt intake (14 g) decreased BP by 23/9 mmHg.33 In clinical practice, salt consumption is preferably assessed via 24-hour

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urine sodium excretion. Normal salt excretion, indicating normal salt intake is usually defined as 24-hour urine sodium <220 mmol/24 h (5 g/24 h). Higher urine sodium excretion is associated with a need for a greater number of antihypertensive drugs to achieve sufficient BP control.34 In patients with excess salt excretion, a reduction in salt intake corresponding to a decrease by >50 mmol/ 24 h (optimally 75 mmol/24 h) is advised.35

Treatment

of plasma renin activity and higher levels of brain and atrial natriuretic peptides compared to controls, all representing intravascular fluid retention.40 A high sodium intake, an oedematous state and a large body mass index are traditionally used clinical indices to further increase the diuretic dose with or without the addition of a potassium sparing diuretic such as amiloride. On the other hand, an increase in serum creatinine is to be expected with diuretic use, especially in patients with CKD, while it variably reflects volume depletion when increasing urea levels are also documented.

Lifestyle Measures Lifestyle measures as suggested by current hypertension guidelines should be pursued in all patients with RHT.1 These include sodium restriction, weight loss, an increase in physical activity, smoking cessation and reduced alcohol consumption to less than two drinks a day for men and one drink a day for women.

Pharmacological Approach Optimising the Three-drug Regimen There are well-designed clinical guidelines for the drug management of HT that also apply to patients with RHT.1,2 Yet, there is a lack of trials that compare different drug treatments specifically for RHT. Different classes of drugs have different sites of action. From a mechanistic point of view, sympathetic overactivity, structural vascular changes and increased vascular resistance, renin-angiotensin-aldosterone axis activation and subclinical hypervolaemia are all target dysregulations of pharmacological treatment.36 The optimal drug combination is based on the clinical profile of each patient and the synergistic mechanisms of certain drug categories. For instance, a patient with coronary heart disease needs a beta-blocker while patients of African origin may not respond to RAS blockers. The most widely suggested first-choice, three-drug combination in RHT patients is an angiotensin converting enzyme inhibitor (or angiotensin receptor blocker), a calcium channel blocker (preferably of the dihydropyridine kind) and a thiazide diuretic. Chlorthalidone has been proposed to be superior to hydrochlorothiazide due to its longer duration of action as well as increased potency. At a dose of 25 mg/day, it offers greater 24-hour BP reduction than 50 mg/day hydrochlorothiazide, with the greatest difference observed at night, and may be tried in certain patients with RHT.37 A loop diuretic (furosemide or bumetanide preferably in multiple daily doses to avoid intermittent sodium retention) with or without a thiazide diuretic should be preferred in patients with a glomerular filtration rate below 30–40 ml/min/1.73 m2. Currently there are fixed combinations of up to three drugs and multiple dosing options in a single pill that are generally endorsed in order to improve adherence.17 However, certain drugs (e.g. captopril and centrally acting agents) require multiple daily doses. Evidence of a better BP response with evening administration of drugs in patients with RHT or OSA has also been published.38 Uncontrolled BP even after increasing the doses of a three-drug regimen to maximally tolerated levels is what defines RHT, and therefore escalation of drug doses is critical. This is particularly true for diuretics that are often under dosed. Previous clinical experience, manufacturer’s guide, side effects and patient response set the maximal dose for each drug. Still, it should be kept in mind that adding a drug is more effective than increasing the dose.39 It has also long been suggested that if extracellular fluid volume is expanded, increasing the drug doses will not have any memorable effect on BP. Indeed, patients with RHT have higher aldosterone levels, lower levels

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Adding More Drugs Adding a fourth drug, or more, may be decided early in the treatment plan or after all the previous steps have been exhausted. Of all second-line drugs, an aldosterone receptor blocker (spironolactone or eplerenone in about the double dose to minimise breast pain, gynaecomastia or sexual dysfunction) is the primary choice, in order to counteract the subclinical aldosterone excess and to intensify diuresis.41 In addition, it has been shown that aldosterone levels are not sufficiently suppressed even with dual RAS blockade.42 The drug effects are reportedly independent of baseline serum aldosterone and renin levels or presence of primary hyperaldosteronism. Earlier reports showed BP decreases of up to more than 25 mmHg with the addition of low dose spironolactone (12.5–25 mg daily),43 while the first randomised controlled trial of its kind documented a decrease of 8.6 mmHg in 24-hour ambulatory systolic BP.44 The recently published Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2) study showed that in patients carefully evaluated for true RHT, the addition of spironolactone 25–50 mg daily led to an approximately further 4 mmHg and 4.5 mmHg reduction in BP compared to doxazocin and bisoprolol respectively.45 Even these low doses of such drugs should be applied with caution in patients of older age or with CKD and potassium levels should be carefully monitored. Other second-line drugs may be tried with variable efficacy. Alphablockers are potent vasodilators with a double benefit in patients with benign prostate hyperplasia but with the risk of orthostatic hypotension,46 while some advocate the use of both alpha- and beta-blockade (e.g. carvedilol and labetalol) at least in patients with evidence of sympathetic activation. Drug-induced vasodilation and diuresis may stimulate cathecolamine secretion, further indicating the need for beta-blockade. Direct vasodilators such as hydralazine and centrally acting agents have been traditionally used with a variable clinical benefit and issues of adherence due to the need for multiple dosing and often side effects (namely symptomatic hypotension and fluid retention). Limited data are available for newer drug classes. Initially promising results for darusentan, an endothelin receptor blocker, were accompanied by data on often side effects such as fluid retention and deteriorated renal function.47 Other drugs include the recently introduced aldosterone synthase inhibitors, canrenone and neprilysin inhibitor.48,49

Interventional Treatment of Resistant Hypertension The submaximal rates of BP control even after drug optimisation, the solid pathophysiological concept and the advancements in technology that rekindled the interest in old practices, i.e. splachnic sympathectomy, lead to a burst in the development of and research on interventional approaches to HT.50 A series of methods have been developed that include renal nerve ablation (RNA), carotid

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Hypertension baroreceptor stimulation, central arteriovenous anastomosis, carotid bulb restoration and aortic stimulation.51 Among these, RNA is the richest method with respect to research and clinical data.

ablation covering all four quadrants as provided by basket or spirallike catheters and asymmetric as well as distal renal artery targeting is preferred.56

Catheter-based RNA is meant to halt efferent sympathetic signals to the kidney that lead to reduced renal flow, RAS activation and water retention, as well as afferent signals that, through the brain, augment the sympathetic action on the heart, vessels and neurohumoral loops. This is currently recommended for the treatment of patients with clinic systolic BP persistently ≥160 mmHg or diastolic BP ≥110 mmHg, after confirming true resistance to drug treatment and as long as the patient is managed in a specialised hypertension centre.1,52

Upcoming studies shall test an indication for RNA for younger ages with systolic/diastolic HT without a long history of disease, that have greater sympathetic nervous system activation and a more responsive arterial wall. Effects of RNA beyond BP lowering, such as in improvement of glucose metabolism and target organ damage, have been reported. The holy grail of RNA is still the identification of ad-hoc markers of the optimal BP response.57 Changes in renal norepinephrine spillover and renal haemodynamics are painstaking and have not been tested in large trials.58,59 From a study design point of view, the Renal Denervation for Hypertension (DENER HTN) trial set a new perspective as it showed that a prespecified stepped-care antihypertensive drug treatment with improved adherence helps reveal the antihypertensive effect of RNA beyond conventional treatment.60

Initial data were exciting as they provided evidence of large decreases in BP (up to 30 mmHg in office BP) with a relatively simple procedure. However, the Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-3) trial, the first randomised shamcontrolled study provided results of a non-significant effect on BP even in the longer term and thus led to a decrease in the enthusiasm.53 Symplicity HTN-3 was a well-performed study but certain issues, such as medication changes during follow-up that reached a mean 40 % in both active and control groups, adherence to medication, technical aspects of the procedure and subgroup characteristics, revealed that RNA is a complex therapy with an effect influenced by multiple factors.54 Technical issues are unsettled; the identification of the optimal number, depth and temperature of ablations, whether only the main renal artery or its branches or segment arteries should be ablated or whether small renal arteries (<4 mm), accessory or polar arteries should be treated.55 Currently a circumferential pattern of

Mancia G, Fagard R, Narkiewicz K, et al. Task Force Members. ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31 :1281–357. DOI: 10.1097/01.hjh.0000431740.32696.cc; PMID: 23817082 Calhoun DA, Jones D, Textor S, et al. American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 2008;117 :e510–26. DOI: 10.1161/CIRCULATIONAHA.108.189141; PMID: 18574054 Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003;290 :2805–16. PMID: 14657064 Brambilla G, Bombelli M, Seravalle G, et al. Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe: data from the BP-CARE study. J Hypertens 2013;31 :2018–24. DOI: 10.1097/ HJH.0b013e328363823f; PMID: 23838657 de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension 2011;57 :898–902. DOI: 10.1161/ HYPERTENSIONAHA.110.168948; PMID: 21444835 Pierdomenico SD, Lapenna D, Bucci A, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005;18 :1422–8. PMID: 16280275 Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens 2014;32 :635–43. DOI: 10.1097/HJH.0000000000000051; PMID: 24299915; PMCID: PMC4118668 Tsioufis C, Kasiakogias A, Kordalis A, et al. Dynamic resistant hypertension patterns as predictors of cardiovascular morbidity: a 4-year prospective study. J Hypertens 2014;32 :415–22. DOI: 10.1097/HJH.0000000000000023; PMID: 24241057 Egan BM, Zhao Y, Axon RN, et al. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation 2011;124 :1046–58. DOI: 10.1161/ CIRCULATIONAHA.111.030189; PMID: 21824920; PMCID: PMC3210066

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Conclusion Knowledge and management of RHT has matured in recent years with the help of new epidemiological data, wider application of outof-office BP measurements and the introduction of interventional treatments. Clinical practitioners should first focus on diagnosing true RHT, defined as a properly measured office BP of ≥140/90 mmHg with uncontrolled 24-hour BP in a patient confirmed to be taking at least a triple antihypertensive regimen (preferentially a diuretic, a RAS blocker and a calcium channel blocker) at tolerated doses. Accordingly, correct drug manipulation will help resolve some cases while others may benefit from an invasive approach. ■

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medications: plasma aldosterone-renin ratio. Am J Kidney Dis 2001;37 :699–705. PMID: 11273868 21. Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients. Hypertension 2008;51 :1366–71. DOI: 10.1161/ HYPERTENSIONAHA.108.111369; PMID: 18347224 22. Parthasarathy HK, Menard J, White WB, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens 2011;29 :980–90. DOI: 10.1097/HJH.0b013e3283455ca5; PMID: 21451421 23. de Beus E, Bots ML, van Zuilen AD, et al. MASTERPLAN Study Group. Prevalence of apparent therapy-resistant hypertension and its effect on outcome in patients with chronic kidney disease. Hypertension 2015;66 :998–1005. DOI: 10.1161/HYPERTENSIONAHA.115.05694; PMID: 26351024 24. Aqel RA, Zoghbi GJ, Baldwin SA, et al. Prevalence of renal artery stenosis in high-risk veterans referred to cardiac catheterization. J Hypertens 2003;21 :1157–62. PMID: 12777953 25. Wheatley K, Ives N, Gray R, et al. Revascularization vs. medical therapy for renal-artery stenosis. N Engl J Med 2009;361 :1953–62. DOI: 10.1056/NEJMoa0905368; PMID: 19907042 26. Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med 2014;370 :13–22. DOI: 10.1056/NEJMoa1310753; PMID: 24245566; PMCID: PMC4815927 27. Tsioufis C, Kasiakogias A, Thomopoulos C, et al. Managing hypertension in obstructive sleep apnea: the interplay of continuous positive airway pressure, medication and chronotherapy. J Hypertens 2010;28 :875–82. DOI: 10.1097/ HJH.0b013e328336ed85; PMID: 20087211 28. Pimenta E, Stowasser M, Gordon RD, et al. Increased dietary sodium is related to severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism. Chest 2013;143 :978–83. DOI: 10.1378/chest.12-0802; PMID: 23288434; PMCID: PMC3616687 29. Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension 2011;58 :811–7. DOI: 10.1161/HYPERTENSIONAHA.111.179788; PMID: 21968750 30. Kasiakogias A, Tsioufis C, Thomopoulos C, et al. Effects of continuous positive airway pressure on blood pressure in hypertensive patients with obstructive sleep apnea: a 3-year follow-up. J Hypertens 2013;31 :352–60. DOI: 10.1097/ HJH.0b013e32835bdcda; PMID: 23235356

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42. McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999;100 :1056–64. PMID: 10477530 43. Lane DA, Shah S, Beevers DG. Low-dose spironolactone in the management of resistant hypertension: a surveillance study. J Hypertens 2007;25 :891–4. PMID: 17351384 44. Václavík J, Sedlák R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011;57 :1069–75. DOI: 10.1161/ HYPERTENSIONAHA.111.169961; PMID: 21536989 45. Williams B, MacDonald TM, Morant S, et al. British Hypertension Society’s PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, doubleblind, crossover trial. Lancet 2015;386 :2059–68. DOI: 10.1016/S0140-6736(15)00257-3; PMID: 26414968; PMCID: PMC4655321 46. Chapman N, Chang CL, Dahlöf B, et al. ASCOT Investigators. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial. Circulation 2008;118 :42–8. DOI: 10.1161/ CIRCULATIONAHA.107.737957; PMID: 18559700 47. Weber MA, Black H, Bakris G, et al. A selective endothelinreceptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, doubleblind, placebo-controlled trial. Lancet 2009;374 :1423–31. DOI: 10.1016/S0140-6736(09)61500-2; PMID: 19748665 48. Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant 2013;28 :36–43. DOI: 10.1093/ndt/gfs388; PMID: 23045428 49. Bavishi C, Messerli FH, Kadosh B, et al. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J 2015;36 :1967–73. DOI: 10.1093/eurheartj/ehv142; PMID: 25898846 50. Papademetriou V, Rashidi AA, Tsioufis C, et al. Renal nerve ablation for resistant hypertension: how did we get here, present status, and future directions. Circulation 2014;129 :1440–51. DOI: 10.1161/ CIRCULATIONAHA.113.005405; PMID: 24687645 51. de Leeuw PW, Alnima T, Lovett E, et al. Bilateral or unilateral stimulation for baroreflex activation therapy. Hypertension

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2015;65 :187–92. DOI: 10.1161/HYPERTENSIONAHA.114.04492; PMID: 25331845 Tsioufis C, Mahfoud F, Mancia G, et al. What the interventionalist should know about renal denervation in hypertensive patients: a position paper by the ESH WG on the interventional treatment of hypertension. EuroIntervention 2014;9 :1027–35. DOI: 10.4244/EIJV9I9A175; PMID: 24457275 Bakris GL, Townsend RR, Flack JM, et al. SYMPLICITY HTN-3 Investigators. 12-month blood pressure results of catheterbased renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial. J Am Coll Cardiol 2015;65:1314–21. DOI: 10.1016/j.jacc.2015.01.037; PMID: 25835443 Papademetriou V, Tsioufis C, Doumas M. Renal denervation and Symplicity HTN-3: “Dubium sapientiae initium” (doubt is the beginning of wisdom). Circ Res 2014;115 :211–4. DOI: 10.1161/CIRCRESAHA.115.304099; PMID: 24989489 Mahfoud F, Böhm M, Azizi M, et al. Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. Eur Heart J 2015;36 :2219–27. DOI: 10.1093/eurheartj/ehv192; PMID: 25990344 Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 2013;34 :2132–40. DOI: 10.1093/eurheartj/eht197; PMID: 23782649; PMCID: PMC3717311 Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J 2015;36 :219–27. DOI: 10.1093/eurheartj/ehu441; PMID: 25400162; PMCID: PMC4301597 Grassi G, Seravalle G, Brambilla G, et al. Blood pressure responses to renal denervation precede and are independent of the sympathetic and baroreflex effects. Hypertension 2015;65 :1209–16. DOI: 10.1161/ HYPERTENSIONAHA.114.04823; PMID: 25824245 Tsioufis C, Papademetriou V, Dimitriadis K, et al. Catheterbased renal sympathetic denervation exerts acute and chronic effects on renal hemodynamics in swine. Int J Cardiol 2013;168 :987–92. DOI: 10.1016/j.ijcard.2012.10.038; PMID: 23164584 Azizi M, Sapoval M, Gosse P, et al. Renal Denervation for Hypertension (DENERHTN) investigators. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015;385 :1957–65. DOI: 10.1016/ S0140-6736(14)61942-5; PMID: 25631070

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Guest Editorial Challenges in Resistant Hypertension Th o m a s Ka h a n Karolinska Institute, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine; Department of Cardiology, Danderyd University Hospital Corporation, Stockholm, Sweden

Abstract Hypertension is the major risk factor for disease and premature death. Although the efficacy of antihypertensive therapy is undisputed, few patients reach target blood pressure. Steps to improve treatment and control include assessment of global cardiovascular risk for the individual patient, improving caregiver support, education and organisation, increasing treatment persistence, using out of office blood pressure monitoring more often, detecting secondary hypertension forms, and referring patients with remaining uncontrolled hypertension to a specialist hypertension centre. In conclusion, there is room for improvement of blood pressure control in hypertensive patients. The clinical benefit of improved blood pressure control may be considerable. This may be particularly true for patients with resistant hypertension.

Keywords Prognosis, resistant hypertension Disclosure: Thomas Kahan has received research grants from Medtronic, Pfizer, ReCor and Servier; all outside the submitted work. Citation: European Cardiology Review, 2016;11(1):18–9 Correspondence: Thomas Kahan, Department of Cardiology, Danderyd University Hospital Corporation, SE-182 88 Stockholm, Sweden. E: thomas.kahan@ds.se

High blood pressure is the major risk factor for disease and premature death worldwide.1 The associations between blood pressure and fatal coronary artery disease and fatal stroke have been well demonstrated.2 Also, associations between blood pressure and morbidity and mortality on specific cardiovascular disease conditions in different age groups, and results concerning the lifetime risk for specific cardiovascular complications associated with hypertension have recently been reported.3 The efficacy of antihypertensive drug therapy is undisputed. However, observational studies show that few patients reach target blood pressure.4 We must thus take several steps to improve antihypertensive treatment and control: • Assessment of global cardiovascular risk is essential to offer the best treatment for the individual patient. • Improve caregiver support, education and organisation. • Consider factors that influence drug adherence, reduce drug discontinuation rate and increase treatment persistence to prescribed treatment. • Increase the use of home blood pressure monitoring and ambulatory blood pressure monitoring to identify patients with a white coat effect, improve risk stratification and increase patient engagement. • Consider secondary hypertension forms in patients with apparent resistant hypertension. • C onsider referring patients with remaining uncontrolled hypertension to a specialist hypertension centre, as most patients can be well controlled.

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Firstly, assessment of global cardiovascular risk is essential to offer the best treatment for the individual patient. Risk assessment can be achieved by taking cardiovascular risk markers, blood pressure level and other risk factors, signs of hypertensive target organ damage, and concomitant cardiovascular and other disease conditions into account.5 Secondly, we should consider improving caregiver support and education. Caregivers may think that side effects with antihypertensive drugs treatment are a problem, or that the available evidence to treat high blood pressure in some people is insufficient. However, evidence suggests that quality of life is improved by antihypertensive treatment6,7 and there is evidence of the benefit of treating elderly hypertensive patients.7 Drugs may be prescribed with an inappropriate dosing or inadequate drug combinations may be used. Recent evidence shows that adding a mineralocorticoidreceptor antagonist to patients with apparent treatment resistant hypertension provides better blood pressure reduction than other drug classes.8 Caregiver organisation and systematic follow-up may also need improvement. Thirdly, key factors to improve drug compliance and treatment persistence must be better understood. We have reported that 35 % of patients attending primary healthcare newly initiated on antihypertensive drug therapy discontinued treatment within 2 years.9 Male patients, younger age, mild blood pressure elevation, low income and birth in a foreign country were factors associated with discontinuation. Of note, discontinuation rates were similar for all major antihypertensive drug classes when comorbidity and other potential confounding factors were taken into account (which has

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Guest Editorial: Resistant Hypertension

rarely been done in previous studies).10 Also, in patients referred for apparent treatment resistant hypertension, many do not appear to take their prescribed medication.11 Fourthly, the use of home blood pressure monitoring and ambulatory blood pressure monitoring is important. The use of out of office blood pressure monitoring will identify patients with a white coat effect, improve risk stratification and increase patient engagement. Finally, approximately one out of ten hypertensive patients have secondary forms of hypertension, of which primary aldosteronism, renal hypertension and obstructive sleep apnoea are considered the most common causes. Patients with secondary hypertension can often be offered specific treatment and are thus important to identify, in particular among people with apparent treatment resistant hypertension. Of note, standard screening procedures to assess the aldosterone-to-renin ratio in blood to indicate a diagnosis of primary aldosteronism have been much simplified in recent guidelines, as compared with previous recommendations.12 Screening for renal hypertension can now largely be performed by non-invasive renal ultrasound and renal artery duplex ultrasound, with no exposure to contrast media or radiation. Screening methods for obstructive sleep apnoea are also simplified with a trend for assessment of fewer variables, computerised air flow evaluation and automated analyses for improved diagnostic accuracy. Several guidelines and recommendations define resistant hypertension as a blood pressure ≥140/90 mm Hg despite treatment with three different antihypertensive drug classes, appropriately chosen and dosed, and often a thiazide diuretic is mandatory.5 Apparent resistant hypertension is prevalent in approximately 10 % of all treated hypertensive patients attending primary healthcare, and is associated with concomitant cardiovascular disease and diabetes mellitus.13 More important, apparent resistant hypertension is associated with a worse prognosis, when blood pressure levels and comorbidity are also taken into account. Thus, it is particularly important to identify patients with apparent resistant hypertension, and to bring their blood pressure under control. In this context, the comprehensive overview of the diagnosis and management of resistant hypertension by Tsioufis and colleagues in this issue of European Cardiology

Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380 :2224–60. DOI: 10.1016/ S0140-6736(12)61766-8; PMID: 23245609 Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360 :1903–13. PMID: 12493255 Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases; life time risks, healthy years lost, and age-specific associations in 1.25 million people. Lancet 2014;383 :1899–911. DOI: 10.1016/ S0140-6736(14)60685-1; PMID: 24881994 Qvarnström M, Wettermark B, Ljungman C, et al. Antihypertensive treatment and control in a large primary care population of 21167 patients. J Hum Hypertens 2011;25 :484–91. DOI: 10.1038/jhh.2010.86; PMID: 20720572 Mancia G, Fagard R, Narkiewitcz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34 :2159–219. DOI: 10.1093/eurheartj/eht151; PMID: 23771844

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Review is of great value.14 The authors correctly emphasise the importance to recognise the many reasons for apparent resistant hypertension, and how this is best performed in clinical practice. It is important to appreciate that most patients with apparent resistant hypertension can be well controlled when referred to a specialist hypertension centre.15 However, some patients continue to present true drug treatment resistant hypertension. As described by Tsioufis et al.,14 other interventional techniques to lower blood pressure can be considered in these patients. The first studies of catheter-based endovascular renal sympathetic denervation in patients with treatment resistant hypertension showed marked and sustained reductions in office blood pressure. However, these initial studies were generally uncontrolled or limited to a non-interventional control arm and included patients based on their office blood pressure values.16 Indeed, compared with office blood pressure measurements, the effects of renal denervation on ambulatory blood pressure were considerably smaller. More recently, some randomised controlled studies have failed to show reductions in office blood pressure or ambulatory blood pressure by renal denervation.6 Current focus on endovascular renal sympathetic denervation is on: • the development of new devices and procedures to ascertain successful renal nerve ablation; • identifying the proper target population to offer renal denervation; • improvement and control of drug persistence; and • the use of ambulatory blood pressure monitoring for patient selection and evaluation of efficacy. Interventional techniques other than renal nerve ablation included baroreceptor activation therapy, with promising preliminary results in patients with resistant hypertension.17 In conclusion, there is room for improvement of blood pressure control in hypertensive patients. The clinical benefit of an improved risk assessment and appropriate treatment may be considerable. This may be particularly true for patients with resistant hypertension. ■

Wiklund I, Halling K, Rydén-Bergsten T, Fletcher A. Does lowering the blood pressure improve the mood? Quality-of-life results from the Hypertension Optimal Treatment (HOT) study. Blood Press 1997 ;6 :357–64. PMID: 9495661 7. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358 :1887–98. DOI: 10.1056/NEJMoa0801369; PMID: 18378519 8. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015;386 :2059–68. 9. Qvarnström M, Kahan T, Kieler H, et al. Persistence to antihypertensive drug treatment in Swedish primary healthcare. Eur J Clin Pharmacol 2013;69 :1955–64. DOI: 10.1007/s00228-013-1555-z; PMID: 23857249 10. Qvarnström M, Kahan T, Kieler H, et al. Persistence to antihypertensive drug classes: A cohort study using the Swedish Primary Care Cardiovascular Database (SPCCD). Medicine (In press). 11. Strauch B, Petrák O, Zelinka T, et al. Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis. J Hypertens 2013;31 :2455–61. DOI: 10.1097/ HJH.0b013e3283652c61; PMID: 24220593

12. Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101 :1889–916. DOI: 10.1210/ jc.2015-4061; PMID: 26934393 13. Holmqvist L, Bengtsson Boström K, Kahan T, et al. Prevalence of treatment resistant hypertension, and important associated factors – Results from the Swedish Primary Care Cardiovascular Database (SPCCD). J Am Soc Hypertens (In press). 14. Tsioufis C, Kasiagoigias A, Tousoulis D. Clinical diagnosis and management of resistant hypertension. Eur Cardiol Rev 2016;11 :12–7. 15. Persu A, Jin Y, Baelen M, et al. Eligibility for renal denervation: experience at 11 European expert centers. Hypertension 2014;63 :1319–25. DOI: 10.1161/ HYPERTENSIONAHA.114.03194; PMID: 24664290 16. Persu A, Kjeldsen S, Staessen JA, Azizi M. Renal Denervation for Treatment of Hypertension: a Second Start and New Challenges. Curr Hypertens Rep 2016;18 :6. DOI: 10.1007/ s11906-015-0610-9; PMID: 26739586 17. Hoppe UC, Brandt MC, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens 2012;6 :270–6. DOI: 10.1016/j.jash.2012.04.004; PMID: 22694986

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Cardiac Imaging | Myocarditis | Endocarditis

Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis R oc io Hinojar 1 ,2 , E i k e N a g e l 1 a n d V a l e n t i n a O Pu n t m a n n 1 ,3 1. Institute for experimental and translational cardiovascular Imaging, Goethe University Hospital Frankfurt, Frankfurt, Germany; 2. Department of Cardiology, University Hospital Ramón y Cajal, Alcala University, Madrid, Spain; 3. Department of Cardiology, Division of Internal Medicine III, Goethe University Hospital Frankfurt, Frankfurt, Germany

Abstract Tissue characterisation capabilities are continuing to evolve and proving to be valuable in the non-invasive diagnosis of clinicallyheterogeneous manifestations of myocarditis. The authors investigate how cardiovascular magnetic resonance imaging offers an increasingly reliable alternative to invasive biopsy for clinically-stable patients, and how this tool – with further longitudinal study – will improve the overall understanding of the natural course of myocarditis.

