ECR 9.1 by Radcliffe Cardiology

European Cardiology Review Volume 9 • Issue 1 • Summer 2014

Volume 9 • Issue 1 • Summer 2014

www.ECRjournal.com

Mitral Regurgitation – A Multidisciplinary Challenge Eduardo Alegria-Barrero and Olaf W Franzen

Antiplatelet and Lipid-lowering Drugs in Hypertension Renata Cifkova

Diabetes Management – Lowering Cardiovascular Risk Dan Gaiţ ă , Svetlana Mo ş teoru and Laurence Sperling

Pharmacological Treatment of Patients with Chronic Systolic Heart Failure Christoph Maack and Michael Böhm

ISSN: 1758-3756

Three-dimensional Transoesophageal Echocardiogram Guidance During MitraClip® Implantation

Magnetic Resonance Angiography Shows Subclavian Stenosis in a Patient with Takayasu Disease

Ectatic Right Coronary Artery in a Patient with Microscopic Polyangiitis

Radcliffe Cardiology

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This programme is accredited by the European Board for Accreditation in Cardiology (EBAC) for 1 hour of external CME credit(s). Each participant should claim only those hours of credit that have actually been spent in the educational activity. EBAC works according to the quality standards the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Union of Medical Specialists (UEMS).

RHYTHM MANAGEMENT OF THE ATRIAL FIBRILLATION PATIENT Practical Implementation of the 2012 ESC Guidelines

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EBAC Accredited Educational Programme 2nd September 2014 12.45pm – 1.45pm, RIGA Village 5 To register, please visit

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Supported by an unrestricted educational grant from Biosense Webster. “In compliance with EBAC/ EACCME guidelines, all speakers/ Chairpersons participating in this programme have disclosed or indicated potential conflicts of interest which might cause a bias in the presentations. The Organising Committee/ Course Director is responsible for ensuring that all potential conflicts of interest relevant to the event are declared to the audience prior to the CME activities.”

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Volume 9 • Issue 1 • Summer 2014

www.ECRjournal.com

Editor-in-Chief Juan Carlos Kaski Director, Cardiovascular and Cell Sciences Research Institute St George’s, University of London

Editorial Board Luigi Paolo Badano

Department of Cardiac, Vascular and Thoracic Sciences, University of Padua, Italy

Alberto Cuocolo

Department of Advanced Biomedical Sciences, University of Naples Federico II, Italy

Simon Gibbs

National Heart and Lung Institute, Imperial College London, UK

Martin Halle

Technische Universitaet Muenchen, Germany

Sverre E Kjeldsen

Division of Cardiology, Department of Internal Medicine, Ullevaal Hospital, Norway

Steen Dalby Kristensen

Department of Cardiology, Aarhus University Hospital, Denmark

Patrizio Lancellotti

University of Liège, Belgium

Giuseppe Mancia

Department of Clinical Medicine & Prevention, University of Milano-Bicocca, Italy

Zoltan Papp

University of Debrecen, Hungary

Antonio Pelliccia

Institute of Sports Medicine, Italian National Olympic Committee, Italy

Joep Perk

School of Health and Caring Sciences, Linnaeus University, Kalmar, Sweden

Piotr Ponikowski

Centre for Heart Disease, Clinical Military Hospital, Wroclaw, Poland

Fausto Rigo

Mestre-Venice Hospital, Italy

Rosa Sicari

CNR, Institute of Clinical Physiology, Italy

José Luis Zamorano

University Clinic San Carlos, Spain

Design & Production Tatiana Losinska • Publication Manager Michael Schmool Publishing Director Liam O’Neill • Managing Director David Ramsey Managing Editor editor@radcliffecardiogy.com •

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool michael.schmool@radcliffecardiology.com •

Cover image

Human heart glowing in chest 3D render CGI © janulla | shutterstock.com

Radcliffe Cardiology

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. 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, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2014 All rights reserved

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Established: April 2005 Frequency: Bi-annual Current issue: Summer 2014

Aims and Scope • 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.

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 Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of E uropean 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 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.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Managing Editor with guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Managing Editor 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.

Reprints All articles included in European Cardiology Review are available as reprints. 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.

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 and Interventional Cardiology Review. n

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ESC Congress 2014 Visit Village 9 to be updated to the modern management of arrhythmias from diagnostic to therapeutic options. www.escardio.org/ESC2014

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Contents

Foreword 06

European Cardiology Review – New Beginnings

Cardiovascular Risk 07

Diabetes Management – Lowering Cardiovascular Risk Dan Gaiţă, Svetlana Moşteoru and Laurence Sperling

Lipids 10

The Role of Non-alcoholic Fatty Liver Disease in Cardiovascular Disease Sven M Francque

Hypertension 16

Antiplatelet and Lipid-lowering Drugs in Hypertension Renata Cífková

Cardiac Imaging 21

Clinical Use of Cardiac Magnetic Resonance in Systemic Heart Disease Sophie Mavrogeni, George Markousis-Mavrogenis and Genovefa Kolovou

Heart Rhythm Disease 28

Syncope in the Elderly Helen O’ Brien and Rose Anne Kenny

Heart Failure 37

Diabetes Mellitus and Heart Failure

Pharmacological Treatment of Patients with Chronic Systolic Heart Failure

Dimitris Tousoulis, Evangelos Oikonomou, Gerasimos Siasos and Christodoulos Stefanadis

Christoph Maack and Michael Böhm

49 54

ECR9.1_contents.indd 4

Mitral Regurgitation – A Multidisciplinary Challenge Eduardo Alegria-Barrero and Olaf W Franzen

Ventricular Assist Devices – Evolution of Surgical Heart Failure Treatment Dominik Wiedemann, Thomas Haberl, Julia Riebandt, Paul Simon, Günther Laufer and Daniel Zimpfer

INTERVENTIONAL CARDIOLOGY REVIEW

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Supporting life-long learning for cardiovascular professionals Guided by 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

European Cardiology Review – New Beginnings

fter a publishing hiatus, it brings us great pleasure to announce the return of European Cardiology Review (ECR); formerly European Cardiology.

ECR’s editorial mission is to provide free, high quality review papers on salient issues in cardiovascular disease for the general cardiology community. Conscious of the massive amount of information cardiology practitioners are confronted with on a daily basis, ECR aims to provide the readers with concise, practical reviews on the most current and relevant cardiology topics. All review articles in ECR are written by experienced cardiologists and undergo a stringent peer-review process. The current issue addresses a broad range of topics for the cardiologist including reviews on diabetes and cardiovascular risk, hypertension, Non-Alcoholic Fatty Liver Disease, Syncope and Cardiac Magnetic Resonance. There is also a focus on the topical issue of Heart Failure, with articles on pharmacological management of systolic heart failure and the role of ventricular assist devices, as well as papers dealing with the treatment of mitral regurgitation, and the pathogenic links between diabetes and heart failure. The publishers, Radcliffe Cardiology, would like to express their thanks to all authors for their submissions, as well as the editorial board for their guidance. We are also pleased to announce that Prof. Juan-Carlos Kaski, Professor of Cardiovascular Science and Director of the Cardiovascular and Cell Sciences Research Institute at St. George’s, University of London has recently been appointed Editor-in-Chief of ECR.

We hope that you will find this issue of ECR a valuable resource for your continued professional development. n Liam O’Neill David Ramsey Publishing Director & Managing Director

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Cardiovascular Risk

Diabetes Management – Lowering Cardiovascular Risk Dan Gai ţ ă, 1 Svetlana Mo ş teoru 1 and Laurence Sperling 2 1. Victor Babeş University of Medicine and Pharmacy Timişoara, Institute for Cardiovascular Medicine Timişoara, Cardiology Department; 2. Emory University School of Medicine, Heart Disease Prevention Center, Atlanta, US

Abstract Diabetes mellitus is one of the most common diseases to plague the present day. Sixty percent of mortality in diabetic patients is caused by coronary artery disease. Numerous studies have shown that improving glycaemic control helps manage microvascular complications. On the other hand, some studies have shed light on the fact that a too tight glycaemic control can have adverse effects, especially on patients with high cardiovascular risk. Thus ‘the lower the better’ attitude should be exchanged for ‘the earliest the best’ attitude. A multidisciplinary approach should therefore be undertaken in order to achieve a proper management of the cardiovascular risk for diabetic patients. This includes using hypoglycaemic agents, antihypertensive medication and statins to balance the myriad of cardiovascular risk factors.

Keywords Diabetes mellitus, cardiovascular risk, risk factors, glycaemic control, microvascular complications, macrovascular complications Disclosure: The authors have no conflicts of interest to declare. Received: 21 May 2014 Accepted: 5 July 2014 Citation: European Cardiology Review, 2014;9(1):7–9 Correspondence: Svetlana Moşteoru, Victor Babeş University of Medicine and Pharmacy Timişoara, Institute for Cardiovascular Medicine Timişoara, Cardiology Department, Pta Murgu Eftimie, 2, Timis, Timisoara 300041, Romania. E: tanaly@gmail.com

The increasing worldwide prevalence of diabetes mellitus (DM) means almost 360 million people are suffering from this disease (in 2011) and it is estimated to reach 552 million people by 2030.1 The latest European Action on Secondary Prevention by Intervention to Reduce Events (EuroASPIRE) study (2013) has revealed that the mean prevalence of DM in European patients with coronary artery disease (CAD) is around 38 %, with Cyprus leading the way with 55 % and Russia coming last with 27 %.2 Morbidity and mortality from cardiovascular disease is 2–5 times higher in patients with DM compared with the general population, and diabetes provides a two-fold increase of risk of other vascular diseases independent of other risk factors.3 Multiple studies have shown that hyperglycaemia is associated with an increased risk for coronary heart disease as well as atherosclerotic disease. This is true both for diabetic patients and those with impaired glucose tolerance, although the risk varies between 2–4 times in diabetic patients and 1.5 times for patients with impaired glucose tolerance. Whether impaired fasting glucose also carries additional risk is controversial. Glycaemic control therefore appears to be of utter importance especially since just half of the European patients with CAD screened by EuroASPIRE IV attained a <7.0 % glycated haemoglobin (HbA1c) and only 35 % of them scored <6.5 %.2 Based on the results of several studies, a HbA1c reduction of ~1 % is associated with 15 % relative risk reduction in non-fatal myocardial infarction but without benefits on stroke or all-cause mortality.4 A HbA1c <7.0 % target was shown to reduce microvascular disease but has yet to prove a major benefit on macrovascular risk. Tight glycaemic control exerts a favourable effect on cardiovascular diseases, which is visible only after many years. However, a combination of glucose control with lipid-lowering medication and antihypertensive medication leads to an improvement in the rate of cardiovascular events.1

Gaita_FINAL.indd 7

Moreover, although the remaining normoglycaemic population appears to be larger than previously recorded by the EuroASPIRE III trial (33.7 versus 29.5 %), the prevalence of DM has increased from 23.5 % to 26.8 %, not counting the newly diagnosed cases (13.4 %). This was probably owing to the decrease in the population with impaired fasting glucose and impaired glucose tolerance who have likely developed DM between the two EuroASPIRE trials.2 Yet, as crucial as glycaemic control is, just half of the European population is aware of their glucose levels, ranging from 96 % in Slovenia to 8 % in Belgium.2 This attitude should be changed since successful glucoselowering therapy is most efficient when supported by self-monitoring of blood glucose. However, macrovascular complications gradually emerge long before the actual diagnosis of DM occurs, due to impaired glucose tolerance characterised by long-standing insulin resistance, compensatory hyperinsulinaemia and varying degrees of elevated plasma glucose, which lead in the end to the onset of DM. This process is identified by the development of an atherosclerotic plaque, which in the presence of enhanced inflammatory content becomes unstable and prone to rupture. Atheroma from patients with DM has more lipid, inflammatory changes and thrombus than a normal subject.1 By contrast, microvascular complications slowly begin to unfold only after the onset of clinical diabetes. Two important trials, Diabetes Control and Complication Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), have demonstrated the continuous relationship between the increase of HbA1c and microvascular complications, without an apparent threshold.5 Conversely, a decrease by 2 % in HbA1c significantly lowers the risk of developing nephropathy and retinopathy in DM type 1.6

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Cardiovascular Risk Figure 1: SCORE Risk Diagram for Diabetic Patients

that an oral glucose tolerance test should be performed on a routine basis for such patients, as fasting glycaemia proves to be insufficient.9

AFR D People with Diabetes Mellitus Age (year)

Male Non-smoker

Smoker

Female Non-smoker

Smoker

SBP (mmHg) 180 160 140 120

180 160 140 120

4 5 6 7 8

Risk Level <10 %

4 5 6 7 8

Cholesterol (mmol/l) < 10% TO <20 %

Source: World Heath Organization,

< 20 % TO <30 %

<30% TO <40%

> 40 %

2010.3

Assessing cardiovascular risk in patients with DM can be achieved through various methods, one of the most popular being the Systematic Coronary Risk Evaluation (SCORE) risk diagrams. According to these, DM or chronic kidney disease, or very elevated cholesterol or blood pressure places the patient at a high risk (5–10 %) of developing a fatal cardiovascular event in the next ten years (see Figure 1). On the other hand, assessing the risk of type 2 DM can be conducted using the Finnish Diabetes Risk Score (FINDRISC) questionnaire, which addresses the risk of developing type 2 DM in the next ten years, by dividing it in low, moderate, high and very high risk. CAD accounts for over 60 % mortality in people with DM, more than twice the non-diabetic population, while impaired glucose metabolism, comprising of impaired fasting glycaemia and impaired glucose tolerance, is also linked to CAD – since moderately elevated glucose levels below the threshold for DM also represent an increased risk.7 Moreover, established DM is associated with impaired prognosis after myocardial infarction.8 The Euro Heart Survey programme carried out a study on diabetes and the heart, trying to assess the prevalence of DM and impaired glucose regulation in adult patients with CAD, and to compare diagnostic and therapeutic tools suitable for these patients.9 In their 4,961 cohort of people from 110 European countries admitted with CAD, only 29 % with acute CAD and 34 % with stable CAD were normoglycaemic, thereby concluding that it was unusual to have normal glucose tolerance in patients with CAD.9 The results from the Euro Heart Survey showed that out of the population classified as normoglycaemic by the WHO criteria of 1999 (fasting plasma glucose <6.1 mmol/L), when performed an oral glucose tolerance test, 27 % of these patients proved to have impaired glucose tolerance and 8 % diabetes. Five percent of the group with impaired fasting glucose proved to have actual diabetes. Judging by the American Diabetes Association (ADA) criteria of 2003 (fasting plasma glucose <5.6 mmol/L), 21 % of the normoglycaemic patients were discovered to have impaired glucose tolerance, while 5 % diabetes.9 However, abnormal glucose tolerance seems to be quite common in the general population, as a study on the Australian population aged 65 discovered similar results, 8 % having undiagnosed diabetes and 25 % impaired glucose metabolism.10 While this conclusion appears to be true, it also suggests that it is more common in people with CAD and

Gaita_FINAL.indd 8

An international expert committee issued a report in 2009 on the role of HbA1c in diagnosing diabetes and concluded that HbA1c between 5.7 % and 6.5 % places the patient at high-risk for developing diabetes, while values over 6.5 % signify undiagnosed diabetes.11 A statistic concerning the mortality rate among the diabetic population places cardiovascular disease in the top leading causes of death. Therefore, ischaemic heart disease is by far the most important cause of death for patients with type 2 DM followed by other heart diseases and stroke, while diabetes itself comes in fourth.12 UKPDS, a landmark study with a major impact on clinical care, showed that in newly diagnosed patients with type 2 DM, intensive glucoselowering therapy reduced the risk for clinically important diabeticrelated endpoints. Although mortality and cardiovascular events were not reduced in the main trial, important benefits emerged during a 10-year post-trial monitoring, including a 24 % reduction in microvascular disease, a 15 % reduction in myocardial infarction and lower mortality.13 The most controversial of recent trials is the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which tested the hypothesis that when compared with conventional therapy, normalising glucose levels (target HbA1c 6.0 %) would reduce incident cardiovascular death or events in high-risk patients with type 2 DM.14 After 3.5 years, the trial was stopped prematurely because of a 22 % higher mortality in the intensive therapy group. With regard to the hospitalisation costs of diabetic patients, cardiovascular disease accounts for more than 60 % of total costs, while renal disease, neurological disease and peripheral arterial disease accounts for around 10 %, placing prevention of cardiovascular disease among the top priorities for diabetic patients.15 Therefore, a multifactorial approach should be taken into consideration for an effective risk reduction. This includes glucose control, blood pressure control, lipid control, antithrombotic agents, diet and physical activity for an adequate management of the micro- and macrovascular complications.16 Since type 2 DM is in fact a cardiometabolic disease, the treatment goals are multifactorial. Thus, the aim for HbA1c should be lower than 7 %, while still avoiding hypoglycaemia, blood pressure <140/85 mmHg, low density lipoprotein (LDL) -cholesterol <70 mg/dL and diet controlled weight reduction.1 In order to achieve these goals, hypoglycaemic agents will be necessary besides diet control, and metformin can be used as a first-line agent in patients who do not have renal insufficiency, liver disease or hypoxia.3 Evidence for this indication arises from a Cochrane review of randomised controlled trials and the much feared side effect of lactic acidosis proved to be low and no higher than with other hypoglycaemic agents. However, the review was not able to assess the risk of lactic acidosis in the presence of hypoxic co-conditions, so more research should be undertaken on this population.3 In a subgroup of overweight patients randomised to metformin or conventional therapy in the UKPDS trial, metformin reduced the risk for any diabetesrelated endpoint, myocardial infarction and all-cause mortality by approximately one-third; benefits which remained during 10 years of monitoring.17 Sulphonylurea can be used for patients who have contraindications to metformin or in whom metformin was not able to control their glycaemia. The guidelines advise that in patients with fasting plasma glucose >14 mmol/L despite maximal treatment with metformin and sulphonylurea should be referred to the next level of

EUROPEAN CARDIOLOGY REVIEW

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Diabetes Management – Lowering Cardiovascular Risk

care.3 Several other hypoglycaemic drugs are commonly employed for diabetes but lack enough data to recommend their use as treatments to reduce cardiovascular events.18 Acarbose, an alpha-glucosidase inhibitor, reduced the rate of myocardial infarction by 91 % and a composite of cardiovascular events by 49 % in patients with impaired glucose tolerance in the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial.19 However, cardiovascular risk reduction with acarbose has not been reported in diabetes. Neither incretin mimetics, dipeptidyl peptidase IV (DPP IV) nor sodium-glucose co-transporter 2 (SGLT2) inhibitors have thus far (in clinical trial data) demonstrated cardiovascular event reduction.18 Statins should be given to all type 2 diabetic patients over the age of 40 years who do not have established cardiovascular disease, but with cardiovascular risk factors (one of which is DM), in order to prevent major cardiovascular events. Trials which reported the outcome of coronary events in diabetic patients showed a 17–36 % reduction in the odds of people receiving statins.3 A subsequent meta-analysis regarding the use of statins in primary and secondary prevention confirmed that statins offer benefits for people at high-risk of cardiovascular diseases including patients with diabetes.3

management of hypertension in patients with DM, but can be used if thiazides or ACE inhibitors are contraindicated.3 However, in clinical practice approximately only 12.2 % of patients achieve treatment goals.20 According to the National Health and Nutrition Examination Survey (NHANES), during the 1999 and 2002 period, 7 % of the patients were achieving all three goals, HbA1c <7 %, blood pressure <130/80 mmHg and cholesterol <100 mg/dL (which rose to 12.2 % between 2003 and 2006).20 Due to the fact that microvascular disease develops later in the progress of diabetes and is a direct manifestation of glucose toxicity, tight glycaemic control improves the outcome. By contrast, macrovascular disease can unfold up to 15 years prior to the diagnosis of DM and with HbA1c much lower than expected, increasing the risk of complications. Furthermore, epidemiological studies have shown that tight glycaemic control can in fact pose risks of a cardiovascular nature to individuals with high cardiovascular risk factors, possibly through pathological hypoglycaemic events. Therefore, further research into the effects of micro- and macrovascular complications is rendered necessary.21

Lowering blood pressure in diabetic patients reduces the risk of micro- and macrovascular complications. Low-dose thiazides/

It could be said that lower is not always better when it comes to HbA1c levels but that the earliest is the best concerning the management of DM and cardiovascular risks. Prevention of cardiovascular disease should

angiotensin-converting enzyme (ACE) inhibitors are recommended as first-line treatment of hypertension in diabetic patients, and they can be combined. Beta-blockers are not recommended for initial

be based on total cardiovascular risk, and since DM is an independent risk factor by itself, a need for an interdisciplinary approach, such as between the cardiologist and the diabetologist, arises. n

ydén L, Grant PJ, Anker SD, et al., ESC Guidelines on R diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD), Eur Heart J , 2013;34:3035–87. Kotseva K, ESC Congress 365, EuroASPIRE IV European Survey of Cardiovascular Disease Prevention and Diabetes, Principal results: Medical Risk Factors, presentation during the ESC Congress 2013. Available at: http://congress365. escardio.org/Search-Results?Years=C365YEAR2013&vgnext keyword=Kotseva#.U3yJW3bYG8R (accessed 4 July 2014). World Heath Organization, Implementation tools: package of essential non communicable (PEN) disease interventions for primary health care in low resource settings, 2010. Available at: http://whqlibdoc.who.int/ publications/2010/9789241598996_eng.pdf?ua=1 (accessed 7 July 2014). Turnbull FM, Abraira C, Anderson RJ, et al., Intensive glucose control and macrovascular outcomes in type 2 diabetes, Diabetologia, 2009;52:2288–98. Stratton IM, Adler AI, Neil HA, et al., Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study, BMJ, 2000;321:405–12. The effect of intensive treatment of diabetes on the development and progression of long-term complications in

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10.

11.

12.

13.

insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group, N Engl J Med, 1993;329:977–86. Colagiuri S, The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe, Eur Heart J, 2004;25(21):1861–2. Haffner SM, Lehto S, Ronnemaa T, et al., Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction, N Engl J Med , 1998;339:229–34. Bartnik M, Rydén L, Ferrari R, et al., The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart, Eur Heart J, 2004;25:1880–90. Dunstan DW, Zimmet PZ, Welborn TA, et al., The rising prevalence of diabetes and impaired glucose tolerance: the Australian Diabetes, Obesity and Lifestyle Study, Diabetes Care, 2002;25:829–34. Nathan DM, Balkau B, Bonora E, et al., International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes, Diabetes Care , 2009;32(7):1327–34. Geiss LS, Herman WH, Smith PJ, Mortality in non-insulindependent diabetes. In: National Diabetes Data Group, (editors), Diabetes in America 2nd ed , Washington, US: U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995;233–57. Rutter MK, Nesto RW, Blood pressure, lipids and glucose

14.

15. 16.

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in type 2 diabetes: how low should we go? Re-discovering personalized care, Eur Heart J, 2011;32:2247–55. Gerstein HC, Miller ME, Byington RP, et al., Effects of intensive glucose lowering in type 2 diabetes, N Engl J Med, 2008;358:2545–59. American Diabetes Association, Economic Costs of Diabetes in the U.S. in 2007, Diabetes Care, 2008;31:596–615. Mohamed Q, Gillies MC, Wong TY, Management of diabetic retinopathy: a systematic review, JAMA , 2007;298(8):902–16. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group, Lancet, 1998;352:854–65. Beckman JA, Paneni F, Cosentino F, Creager MA, Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II, Eur Heart J, 2013;34(31):2444–52. Chiasson JL, Josse RG, Gomis R, et al., Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial, JAMA, 2003;290:486–94. Cheung BMY, Ong KL, Sham PC, et al., Diabetes Prevalence and Therapeutic Target Achievement in the United States, 1999 to 2006, American Journal of Medicine , 2009;122,5:443–53. Taub PR, Higginbotham E, Henry RR, Beneficial and detrimental effects of glycemic control on cardiovascular disease in type 2 diabetes, Curr Cardiol Rep, 2013;15:332.

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Lipids

le ation.

The Role of Non-alcoholic Fatty Liver Disease in Cardiovascular Disease Sven M Francque Department of Gastroenterology Hepatology, University Hospital Antwerp & Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Abstract Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in western countries and is closely related to the metabolic syndrome. When NAFLD is associated with hepatocellular damage and inflammation (non-alcoholic steatohepatitis [NASH]) it can lead to severe liver disease. However, it has become clear that NAFLD is also associated with an increased risk of cardiovascular disease (CVD), independently of classical known risk factors for the latter. In the current review we briefly summarise the current clinical evidence on the role of NAFLD in CVD and discuss the potential mechanisms by which NAFLD can be linked to the pathophysiology of CVD.

Keywords non-alcoholic fatty liver disease, steatosis, cardiovascular events, pathophysiology Disclosure: The author has no conflicts of interest to declare. Received: 19 May 2014 Accepted: 20 June 2014 Citation: European Cardiology Review, 2014;9(1):10–5 Correspondence: Sven M Francque, Department of Gastroenterology Hepatology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Antwerp, Belgium. E: Sven.francque@uza.be

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in western countries.1,2 It is closely associated with obesity, diabetes, dyslipidaemia and the metabolic syndrome, and shares common risk factors and pathophysiological mechanisms with these entities.2,3 NAFLD can be associated with hepatocellular damage and inflammation and is then called non-alcoholic steatohepatitis (NASH).4 Other than the associated liver-related morbidity and mortality, it has become clear that NAFLD is also associated with an increased risk of cardiovascular disease (CVD). The link between NAFLD and CVD can in part be explained by the common risk factors that they share. However, evidence is increasing that NAFLD is an aetiological factor contributing to the development of CVD, independently of classical known risk factors for the latter.5,6 In this review we briefly summarise the current clinical evidence on the role of NAFLD in CVD and discuss the potential mechanisms by which NAFLD can be linked to the pathophysiology of CVD.

Non-alcoholic Fatty Liver Disease Steatosis is defined by the accumulation of fat in the hepatocytes.7 Other than in cases of mitochondrial toxicity (e.g. acute fatty liver of pregnancy, Reye’s syndrome) where bipolar lipids accumulate in micelles (often called microvesicular steatosis), 8 steatosis mainly consists of fat-filled vacuoles delineated by a bi-layer lipid membrane and predominantly accumulating triglycerides.9 The fat vacuoles may differ in size, from small vesicles up to large vacuoles that fill the cytoplasm and displace the nucleus towards the border of the cell. This results in the term macrovesicular steatosis. 7,10 If smaller vacuoles are present, the term mesovesicular is often used. If the dimensions of the vacuoles vary, steatosis is often called mixed type steatosis, although this implies the presence of typical fat vacuoles of varying diameter, and not necessarily the

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concomitant presence of macrovesicular steatosis and micelles as seen in acute mitochondrial toxicity. 8 Steatosis can be secondary to several causes, such as the use of alcohol and certain drugs (e.g. furadantin, methotrexate, amiodarone, corticosteroids) to chronic hepatitis C (especially genotype 3).4 In the absence of these causes, steatosis is called NAFLD.7,11 NAFLD thus not only necessitates the absence of significant alcohol use (defined as >20 g/day in women and >30 g/day in men) but also the exclusion of all other causes of secondary steatosis, making the term NAFLD not an ideal denominator of this entity.11,12 The term has, however, been widely adopted. NAFLD comprises a wide spectrum of histological liver lesions. If steatosis is the only histological abnormality, it is called non-alcoholic fatty liver (NAFL).12 However, if steatosis is accompanied by inflammation and signs of hepatocyte degeneration (ballooning or swelling of hepatocytes because of cytoskeleton damage), it is called NASH.4,7 NASH requires the combination of steatosis, lobular inflammation (portal inflammation is not included in the diagnosis) and ballooning of any degree.7,12 These features can only be reliably assessed by liver histology, implying NASH to be a histological diagnosis.10,12,13 NAFLD can be accompanied by fibrosis, which can progress to cirrhosis and its inherent complications. It is generally accepted that the risk of fibrosis and progression to cirrhosis is confined to patients with NASH (but fibrosis is not part of the definition of NASH), whereas NAFL is believed to run a benign course, at least in terms of liver disease.10,14,15 Typical features of NASH and even steatosis can disappear in the cirrhotic stage, making it difficult to establish an aetiological diagnosis in some cases of cryptogenic cirrhosis, part of which are considered burned-out NASH based on the presence of metabolic risk factors for NAFLD and NASH.14

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The Role of Non-alcoholic Fatty Liver Disease in Cardiovascular Disease

Despite extensive research conducted so far, the pathophysiology of NAFLD and NASH remains poorly understood. Epidemiologically, NAFLD and NASH are closely related to obesity, to dyslipidaemia, to disturbances of glycaemic control and to the metabolic syndrome (MetS).16 Therefore, NAFLD is sometimes considered as the hepatic manifestation of the MetS.3,17 For some time NAFLD was considered to be secondary to these metabolic features, but insight is growing in the aetiological role of NAFLD in the development of the MetS or type 2 diabetes mellitus (T2DM), which it often precedes.17,18 Currently the pathophysiology of NASH is considered to be a parallel multi-hit process involving nutrients, the gut microbiome, the intestinal barrier, the adipose tissue (producing adipokines), the immune system and the liver, together with genetic and environmental factors.19 Although exact data vary because of differences in modes of diagnosis and selection of patients, NAFLD seems to affect about 15–30 % of the adult population in western countries, making it the most prevalent liver disease worldwide.1,2 The prevalence of NASH is estimated at 2–5 %, with progressive fibrosis in about 45–50 %, with a risk of ultimately developing cirrhosis in 10–20 %.2,15 The risk of hepatocellular carcinoma (HCC) is not well-defined, and some concern has risen about the risk of HCC in non-cirrhotic NAFLD.20,21

Non-alcoholic Fatty Liver Disease and Cardiovascular Disease Whereas the liver-related morbidity and mortality related to NAFLD/ NASH are well-documented and well-known, the consequences of NAFLD outside the setting of liver disease has long been unrecognised but gains growing attention. As already mentioned, NAFLD sometimes precedes the development of T2DM or the MetS, suggesting NAFLD is not simply a consequence but also a causal factor (and probably both) in their pathophysiology.5,17,18 Data are accumulating that patients affected by NAFLD have a higher risk of developing cardiovascular (CV) abnormalities, clinical CV events and even CV death.5,22 A first specific challenge in the interpretation of these data on the link between CVD and NAFLD is to distinguish between a timely correlation simply based on underlying risk factors that are shared by both conditions, or an independent contribution of NAFLD (after correction for these shared metabolic risk factors) in the subsequent development of CVD. The latter implies a specific pathophysiological contribution of the liver affected by NAFLD to the development of CV abnormalities. Elucidating the role of NAFLD in the development of CVD therefore constitutes a second challenge, in which, besides clinical data, studies in animal models might be helpful. Finally the question whether the role of NAFLD in the development of CVD is confined to NASH or is already present in NAFL needs to be answered. This question is particularly relevant for the treatment of NAFLD. If indeed the development of CVD is substantially influenced by NAFLD and NASH, its prevention might constitute an indication to treat NAFLD and its subtypes.

Clinical Data The most convincing data on the role of NAFLD in CVD are those on the link between NAFLD and subclinical coronary heart disease (CHD). NAFLD, mostly diagnosed by ultrasound, has been shown to be an independent risk factor for the presence or future development of increased intima-media thickness, impaired flow-mediated vasodilatation, the presence of carotid atherosclerotic plaques, an increased coronary artery calcium score on cardiac computed

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tomography and abnormal coronary flow reserve as a marker for impaired coronary microcirculation, both in cross-sectional and in follow-up studies, after correction for classical risk factors for CHD.23–36 For clinical CHD, data are also emerging from large cohorts of patients, both cross-sectional and longitudinal studies, in community-based cohorts and in more selected patient groups (e.g. patients with T2DM, type 1 diabetes, patients undergoing coronary angiography or patients with documented NAFLD), that NAFLD is an independent predictor for clinical CHD, being the severity of the atherosclerotic lesions on coronarography or the occurrence of fatal and non-fatal CHD events.37–41 These data have been extensively reviewed elsewhere.5,6 Only a few studies did not confirm the independent relationship of NAFLD with incident CHD or showed it to be confined to patients with NAFLD who concomitantly met the diagnosis of the MetS.42,43 Overall the data strongly support the independent contribution of NAFLD to an increased risk of clinically relevant CHD, even after correction for an extended set of well-established risk factors for CHD. Several studies also showed a link between NAFLD and alterations in cardiac metabolism,35,44 structure and haemodynamic function, such as myocardial insulin resistance and mitochondrial adenosine triphosphate (ATP) production, cardiac steatosis, myocardial hypertrophy and left ventricular diastolic dysfunction, not attributable to concomitant diabetes, obesity or arterial hypertension.44–50 The severity of these cardiac abnormalities correlated with the severity of the NAFLD. Finally NAFLD has been associated with an increased risk of autonomic dysfunction and cardiac arrhythmias (mainly atrial fibrillation).51–53 Interestingly, recent data have shown that NAFLD is also independently linked with QTc interval prolongation, a major risk factor for ventricular arrhythmias and sudden cardiac death, which might explain in part the increased CV mortality associated with NAFLD.54 Finally, congestive heart failure and aortic valve sclerosis have also been linked with NAFLD independently of known risk factors.55–57 Overall, although not all data are methodologically solid and most of the studies lack a diagnosis by the gold standard, the concept of NAFLD as being an independent contributor to the development of atherosclerosis and other functional and structural CV alterations, which subsequently lead to clinical CVD, seems sufficiently substantiated by the current evidence to integrate it in the clinical approach of both the NAFLD patient and the patient with CVD.

Pathophysiological Considerations The mechanisms by which NAFLD influences the development of atherosclerosis and CVD is incompletely understood. NAFLD, T2DM, the MetS and CVD share many metabolic features and risk factors, leading to the concept that they belong to a complex multisystem disease with several organ manifestations and a complex interplay between the different entities, with multiple bidirectional cause–effect relationships. The specific contribution of one entity to the others is therefore difficult to discern, and there might be substantial inter-individual variability. The contribution of NAFLD to CVD, seen as a unidirectional cause–effect relationship, can be either indirect or direct – the potential mechanisms are summarised in Figure 1. Firstly, as the liver is a key organ in both glucose and lipid homeostasis, it is not surprising that evidence is accumulating that NAFLD plays a role

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Lipids Figure 1: Schematic Overview of the Mechanisms that may Link Indirectly or Directly the Liver Affected by Non-alcoholic Fatty Liver Disease to Alterations in the Cardiovascular System risk for diabetes pro-inflammatory mediators atherogeniclipid profile adiponectin

endothelial dysfunction NAFLD

structural vascular change

CVD

angiogenic factors Imbalance Vasodilators/vasoconstrictors imbalance prothrombotic factors CVD = cardiovascular disease; NAFLD = non-alcoholic fatty liver disease.

in the development of T2DM and the MetS, which are by themselves risk factors for CVD.5,17,18 This links NAFLD only indirectly to CVD. NAFLD has indeed been shown to contribute to the development of T2DM. Several studies, mostly diagnosing NAFLD by ultrasound or liver enzymes, have shown that NAFLD precedes and predicts the future development of T2DM independent of obesity and other factors of the MetS. 58,59 As insulin suppresses hepatic gluconeogenesis, NAFLD-associated hepatic insulin resistance results in mild hyperglycaemia, with a need for an increased insulin production to suppress hepatic glucose output and keep it within normal ranges. If Beta (Î˛) cells cannot sustain this increased insulin secretion, patients develop impaired glucose tolerance and diabetes. Inflammatory mediators released by the inflamed liver in NASH might accelerate this process. 60 Secondly, the liver might also contribute directly to the development of CVD. It is clear that NAFLD is associated with an atherogenic lipid profile.61 In NAFLD, production of triglyceride-rich very-low-density lipoprotein (VLDL) particles is increased.62 Insulin normally inhibits adipose tissue lipolysis (which is the main source of free fatty acids flux to the liver for incorporation in hepatic triglycerides) and hepatic VLDL secretion, both of which are hence increased in association with hepatic and adipose tissue insulin resistance.17,63 Subsequently, high-density lipoprotein cholesterol lowers and small dense low-density lipoprotein particles increase. Both conditions are highly atherogenic. Endothelial dysfunction has been shown to be an early event in the development of atherosclerosis.64,65 Several studies have recently highlighted that insulin resistance at the endothelial level occurs early in the development of NAFLD and is already present after a few days of high-fat feeding, when steatosis develops but inflammation seems to still be absent.66â&#x20AC;&#x201C;68 In the endothelium, insulin stimulates nitric oxide (NO) release leading to vasodilatation, and an impairment of insulin signaling leads to a reduced vasodilatory response to acetylcholine (ACh), which is used as a well-established hallmark of endothelial dysfunction.68 Steatosis leads to impaired endothelial NO synthase (eNOS) phosphorylation and hence impaired NO response to insulin, contributing to an increase in intrahepatic resistance.66 Conversely,

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insulin-sensitizing drugs improve endothelial function in NAFLD, as demonstrated by an improvement in the vasodilatory response to ACh.66 These changes occur early in the development of NAFLD, before the development of inflammation and before peripheral insulin resistance can be documented.68 Although the exact mechanisms need to be further elucidated, these findings point towards a pivotal role of steatosis in the impairment of endothelial function as a primary event preceding extrahepatic events. The increased intrahepatic resistance is not only attributable to endothelial dysfunction based on reduced NO production because of endothelial cell insulin resistance. An imbalance in locally produced vasodilators and vasoconstrictors has also been documented.68 Steatosis was shown to be associated with a disturbed production of endothelin 1 and of cyclooxygenase-mediated vasoactive prostaglandins. Although data in humans are scarce and mainly restricted to the measurement of metabolites of vasoactive substances in peripheral blood (both in cirrhosis and in NAFLD patients), alterations have been documented and reflect potential systemic effects of what happens inside a liver affected by NAFLD, and hence its contribution to the development of CV alterations.69 Furthermore, steatosis also induces structural abnormalities of liver vasculature that also contributes to the associated increase in intrahepatic resistance. 68 The pathophysiology of these structural alterations is currently unknown. Angiogenic factors have been shown to play a role in the intrahepatic vascular changes in cirrhosis and are also studied in NASH. 70 Altered levels of angiogenic factors (vascular endothelial growth factor and its soluble receptors 1 and 2) have also been documented in the peripheral blood of patients with NASH. 69 This is used as an argument to support the hypothesis of the role of angiogenic factors in the pathophysiology of NASH, but it also might help us to understand the link between the liver and CVD. Although this has not been proven so far, it can be hypothesized that the altered concentrations of angiogenic factors exert their effects in the extrahepatic vascular beds. The role of angiogenic factors, which not only influence vascular growth but also have vasoactive properties in the pathogenesis of atherosclerosis, has been well-documented.71 Prothrombotic factors have also shown to play a role in the progression of liver disease.72 Several metabolic risk factors are prothrombotic,73 but the role of the liver in this prothrombotic state has been poorly documented. Increased levels of prothrombotic factors have been described in patients with NASH.74 Although the liver is the main source of most of these coagulation factors, the causal role of the liver has not been proven. We studied an extensive panel of coagulation factors in a large series of histologically proven NAFLD patients, showing that mainly plasminogen activator inhibitor 1 (PAI-1) is increased in association with NASH, whereas some of the other factors (e.g. factor VIII, protein S) are elevated in relation with metabolic parameters, as was shown previously73,75 but the alterations of the latter do not correlate with liver histology.74 Furthermore, PAI-1 was also elevated in relation to the severity of liver histology. Together these findings point towards an independent contribution of NAFLD severity to a prothrombotic state that might contribute to CVD. Adiponectin is another factor that might represent a link between NAFLD and CVD. Adiponectin, secreted by adipocytes, is decreased in obesity76,77 but also in NAFLD in relation to the histological severity

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The Role of Non-alcoholic Fatty Liver Disease in Cardiovascular Disease

Table 1: Prospective Patient-based Cohort Studies on the Risk of Coronary Heart Dsease in Relation to Non-alcoholic Fatty Liver Disease Diagnosed by Liver Histology Reference

Year of

Publication Matteoni et al.92

1999

Dam-Larsen et al.93 2004

132

109

Mean

Histological

Follow-up (y)

Subtypes

18.0

Different subtypes

16.7

NAFL

Comparator

Conclusion

Remark

4 histological

All-cause and CV mortality

Increased liver-related

subtypes within

not different between

mortality

the cohort

histological subtypes

General population

All-cause and CV

mortality not different Adams et al.94 Ekstedt et al.95

2005 2006

420 129

7.6 13.7

NAFLD NAFL/NASH

General population Reference population

Increased all-cause

CHD second cause

mortality

of death

Increased liver-related

NAFL not significantly

and CV mortality in NASH

different from reference population

Rafiq et al.96

Söderberg et al.97

2009

2010

173

118

13.0

24.0

NAFL/NASH

NAFL versus NASH

CHD first cause of

Increased liver-related

death in both

mortality in NASH

NAFL and NASH

compared with NAFL

NAFL versus NASH

Increased CV mortality in

No difference between

versus general

NASH compared with NAFL

NAFL and general

population

and general population

population

CHD = coronary heart disease; CV = cardiovascular; n = number of patients; NAFL = non-alcoholic fatty liver; NAFLD = non-alcoholic fatty liver disease; NASH = non-alcoholic steatohepatitis; y = year.

of NAFLD after correction for body mass index (BMI).78,79 Adiponectin has insulin-sensitizing, anti-inflammatory and anti-atherogenic properties80 and directly affects endothelial function by eNOS messenger RNA (mRNA) stabilisation and eNOS phosphorylation.81 Furthermore, adiponectin stimulates circulating angiogenic cells.82 NAFLD-associated adiponectin decrease might therefore contribute to the development of CVD. Inflammatory mediators can also contribute to the increased risk of CVD. NASH is associated with an increased intrahepatic production of pro-inflammatory cytokines, which are also increased systemically.83–85 One of the cytokines that are increased in NASH is Interleukin 6 (IL6), which stimulates angiotensin II in vascular smooth muscle cells with an associated production of reactive oxygen species, which in turn interact with NO production and activity.69 Other inflammatory mediators released by the liver might also contribute to atherogenesis. Although all these mechanisms are plausible links between the liver affected by NAFLD and the development of CVD, no studies to date have scientifically proven to really represent a cause–effect relationship. Several mechanisms are most probably concomitantly present, and might substantially differ between patients. Further study is hence needed to gain mechanistic insight into the pathophysiology of the NAFLD–CVD axis, with an individualised approach, both preventive and therapeutic, as the ultimate goal.

Non-alcoholic Fatty Liver or Non-alcoholic Steatohepatitis? The question whether the role of NAFLD in the development of CVD is confined to NASH or is already present in NAFL is important. Only about 5–10 % of NAFLD patients have NASH,2 so if the risk were to be confined to NASH, this would substantially reduce the CVD burden attributable to NAFLD. This might be in contrast with the current data on the impact of NAFLD on CVD, which does not seem to fit with the relatively small number of NASH patients within the NAFLD group. The answer to this question has potential implications for the management of NAFLD patients. Indeed, if not only NASH but also

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NAFL were to be associated with an increased risk of CVD, one might argue that NAFLD should be treated regardless of the presence of NASH. NAFL would then turn out not to be a benign condition, as it still is generally regarded nowadays,2,11,12,15 and guidelines for the treatment of NAFLD might have to consider treating NAFL, with prevention of CVD as treatment indication. However, the question remains largely unanswered. The main reason is that most of the data come from studies where NAFLD is diagnosed based on ultrasound or on liver biochemistry or both.5,6 In these studies no distinction is made between NAFL and NASH. This distinction still requires a biopsy.13 Series including histology have smaller patient numbers and patients are usually more selected, leading to a potential overrepresentation of more severe liver disease compared with the general population. Furthermore, most of these studies have rather short mean follow-up times. The methodological limitations of these studies hamper the general applicability of their results. Nevertheless, several data give an indication that the risk is confined to NASH, or is at least higher in NASH patients compared with NAFL. A first indication comes from the studies using liver biochemistry to diagnose NASH. Although it has been well-established that transaminases and gamma-glutamyl transpeptidase (GGT) are not perfectly correlated to the severity of the liver lesions, and that transaminases can be normal in patients with NASH79 as well as NASH can be present in patients with normal transaminases,86 overall liver enzymes are higher in NASH versus NAFL patients.79,87 Moreover, several scoring systems for NASH and NASH-related fibrosis include transaminases or GGT.79;88–91 A second indication comes from the studies that did include a liver biopsy and hence a histological classification of NAFLD. These studies are summarised in Table 1. Matteoni et al. only found differences in liver-related mortality but not in all-cause or other cause mortality according to histological subtype of NAFLD.92 Dam-Larsen et al. did not find differences in mortality comparing histologically proven patients with NAFL compared to the general population.93 However, more

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Lipids recent studies consistently show CVD being more prevalent in NAFLD patients, three out of four confining this risk to patients with NASH.94–97 In the study examining prothrombotic factors, we also found an increase mainly in PAI-1 in association with more severe histological lesions, mainly confining the elevations in PAI-1 to patients with NASH.74 Studies on levels of angiogenic factors in patients with NAFLD also showed the most pronounced changes in patients with NASH.69 Although these most recent data suggest that the risk is mainly associated with NASH, or is at least more pronounced in patients with NASH compared with NAFLD, further methodologically stringent studies with long-term follow-up are needed to solve this question.

Treatment of Non-alcoholic Fatty Liver Disease – Impact on Cardiovascular Disease? Currently there is no approved pharmacological treatment for NAFLD.12 Metformin and statins do not seem to improve liver histology, at least not in terms of fibrosis.98 Glitazones have a beneficial effect, as well as vitamin E, but not in all patients.99–102 Lifestyle modification (diet and increased physical activity), if successful, improves NAFLD and also Roux-en-Y gastric bypass surgery ameliorates liver histology.11,12,103,104 Although it can be hypothesized that improving NAFLD reduces the risk of CVD, there is currently little data on potential changes in the risk of CVD in relation to the success of NAFLD treatment. Interestingly, two recent studies on the effects of statins on CV events demonstrated a significantly more reduced CV event rate on statin treatment in patients with baseline elevation of liver tests (used as a surrogate marker for the presence of NAFLD), in relation to a significant improvement of liver tests in one study.105,106 The cardioprotective

1. Francque S, Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH). In: van Damme P, Van Herck K, Michielsen P, et al., Chronic hepatitis and liver disease, Oxford Textbook of Public Health , 5th edition, Oxford: Oxford University Press, 2009;1249–63. 2. Vernon G, Baranova A, Younossi ZM, Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults, Aliment Pharmacol Ther, 2011;34(3):274–85. 3. Verrijken A, Francque S, Van Gaal L, The metabolic syndrome and the liver, Acta Gastroenterol Belg, 2008;71(1):48–59. 4. Brunt EM, Janney CG, Di Bisceglie AM, et al., Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions, Am J Gastroenterol, 1999;94(9):2467–74. 5. Anstee QM, Targher G, Day CP, Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis, Nat Rev Gastroenterol Hepatol , 2013;10(6):330–44. 6. Ballestri S, Lonardo A, Bonapace S, et al., Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease, World J Gastroenterol, 2014;20(7):1724–45. 7. Brunt EM, Histopathology of non-alcoholic fatty liver disease, Clin Liver Dis, 2009;13(4):533–44. 8. Begriche K, Massart J, Robin MA, et al., Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver, J Hepatol, 2011;54(4):773–94. 9. Kotronen A, Seppänen-Laakso T, Westerbacka J, et al., Comparison of lipid and fatty acid composition of the liver, subcutaneous and intra-abdominal adipose tissue, and serum, Obesity (Silver Spring) , 2010;18(5):937–44. 10. Paradis V, Bedossa P, Definition and natural history of metabolic steatosis: histology and cellular aspects, Diabetes Metab, 2008;34(6 Pt 2):638–42. 11. Ratziu V, Bellentani S, Cortez-Pinto H, et al., A position statement on NAFLD/NASH based on the EASL 2009 special conference, J Hepatol, 2010;53(2):372–84. 12. Chalasani N, Younossi Z, Lavine JE, et al., The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association, Am J Gastroenterol, 2012;107(6):811–26. 13. Brunt EM, Liver biopsy diagnosis of hepatitis: clues to clinicallymeaningful reporting, Mo Med, 2010;107(2):113–8. 14. Bugianesi E, Leone N, Vanni E, et al., Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma, Gastroenterology, 2002;123(1):134–40.

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effect of statins was less pronounced in patients with normal liver tests at baseline. Glitazones also improve CV risk, but it is unclear to what extent this can be attributed to their beneficial effect on NAFLD.107–109 Furthermore, as outlined before, it is not clear whether the risk of CVD is increased in all subtypes of NAFLD. Therefore, no evidence-based recommendations can be formulated at present. Nevertheless, it can be recommended to screen for NAFLD in every patient with risk factors for CVD or with established CVD, as well as to screen for CVD in every patient with NAFLD, and to treat accordingly with lifestyle modification. This recommendation is debated, as there are no data on cost-effectiveness and no pharmacological treatment when NAFLD is diagnosed.12 Metformin is frequently used, as it seems to have beneficial effects on CV risk,110–112 although also debated,113 in patients with insulin resistance. However, as outlined previously, metformin failed to show beneficial effects on liver histology.2,98 Other metabolic factors should be treated according to the corresponding guidelines.

Conclusion The role of NAFLD in the pathophysiology of CV abnormalities and hence its independent contribution to an increased risk of CV morbidity and mortality is increasingly evidenced by studies in animal models and by clinical data. Whether NAFL is still to be considered benign in this regard and whether the risk is hence confined to NASH is currently unclear but the risk seems at least to be more pronounced in NASH patients compared with NAFL. As the role of NAFLD in CVD becomes clearer, this aspect of NAFLD should probably be incorporated in the future guidelines on its treatment indications and paradigms. n

15. Musso G, Gambino R, Cassader M, Pagano G, Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity, Ann Med, 2011;43(8):617–49. 16. Bugianesi E, Bellentani S, Bedogni G, et al., Clinical update on non-alcoholic fatty liver disease and steatohepatitis, Ann Hepatol, 2008;7(2):157–60. 17. Yki-Järvinen H, Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome, Lancet Diabetes Endocrinol, 2014;pii: S2213–8587(14)70032–4. 18. Vanni E, Bugianesi E, Kotronen A, et al., From the metabolic syndrome to NAFLD or vice versa?, Dig Liver Dis, 2010;42(5):320–30. 19. Tilg H, Moschen AR, Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis, Hepatology, 2010;52(5):1836–46. 20. Paradis V, Zalinski S, Chelbi E, et al., Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis, Hepatology, 2009;49(3):851–9. 21. Takuma Y, Nouso K, Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: Our case series and literature review, World J Gastroenterol, 2010;16(12):1436–41. 22. Targher G, Day CP, Bonora E, Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease, N Engl J Med, 2010;363(14):1341–50. 23. Targher G, Bertolini L, Padovani R, et al., Associations between liver histology and carotid intima-media thickness in patients with nonalcoholic fatty liver disease, Arterioscler Thromb Vasc Biol, 2005;25(12):2687–8. 24. Colak Y, Senates E, Yesil A, et al., Assessment of endothelial function in patients with nonalcoholic fatty liver disease, Endocrine, 2013;43(1):100–7. 25. Fracanzani AL, Burdick L, Raselli S, et al., Carotid artery intima-media thickness in nonalcoholic fatty liver disease, Am J Med, 2008;121(1):72–8. 26. Villanova N, Moscatiello S, Ramilli S, et al., Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease, Hepatology, 2005;42(2):473–80. 27. Pacifico L, Anania C, Martino F, et al., Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease, Hepatology, 2010;52(5):1643–51. 28. Brea A, Mosquera D, Martin E, et al., Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study, Arterioscler Thromb Vasc Biol, 2005;25(5):1045–50. 29. Volzke H, Robinson DM, Kleine V, et al., Hepatic steatosis is associated with an increased risk of carotid atherosclerosis, World J Gastroenterol, 2005;11(12):1848–53.

30. Jung DH, Lee YJ, Ahn HY, et al., Relationship of hepatic steatosis and alanine aminotransferase with coronary calcification, Clin Chem Lab Med. 2010;48(12):1829–34. 31. Kim D, Choi SY, Park EH, et al., Nonalcoholic fatty liver disease is associated with coronary artery calcification, Hepatology, 2012;56(2):605–13. 32. Liu J, Musani SK, Bidulescu A, et al., Fatty liver, abdominal adipose tissue and atherosclerotic calcification in African Americans: the Jackson Heart Study, Atherosclerosis, 2012;224(2):521–5. 33. Sookoian S, Pirola CJ, Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review, J Hepatol, 2008;49(4):600–7. 34. Yilmaz Y, Kurt R, Yonal O, et al., Coronary flow reserve is impaired in patients with nonalcoholic fatty liver disease: association with liver fibrosis, Atherosclerosis, 2010;211(1):182–6. 35. Lautamäki R, Borra R, Iozzo P, et al., Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes, Am J Physiol Endocrinol Metab, 2006;291(2):E282–90. 36. Nakamori S, Onishi K, Nakajima H, et al., Impaired myocardial perfusion reserve in patients with fatty liver disease assessed by quantitative myocardial perfusion magnetic resonance imaging, Circ J, 2012;76(9):2234–40. 37. Açikel M, Sunay S, Koplay M, et al., Evaluation of ultrasonographic fatty liver and severity of coronary atherosclerosis, and obesity in patients undergoing coronary angiography, Anadolu Kardiyol Derg, 2009;9(4):273–9. 38. Wong VW, Wong GL, Yip GW, et al., Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease, Gut, 2011;60(12):1721–7. 39. Targher G, Pichiri I, Zoppini G, et al., Increased prevalence of cardiovascular disease in Type 1 diabetic patients with non-alcoholic fatty liver disease, J Endocrinol Invest, 2012;35(5):535–40. 40. Targher G, Bertolini L, Padovani R, et al., Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes, J Hepatol, 2010;53(4):713–8. 41. Treeprasertsuk S, Leverage S, Adams LA, et al., The Framingham risk score and heart disease in nonalcoholic fatty liver disease, Liver Int, 2012;32(6):945–50. 42. Stepanova M, Younossi ZM, Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population, Clin Gastroenterol Hepatol, 2012;10(6):646–50. 43. Lazo M, Hernaez R, Bonekamp S, et al., Non-alcoholic fatty liver disease and mortality among US adults: prospective

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cohort study, BMJ, 2011;343:d6891. 44. Perseghin G, Lattuada G, De Cobelli F, et al., Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver, Hepatology, 2008;47(1):51–8. 45. Bonapace S, Perseghin G, Molon G, et al., Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes, Diabetes Care, 2012;35(2):389–95. 46. Rijzewijk LJ, Jonker JT, van der Meer RW, et al., Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes, J Am Coll Cardiol, 2010;56(3):225–33. 47. Rijzewijk LJ, van der Meer RW, Smit JW, et al., Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus, J Am Coll Cardiol, 2008;52(22):1793–9. 48. Goland S, Shimoni S, Zornitzki T, et al., Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic and tissue Doppler imaging assessment, J Clin Gastroenterol, 2006;40(10):949–55. 49. Mantovani A, Zoppini G, Targher G, et al., Non-alcoholic fatty liver disease is independently associated with left ventricular hypertrophy in hypertensive Type 2 diabetic individuals, J Endocrinol Invest, 2012;35(2):215–8. 50. Hallsworth K, Hollingsworth KG, Thoma C, et al., Cardiac structure and function are altered in adults with nonalcoholic fatty liver disease, J Hepatol, 2013;58(4):757–62. 51. Liu YC, Hung CS, Wu YW, et al., Influence of non-alcoholic fatty liver disease on autonomic changes evaluated by the time domain, frequency domain, and symbolic dynamics of heart rate variability, PLoS One, 2013;8(4):e61803. 52. Targher G, Mantovani A, Pichiri I, et al., Non-alcoholic fatty liver disease is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes, Clin Sci (Lond) , 2013;125(6):301–9. 53. Sinner MF, Wang N, Fox CS, et al., Relation of circulating liver transaminase concentrations to risk of new-onset atrial fibrillation, Am J Cardiol, 2013;111(2):219–24. 54. Targher G, Valbusa F, Bonapace S, et al., Association of nonalcoholic fatty liver disease with QTc interval in patients with type 2 diabetes, Nutr Metab Cardiovasc Dis, 2014;24(6):663–9. 55. Wannamethee SG, Whincup PH, Shaper AG, et al., Gammaglutamyltransferase, hepatic enzymes, and risk of incident heart failure in older men, Arterioscler Thromb Vasc Biol, 2012;32(3):830–5. 56. Markus MR, Baumeister SE, Stritzke J, et al., Hepatic steatosis is associated with aortic valve sclerosis in the general population: the Study of Health in Pomerania (SHIP), Arterioscler Thromb Vasc Biol, 2013;33(7):1690–5. 57. Bonapace S, Valbusa F, Bertolini L, et al., Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus, PLoS One, 2014;9(2):e88371. 58. Kim CH, Park JY, Lee KU, et al., Fatty liver is an independent risk factor for the development of Type 2 diabetes in Korean adults, Diabet Med, 2008;25(4):476–81. 59. Sung KC, Jeong WS, Wild SH, Byrne CD, Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes, Diabetes Care, 2012;35(4):717–22. 60. Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G, Insulin resistance in nonalcoholic fatty liver disease, Curr Pharm Des, 2010;16(17):1941–51. 61. Toledo FG, Sniderman AD, Kelley DE, Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes, Diabetes Care, 2006;29(8):1845–50. 62. Adiels M, Westerbacka J, Soro-Paavonen A, et al., Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance, Diabetologia, 2007;50(11):2356–65. 63. Adiels M, Taskinen MR, Packard C, et al., Overproduction of large VLDL particles is driven by increased liver fat content in man, Diabetologia, 2006;49(4):755–65. 64. Lerman A, Zeiher AM, Endothelial function: cardiac events, Circulation, 2005;111(3):363–8. 65. Schalkwijk CG, Stehouwer CD, Vascular complications in diabetes mellitus: the role of endothelial dysfunction, Clin Sci (Lond) , 2005;109(2):143–59. 66. Pasarin M, Abraldes JG, Rodriguez-Vilarrupla A, et al., Insulin resistance and liver microcirculation in a rat model of early

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NAFLD, J Hepatol, 2011;55(5):1095–102. 67. Pasarin M, La Mura V, Gracia-Sancho J, et al., Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD, PLoS One, 2012;7(4):e32785. 68. Francque S, Laleman W, Verbeke L, et al., Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture, Lab Invest, 2012;92(10):1428–39. 69. Coulon S, Francque S, Colle I, et al., Evaluation of inflammatory and angiogenic factors in patients with nonalcoholic fatty liver disease, Cytokine, 2012;59(2):442–9. 70. Coulon S, Heindryckx F, Geerts A, et al., Angiogenesis in chronic liver disease and its complications, Liver Int, 2011;31(2):146–62. 71. Khurana R, Simons M, Martin JF, Zachary IC, Role of angiogenesis in cardiovascular disease: a critical appraisal, Circulation, 2005;112(12):1813–24. 72. Targher G, Chonchol M, Miele L, et al., Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome, Semin Thromb Hemost, 2009;35(3):277–87. 73. Van Gaal LF, Mertens IL, De Block CE, Mechanisms linking obesity with cardiovascular disease, Nature, 2006;444(7121):875–80. 74. Verrijken A, Francque S, Mertens I, et al., Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, Hepatology, 2014;59(1):121–9. 75. Mertens I, Van Gaal LF, Visceral fat as a determinant of fibrinolysis and hemostasis, Semin Vasc Med, 2005;5(1):48–55. 76. Ruige JB, Ballaux DP, Funahashi T, et al., Resting metabolic rate is an important predictor of serum adiponectin concentrations: potential implications for obesity-related disorders, Am J Clin Nutr, 2005;82(1):21–5. 77. Bruyndonckx L, Hoymans VY, Van Craenenbroeck AH, et al., Assessment of endothelial dysfunction in childhood obesity and clinical use, Oxid Med Cell Longev, 2013;2013:174782. 78. Bianchi G, Bugianesi E, Frystyk J, et al., Adiponectin isoforms, insulin resistance and liver histology in nonalcoholic fatty liver disease, Dig Liver Dis, 2011;43(1):73–7. 79. Francque SM, Verrijken A, Mertens I, et al., Noninvasive assessment of nonalcoholic fatty liver disease in obese or overweight patients, Clin Gastroenterol Hepatol, 2012;10(10):1162–8. 80. Marra F, Bertolani C, Adipokines in liver diseases, Hepatology, 2009;50(3):957–69. 81. Ouedraogo R, Wu X, Xu SQ, et al., Adiponectin suppression of high-glucose-induced reactive oxygen species in vascular endothelial cells: evidence for involvement of a cAMP signaling pathway, Diabetes, 2006;55(6):1840–6. 82. Adams V, Heiker JT, Höllriegel R, et al., Adiponectin promotes the migration of circulating angiogenic cells through p38mediated induction of the CXCR4 receptor, Int J Cardiol, 2013;167(5):2039–46. 83. Lima-Cabello E, Garcia-Mediavilla MV, Miquilena-Colina ME, et al., Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in nonalcoholic fatty liver disease and hepatitis C, Clin Sci (Lond), 2011;120(6):239–50. 84. Espinola-Klein C, Gori T, Blankenberg S, Munzel T, Inflammatory markers and cardiovascular risk in the metabolic syndrome, Front Biosci (Landmark Ed) , 2011;16:1663–74. 85. Pihlajamäki J, Kuulasmaa T, Kaminska D, et al. Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans, J Hepatol, 2012;56(3):663–70. 86. Mofrad P, Contos MJ, Haque M, et al., Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values, Hepatology, 2003;37(6):1286–92. 87. Suzuki A, Lymp J, Sauver JS, et al., Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis, Liver Int, 2006;26(10):1209–16. 88. Bedogni G, Bellentani S, Miglioli L, et al., The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population, BMC Gastroenterol, 2006;6:33. 89. Angulo P, Hui JM, Marchesini G, et al., The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD, Hepatology, 2007;45(4):846–54. 90. Kotronen A, Peltonen M, Hakkarainen A, et al., Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors, Gastroenterology, 2009;137(3):865–72.

91. Younossi ZM, Jarrar M, Nugent C, et al., A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH), Obes Surg, 2008;18(11):1430–7. 92. Matteoni CA, Younossi ZM, Gramlich T, et al., Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity, Gastroenterology, 1999;116(6):1413–9. 93. Dam-Larsen S, Franzmann M, Andersen IB, et al., Long term prognosis of fatty liver: risk of chronic liver disease and death, Gut, 2004;53(5):750–5. 94. Adams LA, Lymp JF, St Sauver J, et al., The natural history of nonalcoholic fatty liver disease: a population-based cohort study, Gastroenterology, 2005;129(1):113–21. 95. Ekstedt M, Franzén LE, Mathiesen UL, et al., Long-term follow-up of patients with NAFLD and elevated liver enzymes, Hepatology, 2006;44(4):865–73. 96. Rafiq N, Bai C, Fang Y, et al., Long-term follow-up of patients with nonalcoholic fatty liver, Clin Gastroenterol Hepatol, 2009;7(2):234–8. 97. Söderberg C, Stål P, Askling J, et al., Decreased survival of subjects with elevated liver function tests during a 28-year follow-up, Hepatology, 2010;51(2):595–602. 98. Musso G, Gambino R, Cassader M, Pagano G, A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease, Hepatology, 2010;52(1):79–104. 99. Ratziu V, Pienar L, Pharmacological therapy for non-alcoholic steatohepatitis: How efficient are thiazolidinediones?, Hepatol Res, 2011;41(7):687–95. 100. Ratziu V, Charlotte F, Bernhardt C, et al., Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial, Hepatology, 2010;51(2):445–53. 101. Sanyal AJ, Chalasani N, Kowdley KV, et al., Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, N Engl J Med, 2010;362(18):1675–85. 102. Mahady SE, Webster AC, Walker S, et al., The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis, J Hepatol, 2011;55(6):1383–90. 103. Lassailly G, Caïazzo R, Pattou F, Mathurin P, Bariatric surgery for curing NASH in the morbidly obese?, J Hepatol, 2013;58(6):1249–51. 104. Centis E, Marzocchi R, Suppini A, et al., The role of lifestyle change in the prevention and treatment of NAFLD, Curr Pharm Des, 2013;19(29):5270–9. 105. Athyros VG, Tziomalos K, Gossios TD, et al., Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis, Lancet, 2010;376(9756):1916–22. 106. Tikkanen MJ, Fayyad R, Faergeman O, et al., Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-tomoderate baseline elevations in alanine aminotransferase levels, Int J Cardiol, 2013;168(4):3846–52. 107. Genovese S, De Berardis G, Nicolucci A, et al., Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes, Adv Ther, 2013;30(2):190–202. 108. Zou C, Hu H, Use of pioglitazone in the treatment of diabetes: effect on cardiovascular risk, Vasc Health Risk Manag, 2013;9:429–33. 109. Vaccaro O, Masulli M, Bonora E, et al., Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial, Nutr Metab Cardiovasc Dis, 2012;22(11):997–1006. 110. Lexis CP, Wieringa WG, Hiemstra B, et al., Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction, Cardiovasc Drugs Ther, 2014;28(2):163–71. 111. Lexis CP, van der Horst IC, Lipsic E, et al., Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial, JAMA, 2014;311(15):1526–35. 112. Preiss D, Lloyd SM, Ford I, et al., Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial, Lancet Diabetes Endocrinol, 2014;2(2):116–24. 113. Lexis CP, van der Horst IC, Metformin for cardiovascular disease: promise still unproven, Lancet Diabetes Endocrinol, 2014;2(2):94–5.

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Hypertension

Antiplatelet and Lipid-lowering Drugs in Hypertension Re n a t a Cí f k o v á Head of Department, Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer Hospital, Prague; Department of Medicine II, Charles University in Prague, First Faculty of Medicine, Prague; International Clinical Research Center, Brno, Czech Republic

Abstract Antiplatelet therapy, and low-dose acetylsalicylic acid (ASA) in particular, is recommended in hypertensive patients with previous cardiovascular events and is considered in hypertensive patients with reduced renal function or a high cardiovascular (CV) risk, provided blood pressure is well-controlled. Acetylsalicylic acid is not recommended in low-to-moderate risk hypertensive patients in whom absolute benefit and harm are equivalent. Further trials evaluating antithrombotic therapy including newer agents in hypertension are needed. Women at high and moderate risk of pre-eclampsia are advised to take a low dose of ASA daily from 12 weeks of gestation until delivery. In addition to their lipid-lowering effects, statins induce a small blood pressure reduction. The 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines recommend using statin therapy in hypertensive patients at moderate-to-high CV risk to achieve the target low-density lipoprotein (LDL) cholesterol value <3 mmol/l (115 mg/dl). For individuals with manifest CV disease or at very high CV risk, a more aggressive LDL target of <1.8 mmol/l (70 mg/dl) is recommended.

Keywords Acetylsalicylic acid, pre-eclampsia, bleeds, cardiovascular mortality, statins, LDL cholesterol, chronic kidney disease, HOT study, ASCOT, target LDL cholesterol, target blood pressure Disclosure: The author has no conflicts of interest to declare. Received: 18 May 2014 Accepted: 29 June 2014 Citation: European Cardiology Review, 2014;9(1):16–20 Correspondence: Renata Cífková, Center for Cardiovascular Prevention, Thomayer Hospital, Videnska 800, 140 59 Prague 4, Czech Republic. E: renata.cifkova@ftn.cz

Hypertension is the most prevalent cardiovascular disease affecting 20–50 % of the adult population.1 Elevated blood pressure has been identified as a risk factor for coronary heart disease (CHD), heart failure, stroke, peripheral arterial disease, renal failure and atrial fibrillation both in men and women in a large number of epidemiological studies.2–4 So far, the largest meta-analysis of randomised trials of blood pressure reduction has shown that lowering systolic blood pressure by 10 mmHg and diastolic blood pressure by 5 mmHg using any of the main classes of blood pressure-lowering drugs reduces CHD events and heart failure by about a quarter, and stroke by about a third.5 The benefit of antihypertensive medication is due mostly to blood pressure lowering per se.

Antiplatelet Drugs in Hypertension As hypertension is associated with increased intravascular pressure, most of the expected complications should be of haemorrhagic origin; however, most of the hypertension-related complications in developed countries are nowadays thrombotic ones, with CHD and ischaemic stroke being the most prevalent events. In addition, some hypertension complications such as heart failure or atrial fibrillation are themselves associated with increased risk of stroke and thromboembolism. Therefore, antithrombotic therapy should possibly reduce thrombotic complications in hypertensive patients.

Hypertension Optimal Treatment Hypertension often clusters with other cardiovascular (CV) risk factors associated with increased risk of CV events. Hypertension and dyslipidaemia are two major CV risk factors highly prevalent either alone or in combination.6 Due to interaction of CV risk factors, the probability of a CV event is frequently greater in patients with only moderate blood pressure and cholesterol abnormalities in the presence of additional risk factors. A major aim of treating hypertension is a maximal decrease of long-term total CV risk, which could only be achieved by treatment of all reversible risk factors and associated conditions in addition to treatment of raised blood pressure per se. The aim of this review is to analyse whether there is further benefit from antiplatelet and lipid-lowering drugs in hypertension.

Cifkova_FINAL.indd 16

So far the only study assessing the potential benefit of a low dose of acetylsalicylic acid (ASA) in hypertension is the Hypertension Optimal Treatment (HOT) randomised trial.7 A total of 18,790 patients aged 50–80 years were randomly assigned to three target diastolic blood pressures: ≤90 mmHg, ≤85 mmHg and ≤80 mmHg. Within each group, the patients were randomised to 75 mg/day ASA or placebo. Low-dose ASA reduced major CV events and all myocardial infarctions (see Table 1). Fatal bleeds including cerebral ones did not differ in the two groups but non-fatal major and minor bleeds were significantly more frequent among patients receiving ASA than in those taking placebo (see Table 2). Before the publication of the HOT study, hypertension was often considered a contraindication to ASA because of the potentially increased risk of bleeding (cerebral in particular).7

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Antiplatelet and Lipid-lowering Drugs in Hypertension

Table 1: Hypertension Optimal Treatment Trial – Events in Relation to Acetylsalicylic Acid or Placebo Events

Number of Events

Events/1,000 Patient-years

Acetylsalicylic acid

315

8.9

Placebo

368

10.5

Relative Risk (95 % CI)

Major cardiovascular events 0.030

0.85 (0.73–0.99)

Major cardiovascular events, including silent myocardial infarction Acetylsalicylic acid

388

11.1

Placebo

425

12.2

Acetylsalicylic acid

2.3

Placebo

127

3.6

0.170

0.91 (0.79–1.04)

All myocardial infarction 0.002

0.64 (0.49–0.85)

All myocardial infarction, including silent cases Acetylsalicylic acid

157

4.4

Placebo

184

5.2

Acetylsalicylic acid

146

4.1

Placebo

148

4.2

Acetylsalicylic acid

133

3.7

Placebo

140

3.9

Acetylsalicylic acid

284

8.0

Placebo

305

8.6

0.130

0.85 (0.69–1.05)

All stroke 0.880

0.98 (0.78–1.24)

Cardiovascular mortality 0.650

0.95 (0.75–1.20)

Total mortality 0.360

0.93 (0.79–1.09)

CI = confidence interval. Reproduced from Hansson, et al., 1998.7

A later publication from the HOT study showed gender differences in the preventive effect of ASA, which significantly reduced myocardial infarction only in men by 42 %; but the reduction in myocardial infarction was only 19 %, and thus not significant in women. This was due to less statistical power when subdivided into men and women.8 Subgroup-treatment interaction analyses indicated that only patients with serum creatinine >1.3 mg/dl had a significantly greater reduction of CV events and myocardial infarction, while the risk of bleeding was not significantly different between the subgroups.9 A favourable balance between benefit and harm of ASA was documented in subgroups of patients at higher global baseline risk and baseline systolic blood pressure (≥180 mmHg). More recently, the benefit of ASA was significantly greater in a subgroup with low estimated glomerular filtration rate (eGFR) (<45 ml/min/1.73 m2), for which an increased risk of major bleeding appears to be outweighed by substantial benefit.10

Cochrane Collaboration Review of Antiplatelet Agents For Hypertension Lip et al. found four trials including a total of 44,012 patients to be subject of the meta-analysis.11 ASA did not reduce stroke or all CV events compared with placebo in primary prevention patients with elevated blood pressure and no prior CV disease. On the other hand, myocardial infarction was reduced with ASA in primary prevention; however, the benefit was negated by harm of similar magnitude due to an increase in major haemorrhage. The benefit of antiplatelet therapy for secondary prevention in patients with hypertension is many times greater than the harm. No benefit for warfarin therapy alone or in combination with ASA was found in patients with elevated blood pressure. Diclopidine,

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Table 2: Hypertension Optimal Treatment Trial – Bleeding Events

Acetylsalicylic Placebo Acid (n=9,399) (n=9,391)

Fatal bleeds Total

7 8

Gastrointestinal

5 3

Cerebral

2 3

Other

- 2

Non-fatal major bleeds Total

129 70

Gastrointestinal

72 34

Cerebral

12 12

Nasal

22 12

Other

23 12

Minor bleeds Total

156 87

Gastrointestinal

30 18

Nasal

66 24

Purpura

45 25

Other Reproduced from Hansson, et al., 1998.