Keywords Inflammation, myocarditis, Lake Louise criteria, T1 and T2 mapping Disclosure: The authors have no conflicts of interest to declare. Received: 29 May 2016 Accepted: 29 June 2016 Citation: European Cardiology Review, 2016;11(1):20–4 DOI: 10.15420/ecr.2016:18:2 Correspondence: Dr Valentina O Puntmann, Department of Cardiology, Division of Internal Medicine III, Goethe University Frankfurt, Frankfurt, Germany. E: vppapers@icloud.com

Myocarditis is difficult to diagnose due to its heterogeneous clinical presentation. Patients often present with nonspecific symptoms and there is no easy-to-use and widely available diagnostic test. Although the clinical manifestations of myocarditis are heterogeneous, up to one-third of cases progress toward dilated cardiomyopathy (DCM).1,2 Myocarditis is a major cause of DCM, which is a significant cause of heart failure and sudden cardiac death in young adults.3 DCM due to myocarditis is the major underlying reason for cardiac transplantation. Patients with acute myocarditis often present with acute coronary syndrome-like symptoms;3,4 those with chronic myocarditis are likely to have symptoms of DCM and heart failure. Myocarditis due to viral infection is the most common and best understood clinical presentation of inflammatory cardiomyopathy;5,6 however, other triggers, including systemic autoimmune inflammation and cardiac toxins such as alcohol and chemotherapy, are also increasingly recognised causes of myocarditis.7,8 Irrespective of the original trigger, the pathophysiology of myocardial injury in all forms of myocarditis is underlined by autoimmune myocardial inflammation that progresses through several disease stages. After the initial trigger, acute myocarditis is characterised by inflammation, oedema and necrosis due to autoimmune responses to cardiac antigens, leading to regional myocardial injury and scarring.8,9 The chronic stage features diverse phenotypes, including healed myocardium (with possible residual scarring) or latent low-grade autoimmune myocardial inflammation, leading to remodelling, DCM and heart failure (Figure 1).10,11 There are several challenges in the clinical management of myocarditis.12 There is no specific treatment available for myocarditis or its sequelae. Studies using anti-inflammatory treatment in haemodynamically-stable

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patients have not shown any benefit, partly because they have recruited chronic myocarditis patients in the advanced stages of DCM and heart failure.7 The broad range of clinical manifestations may also present a challenge. Despite significant research, little is known about the mechanisms involved in post-inflammatory cardiac remodelling leading to DCM. Alterations in the myocardial extracellular matrix by matrix metalloproteinases and tissue inhibitors of metalloproteinases are critical during myocardial fibrosis and cardiac remodelling; however, the pathways that lead to progression to DCM are unclear. Studies on experimental models of myocarditis have led to the discovery that the autoimmune inflammatory process plays a decisive role in acute inflammatory injury and progression to chronic inflammation and remodelling.6,8,13 The interplay between the pro- and anti-inflammatory cytokine pathways seems to determine the course of disease, and in predisposed individuals leads to the development of DCM.13–17 The role of interleukin-17 in moderating the progression from acute myocarditis to chronic inflammation and remodelling has been highlighted in several studies.10,14,18 In animal models, short-term use of anti-interleukin-17 has ameliorated the disease, identifying a potential treatment target.19–21 In line with European Society of Cardiology clinical practice guidelines, the diagnosis of myocarditis relies on confirmation by endomyocardial biopsy.8 This is an invasive, complex procedure with attendant risks and variable diagnostic yield. With expertise largely limited to the tertiary centres, the use of endomyocardial biopsy in clinical practice varies; in most centres it is reserved for patients with severe presentation and an aggressive disease course, where histological confirmation of giant cell myocarditis offers the hope of treatment with steroids. In addition to the issues already outlined, its limited sensitivity as a result of sampling-error and inconsistencies regarding

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CMR and Myocarditis

the histological and immunohistochemical criteria for diagnosis have restricted its use.22 The lack of a simple, reliable non-invasive test leaves a considerable proportion of patients undiagnosed and has contributed to the difficulty in finding new treatments as patients often present with advanced disease that is harder to manage. Cardiovascular magnetic resonance (CMR) imaging is gaining recognition over and above the other non-invasive imaging techniques in the diagnosis of clinicallystable patients.23,24 In addition to its more accurate measurement of biventricular volumes and systolic function, CMR imaging is capable of giving clues as to the presence and distribution of inflammatory damage in the myocardium through its tissue characterisation capabilities. CMR imaging based on the Lake Louise criteria (LLC) represented the first steppingstone to a non-invasive diagnostic option.25 Previous studies had found a variable correlation between clinical and histological evidence of myocarditis and abnormal findings in CMR imaging when focusing on the three main hallmarks of myocardial inflammation: oedema, hyperaemia/capillary leak and necrosis or fibrosis. CMR-LLC is based on a comprehensive protocol that includes T2-weighted, T1-weighted (before and immediately after contrast administration) and late gadolinium enhancement (LGE) imaging sequences. Positive findings include the identification of oedema on T2-weighted images (oedema ratio >1.9 or qualitative presence of an area of regional high signal intensity), hyperaemia and capillary leakage on T1-weighted images (increased global myocardial early gadolinium enhancement ratio between the myocardium and skeletal muscle; relative enhancement ratio >4), and at least one focal lesion with non-ischaemic regional distribution in sequence. Several LGE patterns are characteristic in patients with myocarditis. Areas of focal LGE are typically localised to the sub-epicardial regions of the left ventricle and extend to a variable extent through the ventricular wall. LGE may, however, appear patchy or diffuse. The sub-endocardium is not usually involved, allowing differentiation from ischaemic injury. Any LGE/T2 pattern or finding can definitively suggest the different aetiology of myocardial inflammation. Although additional findings – such as pericardial effusion, global or regional left ventricular systolic function, or transient increase in wall thickness – may support the diagnosis of active myocarditis, they are not included in the proposed diagnostic criteria. In the current guidelines, CMR supports endomyocardial biopsy, by informing on the likelihood of myocarditis prior to the procedure.8 The strength of LLC is in allowing confirmation of disease when the imaging findings are present, leading to improved insights of disease in terms of its natural history and sequelae. It supports the diagnosis in a significant percentage of patients; however it lacks sufficient sensitivity, i.e. it has poor ability to exclude disease, despite giving a convincing clinical picture. This is due to the limitations of the criteria used to detect the more diffuse inflammatory involvement of acute myocarditis. The predominant diffuse myocardial inflammation and intracellular and interstitial oedema7 leads to insufficient regional redistribution of gadolinium, which results in a normal LGE image.26 Abundant interstitial oedema and faster water exchange with cells with dysfunctional membranes lead to magnetisation transfer from the extracellular gadolinium to the intracellular water, further reducing the contrast.27 Similarly, appreciation of the increased T2 signal intensity relies on regional differences. The oedema ratio is based on the relative comparison of signal to skeletal muscle. This can be also affected, thus resulting in a pseudo-normalised value.28

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Figure 1: Natural Course of Myocarditis as Seen by Cardiovascular Magnetic Resonance using Quantitative Techniques and Late Gadolinium Enhancement

Acute phase (days‐weeks)

Chronic phase (months) Complete resolution of inflammation (normal nativeT1 and T2)

Healed

Acute myocarditis

LGE

Chronic myocarditis

DCM

Oedema Necrosis Inflammation

Heart failure

Diffuse fibrosis Inflammation

Diffuse fibrosis

native T1 +++

native T1 ++

native T2 +++

native T2 ++

native T2 ‐/+

T1 and T2 mapping readouts reflect the phenotypical expression of the complex pathophysiology underlying the different stages of myocardial inflammation. Acute myocarditis is defined by widespread intracellular changes related to viral replication and an extracellular spill of debris within days of viral infection, followed by an acute inflammatory response and autoimmune reactions. This initial stage is defined by ‘markedly’ increased native T1 (>5 standard deviations [SD] above the normal range) and T2 values reflecting the underlying oedema, hyperaemia/capillary leak and necrosis that are expected in active myocardial inflammation. Subsequent convalescence or healing stages are characterised by contained disease with regional scarring (non-ischaemic area of late gadolinium enhancement and normal readouts of native T1 and T2) or chronic prolonged low-grade inflammation and diffuse fibrosis, defined with slightly increased T1 (2–5 SD above the normal range) and T2 values. Both stages can result in myocardial remodelling and dilated cardiomyopathy leading to heart failure. In this end-stage phase, native T1 will remain slightly increased and T2 may or may not be high depending on the presence of inflammation. Commonly, however, there is complete resolution of changes (defined by normal native T1 and T2). DCM = dilated cardiomyopathy; LGE = late gadolinium enhancement.

Figure 2: Representative Images of Conventional Cardiovascular Magnetic Resonance Findings in Acute Myocarditis

Upper panel. (A) Short axis. (B) Four-chamber view. T2-weighted imaging enables visualisation areas of myocardial oedema in the lateral wall concordant with regional late gadolinium enhancement with an epi- and mid-myocardial distribution (arrows). Lower panel. (C) Late gadolinium enhancement imaging, short axis. (D) Four-chamber view.

Relative enhancement is technically limited by low reproducibility and susceptibility to artefacts. The contribution of relative enhancement to diagnostic accuracy was based on two relatively small studies27–30 and was subsequently shown to be of little relevance; a prospective study applying LLC with T2 and/or LGE resulted in higher diagnostic

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Cardiac Imaging | Myocarditis | Endocarditis Figure 3: Representative Images of Conventional Cardiovascular Magnetic Resonance Findings in Chronic Myocarditis

Upper panel. (A, B, C) Normal T2 images without areas of increased regional signal. Lower panel. (D, E, F) Epicardial layer of late gadolinium enhancement in the inferolateral wall (red arrows).

Figure 4: Representative T1 and Late Gadolinium Enhancement Imaging in Acute and Chronic Myocarditis ACUTE MYOCARDITIS

T1 map

1,246 msec

LGE

1,372 msec

CHRONIC MYOCARDITIS

3T Normal range: <1,090 msec (1,050 msec ± 20 msec)

T1 map

LGE

1,100 msec

Both stages (acute and chronic) show patchy areas of late gadolinium enhancement with a typical distribution (arrows). An increased native T1 value of 5 SD or more above the mean of the normal range confirms the acute stage of disease, whereas chronic myocarditis is characterised by a low degree of persistent inflammation (native T1 within 2-5 SD above the normal range). LGE = late gadolinium enhancement.

accuracy and negative predictive value in comparison to any two out of three approach.31 As such, the Society for Cardiovascular Magnetic Resonance recommendations classify the relative enhancement ratio as ‘optional’ in the myocarditis imaging protocol.32 When CMR imaging is performed in patients with chronic myocarditis or symptoms of heart failure the diagnostic challenge is even harder: the predominant signs (if present) are the functional impairment and non-ischaemic LGE patterns (midwall stria), which may more readily underpin the diagnosis of idiopathic DCM.33–35 Persistent low-grade interstitial myocardial inflammation is not visualised with T2-imaging or picked up by LGE, which will only reveal the presence of residual and regional cell death. These patients frequently remain unidentified and are classified as having non-specific nonischaemic DCM.34,36,37

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Figure 5: Representative Findings in a Health Subject and in Subjects with Acute and Chronic Myocarditis

Representative images of cine, T2-weighted, late gadolinium enhancement imaging and T1 mapping using the modified look-locker sequence in a healthy subject (A, B, C, D), acute myocarditis (E, F, G, H) and chronic myocarditis (I, J, K, L). Native T1 in (D) a healthy subject: 1,049 msec, (H) acute myocarditis: 1,195 msec and (L) chronic myocarditis: 1,108 msec.

Novel CMR Techniques In the past few years, novel quantitative techniques have been developed and have evolved rapidly, leading to the expectation that they will improve the understanding of non-ischaemic cardiomyopathies. Parametric maps encoding quantitative measurement of magnetic T1 and T2 relaxation times have enabled more detailed tissue characterisation, offering the possibility of overcoming some of the limitations of LLC in the diagnosis of myocarditis. Both parameters have shown superior diagnostic performance compared to LLC, significantly adding to the ability of CMR to confirm or exclude the presence of myocardial inflammation.37–39 T1 and T2 mapping has outperformed relative enhancement and T2-weighted imaging in clinical studies with active myocarditis. Evidence supports the use of native T1 and T2 measurements to detect myocardial inflammation over and above T2-weighted imaging, given its higher sensitivity to detect water.38,39 Native T1 and T2 reflect the intracellular and diffuse interstitial components of inflammation. Furthermore, as the inflammatory response (i.e. oedema and hyperaemia) is expected to regress after the early acute stage, native T1 shows a progressive reduction over time.38 The readouts of both parameters have the potential to approximate pathophysiological complexity during the different stages and grades of acute myocarditis. Convalescent stages of the disease can be defined by quiescent readouts (native T1 within normal range, absence of LGE, areas of resolved injury by LGE), or a low-grade persistent inflammation (native T1 within 2-5 standard deviations above the normal range, presence or absence of LGE) (Figure 1). Native T2 mapping has improved our understanding of the underlying pathological processes in the different stages of myocardial inflammation and deciphered the nature of the signal captured with T1 mapping, particularly in the chronic stages where native T1 also reacts to diffuse fibrosis.37,40 Native T2 has higher diagnostic accuracy than LLC in the detection of myocarditis in patients with chronic myocarditis and recent-onset heart failure and reduced left ventricular function.33 A recent study investigated concordance between quantitative techniques and histological readouts in myocarditis, showing a good concordance between T1 and T2 mapping and histological evidence of myocardial inflammation. Furthermore, whereas native T1 was

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CMR and Myocarditis

able to detect all patients with abnormal myocardium, native T2 identified those subjects with chronic myocarditis where inflammation remained active.35 Native T1 detected all patients, including those with DCM, related to their functional impairment41–43, as well as inform on their significantly worse prognosis, better than late gadolinium enhancement and ejection fraction.43 As novel diagnostic techniques, mapping methods remain site- and vendor-specific, and the accuracy and precision of T1 measurements may vary between CMR systems, sequences and post-processing approaches.44 Local normal ranges and abnormal cut-off values need to be determined in each particular centre before such methods are included in clinical protocols. The use of different T1 and T2 methods can explain thus some of the disparities between the findings of different studies. Histological correlation is clearly informative, as it reveals the difficulty of clinically diagnosing myocarditis in practice. Endomyocardial biopsies are often performed late in the course of disease; whereas they can inform on the presence of myocardial inflammation based on the cellular infiltrate, they cannot evaluate the extent of myocardial oedema, an important disease marker. T1 and T2 mapping indices, in contrast, strongly relate to water signals, clarifying the histological blind spots in inflammatory myocardial disease.

Future Molecular Imaging Research One potential focus for research in the field is the development of molecular imaging. Few studies in animal models have explored the potential of molecular imaging to detect or monitor the effectors and/or modulators of inflammation based on the ability of radiolabeled ligands to measure pathophysiological processes. Although nonspecific, 18F-fluorodeoxyglucose positron emission tomography

Felker GM, Hu W, Hare JW, et al. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience in 1278 patients. Medicine 1999;78 :270–283. 2. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006;296 :1867–1876. 3. Assomull RG, Lyne JC, Keenan N, et al. The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. Eur Heart J 2007;28 :1242–9. DOI: 10.1007/s12410015-9345-x; PMID: 17478458 4. Buschmann IR, Bondke A, Elgeti T, et al. Positive cardiac troponin I and T and chest pain in a patient with iatrogenic hypothyroidism and no coronary artery disease. Int J Cardiol 2007;115 :e83–5. DOI: 10.1016/j.ijcard.2006.08.016; PMID: 17084920 5. Feldman AM, McNamara D. Myocarditis. N Engl J Med 2000;343 :1388–98. DOI: 10.1056/NEJM200011093431908; PMID: 11070105 6. Fairweather D, Stafford KA, Sung YK. Update on coxsackievirus B3 myocarditis. Curr Opin Rheumatol 2012;24 :401–7. DOI: 10.1097/BOR.0b013e328353372d; PMID: 22488075; 7. Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol 2012;59 :779–92. DOI: 10.1016/ j.jacc.2011.09.074; PMID: 22361396 8. Caforio ALP, Pankuweit S, Arbustini E, et al. European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34 :2636–48. DOI: 10.1093/eurheartj/eht210; PMID: 23824828 9. Elamm C, Fairweather D, Cooper LT. Pathogenesis and diagnosis of myocarditis. Heart 2012;98 :835–40. DOI: 10.1136/ heartjnl-2012-301686; PMID: 22442199 10. Baldeviano GC, Barin JG, Talor MV, et al. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ Res 2010;106 :1646–55. DOI: 10.1161/CIRCRESAHA.109.213157; PMID: 20378858 11. Mahrholdt H. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation 2004;109 :1250–8. DOI: 10.1161/01.CIR.0000118493.13323.81; PMID: 14993139 12. Schultheiss HP, Kuhl U, Cooper LT. The management of myocarditis. Eur Heart J 2011;32 :2616–25. DOI: 10.1093/

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is the most frequently used radioligand for non-invasive detection of inflammation.8,45 Radioligands that bind to translocator protein 18 kDa, which is a well-established biomarker for brain injury and inflammation, are also being developed for the early detection of myocarditis. Besides this, the detection of immune cell infiltration in a murine model of autoimmune myocarditis by 19F-flurorine CMR in vivo has been explored with the use of biochemically-inert perfluorocarbons. These perfluorocarbons are taken up by circulating monocytes/ macrophages after intravenous injection and are specifically recruited to areas of inflamed myocardium, which can be seen with CMR.46 An alternative potential focus for research is the development of molecular labels for CMR-based virus detection.47,48 The development of CMR agents directed against antigens in the viral capsid might enable the non-invasive detection of myocardial inflammation. Furthermore, the potential contribution of positron emission tomographic cardiac imaging for diagnosing inflammatory cardiomyopathies has been explored in cardiac sarcoidosis.49–51 Its role in the setting of viral myocarditis has yet to be investigated.

Conclusion Among the imaging techniques available, CMR is an important noninvasive diagnostic tool in patients with suspected myocarditis. Tissue characterisation capabilities are continuing to evolve, enabling CMR to offer a stronger and increasingly reliable alternative to invasive biopsy in clinically-stable patients. Longitudinal studies with non-invasive imaging techniques, which are risk- and radiation-free, will improve the overall understanding of the natural course of myocarditis. Future research will decipher whether a complementary approach with T1 and T2 mapping may lead to an updated CMR algorithm in practice. ■

eurheartj/ehr165; PMID: 21705357 13. Cruz-Adalia A, Jimenez-Borreguero LJ, Ramirez-Huesca M, et al. CD69 limits the severity of cardiomyopathy after autoimmune myocarditis. Circulation 2010;122 :1396–404. DOI: 10.1161/CIRCULATIONAHA.110.952820; PMID: 20855659 14. Nindl V, Maier R, Ratering D, et al. Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. Eur J Immunol 2012;42 :2311–21. DOI: 10.1002/eji.201142209; PMID: 22730043 15. Yu M, Hu J, Zhu M-X, et al. Cardiac fibroblasts recruit Th17 cells infiltration Into myocardium by secreting CCL20 in CVB3-induced acute viral myocarditis. Cell Physiol Biochem 2013;32 :1437–50. DOI: 10.1159/000356581; PMID: 24296428 16. Goser S. Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy. Circulation 2005;112 :3400–7. DOI: 10.1161/ CIRCULATIONAHA.105.572396; PMID: 16316965 17. Chen P, Baldeviano GC, Ligons DL, et al. Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4 +T cells. Clin Exp Immunol 2012;169 : 79–88. DOI: 10.1111/j.1365-2249.2012.04598.x; PMID: 22774982 18. Liu Y, Zhu H, Su Z, et al. IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKC /Erk1/2/NF- B-dependent signaling pathway. Int Immunol 2012;24 :605–12. DOI: 10.1093/intimm/dxs056; PMID: 22531062 19. Wu L, Ong S, Talor MV, et al. Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J Exp Med 2014 ;211 :1449–64. DOI: 10.1084/jem.20132126 20. Yang F, Wu W-F, Yan Y-L, et al. Expression of il-23/th17 pathway in a murine model of coxsackie virus b3-induced viral myocarditis. Virol J 2011;8 :301. DOI: 10.1186/1743-422X8-301; PMID: 21672246 21. Fan Y, Weifeng W, Yuluan Y, et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of coxsackievirus b3-induced viral myocarditis reduces myocardium inflammation. Virol J 2011;8 :17. DOI: 10.1186/1743-422X-8-17; PMID: 21235788 22. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the

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39. Ferreira VM, Piechnik SK, Dall’Armellina E, et al. T1 mapping for the diagnosis of acute myocarditis using CMR. JACC Cardiovasc Imaging 2013;6 :1048–58. DOI: 10.1016/ j.jcmg.2013.03.008; PMID: 24011774 40. Puntmann VO, D’Cruz D, Smith Z, et al. Native myocardial T1 mapping by cardiovascular magnetic resonance imaging in subclinical cardiomyopathy in patients with systemic lupus erythematosus. Circ Cardiovasc Imaging 2013;6 :295–301. DOI: 10.1161/CIRCIMAGING.112.000151; PMID: 23403334 41. Puntmann VO, Voigt T, Chen Z, et al. Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovasc Imaging 2013;6 :475–84. DOI: 10.1016/j.jcmg.2012.08.019; PMID: 23498674 42. Puntmann VO, Arroyo Ucar E, Hinojar Baydes R, et al. Aortic stiffness and interstitial myocardial fibrosis by native T1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy. Hypertension 2014; 64 :762–8. DOI: 10.1161/HYPERTENSIONAHA.114.03928; PMID: 25024285 43. Puntmann VO, Carr-White G, Jabbour A, et al. T1-mapping and outcome in nonischemic cardiomyopathy. JACC Cardiovasc Imaging 2016;9 :40–50. DOI: 10.1016/j.jcmg.2015.12.001; PMID: 26762873 44. Rogers T, Dabir D, Mahmoud I, et al. Standardization of T1 measurements with MOLLI in differentiation between health and disease – the ConSept study. J Cardiovasc Magn Reson 2013;15 :78. DOI: 10.1186/1532-429X-15-78; PMID: 24025486 45. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias

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Accuracy of Positron Emission Tomography as a Diagnostic Tool for Lead Endocarditis: Design of the Prospective Multicentre ENDOTEP Study Sa na Amra oui, 1 Ghou f r a n e Tl i l i , 2 E l i f H i n d i é , 2 Pa u l Pe r e z , 3 O l i v i a Pe u c h a n t , 4 La ure n c e B o r d e n a v e 2 a n d Pi e r r e B o r d a c h a r 1 1. Cardiologic Haut-Lévêque hospital, Bordeaux university, INSERM U1045, LIRYC institute, Bordeaux, France; 2. Nuclear medicine center, Bordeaux university, Bordeaux, France; 3. ISPED center, Bordeaux university, Bordeaux, France

Abstract Background: Rates of pacemaker implantation are steadily increasing and as patients are living longer, endovenous leads remain implanted for an extended period of time thereby increasing the risk of cardiac implantable electronic device (CIED) infection. Investigating fever of unknown origin in patients with implanted pacemakers can be challenging. Recently, 18F-fluorodeoxyglucose positron emission tomography/computerised tomography (18F-FDG-PET/CT) scanning has been used as a diagnostic tool for lead endocarditis in small studies. Objectives: ENDOTEP is a prospective and multicentre study designed to evaluate the accuracy of 18F-FDG-PET/CT scanning in the diagnosis of lead endocarditis. Methods: A total of 250 patients referred for pacemaker extraction due to suspicion of an infected device will be prospectively enrolled in six French regional centres for investigation and treatment of CIED infection. 18F-FDG-PET/CT scanning (index test) will be performed in each patient in the 48 hours preceding lead extraction. Bacteriological cultures (reference standard) will assess the presence of lead endocarditis, blind to 18F-FDG-PET/CT results. Enrolment started in June 2015 and is expected to end by June 2017. The primary objective will be to establish the sensitivity of the 18F-FDG-PET/CT scan for lead endocarditis. Secondary objectives will include other accuracy parameters, inter-observer agreement in the interpretation of 18F-FDG-PET/CT scanning, the influence of previous antibiotic therapy on 18F-FDG-PET/CT diagnostic accuracy and assessment of septic emboli associated to lead endocarditis. Conclusion: The ENDOTEP study will examine the ability of 18F-FDG-PET/CT scanning to avoid possible false-positive results, as is common using the current usual diagnostic strategy and may lead to unnecessary extraction of implants in patients with suspected lead infection.

Keywords 18

F-FDG-PET/CT scanning, diagnostic accuracy, lead endocarditis, pacemaker infection, septic emboli

Disclosures: This research was conducted with the financing of Bordeaux University Hospital (source of grants: PHRC Hospital Program of Clinical Research). Received: 29 January 2016 Accepted: 5 May 2016 Citation: European Cardiology Review, 2016;11(1):25–8 DOI: 10.15420/ecr.2016:6:2 Correspondence: Sana Amraoui, Cardiologic Haut-Lévêque Hospital, 33604 Bordeaux-Pessac, France. E-mail: sana.amraoui@hotmail.com

With ageing of the general population and broadening indications, the number of pacemaker recipients is steadily increasing. The incidence of cardiac implantable electronic device (CIED) infection, a dreaded major complication, is also rising.1 The diagnosis is based on the presence of an abscessed pocket, cutaneous breakthrough of the pulse generator or vegetations attached to the pacemaker lead.2–4 On the other hand, a number of patients present with less specific clinical manifestations and a pacemaker recipient may be recurrently hospitalised for an infectious disorder of unknown origin despite detailed investigations. In the absence of proof of lead infection, further clinical management is challenging and removal of the system without confirmation of its infection is usually proposed, despite the known morbidity and mortality risks associated with the extraction procedure (0.5–2.0 %).5,6 An additional diagnostic tool to identify the presence of pacemaker system infections is therefore much needed to help solve this diagnostic problem.

and preliminary studies suggest that 18F-FDG-PET/CT scanning may be useful in the diagnosis of pacemaker infection.8–14 Absence of hyperfixation of the lead, identified by 18F-FDG-PET/CT scanning may be an accurate sign of absence of pacing system infection. However, the limited sample sizes of previous studies do not allow the formulation of definitive conclusions. The Diagnostic Accuracy of 18FDG-PET-CT for Pacing or Defibrillation Lead Infection (ENDOTEP) study has been designed with a sample size large enough to assess the diagnostic accuracy of 18F-FDG-PET/CT scanning in patients with suspicion of lead infection and to validate a new management algorithm in the diagnosis of lead endocarditis that includes 18F-FDG-PET/CT scanning. Here, we present the study design of the ENDOTEP study.

Methods Study Design

In recent years, 18F-fluorodeoxyglucose positron emission tomography/ computerised tomography ( 18F-FDG-PET/CT) scanning has made promising contributions in a number of therapeutic areas, including imaging to detect infection in a number of organs.7 Case reports

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This multicentre, prospective, cross-sectional study has been registered at www.clinicaltrials.gov (registration number NCT02251262) and will include 250 consecutive patients with suspected lead endocarditis over a 24-month period in six French regional centres for the

Access at: www.ECRjournal.com

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Cardiac Imaging | Myocarditis | Endocarditis investigation and treatment of CIED infection. We will include patients: 1) with clinical infection signs localised to the box (possibility of absence of lead endocarditis with negative lead culture) and; 2) patients referred for lead infection (high probability of positive lead culture). All patients satisfying the eligibility criteria will be included prospectively and consecutively in order to minimise selection bias. A whole-body 18 F-FDG-PET/CT scanning (index test) will be performed in patients with suspected pacemaker/defibrillator infection 48 hours before extraction of the material and bacteriological culture (reference standard, blind to 18F-FDG-PET/CT results).

Inclusion/Exclusion Criteria Inclusion Criteria Patients will need to fulfill the following criteria for enrolment: • aged >18 years; • referred for extraction of the material (box and leads) in the context of suspicion of material infection; • able to undergo 18F-FDG-PET/CT scanning ≤48 hours before extraction; • provide written informed consent; and • affiliated with a social security system.

Exclusion Criteria Patients who meet any of the following criteria will not be included: • pregnant or breastfeeding women; • recent pacemaker implantation (<2 months); • placement under judicial protection; • participation in another study that includes an exclusion period ongoing at the time of screening; and • unable to provide informed consent.

Study Objective Primary Objective The primary objective of the study is to assess the diagnostic accuracy of 18F-FDG-PET/CT scanning in patients with suspected lead endocarditis.