15 20 7

clopidogrel and newer antiplatelet agents (prasugrel, ticagrelor) have not been sufficiently evaluated in patients with hypertension. There is a need for further trials evaluating antithrombotic therapy, including newer agents in hypertension.

2013 European Society of Hypertension/European Society of Cardiology Guidelines The 2013 European Society of Hypertension (ESH)/European Society of Cardiology guidelines12 concluded that antiplatelet therapy, particularly low-dose ASA, should be prescribed to controlled hypertensive patients with previous CV events and should be considered in

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Hypertension hypertensive patients with reduced renal function or a high CV risk. ASA is not recommended in low-to-moderate risk hypertensive patients in whom absolute benefit and harm are equivalent.

Acetylsalicylic Acid in Preventing Pre-eclampsia Pre-eclampsia (defined as de novo appearance of hypertension in pregnancy accompanied by proteinuria >0.3 g/24 hours) is associated with increased risk of maternal, foetal and neonatal morbidity and mortality. A reliable prediction of development of this condition has so far failed. A meta-analysis by Duley et al.13 showed only a mild risk reduction of developing pre-eclapmsia with low-dose ASA. Therefore, low-dose of ASA was only recommended in pregnant women at high risk of developing pre-eclampsia defined as a history of pre-eclampsia presenting before 28 weeks of gestation.14 In 2010, Bujold et al. pooled data from over 11,000 women enrolled in randomised controlled trials evaluating low-dose ASA in the treatment of pregnant women at moderate or high risk for preeclampsia.15 They concluded that women who initiated treatment at less than 16 weeks of gestation had a relative risk (RR) of 0.47 (confidence interval [CI] 0.34–0.65) for developing pre-eclampsia, and a 0.09 RR (CI 0.02–0.37) for developing severe pre-eclampsia compared with controls. Women at high risk of pre-eclampsia (hypertension in a previous pregnancy, chronic kidney disease,

levels.20,21 This effect is probably another consequence of improved blood flow following treatment with statins. The beneficial effect of statins in preventing renal dysfunction has also been documented and seems to be independent of their lipid-lowering effect.22 Statins significantly reduce albuminuria or proteinuria and are associated with a small reduction in the rate of kidney function loss, particularly in populations with CV disease.23

Effects of Statins on Blood Pressure in Clinical Studies Most of the studies report a small reduction in blood pressure; however, the blood pressure-lowering effect of statins is not consistent. The effect on blood pressure (BP) varied from neutral to most favourable (Δ systolic BP 8–13 mmHg; Δ diastolic BP 5.0–7.8 mmHg) in a review by Milionis et al., including studies within a broad spectrum of patients (normotensives, hypertensives, individuals with normal lipids and dyslipidaemia, diabetic patients) published up to 2005.24 A meta-analysis of all studies published up to 2005 and reporting BP data during treatment with statins included 20 randomised controlled trials (828 patients) lasting from one to 12 months.25 Systolic BP was significantly lower in patients on statins than in those on placebo or a comparative lipid-lowering drug (mean

autoimmune disease such as systemic lupus erythematosus or antiphospholipid syndrome, type 1 or 2 diabetes, chronic hypertension) or with more than one moderate risk factors for preeclampsia (first pregnancy, age ≥40 years, pregnancy interval of >10 years, body mass index (BMI) ≥35 kg/m 2 at first visit, family history of pre-eclampsia and multiple pregnancy) are advised to take 75 mg of ASA daily from 12 weeks until delivery.16

difference: -1.9 mmHg; 95 % CI -3.8 to -0.1). The effect was greater when the analysis was restricted to studies with a baseline systolic BP >130 mmHg (Δ systolic BP -4.0 mmHg; 95 % CI -5.8 to 2.2). There was a trend toward lower diastolic BP in patients receiving statin therapy compared with controls: -0.9 mmHg (95 % CI -2.0 to 0.2) overall and -1.2 mmHg (95 % CI -2.6 to 0.1) in studies with a baseline diastolic BP >80 mmHg.

Lipid-lowering Drugs in Hypertension

The University of California San Diego (UCSD) Statin Study, a randomised, double-blind, placebo-controlled trial with 973 patients allocated equally to simvastatin (20 mg), pravastatin (40 mg) or placebo for six months, showed a modest but significant BP reduction (2.4–2.8 mmHg for both systolic blood pressure [SBP] and diastolic blood pressure [DBP]) with both statins.26 As this effect was seen in patients not receiving antihypertensive treatment (most patients were normotensive), these results are compatible with the above possibility that statins exert a small BP-lowering effect that can be detected only when they are given alone.

Of all the lipid-lowering drugs, only statins have been properly tested in large clinical trials in hypertensive patients showing their ability to reduce CV morbidity and mortality.17

Effects of Statins on Blood Pressure and Renal Function – Pathophysiological Mechanism By blocking the synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins induce consistent and predictable reductions in circulating LDL-cholesterol and triglycerides, and have a small effect on high-density lipoprotein (HDL)-cholesterol. In addition, these agents exhibit ancillary actions attributed to reductions in isoprenoid cholesterol intermediates and reductions in dolichols, geranylgeranoic acid and farsenylfarsenoic acid. These actions may provide a pleiotropic mechanism by which statins exert actions on blood pressure as well as target organ damage associated with hypertension. Statins improve endothelial function by increasing the bioavailability of nitric oxide, promoting reendothelialisation, reducing oxidative stress and inhibiting inflammatory responses.18 Increased angiotensin II sensitivity predisposes to hypertension and plaque instability. The increased sensitivity to angiotensin II in healthy young subjects with isolated hypercholesterolaemia can be partly restored by therapy to reduce the levels of LDL-cholesterol using statins. There is evidence that statins downregulate angiotensin II type 1 (AT1)-receptor expression.19 Clinical trials have demonstrated that aggressive treatment with statins improves serum creatinine, glomerular filtration rate and urate

Cifkova_FINAL.indd 18

By contrast, in the Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS), a randomised, placebo-controlled, double-blind study including 508 patients with mild hypertension and hypercholesterolaemia, administration of a statin (pravastatin 40 mg once daily) in hypertensive patients with BP effectively reduced by concomitant antihypertensive treatment did not have an additional BP-lowering effect.27 The strengths of this study were a 2.6-year follow-up and ambulatory BP monitoring in addition to clinic BP measurement. A recent meta-analysis of 40 studies and 51 comparison groups (22,511 controls and 22,602 patients) reported a decrease in mean SBP in the statin group by 2.62 mmHg (95 % CI -3.41 to -1.84; p<0.001) and DBP by 0.94 mmHg (95 % CI -1.31 to -0.57; p<0.001). In studies including hypertensive patients, the decrease in BP with statins was slightly greater (SBP -3.07 mmHg; 95 % CI -4 to 2.15 and DBP 1.04 mmHg; 95 % CI -1.47 to -0.61).28

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Antiplatelet and Lipid-lowering Drugs in Hypertension

Studies in Blood Pressure – Large Clinical Outcome Trials Statins and Blood Pressure – Implications of Large Clinical Outcome Trials

Figure 1: Cumulative Incidence of Non-fatal Myocardial Infarction and Coronary Heart Disease, ASCOT-LLA 4

Proportion of patients (%)

Treatment of hypertension is associated with a reduction in stroke and, to a lesser extent, coronary events. It is also well-known that elevated serum total cholesterol significantly increases CHD risk. Therefore, it is logical that co-existing vascular risk factors including abnormal lipid profiles should be an integral part of hypertension management. The benefit of lowering both BP and cholesterol was evaluated in two large-scale trials: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)29 and Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm (ASCOT-LLA).30

In the Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure-Lowering Arm (ASCOT-BPLA) trial, 30 19,342 men and women with hypertension and at least three other CV risk factors were randomised to amlodipine (5–10 mg/d) ± perindopril (4–8 mg/d) or to atenolol (50–100 mg/d) ± bendroflumethiazide (1.25–2.5 mg/d). A total of 10,305 of these patients with normal or slightly elevated total cholesterol were randomised to atorvastatin 10 mg/d or placebo.17 The atorvastatin arm was stopped prematurely at 3.3 years due to a significant reduction in the primary endpoint (-36 %; p=0.0005) (see Figure 1). The benefit of atorvastatin treatment was apparent within the first year of treatment. Fatal/ non-fatal stroke and total CV/coronary events were also reduced with atorvastatin. At one year, atorvastatin reduced total cholesterol by 24 % and LDL-cholesterol by 35 %. However, in the period between six weeks and 18 months, a significant 1.1/0.7 mmHg difference in BP was seen in favour of atorvastatin regardless of titration of doses and numbers of drugs. Overall, amlodipine-perindopril therapy was superior to atenolol-bendroflumethiazide therapy,30 and a further analysis of early monotherapy data comparing amlodipine with atenolol suggested a positive interaction between atorvastatin and amlodipine.31 Compared with placebo, allocation to atorvastatin reduced the incidence of the primary endpoint significantly by 53 % (hazard ratio [HR] 0.47; 95 % CI 0.32–0.69; p<0.0001) among those allocated the amlodipine-based regimen, whereas it reduced the incidence of this outcome by only 16 % (HR 0.84; 95 % CI 0.60–1.17; p=0.30). The difference between these risk reductions with atorvastatin was of borderline significance (heterogeneity; p=0.025) (see Figure 2).

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Cifkova_FINAL.indd 19

1 HR=0.64 CI 0.50–0.83 p=0.0005 0

Number at risk Placebo 5,137 Atorvastatin 5,168

0.5

1.5

2.5

3.5

Time (years) 5,085 5,042 5,134 5,103

5,007 4,964 5,063 5,035

4,603 3,259 4,679 3,263

1,801 1,801

ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm; HR = hazard ratio. Reproduced from Sever, et al., 2003.17

Figure 2: Cumulative Incidence of Non-fatal Myocardial Infarction and Coronary Heart Disease Subdivided Based on Blood Pressure-lowering Treatment, ASCOT-LLA 4

Cumulative incidence (%)

care compared with other statin trials. Adherence to the treatment assigned declined over time. For those assigned to pravastatin, adherence dropped from 87.2 % at year two to 80 % at year four, and 77 % at year six, although the number of participants was small. On the other hand, in the usual care group, crossovers to statin treatment increased from 8 % at year two to 17 % by year four. This increase continued at year six, but the number of participants was small.

Amlodipine-based treatment Atorvastatin Placebo

1 HR=0.47, CI 0.32–0.69 p<0.001 0 0

0.5

1.5

2.5

3.5

Time (years) 4 Cumulative incidence (%)

Part of ALLHAT was designed to determine whether pravastatin compared with usual care would reduce all-cause mortality in 10,355 patients with hypertension and moderate hypercholesterolaemia, plus at least one additional CHD risk factor.29 At four years, total cholesterol was reduced by 17.2 % with pravastatin versus 7.6 % with usual care. All-cause mortality was similar in the two groups and CHD event rates were not different between the two groups; six-year CHD event rates were 9.3 % (pravastatin) and 10.4 % (usual care). These results could be attributed to the small difference in total cholesterol (9.6 %) and LDL-cholesterol (16.7 %) between pravastatin and usual

Atorvastatin Placebo

Atenolol-based treatment Atorvastatin Placebo

1 HR=0.84, CI 0.60–1.17 p=0.30 0 0

0.5

1.5

2.5

3.5

Time (years) ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm; CI = confidence interval; HR = hazard ratio. Reproduced from Sever, et al., 2003.17

Despite extensive crossovers from and to statin usage, the RR reduction in primary events among those originally assigned to atorvastatin remained at 36 % (HR 0.64; 95 % CI 0.53–0.78; p<0.0001) (carryover effect) 2.2 years after the end of the ASCOT-BPLA.32 In the UK ASCOT population, all-cause mortality remained significantly lower in those originally assigned atorvastatin (HR 0.86, 95 % CI 0.76–0.98; p<0.02) 11 years after initial randomisation and

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Hypertension approximately eight years after closure of the lipid-lowering arm (LLA), which may be due to legacy effect.33 A meta-analysis of large clinical trials, including only those with more than 1,000 patients followed for more than two years, was published by Messerli et al. 34 Besides ASCOT-LLA and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), 12 trials enrolling 69,284 patients met the inclusion criteria. Overall, in these 12 trials, statin therapy decreased cardiac death by 24 % (RR 0.76; 95 % CI 0.71–0.82). There was no evidence of a difference in RR estimates for

1. Kearney PM, Whelton M, Reynolds K, et al., Global burden of hypertension: analysis of worldwide data, Lancet , 2005;365:217–23. 2. Kannel WB, Blood pressure as a cardiovascular risk factor: prevention and treatment, JAMA , 1996;275(20):1571–6. 3. Walker WG, Neaton JD, Cutler JA, et al., Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group, JAMA , 1992;268(21):3085–91. 4. Lloyd-Jones DM, Wang TJ, Leip EP, et al., Lifetime risk for development of atrial fibrillation: the Framingham Heart Study, Circulation , 2004;110(9):1042–6. 5. Law MR, Morris JK, Wald NJ, Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies, BMJ , 2009;338:b1665. 6. Assmann G, Schulte H, The Prospective Cardiovascular Munster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease, Am Heart J , 1988;116(6 Pt 2):1713–24. 7. Hansson L, Zanchetti A, Carruthers SG, et al., Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group, Lancet , 1998;351:1755–62. 8. Kjeldsen SE, Kolloch RE, Leonetti G, et al., Influence of gender and age on preventing cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT study. Hypertension Optimal Treatment, J Hypertens , 2000;18:629–42. 9. Zanchetti A, Hansson L, Dahlöf B, et al., Benefit and harm of low-dose aspirin in well-treated hypertensives at different baseline cardiovascular risk, J Hypertens , 2002;20:2301–7. 10. Jardine MJ, Ninomiya T, Perkovic V, et al., Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial, J Am Coll Cardiol , 2010;56:956–65. 11. Lip GY, Felmeden DC, Dwivedi G, Antiplatelet agents and anticoagulants for hypertension, Cochrane Database Syst Rev , 2011;(12):CD003186. 12. 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 , 2013;31:1281–357. 13. Duley L, Henderson-Smart D, Knight M, King J,

Cifkova_FINAL.indd 20

hypertensive and normotensive patients. In conclusion, statin therapy effectively decreased CV morbidity and mortality to the same extent in hypertensive and normotensive patients.

2013 European Society of Hypertension/European Society of Cardiology Guidelines The 2013 ESH/ESC guidelines12 recommend using statin therapy in hypertensive patients at moderate-to-high CV risk to achieve the target LDL cholesterol value <3 mmol/l (115 mg/dl). For individuals with manifest CV disease or at very high CV risk35 a more aggressive LDL target of <1.8 mmol/l (70 mg/dl) is recommended. n

Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review, BMJ , 2001;322:329–33. 14. Mancia G, De Backer G, Dominiczak A, et al, 2007 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 , 2007;25:1105–87. 15. Bujold E, Roberge S, Lacasse Y, et al., Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis, Obstet Gynecol , 2010;116 (2 Pt 1):402–14. 16. National Collaborating Centre for Women’s and Children’s Health (UK), Hypertension in Pregnancy. The Management of Hypertensive Disorders During Pregnancy, NICE Clinical Guidelines No. 107 , London, UK: RCOG Press, 2010. 17. Sever PS, Dahlöf B, Poulter NR, et al., Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial, Lancet , 2003;361:1149–58. 18. Wolfrum S, Jensen KS, Liao JK, Endothelium-dependent effects of statins, Arterioscler Thromb Vasc Biol , 2003;23:729–36. 19. Wassmann S, Faul A, Hennen B, et al., Rapid effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition on coronary endothelial function, Circ Res, 2003;93:e98–103. 20. Collins R, Armitage J, Parish S, et al., MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial, Lancet , 2003;361:2005–16. 21. Athyros VG, Elisaf M, Papageorgiou AA, et al., Effects of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronaryheart-disease Evaluation (GREACE) study, Am J Kidney Dis , 2004;43:589–99. 22. Sukhija R, Bursac Z, Kakar P, et al., Effects of statins on the development of renal dysfunction, Am J Cardiol , 2008;101:975–9. 23. Sandhu S, Wiebe N, Fried LF, Tonelli M, Statins for improving renal outcomes: a meta-analysis, J Am Soc Nephrol , 2006;17:2006–16. 24. Milionis HJ, Liberopoulous EN, Elisaf MS, Mikhailidis DP, Analysis of antihypertensive effects of statins, Curr Hypertens Rep , 2007;9:175–83. 25. Strazzullo P, Kerry SM, Barbato A, et al., Do statins reduce

blood pressure? A meta-analysis of randomized, controlled trials, Hypertension , 2007;49:792–8. 26. Golomb BA, Dimsdale JE, White HL, et al., Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial, Arch Intern Med, 2008;168:721–7. 27. Mancia G, Parati G, Revera M, et al., Statins, antihypertensive treatment, and blood pressure control in clinic and over 24 hours: evidence from PHYLLIS randomized double blind trial, BMJ , 2010;340:c1197. 28. Briasoulis A, Agarwal V, Valachis A, Messerli FH, Antihypertensive effects of statins: a meta-analysis of prospective controlled studies, J Clin Hypertens (Greenwich) , 2013;15:310–20. 29. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), JAMA , 2002;288:2998–3007. 30. Dahlöf B, Sever PS, Poulter NR, et al., Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicenter randomised controlled trial, Lancet , 2005;366:895–906. 31. Sever P, Dahlöf B, Poulter N, et al., Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial, Eur Heart J , 2006;27:2982–8. 32. Sever PS, Poulter NR, Dahlof B, et al, The AngloScandinavian Cardiac Outcomes Trial lipid lowering arm: extended observations 2 years after trial closure, Eur Heart J , 2008;29:499–508. 33. Sever PS, Chang CL, Gupta AK, et al., The AngloScandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the U.K, Eur Heart J , 2011;32:2525–32. 34. Messerli FH, Pinto L, Tang SS, et al., Impact of systemic hypertension on the cardiovascular benefits of statin therapy--a meta-analysis, Am J Cardiol , 2008;101:319–25. 35. Perk J, De Backer G, Gohlke H, et al., European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (version 2012). The Fifth Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts), Eur Heart J , 2012;33:1635–701.

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Cardiac Imaging

LE ATION.

Clinical Use of Cardiac Magnetic Resonance in Systemic Heart Disease Sophie Ma v rog eni, G e o r g e M a r k o u s i s - M a v r o g e n i s a n d G e n o v e f a Ko l o v o u Onassis Cardiac Surgery Center, Athens, Greece

Abstract A systemic disease is one that affects a number of organs and tissues, or the body as a whole. Systemic diseases include endocrine, metabolic, nutritional, multisystem (rheumatic) and HIV disease. Cardiovascular involvement is a common and underestimated problem in systemic diseases, and may present with disease associated cardiac involvement at diagnosis or later in the course of the systemic disease. The cardiac involvement in these diseases is usually silent or oligo-symptomatic and includes different pathophysiological mechanisms such as, myocardial inflammation, infarction, diffuse, subendocardial vasculitis, valvular disease and different patterns of fibrosis. Furthermore, acuity of heart involvement may be underestimated due to non-specific cardiac signs, and finally, most of patients are female and unable to exercise, due to arthritis or muscular discomfort/weakness or may have limited acoustic window, due to increased breast size. Cardiovascular magnetic resonance (CMR), due to its ability to reliably assess cardiac anatomy, function, inflammation, stress perfusion-fibrosis, aortic distensibility, and iron and fat deposition, constitutes an excellent tool for early diagnosis of heart involvement, risk stratification, treatment evaluation and long-term follow-up of patients with cardiac disease due to systemic diseases.

Keywords Rheumatic diseases, metabolic diseases, iron overload, cardiovascular magnetic resonance imaging Disclosure: The authors have no conflicts of interest to declare. Received: 25 March 2014 Accepted: 28 June 2014 Citation: European Cardiology Review, 2014;9(1):21–7 Correspondence: Sophie Mavrogeni, Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61, P. Faliro, Athens, Greece. E: soma13@otenet.gr

Systemic means ‘pertaining to or affecting the whole body’ as opposed to a localised condition. A systemic disease is one that affects a number of organs and tissues, or the body as a whole. Systemic diseases, according to WHO classification,1 and cardiac diseases that developed during their course, are listed in Table 1.

Finally, HIV-infected patients have an increased risk of coronary artery disease (CAD) and myocardial inflammation frequently leading to heart failure. This is due to different factors including: conventional risk factors, HIV-specific processes driving inflammation, coagulation and endothelial dysfunction.5

Thyroid diseases, pheochromocytoma and growth hormone excess may contribute to usually reversible dilated cardiomyopathy.2 Hereditary haemochromatosis is an inherited disorder of iron metabolism; if left untreated, leads to tissue iron overload, iron cardiomyopathy and heart failure. Cardiac amyloidosis is the result of amyloid deposition in the heart, formed from breakdown of normal or abnormal proteins that lead to increased heart stiffness, restrictive cardiomyopathy and heart failure. Finally, nutritional disturbances and metabolic diseases, such as Kwashiorkor, Beri-beri, obesity and diabetes mellitus may also lead to dilated cardiomyopathy and heart failure.3

Cardiovascular magnetic resonance (CMR) through its ability to reliably assess cardiac anatomy, function, inflammation, stress perfusion-fibrosis, aortic distensibility, and iron and fat deposition, constitutes an excellent tool for early diagnosis of cardiovascular involvement, risk stratification, treatment evaluation and long-term follow-up of patients with cardiovascular disease due to systemic diseases.

Cardiovascular involvement is a common and underestimated problem in multisystem (rheumatic) diseases and may present with disease associated cardiac involvement at diagnosis or later in the course of the systemic disease. It usually has a silent or oligo-symptomatic cardiac presentation and includes different pathophysiological mechanisms such as, myocardial inflammation, infarction, diffuse, subendocardial vasculitis, valvular disease and different patterns of fibrosis; furthermore, acuity of heart involvement may be underestimated due to non-specific cardiac signs, and most of patients are female and unable to exercise due to arthritis or muscular discomfort/weakness or may have limited acoustic window due to increased breast size.4

Measurement of Volumes – Ejection Fraction

Mavrogeni_FINAL.indd 21

Cardiovascular Magnetic Resonance Applications of Special Interest for Cardiovascular Evaluation in Systemic Diseases CMR measures ventricular volumes and ejection fraction non-invasively and without contrast agent.6 Due to its high reproducibility, it is ideal for serial follow-up of ventricular volumes, mass and function; compared with echocardiography, which is an operator-dependent technique, with the limitations of acoustic window, CMR is operator-independent and has high reproducibility.7 The majority of CMR data regarding volumes and mass in systemic disease are referred to patients with metabolic diseases and mainly to diabetes mellitus. In patients with type 1 diabetes mellitus (T1DM), it was documented by CMR that in addition to traditional

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Cardiac Imaging Table 1: Systemic Diseases, According to WHO Classification, and Cardiac Diseases that may be Developed During their Course Endocrine and Metabolic Diseases

Nutrition

Multisystem (Rheumatic) Diseases

HIV Infection

Diabetes mellitus

Malnutrition

Rheumatoid arthritis and other

Myocarditis

Coronary artery disease

Low output heart failure

seronegative arthritis

Cardiomyopathy

Diabetic cardiomyopathy

Arrhythmia

Myocarditis

Coronary artery disease

Heart failure

Sudden death

Dilated Cardiomyopathy

Sudden death

Coronary artery disease Valvular disease Heart failure Hyperthyroidism

Thiamine deficiency

Systemic lupus erythematosus

Supraventricular and ventricular

Heart failure

Myocarditis

tachycardia

Dilated cardiomyopathy

Coronary artery disease

Heart failure

Valvular disease Heart failure

Hypothyroidism

Obesity

Small-medium-great vessels vasculitis

Pericarditis

Myocardial hypertrophy

Myocarditis

Bradycardia

Heart failure

Vasculitis

Dilated cardiomyopathy

Coronary artery disease (ectatic/aneurysmatic) Dilated cardiomyopathy Heart failure

Malignant carcinoid

Inflammatory myopathies

Dilated cardiomyopathy

Myocarditis Dilated cardiomyopathy Heart failure

Phaeochromocytoma

Systemic sclerosis (Scleroderma)

Supraventricular and ventricular

Myocardial fibrosis

tachycardia

Pulmonary hypertension

Cardiomyopathy

Heart failure (right)

Heart failure Acromegaly

Amyloidosis

Dilated cardiomyopathy

Restrictive cardiomyopathy

Haemochromatosis

Sarcoidosis

Iron overload

Myocarditis

Dilated cardiomyopathy

Heart failure

Anderson-Fabry disease Hypertrophic cardiomyopathy Arrhythmia

cardiovascular disease risk factors, elevated mean haemoglobin A (1c) and macroalbuminuria were significantly associated with alterations in left ventricular (LV) structure and function.8 In overweight and obese women, insulin resistance is associated with increased cardiac remodelling and reduced diastolic function, assessed by CMR.9 Finally, osteoprotegerin (OPG) was inversely associated with aortic distensibility, LV volumes and LV diastolic function assessed by CMR, while adipocytokine adiponectin (ADPN) was positively associated with myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography.10 In another study, CMR was used to assess the effect of rosiglitazone on cardiovascular performance and cardiac function in type 2 diabetes mellitus (T2DM) and proved that rosiglitazone increased peripheral oedema but had no pernicious effects on cardiovascular performance or cardiac function, with modest improvement in selected CMR measures. 11 Although insulin and glucose indices are associated with abnormalities in cardiac structure, insulin resistance and worsening glycaemia are consistently and independently associated with left ventricular mass (LVM)/LV end-diastolic volume (LVEDV). These data implicate hyperglycaemia and insulin resistance in concentric LV remodelling.12

Mavrogeni_FINAL.indd 22

CMR also documented that few patients with HIV may have a marginally reduced right ventricular ejection fraction (RVEF) but normal right ventricular (RV) dimensions and mass.13 Finally, the progression to heart failure in rheumatoid arthritis (RA) may occur through reduced myocardial mass rather than hypertrophy, and both modifiable and non-modifiable factors may contribute to lower levels of left ventricular mass and volume.14

Myocardial Ischaemia CMR can detect ischaemia by two different ways: • Observation of wall motion abnormalities (abnormal wall motion and wall thickening) using the stress factor dobutamine. Compared with stress echocardiogram, stress CMR using dobutamine has better sensitivity (86 % versus 74 %) and specificity (86 % versus 70 %).15–17 • Observation of myocardial perfusion by the first-pass of a bolus of a T1-shortening contrast agent (first-pass gadolinium) injected into a peripheral vein.18,19 Data acquired during intravenous vasodilatorstress (most commonly adenosine) delineate the underperfused

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Cardiac Magnetic Resonance in Systemic Diseases

regions associated with myocardial ischaemia. The spatial resolution of CMR myocardial perfusion imaging of 2–3 mm is greatly superior to other imaging modalities, such as nuclear techniques, so that subendocardial ischaemia can be more reliably identified.20,21 Recent developments led to further improvements in spatial resolution to around 1 mm in the imaging plane.22–24 The interpretation of CMR myocardial perfusion studies in clinical practice have been validated against X-ray angiography, single-photon emission computed tomography (SPECT) and positron emission tomography (PET).25,26 Recently, the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) study (the largest, prospective, real-world evaluation of CMR) has established its high diagnostic accuracy in coronary heart disease and superiority over SPECT; therefore it should be adopted more widely than at present for the investigation of coronary heart disease.27 Stress perfusion CMR has already been used for the evaluation of diabetic patients. In T1DM, myocardial perfusion reserve index (MPRI) was independently associated with increased LV torsion.28 In another study, it was documented that young subjects with uncomplicated T1DM have impaired myocardial energetics, irrespective of the duration of diabetes and the impaired cardiac energetics status results from metabolic dysfunction rather than microvascular impairment.29 Finally in a study by our group, adenosine stress CMR, using MPRI evaluation, detected early perfusion changes in asymptomatic T1DM, missed by the usual non-invasive evaluation.30 Stress perfusion CMR has also been applied in multisystem (rheumatic diseases). A 44 % prevalence of abnormal stress myocardial perfusion by CMR in the absence of obstructive CAD was documented in systemic lupus erythematosus (SLE) patients with anginal symptoms. Compared with controls, reduced MPRI was observed in SLE patients and SLE presence was a significant predictor of an abnormal MPRI. These findings are consistent with the hypothesis that anginal chest pain (CP) in SLE patients without obstructive CAD is due to myocardial ischaemia potentially caused by microvascular coronary dysfunction. 31 Stress myocardial perfusion abnormalities were frequent in RA patients without known cardiac disease. Abnormal CMR perfusion findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA.32 Subclinical myocardial involvement, as detected by stress perfusion CMR, was frequent in asymptomatic patients with systemic sclerosis (SSc). 33,34 Finally, in sarcoidosis without cardiac symptoms and normal routine assessment, stress perfusion CMR and myocardial inflammation assessment detected early cardiac involvement that may in some cases necessitate immediate treatment.35

Figure 1: Anterior Myocardial Scar, Due to Myocardial Infarction, in a Patient with Systemic Lupus Erythematosus

vivo assessment of myocardial scar (see Figure 1). CMR can detect infarction in as little as 1 cm3 of tissue, substantially less than other in vivo methods, such as echocardiography and nuclear techniques. Furthermore, CMR can detect subendocardial myocardial infarction, missed by SPECT/PET. The CMR extent of scar predicts the potential for functional recovery after revascularisation.36–38 Subendocardial and/or transmural LGE, following the distribution of coronary arteries, are indicative of CAD. However, not only the presence but also the LGE amount plays an important role in patients’ prognosis, because even a small area of LGE (<2 % of LV mass) was associated with a greater than seven-fold increase in risk for a major adverse cardiac event.39 CMR can characterise silent scar consistent with myocardial infarction (MI) in diabetic patients without clinical evidence of MI, and has strong association with major adverse cardiovascular events (MACE) and mortality hazards that is incremental to clinical, electrocardiogram (ECG) and LV function combined.40 LGE has already been described in vasculitis, myositis, SLE and RA; it may present different patterns including subendocardial or transmural lesions in the territory supplied by the occluded coronary artery, intra-myocardial or subepicardial not following the distribution of coronary arteries, mimicking the pattern of viral myocarditis and/or diffuse subendocardial pattern due to vasculitis.41 Finally, global subendocardial LGE was identified by CMR in severe cardiac amyloidosis.42

Myocardial Viability (Fibrosis Detection or Viability Study)

Iron Deposition Assessment

Late Gadolinium Enhanced Imaging

Patients with haemochromatosis are in great risk of iron overload. ‘T2-star’ (T2*) technique, assessed by CMR, is a non-invasive method for measuring liver and cardiac iron deposition (see Figure 2). A significant curvilinear, inverse correlation between iron concentration measured by biopsy and liver T2* was found. Myocardial iron deposition can be reproducibly quantified using T2*. This is the most significant variable for predicting a requirement for targeted treatment of myocardial iron overload and it cannot be replaced by serum ferritin, liver iron or any other measurement. Excellent T2* reproducibility between scanners produced by two different manufacturers supports the feasibility of

CMR is the most reliable imaging way to detect and quantify scar or fibrotic tissue, due to irreversible myocardial damage (viability study). Following acute ischaemic injury, the myocardial distribution volume of gadolinium is increased due to sarcolemmal rupture and abnormal wash-out kinetics. The preferred imaging time for scar detection is between 10 and 20 minutes after contrast agent administration, when the differences between scar, normal myocardium and blood pool are maximal. This method is referred in the literature as late gadolinium enhanced (LGE) CMR and is the gold standard for the in

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Cardiac Imaging Figure 2: T2* Image From a Patient with Iron Deposition, Due to Haemochromatosis

diastolic LV function.46 Additionally, aortic elastic function is abnormal in obese subjects without other cardiovascular risk factors.47 Finally, juvenile idiopathic arthritis (JIA) is associated with increased aortic stiffness that might suggest subclinical atherosclerosis.48

Epicardial Fat Fat deposits are often found around the heart. This fat can be separated into different compartments. Epicardial fat (EF) is the adipose tissue accumulated between the visceral pericardium and the myocardium, without a structure or fascia separating it from the myocardium and the epicardial vessels. EF has a variable distribution, being more prominent in the atrioventricular and interventricular grooves and right ventricular lateral wall.49 Adipocytes’ infiltration into the myocardium as well as triglyceride infiltration into myocytes may also occur.

Figure 3: Magnetic Resonance Angiography Shows Subclavian Stenosis in a Patient with Takayasu Disease

The fat located on the outer surface of the fibrous pericardium differs from EF in their biochemical, molecular and vascular nutrition properties. It is nourished by the pericardiophrenic artery, a branch of the internal thoracic artery,49 while EF is nourished by the coronary arteries. The structure that delimitates these layers is the pericardium, seen on imaging tests as a thin layer around the heart, between 1.0 and 4.0 mm, of which visualisation is sometimes difficult. CMR is considered as the gold standard for the assessment of total body fat and reference modality for the analysis of ventricular volumes and mass, thus making it a natural choice for the detection and quantification of EF.50 The total volume of EF can be estimated using the modified Simpson method, in which the epicardial tissue is contoured in each short axis at end of diastole. The interobserver reproducibility of EF volume measurement is superior to the EF thickness measurement (coefficient of variability of 5.9 % for the volumetric method and 13.6 % for EF thickness at the long axis); however, it is technically more difficult.50

widespread implementation of the technique. Myocardial T2* seems to be the most sensitive and easily reproducible index of myocardial iron deposition currently available.43 Therapeutic phlebotomy and iron chelation are the cornerstones of haemochromatosis therapy. The average survival is less than a year in untreated patients with severe cardiac impairment. However, if treated early and aggressively, the survival rate approaches that of the usual population with heart failure. CMR, using T2* measurements, can quantify myocardial iron overload and response to iron reduction therapy by serial imaging evaluation.43

In prepubertal and early pubertal obese children, EF is a significant marker of increased insulin resistance and associated cardiovascular risk.51 Additionally, subjects with type 1 diabetes have higher EF than non-diabetic subjects.52

Magnetic Resonance Angiography Magnetic resonance angiography (MRA) is an imaging modality that comprises various techniques based on two concepts: methods relying on the natural flow effects, the time-of-flight and phase-contrast technique, either in two- or three-dimensional acquisition mode and the more recently developed contrast-enhanced (CE) MRA methods.