F-Fluorodeoxyglucose Positron Emission Tomography/ Computerised Tomography Scanning

Whole-body 18FDG-PET/CT scanning will be performed within 48 hours of extraction of the entire device, after injection of 2.5–3.0 MBq/kg of 18 F-FDG intravenously following a 12-hour fasting period. Patients will have a specific high-fat and low-carbohydrate diet the day before. PET/CT imaging will be performed 1 hour after 18F-FDG injection. A low-dose CT will be obtained for attenuation correction and anatomic localisation, without the use of contrast enhancement. The acquisition parameters will be: 140 kV, 80 mAs, slice thickness of 3.75 mm, pitch 1 and reconstruction interval of 1.75 mm. PET data will be acquired in 3D mode at 2 min per step. Glucose levels will be <9 mmol/l. An experienced reporter, blinded to the clinical data, will analyse the 18F-FDG-PET/CT images. The analysis will begin with visualisation of maximum intensity projection to look for pathological foci. Corrected attenuation images will be used to locate the position of the hypermetabolic foci. Then, the diagnosis of lead endocarditis will be made on non-corrected attenuation images (see Figure 1).15 This approach will also allow for assessment of septic emboli (see Figures 2 and 3). A blinded nuclear medicine physician will interpret the 18F-FDG-PET/CT scan. All 18F-FDG-PET/CT recordings will be stored until interpretation, and not used for the clinical management of the patient. Moreover, all 18F-FDG-PET/CT recordings will be sent to the coordinating centre (Bordeaux centre) to centralise interpretation blinded to the preceding one. Index test interpretations will be blinded to any other information on the patient (clinical, biology, etc).

Pacemaker Extraction All extraction procedures will be performed in a surgical theatre by a cardiologist with the patient under general anaesthesia. When possible, extraction will be performed initially from a superior approach using a combination of simple traction or laser sheath (CVX-300® Excimer laser system; Spectranetics) as required. Where the superior approach is unsuccessful/not possible, extraction will be performed from a femoral approach using a dedicated femoral workstation (Byrd Workstation™, Cook Vascular) using a needle’s eye or gooseneck snare as appropriate.5 The pacing box and the leads will be sent separately for microbial culture.

Secondary Objectives The secondary objectives of the study are to:

Microbial Culture of the Extracted Material

• quantify the uptake along a lead in patients with and without lead infection; • assess the inter-observer variability in the interpretation of 18 F-FDG-PET/CT scanning in this clinical situation; • assess the impact of a previous antimicrobial treatment on the interpretation and the diagnostic accuracy of 18F-FDG-PET/CT scanning in this clinical situation; • assess the use of whole-body 18F-FDG-PET/CT scanning for assessment of septic emboli associated with lead endocarditis; and • assess the role of 18F-FDG-PET/CT scanning in providing differential diagnoses.

Lead culture will be performed after the extraction procedure for all samples4,16 onto aerobic horse, chocolate PolyViteX and anaerobic sheep blood agars. The three types of agar plates will be incubated at 37°C for 10 days in aerobic, 5 % CO2 and anaerobic atmospheres, respectively. A brain heart infusion broth supplemented with meat liver agar and IsoVitaleX™ (BD Diagnostic Systems) will be also inoculated and will be subcultured for 10 days on PolyViteX™ (bioMérieux) chocolate agar plates in a 5 % CO2 atmosphere if cloudy (or systematically at 1 month). Strain identification will be performed using by mass spectrometry, using matrix-assisted laser desorption/ ionisation. Antibiotic susceptibility testing (AST) will be performed for all detected strains, using the disk diffusion method.

Study Protocol

The diagnosis of lead endocarditis will be confirmed in the following cases:

The planned data collection schedule is summarised in Table 1. At the time of patient enrolment, inclusion and exclusion criteria will be checked. The following baseline characteristics will be reported: clinical examination (local signs, fever), routine blood tests with inflammatory markers, blood cultures, transthoracic and trans-oesophageal echocardiography, and presence and duration of the antibiotic therapy.

• lead culture growing the same microorganism as one or more blood cultures; • lead culture growing the same organism as the pulse generator culture; or • cultures from at least two leads growing the same organism.

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We will consider the bacterial strains to be the same when the identification and the AST results are identical for both samples.

Sample Size Calculation and Statistical Analysis A negative bacteriological lead culture result may be found in 10–25 % of cases,16 even in absence of previous antimicrobial therapy prior to the extraction procedure. The first hypothesis of the ENDOTEP study is that a new strategy adding 18F-FDG-PET/CT scanning to the current diagnosis strategy applied before extraction may avoid or reduce these false-positive results. To evaluate the potential benefits and risks of this new strategy, we will need a randomised trial comparing it with the standard strategy. However, the decision to carry out such a trial has to be justified by valid data on the diagnostic accuracy of the 18F-FDG-PET/CT scanning, attesting of a high sensitivity of this test. High sensitivity would maximise the negative predictive value, which is needed to validate the safety of not extracting a pacemaker in patients with a negative 18 F-FDG-PET/CT scan result. In addition, high sensitivity would enable the diagnosis of lead endocarditis in patients with fever of unknown origin. Thus, the primary objective of this study is the estimation of the sensitivity.17,18 The main analysis will estimate the 95 % confidence interval of PET/CT sensitivity, and compare its lower bound with the predefined value of 90 %. If 250 patients are included, and assuming a prevalence of at least 75 % of cases with positive bacteriological cultures, this comparison will have at least a 90 % power with a type I error of 5 % if the observed sensitivity is ≥96 %. In that case, if the specificity is >90 %, the negative predictive value of PET/CT will be between 71 and 88 % when the prevalence of infection is between 75 and 90 %. Possible variations of the diagnostic accuracy of 18F-FDG-PET/CT scanning

F-FDG-PET/CT Scanning and Lead Endocarditis

Table 1: Data Collection Schedule Data collected

Baseline

Informed consent

Demographic information

Medical history

Clinical examination

Presence of AB

C-reactive protein

Plasmatic beta-HCG

Blood cultures

Echocardiography

Follow-up (maximum 48 hours after inclusion)*

F-FDG-PET-CT scan

Extraction of the infected device

Bacteriological cultures

*Or, exceptionally, up to 7 days if the patient is not receiving antibiotic therapy. 18F-FDG-PET-CT = 18 F-fluorodeoxyglucose positron emission tomography/computerised tomography; AB = antibiotic; beta-HCG = beta human chorionic gonadotropin.

Figure 1: 18F-FDG-PET/CT Scanning Identifying Pacing Box Infection With Lead Endocarditis

according to previous antimicrobial therapy and pocket infection will be analysed with an adjusted logistic model if necessary. Inter-observer agreement of visual interpretation of 18F-FDG-PET/CT scanning will be estimated using the Cohen’s kappa coefficient.

Discussion F-FDG is a nonspecific tracer of increased glucose metabolism that has a high sensitivity for the detection of malignant cells. In recent years, 18F-FDG-PET/CT scanning has made promising contributions in different areas including imaging to detect infection at different organ sites. In this study, we will evaluate the accuracy of the 18F-FDG-PET/CT scanning for lead endocarditis diagnosis, by performing this exam in all consecutive patients referred for pacemaker extraction. 18

Transaxial CT (A and B), FDG-PET (C and D), and fused PET/CT views (E and F), as well as maximal intensity projection FDG-PET (G) at the level of the pacing box and the intra-cardiac portion of the lead. There is an increased FDG uptake at the level of the pacing box and in the extra-vascular and extra-cardiac portion of the lead (arrows in C, E and G) corresponding to pacing box infection with lead infection spreading by contiguity (SUV max 7.0). An important hotspot (SUV max 5.3) corresponding to lead endocarditis was also identified in the intra-cardiac portion of the lead at the right atrial level (arrows in D, F and G). 18F-FDGPET/CT = 18F-fluorodeoxyglucose positron emission tomography/computerised tomography.

Figure 2: 18F-FDG-PET/CT Scanning Identifying Lead Endocarditis and Gastro-Intestinal Polyps

The high number of planned patients (250) will allow for the assessment of: • inter-observer variability in the interpretation of 18F-FDG-PET/CT scanning in this clinical situation – this point is the first step before integrating this tool into a new diagnostic algorithm; • the diagnostic accuracy of 18F-FDG-PET/CT scanning in patients with a suspicion of infection of pacemaker or defibrillator leads – we will include a large number of patients with expected positive (lead endocarditis) and negative (infection restricted to the box) culture of the leads and, therefore, it will be possible to evaluate sensitivity, specificity and predictive values; • the impact of a previous antimicrobial treatment in the interpretation of 18F-FDG-PET/CT scanning in this clinical situation – including patients who have and have not received antibiotics will help clarify the impact of previous antimicrobial treatment on the accuracy of 18 F-FDG-PET/CT scanning for lead endocarditis diagnosis; and

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Transaxial CT (A and B), FDG-PET (C and D), and fused PET/CT (E and F) views at the level of the pacing lead and the sigmoid. There is an increased FDG uptake in the intra-cardiac portion of the right ventricular lead (arrows in C and E) corresponding to lead endocarditis (SUV max 7.0). An important hotspot was also localised to the sigmoid (arrows in D and F) with a SUV max at 12.1. Colonoscopy was performed with focal lesions corresponding to benign polyps, which are among potential portals of entry. 18F-FDG-PET/CT = 18 F-fluorodeoxyglucose positron emission tomography/computerised tomography.

• the role of whole-body other areas of infection.

F-FDG-PET/CT scanning in diagnosing

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Cardiac Imaging | Myocarditis | Endocarditis Figure 3: Diffuse Spondylodiscitis Revealed By 18F-FDG-PET/CT Scanning in an Asymptomatic Patient With Lead Endocarditis

Sagittal CT (A), FDG-PET (B) and fused PET/CT (C) views images show increased FDG uptake along the vertebral column: C5/C6/C7, T4/T5 and T6/T7 (arrows in B and C) corresponding to diffuse spondylodiscitis in a patient with lead endocarditis. 18F-FDG-PET/ CT = 18F-fluorodeoxyglucose positron emission tomography/computerised tomography; C = cervical; T = thoracic.

High mortality rates associated with lead endocarditis is partly due to the presence of septic embolisms; septic pulmonary embolisms and spondylodiscitis seem to be the most frequent types.19–21 The diagnosis of septic embolisms in patients with lead endocarditis can be challenging. Indeed, magnetic resonance imaging cannot be performed in the vast majority of patients with a cardiac implantable device. The risk of septic embolism associated with lead endocarditis is therefore probably under-estimated as septic embolisms are not systematically sought in many cases despite possible important

Voigt A, Shalaby A, Saba S. Continued rise in rates of cardiovascular implantable electronic device infections in the United States: temporal trends and causative insights. Pacing Clin Electrophysiol 2010;33 :414–9. DOI: 10.1111/j.15408159.2009.02569.x; PMID: 19793359. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994;96 :200–9. PMID: 8154507. Sohail MR, Uslan DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49 :1851–9. PMID: 17481444. Klug D, Wallet F, Lacroix D, et al. Local symptoms at the site of pacemaker implantation indicate latent systemic infection. Heart Br Card Soc 2004;90 :882–6. PMID: 15253959. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association (AHA). Heart Rhythm 2009;6 :1085–104. DOI: 10.1016/j.hrthm. 2009.05.020; PMID: 19560098. Bordachar P, Defaye P, Peyrouse E, et al. Extraction of old pacemaker or cardioverter-defibrillator leads by laser sheath versus femoral approach. Circ Arrhythm Electrophysiol 2010;3 :319–23. DOI: 10.1161/CIRCEP.109.933051; PMID: 20562442. De Winter F, Vogelaers D, Gemmel F, Dierckx RA. Promising role of 18-F-fluoro-D-deoxyglucose positron emission tomography in clinical infectious diseases. Eur J Clin Microbiol Infect Dis 2002;21 :247–57. PMID: 12072934. Amraoui S, Tlili G, Sohal M, et al. Contribution of PET imaging to the diagnosis of septic embolism in Patients with pacing lead endocarditis. JACC Cardiovasc Imaging 2016;9 :283–90. DOI: 10.1016/j.jcmg.2015.09.014; PMID: 26897683.

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10.

11.

12.

13.

14.

15.

clinical implications (adaptation in terms of type, administration mode and duration of antibiotic therapy).22,23 This prospective study may help position 18F-FDG-PET/CT scanning in the diagnostic algorithm for lead endocarditis. It is not a substitute for trans-oesophageal echocardiography, which contributes different information; for example, the size of vegetations is an important factor when planning the lead extraction procedure.5 On the other hand, trans-oesophageal echocardiography provides information restricted to the intra-cardiac portion of the leads and requires the presence of visible vegetations. In contrast, 18F-FDG-PET/CT scanning provides information on the intra- and extra-cardiac portions of the leads and may be highly beneficial when vegetations are not visible. This tool may prove to be effective in diagnosing septic emboli and therefore may be proposed in all the patients referred for device extraction as the demonstration of the presence of asymptomatic spondylodiscitis, for example, may have direct therapeutic implications. 18F-FDGPET/CT scanning may also be proposed in pacemaker recipients hospitalised for an infectious disorder of unknown origin despite detailed investigations including trans-oesophageal echocardiography. If the 18F-FDG-PET/CT scan is positive (hyperfixation on a lead) then the pacing system should be extracted. If the 18F-FDG-PET/CT scan is negative (no hyperfixation on a lead) then the pacing system may be left in situ with close clinical monitoring and follow-up. The potential disadvantages of this diagnostic tool include its limited availability and relatively high cost; 18F-FDG-PET/CT scans performed in France costs approximately 589 euros. However, it may prove to be costeffective given that its used could avoid unnecessary implant extractions.

Conclusion The ENDOTEP study will examine the potential use of 18F-FDG-PET/CT scanning as a diagnostic tool for lead infection diagnosis in patients with fever of unknown origin. Here, we have presented the design of this prospective, multicentre trial. ■

Ploux S, Riviere A, Amraoui S, et al. Positron emission tomography in patients with suspected pacing system infections may play a critical role in difficult cases. Heart Rhythm 2011;8:1478–81. DOI: 10.1016/j.hrthm.2011.03.062; PMID: 21463705. Tlili G, Amraoui S, Mesguich C, et al. Erratum to: High performances of (18)F-fluorodeoxyglucose PET-CT in cardiac implantable device infections: A study of 40 patients. J Nucl Cardiol 2015;22 :799. DOI: 10.1007/s12350-015-0190-8; PMID: 26041258. Sarrazin J-F, Philippon F, Tessier M, et al. Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections. J Am Coll Cardiol 2012;59 : 1616–25. DOI: 10.1016/j.jacc.2011.11.059; PMID: 22538331. Graziosi M, Nanni C, Lorenzini M, et al. Role of 18F-FDG PET/ CT in the diagnosis of infective endocarditis in patients with an implanted cardiac device: a prospective study. Eur J Nucl Med Mol Imaging 2014;41 :1617–23. DOI: 10.1007/s00259014-2773-z; PMID: 24802193. Cautela J, Alessandrini S, Cammilleri S, et al. Diagnostic yield of FDG positron-emission tomography/computed tomography in patients with CEID infection: a pilot study. Europace 2013;15:252–7. DOI: 10.1093/europace/eus335; PMID: 23148119. Rouzet F, Hyafil F, Le Guludec D. FDG PET/CT in cardiac electronic devices infection: Now is the time to target guidelines implementation. J Nucl Cardiol 2015;22:800–3. DOI: 10.1007/s12350-015-0102-y; PMID: 25910755. Metser U, Even-Sapir E. Increased (18)F-fluorodeoxyglucose uptake in benign, nonphysiologic lesions found on wholebody positron emission tomography/computed tomography (PET/CT): accumulated data from four years of experience with PET/CT. Semin Nucl Med 2007;37 :206–22. PMID: 17418153.

16. Golzio P-G, Vinci M, Anselmino M, et al. Accuracy of swabs, tissue specimens, and lead samples in diagnosis of cardiac rhythm management device infections. Pacing Clin Electrophysiol 2009;32 Suppl 1:S76–80. DOI: 10.1111/j.15408159.2008.02257.x; PMID: 19250117. 17. Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem 2003;49 :1–6. PMID: 12507953. 18. Whiting PF, Rutjes AWS, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011;155 :529–36. DOI: 10.7326/0003-4819-155-8-201110180-00009; PMID: 22007046. 19. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection. Circ Arrhythm Electrophysiol 2009;2 :129–34. DOI: 10.1161/ CIRCEP.108.816868; PMID: 19808457. 20. Athan E, Chu VH, Tattevin P, et al. Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. JAMA 2012;307 :1727–35. DOI: 10.1001/ jama.2012.497; PMID: 22535857. 21. Rodriguez Y, Greenspon AJ, Sohail MR, Carrillo RG. Cardiac device-related endocarditis complicated by spinal abscess. Pacing Clin Electrophysiol 2012;35 :269–74. DOI: 10.1111/j.1540-8159.2011.03288.x; PMID: 22150338. 22. Amraoui S, Texier-Maugein J, Bordachar P. PET scan in suspected but unproven pacemaker endocarditis. Arch Cardiovasc Dis 2012;105 :125–6. DOI: 10.1016/ j.acvd.2011.04.011; PMID: 22424331. 23. Pizzi MN, Roque A, Fernández-Hidalgo N, et al. Improving the diagnosis of infective endocarditis in prosthetic valves and intracardiac devices with 18F-fluordeoxyglucose positron emission tomography/computed tomography angiography: initial results at an infective endocarditis referral center. Circulation 2015;132:1113–26. DOI: 10.1161/ CIRCULATIONAHA.115.015316; PMID: 26276890.

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Cardiomyopathy | Cardiac Protection

Left Ventricular Remodelling: A Problem in Search of Solutions Dennis V Co k k i n o s a n d Ch r i s t o s B e l o g i a n n e a s Biomedical Research Foundation Academy of Athens, Onassis Cardiac Surgery Centre, Athens, Greece

Abstract Cardiac remodelling (REM) is a generally unfavourable process that leads to left ventricular dilation in response to cardiac injury, predominantly acute myocardial infarction (AMI). REM occurs in around 30 % of anterior infarcts despite timely primary coronary intervention and the use of drugs, i.e. angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs), betablockers, aldosterone inhibitors and statins. In order to diagnose REM, many imaging modalities (echocardiography, cardiac magnetic resonance, scintigraphy) are employed together with an increasing number of serum biomarkers including microRNAs. The most widely used definition of REM is a >20 % increase in left ventricular end-diastolic volume (LVEDV). There is also evidence that regression of REM can occur, i.e. reverse REM. The latter is defined as a ≥10 % decrease in left ventricular end-systolic volume (LVESV) and confers a more favourable outcome. Many therapeutic agents may be used during primary intervention and over the long term; however, few have demonstrated significant benefits. Revascularisation, anti-REM surgery and, where indicated, cardiac resynchronisation therapy can be of benefit. Gene therapy by sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA-2a) transfer has been investigated but data from the Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2) trial were disappointing. Progenitor cell therapy shows promise. In conclusion, therapy for REM remains inadequate.

Keywords Acute myocardial infarction, myocardial remodelling, left ventricular function, myocyte biology Disclosure: The authors have no conflicts of interest to declare. Received: 22 June 2015 Accepted: 25 May 2016 Citation: European Cardiology Review, 2016;11(1):29–35 DOI: 10.15420/ecr.2015:9:3 Correspondence: Dennis V Cokkinos, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 11527 Athens, Greece. E: dcokkinos@bioacademy.gr

The term cardiac remodelling (REM) is used to define changes that produce geometrical rearrangement of the normal structures of the heart, together with complex biological and molecular alterations. REM affects the heart at the level of the cardiomyocyte, the blood vessels and the extracellular matrix. Proliferation of the latter, resulting in fibrosis, is one of the hallmarks of pathological REM.1,2 REM represents a major cause of heart failure as well as cardiac morbidity and mortality. REM can be considered a universal phenomenon (see Table 1). It is initially considered an adaptive and physiological process but soon becomes maladaptive and pathological.2 REM can be the result of hypertension; cardiomyopathies, either dilated or ‘burnt-out’ hypertrophic obstructive cardiomyopathy; valvulopathies, especially those causing volume overload; antineoplastic drugs such as doxorubicin; diabetes; and senescence of cardiac fibroblasts.2 Arrhythmias are also associated with REM. The term tachycardiomyopathy was introduced approximately 30 years ago, to describe the impairment in left ventricular (LV) function secondary to chronic tachycardia. Tachycardiomyopathy is partially or completely reversible after normalisation of the heart rate. The condition is primarily caused by atrial fibrillation or flutter, atrioventricular tachycardia, atrioventricular nodal tachycardia and other arrhythmias characterised by tachycardia, including multiple premature ventricular contractions. 3 Left bundle branch block (LBBB)

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can also unfavourably affect the myocardium through paradoxical septal motion. This observation has led to the application of arrhythmia ablation or cardiac resynchronisation therapy in REM. However, the most common cause of REM is anterior acute myocardial infarction (AMI). Despite the use of primary percutaneous coronary intervention (PPCI) and optimal standard pharmacotherapy, REM ultimately occurs in 30 % of anterior AMIs. Non-anterior infarcts involve a smaller myocardial mass, thus REM occurs in only approximately 17 % of cases.4 The most well-understood mechanism underlying REM is infarct expansion, which is affected by wall stress.5 There is a need for a precise definition of REM. The historical definition of a 20 % increase of the left ventricular end-diastolic volume (LVEDV), first employed in 1986,6 is still in use today, although the left ventricular end-systolic volume (LVESV) and the LV mass have also been used as clinical endpoints.7 In the Global Utlilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO 1) trial, LVESV was a strong prognostic indicator for early and late mortality.8 In a meta-analysis of 30 mortality trials of 25 drug/device therapies, Kramer et al.9 found that left ventricular ejection fraction (LVEF), LVEDV or LVESV were strongly associated with mortality. However, in studies to date, cut-off values have been arbitrary; continuous measurements are more meaningful. Farah et al.10 used a definition of REM of an increase of 10 % in ventricular endsystolic or end-diastolic diameter, and found a higher (58 %) incidence

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Cardiomyopathy | Cardiac Protection Table 1: Major Causes of Cardiac Remodelling

the most important alteration is the activation of the foetal gene programme.1,2,17 This alteration in myosin gene expression involves the

• Myocardial infarction

increase of the embryonic beta-myosin heavy chain (beta-MHC) and the decrease of alpha-myosin heavy chain (alpha-MHC). The latter is the minor component in humans (not more than 10 % versus >70 % in the rodent), but even a 2 % unit decrease can be associated with myocardial dysfunction. Beta-MCH has lower ATPase activity, which is associated with lower velocity of contraction. In addition, cardiac cells express a variant of Na+/K+-ATPase, which has poorer membrane stabilising capacity. Another major component of the foetal phenotype is the metabolic switch from fatty acid oxidation to glycolysis. This results into a net deficit of adenosine triphosphate (ATP) production and energy starvation.18

• Dilated and hypertrophic cardiomyopathy • Hypertension • Valve disease (e.g. stenosis, insufficiency) • Toxic agents (e.g. chemotherapy, environmental pollution) • Diabetes type 1 or 2 • Obesity • Genetic diseases • Arrhythmias or disturbances of the conduction ° Tachycardiomyopathy ° Dys-synchronisation  Right ventricular stimulation  Left bundle branch block

of REM after an anterior myocardial infarction (MI) compared with other studies. This highlights the need for consensus upon a common definition. In the Acute Myocardial Infarction Contrast Imaging (AMICI) trial, the term ’reverse REM’ was employed to denote a >10 % reduction in LVESV. In this study, Funaro et al.11 found a reverse REM at 6 months in 39 % of patients following PPCI. Reverse REM was the only independent predictor of 2-year event-free survival. In the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study, Gold et al.12 used a definition of reverse REM of >15 % decrease in LVESV, and found that reverse REM improves prognosis. In routine clinical practice, many clinicians utilise ventricular dimension rather than volume. The definition of REM is also crucial for cardiovascular MRI-derived calculations.

Pathophysiology The initial stimulus for ventricular enlargement is myocardial stretch resulting from myocyte loss, rendering an area akinetic or dyskinetic. The remaining normal myocardium overfunctions to compensate for the decline in cardiac function. The ensuing increase in ventricular mass decreases myocardial wall stress according to the law of Laplace, while LV dilation contributes towards the preservation of stroke volume (Starling’s law). The region remote from the MI develops LV hypertrophy, which is initially physiological and adaptive. However, this rapidly becomes pathological and maladaptive.2 According to Frey et al.,13 REM after an AMI represents eccentric hypertrophy due to volume overload and is characterised by the addition of sarcomeres in series and cardiomyocyte elongation. The term physiological REM is used to describe adaptive myocardial growth due to normal demands such as exercise or pregnancy.13,14 Whether the ’athlete’s heart‘ can lead to pathological REM has been the subject of discussion, but most experts agree that it rarely leads to irreversible REM;15 hypertrophy and dilation promptly regress after ’detraining’. In a study by Schiros,16 19 marathon runners had REM as defined by a 35 % LVEDV index (LVEDVI) and 50 % LVESV index (LVESVI) increase, but also had a 34 % increased stroke volume index (SVI) and a normal ejection fraction (EF). In addition, their hearts remained elliptical while those of the comparison group of patients with mitral regurgitation (MR) become more spherical, a characteristic of REM. Regarding molecular changes, the term ’subcellular remodelling’ has been employed by Dhalla et al.17 to include changes in the extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, nucleus, as well as abnormalities in protein content, gene expression and enzyme activities. In terms of myocyte biology,

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Other molecular changes include the decreased expression of many important genes, such as the sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA-2), and the beta1 adrenergic receptors. In addition, the overexpression of natriuretic peptides and genes directing myocyte lengthening have been reported.1 In studies of rats, the thyroid hormone receptor alpha1 (TRalpha1) is downregulated, and an unfavourable balance among stress kinases has been observed.19 Thyroid hormones are responsible for increases in alpha-MHC, SERCA-2 and a decrease in apoptosis,20 while other changes may be attributed to inflammation. Many of these changes are interrelated – SERCA-2 itself is antiapoptotic; however, its level decreases with apoptosis. Thus a vicious circle emerges, centred around the infarct area. However, the area surrounding the infarct, the border zone, is also important.

The Border Zone The concept of the border zone, an area between the infarct zone and the remote area, was introduced almost 35 years ago.21 Its enlargement in the early post-infarct days is considered responsible for the occurrence of infarct expansion, which is a key contributor to REM.5 The border zone has been shown to be a site of apoptosis for up to several months in animal studies and even longer in humans.22 If this area can be salvaged, cell death may be restricted; otherwise the akinetic or dyskinetic area expands and gradually affects the remote area.2 The border zone is also a site of reduced autophagy (a protective mechanism), activated inflammatory process and decreased SERCA-2 activity, and is a major target of therapeutic interventions. Interestingly, it is a preferential site for the engraftment of progenitor cells administered by the intracoronary route, but also the area in which native progenitor cells are expressed after an AMI, together with the activation of pro-regenerative and anti-apoptotic factors.23

Interaction of Processes with Therapeutic Implications During an AMI, necrotic cardiomyocytes induce the production of reactive oxygen species (ROS), as well as the activation of inflammatory factors (toll-like receptors [TLRs], nuclear factor-kappaB [NF-kappaB]) and monocyte/macrophages. These processes are part of innate immunity.24 Replacement fibrosis is the end result of cell death1 and a hallmark of REM; this process is also induced by an increase of endocardial stress through mechanotransduction. Distefano et al.25 state that in REM numerous systems are dysregulated, primarily chronic contractile dysfunction, which is associated with neurohumoral activation. Other important pathways include the renin-angiotensin-aldosterone, endothelin, adrenergic and cytokine and growth factor systems. Therapeutic efforts should be directed towards the correction of these dysregulated processes.

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Burchfield et al.2 describe alterations in various arrhythmogenic processes, which manifest as ’electrophysiological REM’ with malignant ventricular arrhythmias.

Diagnosis Since REM is primarily defined by LV dilation, echocardiography is the major diagnostic modality, and also has prognostic significance, since worse outcomes correlate with an increased end-systolic or end-diastolic volume. Increased sphericity is also a diagnostic criterion of REM.

Table 2: Serum Biomarkers and Cardiac Remodelling (Necessarily Incomplete List) Stretch, myocardial stress: – NT-proBNP, BNP, ANP forms, proadrenomedullin, ST2, copeptin, – GDF 15 Extracellular matrix REM: – MMPs, TIMPs – Galectin-3 – Cystatin C – Osteopontin – Procollagen type 1 and 3

MRI is increasingly being used in the diagnosis of REM. In addition to measurement of LV volumes, it gives important information about the presence and extent of fibrosis and absence of viability.