Aortic Stiffness Aortic distensibility and aortic pulse wave velocity (PWV) are two parameters closely related to the bio-elastic function of the aorta. Quantification of aortic distensibility and PWV by CMR has been shown to be accurate and reproducible and can identify early cardiovascular disease in asymptomatic patients. Gradient echo cine CMR has been applied to assess aortic distensibility and phase-contrast cine CMR to evaluate aortic PWV and to quantify aortic flow.44 In type 1 diabetes there are strong adverse effects of hypertension, chronic hyperglycaemia and macroalbuminuria on aortic distensibility.45 In another study, a combined CMR assessment of aortic PWV, aortic distensibility and heart function reveals abnormal PWV and distensibility in T2DM that is independent of blood pressure and correlates with

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A study in diabetic patients, using whole-body magnetic resonance imaging (WB-MRI) and whole-body magnetic resonance angiography (WB-MRA), found a prevalence of 49 % for peripheral artery disease, 25 % for myocardial infarction, 28 % for cerebrovascular disease and 22 % for neuropathic foot. In all vessels, at least 50 % of pathologies were previously unknown. Additionally, myocardial infarction, chronic ischaemic cerebral lesions and atherosclerotic disease were significantly more common in diabetic than in controls.53 MRA has also been applied in the evaluation of great vessels in large vessels vasculitis, such as Takayasu disease (see Figure 3).54 Coronary magnetic resonance angiography (CMRA) has already been applied in different systemic diseases. In diabetes mellitus,

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Figure 4: Ectatic Right Coronary Artery in a Patient with Microscopic Polyangiitis

Figure 5: Patchy Myocardial Fibrosis, Due to Autoimmune Myocarditis, in a Patient with Hyperthyroidism

techniques (echocardiography or nuclear imaging techniques), because these techniques are unable to distinguish slight tissue structure changes (oedema, cell infiltration), which can occur without CMRA may detect early coronary artery changes. 55 In patients with systemic antineutrophil cytoplasmic antibodies (ANCA)-related vasculitis, CMRA detected ectatic and/or aneurysmatic coronary arteries (see Figure 4).56 Additionally, in Kawasaki disease, CMRA is a useful tool for a radiation free serial coronary artery evaluation.57 Finally, in HIV patients, CMRA may facilitate the early detection of CAD.58

T1 Mapping CMR has the capability to characterise myocardial tissue using T1 and T2 mapping techniques. Quantitative T1 imaging, in particular, can be used to calculate the myocardial extracellular volume fraction (ECV), a measure of microscopic myocardial remodelling that has been associated with underlying diffuse fibrosis Diffuse myocardial fibrosis is an underlying contributor to early diabetic cardiomyopathy, as it was documented by the association between myocardial diastolic dysfunction, post-contrast T1 values and metabolic disturbance.59 Recently, it was documented that non-contrast T1 mapping had high diagnostic accuracy for detecting cardiac AL amyloidosis, correlated well with markers of systolic and diastolic dysfunction and was potentially more sensitive for detecting early disease than LGE imaging; therefore, elevated myocardial T1 may represent a direct marker of cardiac amyloid load.60 In patients with SLE without cardiac symptoms, T1 mapping may detect subclinical myocardial involvement.61

Myocardial Inflammation CMR is the ideal technique for the evaluation of inflammatory processes involving the heart. Myocarditis often has a subclinical course, which cannot be easily detected with standard inflammatory indices evaluated in the blood (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], etc.) and can lead, under special conditions, to dilated cardiomyopathy. 62 During its early stages it can also remain undetected by the commonly used imaging

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associated changes in LVEF, the most often detected parameter by echocardiography. Instead, CMR can perform tissue characterisation, which makes it extremely valuable in myocarditis. According to current experience, in myocardial inflammation due to infectious causes (i.e. viral myocarditis), a decrease in LVEF was not evident during the course of the disease, while an increase in cardiac troponin was found in only 20Â % of cases.20 Additionally, myocardial biopsy is an invasive procedure and according to the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines should be kept only for patients with unexplained new-onset heart failure <2 weeks in duration associated with a normal-sized or dilated left ventricle in addition to haemodynamic compromise, and cannot be used for screening or follow-up tool.62 Furthermore its diagnostic value is limited due to a number of reasons (sampling error, variation in observer expertise, etc.).61 CMR contributes to the diagnosis of myocarditis using three types of images: T2-weighted (T2W), early T1- weighted (T1W) images taken at one minute and delayed enhanced images (LGE) taken 15 minutes after the injection of contrast agent. T2W is an indicator of tissue water content, which is increased in inflammation or necrosis, such as during myocardial infarction or myocarditis. However, it is not possible to differentiate between necrosis and inflammation only by the use of T2W images. To enhance the detection of pathology on CMR, images after early and delayed gadolinium injection should be obtained. Higher levels of early myocardial enhancement after gadolinium administration are due to increased membrane permeability or capillary blood flow. Membrane permeability is a major contributor as inflammation damages cell membranes through both T-cell perforin and B-cell antibody/ complement-mediated processes. The third parameter, which should be also evaluated, is the presence of contrast agent deposition in the delayed images (LGE images) (see Figure 5). Myocardial necrosis in the acute phase appears to play a major role in LGE formation, but

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Cardiac Imaging also severe oedema could increase the gadolinium distribution and cause delayed enhanced areas. A combined CMR approach using T2W, early and late gadolinium enhancement, has a sensitivity of 76 %, a specificity of 95.5 % and a diagnostic accuracy of 85 % for the detection of myocardial inflammation.62,63

• awareness of referring physicians about the applications of the technique; and • claustrophobia, metallic clips, pacemakers (unless CMR compatible), defibrillators.

Conclusions Evaluation of inflammation by CMR has already been applied in pheochromocytoma,64 diabetes mellitus,65 endocrine2 and rheumatic diseases,4 and allowed the detection of pathophysiology of cardiac lesions as well as cardiac disease acuity.

Limitations of Cardiac Magnetic Resonance • Lack of availability; • high cost; • high expertise level needed for accurate diagnosis;

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tomography and coronary angiography, Circulation, 2001;103:2230–5. Plein S, Ryf S, Schwitter J, et al., Dynamic contrast-enhanced myocardial perfusion MRI accelerated with k-t sense, Magn Reson Med, 2007;58:777–85. Gebker R, Jahnke C, Paetsch I, et al., Diagnostic performance of myocardial perfusion MR at 3 T in patients with coronary artery disease, Radiology, 2008;247:57–63. Cheng AS, Pegg TJ, Karamitsos TD, et al., Cardiovascular magnetic resonance perfusion imaging at 3-tesla for the detection of coronary artery disease: a comparison with 1.5-tesla, J Am Coll Cardiol, 2007;49:2440–9. Fritz-Hansen T, Hove JD, Kofoed KF, et al., Quantification of MRI measured myocardial perfusion reserve in healthy humans: a comparison with positron emission tomography, J Magn Reson Imaging, 2008;27:818–24. Al-Saadi N, Nagel E, Gross M, et al., Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance, Circulation, 2000;101:1379–83. Schwitter J, Wacker CM, van Rossum AC, et al., MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial, Eur Heart J , 2008;29(4):480–9. Greenwood JP, Maredia N, Younger JF, et al., Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial, Lancet , 2012;379(9814):453–60. Shivu GN, Abozguia K, Phan TT, et al., Increased left ventricular torsion in uncomplicated type 1 diabetic patients: the role of coronary microvascular function, Diabetes Care , 2009;32(9):1710–2. Shivu GN, Phan TT, Abozguia K, et al., Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus, Circulation , 2010;121(10):1209–15. Mavrogeni S, Bratis K, Gavra P, et al., Stress cardiac magnetic resonance reveals myocardial perfusion impairment in asymptomatic diabetes mellitus type I, missed by the routine non-invasive evaluation, Int J Cardiol , 2013;167(6):e167–9. Ishimori ML, Martin R, Berman DS, et al., Myocardial ischemia in the absence of obstructive coronary artery disease in systemic lupus erythematosus, JACC Cardiovasc Imaging , 2011;4(1):27–33. Kobayashi Y, Giles JT, Hirano M, et al., Assessment of myocardial abnormalities in rheumatoid arthritis using a comprehensive cardiac magnetic resonance approach: a pilot study, Arthritis Res Ther , 2010;12(5):R171. Kobayashi H, Yokoe I, Hirano M, et al., Cardiac magnetic resonance imaging with pharmacological stress perfusion and delayed enhancement in asymptomatic patients with systemic sclerosis, J Rheumatol , 2009;36(1):106–12. Mavrogeni S, Bratis K, van Wijk K, et al., Myocardial perfusion-fibrosis pattern in systemic sclerosis assessed by cardiac magnetic resonance, Int J Cardiol , 2012;159(3):e56–8. Mavrogeni S, Kouranos V, Sfikakis PP, et al., Myocardial stress perfusion-fibrosis imaging pattern in sarcoidosis, assessed by cardiovascular magnetic resonance imaging, Int J Cardiol , 2014;172(2):501–3. Klein C, Nekolla SG, Bengel FM, et al., Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: comparison with positron emission tomography, Circulation, 2002;105:162–7. Wagner A, Mahrholdt H, Holly TA, et al., Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study, Lancet, 2003;361:374–9. Bondarenko O, Beek AM, Nijveldt R, et al., Functional

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outcome after revascularization in patients with chronic ischemic heart disease: a quantitative late gadolinium enhancement CMR study evaluating transmural scar extent, wall thickness and periprocedural necrosis, J Cardiovasc Magn Reson, 2007;9:815–21. Kwong RY, Chan AK, Brown KA, et al., Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease, Circulation, 2006;113:2733–43. Kwong RY, Sattar H, Wu H, et al., Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction, Circulation, 2008;118(10):1011–20. Mavrogeni S, Sfikakis P, Dimitroulas T, et al., Edema and fibrosis imaging by cardiovascular magnetic resonance: How can the experience of Cardiology be best utilized in rheumatological practice?, Semin Arthritis Rheum , 2014; pii: S0049-0172(14)00006-7. Mori M, Kitagawa T, Sasaki Y, et al., Global subendocardial late gadolinium enhancement on cardiac magnetic resonance imaging in severe cardiac AL amyloidosis, Int J Hematol , 2013;97(2):159–60. Gulati V, Harikrishnan P, Palaniswamy C, et al., Cardiac involvement in hemochromatosis, Cardiol Rev , 2014;22:56–68. Voges I, Jerosch-Herold M, Hedderich J, et al., Normal values of aortic dimensions, distensibility, and pulse wave velocity in children and young adults: a cross-sectional study, J Cardiovasc Magn Reson , 2012;14:77. Turkbey EB, Redheuil A, Backlund JY, et al., Aortic distensibility in type 1 diabetes, Diabetes Care , 2013;36(8):2380–7. van der Meer RW1, Diamant M, Westenberg JJ, et al., Magnetic resonance assessment of aortic pulse wave velocity, aortic distensibility, and cardiac function in uncomplicated type 2 diabetes mellitus, J Cardiovasc Magn Reson , 2007;9(4):645–51. Robinson MR, Scheuermann-Freestone M, Leeson P, et al., Uncomplicated obesity is associated with abnormal aortic function assessed by cardiovascular magnetic resonance, J Cardiovasc Magn Reson , 2008;10:10. Argyropoulou MI, Kiortsis DN, Daskas N, et al., Distensibility and pulse wave velocity of the thoracic aorta in patients with juvenile idiopathic arthritis: an MRI study, Clin Exp Rheumatol , 2003;21(6):794–7. Kim HM, Kim KJ, Lee HJ, et al., Epicardial adipose tissue thickness is an indicator for coronary artery stenosis in asymptomatic type 2 diabetic patients: its assessment by cardiac magnetic resonance, Cardiovasc Diabetol , 2012;11:83. Iacobellis G, Ribaudo MC, Assael F, et al., Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk, J Clin Endocrinol Metab , 2003;88(11):5163–8. Manco M, Morandi A, Marigliano M, et al., Epicardial fat, abdominal adiposity and insulin resistance in obese pre-pubertal and early pubertal children, Atherosclerosis , 2013;226(2):490–5. Iacobellis G, Diaz S, Mendez A, Goldberg R, Increased epicardial fat and plasma leptin in type 1 diabetes independently of obesity, Nutr Metab Cardiovasc Dis , 2014;24(7):725–9. Weckbach S, Findeisen HM, Schoenberg SO, et al., Systemic cardiovascular complications in patients with long-standing diabetes mellitus: comprehensive assessment with wholebody magnetic resonance imaging/magnetic resonance angiography, Invest Radiol , 2009;44(4):242–50. Mavrogeni S, Dimitroulas T, Chatziioannou SN, Kitas G, The role of multimodality imaging in the evaluation of Takayasu arteritis, Semin Arthritis Rheum , 2013;42(4):401–12. Abd-Elmoniem KZ, Gharib AM, Pettigrew RI, Coronary vessel wall 3-T MR imaging with time-resolved acquisition of

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phase-sensitive dual inversion-recovery (TRAPD) technique: initial results in patients with risk factors for coronary artery disease, Radiology , 2012;265(3):715–23. 56. Mavrogeni S, Manoussakis MN, Karagiorga TC, et al., Detection of coronary artery lesions and myocardial necrosis by magnetic resonance in systemic necrotizing vasculitides, Arthritis Rheum , 2009;61(8):1121–9. 57. Mavrogeni S, Papadopoulos G, Douskou M, et al., Magnetic resonance angiography, function and viability evaluation in patients with Kawasaki disease, J Cardiovasc Magn Reson , 2006;8(3):493–8. 58. Gharib AM1, Abd-Elmoniem KZ, Pettigrew RI, Hadigan C, Noninvasive coronary imaging for atherosclerosis in human

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immunodeficiency virus infection, Curr Probl Diagn Radiol , 2011;40(6):262–7. 59. Jellis C, Wright J, Kennedy D, et al., Association of imaging markers of myocardial fibrosis with metabolic and functional disturbances in early diabetic cardiomyopathy, Circ Cardiovasc Imaging, 2011;4(6):693–702. 60. Karamitsos TD, Piechnik SK, Banypersad SM, et al., Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis, JACC Cardiovasc Imaging, 2013;6(4):488–97. 61. 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(2):295–301.

62. Dennert R, Crijns HJ, Heymans S, Acute viral myocarditis, Eur Heart J, 2008;29:2073–82. 63. Friedrich MG, Sechtem U, Schulz-Menger J, et al., Cardiovascular magnetic resonance in myocarditis: A JACC White Paper, J Am Coll Cardiol , 2009;53(17):1475–87. 64. Ferreira V, Marcelino M, Piechnik S, et al., 122 Cardiac Abnormalities are Common in Patients Diagnosed with Phaeochromocytoma as Detected by Cardiovascular Magnetic Resonance Imaging, Heart , 2014;100 Suppl 3:A70. 65. Makino K, Nishimae I, Suzuki N, et al., Myocarditis with fulminant type 1 diabetes mellitus diagnosed by cardiovascular magnetic resonance imaging: a case report, BMC Res Notes , 2013;6:347.

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Heart Rhythm Disease

Syncope in the Elderly He l e n O ’ B r i e n a n d Ro s e A n n e Ke n n y Department of Medical Gerontology, TCIN, St James’s Hospital, Dublin, Ireland

Abstract A rapid change in ageing demographic is taking place worldwide such that healthcare professionals are increasingly treating old and very old patients. Syncope in the elderly is a challenging presentation that is under-recognised, particularly in the acute care setting. The reason for this is that presentation in the older person may be atypical: patients are less likely to have a prodrome, may have amnesia for loss of consciousness and events are frequently unwitnessed. The older patient thus may present with a fall rather than transient loss of consciousness. There is an increased susceptibility to syncope with advancing age attributed to age-related physiological impairments in heart rate and blood pressure, and alterations in cerebral blood flow. Multi-morbidity and polypharmacy in these complex patients increases susceptibility to syncope. Cardiac causes and more than one possible cause are also common. Syncope is a major cause of morbidity and mortality and is associated with enormous personal and wider health economic costs. In view of this, prompt assessment and early targeted intervention are recommended. The purpose of this article is to update the reader regarding the presentation and management of syncope in this rapidly changing demographic.

Keywords Syncope, elderly, older person, review, cardiac syncope, reflex syncope, neurally mediated, vasovagal, carotid sinus syndrome, orthostatic hypotension Disclosure: The authors have no conflicts of interest to declare. Received: 27 May 2014 Accepted: 12 June 2014 Citation: European Cardiology Review, 2014;9(1):28–36 Correspondence: Rose Anne Kenny, The Falls and Blackout Unit, St James’s Hospital, Dublin 8, Ireland. E: rkenny@tcd.ie

One of the greatest achievements of public health in the twentieth century has been the almost doubling of life expectancy in the Western world. Yet this now ageing population brings new challenges, as the prevalence of little-understood geriatric conditions increases, together with the rising prevalence of age-related disorders, such as syncope. The definition of syncope, as outlined by the European Society of Cardiology (ESC), is a transient loss of consciousness (T-LOC) due to global cerebral hypoperfusion characterised by rapid onset, short duration and spontaneous complete recovery.1 Previous variations in the definition of syncope have led to its prevalence being poorly appreciated.2 By distinguishing syncope/T-LOC from other causes of loss of consciousness (for example, epileptic seizure, concussion), the present definition aims to minimise conceptual and diagnostic confusion.1 Why is syncope in the elderly important? Presentation in this age group is challenging and often recognition is the first step to optimising management and care of these patients. To start with, syncope in the older patient is under-recognised, particularly in acute care settings because the presentation is frequently atypical. The older patient is less likely to have a warning or prodrome prior to syncope, commonly has amnesia for loss of consciousness and frequently experiences an unwitnessed event,3 thus presenting with a fall rather than T-LOC.4–6 These events are typically described as non-accidental (not a trip or slip) or unexplained falls. Therefore, history alone cannot be relied upon when assessing the older patient. Injurious events such as fractures and head injuries, are also more

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common, further emphasising the importance of thorough early investigation and diagnosis.3 There is an increased susceptibility to syncope with advancing age that is attributed to age-related physiological impairments in heart rate (HR), blood pressure (BP), cerebral blood flow and neurohumoral stability.7 This, combined with multi-morbidity and polypharmacy in these complex patients adds to their vulnerability.7 Furthermore, cardiac causes are more common as patients age.8 Emerging evidence has proposed consideration of early insertion of patient-activated internal loop recorder (ILR) devices in this age group.9,10 In the older patient, syncope is a major cause of morbidity and mortality and is associated with enormous personal and wider health economic costs.7 Quality of life studies have consistently shown that functional impairment induced by syncope is similar to that of chronic diseases such as rheumatoid arthritis and epilepsy11–13 underscoring the significant morbidity attached to syncope. The purpose of this review is to highlight the characteristics and epidemiology of syncope in the older person.

Epidemiology The Irish Longitudinal Study on Ageing (TILDA [www.tilda.ie]) is a population-based study of adults 50 years and over that incorporated questions on syncope and falls in addition to a broad spectrum of health, social and economic questions. A number of community dwelling adults (8,163), mean age 62, range 50–106 years, were asked

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whether they experienced fainting in their youth, throughout their life or over the past 12 months. A total of 23.6 % had one or more episodes in the previous 12 months of which 4.4 % were syncope and 19.2 % were falls (see Table 1). Although the prevalence of syncope rose with age, the increase in falls was much more remarkable, in particular the increase in non-accidental or unexplained falls was most striking. Unwitnessed syncope most commonly presents as non-accidental or unexplained falls, supporting the rising prevalence of atypical syncope with advancing years.

Table 1: Prevalence of Syncope and Falls in One Year from The Irish Longitudinal Ageing Study (TILDA) (Personal Communication)

The General Practitioners’ Transition Project in the Netherlands demonstrated that the age distribution of patients presenting to their GP with syncope shows a peak in females at 15 years of age and a second peak in older patients (see Figure 1).14 The Framingham Offspring study similarly demonstrates a bimodal peak of first syncope in mid-teens and over 70 years.15

Figure 1: Frequency of Fainting as the Reason for Visits to General Practice in The Netherlands

50–64 years 65–74 years

75+ years

4.17 4.74

4.84 4.42

Falls

17.46 19.46

24.43 19.19

Non-accidental/

7.61

11.58

9.41

Total

8.87

unexplained falls

40 Frequency (1 x 1,000 years)

The true prevalence of syncope is underestimated due to the phenomenon of amnesia for T-LOC. Amnesia has been reported in patients with vasovagal syncope (VVS) and carotid sinus syndrome (CSS),3,16 but is likely to be present in all causes of syncope. The overlap between syncope and falls also leads to under-reporting.6

Previous Year % Syncope

Causes of Syncope in the Elderly Reflex syncope and orthostatic hypotension (OH) are the most frequent causes of syncope in all age groups and clinical settings, and responsible for the majority of episodes in younger patients. However, cardiac causes of syncope, structural and arrhythmic, become more common in older patients and are responsible for one-third of syncope in patients attending the Emergency Room and Chest Pain Unit1,17–19 (see Table 2,17–19 Figure 220 and Figure 3.21) The prevalence of unexplained syncope varies according to diagnostic facilities and age from 9 to 41 % (see Table 21,17–19). In the older patient, history may be less reliable and multiple causes of syncope may also be present (see Table 3).4,18,22–24 Multi-morbidity and polypharmacy are more common in older patients with syncope and can add to the complexity of identifying an attributable cause of events.25

0–4

5–14

15–24

25–44

45–64

65–74

>75

Age in years Data are obtained from the general practitioners’ transition project. It concerns an analysis of 93,297 patient–years. The arrow around 1 year is to indicate that a small peak occurs between 6–18 months. Permission from The Dutch Journal of Medicine/Nederlands tijdschrift voor geneeskunde.14

an accurate collateral history is not available.6 The differential diagnosis of syncope most frequently includes epilepsy, strokes and transient ischaemic episodes and falls (see Table 4).1 The absence of T-LOC is important in differentiating between syncope and ‘drop attacks’, which are defined as a loss of postural control when the patient falls without loss of consciousness but with difficulty in resuming the erect position after the event.26

Classification

If syncope remains undiagnosed, further investigation is necessary, including in head-up tilt (HUT), cardiac investigations and ambulatory BP monitoring.24,27 In some studies up to 30 % of older patients with syncope have more than one possible attributable cause, emphasising the necessity for a full comprehensive assessment in the older patient.22,28

Syncope is classified as reflex/neurally mediated syncope, syncope secondary to OH and cardiac syncope.1

1) Reflex Syncope/Neurally Mediated Syncope

Approach to the Older Person Presenting with Syncope

Vasovagal Syncope Assessment Initial Evaluation Initial evaluation should establish whether T-LOC occurred, whether aetiology has been identified and whether there is any evidence of a high risk of cardiovascular events or death.1,21 The initial evaluation in patients over 50 years includes detailed history, collateral history, driving history, physical examination, 12-lead electrocardiogram (ECG), measure of orthostatic BP, routine blood tests and CSM. Where possible, the history should elicit ‘the 3 Ps’ (provokers, prodrome, posture), as well as circumstances leading to the event, description of the event, duration of the event, details of the recovery phase and a thorough medication history,1 coupled with a witness account. History alone cannot be relied upon in the older population as commonly these patients (28 % in one study3) experience amnesia for loss of consciousness.3,18 In 50 % of cases of syncope in the older population

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VVS is a neurally mediated reflex in which there is a relatively sudden change in autonomic nervous system activity leading to a fall in BP, HR and cerebral perfusion.29 In young patients a diagnosis can usually be made from history alone. This is not always the case with older patients. Although VVS is the most common cause of syncope in the older patient, it may not follow the benign course commonly observed in the young.30,31 The classic prodrome usually described as pallor, sweating, nausea and dizziness may be shorter in duration or in some instances non-existent or poorly recognised in the older patient.30,32–34 In the older person, VVS is more likely due to a dysautonomic response representing an inability of the baroreflex to adapt to physiological challenges, which results in a progressive fall in HR ± BP before the onset of symptoms.35 VVS has multiple triggers including a warm environment, prolonged standing, dehydration especially in those on diuretics or anti-hypertensive and vasodilator medications.34

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Heart Rhythm Disease Table 2: Frequency of the Causes of Syncope According to Age 1,17–19 Age Group Source Reflex Orthostatic Cardiovascular Non-syncopal Unexplained (Years) % Hypotension % % Cause % %

Setting

<40

†

2.5

1.1

ED and CPU

40–60

†

ED and CPU

<65

‡

68.5 0.5

60/65 ‡

52 3

†

8.5

ED and CPU

>75 §

36 30

12.5

D = cardiology department; CPU = chest pain unit; ED = emergency department; GD = geriatric department; † = Olde Nordkamp; ‡ = Del Rosso; § = Ungar. With permission from Oxford C University Press (UK) (c) European Society of Cardiology (www.escardio.org/guidelines).

Figure 2: Prevalence of Cardiovascular Disease in Adults ≥20 Years of Age by Age and Sex 100 87.1

Percentage of population

83.0

70.2 70.9

70 60 50

40.0

34.4

30 20 10 0

12.8

10.8

20–39

40–59 60–79 Age (years) Men

80+

Women

(National Health and Nutrition Examination Survey: 2007–2010). Source: National Center for Health Statistics and National Heart, Lung, and Blood Institute. These data include coronary heart disease, heart failure, stroke, and hypertension. With permission from Wolters Kluwer Health.20

Figure 3: Causes of Syncope by Age 21 100 Cases with syncope (%)

The HUT is positive when there is induction of either reflex hypotension/bradycardia or delayed OH associated with syncope or pre-syncope1 with symptom reproduction. In unexplained falls due to reflex syncope, patients may deny witnessed loss of conscioussness induced by HUT. This was the case in 42 % of older patients in one study.3 Responses are vasodepressor (hypotension), cardioinhibitory (bradycardia) or mixed.41 An exception to the classification is chronotropic incompetence, where the patient has no compensatory rise in HR on HUT.24

80 60 40 20 0 <40

40–60

>60

Age group (years) Neurally mediated syncope

Arrhythmia

Orthostatic hypotension With permission from BMJ Publishing Group Ltd.

Cardiac structural disease

If HUT results in a cardio-inhibitory response and syncope, capture of a real-time event with early insertion of an ILR9 should be sought.42 It is also important to remember that HUT does not always replicate real-time syncopal episodes as has been demonstrated in ILR analysis in patients with VVS.43

Implantable Loop Recorder – Use in Reflex Syncope The International Study on Syncope of Unknown Etiology (ISSUE-2)44 trial provided evidence that early ILR insertion to capture syncope in real-time in those with suspected reflex syncope, ensured safe and effective directed therapy in patients experiencing frequent syncope.44 The mean age of trial participants was 66 ± 14 years. Other characteristics of participants were syncope beginning in middle or older age, frequent injury and short prodrome. The study demonstrated a reduction in recurrent syncope rates following ILR-guided therapy ie. pacemaker insertion, following asystole or bradyarrhythmia.44 Fifty per cent of those with recurrent unexplained syncope had asystole during symptoms.44 In the ISSUE-3 trial, patients who were ILR positive (documented asystolic episode) but had negative tilt tests, had the best outcomes from cardiac pacing with a 5 % recurrence of syncope at 2 years.45 However, 25 % of those who were ILR positive and actively paced had a recurrence of syncope at 2 years, when those with positive and negative tilts tests were included.45,46 The study raised questions about the origin of the asystole in the older pacemaker group and whether reflex syncope or age-related conducting tissue disease was responsible.47

Management of Vasovagal Syncope Investigation HUT testing is well tolerated in the older patient34 and is indicated in syncope of unknown origin,36 when history is atypical, driving is a concern, or serious injury sustained,37 and as outlined in the ESC guidelines.1 Even the older, frailer patient with cognitive impairment tolerates HUT,38 including both passive and GTN-provoked HUT.39,40

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Cardiac and psychotropic medications can cause hypotension and VVS, therefore initial treatment focuses on modification of culprit medications (up to 40 %). Management includes education with advice on adequate fluid intake,48 physical counter manoeuvres (PCM),7 compression stockings, tilt training49 and feedback to patients of haemodynamic changes correlating with symptoms at the time of HUT.

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Table 3: Numbers and Percentages of Patients with One or More Causes of Syncope Age Group Number of Diagnoses (Years) 0 1 2 3 4 0–4 <40

49 (21.6)

156 (68.7)

21 (9.2)

1 (0.4)

0 (0.0)

227 (23.0)

40–64

62 (22.9)

164 (60.5)

40 (14.8)

5 (1.8)

0 (0.0)

271 (27.5)

65–75

44 (16.3)

168 (62.2)

50 (18.5)

8 (3.0)

0 (0.0)

270 (27.4)

76–79

19 (16.7)

65 (57.0)

26 (22.8)

4 (3.5)

0 (0.0)

114 (11.6)

≥80

21 (20.0)

57 (54.3)

25 (23.8)

1 (1.0)

105 (10.6)

Total

195 (19.8)

610 (61.8)

162 (16.4)

19 (1.9)

1 (0.1)

987 (100)

Causes include cardiac (bradyarrhythmia, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, hypertrophic obstructive cardiomyopathy (long QT); non-cardiac (reflex – vasovagal syncope, carotid sinus hypersensitivity, autonomic dysfunction/orthostatic hypotension, cerebrovascular disease); other; unknown, stratified by age group (values are number [percentage] of patients). With permission from Elsevier.22

Older patients with VVS are more likely to require cardiac pacing, for example, when spontaneous cardioinhibitory response in the setting of frequent syncope is observed.1 Cardiac pacing in VVS is given a class IIa recommendation in international guidelines, in those over 40 years with recurrent reflex syncope and documented spontaneous cardioinhibitory response during monitoring; a Class IIb recommendation for refractory symptoms in the same age group in the presence of a documented cardio-inhibitory response on HUT.1,50 The ISSUE-3 trial refines this to include those VVS patients over 40 years, with syncope beginning in middle or older age,51 with three or more episodes of syncope in the previous 2 years and spontaneous asystole during monitoring.46,47 These patients correspond with those defined by the ESC guidelines as patients with high risk of injury or high frequency of syncope recurrence.1,51

Carotid Sinus Hypersensitivity and Carotid Sinus Syndrome CSS is exclusively a disorder of ageing and current guidelines advise that carotid sinus massage (CSM) should be performed in patients over 40 years with unexplained syncope.1 Careful history taking may reveal triggers such as head turning, tight collars, shaving and vagal stimuli,24 although micturition, defaecation and known triggers of VVS can also provoke CSS. Contraindications to CSM include transient ischaemic attack/stroke within 3 months,1 recent myocardial ischaemia52 or evidence of carotid bruit1 unless significant stenosis has been excluded by carotid dopplers. Using the exclusion criteria, the risk of stroke or transient ischaemic attack (TIA) from CSM has been reported as one per 1,000 episodes of massage.27 Traditionally, carotid sinus hypersensitivity (CSH) has been defined as a ventricular pause lasting >3 seconds and/or a fall in systolic BP of 50 mmHg during CSM without spontaneous syncope.1 CSS is diagnosed when the above criteria is associated with spontaneous syncope.1 The CSH response is categorised as cardio-inhibitory, vasodepressor or a combination of both. 27,45 Recently, authors proposed new criteria for exaggerated responses to CSM-asystole ≥6 seconds and a fall in mean arterial BP ≥60 mmHg over 6 seconds53 based on data from a population study where the 95th percentile for CSM response was 7.3 seconds of asystole and 77 mmHg drop in systolic BP.8 Wieling et al.54 observed that there was no LOC before 6 seconds of asystole providing a pathophysiological reason to extend the guidelines.54 CSH may be an epiphenomenon of ageing rather than a disease process given that it is evident in up to 35 % of asymptomatic community-dwelling older people. 8 Recently, CSH has been associated with cognitive impairment and dementia; however, it is

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Table 4: Conditions Incorrectly Diagnosed as Syncope 1 Disorders with partial or complete LOC but without global cerebral hypoperfusion • Epilepsy • Metabolic disorders including hypoglycaemia, hypoxia, hyperventilation with hypocapnia • Intoxication • Vertebrobasilar TIA Disorders without impairment of consciousness • Cataplexy • Drop attacks • Falls • Functional (psychogenic pseudosyncope) • TIA of carotid origin LOC= loss of consciousness; TIA= transient ischaemic attack. With permission from Oxford University Press (UK) (c) European Society of Cardiology (www.escardio.org/guidelines).

not clear whether it is a risk factor for development of dementia or consequence of neurodegenerative pathology.55,56

Investigation CSM should be performed in all patients over 40 with syncope of unknown aetiology1 and unexplained falls.7

Management of Carotid Sinus Hypersensitivity and Carotid Sinus Syndrome Although the most common presentation of CSS is syncope, patients can also present with falls and drop attacks.52,57 The ESC guidelines only advise pacing with regard to syncope in CSS.1 The American Geriatrics Society guidelines on falls prevention in older adults recommend cardiac pacing for CSH and unexplained/non-accidental falls. 58 Dual-chamber permanent pacemaker insertion for cardio-inhibitory or mixed subtypes of CSS is the treatment of choice.59

2) Orthostatic Hypotension OH is defined as a reduction in systolic BP of at least 20 mmHg or in diastolic BP of at least 10 mmHg within 3 minutes of standing.60 Orthostatic intolerance (OI) refers to symptoms and signs with upright posture due to circulatory abnormality.1 Syndromes of OI that may cause syncope as per ESC guidelines include: initial OH where symptoms of lightheadedness/dizziness or visual disturbance are experienced seconds after standing; classic OH where dizziness, pre-syncope, fatigue, weakness, palpitations, visual and hearing disturbances are experienced; delayed OH where there is a prolonged prodrome frequently followed by rapid syncope; delayed OH and reflex syncope where there is a prolonged prodrome always followed by syncope; reflex syncope triggered by standing where there is classic prodrome and triggers always followed by

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Heart Rhythm Disease Figure 4: Age Dependence of Cardiovascular Responses to Standing Stratified by Gender Male, 50–59

Male, 60–69

Male, 70–79

seconds after standing. Failure of BP to return to baseline values is associated with adverse physical and cognitive outcomes such as syncope, falls, depression and cognitive dysfunction (Finucane, Impaired Orthostatic Blood Pressure Recovery is Independently Associated with an Increased Risk of Falls in Older Community Dwelling Adults; submitted).

Male, 80+

Systolic blood pressure deficit (mmHg)

0 –20

The TILDA study has also shown that supine systolic hypertension (SSH) coupled with OH is a risk factor for cognitive impairment and depression.64 There is a striking age gradient in impaired orthostatic BP response as evidenced in Figure 4 (Finucane et al., Age related normative changes in phasic orthostatic blood pressure and prevalence of impaired recovery in a large population study: Findings from the Irish Longitudinal Study on Ageing (TILDA) – submitted to Circulation).

–40 –60 Female, 60–69

Female, 50–59

Female, 70–79

Female, 80+

0 -20 –40 –60 0

100

Causes of Orthostatic Hypotension The following are the most common causes of OH in elderly people:

Male, 50–59

Male, 60–69

Male, 70–79

Male, 80+

1. medication induced (commonest cause in the older person); 2. primary autonomic failure associated with Parkinson’s disease, multisystem atrophy etc.; and 3. secondary autonomic failure for example secondary to diabetic neuropathy or alcoholic autonomic failure and dehydration.

Female, 60–69

Female, 70–79

Female, 80+

Differential diagnosis must also include anaemia and diagnosis of its underlying cause, Addison’s disease or malignancy.

Diastolic blood pressure deficit (mmHg)

0 –10 –20 –30 Female, 50–59 0 –10

Medication-induced Orthostatic Hypotension

–20 –30 0

100

Male, 50–59

100

Male, 60–69

100

Male, 70–79

100

Male, 80+

Syncope due to OH is linked to the use of vasoactive medications, most commonly diuretics and nitrates.63 Many medications cause OH: cardiovascular medications such as alpha-blockers, diuretics, nitrates, neurological medications, anti-parkinsonian, anti-depressant medications and benzodiazepines.28,60,65 Multivariate analysis in one recent study found that predictors of OH were varicose veins and treatment with alpha-receptor blockers, nitrates or benzodiazepines.28

Heart rate change (bpm)

–10

Investigation of Orthostatic Hypotension

–20

Active standing or passive and unprovoked HUT resulting in symptoms coinciding with a 20 mmHg systolic or diastolic BP drop of 10 mmHg within 3 minutes of orthostatic stress confirms a diagnosis of OH.60 BP and HR usually recover to baseline values within 30 seconds but this reflex increase changes with age and haemodynamic recovery is delayed in elders (see Figure 4, Finucane et al.)

–30 Female, 60–69

Female, 50–59

Female, 70–79

Female, 80+

0 –10 –20 –30 0

100

Time since stand (seconds) Figure displays mean ± 95% confidence intervals. Finucane et al., Impaired recovery in a large population study: Age related normative changes in phasic orthostatic blood pressure and prevalence of impaired recovery in a large population study: Findings from the Irish Longitudinal Study on Ageing (TILDA) – submitted to Circulation.

syncope and postural orthostatic tachycardia syndrome where there is symptomatic HR increases and instability of BP without syncope.1 Many older patients with OH also have postprandial hypotension. Prevalence of OH in the older-aged community-dwelling adults is 30 %61 and increases to more than 50 % in geriatric ward patients62 making its diagnosis highly relevant. Causes of OH include volume depletion or disturbance of the autonomic nervous system resulting in failure in vasoconstrictor compensatory mechanisms induced by upright posture.63 The prevalence is higher if phasic BP measures are used. In the TILDA population, 50 % of people over 70 years had persistent OH up to 40

Kenny_FINAL.indd 32

Ambulatory BP monitoring in OH patients guides assessment of diurnal variation in BP,1 postprandial hypotension, response to timing of medications and nocturnal supine hypertension.

Management of Orthostatic Hypotension Culprit medications should be modified or eliminated and conservative measures adopted prior to consideration of additional pharmacotherapy.66 Conservative measures include PCM,67 enhanced fluid and salt intake, elevation of the head of bed when sleeping (modifies neuroendocrine control of nocturnal polyuria, redistribution of body fluids and supine hypertension),68,69 compression stockings, abdominal binders70,71 and rapid ingestion of cool water for symptoms of OI and post-prandial hypotension.72 Medications, such as midodrine (an alpha 1 agonist)73–75 and fludrocortisone (a mineralocorticoid that stimulates renal sodium retention and expands intravascular volume), are both well tolerated in the older patient in

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moderate dosages.68 Pyridostigmine, octreotide and desmopressin are adjunct therapies but are less well researched in older patients and less well tolerated in our experience. The combination of SSH and OH poses challenging management decisions as treatment of SSH may worsen symptoms of OH.76 Attention to symptom relief is balanced with treatment of vascular risk associated with SSH.77,78 TILDA researchers reported that beta blockers and anti-depressants were risk factors for OH in people over 50 with SSH.78 Other cardiovascular medications were not associated with OH in people with SSH.

3) Cardiac Syncope One-third of cases of syncope in the older patient are caused by cardiac disorders18 (see Figure 3).21 There is a higher morbidity and mortality associated with cardiac syncope.15,79 Cardiac syncope is characterised by little or no prodrome, occurrence when supine or during exercise and association with palpitations or chest pain.7 However, the older patient may not recall these symptoms. Heart disease is an independent predictor of cardiac syncope – sensitivity 95 % and specificity 45 %;80 the prevalence of cardiac disease, including structural heart disease and arrhythmias, rises dramatically with age as detailed in Figures 2 and 3.20,21,81 Cardiac syncope should be considered when the surface ECG is abnormal or left ventricular systolic dysfunction is present.7

Table 5: Risk Stratification – Short-term High-risk Criteria that Require Prompt Hospitalisation or Intensive Evaluation 1 Severe structural or coronary artery disease (heart failure, low LVEF, or previous myocardial infarction) Clinical or ECG features suggesting arrhythmic syncope • Syncope during exertion or supine • Palpitations associated with syncope • Family history of SCD • Non-sustained VT • Bifascicular-block (LBBB or RBBB combined with left anterior or left posterior fascicular block) or intraventricular conduction abnormalities with QRS duration ≥120ms • Inadequate sinus bradycardia (<50bpm) or sinoatrial block in absence of negative chronotropic medications or physical training • Pre-excited QRS complex • Prolonged or short QT interval • RBBB pattern with ST-elevation in leads V1-V3 (Brugada pattern) • Negative T waves in right precordial leads, epsilon waves and ventricular late potentials suggestive of ARVC Important co-morbidities • Severe anaemia • Electrolyte disturbance ECG = electrocardiogram; L/R BBB = left/right bundle branch block; LVEF = left ventricular ejection fraction; SCD = sudden cardiac death; VT = ventricular tachycardia. With permission from Oxford University Press (UK) (c) European Society of Cardiology (www. escardio.org/guidelines).

Investigation The gold standard for the diagnosis of cardiac syncope is symptomrhythm correlation i.e. contemporaneous HR and rhythm recording during syncope. Cardiac monitoring may also identify diagnostic abnormalities, such as asystole in excess of 3 seconds and rapid supraventricular (SVT) or ventricular tachycardia (VT).82–84 The absence of an arrhythmia during a recorded syncopal event excludes arrhythmia as a cause unless the patient has a dual diagnosis. In patients over 40 years with recurrent unexplained syncope who do not have structural heart disease or abnormal ECG, the attributable cause of syncope is bradycardia in over 50 %.44,85–87

insertion of ILRs in the older person is important to consider in view of the disproportionately high number of cardiac causes of syncope in this group.9 This approach is also more cost-effective.96,97 Difficulties with ILRs include inability to activate the device, particularly if patients have cognitive impairment, however, automated recordings and remote monitoring have much improved diagnostic yield.42 Magnetic resonance imaging (MRI) brain scans are increasingly used for investigation of other symptoms in elderly persons, therefore, MRI compatible devices should always be used.

Echocardiography Cardiac Monitoring Prompt hospital admission or intensive monitoring is recommended when cardiac disease is present in the setting of syncope (see Table 5).1 Although telemetry or in-patient monitoring is indicated if the patient is at high risk of a life-threatening arrhythmia as per ECG abnormalities detailed in Table 5, the diagnostic yield from telemetry is low –16 % in one series.88 Holter monitoring is only indicated if a patient is experiencing episodes of sufficient frequency to detect an abnormality up to 72 hours of recording.1 Diagnostic yield from Holter monitoring is only 1–2 % in unselected populations.1 Incidental arrhythmias are much more common in older persons, for example, atrial fibrillation occurs in one in five men over 80 years.89 External loop recorders have a higher diagnostic yield in older patients; however, some older patients may have difficulty operating the devices,90,91 therefore automated arrhythmia detection is preferred.92 Normal ambulatory ECG (Holter or external loop or otherwise) in the absence of symptoms does not exclude a causal arrhythmia7 and monitoring for longer intervals is imperative to capture rhythm during symptoms.

Echocardiography (ECHO) should be performed in syncope patients in whom a structural abnormality is suspected. The prevalence of structural cardiac abnormalities increases with age.81 The test is of most benefit in older patients with aortic stenosis98 and to evaluate ejection fraction. Cardiac arrhythmias are evident in up to 50 % of patients with an ejection fraction of less than 40 %.99

Ambulatory Blood Pressure Monitoring Patterns of BP behaviour including post-prandial hypotension, hypotension after medication ingestion, orthostatic and exerciseinduced hypotension and SSH can be readily identified by this investigation. Modification of timing of meals and medications is guided by BP patterns.24,100

Exercise Stress Testing Exercise stress testing is indicated to investigate cardiac disease and in patients who present with exercise-induced syncope.1 It is not always possible in older patients who may alternatively require angiography to investigate cardiac status.

Electrophysiological Study Diagnostic rates are much higher in older patients using the ILR,93,94 up to 50 % in patients with syncope and unexplained falls.9,10,95 Early

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Electrophysiological study is indicated in the older non-frail patient with syncope when a cardiac arrhythmia is suspected.24 Diagnosis

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Heart Rhythm Disease Table 6: Recommendations: Treatment of Syncope Due to Cardiac Arrhythmias 1 Recommendations Classa Levelb • Syncope due to cardiac arrhythmias must receive treatment appropriate to the cause I B Cardiac pacing • Pacing is indicated in patients with sinus node disease in whom syncope is demonstrated to be due to sinus arrest

• Pacing is indicated in sinus node disease patients with syncope and abnormal CSNRT

• Pacing is indicated in sinus node disease patients with syncope and asymptomatic pauses ≥ 3 s (with the possible

(symptom – ECG correlation) without a correctable cause

exceptions of young trained persons, during sleep and in medicated patients) • Pacing is indicated in patients with syncope and second degree Mobitz II, advanced or complete AV block

• Pacing is indicated in patients with syncope, BBB, and positive EPS

• Pacing should be considered in patients with unexplained syncope and BBB

IIa

• Pacing may be indicated in patients with unexplained syncope and sinus node disease with persistent sinus bradycardia

IIb

III

IIb

IIa

• ICD is indicated in patients with documented VT and structural heart disease

• ICD is indicated when sustained monomorphic VT is induced at EPS in patients with previous myocardial infarction

• ICD should be considered in patients with documented VT and inherited cardiomyopathies or channelopathies

IIa

itself asymptomatic • Pacing is not indicated in patients with unexplained syncope without evidence of any conduction disturbance Catheter ablation: • Catheter ablation is indicated in patients with symptom – arrhythmia ECG correlation in both SVT and VT in the absence of structural heart disease (with exception of atrial fibrillation) • Catheter ablation may be indicated in patients with syncope due to the onset of rapid atrial fibrillation Antiarrhythmic drug therapy • Antiarrhythmic drug therapy, including rate control drugs, is indicated in patients with syncope due to onset of rapid atrial fibrillation • Drug therapy should be considered in patients with symptom –arrhythmia ECG correlation in both SVT and VT when catheter ablation cannot be undertaken or has failed Implantable cardioverter defibrillator

a – Class of recommendation; b – Level of evidence. AV = atrioventricular; BBB = bundle branch block; CSNRT = corrected sinus node recovery time; ECG = electrocardiogram; EPS = electrophysiological study; ICD = implantable cardioverter defibrillator; SVT = supraventricular tachycardia; VT = ventricular tachycardia. With permission from Oxford University Press (UK) (c) European Society of Cardiology (www.escardio.org/guidelines).

is based on confirmation of an inducible arrhythmia or conduction disturbance.101 The benefit is dependent on pretest probability based on the presence of organic heart disease or an abnormal ECG.102

exhaustion and unintentional weight loss. Frailty is a predictor of falls, hospitalisation, disability and death.103

Unwitnessed Events in the Older Person Electrophysiological study has the advantage of providing both diagnosis and treatment in the same session (i.e. transcatheter ablation).24 It is most effective for identification of sinus node dysfunction in the presence of significant sinus bradycardia of 50 bpm or less; prediction of impending high-degree atrioventricular (AV) block in patients with bifascicular block; inducible monomorphic VT (in patients with previous myocardial infarction [MI]) and inducible SVT with hypotension in patients with palpitations.24

Management of Cardiac Syncope Management of cardiac syncope is dependent on specific cardiac diagnosis as outlined in see Table 6.1

Challenges in the Older Patient

In the older adult a witness account may not be available for falls or syncopal events in up to 40 % of patients.16

Medications, Polypharmacy and Syncope Polypharmacy is more common with advancing age. Some of the most frequently prescribed syncope-related medications used in combination are anti-hypertensives, anti-anginals, anti-histamines, anti-psychotics, tricyclic anti-depressants and diuretics. These cause bradycardia, QT interval prolongation, OH and VVS. Drug interactions can also cause syncope particularly in the older patient with multi-morbidity and polypharmacy.104 A temporal association between onset or change of medication and symptoms may be evident although progression of age-related physiological changes may cause syncope even with longstanding established medication use.24

Frailty As people are living longer, frailty and pre-frailty are more commonly encountered in clinical practice. Frailty is a reduction in the ability to respond to stressors and an increased vulnerability to adverse outcomes.103 There is no consensus on how best to operationalise or define frailty but two types of definitions have emerged as the most commonly used constructs: the Cumulative Burden Index as proposed where frailty is defined as an accumulation of health conditions and deficits, and the ‘Biological Syndrome Model’ as proposed by Fried:103 a person is deemed to be frail if they present with three or more of: poor grip strength, slow walking speed, low levels of physical activity,

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TILDA reported an increased risk and frequency of syncope with use of tricyclic anti-depressants.105 The side effect most frequently reported is hypotension, but bradycardia and tachycardia have also been reported.106,107

Cognition Cognitive impairment rises with age: 20 % of people over 80 years have established dementia,108 rising to 40 % over 90 years.109 Cognitive impairment is characterised by memory problems, attention difficulties and executive dysfunction – hence compliance with cardiac monitoring systems may be compromised.

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Syncope in the Elderly

Cognitive impairment is particularly high in older patients with CSH.55 Likewise, patients with some subtypes of dementia such as Lewy Body dementia55 and Alzheimer’s dementia have a higher prevalence of syncope, OH and CSH.108 Establishing a causal relationship between symptoms and arrhythmia or hypotension is particularly difficult in these patients given that the history is not reliable and events are often unwitnessed.3,6,110 There is emerging evidence that low BP may cause or exaggerate cognitive dysfunction,111 possibly because cerebral hypoperfusion is associated with cerebral damage via small vessel arteriosclerosis and cerebral amyloid angiopathy, as well as exaggerated white matter disease.112

Dual Diagnosis In the older patient multiple causes of syncope may be present including cardiac (bradyarrhythmia, SVT tachyarrhythmias, ventricular tachyarrhythmias, long QT) and reflex syncope or autonomic impairment Table 3.22 Attribution of cause in the context of multiple abnormalities is not always possible, and treatment of all possible causes is recommended. In one series of patients with syncope, mean age 66.5 years ± 18 years; 23 % had a dual diagnosis. The principal predictors of dual diagnosis were advanced age, treatment with alpha-receptor blockers and

1. Moya A, Sutton R, Ammirati F, et al., Guidelines for the diagnosis and management of syncope (version 2009), Eur Heart J , 2009;30(21):2631–71. 2. Kenny RA, Bhangu J, King-Kallimanis BL, Epidemiology of syncope/collapse in younger and older Western patient populations, Prog Cardiovasc Dis , 2013;55(4):357–63. 3. O’Dwyer C, Bennett K, Langan Y, et al., Amnesia for loss of consciousness is common in vasovagal syncope, Europace , 2011;13(7):1040–5. 4. Kenny RA, Syncope in the elderly: diagnosis, evaluation, and treatment, J Cardiovasc Electrophysiol , 2003;14(Suppl. 9):S74–7. 5. Parry SW, Steen IN, Baptist M, Kenny RA, Amnesia for loss of consciousness in carotid sinus syndrome: implications for presentation with falls, J Am Coll Cardiol , 2005;45(11):1840–3. 6. Shaw FE, Kenny RA, The overlap between syncope and falls in the elderly, Postgrad Med J ,1997;73(864):635–9. 7. Marrison VK, Fletcher A, Parry SW, The older patient with syncope: practicalities and controversies, Int J Cardiol , 2012;155(1):9–13. 8. Kerr SR, Pearce MS, Brayne C, et al., Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls, Arch Intern Med , 2006;166(5):515–20. 9. Brignole M, Menozzi C, Maggi R, et al., The usage and diagnostic yield of the implantable loop-recorder in detection of the mechanism of syncope and in guiding effective antiarrhythmic therapy in older people, Europace , 2005;7(3):273–9. 10. Ruwald MH, Lock Hansen M, Lamberts M, et al., Unexplained Syncope and Diagnostic Yield of Tests in Syncope According to the ICD-10 Discharge Diagnosis, J Clin Med Res , 2013;5(6):441–50. 11. Linzer M, Pontinen M, Gold DT, et al., Impairment of physical and psychosocial function in recurrent syncope, J Clin Epidemiol , 1991;44(10):1037–43. 12. van Dijk N, Sprangers MA, Colman N, et al., Clinical factors associated with quality of life in patients with transient loss of consciousness, J Cardiovasc Electrophysiol, 2006;17(9):998–1003. 13. Santhouse J, Carrier C, Arya S, et al., A comparison of selfreported quality of life between patients with epilepsy and neurocardiogenic syncope, Epilepsia , 2007;48(5):1019–22. 14. Wieling W, Ganzeboom KS, Krediet CT, et al., [Initial diagnostic strategy in the case of transient losses of consciousness: the importance of the medical history], Ned Tijdschr Geneeskd , 2003;147(18):849–54. 15. Soteriades ES, Evans JC, Larson MG, et al., Incidence and prognosis of syncope, N Engl J Med , 2002;347(12):878–85. 16. McIntosh S, Da Costa D, Kenny RA, Outcome of an integrated approach to the investigation of dizziness, falls and syncope in elderly patients referred to a ‘syncope’ clinic, Age Ageing , 1993;22(1):53–8. 17. Olde Nordkamp LR, van Dijk N, Ganzeboom KS, et al., Syncope prevalence in the ED compared to general practice and population: a strong selection process, Am J Emerg Med , 2009;27(3):271–9. 18. Del Rosso A, Alboni P, Brignole M, et al., Relation of clinical

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benzodiazepines. The most frequent dual diagnoses were OH and VVS: 2.8 % had a triple diagnosis, and these were the oldest old.28

Focal Neurology with Syncope Transient ischaemic attacks or stroke and syncope are considered mutually exclusive presentations. However, one recent series reported that 5.7 % of syncope patients experienced focal neurological events at the time of syncope or pre-syncope. Awareness of this phenomenon is important to prevent misdiagnosis of stroke and inappropriate increase of anti-hypertensive medications, which would further exacerbate hypotensive symptoms.113,114

Conclusion/Summary One of the greatest achievements of public health in the twentieth century has been the almost doubling of life expectancy in the Western world. Healthcare professionals are increasingly treating more old and very old patients. The prevalence of syncope rises with age and is challenging because of atypical presentation, overlap with falls and poor recall of events. Elders are less likely to have a prodrome, may have amnesia for loss of consciousness and unwitnessed events. Cardiac causes and dual pathology are more common and compliance with newer monitoring technologies is inadequate. Consequent morbidity and mortality is higher than in younger patients. A high index of suspicion for cardiovascular causes of falls and dual pathology will increase diagnosis and early targeted intervention. n

presentation of syncope to the age of patients, Am J Cardiol , 2005;96(10):1431–5. 19. Ungar A, Mussi C, Del Rosso A, et al., Diagnosis and characteristics of syncope in older patients referred to geriatric departments, J Am Geriatr Soc , 2006;54(10):1531–6. 20. Go AS, Mozaffarian D, Roger VL, et al., Heart disease and stroke statistics – 2013 update: a report from the American Heart Association, Circulation , 2013;127(1):e6-e245. 21. Parry SW, Tan MP, An approach to the evaluation and management of syncope in adults, BMJ , 2010;340:c880. 22. Chen LY, Gersh BJ, Hodge DO, et al., Prevalence and clinical outcomes of patients with multiple potential causes of syncope, Mayo Clin Proc , 2003;78(4):414–20. 23. Romme JJ, van Dijk N, Boer KR, et al., Influence of age and gender on the occurrence and presentation of reflex syncope, Clin Auton Res , 2008;18(3):127–33. 24. Tan MP, Kenny RA, Cardiovascular assessment of falls in older people, Clin Interv Aging , 2006;1(1):57–66. 25. Colman N, Nahm K, Ganzeboom KS, et al., Epidemiology of reflex syncope, Clin Auton Res , 2004;14(Suppl. 1):9-17. 26. Overstall P, Drop attacks. In: Syncope in the Older Patients: Causes, Investigations and Conequences of Syncope and Falls, London, UK: Chapman & Hall Medical, 1996;299–308. 27. Parry SW, Reeve P, Lawson J, et al., The Newcastle protocols 2008: an update on head-up tilt table testing and the management of vasovagal syncope and related disorders, Heart , 2009;95(5):416–20. 28. Rafanelli M, Morrione A, Landi A, et al., Neuroautonomic evaluation of patients with unexplained syncope: incidence of complex neurally mediated diagnoses in the elderly, Clin Interv Aging , 2014;9:333–9. 29. Freeman R, Wieling W, Axelrod FB, et al., Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome, Clin Auton Res, 2011;21(2):69–72. 30. Duncan GW, Tan MP, Newton JL, et al., Vasovagal syncope in the older person: differences in presentation between older and younger patients, Age Ageing , 2010;39(4):465–70. 31. Alboni P, Brignole M, Degli Uberti EC, Is vasovagal syncope a disease?, Europace , 2007;9(2):83–7. 32. Alboni P, Brignole M, Menozzi C, et al., Clinical spectrum of neurally mediated reflex syncopes. Europace , 2004;6(1):55–62. 33. Graham LA, Kenny RA, Clinical characteristics of patients with vasovagal reactions presenting as unexplained syncope, Europace , 2001;3(2):141–6. 34. Tan MP, Parry SW, Vasovagal syncope in the older patient, J Am Coll Cardiol , 2008;51(6):599–606. 35. Grubb BP, Karas B, Diagnosis and management of neurocardiogenic syncope, Curr Opin Cardiol , 1998;13(1):29–35. 36. Kenny RA, Ingram A, Bayliss J, Sutton R, Head-up tilt: a useful test for investigating unexplained syncope, Lancet , 1986;1(8494):1352–5. 37. Kenny RA, O’Shea D, Parry SW, The Newcastle protocols for head-up tilt table testing in the diagnosis of vasovagal syncope, carotid sinus hypersensitivity, and related disorders, Heart , 2000;83(5):564–9.

38. Shaw FE, Bond J, Richardson DA, et al., Multifactorial intervention after a fall in older people with cognitive impairment and dementia presenting to the accident and emergency department: randomised controlled trial, BMJ , 2003;326(7380):73. 39. Parry SW, Gray JC, Newton JL, et al., ‘Front-loaded’ head-up tilt table testing: validation of a rapid first line nitrateprovoked tilt protocol for the diagnosis of vasovagal syncope, Age Ageing , 2008;37(4):411–5. 40. Bartoletti A, Alboni P, Ammirati F, et al., ‘The Italian Protocol’: a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace , 2000;2(4):339–42. 41. Brignole M, Menozzi C, Del Rosso A, et al., New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Vasovagal Syncope International Study, Europace , 2000;2(1):66–76. 42. Parry SW, Matthews I, The implantable loop recorder in older patients with syncope: is sooner better?, Age Ageing , 2010;39(3):284–5. 43. Brignole M, Sutton R, Menozzi C, et al., Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope, Eur Heart J , 2006;27(18):2232–9. 44. Brignole M, Sutton R, Menozzi C, et al., Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope, Eur Heart J , 2006;27(9):1085–92. 45. Brignole M, Donateo P, Tomaino M, et al., Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3), Circ Arrhythm Electrophysiol , 2014;7(1):10–6. 46. Brignole M, Menozzi C, Moya A, et al., Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial, Circulation , 2012;125(21):2566–71. 47. Parry SW, Matthews IG, Update on the role of pacemaker therapy in vasovagal syncope and carotid sinus syndrome, Prog Cardiovasc Dis , 2013;55(4):434–42. 48. Mathias CJ, Young TM, Water drinking in the management of orthostatic intolerance due to orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome, Eur J Neurol , 2004;11(9):613–9. 49. Tan MP, Newton JL, Chadwick TJ, et al., Home orthostatic training in vasovagal syncope modifies autonomic tone: results of a randomized, placebo-controlled pilot study, Europace , 2010;12(2):240–6. 50. Epstein AE, DiMarco JP, Ellenbogen KA, et al., ACC/AHA/ HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/

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Heart Rhythm Disease AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons, Circulation , 2008;117(21):e350–408. 51. Sutton R, Ungar A, Sgobino P, et al., Cardiac pacing in patients with neurally mediated syncope and documented asystole: effectiveness analysis from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3) Registry, Europace, 2014;16(4):595–9. 52. Parry SW, Kenny RA, Drop attacks in older adults: systematic assessment has a high diagnostic yield, J Am Geriatr Soc , 2005;53(1):74–8. 53. Krediet CT, Parry SW, Jardine DL, et al., The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive?, Europace , 2011;13(1):14–22. 54. Wieling W, Thijs RD, van Dijk N, et al., Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain , 2009;132(Pt 10):2630–42. 55. Kenny RA, Shaw FE, O’Brien JT, et al., Carotid sinus syndrome is common in dementia with Lewy bodies and correlates with deep white matter lesions, J Neurol Neurosurg Psychiatry , 2004;75(7):966–71. 56. Ballard C, O’Brien J, Barber B, et al., Neurocardiovascular instability, hypotensive episodes, and MRI lesions in neurodegenerative dementia, Ann N Y Acad Sci , 2000;903:442–5. 57. McIntosh SJ, Lawson J, Kenny RA, Clinical characteristics of vasodepressor, cardioinhibitory, and mixed carotid sinus syndrome in the elderly, Am J Med , 1993;95(2):203–8. 58. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons, J Am Geriatr Soc , 2011;59(1):148–57. 59. Brignole M, Menozzi C, Lolli G, et al., Long-term outcome of paced and nonpaced patients with severe carotid sinus syndrome, Am J Cardiol , 1992;69(12):1039–43. 60. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology, Neurology , 1996;46(5):1470. 61. Luukinen H, Koski K, Laippala P, Kivela SL, Prognosis of diastolic and systolic orthostatic hypotension in older persons, Arch Intern Med , 1999;159(3):273–80. 62. Vloet LC, Pel-Little RE, Jansen PA, Jansen RW, High prevalence of postprandial and orthostatic hypotension among geriatric patients admitted to Dutch hospitals, J Gerontol A Biol Sci Med Sci , 2005;60(10):1271–7. 63. Mussi C, Ungar A, Salvioli G, et al., Orthostatic hypotension as cause of syncope in patients older than 65 years admitted to emergency departments for transient loss of consciousness, J Gerontol A Biol Sci Med Sci , 2009;64(7):801–6. 64. Frewen J, Finucane C, Savva GM, et al., Orthostatic Hypotension Is Associated With Lower Cognitive Performance in Adults Aged 50 Plus With Supine Hypertension, J Gerontol A Biol Sci Med Sci , 2014;69(7):878–85. 65. Linzer M, Yang EH, Estes NA, 3rd, et al., Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Clinical Efficacy Assessment Project of the American College of Physicians, Ann Intern Med , 1997;126(12):989–96. 66. Low PA, Singer W, Management of neurogenic orthostatic hypotension: an update, Lancet neurology , 2008;7(5):451–8. 67. van Lieshout JJ, ten Harkel AD, Wieling W, Physical manoeuvres for combating orthostatic dizziness in autonomic failure, Lancet , 1992;339(8798):897–8. 68. van Lieshout JJ, ten Harkel AD, Wieling W, Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure, Clin Auton Res , 2000;10(1):35–42. 69. Omboni S, Smit AA, van Lieshout JJ, et al., Mechanisms underlying the impairment in orthostatic tolerance after nocturnal recumbency in patients with autonomic failure, Clin Sci (Lond) , 2001;101(6):609–18. 70. Podoleanu C, Maggi R, Brignole M, et al., Lower

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limb and abdominal compression bandages prevent progressive orthostatic hypotension in elderly persons: a randomized single-blind controlled study, J Am Coll Cardiol , 2006;48(7):1425–32. 71. Smit AA, Wieling W, Fujimura J, et al., Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction, Clin Auton Res , 2004;14(3):167–75. 72. Schroeder C, Bush VE, Norcliffe LJ, et al., Water drinking acutely improves orthostatic tolerance in healthy subjects, Circulation , 2002;106(22):2806–11. 73. Jankovic J, Gilden JL, Hiner BC, et al., Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine, Am J Med , 1993;95(1):38–48. 74. Low PA, Gilden JL, Freeman R, et al., Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group, JAMA , 1997;277(13):1046–51. 75. Wright RA, Kaufmann HC, Perera R, et al., A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension, Neurology , 1998;51(1):120–4. 76. Naschitz JE, Slobodin G, Elias N, Rosner I, The patient with supine hypertension and orthostatic hypotension: a clinical dilemma, Postgrad Med J , 2006;82(966):246–53. 77. Kearney F, Moore A, Treatment of combined hypertension and orthostatic hypotension in older adults: more questions than answers still remain, Expert Rev Cardiovasc Ther , 2009;7(6):557–60. 78. Romero-Ortuno R, O’Connell MD, Finucane C, et al., Insights into the clinical management of the syndrome of supine hypertension – orthostatic hypotension (SH-OH): the Irish Longitudinal Study on Ageing (TILDA), BMC Geriatr , 2013;13:73. 79. Kapoor WN, Karpf M, Wieand S, et al., A prospective evaluation and follow-up of patients with syncope, N Engl J Med , 1983;309(4):197–204. 80. Alboni P, Brignole M, Menozzi C, et al., Diagnostic value of history in patients with syncope with or without heart disease, J Am Coll Cardiol , 2001;37(7):1921–8. 81. Aronow WS, Ahn C, Kronzon I, Echocardiographic findings associated with atrial fibrillation in 1,699 patients aged > 60 years, Am J Cardiol , 1995;76(16):1191–2. 82. Krahn AD, Klein GJ, Yee R, Skanes AC, Detection of asymptomatic arrhythmias in unexplained syncope, Am Heart J , 2004;148(2):326–32. 83. Ermis C, Zhu AX, Pham S, et al., Comparison of automatic and patient-activated arrhythmia recordings by implantable loop recorders in the evaluation of syncope, Am J Cardiol , 2003;92(7):815–9. 84. Moya A, Brignole M, Sutton R, et al., Reproducibility of electrocardiographic findings in patients with suspected reflex neurally-mediated syncope, Am J Cardiol , 2008;102(11):1518–23. 85. Moya A, Brignole M, Menozzi C, et al., Mechanism of syncope in patients with isolated syncope and in patients with tiltpositive syncope, Circulation , 2001;104(11):1261–7. 86. Solano A, Menozzi C, Maggi R, et al., Incidence, diagnostic yield and safety of the implantable loop-recorder to detect the mechanism of syncope in patients with and without structural heart disease, Eur Heart J , 2004;25(13):1116–9. 87. Pezawas T, Stix G, Kastner J, et al., Implantable loop recorder in unexplained syncope: classification, mechanism, transient loss of consciousness and role of major depressive disorder in patients with and without structural heart disease, Heart , 2008;94(4):e17. 88. Croci F, Brignole M, Alboni P, et al., The application of a standardized strategy of evaluation in patients with syncope referred to three syncope units, Europace , 2002;4(4):351–5. 89. Frewen J, Finucane C, Cronin H, et al., Factors that influence awareness and treatment of atrial fibrillation in older adults, QJM , 2013;106(5):415–24. 90. Rockx MA, Hoch JS, Klein GJ, et al., Is ambulatory monitoring for “community-acquired” syncope economically attractive? A cost-effectiveness analysis of a randomized trial of external loop recorders versus Holter monitoring, Heart , 2005;150(5):1065.

91. Sivakumaran S, Krahn AD, Klein GJ, et al., A prospective randomized comparison of loop recorders versus Holter monitors in patients with syncope or presyncope, Am J Med , 2003;115(1):1–5. 92. Balmelli N, Naegeli B, Bertel O, Diagnostic yield of automatic and patient-triggered ambulatory cardiac event recording in the evaluation of patients with palpitations, dizziness, or syncope, Clin Cardiol , 2003;26(4):173–6. 93. Farwell DJ, Freemantle N, Sulke AN, Use of implantable loop recorders in the diagnosis and management of syncope, Eur Heart J , 2004;25(14):1257–63. 94. Krahn AD, Klein GJ, Yee R, et al., Use of an extended monitoring strategy in patients with problematic syncope. Reveal Investigators, Circulation , 1999;99(3):406–10. 95. Armstrong VL, Lawson J, Kamper AM, et al., The use of an implantable loop recorder in the investigation of unexplained syncope in older people, Age Ageing , 2003;32(2):185–8. 96. Benditt DG, Ermis C, Pham S, et al., Implantable diagnostic monitoring devices for evaluation of syncope, and tachy- and brady-arrhythmias, J Interv Card Electrophysiol, 2003;9(2):137–44. 97. Krahn AD, Klein GJ, Yee R, et al., Cost implications of testing strategy in patients with syncope: randomized assessment of syncope trial, J Am Coll Cardiol , 2003;42(3):495–501. 98. Omran H, Fehske W, Rabahieh R, et al., Valvular aortic stenosis: risk of syncope, J Heart Valve Dis , 1996;5(1):31–4. 99. Sarasin FP, Junod AF, Carballo D, et al., Role of echocardiography in the evaluation of syncope: a prospective study, Heart , 2002;88(4):363–7. 100. Senard JM, Chamontin B, Rascol A, Montastruc JL, Ambulatory blood pressure in patients with Parkinson’s disease without and with orthostatic hypotension, Clin Auton Res, 1992;2(2):99–104. 101. Lu J, Lu Z, Voss F, Schoels W, Results of invasive electrophysiologic evaluation in 268 patients with unexplained syncope, J Huazhong Univ Sci Technolog Med Sci , 2003;23(3):278–9. 102. Linzer M, Yang EH, Estes NA, 3rd, et al., Diagnosing syncope. Part 2: Unexplained syncope. Clinical Efficacy Assessment Project of the American College of Physicians, Ann Intern Med , 1997;127(1):76–86. 103. Fried LP, Tangen CM, Walston J, et al., Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56(3):M146–56. 104. Gaeta TJ, Fiorini M, Ender K, et al., Potential drug–drug interactions in elderly patients presenting with syncope, J Emerg Med , 2002;22(2):159–62. 105. Bhangu JS, King-Kallimanis B, Cunningham C, Kenny RA, The relationship between syncope, depression and antidepressant use in older adults, Age Ageing , 2014;43(4):502–9. 106. Kremastinos DT, Cardiogenic syncope and serotonin reuptake inhibitors, Hellenic J Cardiol , 2008;49(5):375–6. 107. Vieweg WV, Wood MA, Fernandez A, et al., Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging , 2009;26(12):997–1012. 108. Ballard C, Shaw F, McKeith I, Kenny R, High prevalence of neurovascular instability in neurodegenerative dementias, Neurology , 1998;51(6):1760–2. 109. Lobo A, Launer LJ, Fratiglioni L, et al., Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group, Neurology , 2000;54(11):S4–9. 110. Cummings SR, Nevitt MC, Kidd S, Forgetting falls. The limited accuracy of recall of falls in the elderly, J Am Geriatr Soc , 1988;36(7):613–6. 111. Frewen J, Savva GM, Boyle G, et al., Cognitive performance in orthostatic hypotension: findings from a nationally representative sample, J Am Geriatr Soc , 2014;62(1):117–22. 112. O’Sullivan M, Lythgoe DJ, Pereira AC, et al., Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis, Neurology , 2002;59(3):321–6. 113. Roughton M, Campbell JT, Kavanagh SJ, et al., Stroke, Age Ageing , 2013;42(Suppl. 2):ii31–ii2. 114. R yan DJ, Mahon O, Kenny RA, Harbison JA, Focal neurology occurs with syncope and presyncope, Cerebrovasc Dis , 2013;35(Suppl. 3):172.

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Heart Failure

le ation.