Inflammation: – (hs)CRP – Interleukins – TNFalpha – Osteoprotegerin

Traditional radioisotopic techniques provide indirect information regarding viability and as predictors of REM.26 Another emerging technique is in vivo imaging of molecular markers, some of which may have clinical application in the near future, such as those regulating collagen (metalloproteinases and their tissue inhibitors), vasculogenesis (integrins, vascular endothelial growth factor, smooth muscle actin) and those involved in growth and viability, including transforming growth factor-beta (TGF-beta), myofibroblasts and apoptotic markers. Many other markers, either radioisotopic or provided by MRI are also under clinical investigation.27 Numerous molecular processes are involved in the pathogenesis of REM. To date, these have only been studied in animal models. However, increasing numbers of biomarkers are being detected in the serum, as shown in Table 2. Many of these, such as N-terminal pro b-type natriuretic peptide (NT-proBNP) and suppression of tumorigenicity 2 (ST2), have not only diagnostic but also prognostic value. Most of these biomarkers represent the initial adaptive processes of REM. Thus the natriuretic peptides have vasodilator activities28 and growth differentiation factor 15 (GDF 15) is a regenerative factor.29 Syndecan is anti-apoptotic30 and ST2 is cardioprotective.31 MicroRNAs are potentially important biomarkers of REM.32 These ubiquitous non-coding RNA molecules (approximately 18–25 nucleotides in size) contribute in diverse ways to the pathogenetic mechanisms of REM, and may be reliable biomarkers because their plasma levels change in time-dependent mode after MI, particularly those that are relative to growth, fibrosis, angiogenesis and viability.

– MCP-1 – GDF15 Proliferation and differentiation – Syndecan 1,4 Oxidative stress: – Malondialdehyde – Myeloperoxidase – Thiobarbituric acid reactive substances (TBARs) – Oxidized low-density lipoproteins – Superoxide Dismutase – Catalase – Glutathione forms – Total plasma polyphenols Myocardial injury, apoptosis: – (hs)TnI, T – CK-MB – Myosin light-chain kinase I – sFas – Heart-type fatty-acid protein Neurohormonal activation: – Norepinephrine – Angiotensin II, renin, aldosterone – Antidiuretic hormone/copeptin – Endothelin, prolactin Thyroid hormones – FT3, FT4, TT3 MicroRNAs: – Myocardial hypertrophy: upregulated: 1, 133a,b, 21, 23a,b, 24, 195, 199a, 214 downregulated: 150, 181b – Excitation-contraction coupling:

Therapeutic Approaches Early Efforts The main aim of early therapeutic approaches is to limit the size of the infarct. Death of ≥40 % of the LV myocardium is fatal; a diminution of MI size to 20 % of the left ventricle significantly improves prognosis. This may be achieved by: • Revascularisation by PPCI as early as possible. In the absence of PPCI, early thrombolysis should be considered. Ndrepepa et al.33 studied 626 patients with first AMI who underwent PPCI. Patients with an anterior infarct and initially worse LV function had the greatest EF improvement at 6 months. Diabetics and smokers had a worse clinical course. Overall, 366/626 (58.4 %) improved while 130/626 (20.7 %) decreased their EF. Patients with decreased LV function had a worse prognosis at 3 years, (5.6 % mortality versus 1.2 % in those whose LV function improved).

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1, 133, 208 – Cytoskeleton regulation: 1, 133 – Extracellular matrix regulation: 1, 133, 29, 208a – Fibrosis: 21, 208 – Apoptosis: pro: 1, 320 anti: 21, 133, 199a – Cell fate: 1, 133, 320 – Heart failure: 423 5P, 499 5P ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; CK-MB = creatine kinaseMB; GDF 15 = growth differentiation factor 15; (hs)CRP = high-sensitivity C-reactive protein; (hs)TnI, T = high-sensitivity cardiac troponin; MCP-1 = Monocyte chemoattractant protein-1; MMP = matrix metalloproteinases; NT-proBNP = N-terminal pro b-type natriuretic peptide; REM = Cardiac remodelling; sFas = soluble Fas receptor; ST2 = suppression of tumorigenicity 2; TIMP = tissue inhibitors of metalloproteinases; TNFalpha = tumour necrosis factor alpha.

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Cardiomyopathy | Cardiac Protection • Adjunctive measures. Numerous approaches exist and are mostly directed towards mitigation of ischaemia/reperfusion injury, which accounts for up to 40–50 % of the total infarct size.34 A report from the European Society of Cardiology Working Group on Cellular Biology of the Heart35 listed 14 proven, 15 promising/uncertain and 17 negative drug studies and interventions, and concluded that most of these techniques did not reduce infarct size. Furthermore, the report concluded that there is currently no effective clinical therapy for protecting the heart against the detrimental effects of acute ischaemia/reperfusion injury.35 Adenosine and nicorandil have not gained wide clinical acceptance. However, new data on an old drug are interesting. The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial showed that metoprolol is effective when administered intravenously in conjunction with PPCI.36 Another proposed intervention is postconditioning, which comprises the application of brief periods of ischaemia early after reperfusion, and may be administered during PPCI. Most studies to date have involved remote postconditioning, which consists of 3–4 periods of inflating-deflating a sphygmomanometer in one or both arms and/or the thigh. Studies have shown that remote post-conditioning can induce reduction of infarct size in patients with ST-segment elevation MI.37

differences between ‘mice and men’ – animal hearts are intrinsically normal, while the majority of patients suffering an AMI have widespread coronary artery disease that may adversely affect non-infarct areas. It has also been shown that myocardial areas subtended by a stenotic coronary artery cannot be preconditioned. Moreover, the majority of patients suffering AMI are taking multiple drugs, which may have important interactions. In addition, laboratory animals are genetically homogeneous, while humans have numerous polymorphisms (at least 50 have been proposed), which can affect infarct size and subsequently REM.47

Long-term Therapy

• Insulinotropic and insulin-mimetic. To date, metformin is the most promising drug in this category.49 Exenatide and liraglutide have been successfully studied in animal models and would be easy to use in humans. • Drugs affecting the shift from free fatty acids (FFA) to glucose oxidation. Trimetazidine has been successful in chronic congestive heart failure but has not been studied following AMI.50 It must be stressed that ’shifting’ energy production is difficult.

Subsequent therapeutic approaches are administered immediately after PPCI. These include the ’big 4’, i.e. angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs), beta-blockers, aldosterone antagonists and statins. 38 ACE inhibitors, ARBs and beta-blockers have been successful in reducing heart failure morbidity and mortality following REM. 39 In the Perindopril and Remodelling in Elderly with Acute Myocardial Infarction (PREAMI) study, the ACE inhibitor perindopril prevented the increase in LVEDV and also decreased REM by 45 % as compared with a placebo. 40 In the large (n=6,405) Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico: effects of lisinopril and transdermal glyceryl trinitrate, both singly and combined, on 6-week mortality and ventricular function after acute MI (GISSI-3) trial, lisinopril also decreased REM. Interestingly, REM occurred only in patients with a wall asynergy ≥27 %.41 In the Valsartan in Acute Myocardial Infarction (VALIANT) study, valsartan also proved effective in decreasing REM.42 Beta-blockers have been shown to exert anti-REM effects both in the experimental animal and in clinical studies.38,39,43 Hayashi et al. have shown that immediate administration of spironolactone prevents LV REM in patients with first anterior MI.44 However, the results of the recent Aldosterone Receptor Blockade in Diastolic Heart Failure (ALBATROSS) trial were disappointing – intravenous canrenoate followed by oral spironolactone for 6 months in patients with MI without heart failure (77 % ST-segment elevation myocardial infarction [STEMI], 23 % non-ST-segment elevation myocardial infarction [NSTEMI]) failed to decrease worsening heart failure, an indirect indication of REM.45 Statins have demonstrated antiinflammatory effects in animal models but have not proven effective against REM in clinical studies.46 However, Kjekshus47 suggests that by decreasing subsequent acute coronary events, producing new loss of cardiomyocytes, statins may prevent REM in the long term. It should be noted that a large number of animal studies have demonstrated substantial reductions in REM. This highlights the

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Novel Drugs and Therapies Some newly emerging drugs are non-toxic and can easily be administered for long periods of time. Ivabradine. Apart from its heart rate lowering benefit, this drug has been shown to reduce apoptosis and REM in the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT).7 Ivabradine is a useful alternative to useful al in patients who cannot tolerate the beta-blockers.48 Metabolic modulators. These can be divided in two subgroups:

Another potentially important therapeutic target is chronic post-AMI ongoing ischaemia. This induces ROS production, Ca2+ dyshomeostasis and cell death. Ranolazine, a late Na+ inward channel inhibitor that is used in chronic angina pectoris, is currently being investigated.51 Tetracyclines are anti-apoptotic and promote SERCA-2 expression; doxycycline has proven beneficial in post-AMI patients with a low post-percutaneous coronary intervention (PCI) residual flow.52 Other agents under investigation include omega3 fatty acids and antioxidants. Allopurinol, a widely used xanthine oxidase inhibitor, has been shown to decrease experimental post-MI REM.53 In an initial study of a small number of patients, cyclosporine administered at the time of AMI was effective against REM.54 However, in the Cyclosporine to Improve Clinical Outcome in ST-elevation Myocardial Infarction Patients (CIRCUS) trial, at 1-year, outcomes in the 390 patients in the cyclosporine group did not differ from those of the 396 patients in the placebo group.55 Monoamine oxidase (MAO) inhibitors, while primarily neuroprotective, are also anti-apoptotic in the myocardium. Promising initial results have been reported with the use of rasagiline in the post-MI rat.56 Thyroid hormones increase alpha-MHC, SERCA-2 and decrease apoptosis; studies have shown that thyroid supplementation in the animal prevents or reverses REM.20,57,58 Around 30 % of patients with congestive heart failure have low triiodothyronine (T3) levels, constituting the ’low T3 syndrome’.59 The ongoing Thyroid Hormone

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Replacement Therapy in ST Elevation Myocardial Infarction (THiRST) study60 has shown promising initial results. Exercise is successful in reducing REM both in the animal and human,61 and is beneficial in patients that have undergone left ventricular assist device (LVAD) placement.62 Another emerging concept is post-MI continuous remote conditioning, which is successful in the animal.63 Currently three large multicentre clinical trials are ongoing.

Interventions, Revascularisation Surgery, Left Ventricular Assist Devices Revascularisation surgery has been investigated over many years. Its success is dependent upon the persistence and extent of viability, according to two clinical studies.64,65 In the study by Carluccio et al.65 the degree of reverse REM did not differ between patients who underwent percutaneous interventions or bypass surgery. The AMICI study showed that PPCI produces long-term reverse REM in up to 39 % of patients, and is associated with a better 2-year eventfree survival rate.11 The concept of the utility of surgical restoration of REM is under discussion. According to the results of the Surgical Treatment for Ischaemic Heart Failure (STICH) trial, an additional benefit over revascularisation alone was seen only when the post-operative end-systolic volume index was 70 ml/m2 or less.66 In addition, with both coronary artery bypass grafting (CABG) and CABG plus volume reduction, a decrease of LVESVI >30 % at 4 months was seen in 26 % of patients with a baseline LVESVI <60 ml/m2, in 36 % in those with a baseline LVESVI 60–90 ml/m2 and in 45 % of those with a baseline LVESVI >90 ml/m2. Numerous techniques have been proposed for reducing the size of the left ventricle, some of which have entered clinical practice.67 LVADs are increasingly being employed, not only as a bridge to transplantation but also as a destination therapy. These devices induce effective reverse REM expressed by an important decrease in chamber size together with molecular changes that can be summarised as follows:68,69 • an increase of beta-adrenergic receptor density and reactivity toward adrenergic stimulation; • an improvement in calcium handling (increase of Na +/Ca2+ exchanger and SERCA-2); • an increase of insulin-like growth factor 1 (IGF-1); • a decrease of atrial natriuretic peptide (ANP) and chromogranin A and a normalisation of the matrix metalloproteinases (MMP)/tissue inhibitors of metalloproteinases (TIMP) ratio; • a decrease in tumour necrosis factor alpha (TNFalpha) in tissue and plasma; and • a decrease of plasma epinephrine, norepinephrine, renin, angiotensin II and arginine vasopressin levels. Hall et al.70 studied six paired human heart samples harvested at the time of LVAD implant and at the time of LVAD explant. Improvements in ventricular function were maintained over 3.8 years and were associated with a molecular ‘signature’ that correlated to the integrin pathway signalling.

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Mann and Burkhoff71 differentiate between ’reverse remodelling’ and myocardial recovery; although these entities share many pathways, the former term does not represent normalisation of the pathological condition. They argue that following LVAD support only 5 % of dysregulated genes actually revert to normal. Moreover, although LV chamber geometry may normalise, the LV wall thickness/radius ratio and subsequent wall stress do not normalise. Resynchronisation therapy can prevent and also reverse REM, mainly in patients with a QRS >150 msec, and more in dilated than in ischaemic cardiomyopathy. LV dimensions are a critical prognostic factor. If the LV diastole volume index exceeds 125 mL/m2 a superior response has been reported.72 In addition, a greater 5-year decrease in mortality was seen in patients with a >15 % decrease in LVESV index.12

Future Therapies Novel drugs are continuously being sought. In addition to the remarkable clinical improvements attributed to LCZ696 in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial,73 the findings of von Lueder et al.74 suggest that LCZ696 improves REM in animal models.75 MicroRNAs are being studied as biomarkers in all phases of MI. The inhibition of pro-REM members is currently under investigation.76 Gene transfer is an area of active clinical research. To date, SERCA-2 appears the most promising; the CUPID1 phase I/phase II trial (n=39) showed a continued benefit at 3 years of follow-up,77 with an 82 % decrease in cardiovascular events. However, results of the CUPID2 phase II trial (n=343)78 were disappointing – the use of SERCA-2, delivered by an adeno-associated virus serotype 1 vector, did not result in any improvement at a 17.5 months follow-up compared to the control group. The high cost of this therapy precludes continued research in a large number of patients. It is important to highlight the need for complete evaluation of the degree of viable/non-fibrotic myocardium before any novel therapy is contemplated. Progenitor cell efforts have been ongoing for the past 12 years.38,79 If administered early (within 5–10 days of AMI) they can produce a gain in EF of 5 units in large anterior infarcts. A large multicentre trial with a primary endpoint of 2-year mortality is ongoing. At present, endogenous progenitor cell regeneration is inadequate to compensate for cell loss; its pharmacological boosting is a novel concept.79

Summary: Future Directions A holistic approach should be applied against post-MI REM that constitutes a main cause of morbidity and mortality from ischaemic heart disease. This should comprise early revascularisation, appropriate drugs (including neurohormonal antagonism), metabolism optimisation80 and possibly post-conditioning supplementation. In the case of an anterior infarct radioisotopes, additional echocardiographic techniques, MRI and enlistment of new biomarkers may provide a better insight into the mechanisms of REM. Judicious use of diagnostic and therapeutic modalities may prevent and/or reverse REM, and improve life quality and span. This is a worthwhile though arduous task. Recently, Gerber et al.81 reported that between 1990 and 2000 and from 2001 to 2010 the 5 years’ survival in post-MI patients with heart failure improved from 61 to 54 %; an encouraging finding. ■

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receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15 :1062–73. DOI: 10.1093/eurjhf/hft052; PMID: 23563576 74. von Lueder TG, Wang BH, Kompa AR, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail 2015;8 :71–8. DOI: 10.1161/CIRCHEARTFAILURE.114.001785; PMID: 25362207 75. Sanganalmath SK, Bolli R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013;113 : 810–34. DOI: 10.1161/CIRCRESAHA.113.300219; PMID: 23989721 76. Bernardo BC, Gao XM, Winbanks CE, et al. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci U S A 2012;109 :17615–20. DOI: 10.1073/

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Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection Alessa ndro Pi n g i t o r e , G i o r g i o I e r v a s i a n d F r a n c e s c a F o r i n i Clinical Physiology Institute, National Research Council (CNR), Pisa, Italy

Abstract Cardioprotection is a common goal of new therapeutic strategies in patients with coronary artery disease and/or left ventricular dysfunction. Myocardial damage following ischaemia/reperfusion injury lead to left ventricular adverse remodelling through many mechanisms arising from different cell types in different myocardial districts, namely the border and remote zone. Cardioprotection must face this complex, dynamic network of cooperating units. In this scenario, thyroid hormones can represent an effective therapeutic strategy due to the numerous actions and regulating mechanisms carried out at the level of the myocytes, interstitium and the vasculature, as well as to the activation of different pro-survival intracellular pathways involved in cardioprotection.

Keywords Cardioprotection, acute myocardial infarction, left ventricular remodelling, heart failure, thyroid hormone, low T3 syndrome, hypothyroidism Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: We are grateful to Karin J Tyack for the English revision of the manuscript. Received: 3 February 2016 Accepted: 17 June 2016 Citation: European Cardiology Review, 2016;11(1):36–42 DOI: 10.15420/ecr.2016:9:2 Correspondence: Professor Alessandro Pingitore, Clinical Physiology Institute, CNR, Via Moruzzi 1, 56124 Pisa, Italy. E: pingi@ifc.cnr.it

Cardioprotection includes all methods and mechanisms that lead to the reduction in infarct size, and is thus involved in the evolution of post-ischaemic heart failure (HF). This is a growing research issue since ischaemic heart disease is the leading cause of morbidity and mortality worldwide. A key challenge for these studies is the unravelling of cardioprotection complexities such as the mechanisms leading to myocardial damage, the cascade of activated cellular signalling pathways, and the cellular and extracellular districts involved, which are strictly interconnected. This liaison between the heart and thyroid hormone (TH) adds complexity as it arises from the numerous TH effects on the heart, starting with cardiac differentiation in the transition from foetal to postnatal growth, during which THs induce transcriptional programming leading to the typical gene expression profile of the adult heart, as well as the maintenance of cardiovascular homeostasis directly through genomic and non-genomic actions and indirectly by TH regulating effects on other systemic pathways. Recent evidence highlights multiple actions of the TH system on the heart that can have a relevant role in cardioprotection, including the regulation of different intracellular pro-survival pathways, the preservation of mitochondrial function and morphology, the antifibrotic and proangiogenic effect, and also the potential induction of cell regeneration and growth. This review mainly focuses on these new actions of TH on the heart in relation to cardioprotection.

Definition of Cardioprotection According to Heusch,1 cardioprotection is a highly concerted spatiotemporal programme in which different factors with different pathophysiological mechanisms are involved, at different times, in minimising irreversible ischaemic damage and favouring the functional recovery of the injured myocardium. In this context intracellular prosurvival pathways are activated in a complex cross-talking system. Taken

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as whole, cardioprotection can actually be defined as a complex dynamic network of cooperating units, which is characterised by global properties independent of the details of the units in the absence of cooperation.2 This suggests the need to take into account the intertwisted actions of the large number of components to understand the network of cardioprotection in order to give effectiveness to the therapeutic approaches. There are three main stages of myocardial damage: • in the acute phase, coronary occlusion is the ’primum movens‘ of myocardial damage, causing ischaemic injury; • this is followed by coronary revascularisation, i.e. percutaneous coronary angiography that causes reperfusion injury; • in the chronic phase, when left ventricular dysfunction develops, the post-ischaemic remodelling process is another dynamic mechanism influencing myocyte function and survival. Furthermore, the complexity of cardioprotection lies in the activation of the molecular mechanisms of cytoprotection, including activation of heat shock proteins (HSP), protein kinase C (PKC), extracellular signalregulated kinases (ERK), protein kinase B (AKT), p38 mitogen-activated protein kinase (p38MAPK), as well as the stimulation of cell growth, angiogenesis and metabolic adaptation. In addition, the maintenance of mitochondrial integrity is an emerging aspect of cardioprotection. Mitochondria participate in the regulation of myocardial calcium flux, myocyte cell death reactive oxygen species (ROS) generation and antioxidant response.3 The mechanisms of mitochondrial injury are different during ischaemic/reperfusion (I/R): • The activation of the proapoptotic B-cell lymphoma 2 (BCL-2) proteins leads to mitochondrial outer membrane permeabilization, the release of cytochrome complex, caspase activation and apoptosis.4

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• Oxidative stress can lead to a sudden increase in inner mitochondrial membrane permeability that is attributable to the opening of the so-called permeability transition pore (PTP), whose opening is accompanied by the release of ROS and calcium.5,6 This can culminate in the activation of calcium-dependent proteases (calpains) and lipases (cPLA2), inducing necrotic cell death.7,8 In the chronic phase, the activation of the neuroendocrine system, gathering renin-angiotensin-aldosterone and natriuretic peptides in the sympathetic autonomic nervous system, as well as prompting the inflammatory system, is initially protective and adaptive to haemodynamic changes induced by reduced cardiac output, conferring resistance to myocardial hypoxic injury.9 However, when these systems are continuously activated, their initial protective mechanisms become at first less effective, then maladaptive and dangerous for the entire body and heart, contributing to myocardial damage and progression of HF syndrome.10–12

Thyroid System in Patients with Acute Myocardial Infarction In the clinical setting of acute myocardial infarction (AMI) the most frequent alteration of TH metabolism is low triiodothyronine (T3) syndrome.13 This occurs within 12 hours from the onset of symptoms, reaching the nadir at 72 hours. Low T3 syndrome is associated with a larger myocardial infarction (MI) and intense pro-inflammatory and stress response14,15 and, similarly to higher post-ischaemic levels of reverse T3, the TH inactive metabolite is considered an independent predictor of short-term and long-term mortality.16 Additionally, a large amount of clinical data support the clinical and prognostic role of altered thyroid metabolism in HF patients.17–22 T3 circulating levels were higher in patients with New York Heart Association (NYHA) class I and II with respect to patients in NYHA class III and IV with high brain natriuretic peptide (BNP) levels and lower left ventricular ejection fraction (LVEF).18,20,23

Thyroid System in Patients with Heart Failure Low T3 syndrome and subclinical hypothyroidism have been associated with a worse prognosis in patients with HF. In particular, the prognostic power of low T3 syndrome was independent and additive with respect to conventional clinical and cardiac variables, such as LVEF. Furthermore, the negative prognostic power is enhanced in patients with higher BNP concentration both in acute decompensated and chronic compensated HF.23,24 Moreover, in patients with clinically stable HF, short-term synthetic T3 replacement therapy significantly improved neuroendocrine profiles and ventricular performance, characterised by an increase in stroke volume and reduction in the plasma circulating levels of noradrenaline, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and aldosterone.25 According to the clinical data, experimental evidence shows that abnormal TH metabolic patterns, such as hypothyroidism and low T3 syndrome, can cause several histological, molecular and structural abnormalities within the myocardium that can be reversed after normalisation of the TH metabolic profile.26

Thyroid System and Cardioprotection A large amount of experimental evidence highlights that TH can effectively play a role in the complex scenario of cardioprotection (see Table 1),27–43 and that this role is multifaceted due to the numerous actions and regulating mechanisms mediated directly or indirectly by the TH system (see Figure 1). In fact, TH-mediated actions are carried out at the level of the myocytes, the interstitium and the vasculature. TH also plays an important role in orchestrating the activation and

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function of different pro-survival intracellular pathways that are involved in cardioprotection. Furthermore, TH influences the neuroendocrine hormonal pathways activated in HF, as well as the inflammatory system.

Thyroid System and Pro-survival Intracellular Pathways THs regulate the activation and function of the phosphatidylinositol 3-kinase (PI3K)/Akt and PKC signalling cascade, the expression, phosphorylation and translocation of HSP70 and HSP27;36,44 and the suppression of p38MAPK signalling.35 In particular, T3 treatment for 3 days after AMI reduced myocyte apoptosis in the border area of infarction via AKT signalling activation and also through decreased p38MAPK activation.32,36 Importantly, TH has a dose-dependent effect on AKT phosphorylation that can be mild45 and beneficial at low TH dose, while further induction of AKT signalling by higher doses of TH can be accompanied by increased mortality and activation of ERK, a kinase that has been associated with pathological remodelling.36 In addition, 2 weeks of thyroxine (T4) administration increased HSP70 expression and decreased p38MAPK activation in response to ischaemia, changes that closely resemble ischaemic preconditioning.36 The same treatment led to an increase in the basal expression and phosphorylation of HSP27, and earlier and sustained redistribution of HSP27 from the cytosolmembrane to the cytoskeleton-nucleus cellular fraction.35 Such changes might help to protect the myocardium against ischaemic insult, resulting in the improvement of post-ischaemic functional recovery.

Thyroid System and Mitochondria The TH system has multiple actions to protect mitochondria. Among them, the TH is an important regulator of the tumour suppressor p53. This protein network is activated under stress conditions such as AMI and enhances the mitochondrial pathway of cell death.46 p53 expression is blunted by microRNA 30a (miR-30a) through direct targeting.47 In the post-ischaemic setting the miR-30a levels drop, which contributes to p53 accumulation, enhanced mitochondrial dysfunction and bcl-2-like protein 4 (BAX) activation, with the result of extended myocardial cell loss. In the post-ischaemic setting, T3 treatment counteracts the decrease in miR-30a levels, thus limiting the activation of p53 and the cascade leading to mitochondrial injury and cell death in the border zone of MI.38 Translationally, in patients with de novo post-ischaemic HF within 1 year of AMI, the levels of p53-responsive microRNAs (miR-192, miR-194 and miR-34a) were elevated in the early phase of AMI and were associated with increased left ventricular diastolic dimension.48 Moreover, T3 can protect mitochondrial integrity through a mitochondrial adenosine triphosphate-dependent potassium pathway, and by increasing the expression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) and the mitochondrial transcription factor A (mtTFA) in the border zone of infarction.31 These are key intracellular signals that control mitochondrial activity and biogenesis, and whose overexpression limits post-ischaemic left ventricular (LV) remodelling and preserves cardiac performance. 49,50 Further T3 treatment preserves the expression of hypoxia-inducible factor 1-alpha (HIF-1 alpha), whose protective effect against reperfusion injury is mediated by inhibiting the mitochondrial opening of the PTP.7,8,51,52

Thyroid System and Foetal Recapitulation During the evolution of HF, a foetal profile of gene expression is observed. This condition known as foetal recapitulation, is characterised by an isoform switch from the fast contracting alpha-myosin heavy

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Cardiomyopathy | Cardiac Protection Table 1: Experimental Conditions in which Thyroid Hormone Exert a Cardioprotective Effect Cardiac Disease

Mode of Thyroid Hormone

Timing and Duration of Thyroid

Model Post-ischaemic HF

Administration and Dose

Hormone Administration

T3 (0.42 µg/mg)

24 h post-ischaemia for 2 weeks

T4 (1.7 µg/mg) in rat chow

Extent

References

(rat)

T3 (0.42 µg/mg)

T4 (1.7 µg/mg) in rat chow

Cardiac haemodynamics

LV adverse remodelling 24 h post-ischaemia for 13 weeks

Cardiac haemodynamics

LV adverse remodelling 13 weeks post-ischaemia for 2 weeks

Cardiac function

T3 (0.42 µg/mg) and

T4 (1.7 µg/mg) in rat chow

T3 at 3 µg/kg/day

1 week post-infarction for up to

Systolic function with the)

T3 at 6 µg/kg/day

9 weeks

replacement dose

T3 at 60 µg/kg/day

Constant subcutaneous infusion

T3 (1.2 µg/kg/day)

Constant subcutaneous infusion

Positive LV reshaping

72 h post-infarction for 4 weeks

(6 mg/kg/day)

Cardiac function

Mitochondrial function

Scar size

Adverse LV remodelling

T4 3.3 mg pellet

Immediately following infarction for

Arteriolar network in the

60-day sustained release form

8 weeks

non-infarcted area

Subcutaneously

Survival of myocytes in the

peri-infarct area

T4 3.3 mg pellet

60-day sustained release form

2 weeks post-infarction for 2 month

Atrial remodelling

Atrial fibrillation inducibility

Subcutaneously

T3 about 6 μg/kg/day

Immediately following surgery for

Myocardial function

In drinking water

2 months

Reduction atrial arrhythmias

Adverse LV remodelling

IR in perfused heart (rat)

T4 (25 µg/100 g/day)

Subcutaneously

Pre-treatment for 2 weeks before I/R

T3 (40 µg/l)

In reperfusion medium

At reperfusion

Post-ischaemic cardiac

function Post-ischaemic cardiac

function cell death

At reperfusion

Post-ischaemic cardiac

T3 60 nM

or T4 60 nM

contractility (only with

or T4 400 nM

T3 treatment)

In reperfusion medium

Myocardial IR (rat)

T3 (6 µg/kg/day)

Constant subcutaneous

At 24 h from infarction for 48 h

Mitochondrial dependent

infusion

cell death

Post-IR cardiac function

Mitochondrial function

T3 (6 µg/kg/day)

Constant subcutaneous

At 24 h from infarction for 48 h

infusion

Post-ischaemic cardiac Adverse chamber remodelling Profibrotic signalling Inhibition of the scar size

at 3 days and 14 days post

infarction

ECR_Pingitore_v04.indd 38

function

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Table 1: Cont. Model of Cardiac

Dosage and Mode of Thyroid

Timing and Duration of Thyroid

Disease Diabetes mellitus

Hormone Administration

Extent

References

(rat)

T3 (0.03 μg/ml)

At 1 month from diabetes mellitus

Cardiac function

In drinking water

induction for 2 months

Reversal of foetal

gene expression

Arteriole resistance

vessel network

Hypothyroidism (rat)

T3 (14 µg/kg/day)

After hypothyroidism establishment

Atrophy of myocardial

every 24 h for 36 h and 72 h

small arterioles

IR, cardiopulmonary bypass (piglet)

T3 0.6 μg/kg bolus followed

by T3 continuous infusion

At reperfusion for 8 h

Myocardial oxidative

(0.2 μg/kg per hour)

capacity

Substrate flux

Cardiac function

At 80 min and 110 min

Myocardial function and

from reperfusion

Pyruvate entry into the

T3 0.6 μg/kg bolus

citric acid cycle

= Heart failure; IR = ischaemia and reperfusion; LV = left ventricle; T3 = triiodothyronine; T4 = thyroxine.

chain to the slow beta-myosin heavy chain, by a decrease in sarco/ endoplasmic reticulum calcium ATPase (SERCA)/phospholamban (PLB) ratio, and also by the preference of glucose metabolism over fatty acids.51 At its onset in response to stress conditions, such as hypoxia or ischaemia and reperfusion injury, this mechanism may be beneficial to lower energy expenditure and oxygen consumption of the diseased myocardium. It is now understood that it may become maladaptive if continuously maintained.52,53 Altered expression of the TH receptor (TR) isoforms seems to contribute to the reactivation of the foetal transcriptional profile.54 Increased beta-myosin isoform expression, as well as impairment of calcium handling and cell contraction, were associated with the overexpression of unliganded TH receptor alpha 1 (TR alpha 1) in neonatal cardiomyocytes.55,56 Inhibition of T3 binding to TR alpha 1 prevented the differentiation of cardiac embryonic cells.57 Furthermore, phenylephrine administration in the absence of TH induced a switch of myosin isoform expression to a foetal pattern, which was associated to the redistribution of TR alpha 1 from the cytosolic to the nuclear compartment.57 The inhibition of the mammalian target of rapamycin (mTOR) signalling abolished this TR alpha 1 response and favoured cell atrophy.58 Recent evidence indicates that myosin isoform switching is under the control of a complex network of microRNA, including miR-208a and b and miRNA 499, that also presides over cardiac hypertrophy mechanisms.59 miR208 family b is a cardiac-specific miRNA enclosed within the myosin heavy chain (MHC) genes. Therefore, the expression of miR-208a and miR-208b is associated with the expression of the MHC alpha and MHC beta, respectively.59 T3 induces MHC alpha up-regulation and vice-versa downregulation of MHC beta.30 Deregulation of TH signalling in cardiac disease leads to inhibition of alpha-MHC and miRNA-208a expression, while in vitro treatment with THs significantly upregulates alpha-MHC and miRNA-208a and reduces beta-MHC and miRNA-208b expression, as well as miRNA-499.60 Based on this, physiological TH concentration seems necessary to guarantee adequate miRNA levels and to avoid foetal myosin isoform switching.

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Figure 1: A Synopsis of the Thyroid Hormone-mediated Cardioprotection and the Relative Mechanisms to Limit Myocardial Damage in the Acute Phase of Myocardial Infarction, Ischaemia/Reperfusion Injury and in the Chronic Phase, Adverse Left Ventricular Remodelling Post-ischaemic Cardiac Disease Evolution AMI

Acute phase

Ischaemia and Reperfusion Injury Anti-apoptosis PI3K/AKT, Heat Shock Protein p38MAPK, p53

Mitochondrial protection miR-30a p53 mitoKAPT PGC-1 Alpha, mtTFA HIF-1 Alpha

Chronic phase

Heart Failure

Adverse Remodelling Neoangiogenesis ERK1/2, HIF-1 Alpha

Antifibrosis MMP-1 and 2 TIMP 1 to 4 TGF-Beta 1 miRNA -29c, -30c and 133

Cell growth and redifferentiation miRNA-208a miRNA-208b

Beta-MHC Alpha-MHC

Myocardial Hypertrophy PI3K/AKT/m/ TOR and GSK3 Beta axes

Thyroid Hormone-mediated Cardioprotection AMI = acute myocardial infarction; AKT = protein kinase B; ERK1/2 = extracellular signalregulated kinases; GSK3 beta = mitochondrial adenosine Glycogen Synthase Kinase 3 beta; HIF-1 alpha = hypoxia-inducible factor 1-alpha; MHC = myosin heavy chain; mitoKATP = mitochondrial adenosine triphosphate-dependent potassium; MMP-1 = matrix metalloproteinases; mtTFA = mitochondrial transcription factor A; mTOR = mammalian target of rapamycin; PGC-1 alpha = peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K = phosphatidylinositol 3-kinase; TGF-beta 1 = transforming growth factor beta-1; TIMP 1 = tissue inhibitors of MMPs.

Thyroid System and Myocardial Interstitium Besides cardiomyocytes, other myocardial cell types contribute to cardioprotection including fibroblast and endothelial cells that play a key role for the maintenance of cardiac architecture and function, and are involved in the pathophysiological evolution of HF. The

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Cardiomyopathy | Cardiac Protection function of these cells is critical for the synthesis and degradation of extracellular matrix components, as well as for the regulation of cell proliferation, migration, differentiation and apoptosis.61,62 In the post-ischaemic wound healing process, an interstitial remodelling occurs due to abnormal synthesis and deposition of collagen along with the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of MMPs (TIMPs).63 It has been demonstrated that MMPs increase whereas TIMPs reduce their activity following MI. A temporal and spatial pattern of MMPs and TIMPs activation has been documented where MMP-1,2,3,7,9 activate early, and MMP-8,13 and 14 later following AMI.64 TIMPs 1–3 expression is also reduced in both the remote and border infarcted zone, whereas TIMP-4 is decreased only in the border infarcted zone.65 TH treatment with both T3 and T4 is paralleled to a reduction of the interstitial fibrosis in animal models of ischaemic and non-ischaemic HF, and this effect may be related, at least in part, to the effect of TH on MMP and TIMP activity.66,67 T3-dependent cardiac hypertrophy was not accompanied by interstitial fibrosis but an increase of MMP-2 and TIMP-2 expression was evidenced.67 Similarly, in rats, cardiac hypertrophy induced by T3 treatment has been associated with an increase of MMP-1 activity, a reduction of collagen I and III and a decrease in TIMP-l and 4 expression.68 More recently, in long-term T4 treated MI rats, a reduction of collagen deposition in the LV noninfarcted area has been reported along with a tendency towards increased MMP-2 and TIMPs-1–4 expression.32 The antifibrotic effect of T3 is further suggested by the evidence that early T3 replacement in a rat model of ischaemia/reperfusion reduced the scar size while improving long-term cardiac performance, and these effects were associated with the inhibition of the profibrotic transforming growth factor beta-1 (TGF-beta 1) signalling cascade and with the maintenance of the antifibrotic miRNA-29c, 30c and 133 expression.39

Thyroid System and Neo-angiogenesis THs exert well-documented pro-angiogenic effects. Accordingly, chronic hypothyroidism is associated with rarefaction of small arterioles within the myocardium with consequent impaired coronary vasodilation. This alteration is reversed by T3 administration that prompts the proliferation of vascular smooth muscle cells, pericytes and endothelial cells.41,69 This pro-angiogenic action is mediated by several molecular mechanisms and starts as a non-genomic action at the plasma membrane of the endothelial cells through the interaction with the integrin alpha V beta 3.26 The transduction of the TH signal is driven by the mitogen-activated protein kinase ERK1/2 with the consequent transcription of pro-angiogenic genes, such as basic fibroblastic growth factor (bFGF) and vascular endothelial growth factor (VEGF).70 Another molecular cascade implicated in the T3 pro-angiogenic effect is triggered by the expression of HIF-1 alpha, which is induced by the activation of P13K signalling through the binding of TH with cytoplasmic TR beta.71,72 T3 induced angiogenesis has been documented in several experimental rat models of cardiovascular disease, including ischaemia, hypertension and diabetic cardiomyopathy.32,66,73 In a rat model of post-ischaemic HF, T3 supplementation to correct the low T3 state favoured a better retention of capillary density in the border zone in association with HIF-1 alpha stabilisation and TR alpha 1 upregulation.72

peri-infarcted region (border zone) and remote region.74 Myocardial hypertrophy is one of the adaptive mechanisms involved in left ventricular remodelling and is influenced by TH dyshomeostasis. Hypothyroidism induces abnormal myocyte growth characterised by cell lengthening from the addition of sarcomeres in series, a change specific to dilated HF.75 In the study by Tang et al.,75 chronic hypothyroidism in rats, treated with propylthiouracil (PTU) for 1 year, caused progressive systolic dysfunction and heart dilatation associated with myocyte lengthening due to series sarcomere addition, which is a typical myocyte remodelling in HF76 Similarly, myocyte atrophy of myocytes characterised by an increase in length:width ratio occurred after 4 weeks treatment with PTU in rats. These changes were reversible 6 weeks after discontinuing PTU treatment.77 Conversely, TH treatment favours physiological hypertrophy through the activation of PI3K/AKT/mTOR and GSK3 beta axes, and through genomic regulation of specific target genes that encode both structural and functional proteins.78 As evidenced by a histological study, TH treatment of rats with hypertension and dilated HF, induced growth in myocyte transverse dimensions only, a change that reduced systolic wall stress.79 Furthermore, angiotensin type 1 receptor (AT1R) is a determinant of cardiac hypertrophy induced by hyperthyroidism, and also mediates TH induction of cardiac miR-208a and reduction of cardiac miR-208b levels in hyperthyroid rats. These data strongly suggest that AT1R might have an important regulatory role in cardiac muscle strength and contractility, influencing the efficiency of the cardiac function in hyperthyroidism.80

Thyroid System and Neuroendocrine Activation In general, TH modulates the sympathetic and plasma reninangiotensin-aldosterone axis, and natriuretic peptide increasing their release and function.81 At the level of cardiac myocytes T3 promotes BNP gene transcription and regulates the cardiac betaadrenergic receptor-adenylate cyclase system by controlling the rate of transcription of the beta-1 adrenergic receptor gene. The net effect is the increase in BNP and catecholamines.82,83 In hyperthyroid rats the levels of norepinephrine in the cardiac muscle increased significantly, whereas it was undetectable in hypothyroid rats. Accordingly, increased and decreased NT-proBNP levels have been observed in patients with hyperthyroidism or hypothyroidism, respectively.84 Furthermore, in patients with HF and low T3 syndrome dobutamine infusion was associated with the TH metabolic normalisation and this, in turn, with short-term haemodynamic and neurohormonal improvement.85 Similarly, the same results have been obtained in the same patients through continuous L-T3 infusion for 3 days.25

Thyroid System and Inflammation Plasma cytokines, in particular interleukin 6 (IL-6) and tumour necrosis alpha (TNF-alpha), are elevated in AMI and HF, and this is associated with the severity of the clinical status and a worse outcome. 86,87 A cross-talk between TH and inflammation has been documented in experimental and human studies showing that administration of IL-6 in animals caused T3 decrease, due to the reduction in peripheral conversion of T4 into T3 following the inhibition of the 5’deiodinase activity. 88–92

Thyroid System and Myocardial Hypertrophy

Conclusion

Post-ischaemic LV remodelling is the final result of molecular, subcellular, cellular and interstitial processes leading to changes in cardiomyocytes, extracellular matrix and vasculature within the

Cardioprotection can be considered an example of complexity applied to the human biological system, which is comparable to a non-linear, dynamic and intertwisted network in which small changes

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can result in important consequences and big changes may result in no or small consequences. In this complex dynamic network, the TH system may be a newly identified player orchestrating the different molecular, tissue and cellular elements involved both in the acute phase, when ischaemic/reperfusion injuries occur, and in the chronic phase, when the post-ischaemic remodelling process evolves. Notwithstanding the large amount of experimental data showing the potential effective role of TH on cardioprotection, there are still few clinical data available, in particular in the acute setting of AMI. It is important to underpin that the goal of TH treatment in patients with AMI and HF should be to restore and maintain euthyroidism in those patients with altered peripheral TH metabolism, and to avoid potentially dangerous pharmacological hyperthyroidism, as shown in two studies using TH replacement therapy in cardiac patients. The Coronary Drug Project (CDP), carried out in the early 1970s,93 demonstrated adverse outcomes, particularly with respect to the pro-arrhythmic effects of D-T4 (the inactive form of thyroxine). Patients were given 6 mg/ day D-T4, which is equivalent to 225 μg of L-T4, corresponding to more than double the endogenous production of T4, which is ∼

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Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 2015;116 :674–99. DOI: 10.1161/ CIRCRESAHA.116.305348; PMID: 25677517 West BJ, Geneston EL, Grigolini P. Maximizing information exchange between complex networks. Physics Reports 2008;468 :1–99. DOI:10.1016/j.physrep.2008.06.003 Marín-García J, Goldenthal MJ. Mitochondrial centrality in heart failure. Heart Fail Rev 2008;13 :137–50. DOI: 10.1007/ s10741-007-9079-1; PMID: 18185992 Baines CP. The cardiac mitochondrion: nexus of stress. Annu Rev Physiol 2010;72 :61–80. DOI: 10.1146/annurevphysiol-021909-135929; PMID: 20148667 Brady NR, Hamacher-Brady A, Gottlieb RA. Proapoptotic BCL-2 family members and mitochondrial dysfunction during ischemia/reperfusion injury, a study employing cardiac HL-1 cells and GFP biosensors. Biochim Biophys Acta 2006;1757 :667–78. PMID: 16730326 Zorov DB, Filburn CR, Klotz LO, et al. Reactive oxygen species (ROS)-induced ROS release: A new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 2000;192:1001–14. PMID: 11015441 Assaly R, de Tassigny Ad, Paradis S, et al. Oxidative stress, mitochondrial permeability transition pore opening and cell death during hypoxia-reoxygenation in adult Cardiomyocytes. Eur J Pharmacol 2012;675 :6–14. DOI: 10.1016/j.ejphar .2011.11.036; PMID: 22173126 Garcia-Dorado D, Ruiz-Meana M, Inserte J, et al. Calciummediated cell death during myocardial reperfusion. Cardiovasc Res 2012;94:168–80. DOI: 10.1093/cvr/cvs116; PMID: 22499772 Gerdes AM, Kellerman SE, Moore JA, et al. Structural remodelling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation 1992;86 :426–30. PMID: 1638711 Daly PA, Sole MJ. Myocardial catecholamines and the pathophysiology of heart failure. Circulation 1990; 82 (2 Suppl):I35–43. PMID: 2197023 Wong GH, Goeddel DV. Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science 1988;242 :941–4. PMID: 3263703 Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257 :387–9. PMID: 1631560 Li L, Guo CY, Yang J, et al. Negative association between free triiodothyronine level and international normalized ratio in euthyroid subjects with acute myocardial infarction. Acta Pharmacol Sin 2011;32 :1351–6. DOI: 10.1038/aps.2011.118; PMID: 21963894 Friberg L, Werner S, Eggetsen G, Ahnve S. Rapid downregulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch Intern Med 2002;162 :1388–94. PMID: 12076238 Kimur T, Kotajima N, Kanda T, et al. Correlation of circulating interleukin-10 with thyroid hormone in acute myocardial infarction. Res Commun Mol Pathol Pharmacol 2001;110 :53–8. PMID: 12090356 Friberg L, Drvota V, Bjelak AH, et al. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med 2001;111 : 699–703. PMID: 11747849 Iervasi G, Pingitore A, Landi P, et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107 :708–13. PMID: 12578873 Pingitore A, Landi P, Taddei MC, et al. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118 :132–6. PMID: 15694896 Iervasi G, Molinaro S, Landi P, et al. Association between

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90–100 μg/day.94 It was later found that the D-T4 preparation used in the CDP was contaminated with a high level of active L-T4,95 which is the active form of thyroxine. Therefore, the cumulative dose of the D-T4 and L-T4 being administered was equivalent to several times the L-T4 dose that would be given to a patient to correct overt hypothyroidism. Furthermore in the study by Goldman et al., the TH analogue 3,5 diiodothyropropionic acid (DITPA) was administered to patients with HF.96 No improvement on outcome was observed, but rather fatigue was more frequent in the DITPA group, in association with weight loss, reduction in serum cholesterol and increase in heart rate, all signs and symptoms suggesting thyrotoxicosis. Therefore, several questions need to be answered, including: the type of hormone to administer, T3 or T4 or both; the dosage and duration of the treatment to reach the goal that is the restoration of euthyroidism; the starting point of the treatment, for example before, during or late after the revascularisation procedure; the patient selection, i.e. patients with altered TH metabolism; and finally the clinical, functional and prognostic targets to assess the effective benefit of TH treatment. ■

increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167 :1526–32. PMID: 17646607 Chen P, Li S, Lei X, et al. Free triiodothyronine levels and short-term prognosis in chronic heart failure patients with type 2 diabetes. Am J Med Sci 2015;350 :87–94. DOI: 10.1097/ MAJ.0000000000000524; PMID: 26164865 Ning N, Gao D, Triggiani V, et al. Prognostic Role of Hypothyroidism in Heart Failure: A Meta-Analysis. Medicine (Baltimore) 2015;94 :e1159. DOI: 10.1097/ MD.0000000000001159; PMID: 26222845 Li X, Yang X, Wang Y, et al. The prevalence and prognostic effects of subclinical thyroid dysfunction in dilated cardiomyopathy patients: a single-center cohort study. J Card Fail 2014;20 (7):506–12. DOI: 10.1016/j.cardfail.2014.05.002; PMID: 24858054 Passino C, Pingitore A, Landi P, et al. Prognostic value of combined measurement of brain natriuretic peptide and triiodothyronine in heart failure. J Card Fail 2009;15 (1):35–40. DOI: 10.1016/j.cardfail.2008.08.008; PMID: 19181292 Chuang CP, Jong YS, Wu CY, Lo HM. Impact of triiodothyronine and N-terminal pro-B-type natriuretic peptide on the long-term survival of critically ill patients with acute heart failure. Am J Cardiol 2014;113 :845–50. DOI: 10.1016/j.amjcard.2013.11.039; PMID: 24406111 Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2008;93(4): 1351–8. DOI: 10.1210/jc.2007-2210; PMID: 18171701 Gerdes AM. Restoration of thyroid hormone balance: a game changer in the treatment of heart failure? Am J Physiol Heart Circ Physiol 2015;308 :H1–10. DOI: 10.1152/ ajpheart.00704.2014; PMID: 25380818 Pantos C, Mourouzis I, Markakis K, et al. Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early after acute myocardial infarction in rats. Eur J Cardiothorac Surg 2007;32 (2):333–9. PMID: 17560116 Pantos C, Mourouzis I, Markakis K, et al. Long-term thyroid hormone administration reshapes left ventricular chamber andimproves cardiac function after myocardial infarction in rats. Basic Res Cardiol 2008;103 :308–18. DOI: 10.1007/s00395008-0697-0; PMID: 18274800 Pantos C, Mourouzis I, Tsagoulis N, et al. Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improvescardiac function in rats with old myocardial infarction. J Physiol Pharmacol 2009;60 :49–56. PMID: 19826181 Henderson KK, Danzi S, Paul JT, et al. Physiological replacement of T3 improves left ventricular function in an animal model of myocardial infarction-induced congestive heart failure. Circ Heart Fail 2009;2 :243–52. DOI: 10.1161/ CIRCHEARTFAILURE.108.810747; PMID: 19808346 Forini F, Lionetti V, Ardehali H, et al. Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats. J Cell Mol Med 2011;15 (3):514–24. DOI: 10.1111/j.1582-4934.2010.01014.x; PMID: 20100314 Chen YF, Weltman NY, Li X, et al. Improvement of left ventricular remodeling after myocardial infarction with eight weeks L-thyroxine treatment in rats. J Transl Med 2013;11 :40. DOI: 10.1186/1479-5876-11-40; PMID: 23409791 Zhang Y, Dedkov EI, Lee B 3rd, et al. Thyroid hormone replacement therapy attenuates atrial remodeling and reduces atrial fibrillation inducibility in a rat myocardial infarction-heart failure model. J Card Fail 2014;20 :1012–9. DOI: 10.1016/j.cardfail.2014.10.003; PMID: 25305503 Rajagopalan V, Zhang Y, Ojamaa K, et al. Safe Oral Triiodo-

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EUROPEAN CARDIOLOGY REVIEW

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Cardiomyopathy | Cardiac Protection

Cardiac Repair and Regeneration: The Value of Cell Therapies Da niel Aleja ndro Lerma n1,4, N a s r i A l o t t i 2, K i d d y L e v e n t e U m e 3 a n d B r u n o Pé a u l t 4,5 1. Department of Cardiothoracic Surgery, Royal Infirmary Hospital of Edinburgh (NHS Lothian), University of Edinburgh, Scotland, UK; 2. Zala County Hospital, Pécs University, Hungary; 3. University of Maryland School of Medicine, Baltimore, Maryland, USA; 4. MRC Centre for Regenerative Medicine and College of Medicine and Veterinary, University of Edinburgh, Scotland, UK; 5. David Geffen School of Medicine at UCLA, Orthopaedic Hospital Research Centre, University of California at Los Angeles, USA

Abstract Ischaemic heart disease is the predominant contributor to cardiovascular morbidity and mortality; one million myocardial infarctions occur per year in the USA, while more than five million patients suffer from chronic heart failure. Recently, heart failure has been singled out as an epidemic and is a staggering clinical and public health problem associated with significant mortality, morbidity and healthcare expenditures, particularly among those aged ≥65 years. Death rates have improved dramatically over the last four decades, but new approaches are nevertheless urgently needed for those patients who go on to develop ventricular dysfunction and chronic heart failure. Over the past decade, stem cell transplantation has emerged as a promising therapeutic strategy for acute or chronic ischaemic cardiomyopathy. Multiple candidate cell types have been used in preclinical animal models and in humans to repair or regenerate the injured heart, either directly or indirectly (through paracrine effects), including: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), neonatal cardiomyocytes, skeletal myoblasts (SKMs), endothelial progenitor cells, bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and, most recently, cardiac stem cells (CSCs). Although no consensus has emerged yet, the ideal cell type for the treatment of heart disease should: (a) improve heart function; (b) create healthy and functional cardiac muscle and vasculature, integrated into the host tissue; (c) be amenable to delivery by minimally invasive clinical methods; (d) be available ‘off the shelf’ as a standardised reagent; (e) be tolerated by the immune system; (f) be safe oncologically, i.e. not create tumours; and (g) circumvent societal ethical concerns. At present, it is not clear whether such a ‘perfect’ stem cell exists; what is apparent, however, is that some cell types are more promising than others. In this brief review, we provide ongoing data on agreement and controversy arising from clinical trials and touch upon the future directions of cell therapy for heart disease.

Keywords Acute myocardial infarction, bone marrow stem cells, cardiac repair, cardiac regeneration, cardiac stem cells, cardiac stem/progenitor cells, embryonic stem cells, ischaemic cardiomyopathy, mesenchymal stem cells, pericytes, skeletal myoblasts Disclosure: The authors have no conflicts of interest to declare. Received: 27 January 2016 Accepted: 29 February 2016 Citation: European Cardiology Review, 2016;11(1):43–8 DOI: 10.15420/ecr.2016:8:1 Correspondence: Daniel A Lerman, Royal Infirmary Hospital of Edinburgh (NHS Lothian), University of Edinburgh, Scotland, UK. MRC Centre for Regenerative Medicine and College of Medicine and Veterinary Medicine, University of Edinburgh, Scotland, UK. E: s0978484@staffmail.ed.ac.uk

Acute myocardial infarction (AMI) is still a major public health problem worldwide, causing high rates of morbidity and mortality. In the United States, nearly one million patients suffer from AMI each year.1 In the UK, around 80,000 people died from coronary heart disease (CHD) in 2010.2 The current approach to the treatment of myocardial infarction involves early revascularisation with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), followed by the medical management of atherosclerotic risk factors, late ventricular remodelling and cardiac arrhythmias. Improvements in the treatment of AMI, especially use of reperfusion therapy, have led to larger numbers of survivors. In patients who would have survived despite reperfusion therapy, use of this treatment should lead to greater myocardial salvage and a reduced extent of ventricular injury in many. However, others who might not have survived previously may now do so, but with substantial left

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ventricular damage.3,4 The net consequence of these two opposing effects on the early and later risk of developing heart failure after AMI is uncertain. Several clinical trials and registries, despite methodological differences, tend to agree that heart failure is a common occurrence after AMI, and there has been concern that an increasing pool of survivors of AMI might fuel an ‘epidemic’ of heart failure.5,6 Patients with chronic heart failure (CHF) have a mortality of 20 % within the first year after diagnosis.2 CHF accounts for roughly 70,000 deaths in the UK each year, corresponding to an average of 190 deaths per day.2 Despite recent advances in medical and device therapy and improvements in care over the past 20 years, the outlook for patients with heart failure remains poor, and survival rates are worse than those for bowel, breast or prostate cancer.7–9 Therefore, any new treatment modality that benefits heart failure patients has the

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Cardiomyopathy | Cardiac Protection potential to result in a dramatic improvement in health outcomes and substantial cost savings for the community. Ventricular remodelling after AMI involves replacing a significant amount of cardiomyocyte cell mass with fibrotic tissue, which results in contractile dysfunction. This degenerative process is not always irreversible; depending on the extent of damage and age of the subject, some spontaneous regeneration of the cardiac muscle may occur, which might be of key importance in the next generation of treatment modalities for such a severe and frequently deadly condition. The identity of the stem cells involved in cardiac repair is, however, still uncertain. Several novel treatment strategies are emerging, aiming at each stage of the pathological remodelling process, including stem cell treatments, paracrine signalling, microRNA-modification of key signalling events and tissue engineering. Cardiomyoplasty and stem cell therapy are generating great expectation to treat different types of cardiac diseases, including AMI, refractory angina and CHF. Effective medical treatments of these conditions will produce crucial improvement in overall health outcomes and substantial cost savings for the National Health Service (NHS).