Diabetes Mellitus and Heart Failure Dimitris T ousoulis, Ev a ng elos O i k o n o m o u , G e r a s i m o s S i a s o s a n d Ch r i s t o d o u l o s S t e f a n a d is 1st Cardiology Department, University of Athens Medical School, “Hippokration” Hospital, Athens, Greece

Abstract Diabetes mellitus and heart failure are two multifaceted entities characterised by high morbidity and mortality. Early epidemiological and prospective studies have observed the frequent co-existence of both conditions. Importantly, diabetes mellitus can precipitate or worsen heart failure due to the accumulation of advanced glycation end products, oxidative stress, inflammatory status impairment, decay of intracellular calcium, changes in microRNAs expression, not to mention atherosclerosis progression and coronary artery disease. Heart failure also impairs glucose metabolism through less well-known mechanisms. Attention must especially be given in the treatment as there are frequently adverse interactions between the two diseases and novel agents against diabetic cardiomyopathy are under investigation. As several missing links still exist in the connection between heart failure and diabetes mellitus we will review, in this article, the most recent data underlying the interaction of them and provide an overview of the most important clinical perspectives.

Keywords Diabetes mellitus, heart failure, treatment, oxidative stress, inflammation, pathophysiology Disclosure: The authors have no conflicts of interest to declare. Received: 24 April 2014 Accepted: 13 June 2014 Citation: European Cardiology Review, 2014;9(1):37–42 Correspondence: Dimitris Tousoulis, 1st Cardiology Department, University of Athens Medical School, Vasilissis Sofias 114, TK 115 28, “Hippokration” Hospital, Athens, Greece. E: drtousoulis@hotmail.com

Diabetes mellitus (DM) is a group of diseases characterised by metabolic disturbances with increasing prevalence worldwide.1 Individuals with DM present several detrimental micro- and macrovascular complications such as retinopathy, nephropathy, neuropathy, atherosclerosis and coronary heart disease.2,3 Accordingly, efforts for early diagnosis and appropriate management are of ultimate importance. Despite the emphasis by clinicians in the prompt control of DM several cardiovascular diseases such as hypertension, coronary heart disease, stroke, peripheral vascular disease, etc., have been linked to impaired glucose management.4 Recently, the awareness in the scientific community of the two-way association between DM and heart failure (HF) has steadily increased and has gained research interest. HF is a syndrome with a complex pathophysiology, several aetiologies and different clinical presentations characterised by high morbidity and mortality.5–7 According to some reports the co-existence of HF and DM is as high as almost 40 %,8 growing the necessity for more in-depth understanding of the common pathophysiological pathways and for effective management of both entities. As several missing links still exist in the connection between HF and DM we review in this article the most recent data underlying the interaction between them and provide an overview of the most important clinical perspectives.

Diabetes Mellitus and Heart Failure – A Bidirectional Relationship From Diabetes Mellitus to Heart Failure The concept that DM can cause or precipitate HF has been generated even from the Framingham study who estimated that men and

Tousoulis_FINAL.indd 37

women with DM have a two and four times, respectively, increased risk to develop HF compared with non-DM subjects.9 Epidemiological studies have confirmed this relationship and revealed that impaired glucose tolerance, increased serum glucose levels and glycated haemoglobin levels are associated not only with incidence of systolic HF but also with the prevalence of diastolic dysfunction (see Table 1). Accordingly, guidelines have accepted DM and metabolic syndrome as risk factors for HF,17 and the term diabetic cardiomyopathy was used to define either systolic or diastolic left ventricular dysfunction in otherwise healthy diabetic persons in the absence of clinically significant coronary, valvular or hypertensive disease.18 Thus, patients with DM can be categorised in the stage A of the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) classification of HF, meaning that diabetic subjects are at high-risk for HF but without structural heart disease or symptoms of HF. Therapeutic interventions aim to modify risk factors and guidelines draw attention to monitor and treat DM as early as possible.17

Pathophysiological Connections Despite the close relationship of these two conditions the difficulties in making a causal pathophysiological connection between DM and HF are formidable as we have to distinguish between insulin deficient and insulin resistant DM and between systolic HF, diastolic HF or HF caused by other aetiologies such as conduction disturbances, tachycardiomyopathy, HF of valvular aetiology, etc. (see Figure 1). Advanced glycation end products, which are formed in DM subjects after non-enzymatic reaction between protein and sugar residues, can possibly explain the link between DM and HF.19 Advanced glycation end

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Heart Failure Table 1: Studies Examined the Association between Diabetes Mellitus and Heart Failure Study/Author Nichols et al. 200410

Design Retrospective cohort

Iribarren et al. 200111

Prospective cohort (2.2 years

Subjects 8,231 patients with DM and

Results The incidence rate of HF in DM subjects

8,845 non-DM patients

was 3 times that of non-DM

49.000 DM patients

Increased levels were associated with greater risk of HF

4,585 DM patients

In type 2 DM patients the risk of diabetic complications and

follow-up) Stratton et al. 2000

Prospective observational

(UKPDS 35)12

study

Matsushita et al. 2010 (ARIC

Prospective cohort

11.000 subjects free of DM

Elevated HbA1c (≥5.5–6.0 %) was associated with

study)13

(14.1 years follow-up)

or HF at baseline

incident HF

He et al. 2001 (NHANES I)14

Prospective cohort (19 years

13.643 subjects without HF

DM is an independent risk factor for HF (relative risk 1.85)

605 patients with type 2 DM

HF (28 %) and left ventricular dysfunction (23 %) are highly

HF was strongly associated with previous hyperglycaemia

follow-up) Boonman-de Winter et

Cross-sectional study

al. 201215 Vasilliadis et al. 2014 Bertoni et al. 200416

prevalent in DM patients 8

Cross-sectional

200 HF patients

From HF subjects 27 % had type 2 DM and 10 % type 1 DM

Prospective cohort study

151.000 DM subjects over 65

The incidence rate of HF was estimated at 12.6 per 100

(5 years follow-up)

years old

person-years

ARIC = Atherosclerosis Risk in Community; DM = diabetes mellitus; HbA1c = glycated haemoglobin; HF = heart failure; NHANES I = First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study; UKPDS = UK Prospective Diabetes Study.

Figure 1: Schematic Depiction of the Bidirectional Relationship between Diabetes Mellitus and Heart Failure Diabetes Mellitus

Diabetic Cardiomyopathy

Bidirectional relationship

• • • • • •

Undiagnosed DM at early stages of HF Metabolic effects of diuretics Metabolic effects of β-blockers Hypoperfusion and congestion of pancreas and liver Increased catecholamines levels, sympathetic activity Decrease physical activity

• • • • • • • • • •

Advanced glycation end products Fibrosis Increased fatty acid utilisation Mitochondrial dysfunction Oxidative stress Inflammation microRNAs Mitochondrial dysfunction Impaired calcium accumulation Epigenetics

DM = diabetes mellitus; HF = heart failure.

products are increased in patients with chronic HF, they correlate inversely with left ventricular ejection fraction and are related to the severity and prognosis of the disease.20,21 Advanced glycation end products upregulate the hypertrophy-associated genes in cardiomyocytes via the activation of dendritic cells and may be responsible for the hypertrophic and fibrotic phenotype in DM subjects.22 A plethora of other mechanisms have also been proposed. Diabetes-related alterations in the expressions of some calciumassociated proteins may lead to progressive intracellular decay of calcium and in the development of diabetic cardiomyopathy.23 In rats with diabetic cardiomyopathy there are also decreased serum and myocardial levels of adiponectin implying a possible connection between this anti-inflammatory protein and HF.24 Hearts in humans with DM are characterised by increased fatty acid metabolism and oxidation, which is considered a pathophysiological mechanism in the development of HF.25 Moreover, animal studies have revealed increased myocardial levels of cardiotoxic inflammatory cytokines (tumour necrosis factor-alpha, intereukin-6, etc.) in diabetic models.26

Tousoulis_FINAL.indd 38

Hyperinsulinaemia also impairs phosphatidylinositol 3-kinases pathway and can precipitate myocardial dysfunction.27 Furthermore, accumulation of reactive oxygen species affects the coronary circulation and causes myocardial hypertrophy and fibrosis.28 Carbonic anhydrases have been shown to play a major role in diabetic microangiopathy. Recently, carbonic anhydrases I and II were found elevated in myocardial tissues from post-infarction HF patients with DM. They can induce cardiomyocyte hypertrophy and death in vitro, which are prevented by sodium-hydrogen exchanger-1 inhibition.29 MicroRNAs are also differentially expressed in myocardial tissues from subjects with diabetic cardiomyopathy compared with non-diabetic HF, and specific patterns have been recognised.30–32 These data may provide new targeted treatment of diabetic HF. We also notice that diabetes frequently precedes coronary heart disease,33 chronic kidney disease34 and hypertension,35 which are major risk factors and account for the majority of HF cases,5 further explaining the close relationship between DM and HF observed in epidemiological studies.

Clinical and Epidemiological Connections Further to pathophysiological connections, several clinical data have confirmed the detrimental impact of DM in HF course and prognosis. DM predicts readmissions of HF patients36 and increases mortality in subjects with left ventricular dysfunction.37 Elevated troponin levels in patients with DM are also associated with increased HF and cardiovascular mortality.38 Recently, it was also confirmed that DM can be used in a model to predict chronic HF patients at risk of hospitalisation.39 Moreover, in patients with type 2 DM, glycated haemoglobin significantly predicts future HF hospitalisation independently of baseline b-type natriuretic peptide (BNP) level or echocardiographic parameters.40

From Heart Failure to Diabetes Mellitus The dual nature of the relationship of HF and DM is supported by prospective cohort studies. DM was developed in 29 % of HF subjects compared with 18 % of matched control subjects during a three-year follow-up study.41 Moreover, in a cohort of 50.874 patients, HF severity (as determined by loop diuretic dosages) predicts the risk of developing diabetes after myocardial infarction.42

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Nevertheless, the mechanisms precipitating DM and HF are not well-studied. Firstly, we have to notice the possibility that the increased incidence of DM during the course of HF may be an epiphenomenon of the lenient monitoring for impaired glucose metabolism, with glycated haemoglobin and with oral glucose tolerance tests in the early stages of HF. Accordingly, guidelines emphasise the importance of proper diagnosis of DM in HF subjects.5 We can also hypothesise that the decreased physical activity in HF patients may lead to decreased insulin sensitivity and to compensatory insulin requirements and hyperglycaemia. In addition, increased catecholamines levels and sympathetic activity stimulate gluconeogenesis and glycogenolysis.43 Indeed, there is a decrease in insulin sensitivity according to New York Heart Association (NYHA) functional status of HF patients.44 Furthermore we can hypothesise that the haemodynamic consequences accompanying HF (decreased forward blood flow and increased central venous pressure) lead to hypoperfusion and congestion of the pancreas and liver, which may impair their ability to regulate metabolic homeostasis. Confirmatory data are provided by a recent study, which concludes that left ventricular assist devices improve blood glucose control in DM patients.45 Finally, we have to notice the possible adverse effects of established HF treatments, such as beta (β)-blockers and diuretics in blood glucose control. 46

Table 2: Key Points in the Management of Heart Failure in Patients with Diabetes Mellitus Diuretics

• Diuretics increase the incidence of DM51 • Loop diuretics may be better tolerated, as thiazides promote hyperglycaemia52

β-blockers

• Precipitate DM46 • Carvedilol and nebivolol with vasodilating actions are less metabolic effective53,54 • MERIT HF trial has shown that metoprolol improves survival similarly to DM and non-DM patients55

Mineralocorticoid receptor antagonists

• EPHESUS study has shown that in post-myocardial infraction patients with DM eplerenone decreases mortality56 • Especially attention must be given to renal function and hyperkalaemia

DM = diabetes mellitus; EPHESUS = Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; MERIT HF = Metoprolol Randomized Intervention Trial in Congestive Heart Failure.

Table 3: Key Points in the Management of Diabetes Mellitus in Patients with Heart Failure • Glycaemic control is of major importance in DM patients with HF57 • Intensive treatment with HbA1c target ≤6.5 % increased side effects and failed to influence macrovascular complication58,59 Thiazolidinediones

• Induce sodium retention and HF, and must be avoided in HF patients60 • Novel selective PRAPγ modulators free of sodium

Diabetes Mellitus and Heart Failure Diagnosis As HF diagnosis is based on the combination of clinical data and diagnostic tests, BNP levels can help to distinguish between cardiac and non-cardiac causes of acute dyspnoea in the emergency department.47 BNP levels and reference limits can be affected by several factors such as age, obesity, renal impairment, etc.48 Nevertheless, data from the Breathing Not Properly Multinational Trial suggest that diabetes status is not a confounding variable to be considered when interpreting BNP concentrations in patients who present acutely with dyspnoea.47 However, in asymptomatic diabetic patients there was no significant difference among non-HF patients, HF patients and those with a HF history,49 and no conclusions could be rendered as to the role of BNP testing for screening asymptomatic diabetic patients for left ventricular dysfunction because the degree of disease severity among the diabetic patients could not be assessed. Therefore, in the diagnostic work-up of diabetic patients presented not emergently in primary care centres, we must follow the diagnostic algorithm proposed by the guidelines, which emphasises that patients with high pre-test likelihood of HF may be referred directly for echocardiography.5 Moreover, clinicians should not overlook that DM patients with stable coronary heart disease may present with atypical symptoms, such as shortness of breath. Accordingly, we must be cautious in the interpretation of dyspnoea in these patients.50

retention are now tested in preclinical trials61 Incretins

• In animal with dilated cardiomyopathy infusion of glucagon-like peptide-1 improved left ventricle function and stroke volume62,63 • In HF patients glucagon-like peptide-1 improved ejection fraction64

Metformin

• The risk of lactic acidosis does not seem to be of clinical significance65,66

Sulphonylureas

• Neutral effect concerning HF66

Insulin

• Neutral effect concerning HF67

DM = diabetes mellitus; HbA1c = glycated haemoglobin; HF = heart failure; PRAPγ = peroxisome proliferator-activated receptor gamma.

Heart Failure Treatment – Interaction with Diabetes Mellitus Diuretics Diuretics, especially furosemide, are one of the most useful treatments in HF patients for symptom relief and are used to achieve euvolaemia.5 Data from studies and meta-analyses (mostly in hypertensive subjects) suggest an association between incident diabetes and diuretics.46 Hypokalaemia, changes in autonomic nervous system function, in beta (β)-cell insulin release and in insulin’s peripheral effects are the proposed mechanisms.51,68 Accordingly, in HF patients under diuretic treatment attention to keep potassium levels and glycaemic status under control must be attained. Thiazides have been shown to promote hyperglycaemia and loop diuretics may be better tolerated in DM patients.52

Management of Heart Failure and Diabetes Mellitus

Beta-blockers

As both entities (HF and DM) are characterised by high morbidity and mortality, efforts for the best possible management must be taken. Nevertheless, treatment of HF may adversely interact with DM and vice versa (see Tables 2 and 3).

Beta (β)-blockers especially when they are combined with diuretics can precipitate DM.46 Newer β-blockers with vasodilating actions, such as carvedilol and nebivolol, are less metabolic effective compared with metoprolol, do not affect glycaemic control and improve some

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Heart Failure Table 4: Non-conventional and Experimental Treatment of Diabetic Cardiomyopathy Superoxide dismutase

Transgenic mice with DM expressing cardiac specific superoxide dismutase have shown improvement in cardiac remodeling and left ventricle function77

Coenzyme Q10

Effectively targets reactive oxygen species in diabetic mice and prevented effectively diabetic cardiomyopathy78

Phosphoinositide 3-kinase

In transgenic mice prevented diabetesinduced cardiomyopathy79

Omega-3 (n-3) polyunsaturated

Improved ejection fraction in a rat model

fatty acids

of DM80

B-type natriuretic peptide

Chronic treatment at low doses improved the metabolic profile and prevented the development of myocardial dysfunction in obese diabetic mice81

p38 MAPK

Inhibition of p38 MAPK by SB203580 (a pharmacological inhibitor) prevented cardiac inflammation and attenuated left ventricular dysfunction in a mouse model of diabetic cardiomyopathy82

DM = diabetes mellitus; MAPK = mitogen-activated protein kinase.

components of the metabolic syndrome through improvement of the oxidative stress, insulin sensitivity and adiponectin levels.53,54. Vasodilating b-blockers increase survival in HF patients5 and should be preferred in patients with DM. Another β-blocker that can improve survival and symptoms in HF is metoprolol. Although it adversely affects insulin sensitivity, the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial has shown that it can reduce mortality and HF symptoms similar to DM and non-DM patients.55 A recent prospective study in HF patients with DM also concluded that metoprolol is highly safe and tolerable, and can remarkably improve the clinical status of the patients.69

control can be achieved with glucose lowering drugs of different categories and it seems that there are differences in the way that they affect HF. Nevertheless, most data are based on observational studies. Randomised control trials exist only for thiazolidinediones.

Thiazolidinediones Thiazolidinediones are peroxisome proliferator-activated receptor gamma (PRARγ) agonists, which can induce sodium retention and HF. This effect results from the increase in tubular sodium and water reabsorption in specific nephron segments or from stimulation of sodium reabsorption in the collecting duct.60 Although PRARγ remains an attractive target for glycaemic control, thiazolidinediones’ clinical use is now limited and are avoided in patients with HF.71 Nevertheless, several non-thiazolidinedione selective PPARγ modulators free of sodium retention are now tested in preclinical trials.61

Incretins Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic drugs. Except from their favourable effects in glycaemic control, preclinical data and early clinical reports support their clinical benefit in HF patients. GLP-1 increases cyclic adenosine monophosphate in cardiac myocytes but independently from a toxic increase in calcium levels and in myocytes xsxs.72 Preclinical data in dogs and pigs with dilated cardiomyopathy have demonstrated that infusion of GLP-1 improves left ventricle function and stroke volume.62,63 After myocardial infarction infusion of GLP-1, patients with left ventricle dysfunction showed improved ejection fraction and wall motion.73 A non-randomised study in 12 HF patients concluded that chronic infusion of GLP-1 significantly improves left ventricular function, functional status and quality of life in patients with severe HF.64 In contrast, Halbirk et al. concluded that 48 hours infusion of GLP-1 had no major cardiovascular effects in patients without diabetes but with compensated HF.74 Taken together we can conclude that although there are no definite data on the impact of incretins in HF, early observations favour their use in HF subjects.

Other Glucose Lowering Treatment Mineralocorticoid Receptor Antagonists Eplerenone is a novel minelarocorticoid receptor antagonist, which is useful in HF patients. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) in patients after acute myocardial infarction, ejection fraction <40 % and DM revealed that eplerenone on top of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can decrease mortality.56 As renal dysfunction frequently co-exists with DM and HF,70 attention to renal function and hyperkalaemia must be applied when the combination of eplerenone and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are used.

Diabetes Mellitus Treatment – Interaction with Heart Failure Glycaemic control is of importance in DM subjects with HF as it is supposed to decrease free fatty acid oxidation by myocardial cells and increase the use of glucose as a substrate for metabolic requirements.57 Nevertheless, attention must be given to the results of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials, which have shown that intensive treatment with a glycated haemoglobin target ≤6.5 % failed to influence macrovascular complications.58,59 The glycaemic

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The main concern regarding the use of metformin in HF patients despite their clinical benefits and the lower rates of mortality was the risk of lactic acidosis.65 Novel data do not support this risk.66,75 UK Prospective Diabetes Study (UKPDS) concluded that there was no difference between sulphonylureas and insulin treatment in cardiovascular complication,66 while it seems that metformin compared with sulphonylureas decrease hospitalisations at least in some studies.66,76 Regarding insulin treatment there are no reports that can affect HF status.67

Non-conventional Treatment of Diabetic Cardiomyopathy Beyond the standard HF treatment, several novel approaches have been developed (see Table 4). Ex vivo studies support the notion that superoxide dismutase can offer protection from HF.83 In vivo studies in transgenic DM mice expressing cardiac specific superoxide dismutase show improvement in cardiac remodeling and left ventricle function.77 Coenzyme Q10 is a potent antioxidant free of adverse effects, which can maintain cardiomyocyte and mitochondrial function. Recent preclinical data suggest that chronic supplementation with coenzyme Q10 can represent an effective approach for managing diabetic cardiomyopathy.78,84

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Phosphoinositide 3-kinase is a cardioprotective kinase, which when enhanced in transgenic mice can prevent diabetes-induced cardiomyopathy adverse cardiac remodeling and dysfunction.79 Interestingly, numerous, mostly preclinical, studies have shown that interventions such as omega-3 (n-3) polyunsaturated fatty acids can improve cardiac output and ejection fraction as well as stroke volume and stroke work in a rat model of DM.80 This improvement may be mediated through attenuation of myocardial connexin-43 abnormalities. In contrast n-6 polyunsaturated fatty acids could accelerate myocardial abnormalities in diabetic rats.85

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Conclusion HF and DM frequently co-exist in a bidirectional relationship as it is proposed by pathophysiological and epidemiological data. At the moment several pathophysiological connections have been proposed but we cannot definitively conclude on the pathophysiological mechanisms precipitating this complex interaction. Both entities are characterised by high morbidity and mortality, and treatment must target the overall improvement as DM treatment can decompensate HF and vice versa. Novel therapeutic agents against diabetic cardiomyopathy are under investigation raising hopes for better management in the future. n

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72. Vila Petroff MG, Egan JM, Wang X, Sollott SJ, Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes, Circ Res , 2001;89:445–52. 73. Lønborg J, Vejlstrup N, Kelbaek H, et al., Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction, Eur Heart J , 2012;33:1491–9. 74. Halbirk M, Nørrelund H, Møller N, et al., Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure, Am J Physiol Heart Circ Physiol , 2010;298:H1096–102. 75. Tousoulis D, Koniari K, Antoniades C, et al., Combined effects of atorvastatin and metformin on glucose-induced variations of inflammatory process in patients with diabetes mellitus, Int J Cardiol , 2011;149:46–9. 76. Eurich DT, Majumdar SR, McAlister FA, et al., Improved clinical outcomes associated with metformin in patients with diabetes and heart failure, Diabetes Care , 2005;28:2345–51. 77. Shen X, Zheng S, Metreveli NS, Epstein PN, Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy, Diabetes , 2006;55:798–805. 78. Huynh K, Kiriazis H, Du XJ, et al., Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice, Free Radic Biol Med , 2013;60:307–17. 79. Ritchie RH, Love JE, Huynh K, et al., Enhanced

phosphoinositide 3-kinase(p110alpha) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes, Diabetologia , 2012;55:3369–81. 80. Anna Z, Angela S, Barbara B, et al., Heart-protective effect of n-3 PUFA demonstrated in a rat model of diabetic cardiomyopathy, Mol Cell Biochem , 2014;389:219–27. 81. Plante E, Menaouar A, Danalache BA, et al., Treatment with brain natriuretic peptide prevents the development of cardiac dysfunction in obese diabetic db/db mice, Diabetologia , 2014;57(6):1257–67. 82. Westermann D, Rutschow S, Van Linthout S, et al., Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus, Diabetologia , 2006;49:2507–13. 83. Salvemini D, Riley DP, Cuzzocrea S, SOD mimetics are coming of age, Nat Rev Drug Discov , 2002;1:367–74. 84. Huynh K, Kiriazis H, Du XJ, et al., Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes, Diabetologia , 2012;55:1544–53. 85. Ghosh S, Qi D, An D, et al., Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA, Am J Physiol Heart Circ Physiol , 2004;287:H2518–27.

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Heart Failure

LE ATION.

Pharmacological Treatment of Patients with Chronic Systolic Heart Failure Christoph Maack and Michael Böhm Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany

Abstract Chronic heart failure is characterised by neuroendocrine activation as an attempt of the body to maintain pump function of the heart and blood pressure for the perfusion of peripheral tissues. While this neuroendocrine activation is beneficial in the short term, it induces maladaptive remodeling of the heart with continuous deterioration of left ventricular function. Accordingly, pharmacological treatment of patients with heart failure aims at protecting the heart from this neuroendocrine activation, which is represented in particular by the sympathetic nervous and the renin-angiotensin-aldosterone systems. While this concept is based on evidence from numerous large randomised placebo-controlled studies in patients with systolic heart failure, about half of the patients with heart failure have preserved systolic function, and most studies antagonising neuroendocrine activation were not successful in these latter patients. Here, we review the pathophysiological changes that occur in patients with heart failure and provide an overview on the mechanisms and clinical evidence of currently applied pharmacological treatment in patients with systolic heart failure.

Keywords Heart failure, treatment, neuroendocrine activation, sympathetic nervous system, renin-angiotensin-aldosterone system Disclosure: Christoph Maack received speaker honoraria from Pfizer, Berlin Chemie, Bayer and Servier. Michael Böhm received speaker honoraria from Servier, Pfizer, Novartis, Medtronic, St. Jude and Boehringer Ingelheim. Acknowledgements: Christoph Maack is supported by the Deutsche Forschungsgemeinschaft (Heisenberg Programm, SFB 894) and the Deutsche Herzstiftung (Margret Elisabeth Strauß Projektförderung). Received: 18 June 2014 Accepted: 16 July 2014 Citation: European Cardiology Review, 2014;9(1):43–8 Correspondence: Christoph Maack, Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany. E: christoph.maack@uks.eu

Chronic heart failure is the leading cause of hospitalisation in Germany1 and other European countries. It is the result of various cardiovascular diseases, such as myocardial infarction, arterial hypertension and valvular heart diseases. About 50 % of patients with heart failure have normal systolic, but impaired diastolic function, a condition termed heart failure with preserved ejection fraction (HFpEF), in contrast to heart failure with reduced ejection fraction (HFrEF).2,3 Patients with ischaemic heart disease and/or myocardial infarction are more likely to develop HFrEF, while HFpEF more likely inflicts the elderly, female gender and patients with arterial hypertension.4 While initially it seemed that patients with HFpEF only had a slightly better prognosis than patients with HFrEF (by 4 %),3 more recent evidence suggests that prognosis of HFpEF per se is clearly less adverse than of HFrEF (by 32 %), while frequent co-morbidities affect overall prognosis of patients with HFpEF.4,5 Over the past decades, advancements in the treatment of patients with HFrEF led to continuous improvements of overall prognosis, while in HFpEF, most drugs used in patients with HFrEF were not effective.3,6 In the 2012 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure, definite recommendations for the pharmacological treatment of patients with HFrEF are provided, while recommendations for patients with HFpEF are scarce.6 Hence, we herein will focus on the pharmacological treatment of patients with HFrEF and for simplicity will refer to them as patients with ‘heart failure’ (HF).

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Pathophysiology of Heart Failure Blood pressure (BP) is defined as the product of cardiac output (C.O.) and systemic vascular resistance (SVR), where C.O. is the product of stroke volume (SV) and heart rate (HR). Systolic dysfunction of the left ventricle (LV) reduces SV and thus C.O., which results in decreased BP. A decrease in BP is sensed by baroreceptors in the carotid artery and the aorta, which activates the sympathetic nervous system that is centrally controlled in the brain stem (medulla oblongata), triggering increased release of norepinephrine in the myocardium and of epinephrine from the adrenal glands to the bloodstream (see Figure 1). While epinephrine increases SVR via vascular alpha (α)-adrenergic receptors, norepinephrine has positive inotropic and chronotropic effects in the heart by stimulating beta (β)-adrenergic receptors, increasing HR and SV. Together, sympathetic activation increases BP and therefore has beneficial effects on short-term haemodynamics while in the long run, leads to LV remodeling and dysfunction7 through activating pro-hypertrophic signaling pathways8 and inducing apoptosis.9,10 Furthermore, elevated heart rate per se is associated with adverse prognosis in patients with HF.11 Activation of renal sympathetic efferent nerves to the kidney with subsequent activation of β-adrenergic receptors as well as reduced renal blood flow increase the release of renin from the kidney, which converts angiotensinogen to angiotensin I, which is then converted to angiotensin II (Ang II) by the angiotensin-converting enzyme (ACE;

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Heart Failure Figure 1: Pathophysiological Changes in Patients with Heart Failure, Highlighting the Haemodynamic Alterations and Neuroendocrine Activation as well as the Pharmacological Targets Sympathetic Nervous System

Baroreceptors, kidney

Ivabradine Ao

Adrenaline

Adrenaline/ NE (5:1)

Aldosterone MRA

LA Digitalis LV

NE β-Blocker

Ang’en

Forward failure β-AR

Ang I

C.O.

ACE-I

α-AR

Ang II AT1-R

Vasoconstriction

Blood pressure

ARB Systemic Vascular Resistance

Na+

H2O

Diuretics

ACE = angiotensin-converting enzyme; AG = adrenal gland; Ang = angiotensin; Ang’en = Angiotensinogen; AO = aorta; AR = adrenergic receptor; ARB = AT1-receptor blockers; C.O. = cardiac output; H2O = water; LA = left atrial; LV = left ventricle; MRA = mineralocorticoid antagonist; Na+ = sodium; NE = norepinephrine; SVR = systemic vascular resistance.

see Figure 1). Ang II induces vasoconstriction via type 1 Ang II (AT1) receptors and stimulates the release of aldosterone from the adrenal glands. Aldosterone, in turn, increases sodium (Na+) and water (H2O) retention in the kidney, which elevates intravascular volume and hence, SV and BP. Similar to the sympathetic nervous system, the activation of the renin-angiotensin-aldosterone system (RAAS) has beneficial short-term effects on BP, but adverse long-term effects on LV remodeling and prognosis, which is largely related to the activation of pro-hypertrophic and maladaptive signaling pathways in the heart.12 With progressive LV remodeling and dysfunction, the filling pressure of the LV increases, which triggers the production and release of brain natriuretic peptide (BNP) from LV myocardium, with the N-terminal pro-BNP being used as the currently most sensitive and reliable biomarker for the haemodynamic status and prognosis of patients with HF. Through its natriuretic action, BNP tends to antagonise the effects of RAAS activation. As a consequence of elevated LV filling pressures, left atrial pressure increases, inducing atrial dilation and fibrosis and thus, providing a substrate for atrial fibrillation (AF).13 Furthermore, elevated LV and atrial filling pressures trigger pulmonary congestion, which is the basis for the leading symptom of HF (i.e. dyspnoea). When pulmonary congestion continues to increase pulmonary artery pressures, the right heart is also exposed to elevated afterload and thus, after a prolonged time, right ventricular (RV) decompensation may lead to the development of oedema in arms, legs and potentially the gut. Considering these pathophysiological changes during HF, the treatment of these patients primarily aims to antagonise neuroendocrine

Bohm_FINAL.indd 44

activation and congestion (see Figure 1), which in concert trigger maladaptive remodeling of the LV.12

Pharmacological Treatment The major aims of treating patients with HF are to relieve symptoms, prevent hospitalisation, and to improve functional capacity, quality of life and survival.6 Drugs that fulfil these aims frequently also ameliorate LV remodeling and lower circulating natriuretic peptides. The cornerstones of medical treatment are diuretics, ACE-inhibitors or AT1-receptor blockers (ARB), β-adrenergic receptor antagonists (β-blockers) and mineralocorticoid antagonists (MRA; see Figure 1). Furthermore, in some patients with sinus rhythm in whom HR reduction is insufficient despite β-blockade, the use of ivabradine is justified, and digitalis glycosides may be useful to improve morbidity and to control HR in patients with AF. In the following paragraphs, we give an overview on the use of these drugs, their mechanisms of action, and in particular, the clinical evidence supporting their use.

Diuretics Although the effects of diuretics on morbidity and mortality were never tested in patients with HF, they are absolutely essential for decongestion and thus, improvement of symptoms. Loop diuretics are more effective in inducing diuresis compared with thiazides and can be used intravenously during acute decompensation or orally during stable phases of disease to maintain euvolaemia (patient´s ‘dry weight’). The most commonly used diuretics are furosemide and torasemide, whose doses can be (self-) adjusted depending on signs of fluid retention (monitored by body weight).6 Since ACE-inhibitors/

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AT1-antagonists and MRAs, and in particular the combination of these, can elevate serum potassium, loop diuretics or thiazides are better suited than potassium-sparing diuretics in patients with HF.6

Angiotensin-converting Enzyme Inhibitors The two major trials that established the use of ACE-inhibitors in the treatment of HF are the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)14 and the Studies of Left Ventricular Dysfunction (SOLVD)15 trials. In CONSENSUS, enalapril was tested against placebo in 253 patients with HF in New York Heart Association (NYHA) functional class IV on a stable background therapy consisting of vasodilators and diuretics for a follow-up period of 188 days. Enalapril improved survival by 31 % and also symptoms, but had no effect on sudden cardiac death.14 The fact that enalapril improved prognosis in patients with or without concomitant use of other vasodilators indicated that the beneficial effect of enalapril was the result of reducing Ang II levels (which may ameliorate LV remodeling) rather than of pure haemodynamic improvement (reduction of afterload).14 Since CONSENSUS was performed in severely ill patients (NYHA IV),14 in the SOLVD study enalapril was compared with placebo in 2,569 patients with less severe HF (NYHA functional class II-III) and left ventricular ejection fraction (LVEF) ≤35 %, on a background therapy consisting of spironolactone and digitalis.15 Enalapril reduced total mortality by 16 %, aggravation of HF by 22 % and death or hospitalisation for HF by 26 %, respectively.15 Again, no benefit on sudden cardiac death was achieved.15 It is important to up-titrate ACE-inhibitors to the maximal tolerable dose, since a trial with lisinopril (Assessment of Treatment with Lisinopril and Survival [ATLAS]) indicated a benefit of high-dose over low-dose lisinopril in NYHA functional class II-III HF patients.16 Further support for the use of ACE-inhibitors in HF comes from a metaanalysis17 and three larger trials in patients with HF, LV dysfunction or both after myocardial infarction (Survival and Ventricular Enlargement trial [SAVE], Acute Infarction Ramipril Efficacy [AIRE] and Trandolapril in Cardiac Evaluation [TRACE]).18 Finally, ACE-inhibitors are the only drugs with a proven benefit in asymptomatic patients with HF based on a 20 % relative risk reduction (RRR) in the SOLVD Prevention trial.19 ACE-inhibitors should only be used in patients with sufficient renal function (i.e. creatinine ≤2.5 mg/dl or estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2 and normal potassium levels).6

Beta-blockers A landmark study about the use of β-blockers in patients with HF was published by Waagstein et al.20 in 1975, who reported improved symptoms and LV function in seven patients with dilated cardiomyopathy in response to β-blockers. At that time, β-blockers were strictly contraindicated in patients with HF since it was assumed that the relief of sympathetic activation would deprive the heart of a critical stimulus to maintain contractility. In fact, acute administration of β-blockers in patients with HF can lead to a transient deterioration of C.O.,21 while a more long-term treatment typically increases LVEF21 and reverses remodeling of the LV (decreasing LV chamber size).22 On a cellular level, improvements of cardiac function by β-blockers are associated with a restoration of cardiomyocyte calcium handling proteins and contractile filaments.23 After promising (but not yet significant) results with the second-generation β-blockers, metoprolol tartrate and bisoprolol in the Metoprolol in Dilated (MDC)24 and Cardiac Insufficiency Bisoprolol Study (CIBIS) trials25 in the early 1990s, a study programme with the third-generation β-blocker carvedilol was terminated early due to a 65 % reduction in overall mortality by carvedilol versus placebo.26 In subsequent

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years, larger and better designed randomised clinical trials confirmed the benefits of β-blockade with metoprolol succinate (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF]),27 bisoprolol (CIBIS II)28 and carvedilol (Carvedilol Prospective Randomized Cumulative Survival [COPERNICUS]).29 Importantly, the benefits of β-blockers (~34 % RRR of all-cause mortality by metoprolol succinate,27 bisoprolol28 and carvedilol,29 respectively) were generated on the background of ACE-inhibitor therapy (>90 % of patients) and were overall comparable among the three mentioned agents. Although one trial reported superiority of carvedilol over metoprolol (Carvedilol or Metoprolol European Trial [COMET]30), it has to be taken into account that this trial30 was conducted with short-acting metoprolol tartrate, while the successful MERIT-HF trial27 was conducted with long-acting metoprolol succinate. Further support for the benefit of β-blockers comes from the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial,31 in which the third-generation β-blocker nebivolol was tested versus placebo in elderly (≥70 years) patients with HF, of whom 36 % had a LVEF of >35 %. Nebivolol reduced the combined endpoint of death or cardiovascular mortality, but did not reduce mortality.31 Bucindolol, another third-generation β-blocker with partial agonist activity32 did not reduce mortality in the Beta-Blocker Evaluation in Survival Trial (BEST).33 Taken together, the 2012 ESC Guidelines on the treatment of HF recommend the use of bisoprolol, carvedilol, metoprolol succinate or nebivolol in patients with HF (Class I, Level A recommendation). It is important to start on a low dose (to prevent initial deterioration of HF) and up-titrate the drug to the maximally tolerated dose, ideally aiming at a HR between 60 and 70 beats per minute (bpm). During decompensation of a patient with HF, continuation of the β-blocker is safe, although a dose reduction may be required.34

Mineralocorticoid or Aldosterone Receptor Antagonists Currently there are two lead compounds of this class on the market, spironolactone and eplerenone. While the former is less specific and antagonises mineralocorticoid receptors, the latter is more specific for aldosterone receptors. Together, they are classified as MRAs. The first randomised placebo-controlled outcome study with a MRA was the Randomized Aldactone Evaluation Study (RALES),35 in which HF patients in NYHA functional class III and an LVEF ≤35 % were randomised to spironolactone (25–50 mg once daily) or placebo added to conventional treatment, at that time consisting predominantly of diuretics (100 %), ACE-inhibitors (95 %) and digitalis (~75 %). Compared with placebo, spironolactone improved symptoms, decreased hospitalisation for worsening HF (by 35 %) and overall mortality (by 30 %).35 Of note, this improved survival was due to both reduction of death from progressive HF and sudden death from cardiac causes.35 While hyperkalaemia was rare, gynaecomastia as a side effect occurred in 10 % versus 1 % of patients treated with the MRA versus placebo, respectively.35 In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),36 treatment of patients with acute myocardial infarction complicated by LV dysfunction (LVEF ≤40 %) and HF with the more specific aldosterone antagonist eplerenone reduced overall and cardiovascular mortality by 15 % and 17 %, respectively. Furthermore, hospitalisations for cardiovascular or any reasons were reduced. Interestingly, eplerenone also reduced sudden cardiac death by 21 %.36 An advantage of EPHESUS36 over RALES35 was that in the former, a much higher percentage of patients were treated with β-blockers (75 % versus 11 %).