Pathophysiology of Myocardial Infarction Myocardial ischaemia may result from either a rise in metabolic demand or a reduction of oxygen and nutrient supply to the myocardium. Myocardial infarct occurs if the demand/supply mismatch is enough to trigger cellular necrotic and apoptotic mechanisms within cardiomyocytes. Several conditions are associated with an increased myocardial metabolic demand, such as severe hypertension, severe aortic stenosis, other valvular pathologies and low cardiac output syndromes. Not only do these conditions increase the metabolic demand, but they also have the capability to reduce the coronary perfusion by lowering the mean aortic pressure. Infarction can also be caused by other conditions that are characterised by thromboembolic or atherosclerotic stenosis/occlusion of coronary arteries, leading to ischaemia primarily by decreasing the delivery of oxygen and nutrients to the myocardium.10

Myocardial Repair after Myocardial Infarction There are several cellular changes that occur in the myocardium following myocardial infarction. During the first 6â&#x20AC;&#x201C;12 hours, a process of coagulative necrosis occurs, and the fibres at the periphery of the infarct become elongated and narrowed with signs of vacuolar degeneration. Concomitantly, oedema and neutrophils are observed in the intercellular spaces. This process lasts for 3 to 4 days. Following this stage, the necrotic myocytes are removed by macrophages, which may be actively phagocytic for 7 to 10 days. Finally, granulation tissue with loose collagen fibres and copious capillaries commence the healing and repair processes, in which the necrotic cardiac muscle cells are replaced by a collagen scar.10

Cardiac Regeneration and Cell Therapy The heart, which had been considered as a terminally developed organ with no potential for regeneration in post-natal life, has recently been recognised to possess some intrinsic reparability. Currently, there are two complementary theories about the process of intrinsic repair in the heart after an ischaemic injury: (1) cardiomyocytes re-enter the cell cycle and start the process of proliferation, regeneration and repair of the necrotic tissue;11,12 and (2) certain endogenous cardiac stem cells undergo growth and differentiation, regulated either by secreted inflammatory factors or autocrine regulation.13,14 Both mechanisms may be involved in the process of heart regeneration.15 Currently, the

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research focus is on how to translate the preclinical cell-based results into effective clinical treatment. In order to repair the human heart, it is crucial to identify the appropriate cell type and optimal route to deliver it. The selected cells should be able to differentiate into mature cardiomyocytes and achieve electrical integration with mechanical coupling. They should also have the capability to repair the heart via paracrine effects. Importantly, delivery of such cells should be done with careful consideration of the risks and benefits to the patient. Possible delivery methods include intravenous, intracoronary or intramyocardial.16 In selecting appropriate cells, one needs to know each cellâ&#x20AC;&#x2122;s individual potential: its regenerative activity (ESC, iPSC, and endogenous cardiac stem cells), paracrine effects (MSC) and angiogenesis activity (endothelial precursors).

Endogenous Cardiac Progenitors There are three different embryonic cardiac cell precursors: the cardiac mesoderm; the neural crest cells; and the pro-epicardial territory. Each of the original precursors will turn into different cardiac structures, as follows. (1) Cardiac mesoderm becomes endocardial cells, atrial myocytes and ventricular myocytes. (2) Cardiac neural crest becomes aorta smooth muscle cells and autonomic nervous system. (3) Pro-epicardium becomes smooth muscle of coronary arteries, fibroblasts, endothelium of coronary arteries.17â&#x20AC;&#x201C;19 Recently, multipotent stem cells were identified in each one of the layers of human blood vessels. Myogenic endothelial cells (MECs) are located in the intima of blood vessels, whereas pericytes and adventitial cells (ACs) are located in the media and adventitia, respectively. MECs and pericytes have the capability to regenerate myofibres in dysfunctional skeletal muscles and to improve cardiac contractility following AMI.19 Recently, cardiogenic progenitor cells (CPCs) were detected in the adult heart. It is still not completely clear whether CPCs originate from the bone marrow, or there are populations of embryonic cells localised in the right atrium and right ventricle. Also, there is still ongoing research to determine the participation of these cells in the physiological turnover of cardiac myocytes and vascular endothelial cells in the absence of myocardial injury.20 CPCs represent 1 % of the total cell population in the heart and are divided into three groups so far identified (c-Kit+, Sca-1+ and ISL-1+ cells) according to the expression of membrane markers.20 c-Kit+ cardiogenic stem cells express pluripotency, clonogenicity and self-renewal capabilities, and differentiate into myogenic, vascular endothelial and smooth muscle lines in vitro. These cells can regenerate the ischaemic myocardium in animal models.21,22 The group of CPCs expressing Sca-1+ interact with a homogeneous cell population in foetal and adult human hearts and show self-renewal properties together with active participation in cell signalling and cell adhesion.23 It is possible to differentiate Sca-1+ CPCs into cardiomyocytes by using 5-azacytidine. 5-Azacytidine is similar to cytidine, a nucleoside found in either DNA or RNA. The mechanism of action of this drug is through inhibition of the enzyme methyltransferase. 5-Azacytidine is incorporated into the structure of DNA and RNA instead of cytidine, inhibiting the synthesis of proteins within the cells.24 Additionally, the activation of extracellular signal-related kinases (ERK) by 5-azacytidine seems to trigger the differentiation of human MSCs into cardiomyocytes in vitro.25 In vitro differentiation to cardiomyocytes appears to involve the receptor for bone morphogenic proteins like BMPR1A.26 Differentiated murine Sca-1+ cells can be detected

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as mature cardiomyocytes after intravenous transfusion following myocardial ischaemia and necrosis in rats.26 A group of stem cells is found in the hearts of newborn mice, rats and humans. Neonatal mouse hearts have cells that express the transcription factor ISL-1 together with two more factors: Nkx2.5 and GATA4, which are crucial transcription factors that participate actively in the initial stages of cardiogenesis, but don’t express either c-Kit or Sca1.26,27 These cells can differentiate into cardiomyocyte phenotypes with intact calcium cycling. They produce action potentials when cultured together with neonatal myocytes.27,28 These findings allow the study of the molecular pathways linked to the differentiation of ISL-1+ cells into the different lineages in either postnatal or embryonic hearts. The limited capacity of human cardiomyocytes to regenerate in vivo is responsible for the development of heart failure after infarction. Understanding the molecular mechanisms involved in the differentiation of the embryonic heart is of crucial importance in the design of effective regenerative stem cell therapies to treat patients with cardiac injury.

The CADUCEUS trial uses a mixed population of stem cells denominated by cardiospheres of which mesenchymal stem cells are a big proportion.39,40 The SCIPIO trial works with c-Kit cells; whereas ALCADIA uses a mixed population extracted from endomyocardial biopsies and cultured for a month. Within the pool of pluripotent stem cells, human ESCs could be committed toward cardiac lineage in vitro. These cells were obtained from disposed embryos in the context of assisted fertilisation. Results show good engraftment of differentiated cardiomyocytes, although the risk for teratomas and immune rejection needs further investigation.41–43 Another source of potential cells could be the pool of iPSCs that are selected from the patient’s somatic cells and reprogrammed to embryonic pluripotent status. Because of their oncogenic potential, they still need larger animal trials before they can be introduced to the market.44 MSCs and fibroblasts could be manipulated in vitro towards enhanced cardiopoiesis, thus increasing the intrinsic therapeutic benefit of the treated cells.45–47

Selection of Cell Types There are two important mechanisms by which stem cells may work. (1) Paracrine effect of the cells: SKMs, BMMNCs and MSCs produce several cytokines and growth factors that increase angiogenesis, reduce apoptosis, decrease fibrosis and induce cardiac regeneration. Ischaemic patients can especially benefit from the paracrine effect, which enhances perfusion.29–31 (2) Trans-differentiation of the stem cells’ phenotypes into cardiomyocytes and replacement of injured cells, increasing the contractility of the injured tissue. Bone marrow MSCs, adipose-tissue-derived stromal cells and pericytes are known to produce cardio-protective cytokines that could be enhanced by genetic engineering.30–32 These cells also have immunosuppressive properties, which allows their usage as potential allogenic drugs.33 Additionally, the cell factors can induce regeneration from myocardial niches of tissue-resident stem cells. The paracrine effect alone would not be enough to relieve severe heart failure with extended scars as it would require cardiac regeneration to complete the healing process. The cells should be able to contract and coordinate each other through Connexin-43, a protein involved in the myofibrillar coupling structure, thus avoiding lethal arrhythmias.34 Cardiac-committed stem cells could be extracted from endomyocardial biopsies or during CABG, expanded in vitro and reinjected. Current clinical human trials, such as Stem Cell Infusion in Patients with Ischaemic Cardiomyopathy (SCIPIO: cells harvested from right atrial appendage during CABG, which uses c-Kit + CSCs) and Cardiospherederived Autologous SCs to Reverse Ventricular Dysfuntion (CADUCEUS: endomyocardial biopsy, which uses CDCs), have been showing promising results.35,36 In these trials, the cells expanded in vitro are injected into the coronary arteries in the catheterisation laboratory. In contrast, the Autologous Human Cardiac-derived Stem Cell to Treat Ischaemic Cardiomyopathy (ALCADIA) trial involves the delivery of the cells into the myocardium during CABG. Cardiac-derived stem cells are extracted from endomyocardial biopsies, expanded and then delivered to the heart during CABG surgery by intramyocardial injections then a biodegradable gelatin hydrogel sheet containing fibroblast growth factor is implanted on the epicardium.37 The ongoing problem is to clarify the characterisation of the cell phenotypes, as current phenotypic differences could correspond to the same cell in a different stage of development.38

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Perivascular/Mesenchymal Stem Cells The pericyte is the second most common cardiac cell type and its participation in cardiac pathophysiology and regenerative medicine is crucial.48 Pericytes are perivascular cells with contractile capability similar to those of the smooth muscle cells that wrap around blood vessels. These cells carry out several functions, including active participation in the development of vessels and their structural maintenance. Additionally, they can communicate with surrounding cells during the angiogenic process, either by direct contact or paracrine signalling.49 New insights into the use of pericyte transfusion as a potential new treatment for AMI showed that there was a significant improvement in the infarcted heart in a mouse model. The effect was achieved through lowering the threshold and the activation of an angiogenic program in the recipient model.50 The identification of pericytes in tissue is a complex process because there is no single reliable marker. Currently, several markers, such as NG2 (neuron-glial antigen 2), α-SMA (alpha smooth muscle actin) and PDGFR-β (beta-type platelet-derived growth factor receptor), are used, each staining a subset of pericytes. Additionally, CD146 stains pericytes and a subset of endothelial cells; CD34 stains endothelial and progenitor cells; and CD31 and CD144 stain mature endothelial cells. Histologically, pericytes are identified as cells positive for CD146 but negative for endothelial markers such as CD34, CD31 or CD144. The NG2 marker is a chondroitin sulphate proteoglycan that can be found on the surface of pericytes and a small subset of glial and endothelial cells and is expressed by SMA-negative pericytes, either in micro-vessels or in the intimal layer of large vessels.51 α-SMA is present in vascular smooth muscle cells and in pericytes. This marker was identified in the microfilament bundles responsible for pericyte contractile functions.52 PDGFR-β is a useful abundant pericyte marker.53 Pericytes from mice that have abnormal PDGFR-β receptors exhibit micro-vascular abnormalities leading to lethal micro-haemorrhages and oedema.54 CD146, also known as Mel-CAM, MUC18, A32 antigen and S-Endo-1, is a specific membrane glycoprotein that can function as a Ca2+ independent cell adhesion molecule with participation in heterophilic activity between cells. CD146 is part of the immunoglobulin gene superfamily.55 CD34 is a trans-membrane protein expressed in either haematopoietic progenitor cells or vascular endothelial cells. In addition, CD34 takes an active part in the regulation of cell migration and differentiation.56

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Cardiomyopathy | Cardiac Protection Figure 1: Origin of Potential Stem Cells. Modified from an Original Drawing by Mirko Corselli 58 Artery

Vein Arterioles

Venules Capillaries Collagen Adventitial progenitor Smooth muscle cell Pericyte

Endothelial cell Pericyte-derived MSC Adventitia-derived MSC

Pericytes have been identified in several human organs, including skeletal muscle, pancreas, adipose tissue and placenta, using markers such as CD146, NG2, and PDGFR-β and absence of haematopoietic, endothelial and myogenic cell markers.57 Recent research demonstrated that human pericytes that are located around capillaries and microvessels can produce MSCs while in culture. Additionally, during the process of vascular regeneration and under the effect of growth factors, adventitial cells can undergo a phenotypic trans-differentiation into pericyte-like cells (see Figure 1).58 Furthermore, there is clear evidence that pericytes contribute to cardiac repair by down-regulating immune cells via interaction with immunomodulatory cytokines and growth factors, following pericyte injection into ischaemic tissues.59

vascular growth, favours cardiac repair and reduces local fibrosis.79 Latest evidence from trials shows that adult bone marrow stem cell treatment significantly improves cardiac function in post MI patients and there is no evidence of any increase in morbidity or mortality in this treated group of patients.80 Research into more effective stem cell treatments allowed the isolation of neonatal and ischaemic myocardial cells expressing the c-Kit, MRD-1, ISL-1 or Sca-1 stem cell markers but no haematopoietic cell markers.26,81 The number of these cells increased after an AMI, suggesting an active role of these cells in cardiac repair.82

Application in Acute Myocardial Infarction with Concurrent CABG Intra-myocardial injection of BMMNCs during CABG is shown to have improved outcomes compared with those of CABG alone.83 The aim of treating patients with stem cells after or during CABG following an episode of acute MI is to reduce later remodelling, which is known to have a negative impact on long-term outcomes.83 Such treatment is carried out by the interventional cardiologist and consists of delivering BMMNCs into the new coronary bypass graft. Unfortunately, there is still a need for more randomised trials to assess the potential benefits currently observed.83–85 Patients with poor left ventricular function undergoing CABG seem to be better at 6 months post-operative if trans-epicardial injection of CD133+ cells was performed intraoperatively.84,85 These observations likely result from the angiogenic potential of cells rather than cardiomyocyte regeneration, since the CD133+ marker is expressed in the membrane of the endothelial cells. The PRECISE (Percutaneous Robotically-enhanced Coronary Intervention) trials use adipose-tissue-derived cells collected with lipo-aspiration from patients at the time of surgery. These cells are subsequently reinfused into the endocardium of the left ventricle. The final results of this technique are still pending.86

Application in Refractory Angina

Clinical Applications Current treatment protocols for AMI focus on reducing myocardial necrosis and irreversible damage by improving perfusion to the ischaemic area via medical or mechanical treatment such as CABG or PCI.60–62 The new potential cell-based treatments to deal with AMI derive from animal research in which mononuclear cells from bone marrow or peripheral blood were used in cardiac repair.63–68 Ongoing research in cardiac developmental and stem cell biology, as well as recent results from clinical trials SCIPIO and CADUCEUS using resident cardiac stem cells, have improved our understanding of in situ heart stem progenitor cells.69,70 The first non-randomised trials in humans showed that there was an improvement in cardiac function after the infusion of bone marrow stem cells and progenitor stem cells into the myocardium affected by the infarction.71–75 The stem cell types involved in the repair of cardiac tissue were first characterised by Stamm’s group in 2003, when the infusion of CD133+ progenitor cells extracted from haematopoietic tissues were applied into the ischaemic cardiac myocardium. The result of this treatment was an improvement in the general revascularisation process.76 The first randomised multicentre trial in 2009 studied patients with severe left ventricular dysfunction as a consequence of AMI. The patients, who were infused with selected CD34+ and CXCR4+ cells and non-selected mononuclear cells into the lumen of their coronary tree, saw significant improvement in their left ventricular ejection fractionafter 6 months.77 The mechanism of action of such treatment seems to be either an increase in the angiogenesis activity and/or trans-differentiation of the cells into myocytes.78 The paracrine secretion of cytokines and other factors also increases

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A second treatment indication under investigation is for refractory angina (angina caused by coronary insufficiency in the presence of coronary artery disease that cannot be controlled by a combination of medical therapy, angioplasty and coronary bypass surgery), which would involve stem cell treatment alone or complemented with surgery. The aim in this subset of patients would be to use the different cell types as carriers of multiple cytokines and growth factors in order to induce angiogenesis in the affected territory and thus relieve ischaemic symptoms.87,88 Patients with refractory angina are currently under investigation in randomised trials to assess the apparent efficacy of catheter-based endoventricular injection of CD34+ cell progenitors following treatment with granulocyte colony stimulating factor for 5 days in order to induce autologous cell mobilisation.89 Another randomised trial in the population of patients with refractory angina used trans-cathether endomyocardial injections of bone marrow unfractionated derived cells (MNC), which seem to have some efficacy in improving clinical parameters but more data is needed to find significant differences between the study arms.90

Application in Chronic Heart Failure A third application under research is the treatment of chronic heart failure patients in whom the aim is to regenerate areas of non-contractile myocardial fibrosis to achieve physiological and functional contractility.88 Patients with chronic heart failure were included in the randomised, double-blinded placebo-controlled Myoblast Autologous Grafting trial. In addition to CABG, patients with severe left ventricular function underwent trans-epicardial injections of either autologous SKMs from a skeletal muscle biopsy or placebo injected in and around the scar.91

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The preliminary results showed that there was no improvement in the ejection fraction at 6 months, but patients injected with 800 million cells presented a reduction in left ventricular volumes.91 The effects of such treatment on early post-operative rhythm abnormalities and left ventricular remodelling require further investigation. Intracoronary injection of bone-marrow-derived cells with and without CABG was tested in trials, but the results remain inconclusive.92,93 Regarding complications related to the type of cells, ventricular arrhythmia with myoblast implantation is the most worrisome.

attention in cardiac pathophysiology and regenerative medicine.99 There is ongoing research on the role of pericytes in the activation of endogenous cardiac progenitors during cardiac repair.

Future Prospects

Conclusions

The future of cardiac repair may rely on understanding the intrinsic mechanisms that regulate endogenous mobilisation and or delivery of these cells. Additionally, further studies are needed to develop a deeper understanding of the properties of pericytes and their potential to migrate to different tissues away from their perivascular location and to play an active role in cardiac repair after ischaemia.49 This would involve a more modern interpretation of the pericyte’s role as a cell type involved in reducing the threshold for the activation of an angiogenic program in cardiac repair.50 It has been shown that exogenous administration of MSCs could stimulate cardiac precursors to proliferate and differentiate either by stimulation of the endogenous c-Kit+ CSCs or by improving cardiomyocyte cell cycling.94

Autologous cardiac cellular therapies appear to be safe and effective. The future of cardiac repair may rely on understanding the intrinsic mechanisms that regulate endogenous mobilisation and/or delivery of these cells. However, a considerable amount of work is to be performed before cardiomyoplasty (cell therapy of the heart) can be proposed as a routine treatment. The first question is which cells to use, as a variety of embryonic stem cells, reprogrammed adult stem cells, natural adult multi-lineage stem cells and lineage-committed stem cells are presently available. Arguably, the latter endogenous cardiomyogenic stem cells might be the best choice for cardiac repair. Ideally, these cells should be directly stimulated in situ, avoiding extraction, purification, culture and reinjection. It is therefore of uttermost importance to understand the identity and function of the cells that constitute the natural environment of cardiac progenitors and support their quiescence, self-renewal and activation. Additionally, further studies are needed to develop a deeper understanding about the properties of pericytes, as these cells have the potential to migrate to different tissues away from their perivascular location and play an active role in the activation of cardiac repair after ischaemia.49 This would involve a modern interpretation of the pericyte’s

Despite advancements in the field of cardiac regenerative biology, the perivascular cell compartment within the myocardium and its regenerative capability have not yet been studied in-depth. Pericytes and perivascular cells have a crucial role in physiological functions, as well as in the development of pathological conditions.95–98 Additionally, the participation of perivascular cells in post-injury tissue fibrosis has been shown in recent studies. The cardiac pericyte is the second most common cardiac cell type, and has started to attract

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Transplantation of human pericyte progenitor cells Improves the repair of Infarcted Heart through activation of an angiogenic program Involving Micro-RNA-132. Circ Res 2011;109:894–906. DOI: 10.1161/ CIRCRESAHA.111.251546; PMID: 21868695 Ozerdem U, Grako KA, Dahlin-Huppe K, et al. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn 2001;222:218–27. DOI: 10.1002/dvdy.1200; PMID: 11668599 Skalli O, Pelte MF, Peclet MC, et al. Alpha-smooth muscle actin, a differentiation marker of smooth muscle cells, is present in microfilamentous bundles of pericytes. J Histochem Cytochem 1989;37:315–21. DOI: 10.1177/37.3.2918221; PMID: 2918221 Winkler EA, Bell RD, Zlokovic BV. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signalling. Mol Neurodegener 2010;5:32. DOI: 10.1186/1750-1326-5-32; PMID: 20738866 Abramsson A, Lindblom P, Betsholtz C. 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DOI: 10.1016/S0140-6736(12)60195-0; PMID: 22336189 71. Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106:3009–17. DOI: 10.1161/01.CIR.0000043246.74879.CD; PMID: 12473544 72. Fernandez-Aviles F, San Roman JA, Garcia-Frade J, et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circulation 2004;95:742–8. DOI: 10.1161/01.RES.0000144798.54040.ed; PMID: 15358665 73. Meyer GP, Wollert KC, Drexler H. Stem cell therapy: a new perspective in the treatment of patients with acute myocardial infarction. Eur J Med Res 2006;11:439–46. PMID: 17107878 74. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–8. DOI: 10.1161/01.CIR.0000034046.87607.1C; PMID: 12370212 75. Tse HF, Kwong YL, Chan JK, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003;361:47–9. DOI: 10.1016/S0140-6736(03)12111-3; PMID: 12517468 76. Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003;361:45–6. DOI: 10.1016/S01406736(03)12110-1; PMID: 12517467 77. Tendera M, Wojakowski W, Ruzylllo W, et al. Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration Infarction (REGENT) Trial. Eur Heart J 2009;30:1313–21. DOI: 10.1093/eurheartj/ehp073; PMID: 19208649 78. Leri A, Kajstura J, Anversa P, et al. Myocardial regeneration and stem cell repair. Curr Probl Cardiol 2009;33:91–153. DOI: 10.1016/j.cpcardiol.2007.11.002; PMID: 18243902 79. Bartunek J, Vanderheyden M, Hill J, et al. Cells as biologics for cardiac repair in ischaemic heart failure. Heart 2010;96:792– 800. DOI: 10.1136/hrt.2007.139394; PMID: 20448133 80. Clifford DM, Fisher SA, Brunskill SJ, et al. Stem cell treatment

for acute myocardial infarction. Cochrane Database Syst Rev 2012;2:CD006536. DOI: 10.1002/14651858.CD006536.pub3; PMID; 22336818 81. Urbanek K, Torella D, Sheikh F, et al. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci U S A 2005;102:8692–7. DOI: 10.1073/pnas.0500169102; PMID: 15932947 82. Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001;344:1750–7. DOI: 10.1056/ NEJM200106073442303; PMID: 11396441 83. Janssens S. Stem cells in the treatment of heart disease. Annu Rev Med 2010;61:287–8. DOI: 10.1146/annurev. med.051508.215152; PMID: 20059339 84. Zhao Q, Sun Y, Xia L, et al. Randomized study of mononuclear bone marrow cell transplantation in patients with coronary surgery. Ann Thorac Surg 2008;86:1833–40. DOI: 10.1016/j.athoracsur.2008.08.068; PMID:19021989 85. Akar AR, Durdu S, Arat M, et al. Five years follow up after transepicardial implantation of autologous bone marrow mononuclear cells to ungraftable coronary territories for patients with ischaemic cardiomyopathy. Eur J Cardiothoracic Surg 2009;36:633–43. DOI: 10.1016/j.ejcts.2009.04.045; PMID: 19524451 86. Sridhar P, Hedrick M, Baker T, et al. Adipose-derived regenerative cells for the treatment of patients with nonrevascularisable ischaemic cardiomyopathy – The PRECISE Trial. Intervent Cardiol Rev 2012;7:77–80. DOI: 10.15420/ icr.2012.7.2.77 87. Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 2010;7: 204–15. DOI: 10.1038/nrcardio.2010.1; PMID: 20177405 88. Vrijsen KR, Chamuleau SA, Noort WA, et al. Stem cell therapy for end-stage heart failure: indispensable role for the cell? Curr Opin Organ Transplant 2009;14:560–5. DOI: 10.1097/ MOT.0b013e328330389e; PMID: 19623073 89. Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double blind, randomized controlled trial.Circulation.2007;115:3165–72. DOI: 10.1161/ CIRCULATIONAHA.106.687376; PMID: 17562958 90. Van Ramshorst J, Bax JJ, Beeres SL, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischaemia: a randomized controlled trial. JAMA 2009;301:1997–2004. DOI: 10.1001/jama.2009.685; PMID: 19454638 91. Menache P, Alfieri O,Janssens S, et al. The myoblast autologus grafting in ischaemic cardiomyopathy (magic) trial. First randomized placebo-controlled study of myoblast transplantation. Circulation 2008;117:1189–200. DOI: 10.1161/CIRCULATIONAHA.107.734103; PMID: 18285565 92. Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACS Study. J Am Coll Cardiol 2005;46:1651–8. DOI: 10.1016/j.jacc.2005.01.069; PMID: 16256864 93. Fischer-Rasokat U, Assmus B, Seeger FH, et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischaemic dilated cardiomyopathy: final 1-year results of the TOPCARE-DCM trial. Circ Heart Fail 2009;2:417–23. DOI: 10.1161/CIRCHEARTFAILURE.109.855023; PMID: 19808371 94. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 2010;107:913–22. DOI: 10.1161/CIRCRESAHA.110.222703; PMID: 20671238 95. Dellavalle A, Maroli G, Covarello D, et al. Pericytes resident in postnatal skeletal muscle differentiate into muscle fibers and generate satellite cells. Nat Commun 2011;2:499. DOI: 10.1038/ncomms1508; PMID: 21988915 96. Tang W, Zeve D, Suh JM, et al. White fat progenitor cells reside in the adipose vasculature. Science 2008;322:583–6. 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Atrial Fibrillation | Stroke Prevention | Dementia

Atrial Fibrillation, Cognitive Decline and Dementia Alv a ro A l o n s o 1 a n d A n t o n i o P A r e n a s d e L a r r i v a 2 ,3 1. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA; 2. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA; 3. Lipid and Atherosclerosis Unit, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain and Center for Biomedical Research in Networks—Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain

Abstract Atrial fibrillation (AF) is a common cardiac arrhythmia. There is growing evidence that AF is a risk factor for cognitive decline and dementia. In this review, we summarise epidemiological observations linking AF with cognitive outcomes, describe potential mechanisms and explore the impact of AF treatments on cognitive decline and dementia. Community-based observational studies show a consistently higher rate of cognitive decline and increased risk of dementia in persons with AF. These associations are partly due to the increased risk of clinical stroke in AF, but other mechanisms, including the incidence of silent cerebral infarcts, microbleeds and cerebral hypoperfusion, are likely additional contributors. Adequate oral anticoagulation and improved management of the overall cardiovascular risk profile in individuals with AF offer the promise of reducing the impact of AF on cognitive decline and dementia.

Keywords Atrial fibrillation, dementia, cognitive decline, cognitive impairment, epidemiology Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: AA was supported by grants U01-HL096902 and R01-HL122200 from the National Heart, Lung, and Blood Institute, and by grant 16EIA26410001 from the American Heart Association. Received: 11 March 2016 Accepted: 10 June 2016 Citation: European Cardiology Review, 2016;11(1):49–53 DOI: 10.15420/ecr.2016:13:2 Correspondence: Alvaro Alonso, MD, PhD, Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Room 3051, Atlanta, GA 30322, USA. E: alvaro.alonso@emory.edu

Atrial fibrillation (AF) is the most common clinically-significant arrhythmia in the world.1 It is estimated that, in the US alone, approximately 2.5 million people have AF, with the condition being 1.5 times more common in men than in women.2 Despite the decline in morbidity and mortality from cardiovascular diseases in general due to advances in prevention and treatment, AF has not followed a similar trend. Over the coming years, the incidence of AF is expected to increase.3 AF is a well-established risk factor for other cardiovascular diseases, including ischaemic stroke and heart failure.4 Growing evidence, however, indicates that AF can have deleterious effects beyond an increased risk of cardiovascular diseases. Specifically, many recent studies have explored the impact of AF on cognition and dementia risk. With the ageing population, the burden of dementia is expected to increase globally. More than 20 % of people aged >70 years have mild cognitive impairment (MCI).5 Approximately 800,000 individuals develop MCI and >500,000 develop dementia annually in the US.6 The total number of new cases of dementia each year worldwide is about 7.7 million, which means a new case is diagnosed every 4 seconds. It is estimated that 35.6 million people worldwide were living with dementia in 2010, and this figure is expected to double every 20 years, reaching 65.7 million in 2030 and 115.4 million in 2050.7 A better understanding of the association of AF with dementia and cognitive impairment, the predictors of cognitive impairment among those with AF, and the potential mechanisms explaining such associations would inform strategies for the management of AF and the prevention of

ECR_Alonso_4.indd 49

adverse cognitive outcomes among these patients. We conducted a review of the literature to examine the current evidence supporting an association of AF with cognitive function, dementia and MCI; describe the predictors of cognitive outcomes in people with AF; summarise the potential pathophysiological mechanisms; discuss the preventive interventions specific for AF; and explore the potential impact of current AF treatments on cognitive decline. To inform this review, we searched PubMed for publications available as of 1 June 2016, using the search query [atrial fibrillation AND (dementia OR cognitive impairment OR cognitive decline)], which considered the previous terms in any field as well as occurring as MeSH terms. We considered publications mostly from the past 5 years (since 1 November 2010), although we did not exclude frequentlyreferenced older publications and selected those considered relevant.