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Heart Failure Figure 2: Simplified Flowchart of the Pharmacological Treatment of Patients with Systolic Heart Failure Diuretics

ACE-inhibitor (or ARB, if not tolerated)

ADD a β-Blocker Still NYHA II-IV?

If “no” at any question, no further specific pharmacological treatment.

ADD MR Antagonist Still NYHA II-IV, LVEF≤35 %, SR & HR ≥70 bpm? ADD ivabradine Still NYHA II-IV? Consider digoxin and/or H-ISDN ACE = angiotensin-converting enzyme; ARB = AT1-receptor blockers; bpm = beats per minute; H-ISDN = hydralazine and isosorbite dinitrate; HR = heart rate; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; MR = mineralocorticoid; SR = sinus rhythm. Adapted from the 2012 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure.6

To finally resolve whether, also in patients with stable HF, MRAs would improve prognosis added to a background therapy that included β-blockers, and whether MRAs were efficient also in patients with mild symptoms of HF (RALES was performed in NYHA functional class III patients), the recent Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure study (EMPHASIS-HF)37 enrolled 2,737 patients in NYHA functional class II and a LVEF ≤35 %. In fact, eplerenone reduced the primary composite endpoint of death from cardiovascular causes or hospitalisation for HF by 37 %, and cardiovascular as well as overall mortality per se by 24 %, respectively. Hospitalisations for heart failure and for any cause were also reduced with eplerenone. Mild hyperkalaemia (serum potassium [K+] >5.5 mmol/L) was (as expected) somewhat more frequent (+64 %) in eplerenone- compared to placebo-treated patients, while hypokalaemia was less frequent with eplerenone.37 Taken together, MRAs reduce morbidity and mortality in patients with HF, but also acute myocardial infarction complicated by LV dysfunction and HF. Both MRAs can provoke hyperkalaemia and worsen renal function, while spironolactone, but not eplerenone, can induce gynaecomastia as a side effect. Thus, in the current ESC guidelines, MRAs are recommended in addition to ACE-inhibitors and β-blockers in all patients with HF with a LVEF ≤35 % and maintaining symptoms (NYHA II-IV).6 However, similar to ACE-inhibitors, MRAs should be limited to patients with adequate renal function and normal serum K+ concentrations.6

AT 1 -Receptor Antagonists

A common side effect of ACE-inhibitors is to provoke dry cough due to inhibition of bradykinin breakdown by chymase. Furthermore, some Ang II can still be generated despite ACE-inhibition through the so-called ‘escape phenomenon’. The rationale behind the development

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of ARBs was to circumvent these limitations of ACE-inhibitors. Although ARBs produced less side effects than ACE-inhibitors (in particular, cough), they were not superior to ACE-inhibitors in terms of survival in the Losartan Heart Failure Survival Study (ELITE II).38 However, when patients with HF did not tolerate treatment with an ACE-inhibitor, treatment with ARBs reduced morbidity and mortality when compared with placebo, as revealed by the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative trial39 and a subgroup analysis40 of the Valsartan Heart Failure Trial (Val-HeFT).41 In this scenario (HF patients intolerant to ACE-inhibitors), and in analogy to ACE-inhibitors in the ATLAS trial,16 the Heart Failure Endpoint Evaluation with the Angiotensin II Antagonist Losartan (HEAAL) trial42 revealed that a higher dose of losartan (150 mg) was superior to a lower dose of the same drug (50 mg) in preventing HF hospitalisation. In contrast, the addition of ARBs on top of ACE-inhibitors did not improve overall mortality in the Val-HeFT41 or the CHARM-Added43 trials. However, cardiovascular mortality was improved by 16 % with candesartan in CHARM-Added trial.43 Furthermore, both trials showed reduced hospitalisation for HF deterioration (by 24 % in Val-HeFT and 17 % in CHARM-Added), whereas all-cause hospitalisation remained unchanged. While 35 % (in Val-HeFT) and 55 % of patients (in CHARM-Added) had a β-blocker in their background medication, only a few patients were treated with a MRA.41,43 Importantly, a post hoc analysis of Val-HeFT revealed that the ARB was particularly efficient in patients not taking a β-blocker or ACE-inhibitor (or neither), whereas it was adverse in those patients taking both.41 Since in the EMPHASIS trial with eplerenone, the MRA efficiently reduced mortality and morbidity when added to ACE-inhibitors and β-blockers,37 while ARBs did not achieve this,41,43 ARBs no longer remain a first-choice recommendation in patients with HF, while they received a class I level A recommendation in the current guidelines as an alternative in patients intolerant to an ACE-inhibitor.6

Ivabradine In patients with HF, elevated HR is associated with an adverse prognosis. For instance, HF patients with HR ≥87 bpm have a more than two-fold worse prognosis than patients with a HR between 70 and 72 bpm.11 Since β-blockers, besides their negative chronotropic effects, also have negative inotropic effects8 that may acutely deteriorate C.O.,21 ivabradine was developed as a selective HR-lowering drug by inhibiting the current of the ‘funny’ channel (If), which triggers slow depolarization in sinus node cells. Accordingly, ivabradine reduces HR only in patients with sinus rhythm (SR), while in patients with AF, it has no effect. The prevailing pathophysiological view has long been that HR reduction is beneficial for the heart primarily due to lowering oxygen consumption. However, more recent experimental and clinical evidence also indicates that HR reduction improves vascular function and through this, unloads the heart. In animal models of atherosclerosis, HR reduction prevented vascular oxidative stress and endothelial dysfunction, reduced atherosclerotic plaque formation and stimulated collateral artery growth through improving the bioavailability of nitric oxide and reducing inflammation.44,45 Oxidative stress and inflammation are of particular importance in diastolic HF (HFpEF), where coronary microvascular inflammation is thought to induce hypertrophy and myofilament stiffness.46 Accordingly, HR reduction with ivabradine improved vascular stiffness and LV systolic and diastolic function in a mouse model of HFpEF.47 However, also in patients with systolic HF, ivabradine reduced arterial stiffness, which increased stroke volume by unloading the LV.48,49 Taken together, these data indicate that

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ivabradine may improve myocardial pathologies through actions on the heart and the vessels. The first large randomised placebo-controlled trial with ivabradine was performed in patients with coronary artery disease and a LVEF <40 % (Morbidity-mortality evaluation of the If inhibitor ivabradine in patients with coronary artery disease and left ventricular dysfunction [BEAUTIFUL] trial50). In this trial, 87 % of patients were receiving a β-blocker, and mean HR at baseline was only 72 bpm and hence, the average (placebo-corrected) HR reduction by ivabradine was only six bpm. Accordingly, the primary endpoint (a composite of cardiovascular death, admission to hospital for acute myocardial infarction and admission to hospital for new onset or worsening heart) was completely unaffected by ivabradine (hazard ratio 1.0).50 However, in a pre-specified subgroup analysis of patients with a HR of ≥70 bpm at baseline, ivabradine reduced secondary endpoints, such as admission to hospital for fatal and non-fatal myocardial infarction (by 36 %) and coronary revascularisation (by 30 %).50 Based on these positive, but rather hypothesis-generating data,50 the Systolic Heart failure treatment with the If inhibitor ivabradine trial (SHIFT)51 assigned patients with stable HF (NYHA functional classes II-IV, LVEF≤35 %) who were in SR with a HR of ≥70 bpm to ivabradine or placebo, respectively. Background medication included ACE-inhibitors or ARBs (together 93 %) and MRAs (60 %). While 90 % of patients were treated with a β-blocker, only 26 % of these patients received the full recommended dose. Ivabradine reduced the composite endpoint of cardiovascular death or HF hospitalisation by 18 %, which was driven primarily by a 26 % reduction of HF hospitalisation, while reductions of cardiovascular or all-cause mortality were not significant.51 The most common side effects of ivabradine versus placebo were bradycardia (5 % versus 1 %) and visual side effects (so-called phosphenes; 3 % versus 1 %).

Digoxin and Other Digitalis Glycosides A central deficit in patients with HF is that in cardiac myocytes, calcium ions (Ca2+) handling is impaired, which is a causal factor for contractile dysfunction.52 A classical treatment of patients with HF is the use of digitalis glycosides, which inhibit the Na+/K+ adenosine triphosphatase (ATPase) and thus, elevate intracellular Na+ concentrations. This, in turn, increases Ca2+ influx via the Na+/Ca2+ exchanger, which increases cardiac contractility. As a second effect, digitalis glycosides prolong the refractoriness of the atrioventricular (AV)-node, which accounts for negative chronotropic effects in patients with AF, but less in SR (contrary to ivabradine). The only large randomised placebo-controlled trial with a glycoside was the Digitalis Investigation Group (DIG) trial,53 in which digoxin was compared with placebo in 6,800 patients in NYHA functional classes II-IV and a LVEF ≤45 %, added to a diuretic and an ACE-inhibitor. Published in 1997, this trial was before the time when β-blockers were widely used in patients with HF. The main outcomes of this trial were that digoxin reduced hospital admission for HF by 28 %, but did not affect all-cause mortality over three years.53

1. Neumann T, Biermann J, Erbel R, et al., Heart failure: the commonest reason for hospital admission in Germany: medical and economic perspectives, Dtsch Arztebl Int , 2009;106:269–75. 2. Paulus WJ, Tschöpe C, Sanderson JE, et al., How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology, Eur Heart J , 2007;28:2539–50. 3. Owan TE, Hodge DO, Herges RM, et al., Trends in prevalence and outcome of heart failure with preserved ejection fraction,

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Combination of Hydralazine and Isosorbite Dinitrate A characteristic hallmark in patients with HF is that through neuroendocrine activation, SVR is elevated, imposing an increased afterload to the failing heart. Thus, a therapeutic approach (that proved beneficial with ACE-inhibitors) is to lower SVR by applying vasodilating agents. Three trials investigated the effects of the vasodilatory combination of hydralazine and isosorbite dinitrate (H-ISDN) in patients with HF: first Vasodilator Heart Failure Trial (V-HeFT I),54 second Vasodilator-Heart Failure Trial (V-HeFT II)55 and African-American Heart Failure Trial (A-HeFT).56 In the Valsartan Heart Failure Trial (Val-HeFT I),54 H-ISDN increased exercise capacity and LVEF compared with placebo and showed a trend towards reduction in all-cause mortality.54 However, in that trial, no patient was treated with an ACE-inhibitor or a β-blocker. In V-HeFT II,55 H-ISDN was compared with the ACE-inhibitor enalapril, being inferior by tending to increase mortality by 28 % versus the ACE-inhibitor. A-HeFT compared H-ISDN to placebo added to a background medication including ACE-inhibitors or ARB (combined 84 %), digoxin (60 %), β-blockers (74 %) and spironolactone (39 %) exclusively in AfricanAmerican patients with HF (NYHA III-IV).56 H-ISDN reduced mortality by 43 % and HF hospitalisation by 33 % and improved quality of life.56 Since results in white patients are currently inconclusive, the use of H-ISDN is recommended only for black patients and thus, uncommon in most European countries, while it is more common in the US.

Drugs Not Recommended Despite its accepted benefit in patients with coronary artery disease, statins have not improved outcome in patients with HF. Rosuvastatin was neither efficient in patients with ischaemic nor non-ischaemic cardiomyopathy, based on the data of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)57 and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto MiocardicoHeart Failure (GISSI-HF) trial.58 Also, the renin inhibitor aliskiren was not efficient in decreasing rehospitalisation or cardiovascular death in patients with systolic HF.59 Drugs that could produce harm in patients with HF include thiazolidinediones (glitazones), calciumchannel blockers, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors and therefore should be avoided.6 Finally, the addition of an ARB to an ACE-inhibitor and a MRA is not recommended due to the risk of renal dysfunction and hyperkalaemia.6

Summary Taken together, patients with HF should be treated with diuretics to prevent or treat symptoms of congestion, and with an ACE-inhibitor, β-blocker and MRA to improve morbidity and mortality. For some patients, the use of ivabradine or digoxin and/or H-ISDN may be useful. In Figure 2, a simplified scheme adapted from the current guidelines on the treatment of patients with chronic systolic HF is illustrated that helps to choose the right drugs at the right time in the treatment of these patients. n

N Engl J Med , 2006;355:251–9. 4. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC), The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis, Eur Heart J , 2012;33:1750–7. 5. Campbell RT, Jhund PS, Castagno D, et al., What have we learned about patients with heart failure and preserved ejection fraction from DIG-PEF, CHARM-preserved, and I-PRESERVE?, J Am Coll Cardiol , 2012;60:2349–56. 6. McMurray JJ, Adamopoulos S, Anker SD, et al., Esc Guidelines for the diagnosis and treatment of acute and chronic heart

failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur Heart J , 2012;33:1787–847. 7. Engelhardt S, Hein L, Wiesmann F, Lohse MJ, Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice, Proc Natl Acad Sci U S A , 1999;96:7059–64. 8. Bristow MR, Treatment of chronic heart failure with beta-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology, Circ Res , 2011;109:1176–94.

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Heart Failure 9. Communal C, Singh K, Pimentel DR, Colucci WS, Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway, Circulation , 1998;98:1329–34. 10. Zhu WZ, Wang SQ, Chakir K, et al., Linkage of beta1adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II, J Clin Invest, 2003;111:617–25. 11. Böhm M, Swedberg K, Komajda M, et al., Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebocontrolled trial, Lancet , 2010;376:886–94. 12. Frey N, Olson EN, Cardiac hypertrophy: the good, the bad, and the ugly, Annu Rev Physiol, 2003;65:45–79. 13. Wakili R, Voigt N, Kääb S, et al., Recent advances in the molecular pathophysiology of atrial fibrillation, J Clin Inves, 2011;121:2955–68. 14. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group, N Engl J Med , 1987;316:1429–35. 15. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD investigators, N Engl J Med , 1991;325:293–302. 16. Packer M, Poole-Wilson PA, Armstrong PW, et al., Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure, ATLAS Study Group, Circulation , 1999;100:2312–8. 17. Garg R, Yusuf S, Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials, JAMA, 1995;273:1450–6. 18. Flather MD, Yusuf S, Køber L, et al., Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group, Lancet , 2000;355:1575–81. 19. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD investigattors, N Engl J Med , 1992;327:685–91. 20. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I, Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy, Br Heart J, 1975;37:1022–36. 21. Waagstein F, Caidahl K, Wallentin I, et al., Long-term betablockade in dilated cardiomyopathy. Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol, Circulation , 1989;80:551–63. 22. Doughty RN, Whalley GA, Gamble G, et al., Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group, J Am Coll Cardiol , 1997;29:1060–6. 23. Lowes BD, Gilbert EM, Abraham WT, et al., Myocardial gene expression in dilated cardiomyopathy treated with betablocking agents, N Engl J Med , 2002;346:1357–65. 24. Waagstein F, Bristow MR, Swedberg K, et al., Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group, Lancet , 1993;342:1441–6. 25. A randomized trial of beta-blockade in heart failure.

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The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees, Circulation , 1994;90:1765–73. 26. Packer M, Bristow MR, Cohn JN, et al., The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group, N Engl J Med, 1996;334:1349–55. 27. Effect of metoprolol cr/xl in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF), Lancet , 1999;353:2001–7. 28. The Cardiac Insufficiency Bbisoprolol Study II (CIBIS-II): a randomised trial, Lancet , 1999;353:9–13. 29. Packer M, Coats AJ, Fowler MB, et al., Effect of carvedilol on survival in severe chronic heart failure, N Engl J Med, 2001;344:1651–8. 30. Poole-Wilson PA, Swedberg K, Cleland JG, et al., Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial, Lancet , 2003;362:7–13. 31. Flather MD, Shibata MC, Coats AJ, et al., Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS), Eur Heart J, 2005;26:215–25. 32. Maack C, Böhm M, Vlaskin L, et al., Partial agonist activity of bucindolol is dependent on the activation state of the human beta1-adrenergic receptor, Circulation , 2003;108:348–53. 33. Beta-Blocker Evaluation of Survival Trial Investigators, A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure, N Engl J Med, 2001;344:1659–67. 34. Jondeau G, Neuder Y, Eicher JC, et al., B-CONVINCED: Betablocker CONtinuation Vs. INterruption in patients with Congestive heart failure hospitalizED for a decompensation episode, Eur Heart J, 2009;30:2186–92. 35. Pitt B, Zannad F, Remme WJ, et al., The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators, N Engl J Med, 1999;341:709–17. 36. Pitt B, Remme W, Zannad F, et al., Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction, N Engl J Med, 2003;348:1309–21. 37. Zannad F, McMurray JJ, Krum H, et al., Eplerenone in patients with systolic heart failure and mild symptoms, N Engl J Med, 2011;364:11–21. 38. Pitt B, Poole-Wilson PA, Segal R, et al., Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II, Lancet , 2000;355:1582–7. 39. Granger CB, McMurray JJ, Yusuf S, et al., Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARMAlternative trial, Lancet , 2003;362:772–6. 40. Maggioni AP, Anand I, Gottlieb SO, et al., Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors, J Am Coll Cardiol, 2002;40:1414–21. 41. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators, A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure, N Engl J Med, 2001;345:1667–75. 42. Konstam MA, Neaton JD, Dickstein K, et al., Effects of highdose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised,

double-blind trial, Lancet , 2009;374:1840–8. 43. McMurray JJ, Ostergren J, Swedberg K, et al., Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: The CHARM-Added trial, Lancet , 2003;362:767–71. 44. Custodis F, Baumhäkel M, Schlimmer N, et al., Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice, Circulation , 2008;117:2377–87. 45. Schirmer SH, Degen A, Baumhäkel M, et al., Heartrate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis, Eur Heart J, 2012;33:1223–31. 46. Paulus WJ, Tschöpe C, A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation, J Am Coll Cardiol , 2013;62:263–71. 47. Reil JC, Hohl M, Reil GH, et al., Heart rate reduction by if-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction, Eur Heart J, 2013;34:2839–49. 48. Borlaug BA, Heart rate reduction: it is not just for ventricles anymore, J Am Coll Cardiol , 2013;62:1986–9. 49. Reil JC, Tardif JC, Ford I, et al, Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients, J Am Coll Cardiol, 2013;62:1977–85. 50. Fox K, Ford I, Steg PG, et al., Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial, Lancet , 2008;372:807–16. 51. Swedberg K, Komajda M, Böhm M, et al., Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study, Lancet , 2010;376:875–85. 52. Houser SR, Margulies KB, Is depressed myocyte contractility centrally involved in heart failure?, Circ Res , 2003;92:350–8. 53. Digitalis Investigation Group, The effect of digoxin on mortality and morbidity in patients with heart failure, N Engl J Med, 1997;336:525–33. 54. Cohn JN, Archibald DG, Ziesche S, et al., Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study, N Engl J Med, 1986;314:1547–52. 55. Cohn JN, Johnson G, Ziesche S, et al., A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure, N Engl J Med, 1991;325:303–10. 56. Taylor AL, Ziesche S, Yancy C, et al., Combination of isosorbide dinitrate and hydralazine in blacks with heart failure, N Engl J Med , 2004;351:2049–57. 57. Kjekshus J, Apetrei E, Barrios V, et al., Rosuvastatin in Older Patients with Systolic Heart Failure, N Engl J Med, 2007;357:2248–61. 58. Gissi-HF Investigators, Tavazzi L, Maggioni AP, et al., Effect of rosuvastatin in patients with chronic heart failure (the GISSIHF trial): a randomised, double-blind, placebo-controlled trial, Lancet , 2008;372:1231–9. 59. Gheorghiade M, Böhm M, Greene SJ, et al., Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: The ASTRONAUT randomized trial, JAMA , 2013;309:1125–35.

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Heart Failure

LE ATION.

Mitral Regurgitation – A Multidisciplinary Challenge Edua rd o A l e g r i a - B a r r e r o 1 a n d O l a f W F r a n z e n 2 1. Interventional Cardiology, Torrejon University Hospital, Madrid, Spain; Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK; 2. Interventional Cardiology, Klinik im Park, Hirslanden Zurich, Zurich, Switzerland

Abstract Mitral regurgitation is an increasing valvular disease that represents a difficult management challenge. Surgical treatment for degenerative mitral regurgitation is the standard of care treatment. Percutaneous therapies have emerged rapidly over the past years as an option for treatment of mitral regurgitation for selected, predominantly high-risk patients. Catheter-based devices mimic these surgical approaches with less procedural risk. Mitraclip® implantation mimics the surgical edge-to-edge leaflet repair technique, reducing the regurgitant area. We review the increasing evidence with the Mitraclip device reported to date.

Keywords Mitral valve, mitral regurgitation, mitral valve surgery, mitraclip, functional mitral regurgitation, degenerative mitral regurgitation Disclosure: Olaf W Franzen is a consultant for Abbott Vascular. Eduardo Alegria-Barrero has no conflicts of interest to declare. Received: 24 June 2014 Accepted: 5 July 2014 Citation: European Cardiology Review, 2014;9(1):49–53 Correspondence: Eduardo Alegria-Barrero, Interventional Cardiology, Torrejon University Hospital, Mateo Inurria s/n. 28850, Madrid, Spain. E: ealegriabarrero@secardiologia.es

Diseases of the mitral valve (MV) are the second most frequent clinically significant form of valvular disease in adults. In particular, MV regurgitation occurs with increasing frequency as part of degenerative changes in the ageing process.1 The annual incidence of degenerative MV disease is estimated at approximately 2–3 %. In addition to degenerative valve disease, MV regurgitation can be caused by cardiac ischaemia (functional mitral regurgitation), infective endocarditis and rheumatic diseases (prevalent in less developed countries).1 Severe mitral regurgitation (MR) develops gradually over the years and carries a high annual mortality rate of at least 5 %.2 Medical therapy relieves symptoms but does not reverse the underlying mitral pathology. Conventional surgical repair or replacement has been the standard of care for symptomatic severe MR.3,4 Those with degenerative MR (DMR) have excellent outcomes with repair surgery.5 However, the long-term benefits of surgical treatment of functional MR (FMR) are harder to demonstrate and remain controversial.6,7 Before the emergence of transcatheter valve therapies, optimal medical therapy and cardiac resynchronisation therapy in selected candidates have been the only treatment for patients deemed too high-risk for conventional surgery.8–11 Although a variety of MV transcatheter therapies grew in parallel with aortic valve therapies, the MV therapies have had a slower development path.2 Percutaneous edge-to-edge MV repair with the Mitraclip® system was demonstrated to be a safe and feasible alternative to surgical treatment for severe MR.12–15 Adverse valve morphology and severe left ventricular dysfunction have been the two major challenges for the treatment with the Mitraclip system.16–18

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Multidisciplinary assessment is essential for high-risk patients. A heart team including surgeons, interventional cardiologists, clinical cardiologists and imaging experts should discuss individual cases, considering the surgeon’s/institution experience with MV repair versus replacement.

Degenerative Mitral Regurgitation Degenerative MV disease frequently have leaflet prolapse due to elongation or rupture of the chordal apparatus, resulting in varying degrees of MV regurgitation due to leaflet malcoaptation during ventricular systole. Physiopathology of systolic flow reversal into the left atrium leads to atrial dilatation/fibrillation, ventricular function impairment and dilatation, secondary pulmonary hypertension and risk of sudden death.

Surgical Treatment There are several types of degenerative MV regurgitation19,20 (see Figure 1). Current guidelines recommend MV repair when patients develop New York Heart Association (NYHA) class II symptoms, any deterioration in left ventricular function or an end-systolic diameter of 4.5 cm.21 Recent evidence suggests that the best outcomes after repair of severe DMR are achieved in asymptomatic or minimally symptomatic patients, who are selected for surgery soon after diagnosis on the basis of echocardiography.22 Valve repair in patients with degenerative MV disease is associated with an improved quality of life with less morbidity as well as better long-term survival as opposed to replacement. Recent guidelines on valvular heart disease21 contain a reported mortality for isolated MV repair of 1.6–2.1 % and 4.3–7.8 % mortality for MV replacement. More than 80 % of the patients are free from re-operation at five years.

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Heart Failure Figure 1: Carpentier´s Classification of Mitral Regurgitation A

Chordae tendineae Anterolateral papillary muscle

Posteromedial papillary muscle

Type I

Type II

Type IIIa

Type IIIb (ischaemic) (A) Normal mitral valve anatomy. (B) Types of mitral regurgitation: Type I, normal leaflet motion; Type II, increased leaflet motion (leaflet prolapse); Type IIIa, restricted motion during systole and diastole (restricted leaflet opening); Type IIIb, restricted leaflet motion predominantly during systole (restricted leaflet closure)*. * Modified from Carpentier, et al., 2010.45

However, even in developed countries, MV replacement remains frequent in this setting. In the Euro Heart Survey, repair rates were documented around 50 %, meaning that MV replacement continues to be performed far too frequently in the modern era of reconstructive valve surgery.23 MV repair for degenerative disease follows two fundamental principles: • restore a good surface of leaflet coaptation (5–8 mm); and • correct for annular dilatation – Carpentier´s techniques being the most commonly performed worldwide.19,24 Long-term survival following MV repair is similar to age matched controls if the operation is performed before the onset of symptoms, ventricular dysfunction or atrial fibrillation.25

Percutaneous Edge-to-Edge Repair To date, up to 14,000 patients have been treated with the Mitraclip device worldwide, with nearly 2,000 enrolled in prospective clinical trials. The majority of patients included were considered at high peri-operative risk for MV surgery. After CE mark in 2008, numerous patients have been recruited in several studies. In 2013, the Food and Drug Administration (FDA) approved the Mitraclip device for symptomatic degenerative mitral valve regurgitation for patients at prohibitive risk for MV surgery by a heart team. The Mitraclip system consists of a steerable guide catheter and a clip delivery system (CDS), which includes the clip attached at the end of the CDS (see Figure 2).26,27 The guide catheter is 24 Fr proximally, and tapers to 22 Fr at the point where it crosses the interatrial septum (see Figure 2). These steering controls allow the operator to manoeuvre the clip over the MV. The clip is Dacron-covered with two clip arms that are opened and closed by control mechanisms on the CDS. Leaflet tissue is secured between

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the clip arms and opposing grippers (see Figure 2). The clip arms are then closed to zero degrees, then locked to effect and maintain coaptation of the two leaflets.28 Technical success is achieved in a high number of procedures.29,30 In this technically demanding procedure, the co-operation and communication between the operators and the guidance by transoesophageal echocardiography (see Figure 3) are of great importance. Therefore, the effect of learning curve and co-operation between heart team members could impact on the clinical outcome in terms of MR reduction and complication rates. The safety and efficacy of the percutaneous edge-to-edge with Mitraclip was initially tested in the Endovascular Valve Edge-to-Edge REpair Study (EVEREST I),15 and then compared with surgery in the randomised standard-risk patients EVEREST II trial.31 Procedural success was defined as successful and stable Mitraclip placement with residual MR ≤2+ on discharge. However, most of the patients enrolled in the EVEREST trials had DMR and all patients were surgical candidates. The real-world setting is very different from the original EVEREST trials – most of the patients treated with MitraClip are at high surgical risk and MR is more often functional rather than degenerative (see Table 1). Of note, during the implantation of MitraClip, there is often a compromise between complete reductions of MR and resultant mitral stenosis by placing further clips. Several studies have reported that in these patients, significant improvement in symptoms can still be achieved despite a complete resolution of MR.30,32,33 EVEREST II trial31 included 74 % patients with FMR randomised to surgery or Mitraclip treatment. Latest five-year data have recently been presented at the EuroPCR2014, Paris, France. Mean age in the DMR Mitraclip group was 67 years, 45 % of the patients were in NYHA class III/IV and mean ejection fraction was 64 %. Adverse event rates at 30-days (cardiac, vascular, renal, neurological) were low (25 %) compared with surgical DMR patients (33 %). At one-year, nine patients experienced single leaflet device attachment but no embolisation was observed. From one to five years follow-up, no further single device attachment or embolisation was observed. Survival rates at five years were similar in the Mitraclip and surgical groups (89.4 % versus 85.9 %, respectively). There was a concern on the need of re-operation for the Mitraclip patients. At one-year after the procedure, 75 % of the Mitraclip patients were free from re-operation/MV surgery compared with 100 % of the surgical group. However, from one to five years follow-up, 69 % Mitraclip patients were free from re-operation/MV surgery compared with 96 % of the surgical group, meaning that beyond one-year they observed comparable success rates for surgery and Mitraclip when index Mitraclip procedure was successful (92.2 % versus 95.8 % at five years). MR grade at five years follow-up, was ≤2+ in 81 % of the Mitraclip patients and in all surgical patients (100 %), and both groups exerted reduction of left ventricular (LV) end-diastolic diameters. NYHA I/II functional class at five years was present in DMR in 95 % of the Mitraclip patients compared with 97 % of surgical survivors at five years. Mitraclip patients had comparable stability of mitral annular dimensions at five years compared to baseline (4.0 cm versus 3.9 cm, p=0.18). Improved clinical performance in the six-minute walking test have also been reported.34 In the EVEREST II high surgical risk cohort, a 55 % reduction of the annual rate of hospitalisations was observed (0.71–0.32, p=0.006) after Mitraclip implantation.

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Mitral Regurgitation – A Multidisciplinary Challenge

Figure 2: MitraClip ® Delivery System and Guiding Catheter and Characteristics of the Clip

Figure 3: Three-dimensional Transoesophageal Echocardiogram Guidance During MitraClip ® Implantation A

(A) After transseptal puncture, the position and distance to the mitral valve is measured. A high and posterior puncture is aimed. (B) Orientation of the clip in the mitral valve (MV), perpendicular to the MV opening, assessed by three-dimensional transoesophageal echocardiogram (3D-TOE), from the left atrium (LA). (C) Final result after MitraClip implantation from the LA with two MV orifices, mimicking the Alfieri´s surgical edge-to-edge leaflet technique.

Table 1: Guidelines Recommendations for Percutaneous Edge-to-Edge Mitral Valve Repair ESC/EACTS Guidelines on the management of valvular heart disease (version 2012)21 • Percutaneous edge-to-edge procedure may be considered in patients with symptomatic severe primary MR who fulfil the echo criteria of eligibility, are judged inoperable or at high surgical risk by a ‘heart team’ and have a life expectancy >1 year (recommendation class IIb, level of evidence C) • The percutaneous mitral clip procedure may be considered in patients with symptomatic severe secondary MR despite optimal medical therapy (including CRT if indicated), who fulfil the echo criteria of eligibility, are judged inoperable or at high surgical risk by a team of cardiologists and cardiac surgeons, and who have a life expectancy >1 year (recommendation class IIb, level of evidence C) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 201242 In (secondary MR) patients with an indication for valve repair but judged inoperable or at unacceptably high surgical risk, percutaneous edge-to-edge repair may be considered in order to improve symptoms 2013 ACCF/AHA Guideline for the management of heart failure43 Transcatheter mitral valve repair or mitral valve surgery for functional mitral insufficiency is of uncertain benefit and should only be considered after careful candidate selection and with a background of GDMT (recommendation class IIb, level of evidence B) 2014 AHA/ACC Guideline for the management of patients with valvular heart disease44 Transcatheter MV repair may be considered for severely symptomatic patients (NYHA class III/IV) with chronic severe primary MR (stage D) who have a reasonable life expectancy but a prohibitive surgical risk* because of severe co-morbidities (recommendation class IIb, level of evidence B) * Prohibitive surgical risk is defined as having one of the following: • Predictive risk with surgery of death or major morbidity (all-cause) >50 % at one-year. • ≥3 major organ system compromise not to be improved post-operatively (cardiac – severe left ventricular [LV] systolic or diastolic dysfunction or right ventricular [RV] dysfunction, fixed pulmonary hypertension; chronic kidney disease stage 3 or worse; pulmonary dysfunction with FEV1 <50 % or DLCO2 <50 % of predicted; neurological dysfunction [dementia, Alzheimer’s disease, Parkinson’s disease, vascular disease with persistent physical limitation]; gastrointestinal dysfunction – Crohn’s disease, ulcerative colitis, nutritional impairment or serum albumin <3.0; cancer – active malignancy; and liver – any history of cirrhosis, variceal bleeding or elevated INR in the absence of therapy). • Severe procedure-specific impediment (for example: tracheostomy present, heavily calcified ascending aorta, chest malformation, arterial coronary graft adherent to posterior chest wall or radiation damage). ACC = American College of Cardiology; ACCF = American College of Cardiology Foundation; AHA = American Heart Association; CRT = cardiac resynchronisation therapy; DLCO2 = diffusing lung capacity for carbon dioxide; EACTS = European Association for Cardio-Thoracic Surgery; ESC = European Society of Cardiology; FEV1 = forced expiratory volume in one second; GDMT = guideline-directed medical therapy; INR = international normalised ratio; MR = mitral regurgitation; NYHA = New York Heart Association.