AF and Cognitive Function The most basic evidence supporting an association of AF with worse cognitive function comes from cross-sectional studies comparing cognition in individuals with and without AF. A major limitation of these studies, however, is the difficulty in discerning the temporality of the association. In a study in Germany including 122 stroke-free individuals with AF and 564 individuals without AF undergoing a detailed cognitive assessment, those with AF performed significantly worse in learning, memory and executive function tasks.8 Similarly, the prevalence of AF has been associated with amnestic MCI and impaired global cognitive function in cross-sectional studies in

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31/07/2016 20:41

Atrial Fibrillation | Stroke Prevention | Dementia Table 1: Selected Prospective Studies Reporting the Association of Atrial Fibrillation (AF) with Cognitive Decline Reference Setting Study population International 31,506 (30 % women; Marzona et al., 201212

Follow-up (years) Mean: 4.7

mean age 67)

Cognitive assessment

Main findings

Repeated Mini-Mental

AF associated with increased

State Examination

risk of cognitive decline

Thacker et al., 201313 United States 5,150 (59 % women; Mean: 7.0

100-point modified

Faster decline in individuals with

Mini-Mental State

incident AF, with stronger

mean age 73)

Chen et al., 201414 United States 935 (62 % women;

Median: 10.6

mean age 62)

(HR 1.14; 95 % CI [1.03–1.26])

Examination

impact at older age

Delayed word recall,

Incident AF associated with

digit symbol substitution

faster decline in digit symbol

and word fluency tests

substitution and word fluency tests

CI = confidence interval; HR = hazard ratio.

Europe and the US.9,10 Interestingly, a recent analysis of the US-based Atherosclerosis Risk in Communities (ARIC) study, which included 325 individuals who underwent detailed cognitive assessment and heart rhythm monitoring during a maximum of 14 days, found that persistent but not paroxysmal AF was associated with lower cognitive function.11 These findings suggest that AF burden, in addition to its presence, may influence cognitive function.

AF and Cognitive Decline Cross-sectional studies have methodological problems that limit the interpretation of their results. Longitudinal studies with repeated assessment of cognitive function provide a more rigorous appraisal of the association of AF with cognition. Table 1 presents the summary characteristics of selected prospective studies. An analysis of 31,506 participants in the international Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRASCEND) trial followed up for a median of 5 years found that those who had AF at baseline or developed it during the study had a 13 % increased risk of cognitive decline, defined as a decrease of three or more points in the MiniMental State Examination.12 Similar findings were reported in the Cardiovascular Health Study, a community-based study in the US in which the development of AF was associated with faster decline measured by modified Mini-Mental State Examination score during a mean follow-up of 7 years.13 More recently we found that, among 935 stroke-free participants in the ARIC Study, incident AF was associated with a faster decline in measures of executive function and verbal fluency. This association was only present among individuals with subclinical cerebral infarcts, suggesting that vascular disease may mediate the link between AF and cognitive decline.14

AF and Prevalence of Dementia and Mild Cognitive Impairment In addition to exploring how AF affects cognitive trajectories over time, it would be useful to determine how incident AF is associated with the onset of dementia and MCI. It would be particularly useful to assess whether such association is independent of clinical stroke, since this would point to additional pathways linking AF and neurodegeneration. A few cross-sectional studies have explored differences in the prevalence of dementia/MCI by AF status. Investigators from the Rotterdam study, which included 6,584 participants aged 55 and older, were among the first to report an association between AF and dementia/cognitive impairment. In this community-based prospective cohort in Ommord, a suburb of Rotterdam in the Netherlands, the

ECR_Alonso_4.indd 50

prevalence of dementia was more than double in those with compared to those without AF. The association was stronger in women and younger (<65 years of age) participants. A history of stroke among those with AF was not enough to account for the association, supporting the presence of alternative mechanisms.15 More recent studies conducted in smaller cohorts have replicated these associations, demonstrating a higher prevalence of both Alzheimer’s disease-type and vascular dementia among individuals with AF compared to those without AF, independent of potential confounders.16,17

AF and Incidence of Dementia The elevated incidence of stroke in AF patients explains the relationship between AF and the development of vascular dementia.18 More recently, several prospective studies have shown that AF is also linked with an elevated risk of other dementias, including Alzheimer’s disease, independent of clinical vascular events. Table 2 provides the summary characteristics of relevant studies. An analysis of 3,045 community-dwelling individuals in the Seattle area of the US found that the development of AF was associated with a 50 % increase in the risk of receiving a diagnosis of Alzheimer’s disease. This association was present in individuals with and without clinically-recognised stroke.19 Increased risk of dementia associated with AF has been reported in a secondary analysis of the ONTARGET and TRASCEND trials,12 the Finnish Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study20 and the Rotterdam cohort.21 Further confirmation of this association has come from an analysis of large administrative databases in Taiwan, including >600,000 individuals. This analysis showed a 42 % increased risk of dementia in those with AF versus those without AF.22 A recent systematic review and meta-analysis of previously published studies on the topic reported a hazard ratio (95 % confidence interval) for dementia of 1.42 (1.17–1.72) when comparing individuals with AF to those without AF.23

AF and Brain Abnormalities Evaluating the impact of AF on the prevalence and development of brain abnormalities can help advance our understanding of the mechanisms linking AF with cognitive decline and dementia. Several reports emphasise the presence of signs of cerebrovascular disease in the brains of patients with AF. Overall, AF patients have a higher burden of silent cerebral infarcts and white matter disease, and may have an increased prevalence of cerebral microbleeds.24 These lesions may explain the fast cognitive decline and elevated dementia risk among AF patients.14 The presence of these abnormalities may also have an

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AF and Cognitive Decline

Table 2: Selected Prospective Studies Reporting the Association of Atrial Fibrillation (AF) with Incident Dementia Reference Setting Study population

Mean

follow-up

19 Dublin et al., 2011 Seattle area, 3,045 (60 % women;

(years) 6.8

United States

median age 74)

Dementia ascertainment

Main findings

Cognitive screening followed

AF associated with increased risk of all-

by detailed neuropsychological

cause dementia (HR 1.38; 95 % CI [1.10–1.73])

and clinical assessment

and Alzheimer’s disease (HR 1.50; 95 % CI

12 Marzona et al., 2012 International 31,506 (70 % women; 4.7 New diagnosis of dementia,

[1.16–1.94])

dementia (HR 1.30; 95 % CI [1.14–1.49])

mean age 67)

reported severe cognitive

20 Rusanen et al., 2014 Eastern Finland 1,510 (62 % women;

AF associated with increased risk of

impairment, Mini-Mental State Examination <23 7.8

mean age 65)

Cognitive screening followed by

AF in late life independently associated

detailed neuropsychological and

with dementia (HR 2.61; 95 % CI [1.05–6.47])

clinical assessment

and Alzheimer’s disease (HR 2.54; 95 % CI

21 De Bruijn et al., 2015 Rotterdam, the 6,196 without 12.8 Cognitive screening followed by

Incident AF associated with increased risk

[1.04–6.16])

Netherlands

prevalent AF (59 %

detailed examination, plus review

of dementia in younger (<67 years: HR

women; mean

of medical records

1.81; 95 % CI [1.11–2.95]) but not older

22 Liao et al., 2015 Taiwan

age 68)

participants (≥67: HR 1.12; 95 % CI [0.85–1.46])

665,330 (44 % women; 4.9

Diagnosis codes from medical

AF associated with increased risk of

mean age 70)

claims

dementia (HR 1.42; 95 % CI [1.39–1.45])

CI = confidence interval; HR = hazard ratio.

impact on the management of AF patients, for example influencing decisions about whether or not to prescribe oral anticoagulation.25 Several recent studies have explored the impact of AF on other brain-related phenotypes. In the Icelandic population-based Age, Gene/Environment Susceptibility–Reykjavik Study, which included 4,251 participants, AF was associated with lower brain volume and grey matter.26 Similar findings have recently been reported in a cross-sectional study in individuals from a community-based study in Minnesota, USA.27 An autopsy study including 134 individuals with and 194 without AF found that the prevalence of neuropathological changes (neuritic plaques, neurofibrillary tangles) associated with Alzheimer’s disease was higher in individuals with permanent AF than in those without AF.28

Predictors of Cognitive Impairment and Dementia in People with AF Understanding the determinants of dementia among AF patients may inform interventions that can prevent the cognitive complications of the arrhythmia. Some studies have found that higher CHADS2 and CHA2DS2-VASc scores, which are stratification schemes commonly used to inform anticoagulant treatment in individuals with AF, predict dementia in these patients.22,29 This association is not surprising given that age, possibly the strongest predictor of dementia, is part of the scores. Dementia-specific risk models are likely to provide more accurate predictions. Oral anticoagulation is a mainstay of the treatment of patients with AF. Determination of the influence of anticoagulation control in AF patients on the risk of dementia has been the objective of at least two separate publications. Both studies used data from the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service in Utah, USA. They reported that vitamin K antagonist users whose levels were only within the therapeutic range for a low proportion of time were at a higher risk of dementia due to under- or overcoagulation.30,31 Though informative, these studies are limited

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in that they cannot determine whether baseline cognitive function confounds the association between suboptimal oral anticoagulation and the future risk of dementia. For example, individuals with worse cognitive function at the time of oral anticoagulation initiation may have more problems following an adequate therapeutic regimen and would be at a higher risk of being diagnosed with dementia later on. Additional observational studies with adequate characterisation of baseline cognition or, even better, randomised trials aimed at improving anticoagulation quality are needed to answer this question.

Mechanisms Linking AF, Cognitive Decline and Dementia Risk The published evidence is consistent in supporting an association between AF and cognitive outcomes. The mechanisms underlying this association, however, still need clarification. An obvious pathway linking AF with cognitive decline or dementia is the elevated risk of stroke. AF is associated with at least a doubling of stroke risk32 and the effects of stroke on cognitive function are well established.18 Despite this, elevated stroke risk does not completely mediate the increased risk of dementia and cognitive decline associated with AF.33 Other mechanisms such as silent cerebral infarcts, microbleeds associated with oral anticoagulation and cerebral hypoperfusion are likely to play a role (Figure 1). AF more than doubles the risk of silent cerebral infarcts independent of stroke34 and the presence of silent cerebral infarcts is a risk factor for dementia.35 At least one study has specifically addressed the role of subclinical cerebrovascular disease as a mediator of the association between AF and cognitive impairment. In a subset of stroke-free participants in the ARIC study who underwent repeated brain magnetic resonance imaging after approximately 12 years, we showed that AF was only associated with cognitive decline in those who had developed incident silent cerebral infarcts.14 The hypercoagulable state resulting from AF is certain to play a role in this mechanism and, consequently, anticoagulation may be effective in preventing adverse cognitive outcomes in patients with AF.36

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Atrial Fibrillation | Stroke Prevention | Dementia Figure 1: Potential Mechanisms Linking Atrial Fibrillation (AF) with Cognitive Decline and Dementia Left atrial cardiopathy

Atrial fibrillation

Stroke

Subclinical cerebral infarcts

Cognitive decline MCI Dementia

Microbleeds

Brain hypoperfusion AF increases the risk of stroke and subclinical cerebral infarcts and can lead to brain hypoperfusion. Oral anticoagulation in patients with AF can lead to new or worsening cerebral microbleeds. In turn, these conditions lead to cognitive decline and increased risk of mild cognitive impairment (MCI) and dementia. Independently, left atrial cardiopathy increases the risk of AF and is associated with stroke risk independent of AF.

Similarly, AF could increase dementia risk through its impact on cardiac function. Patients with AF have been found to have reduced cerebral perfusion;37 and restoration of sinus rhythm in AF patients through cardioversion or ablation leads to improvements in cerebral blood flow.38,39 Reduced diastolic function and low cardiac index, both potential consequences of AF, have been associated with incident dementia in prospective studies.40,41 Moreover, AF is an established risk factor for heart failure,42 which in turn can worsen cerebral hypoperfusion.43 Microbleeds may also explain part of the association of AF with cognitive impairment. These brain lesions are relatively frequent and have been linked with an increased risk of cerebral haemorrhage, lacunar infarcts and degenerative changes in brain matter.44 Oral anticoagulation in persons with AF can increase the risk of developing microbleeds or worsen the impact of existing microbleeds on cognitive function. In the community-based Rotterdam study, individuals using coumarin anticoagulants had a higher prevalence and incidence of microbleeds. This risk was notably higher among individuals with a greater variability in anticoagulation control.45 Of recent interest is the potential role that left atrial cardiopathy, as a precursor of AF, can play in cerebrovascular disease and, consequently, the development of cognitive decline and dementia. Analysis of several community-based studies has demonstrated that the presence of electrocardiographic left atrial abnormality, a marker of atrial cardiopathy, is associated with an increased risk of ischaemic stroke, mostly non-lacunar, and vascular brain injury even in the absence of AF.46,47 The impact of left atrial cardiopathy on dementia risk independent of AF needs to be explored.

Prevention of Cognitive Impairment in People with AF Understanding the mechanisms responsible for the increased rates of cognitive decline and dementia in people with AF can inform preventive strategies. Current guidelines recommend oral anticoagulation for

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stroke prevention in most individuals with AF.48,49 The decreased stroke risk in patients receiving adequate anticoagulation should consequently lead to a reduced risk of adverse cognitive outcomes. Improved anticoagulation control could be particularly effective in high-risk individuals, for example those who already have some cognitive impairment. A recent clinical trial including 973 elderly patients with AF found that patients randomised to warfarin had less cognitive decline than those randomised to aspirin after 33 months of follow-up, although the differences were not statistically significant.50 A recent analysis comparing the risk of dementia in patients with AF using warfarin versus non-vitamin K oral anticoagulants reported a lower risk of dementia among non-vitamin K oral anticoagulant users.51 Unfortunately there is currently no additional evidence on the effect of oral anticoagulation on cognitive function as larger randomised trials of oral anticoagulation, whether traditional vitamin K antagonists or the more recent direct oral anticoagulants, have not considered cognitive endpoints. The long-term cognitive effects of other treatments for AF, such as catheter ablation, are unknown. Future studies that collect prospective information on cognitive outcomes should address this gap. A promising novel area in the management of AF, which could eventually translate into the prevention of cognitive complications, is the role of lifestyle changes leading to weight loss and improvement in overall cardiometabolic risk profile. A randomised trial of weight loss and risk factor management in 150 AF patients led to clinicallysignificant reductions in AF burden and symptoms as well as improving cardiac function.52 Similar findings were obtained in 355 AF patients participating in a weight loss intervention; those who sustained weight loss had reductions in AF burden and were more likely to remain in sinus rhythm.53 The impact of these lifestyle interventions on cognitive outcomes in persons with AF has not been assessed to date. Given the role of cardiovascular risk factors in cognition and dementia risk,54 this area would be a fruitful avenue for future research. Finally, primary prevention of AF should be the ultimate goal in reducing the burden of AF-related complications. Unfortunately, we currently lack effective interventions that have consistently demonstrated effectiveness in reducing AF risk in the general population. Although promising, some preventive interventions such as omega-3 fatty acid supplementation, statins or inhibition of the reninâ&#x20AC;&#x201C;angiotensinâ&#x20AC;&#x201C;aldosterone system have failed to reduce AF risk.55,56 Recent studies indicate that dietary intervention and improved blood pressure control can prevent AF.57,58 Whether these interventions can in turn lead to a reduced risk of dementia and cognitive decline remains undetermined.

Conclusion A growing and consistent body of literature supports AF as a risk factor for cognitive decline and dementia. The mechanisms responsible for this association are diverse and go beyond the wellestablished increase in stroke risk in individuals with AF. Future research needs to deepen the understanding of these mechanisms and, more importantly, develop interventions that reduce the burden of adverse cognitive outcomes associated with AF. â&#x2013;

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20. Rusanen M, Kivipelto M, Levalahti E, et al. Heart disease and long-term risk of dementia and Alzheimer’s disease: a population-based CAIDE study. J Alzheimers Dis 2014;42 :183–91. DOI: 10.3233/JAD-132363; PMID: 24825565 21. de Bruijn RFAG, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population. JAMA Neurology 2015;72 :1288–94. DOI: 10.1001/ jamaneurol.2015.2161; PMID: 26389654 22. Liao JN, Chao TF, Liu CJ, et al. Risk and prediction of dementia in patients with atrial fibrillation – a nationwide population-based cohort study. Int J Cardiol 2015;199 :25–30. DOI: 10.1016/j.ijcard.2015.06.170; PMID: 26173170 23. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: A meta-analysis. Heart Rhythm 2012;9 :1761–8.e1762. DOI: 10.1016/j.hrthm.2012.07.026; PMID: 22863685 24. Gaita F, Corsinovi L, Anselmino M, et al. Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol 2013;62 :1990–7. DOI: 10.1016/j.jacc.2013.05.074; PMID: 23850917 25. Haeusler KG, Wilson D, Fiebach JB, et al. Brain MRI to personalise atrial fibrillation therapy: current evidence and perspectives. Heart 2014;100 :1408–13. DOI: 10.1136/ heartjnl-2013-305151; PMID: 24951485 26. Stefansdottir H, Arnar DO, Aspelund T, et al. Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts. Stroke. 2013;44 :1020–5. DOI: 10.1161/STROKEAHA.12.679381; PMID: 23444303 27. Graff-Radford J, Madhavan M, Vemuri P, et al. Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 2016;12 :391–8. DOI: 10.1016/ j.jalz.2015.08.164; PMID: 26607820 28. Dublin S, Anderson ML, Heckbert SR, et al. Neuropathologic changes associated with atrial fibrillation in a populationbased autopsy cohort. J Gerontol A Biol Sci Med Sci 2014;69 :609–15. DOI: 10.1093/gerona/glt141; PMID: 24077599 29. Ball J, Carrington MJ, Stewart S. SAFETY investigators. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart 2013;99 :542–7. DOI: 10.1136/heartjnl-2012-303182; PMID: 23315607 30. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm 2014;11 : 2206–13. DOI: 10.1016/j.hrthm.2014.08.013; PMID: 25111326 31. Jacobs V, Woller SC, Stevens SM, et al. Percent time with a supratherapeutic INR in atrial fibrillation patients also using an antiplatelet agent is associated with long-term risk of dementia. J Cardiovasc Electrophysiol 2015;26 :1180–6. DOI: 10.1111/jce.12776; PMID: 26268931 32. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22 :983–8. PMID: 1866765 33. Kalantarian S, Stern TA, Mansour M, et al. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 2013;158 :338–46. DOI: 10.7326/0003-4819158-5-201303050-00007; PMID: 23460057 34. Kalantarian S, Ay H, Gollub RL, et al. Association between atrial fibrillation and silent cerebral infarctions: a systematic review and meta-analysis. Ann Intern Med 2014;161 :650–8. DOI: 10.7326/M14-0538; PMID: 25364886 35. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348 :1215–22. DOI: 10.7326/M14-0538; PMID: 25364886 36. Kalantarian S, Ruskin JN. Atrial fibrillation and cognitive decline: phenomenon or epiphenomenon? Cardiol Clin 2016;34 :279–85. DOI: 10.1016/j.ccl.2015.12.011; PMID: 27150176 37. Gomez CR, McLaughlin JR, Njemanze PC, Nashed A. Effect of cardiac dysfunction upon diastolic cerebral blood flow. Angiology 1992;43 :625–30. PMID: 1632564 38. Porebska A, Nowacki P, Safranow K, Drechsler H. Nonembolic, hemodynanic blood flow disturbances in the middle cerebral arteries in patients with paroxysmal atrial fibrillation without significant carotid stenosis. Clin Neurol Neurosurg 2007;109 :753–7. PMID: 17658680 39. Efimova I, Efimova N, Chernov V, et al. Ablation and pacing: improving brain perfusion and cognitive function in patients with atrial fibrillation and uncontrolled ventricular rates. Pacing Clin Electrophysiol 2012;35 :320–6. DOI: 10.1111/j.1540-8159.2011.03277.x; PMID: 22126258 40. de Bruijn RF, Portegies ML, Leening MJ, et al. Subclinical cardiac dysfunction increases the risk of stroke and

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Cardiolvascular Risk Factors

Uric Acid and Cardiovascular Disease: An Update Ma ria Lorenza Muiesa n, Cl a u d i a A g a b i t i - R o s e i , A n n a Pa i n i a n d M a s s i m o S a l v e t t i Clinical and Experimental Sciences Department, University of Brescia, Brescia, Italy

Abstract In recent years, serum uric acid (SUA) as a determinant of cardiovascular (CV) risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia SUA are at increased risk of cardiac, renal and vascular damage and CV events. There is now some evidence to suggest that urate-lowering treatment may reduce CV risk in this group and, thus, may represent a new strategy in risk reduction.

Keywords Uric acid, CV disease, xanthine-oxidase inhibitors, AF, heart failure, target organ damage Disclosure: The authors have no conflicts of interest to declare. Received: 6 November 2015 Accepted: 5 May 2016 Citation: European Cardiology Review, 2016;11(1):54–9 DOI: 10.15420/ecr.2016:4:2 Correspondence: Maria Lorenza Muiesan, Clinical and Experimental Sciences Department, University of Brescia, 2° Medicina Generale Spedali Civili, 25121 Brescia, Italy. E: marialorenza.muiesan@unibs.it

Uric acid (UA) represents the final product of purine metabolism, in humans mainly regulated by the xanthine-oxidoreductase enzyme, which converts hyoxantine to xanthine and xanthine to UA. Dietary factors may influence serum UA (SUA), increasing its levels (meat, seafood, fructose, alcohol and sodium) or decreasing them (coffee and ascorbic acid). In addition, high cellular turnover conditions, i.e. in neoplastic diseases, may increase UA concentration. UA may have an opposite role to oxidative stress, according to its intracellular (anti-oxidant) and extracellular (pro-oxidant) localisation.1 The xanthine-oxidoreductase enzyme isoform xanthine-oxidase (XO) generates reactive oxygen species (ROS) as byproducts and may have a detrimental effect on vascular endothelium. The production of ROS induced by UA seems paradoxical since UA is considered to be one of the anti-oxidants that protects the cardiovascular (CV) system from stress. UA prevents the protein nitrosylation induced by peroxynitrite, the peroxidation of lipids and proteins and the inactivation of tetrahydrobiopterin, which results in scavenging free radicals and chelating transitional metal ions.2 UA administration in healthy volunteers and athletes reduced ROS production,3 confirming its intrinsic anti-oxidant activity. Experimental and human studies have demonstrated the role of UA as a pro-oxidant, inducing endothelial dysfunction. This may be improved by the administration of XO inhibitors, while other urate-lowering drugs (ULDs) acting through an uricosuric action are ineffective.4 The increase in oxidative stress resulting from the increased activity of XO could also explain the link between elevated UA and hypertension, as observed in animal models. In rats, the administration of oxonic acid, an inhibitor of uricase, may induce hyperuricaemia and a proportional increase in blood pressure (BP).5 UA may also stimulate the renin–angiotensin system (RAS), further contributing to vascular smooth cell growth, and arterial function impairment and stiffening. The possible role of systemic inflammation – measured by markers such as C-reactive protein (CRP), tumour necrosis

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factor or chemokine associated with hyperuricaemia – has also been explored, showing a further contribution to CV damage.6 The role of SUA in the development of arterial hypertension (AH) was highlighted in 1879 and 10 years later Haig7 proposed a low-purine diet as a means to prevent hypertension and CV diseases (CVDs). In 1909, Huchard described the association between renal arteriosclerosis and chronic hyperuricaemia.8 Since 1960, a number of epidemiological studies have found an association between SUA levels and different CV risk factors or diseases, such as AH, ischaemic stroke and acute and chronic heart failure (HF). The correlation is clearly present at SUA levels of 5–5.5 mg/dl,9 a range that is lower than the <6 mg/dl suggested by the European League Against Rheumatism10 and the American College of Rheumatology.11 The lack of a clear causal mechanism explaining the association between hyperuricaemia and CV risk factors and disease has led to the relevance of SUA being ignored.12 The results of the Framingham study, comprising 6,763 subjects followed for about 20 years, did not confirm an increase in the risk of CV death and SUA in men, but did in women.13 However, the increased risk lost statistical significance after taking into account confounders. On the contrary, Abbott et al.14 described in the same population a significant increase in coronary artery disease (CAD) in men with chronic hyperuricaemia and crystal deposits. A systematic review has confirmed that chronic hyperuricaemia with crystals deposit is strictly related to an increased risk of CV and allcause death.15 The exact role of SUA as a marker or cause of CVD has been extensively discussed.16 In most of the published studies, SUA concentrations are related to age, sex, degree of kidney function, BP levels and metabolic abnormalities.

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Uric Acid and Cardiovascular Disease

An independent relationship between UA and CV events has been frequently observed and a causal role of SUA has been proposed. The evidence that BP values may improve by treatment that lowers SUA seems to support a possible causal link between SUA and CVD.17,18

Vlachopoulos et al.40 observed a close relationship between carotid– femoral pulse wave velocity and SUA in a large cohort of never-treated hypertensive patients, mainly in women; an increase in large artery stiffness and arterial wave reflections are important determinants of LV mass and function and coronary blood flow.

Hyperuricaemia and Target Organ Damage The association between elevated SUA and CV risk factors, all contributing to the development of vascular, cardiac and renal target organ damage, has been extensively evaluated, with some controversial results. Some studies have reported that elevated SUA is strongly associated with coronary19 and carotid20,21 atherosclerosis, especially in women. The Atherosclerosis Risk in Communities (ARIC) study22 observed that the SUA level was significantly associated with B-mode ultrasound carotid intima-media thickness (considered an early measure of atherosclerosis). Subsequently, Mutluay et al. reported that hyperuricaemia is an independent predictor of early atherosclerosis in hypertensive subjects with normal renal function.23 Similar results were obtained by Cicero et al. in an Italian epidemiological study evaluating 248 men and 371 women adult individuals not consuming anti-hypertensive, anti-diabetic, lipid- or UA-lowering drugs.24 These results suggest that SUA may have an atherogenic role in the pathophysiology of CVDs; however, the precise mechanisms have not been fully elucidated. Experimental studies have shown that UA may stimulate vascular smooth muscle cell proliferation in vitro, with the production of pro-inflammatory and pro-oxidative and vasoconstrictive substances.25,26 Moreover humans’ atherosclerotic plaque may contain a considerable amount of UA,27 which may increase platelet adhesion and thrombus formation.28 On the other hand, some studies also show a role for XO, which is responsible for oxidative processes29 and endothelial dysfunction, thus independendtly affecting the occurrence of CVDs. Hypertensive patients with left ventricular hypertrophy (LVH) have higher SUA levels, independent of other CV risk factors, and a more strict association between SUA and LV mass index was observed in women.30–34 When 24-hour BP values were taken into account, a Japanese study confirmed this association.33 In some of these studies the association was more evident in women than in men33 or vice versa.32 More recently, in uncomplicated patients without chronic kidney disease (CKD), and with a recent diagnosis of hypertension34 or at low CV risk,35 the correlation between SUA and LV mass did not reach statistical significance when all the potential confounders, including 24-hour BP, were taken into account. Iwashima et al.36 also observed that hyperuricaemia and LVH were independent predictors of CV events (acute MI, angina, HF, stroke or transient ischaemic attack), but the combination of LVH and hyperuricaemia was associated with a further increase in the incidence of CV events. Several mechanisms may explain the increase in LV mass in the presence of hyperuricaemia, including the systemic inflammatory response, RAS activity,37 endothelial dysfunction38 or the expression of endothelin-1 in cardiac fibroblasts, thus favouring cardiac interstitial fibrosis.39 In addition, some indirect effects of hyperuricaemia, such as increased BP, the parallel decrease of glomerular filtration rate (GFR), the impairment of platelet adhesion and aggregation and the increase in aortic stiffness, could further contribute to the development of LVH.

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In the Framingham Offspring cohort (n=2,169, mean age 57 years, 55 % women) a decrease in systolic function parameters was observed in subjects with SUA >6.2 mg⁄dl compared with those with lower.41 These results, showing an early impairment of LV function in the presence of a modest increase in SUA could, in part, explain the association between elevated SUA and the increased risk of incident HF and poor outcomes in HF patients with elevated SUA, as recently confirmed in a meta-analysis42 and suggested by the Framingham Offspring study.43 A more severe impairment of diastolic function has been observed in hypertensive patients with hyperuricaemia.33 Few data are available on the effect of changes in SUA induced by diet modification or pharmacological treatment. In the Losartan Intervention For Endpoint reduction in Hypertension study (LIFE), patients with electrocardiographic signs of LVH were randomised to losartan or atenolol: a greater decrease in LVH was associated with a less marked increase in SUA level during therapy with losartan compared with atenolol.44 The effect of allopurinol and febuxostat were compared in a small number of patients with gout. A more favourable effect of febuxostat on both carotid–femoral pulse wave velocity and oxidative stress was found.45 Only one study has examined the effect of UA-lowering treatment on target organ damage in patients with CKD,46 which showed a decrease of LV mass (evaluated by nuclear magnetic resonance), and an improvement of flow-mediated vasodilation and of augmentation index after allopurinol treatment compared with placebo. SUA level has also emerged as a risk factor for the development and progression of CKD. Afferent arteriolar thickening and ischaemic renal changes, associated with an increase in systemic BP and renal glomerular pressure, have been described in rats with hyperuricaemia induced by oxonic acid or a high-fructose diet; all these changes may be prevented by lowering SUA with XO inhibitors.47–49 Furthermore, epidemiological studies have reported that asymptomatic hyperuricaemia is strongly associated with both CKD and endstage kidney disease;50–52 however, hyperuricaemia may represent a consequence of reduced renal excretion in patients with CKD and therefore be a marker of kidney function. A recent review and metaanalysis has shown that SUA-lowering therapy with allopurinol may slow the progression of CKD. Further adequately powered randomised trials are required to evaluate the benefits and risks of SUA-lowering therapy in CKD.53

Hyperuricaemia and Cardiovascular Disease In the past 50 years, the results of several studies have assessed and promoted the role of UA as an independent risk factor for CV and renal diseases. In this regard, strong evidence comes from the first National Health and Nutrition Examination Survey (NHANES I), performed in the US between 1971 and 1975 in a general population sample of 20,729 individuals aged 25–74 years. In the National Health Epidemiologic Follow-up Study (NHEFS), all participants in the NHANES

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Cardiovascular Risk Factors I were prospectively followed, and the all-cause, CV and CAD deaths were assessed; in a subgroup of 6,912 subjects data were analysed according to SUA level.54 The results showed a significant positive association between increasing levels of SUA and CV (including CAD) mortality, independent of other traditional risk factors, in both men and women, confirming previous data obtained after a shorter follow-up of the NHANES I population.55 In the previous study55 elevated SUA level was an independent predictor of all-cause and ischaemic heart disease mortality for women only and 1 mg/dl increase of SUA was associated with a 48 % increase in the risk of CAD.55 In a prospective study conducted in Rotterdam, 4,385 men and women >55 years of age without history of stroke or coronary heart disease, an association between baseline SUA levels and risk of both MI and stroke was confirmed.56 In a further analysis, a U-shape relationship between SUA and both all-cause and CV mortality was shown, indicating that both low and high SUA levels were prognostically deleterious.57 A further demonstration of the association between SUA and CV risk is given by the results of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study, in which individuals aged 25–74 years were examined and followed-up for up to 16 years.58 For 2,045 subjects a baseline SUA was available: a mean value of 4.9±1.3 mg/dl was observed with significantly higher values in men with respect to women. During follow-up, 342 subjects died, (32 % from CV causes). Mean SUA (5.54 mg/dl) observed in patients who died was higher when compared with those who survived (4.82 mg/dl); a significant difference in mean SUA level was observed between patients who died of CV causes (5.74 mg/dl) or (4.89 mg/dl).59 A significant increase of the risk of CV death for every 1 mg/dl increase of SUA was observed, while the same was not true for all-cause death after adjustment for confounders. The effect of elevated SUA levels on the incidence of CADs seems to be stronger in women than in men, as shown by an epidemiological study conducted in the US, which originally enrolled 3,102 subjects between 1960 and 1962, with a follow-up of 7 to 9 years. In 2,530 subjects attending the second examination, SUA was measured and urate concentrations were about 1 mg/dl higher in men than in women in the younger decades of age, while in women a consistent increase in SUA was observed after physiological menopause;60 race did not protect significant differences. Other studies have analysed the association between SUA and CV risk in hypertensive and/or patients with diabetes. In the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, which examined 1,720 untreated hypertensive patients enrolled between 1986 and 1996,61 the highest SUA levels (>6.2 mg/ dl in men; >4.6 mg/dl in women) were significant predictors of allcause deaths and of CV events, again independently of traditional confounders, including LVH. Also in this study, a J-shaped curve relationship between SUA levels and CV events was observed, with the lowest risk occurring at UA concentrations of 4.5–5.2 mg/dl in men and 3.2–3.9 mg/dl in women. Almost 8,000 patients with mild to moderate hypertension living in New York, USA were studied by Alderman et al. from 1973 to 1996, showing that baseline SUA levels were associated with the subsequent occurrence of CV events; more precisely, the in-treatment SUA levels were predictive of a worse CV prognosis,

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independently of creatinine, diuretic treatment, race and all traditional CV risk factors. 62 The LIFE study presented data from 9,193 hypertensive patients with electrocardiographic LVH, and showed a greater efficacy of a losartanbased therapeutic regimen compared with atenolol in the regression of LVH and in the prevention of fatal and non-fatal CV events (acute MI, stroke and CV deaths). At study end, UA levels were lower in patients treated with losartan than with atenolol, with a relative risk reduction of 29 % for CV events. This difference reached statistical significance in women, but not in men, after adjustment for all traditional risk factors and confounders,44 supporting again the evidence that hyperuricaemia may confer a less favourable CV prognosis in women rather than in men. In the observational study Blood Pressure control rate and CV Risk profilE (BP-CARE), in which 7,800 treated hypertensive patients from Central and Eastern Europe were included,63 the CV risk profile was positively and significantly related to SUA levels and to the presence of urate deposits (gout). When examining the population with diabetes, similar results have been obtained. In 1993, Rathmann et al. reported a positive correlation between SUA and CAD in women with type 1 or 2 diabetes.64 In a prospective study including 1,017 men and women (aged 45–64 at baseline) patients with type 2 diabetes were followed up for 7 years;65 31 patients died from stroke and 114 patients had a fatal or non-fatal stroke. High SUA levels were associated with the risk of fatal and nonfatal stroke (hazard ratio [HR] 1.93; CI 95 % [1.30–2.86]; P<0.001) and stroke incidence increased significantly by SUA quartiles. In patients with diabetes, the correlation between SUA and CV function has been attributed to the same mechanisms that lead to renal dysfunction, including activation of the renin-angiotensinaldosterone system (RAAS) and ROS pathways, nitric oxide (NO) synthase inhibition, autonomic dysfunction and increase in BP.49,66,67 A large meta-analysis published in 2013, evaluating only prospective studies on CV or all-cause mortality related to SUA confirmed that baseline SUA is an independent predictor of future CV mortality. Elevated SUA appears to significantly increase the risk of all-cause mortality in men, but not women. No conclusive data on whether low SUA predicts mortality were shown.68 Most of the differences and limitations of currently available published studies are the limited number of individuals included and the inclusion criteria. Urate deposits are difficult to evaluate and therefore we do not know whether individuals included in the studies have urate deposits or not. Despite epidemiological data showing lower mean SUA in women, some studies report that an increase in SUA has a detrimental effect on CV health in women30,55 and one meta-analysis has shown a significant relationship between an increase in SUA and coronary events in women but not in men.69 The mechanisms that underlie the unfavourable influence of SUA on major CV events in women remain uncertain and whether different cut-off vales according to sex are needed should be assessed in future studies.

Hyperuricaemia and Atrial Fibrillation Oxidative stress may influence the development of AF, in addition to neurohormonal and inflammatory activation. Both inflammation and

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neurohormones may activate XO and increase SUA. In experimental studies, oxidative stress has been shown to induce atrial electric remodelling, thus favouring the re-entry mechanism70 as well as NO decrease, shortening of action potential plateau duration, increase of the repolarisation velocity and AF.71,72 The relationship between the increase in oxidative stress markers and AF has been observed in patients with valvular diseases or after coronary bypass surgery; after radiofrequency ablation AF recurrence was higher in patients with the higher levels of oxidative stress markers.73 In addition, it is reasonable that other risk factors (RAAS hyperactivity), vascular abnormalities (endothelial dysfunction) or LVH associated with UA increase may further promote the development of AF. A case-control study examining Greek patients with AF was among the first to suggest an association between SUA and AF.74 In the ARIC study, which included 15,382 subjects aged 45–64 years, the incidence of AF paralleled the increase in SUA concentration, and the relationship remained significant after taking into account all the possible confounders, including diuretic treatment and P-wave duration (index of left atrial enlargement). In this study the increase of 1 standard deviation of SUA was associated with a 16 % increase in AF risk, mainly among African Americans and women.75 The rate of hyperuricaemia observed in African Americans could be ascribed to genetic differences, since African Americans have a higher prevalence of the gene SLC2A9, favouring SUA reabsorption in the proximal renal tubule.75 The data have been further confirmed in patients with paroxysmal or permanent AF.76 A recent meta-analysis77 that evaluated six cross-sectional studies (n=7,930) and three cohort studies (n=138,306 subjects without AF) confirmed an increase in the relative risk of AF among those with high SUA (relative risk = 1.67 (95 % CI [1.23–2.27]) compared with those with normal SUA.

Hyperuricaemia and Heart Failure In the Cardiovascular Health Study, the incidence of HF was 21 % in participants with chronic hyperuricaemia and 18 % in those without; the results showed that an increase of 1 mg/dl in SUA conferred a 12 % increase in risk of new HF.78 In the Framingham Offspring study the incidence of HF was sixfold higher among individuals with SUA levels in the higher quartile (>6.3 mg/dl) than those with levels in the lowest quartile (<3.4 mg/dl).79–81 Chronic hyperuricaemia is a frequent finding in patients with HF, with a prevalence >50 % in hospitalised patients with chronic HF.82 The severity of hyperuricaemia is related to New York Heart Association (NYHA) functional class, to higher maximal oxygen consumption and to the degree of diastolic dysfunction impairment. The highest UA concentrations may be observed in patients with advanced chronic HF or cardiac cachessia. In the Derivation study, SUA was the strongest prognostic variable in patients with severe chronic HF (NYHA class III or IV):78,79 in patients with chronic hyperuricaemia (SUA >9.5 mg/dl) the relative risk of death was 7.4. In patients with acute and chronic HF, SUA concentration represents a prognostic marker of all-cause mortality independent of traditional prognostic determinants, as shown by Tamaris et al.81 A more recent meta-analysis addressing the association between SUA and incidents HF and/or the prognosis of HF patients, was performed

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by Huang et al.42 Five studies reporting on incident HF and 28 studies reporting on HF outcomes were included. The results showed that hyperuricaemia was associated with an increased risk of incident HF (HR 1.65; 95 % CI [1.41–1.94]). In addition, for every 1 mg/dl increase in SUA the risk of all-cause mortality and the composite endpoint in HF increased by 4 % and 28 %, respectively. Subgroup analyses supported the positive association between SUA and HF. A retrospective case-control-led analysis of patients with symptomatic HF showed that hyperuricaemia was significantly associated with increased events (HF hospital readmission or all-cause mortality).42 In this study the use of allopurinol was associated with a reduction in events (adjusted relative risk 0.69; 95 % CI [0.60–0.79]).82 In the Greek Atorvastatin and Coronary-Heart-Disease Evaluation (GREACE) study, 1,600 patients with CAD were followed for 3 years, and a reduction in SUA concentrations, possibly induced by the use of atorvastatin, was associated with a lower incidence of CV events, including coronary events.83 SUA plays a role in HF incidence and development that is not still completely understood. The impairment in GFR, even to a mild degree, causes a decrease in renal UA excretion.84–86 The increase in lactate concentration, and the hyperactivity of the sympathetic nervous system and the RAASs, may further contribute to SUA increases by increasing UA reabsorption. Finally, in patients with HF, the use of diuretics may induce a further reduction in UA excretion.87 According to another pathogenetic hypothesis, SUA functionally up-regulates XO, which is a key enzyme in purine metabolism. XO-derived ROS may account for a range of detrimental processes in the pathophysiology of HF, such as cardiac hypertrophy, myocardial fibrosis, LV remodelling and contractility impairment. In addition, UA per se may represent a ‘proinflammatory’ substance, frequently associated with other inflammatory markers such as CRP, interleukin-6 and neutrophil leukocytes. In fact, in a large group of older patients, affected by mild-to-moderate hypertensive and/or ischaemic HF, SUA was inversely related with ejection fraction (EF); the predicted role of SUA was apparently independent of filtration rate and use of diuretics.88 In the Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients With New York Heart Association Class III–IV Congestive HF (OPT-CHF), which enrolled 405 patients with systolic HF (EF >40 %), randomised to treatment with allopurinol or placebo, on top of standard therapy, the use of the XO inhibitor was associated with an increase in EF and to a clinical improvement among patients with elevated SUA.89 Thus, XO inhibition may be associated with an improvement in haemodynamics and clinical outcomes in hyperuricaemic patients.89,90 Conversley, this was not observed when the UA concentration was obtained by treatment with an uricosuric drug (benzbromarone)91 or oxypurinol.92 The US Food and Drug Administration approved a non-purine XO inhibitor, febuxostat, for the treatment of gout. Experimental data have shown that febuxostat may reduce the development of LVH and the amount of cardiac collagen content, thus improving systolic function.93 In a small study, 141 cardiac surgery patients with CKD were randomised to treatment with allopurinol or febuxostat: superior antioxidant and anti-inflammatory effects and a more favourable change in renal dysfunction were observed during treatment with febuxostat than with allopurinol.94

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Cardiovascular Risk Factors New data are needed to establish the clinical benefit of treatment with different XO inhibitors in patients with hyperuricaemia, with and without UA deposits, and HF.

The increase in risk is stronger in patients at high CV risk and in patients with SUA levels >6 mg/dl. Deleterious effects are substantially independent of the presence of urate crystals in the joints.

Conclusion

No strong evidence is available to show that lowering SUA is associated with a decreased incidence of CV events in patients without gout; the use of ULDs is not approved in patients with asymptomatic hyperuricaemia. Large controlled trials are ongoing to assess the effect of SUA-lowering drugs on CV events.95 ■

From the available epidemiological data it is clear that hyperuricaemia is associated with a greater risk of target organ damage and of CV morbidity and mortality.

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Uric Acid and Cardiovascular Disease

eurheartj/ehq394; PMID: 21047877 64. Rathmann W, Hauner H, Dannehl K, Gries FA. Association of elevated serum uric acid with coronary heart disease in diabetes mellitus. Diabete Metab 1993;19:159–66. PMID: 8314420 65. Lehto S, Niskanen L, Ronnemaa T, et al. Serum uric acid is a strong predictor of stroke in patients with non-insulindependent diabetes mellitus. Stroke 1998;29:635–9. PMID: 9506605 66. Yu MA, Sanchez-Lozada LG, Johnson RJ, et al. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acidinduced endothelial dysfunction. J Hypertens 2010;28:1234– 42. PMID: 20486275 67. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 2013;62:3307–15. DOI: 10.2337/db12-1814; PMID: 24065788 68. Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: A meta-analysis of prospective studies. Atherosclerosis 2013;231:61–8. DOI: 10.1016/j.atherosclerosis.2013.08.023; PMID: 24125412 69. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and coronary heart disease: a systematic review and metaanalysis. Arthritis Care Res 2010;62:170–80. DOI: 10.1002/ acr.20065; PMID: 20191515 70. Carnes CA, Chung MK, Nakayama T, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001;89:E32–E38. PMID: 11557745 71. Gonzalez DR, Treuer A, Sun QA, et al. S-nitrosylation of cardiac ion channels. J Cardiovasc Pharmacol 2009;54: 188–95. DOI: 10.1097/FJC.0b013e3181b72c9f; PMID: 19687749 72. Gill JS, McKenna WJ, Camm AJ. Free radicals irreversibly decrease Ca2+ currents in isolated guinea-pig ventricular myocytes. Eur J Pharmacol 1995;292:337–40. PMID: 7796875 73. Shimano M, Shibata R, Inden Y, et al. Reactive oxidative metabolites are associated with atrial conduction disturbance in patients with atrial fibrillation. Heart Rhythm 2009;6:935–40. DOI: 10.1016/j.hrthm.2009.03.012; PMID: 19560081 74. Letsas KP, Korantzopoulos P, Filippatos GS, et al. Uric acid

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elevation in atrial fibrillation. Hellenic J Cardiol 2010;51: 209–13. PMID: 20515852; PMID: 21294900 75. Charles BA, Shriner D, Doumatey A, et al. A genome-wide association study of serum uric acid in African Americans. BMC Med Genomics 2011;4:17. DOI: 10.1186/1755-8794-4-17 76. Liu T, Zhang X, Korantzopoulos P, et al. Uric acid levels and atrial fibrillation in hypertensive patients. Intern Med 2011;50:799–803. DOI: 10.2169/internalmedicine.50.4587 77. Tamariz L, Hernandez F, Bush A, et al. Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 2014;11:1102–8. DOI: 10.1016/ j.hrthm.2014.04.003; PMID: 24709288 78. Bhole V, Krishnan E. Gout and the heart. Rheum Dis Clin North Am 2014;40:125–43. DOI: 10.1016/j.rdc.2013.10.004; PMID: 24268013 79. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003;107:1991–7. PMID: 12707250 80. Ekundayo OJ, Dell’Italia LJ, Sanders PJ, et al. Association between hyperuricemia and incident heart failure among older adults: a propensity-matched study. Int J Cardiol 2010;142:279–87. DOI: 10.1016/j.ijcard.2009.01.010 81. Tamariz L, Harzand A, Palacio A, et al. Uric acid as a predictor of all-cause mortality in heart failure: a meta-analysis. Congest Heart Fail 2011;17:25–30. DOI: 10.1111/j.17517133.2011; PMID: 21272224 82. Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010;170:1358–64. DOI: 10.1001/archinternmed.2010.198; PMID: 20696962 83. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004;43:589–99. PMID: 15042535 84. Culleton BF. Uric acid and cardiovascular disease: a renal-cardiac relationship? Curr Opin Nephrol Hypertens 2001;10:371–5. PMID: 11342800 85. Pascual-Figal DA, Hurtado-Martinez JA, Redondo B, et al. Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients. Eur J Heart Fail

2007;9:518–24. PMID: 17064961 86. Hamaguchi S, Furumoto T, Tsuchihashi-Makaya M, et al. Hyperuricemia predicts adverse outcomes in patients with heart failure. Int J Cardiol 2011;151:143–7. DOI: 10.1016/ j.ijcard.2010.05.002; PMID: 20542341 87. Reyes AJ. The increase in serum uric acid concentration caused by diuretics might be beneficial in heart failure. Eur J Heart Fail 2005;7:461–7. PMID: 15921780 88. Borghi C, Cosentino ER, Rinaldi ER, Cicero AF. Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Invest 2014;44:573–8. DOI: 10.1111/eci.12273; PMID: 24749660 89. Farquharson CA, Butler R, Hill A, et al. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 2002;106:221–6. DOI: 10.1161/01.CIR.0000022140.61460.1D 90. Doehner W, Schoene N, Rauchhaus M, et al. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002;105:2619–24. PMID: 12045167 91. Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010;3:73–81. DOI: 10.1161/ CIRCHEARTFAILURE.109.868604 92. Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPTCHF study. J Am Coll Cardiol 2008;51:2301–9. DOI: 10.1016/ j.jacc.2008.01.068; PMID: 18549913 93. Xu X, Hu X, Lu Z, et al. Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice. J Card Fail 2008;14:746–53. DOI: 10.1016/j.cardfail.2008.06.006; PMID: 18995179 94. Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD). J Cardiol 2015;66:298–303. DOI: 10.1016/j.jjcc.2014.12.017; PMID: 25649025 95. White W, Chohan S, Dabholkar A, et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J 2012;164:14–20. DOI: 10.1016/j.ahj.2012.04.011; PMID: 22795277

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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 Professor Keith AA Fox, University of Edinburgh, Scotland, UK.

Professor Keith AA Fox is Duke of Edinburgh Professor of Cardiology at the University of Edinburgh. Previous posts included Assistant Professor of Internal Medicine and Cardiology at Washington University School of Medicine, St Louis, USA; Senior Lecturer in Cardiology and Honorary Consultant Cardiologist at the University of Wales College of Medicine, Cardiff; Head of Division of Medical and Radiological Sciences of the University of Edinburgh; British Heart Foundation Professor of Cardiology and Consultant Cardiologist in the Royal Infirmary of Edinburgh. His awards include the Silver Medal of the European Society of Cardiology (ESC) in 2010 and again in 2014 and the Mackenzie medal of the British Cardiovascular Society in 2013. He gave the American Heart Association (AHA) “Paul Dudley White Lecture” at the AHA Congress in 2015 and was awarded the Gold Medal of the ESC in 2015. Professor Fox’s major research interest is in the mechanisms and manifestation of acute coronary arterial disease and the work extends from underlying biological mechanisms to in-vitro and in-vivo studies and clinical trials. He is the author of more than 460 scientific papers. He is chair of the RITA studies, Co-Chairman of the Global Registry of Acute Coronary Events (GRACE) Programme and Co-Chairman of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) studies of Clopidogrel in unstable angina/NSTEMI and other settings. Professor Fox was a lead investigator for studies on novel anti-thrombins. The GRACE Programme is the largest international programme in acute coronary disease. It runs across 14 countries and aims to define patients with acute coronary disease, to understand the time course and the disease process and to raise questions for testing in randomised trials and in basic science.

ardiology was never forefront on my mind. I grew up in Central Africa in Zimbabwe where my father was a banker and I went to local schools. I always had an interest in the sciences so during a gap year between school and university I worked in the Queen Elizabeth Hospital in Malawi in the labs and trauma outpatient clinic. This fed my enthusiasm to pursue science and was really quite informative. It was during my degree in immunology and in pathology that I became very interested in mechanisms although at that stage I still had no idea that I would be veering towards cardiology. That said, increasingly I became preoccupied with the fact that about half of those with ST elevation myocardial infarction (STEMI) died within 30 days of their index event, which I found really shocking. Most of the treatments were aimed at just ameliorating the duration of the complications not dealing with the problem; I wanted to do something about it and that led me to specialise in cardiology.

Towards the end of my training in 1981 I decided it would be beneficial to spend some time in the USA so my family and I spent five wonderful years there. I took up a research fellowship at Washington University in St Louis and later joined the faculty. Most of my research at that time was basic science research looking at key mechanisms of myocardial arterial reperfusion and it was here that we produced the original experimental and first clinical studies with tPA for thrombolysis1,2 in collaboration with colleagues at the University of Leuven in Belgium. We also instigated early work on imaging and positron emission tomography looking at the myocardium and its recovery.

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Cardiology Masters: Professor Keith AA Fox

After five years in the USA I returned to the UK in a senior lecturer role at the University of Wales where I stayed for four years, but it was my next appointment that took me to Edinburgh where I’m currently British Heart Foundation Chair. I became Duke of Edinburgh Professor of Cardiology at the University of Edinburgh and it was here that a research group lended itself because there were already groups working in labs across the city in disciplines that included genetics, endocrinology and pharmacology, all with a cardiovascular theme. When I joined the university there were fewer than ten people in cardiovascular research; now there are more than 200, which is enormously gratifying. In fact I’m proud to say that our research department recently won the Queen’s Anniversary Prize, the UK’s most prestigious form of national recognition open to UK academic or vocational institutions. During my career, I’ve been involved in some key international studies but one of the better-known is the Global Registry of Acute Coronary Events (GRACE) Programme (GRACE) study,3 which is the global registry of acute coronary events. I set this up with my co-chair from the University of Massachusetts and we were very fortunate to get leading individuals from around the world to give up their time for nothing to be part of the steering committee. The reason it was so important was because we had no robust information at that time about the characteristics of acute coronary syndromes, how they were defined, how they were managed and what the outcomes were; this enabled us to identify the high-risk features. We thought the program would last a couple of years but actually it lasted 10 and included 102,000 patients in 30 countries! It’s very rewarding to think that the GRACE risk scoring system continues to be used widely internationally and in guidelines to help in the management of patients with non-ST elevation (NSTE) acute coronary syndromes (ACS). It’s also embedded in the National Institute for Health and Care Excellence (NICE) guidelines on acute coronary syndromes. The risk score identifies people by phenotype in terms of baseline characteristics and those who are most at risk of further events, however I think in the future we’re going to be able to base it on both

1. 2. 3.

phenotype and bio- and genetic markers to help only treat people who need it; it’s about getting effective treatment to those most at risk rather than blanket treatment for the whole population. Whilst being involved with the likes of GRACE and Randomised Intervention Trial of Unstable Angina (RITA-3) have always been enormously significant and satisfying to me, and have changed the management of acute coronary artery disease from watchful waiting to expediting admission, reducing clotting and treatment by opening up the artery, I’ve also always strongly felt that as cardiologists we must be involved in prevention. In my spare time I became involved in Action on Smoking and Health (ASH) and am now president of the organisation in Scotland. We were delighted to be one of the key lobby groups to get the cessation of smoking in public places through in Scotland and celebrated the 10th anniversary on 26th March this year. It has been a revolution and amazing to see how law-abiding people have been and the impact both on respiratory and cardiovascular disease. My ambition is to see a smoke free generation; it’s not going to be easy but you have to aim high! Regardless of the progress we’ve made in cardiology, there’s a lot more to do. Some might say that the box is ticked for acute cardiology because the government targets for declining death rates have been exceeded. We have missed out on long-term consequences that occur in people with prior heart attack in those with cardiovascular disease and changing those long-term consequences is of fundamental importance; the possibilities in bespoke treatments for individuals in the future are truly exciting. One of the really exciting areas that our group in Edinburgh is involved in is identifying plaques that are susceptible to rupture. Cardiology has been predominantly focused on putting out the fire once it has happened, but the exciting potential that we have been working on is identifying inflammation and micro-calcification within the plaque with the aim of preventing rupture in the first place. The critical issue is altering the balance between repair and progression so the work we are doing aims to favourably shift the balance towards repair and potentially switch off vulnerable plaques. This work is one of the reasons we won the Queen’s Anniversary Award, so presumably the reviewers think that what we’re doing has potential! n

Bergmann SR, Fox KAA, Ter-Pogossian MM, et al. Clot-selective coronary thrombolysis with tissue-type plasminogen activator. Science 1983;220 :1181–3. PMID: 6602378 Van de Werf F, Ludbrook PA, Bergmann SR, et al. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med 1984;310 :609–3. DOI: 10.1056/NEJM198403083101001; PMID: 6537987 Fox KAA, Steg PG, Eagle KA, et al. GRACE Investigators. Decline in rates of death and heart failure in acute coronary syndromes 1999–2006. JAMA 2007;297 :1892–900. DOI: 10.1001/jama.297.17.1892; PMID: 17473299

Written by Harriett Seager, based on an interview with Professor Keith AA Fox available online at www.radcliffecardiology.com/gallery/interview-pioneer-and-award-winning-cardiologist-dr-keith-fox

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