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Heart Failure Functional Mitral Valve Regurgitation Ischaemic MR is characterised by restrictive mitral leaflet mobility due to dyskinesia or akinesia of the ventricular wall involving one or both papillary muscles, thus, extending the distance between the ventricular wall and the leaflets. The posterior papillary muscle is the most frequently affected. FMR is associated with a poor prognosis in heart failure patients with post-ischaemic or idiopathic dilated cardiomyopathy.3 Surgical MV repair may be considered in severely symptomatic patients with severe FMR despite optimal medical therapy and cardiac resynchronisation therapy.35,36 Although several studies have reported reverse LV remodelling and improvements in symptoms and quality of life after surgical mitral repair,36 operative mortality is not negligible, ranging from 8.8 % to 21.0 %.37 Moreover, there is a high number of patients with severe FMR who are not referred for surgery because of advanced age, high surgical risk and co-morbidities.8

Surgical Treatment Historically, the surgical approach to patients with FMR was to perform MV replacement, but it had a high impact on LV systolic function and exerted high mortality rates. Techniques of MV replacement, such as prosthesis implantation with preservation of the subvalvular apparatus, and prosthesis implantation with preservation of one or both leaflets (usually posterior) have evolved to improve the long-term haemodynamic function and clinical status of these patients38 Replacement should be reserved for cases of acute papillary muscle rupture in relation to acute myocardial infarction.39 In appropriately selected patients, restrictive annuloplasty is associated with low operative mortality and is effective in eliminating MR. Acker et al.40 have recently published the randomised comparison of MV repair versus replacement for severe ischaemic MR. At 12 months, the rate of death was 14.3 % in the repair group and 17.6 % in the replacement group (hazard ratio with repair, 0.79; 95 % confidence interval, 0.42–1.47; p=0.45), with an increased rate of moderate or severe recurrence of MR at 12 months in the repair group compared with the replacement group (32.6 % versus 2.3 %, p<0.001). Patient selection for repair is crucial. When the pre-operative clinical and echocardiographic data suggest that annuloplasty alone is unlikely to be successful and durable, additional surgical procedures should be used to enhance the effectiveness of MV repair.39 Since FMR exerts high mortality and high incidence of recurrence of MR after repair, several alternative treatments have been proposed.

with a 86.0–89.0 % survival for the DMR group. Moreover, 90 % of FMR patients treated with Mitraclip were free from MV surgery of re-operation at five years, compared with 81 % treated surgically. Durability of the Mitraclip repair was confirmed at five years follow-up, with 86 % of the patients in both groups with MV regurgitation grades 1+ or 2+. NYHA I/II functional class at five years was present in FMR in 76 % of the Mitraclip patients compared with 100 % of surgical survivors at five years. Mitraclip patients had comparable stability of mitral annular dimensions at five years compared to baseline (3.8 cm versus 3.7 cm, p=0.20). Taramasso et al.41 have recently published the results of Mitraclip implantation in 109 consecutive patients with FMR and prohibitive surgical risk (logistic EuroSCORE [LogEuroscore] 22 ± 16 %). Mean ejection fraction (EF) was 28 ± 11 %; left ventricular end-diastolic diameter (LVEDD) was 68 ± 8 mm. Procedural success was 99.0 % and 30-day mortality was 1.8 %. At discharge, 87 % patients had MR ≤2+. At 12 months, EF was 34.7 ± 10.4 % (p=0.002 compared with pre-operative value). Actuarial survival at three years was 74.5 ± 7.0 %. Actuarial freedom from MR ≥3+ at 2.5 years was 70 ± 6 %. At one-year follow-up, 86 % of patients were in NYHA Class I-II. Pre-operative pro-B-type natriuretic peptide (pro-BNP) level ≥1,600 pg/ml was identified as an independent risk factor of mortality at follow-up. Recently, the new European guidelines included the MitraClip as a treatment option in high-risk and inoperable patients with FMR and severe symptoms despite optimal medical therapy (class IIb indication with evidence C) (see Table 1).21, 42–44 In the EVEREST II high surgical risk cohort, a 44 % reduction of the annual rate of hospitalisations was observed (0.82–0.46, p=0.0004) after Mitraclip implantation. After EVEREST II trial results (EuroPCR2014), including standard-risk patients, future guidelines may consider Mitraclip treatment as an option for FMR since it exerts sustained reduction of MR severity, sustained improvement in LV volumes and dimensions, and sustained improvement in NYHA functional class at five years, with low rates of conversion to MV surgery overall.

Conclusions MitraClip therapy is a safe procedure in selected high-risk patients and can be accomplished with low morbidity and mortality. MV repair is the preferred treatment for degenerative MV regurgitation. However, Mitraclip implantation should be considered for high-risk surgical patients.

Percutaneous Edge-To-Edge Repair EVEREST II trial included 26 % patients with FMR randomised to surgery or Mitraclip treatment. Recently reported five-year data (EuroPCR2014) have shown that freedom from mortality in Mitraclip patients (n=48) and surgical patients (n=18) is comparable within aetiologies: FMR Mitraclip 59.7 % and FMR Surgery 55.0 %, compared

1. Perlowski A, St Goar F, Glower DG, Feldman T, Percutanenous therapies for mitral regurgitation, Curr Probl Cardiol, 2012;37(2):42–68. 2. Feldman T, Young A, Percutaneous approaches to valve repair for mitral regurgitation, J Am Coll Cardiol, 2014;63(20):2057–68. 3. Franzen O, van der Heyden J, Baldus S, et al., MitraClip® therapy in patients with end-stage systolic heart failure, Eur J Heart Fail, 2011;13(5):569–76. 4. Maisano F, Franzen O, Baldus S, et al., MitraClip therapy

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For FMR, Mitraclip is a valuable clinical option in patients with adequate anatomy who are considered inoperable or with a high surgical risk, and should be considered as an important therapeutic modality in the multidisciplinary treatment of heart failure. We need to treat patients at an earlier stage to achieve better prognostic outcomes. n

demonstrates favourable mid-term outcomes in ACCESSEUROPE heart failure patients with left ventricular ejection fraction 30%: preliminary report from the 6-month ACCESSEU analysis cohort, Eurointerv, 2011;7(Suppl M). 5. Ling LH, Enriquez-Sarano M, Seward JB, et al., Clinical outcome of mitral regurgitation due to flail leaflet, N Engl J Med, 1996;335(19):1417–23. 6. Bonow RO, Carabello BA, Chatterjee K, et al., 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease:

a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons, J Am Coll Cardiol, 2008;52(13):e1–142. 7. Diodato MD, Moon MR, Pasque MK, et al., Repair of ischemic mitral regurgitation does not increase mortality or improve long-term survival in patients undergoing coronary artery

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revascularization: a propensity analysis, Ann of Thoracc Surg, 2004;78(3):794–9. 8. Mirabel M, Iung B, Baron G, et al., What are the characteristics of patients with severe, symptomatic, mitral regurgitation who are denied surgery?, Eur Heart J, 2007;28(11):1358–65. 9. van den Heuvel AFM, Alfieri O, Mariani MA, MitraClip in end-stage heart failure: a realistic alternative to surgery?, Eur J Heart Fail, 2011;13(5):472–4. 10. Otto CM, Verrier ED, Mitral regurgitation--what is best for my patient?, N Engl J Med, 2011;364(15):1462–3. 11. Cabrera-Bueno F, Molina-Mora MJ, Alzueta-Rodriguez FJ, Mitral regurgitation and cardiac resynchronization therapy: how long and what should we expect?, Europace, 2011;13(12):1801–2. 12. Slaughter MS, Rogers JG, Milano CA, et al., Advanced heart failure treated with continuous-flow left ventricular assist device, N Engl J Med, 2009;361(23):2241–51. 13. Franzen O, Baldus S, Rudolph V, et al., Acute outcomes of MitraClip therapy for mitral regurgitation in high-surgical-risk patients: emphasis on adverse valve morphology and severe left ventricular dysfunction, Eur Heart J, 2010;31(11):1373–81. 14. Alqoofi F, Feldman T, Percutaneous approaches to mitral regurgitation, Curr Treat Options Cardiovasc Med, 2009;11(6):476–82. 15. Feldman T, Kar S, Rinaldi M, et al., Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort, J Am Coll Cardiol, 2009;54(8):686–94. 16. Feldman T, Cilingiroglu M, Percutaneous Leaflet Repair and Annuloplasty for Mitral Regurgitation, J Am Coll Cardiol, 2011;57(5):529–37. 17. Taylor J, The percutaneous approach to mitral valve repair, Eur Heart J, 2011;32:249–51. 18. Chan PH, Di Mario C, Franzen O, Dissociation between anatomical and functional results after MitraClip implantation, Int J Cardiol, 2012;155(2):175–6. 19. Carpentier A, Chauvaud S, Fabiani JN, et al., Reconstructive surgery of mitral valve incompetence: ten-year appraisal, J Thorac Cardiovasc Surg, 1980;79(3):338–48. 20. Castillo JG, Solís J, González-Pinto Á, Adams DH, [Surgical echocardiography of the mitral valve], Rev Esp Cardiol, 2011;64(12):1169–81. 21. Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC),

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European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, et al., Guidelines on the management of valvular heart disease (version 2012), Eur Heart J, 2012;33(19):2451–96. 22. Kang DH, Kim JH, Rim JH, et al., Comparison of early surgery versus conventional treatment in asymptomatic severe mitral regurgitation, Circulation, 2009;119(6):797–804. 23. Iung B, Baron G, Tornos P, et al., Valvular heart disease in the community: a European experience, Curr Probl Cardiol, 2007;32(11):609–61. 24. Braunberger E, Deloche A, Berrebi A, et al., Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency, Circulation, 2001;104(12 Suppl 1):I8–11. 25. Enriquez-Sarano M, Sundt TM, Early surgery is recommended for mitral regurgitation, Circulation, 2010;121(6):804–11. 26. Feldman T, Franzen O, Low R, et al., Atlas of Percutaneous Edge-to-Edge Mitral Valve Repair , London, Uk: Springer, 2013;669. 27. Alegría-Barrero E, Chan PH, Di Mario C, Franzen O, Tools and techniques: edge-to-edge percutaneous MitraClip® implantation, EuroIntervention, 2012;7(12):1476–8. 28. Borgia F, Di Mario C, Franzen O, Adenosine-induced asystole to facilitate MitraClip placement in a patient with adverse mitral valve morphology, Heart, 2011;97(10):864. 29. Ledwoch J, Franke J, Baldus S, et al., Impact of the learning curve on outcome after transcatheter mitral valve repair: results from the German Mitral Valve Registry, Clin Res Cardiol, 2014 [Epub ahead of print]. 30. Alegría-Barrero E, Chan PH, Foin N, et al., Concept of the central clip: when to use one or two MitraClips®, EuroIntervention, 2014;9(10):1217–24. 31. Feldman T, Foster E, Glower DD, et al., Percutaneous repair or surgery for mitral regurgitation, N Engl J Med, 2011;364(15):1395–406. 32. Chan PH, She HL, Alegría-Barrero E, et al., Real-world experience of MitraClip for treatment of severe mitral regurgitation, Circ J, 2012;76(10):2488–93. 33. Chan PH, She HL, Alegría-Barrero E, et al., Effects of dynamic annular shape changes on MitraClip therapy and combining mitral cerclage annuloplasty--reply, Circ J, 2013;77(2):551. 34. Maisano F, Franzen O, Baldus S, et al., Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter,

nonrandomized post-approval study of the MitraClip therapy in Europe, J Am Coll Cardiol, 2013;62(12):1052–61. 35. Bolling SF, Deeb GM, Brunsting LA, Bach DS, Early outcome of mitral valve reconstruction in patients with end-stage cardiomyopathy, J Thorac Cardiovasc Surg, 1995;109(4):676–82. 36. Bolling SF, Mitral repair for functional mitral regurgitation in idiopathic dilated cardiomyopathy: a good operation done well may help, Eur J Cardiothorac Surg, 2012;42(4):646–7. 37. Crabtree TD, Bailey MS, Moon MR, et al., Recurrent mitral regurgitation and risk factors for early and late mortality after mitral valve repair for functional ischemic mitral regurgitation, Ann Thorac Surg, 2008;85(5):1537–42. 38. David TE, Uden DE, Strauss HD, The importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation, Circulation, 1983;68(3 Pt 2):II76–82. 39. Madesis A, Tsakiridis K, Zarogoulidis P, et al., Review of mitral valve insufficiency: repair or replacement, J Thorac Dis, 2014;6 (Suppl 1):S39–51. 40. Acker MA, Parides MK, Perrault LP, et al., Mitral-valve repair versus replacement for severe ischemic mitral regurgitation, N Engl J Med, 2014;370(1):23–32. 41. Taramasso M, Maisano F, Latib A, et al., Clinical outcomes of MitraClip for the treatment of functional mitral regurgitation, EuroIntervention, 2014 [Epub ahead of print]. 42. McMurray JJ, Adamopoulos S, Anker S, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur J Heart Fail, 2012;14(8):803–69. 43. Yancy CW, Jessup M, Bozkurt B, et al., 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, Circulation, 2013;128:e240–327. 44. Nishimura RA, Otto CM, Bonow RO, et al., 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol, 2014;63(22):e57–185. 45. Carpentier A, Adams DH, Filsoufi F, Carpentier’s Reconstructive Valve Surgery. From Valve Analysis to Valve Reconstruction, Philadelphia, US: Saunders, Elsevier, 2010.

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Heart Failure

le ation.

Ventricular Assist Devices – Evolution of Surgical Heart Failure Treatment Dominik W iedema nn, T homa s Ha be r l , J u l i a Ri e b a n d t , P a u l S i m o n , G ü n t h e r L a u f e r a n d D a n i e l Zimp f e r Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria

Abstract End-stage heart failure represents a substantial worldwide problem for the healthcare system. Despite significant improvements (medical heart failure treatment, implantable cardioverters, cardiac resyschronisation devices), long-term survival and quality of life of these patients remains poor. Heart transplantation has been an effective therapy for terminal heart failure, but it remains limited by an increasing shortage of available donor organs along with strict criteria defining acceptable recipients. For the last 50 years, mechanical alternatives to support the circulation have been investigated; however, during the early years device development has been marked in general by slow progress. However, in the past two decades, the technology has evolved dramatically. The purpose of this review is to give a short summary on the evolution of ventricular assist device (VAD) therapy and to give perspectives for future treatment of heart failure.

Keywords Ventricular assist device, mechanical circulatory support, heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 24 April 2014 Accepted: 13 June 2014 Citation: European Cardiology Review, 2014;9(1):54–8 Correspondence: Dominik Wiedemann, Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria. E: dominik.wiedemann@meduniwien.ac.at

History of Mechanical Circulatory Support The first reported clinical use of a left ventricular assist device (LVAD) was by Liotta and Crawford in 1963. Via a left thoracotomy, an intracorporeal pneumatically driven pump was implanted using left atrial inflow and descending thoracic aortic outflow. Despite the successful implantation, the patient died within a short period of time after the surgery.1 A few years later, De-Bakey implanted a paracorporeal pneumatic LVAD to support the left ventricle of a woman with left ventricular failure after prior cardiac surgery. The patient recovered and could be weaned from the device successfully.2,3 The first clinical use of a total artificial heart (TAH) was reported in 1969 by Cooley. The Dacron® and Silastic® pneumatic device was placed as a bridge to transplant (BTT) in a patient who could not be weaned from cardiopulmonary bypass. The procedure was successful, heart transplantation could be performed 32 hours after the implantation, but the patient died due to pneumonia.4 Over the subsequent 20 years results after cardiac transplantation improved to modern standards, therefore mechanical circulatory support was not at the centre of investigation and clinical use was scarce, but shortage of donor organs became an increasing problem.5,6 Concerning TAH development, the Jarvik/CardioWest™ device has to be mentioned. This device would ultimately led to the development of today’s SynCardia TAH, which led to extreme publicity but limited clinical use.7 Ventricular assist devices (VADs) were initially primarily used as bridge to recovery (BTR) for patients unable to wean from cardiopulmonary bypass despite inotropic support and intra-aortic Balloon pump (IABP) or as BTT.7,8 A milestone in VAD development was the Thoratec® VAD, engineered at Penn State University. Despite the fact that this

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pneumatically driven pump has undergone several modifications over the years, in its basic structure it is still in clinical use today. McBride et al., published a series of BTT and BTR patients supported on the pneumatic Thoratec device. Major adverse events were: bleeding complications (31–45 %), thromboembolic events (8 %) and device-related infection (18 %). Twelve of 44 patients recovered and 39 of 67 were successfully bridged to heart transplantation (HTx).9 The Thoratec paracorporeal VAD (PVAD) is the direct descendant of this device, and is currently approved as a BTT or BTR (see Figure 1). The more contemporary Levitronix® CentriMag® is an extracorporeal device approved for midterm support for patients in cardiogenic shock as a bridge to decision (BTD) (see Figure 2). It is also approved for use as a right ventricular assist device (RVAD) for up to 30 days of support. In contrast to the PVAD the CentriMag is a continuous flow centrifugal pump with a magnetically levitated rotor, is preload dependent and afterload sensitive and can deliver flows of nearly 10 litres per minute. The advantages of magnetic levitation technology in blood pumps are improved durability and minimisation of blood trauma.10 The CentriMag system has provided satisfying results over the past years: the Utah Artificial Heart Program reported 83 patients (2004 to 2009), 30 RVAD, eight LVAD, 25 biventricular assist device (BiVAD) and 30 patients supported with CentriMag-driven venoarterial extracorporeal membrane oxygenation (ECMO). Survival ranged from 63 % in the LVAD group to 30 % in the veno-arterial (V-A) ECMO group. There were no device failures and bleeding related to anticoagulation was the most common complication.10 Major concerns on the mentioned devices were reduced quality of life especially due to the fact that these devices were extracorporeal.

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With improvements in technology the pumps became smaller and the era of fully implantable devices began. Devices in this category have a driveline, which connects the intracorporeal device to either an external electrical power supply or a pneumatic driver. A broad variety of devices in this category were developed: The HeartMate® XVE, the HeartMate II (HMII), Micromed DeBakey, Jarvik 2000 FlowMaker®, HeartWare VAD (HVAD), DuraHeart and Berlin Heart INCOR. In the following years, long-term implantable LVADs have been studied and approved for BTT and destination therapy (DT) indications. Device development has progressed in a relatively orderly fashion in terms of both strategy for use and pump mechanism. Initially, pumps were conceived as a method of rescue and support to recovery. As experience grew and reliability improved implementation in a BTT scheme became common. Naturally, as data were acquired to support longer-term assistance and the devices themselves became more durable in general, DT implantation accelerated. As pulsatility was felt to be critical for organ recovery, initial LVAD designs featured pulsatile flow. Initial pulsatile devices were pneumatically driven and later electrically driven. Progress in the design and testing of newer continuous flow pumps was relatively rapid. Studies confirmed that pulsatile aortic flow was not required to resuscitate and maintain organ function in patients with end-stage heart failure.11–14 In addition, continuous flow LVADs were shown to provide significant benefits in objective quality of life and functional capacity.15,16

Current Clinically Important Second Generation Devices The Thoratec HMII (see Figure 3) is the most successful of the second generation LVAD cohort, with over 10,000 patients supported worldwide.17–19 It is a rotary continuous axial flow pump with an external electrical power source. Inflow cannula is inserted apically and an outflow graft anastomosed to the ascending aorta (in most of the cases) or alternatively to the subclavian artery as bailout strategy. The pump is preload dependent and afterload sensitive, runs in a fixed speed mode and is capable of up to 10 litres per minute flow at a mean aortic pressure of 100 mm mercury (Hg). The only moving part is the axial rotor, which spins on ruby ball-and-cup bearings, which are continuously washed by the flow stream. It is smaller and lighter than the HeartMate I (HMI) offering the possibility of fully intrathoracic implantation and implantations even in small adults. Recently, even minimal invasive approaches for both pump exchange and pump implantation over a subcostal incision have been described. The HMII is typically implanted into a properly sized preperitoneal pocket in the left subcostal region and utilises a driveline, which generally exits on the upper abdomen. The HMII is Food and Drug Administration (FDA) approved for both BTT and DT and has proven to be safe and effective. However, in the US the device has received approval for DT only recently, while in Europe implantation of the HMII for DT indication has already been performed for several years. The HMII BTT pivotal trial enrolled 133 patients at 26 centres in the US between March 2005 and May 2006.20 Patients were listed for transplantation as either United Network for Organ Sharing (UNOS) status IA or IB, and all had New York Heart Association (NYHA) class IV symptoms. Twenty-five percent were receiving more than one inotrope and 41 % were supported by an IABP. Seventy-five percent of patients reached the primary endpoint (number of patients who either survived to transplant, recovered and survived explant or were still alive on device) at 180 days. Fiftysix patients were transplanted, with an 80 % one-year survival. One

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Figure 1: Thoratec Paracorporeal Ventricular Assist Device Ventricle

Figure 2: CentriMag System

Console Pump

Motor

Flow probe

Figure 3: HeartMate II

patient recovered and had the device explanted. Twenty-five patients died before 180 days (19 %). Seventy-five percent of patients were discharged after LVAD implant; the median length of stay was 25 days. Adverse events included stroke in 11 patients (8 %), five of which occurred within the first 48 hours, device-related infection

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Heart Failure Figure 4: HeartWare Ventricular Assist Device

Figure 5: HeartMate III

HMII group versus 70 % in the comparison group. In-hospital survival in the HMII group was significantly better at 94 % compared with the comparison group at 85 %. Ninety-two percent of the HMII patients were discharged versus 75 % of the comparison group. Adverse events in the HMII included bleeding (21.0 %), device infection (20.2 %), stroke (6.5 %), RV failure (15.0 %) and device replacement (1.2 %). The important aspects of this trial were that it confirmed the good results seen in previous studies, even in an uncontrolled setting, and it suggested that the morbidity and mortality associated with HMII implantation and support are decreasing with time. The encouraging device performance in the BTT pivotal trial resulted in FDA approval for the DT indication.22 In a separate DT trial, 38 centres in the US randomised patients 2:1 to receive either the HMII or the HeartMate XVE. Thirty-three percent of the HMII versus 41 % of the HeartMate XVE patients died within two years. In the HMII group stroke occurred in 11 % and pump replacement in 10 % compared with 36 % and 12 %, respectively in the HeartMate XVE group. The HeartMate XVE replacements were required for bearing wear, valve deterioration or infection, while broken percutaneous leads were the cause of the majority of the HMII replacements. Actuarial survival rates at one and two years for the HMII patients were 68 % and 58 % compared with 55 % and 24 % in the HeartMate XVE patients. This trial showed improved survival and complication rates in advanced heart failure patients supported with the HMII continuous flow LVAD compared with those supported with the pulsatile HeartMate XVE. Very low rates of pump thrombosis of the HMII has been advocated as a major advantage of the system also in comparison with other contemporary devices. However, recently a report came out showing an unexpected sudden increase in rates of pump thrombosis in HMII patients.23 It remains a matter of debate what is causing this increase (changes in anticoagulation management, variability of implantation technique, pump-related factors, patient-related factors, etc.) and it is not clear if this increase in pump thrombosis is only temporary and will return to normal rates again. Nevertheless special attention has to be paid to this phenomenon.

(14 %), bleeding requiring surgery (31 %) and pump thrombosis in two patients. There were no device failures, and improvements in quality of life as well as functional capacity were significant. Survival of patients still on VAD support was 72 % at three years. Main complications were bleeding requiring surgical re-intervention in 26 %, driveline/pump infections in 16 %, right ventricular (RV) dysfunction in 13 % and RV failure requiring a RVAD in 6 %, 5 % had ischaemic stroke and 3 % haemorrhagic stroke. Four pumps have been removed due to thrombus. Likewise to the initial study, quality of life and functional capacity were significantly improved. The HMII was approved for BTT on the basis of the results reported above. Post-approval market analysis as required by the FDA was published in 2011. Implantation of the now commercially available HMII allowed the data to be registered by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), and the comparison group for this study was an INTERMACS cohort of 169 patients receiving another commercially available LVAD for BTT.21 The comparison group contained 135 patients with the Thoratec HeartMate XVE and 34 patients with the Thoratec IVAD, both pulsatile pumps. Ninety percent of the HMII group versus 80 % of the comparison group reached survival to transplant, survival on support or survival after device explant at six months. Overall, 12 months survival was 85 % in the

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The HeartWare® left ventricular assist system (LVAS) is an advanced continuous flow device, which is approved in Europe and recently for BTT indication in the US (see Figure 4).24 This centrifugal pump utilises an innovative combination of passive magnetic levitation and hydrodynamic suspension to eliminate any contact between the impeller and pump housing. There are no mechanical bearings. The HeartWare is small and designed for completely intrapericardial implantation, with inflow from the left ventricular (LV) apex and outflow via a graft to the ascending aorta (HeartWare International Inc, Framingham, MA, US).7 Like other continuous flow pumps it is preload dependent and afterload sensitive, operates at a fixed speed mode and is capable of delivering up to 10 litres per minute. Results of HeartWare trials have been encouraging. In a BTT evaluation in 50 European patients six and 24 months survival to orthotopic heart transplantation (OHT), recovery or ongoing LVAD support was 90 % and 79 %, respectively. Nine deaths were observed: three cases of sepsis, three multiple organ failures and three strokes. RV failure was seen in six cases. There was an 18 % incidence of device-related infection. (mainly driveline related) Seven devices were replaced, two for complications related to the hydrodynamic suspension mechanism and four for pump thrombus.

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Anticoagulation was adjusted for an international normalised ratio (INR) of 2.5–3.5.16 Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) is a BTT trial performed at 30 American centres from 2008 to 2010 and includes 140 patients in the treatment group with end-stage heart failure listed for cardiac transplant. Results in these patients were compared with 499 patient controls from INTERMACS, who had received a LVAD as BTT during the same time period. The primary outcome was survival on the original device, survival to OHT or recovery to explant at 180 days. Success was achieved in 92.0 % of the HeartWare group versus 90.1 % of the controls. Survival at 180 days and one-year in the HeartWare group was 94.0 % and 90.6 % versus 90.2 % and 85.7 % in the controls. Adverse events included bleeding requiring surgery (15.0 %), driveline infection (10.7 %), stroke (10.0 %), RV failure (22.0 %) and pump thrombus requiring replacement (3.0 %).25 Follow-up data was presented at the 2011 meeting of the International Society for Heart and Lung Transplantation (ISHLT) and included 110 additional patients approved by the FDA on a continued access protocol (CAP). The same inclusion criteria were used but the CAP patients, based on INTERMACS classification, had more advanced heart failure. Adverse events among the total 250 patient study group were as follows: bleeding requiring surgery 9.2 %, gastrointestinal bleeding 15.6 %, ischaemic stroke 7.2 %, haemorrhagic stroke 3.2 %, driveline infections 11.6 %, RV failure 19.6 % and death by 180 days 5.0 %. Sixteen pumps developed thrombus (6.4 %), 11 were exchanged and five were treated with intracavitary tissue plasminogen activator (tPA). Seventy-eight patients were transplanted with a 93 % 180 day post-transplant survival.26 A HeartWare DT trial, ‘Evaluation of the HeartWare Ventricular Assist System for Destination Therapy of Advanced Heart Failure (ENDURANCE)’, is currently accruing patients in the US. In the US the HeartWare system is currently only approved for BTT indication, FDA approval for DT is ongoing. In Europe the HVAD is already in use for BTT as well as for DT indication.

Figure 6: HeartWare MVAD®

Figure 7: Thoratec® Percutaneous Heart Pump

There is some evidence that the rate of pump thrombosis in HVAD patients could be slightly higher in comparison with other contemporary devices. Therefore, some centres including our own, started to change the anticoagulation regimen. At our department we give HeartWare patients two doses of 100 mg aspirin daily in addition to the standard treatment with phenprocoumon with a target INR of 2.5. One of the major advantages of the HeartWare device is its easy implantability and its small size. This facilitates even minimally invasive implantation of the HVAD over sternotomy sparing approaches.27

Future Outlook – Third Generation Device HeartMate III, HeartWare MVAD® Driveline Free Devices Currently the field of LVADs is undergoing an evolution towards smaller pumps with less blood trauma. Even catheter-based systems are on the horizon. The closer developments are the HeartMate III (HMIII) from Thoratec and the MVAD® from HeartWare. The HMIII (see Figure 5), a compact LVAD, has been designed and fabricated, featuring a centrifugal pump with a magnetically levitated rotor. The pump has been optimised by in vitro testing to achieve a design point of 7 litres per minute (L/min) against 135 mm Hg at high hydrodynamic efficiency (30 %) and to be capable of up to 10 L/min under such a load. Furthermore, the pump has demonstrated no mechanical failures, low haemolysis (4–10 mg/dl plasma free haemoglobin [Hb]) and low thrombogenicity during six (40, 27, 59,

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42, 27 and 49 day) in vivo bovine studies.28,29 Key features include the device’s ‘bearingless’ (magnetic levitation) design, textured surfaces similar to the HeartMate XVE LVAD to reduce anticoagulation requirements and thromboembolism, a sensorless flow estimator and an induced pulse mode for achieving an increased level of pulsatility with continuous flow assistance. In vitro design verification testing is underway. Preclinical testing has been performed in calves demonstrating good in vivo performance at an average flow rate of 6 L/min (maximum: >11 L/min) and normal end-organ function and host response. Induced pulse mode demonstrated the ability to produce a physiological pulse pressure in vivo. Thirteen LVADs have achieved between 16 and 40 months of long-term in vitro reliability testing and will be continued until failure. Both percutaneous and fully implanted systems are in development, with a modular connection for upgrading without replacing the LVAD.30 HeartWare’s MVAD pump (see Figure 6) is a continuous axial flow pump, approximately one-third the size of the HVAD pump. The

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Heart Failure MVAD pump is based on the same proprietary ‘contactless’ impeller suspension technology used in the HVAD pump, with its single moving part held in place through a combination of passive magnetic and hydrodynamic forces. In vitro and in vivo studies showed promising results. Within one in vivo study the MVAD pump was implanted in an ovine model (n=9) for 90 days. Results demonstrated the safety, reliability, haemocompatibility and biocompatibility of the MVAD pump. Nine animals were implanted for 90 ± 5 days. No complications occurred during surgical implantation. Seven of the nine animals survived until elective sacrifice. Each sheep that survived to the scheduled explant appeared physically normal, with no signs of cardiovascular or other organ compromise.31 Even a transapical implantation approach was tested.32 A new cannula configuration has been developed for transapical implantation, where the outflow cannula is positioned across the aortic valve. The two primary objectives for this feasibility study were to evaluate anatomic fit and surgical approach, and efficacy of the transapical MVAD configuration. Anatomic fit and surgical approach were demonstrated using human cadavers (n=4). Efficacy was demonstrated in acute (n=2) and chronic (n=1) bovine model experiments and assessed by improvements in haemodynamics, biocompatibility, flow dynamics and histopathology. Potential advantages of the MVAD pump include flow support in the same direction as the native ventricle, elimination of cardiopulmonary bypass and minimally invasive implantation. One of the major obstacles of current LVAD therapy is driveline infections. While wireless technologies have become daily routine in

1. Liotta D, Hall CW, Henly WS, et al., PROLONGED ASSISTED CIRCULATION DURING AND AFTER CARDIAC OR AORTIC SURGERY. PROLONGED PARTIAL LEFT VENTRICULAR BYPASS BY MEANS OF INTRACORPOREAL CIRCULATION, Am J Cardiol, 1963;12:399–405. 2. DeBakey ME, Left ventricular bypass pump for cardiac assistance. Clinical experience, Am J Cardiol, 1971;27:3–11. 3. DeBakey ME, Kennedy JH, Mechanical circulatory support: current status, Am J Cardiol, 1971;27:1–2. 4. Cooley DA, Liotta D, Hallman GL, et al., Orthotopic cardiac prosthesis for two-staged cardiac replacement, Am J Cardiol, 1969;24:723–30. 5. Lund LH, Edwards LB, Kucheryavaya AY, et al., The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Official Adult Heart Transplant Report--2013; focus theme: age, J Heart Lung Transplant, 2013;32:951–64. 6. Taylor DO, Edwards LB, Boucek MM, et al., Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report--2005, J Heart Lung Transplant, 2005;24:945–55. 7. Milano CA, Simeone AA, Mechanical circulatory support: devices, outcomes and complications, Heart Fail Rev, 2013;18:35–53. 8. Pierce WS, Parr GV, Myers JL, et al., Ventricular-assist pumping patients with cardiogenic shock after cardiac operations, N Engl J Med, 1981;305:1606–10. 9. McBride LR, Naunheim KS, Fiore AC, et al., Clinical experience with 111 thoratec ventricular assist devices, Ann Thorac Surg, 1999;67:1233–8; discussion 1238–9. 10. Breda JR, Gaia DF, Macedo M, et al., Ventricular assist device implantation with CentriMag VAS® for biventricular mechanical support, Rev Bras Cir Cardiovasc, 2013;28:401–4. 11. Drews T, Jurmann M, Michael D, et al., Differences in pulsatile and non-pulsatile mechanical circulatory support in long-term use, J Heart Lung Transplant, 2008;27:1096–101.

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all our lives it is still not safe enough to run an LVAD. Eliminating of the driveline as a source of infection with VADs powered transcutaneously without wires running through an open wound will make the devices far safer. Currently all major LVAD companies and several researchers are working on this problem and experimental testing is being performed – however, it is not a clinical reality as yet. Another approach to minimise implantation trauma is the percutaneous heart pump (PHP) by Thoratec (see Figure 7). This novel device is a fully catheter-based axial flow pump with a low profile consisting of a collapsible elastomeric impeller and nitinol cannula expandable to about 24 F. It is designed to deliver over 4 litres of flow. This device is currently under investigation. First-in-human use has already been reported.

Conclusion Taken together it can be stated that VAD therapy has developed from a pioneer era towards a solid clinical option for an increasing number of patients. In times of decreasing numbers of available donor organs, mechanical circulatory support might not only be the future of surgical heart failure treatment but also its present. Nevertheless careful patient selection, meticulous surgical handling and post-operative treatment have to be performed at a very high level in order to improve clinical outcome. The future will tell us which devices will be the best for patients. Apart from that the increasing number of LVAD patients represents an increasing challenge for the social systems all over the world. n

12. Sandner SE, Zimpfer D, Zrunek P, et al., Renal function after implantation of continuous versus pulsatile flow left ventricular assist devices, J Heart Lung Transplant, 2008;27:469–73. 13. Radovancevic B, Vrtovec B, de Kort E, et al., End-organ function in patients on long-term circulatory support with continuous- or pulsatile-flow assist devices, J Heart Lung Transplant, 2007;26:815–8. 14. Zimpfer D, Wieselthaler G, Czerny M, et al., Neurocognitive function in patients with ventricular assist devices: a comparison of pulsatile and continuous blood flow devices, ASAIO J, 2006;52:24–7. 15. Kugler C, Malehsa D, Tegtbur U, et al., Health-related quality of life and exercise tolerance in recipients of heart transplants and left ventricular assist devices: a prospective, comparative study, J Heart Lung Transplant, 2011;30:204–10. 16. Strueber M, O’Driscoll G, Jansz P, et al., Multicenter evaluation of an intrapericardial left ventricular assist system, J Am Coll Cardiol, 2011;57:1375–82. 17. Park SJ, Milano CA, Tatooles AJ, et al., Outcomes in advanced heart failure patients with left ventricular assist devices for destination therapy, Circ Heart Fail, 2012;5:241–8. 18. Rose EA, Gelijns AC, Moskowitz AJ, et al., Long-term use of a left ventricular assist device for end-stage heart failure, N Engl J Med, 2001;345:1435–43. 19. Rogers JG, Butler J, Lansman SL, et al., Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial, J Am Coll Cardiol, 2007;50:741–7. 20. Miller LW, Pagani FD, Russell SD, et al., Use of a continuousflow device in patients awaiting heart transplantation, N Engl J Med, 2007;357:885–96. 21. Starling RC, Naka Y, Boyle AJ, et al., Results of the postU.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted

Circulatory Support), J Am Coll Cardiol, 2011;57:1890–8. 22. Slaughter MS1, Rogers JG, Milano CA, et al., Advanced heart failure treated with continuous-flow left ventricular assist device, N Engl J Med , 2009;361(23):2241–51. 23. Starling RC, Moazami N, Silvestry SC, et al., Unexpected abrupt increase in left ventricular assist device thrombosis, N Engl J Med, 2014;370:33–40. 24. Strueber M, Larbalestier R, Jansz P, et al., Results of the postmarket Registry to Evaluate the HeartWare Left Ventricular Assist System (ReVOLVE), J Heart Lung Transplant, 2014;33:486–91. 25. Aaronson KD, Slaughter MS, Miller LW, et al., Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation, Circulation , 2012;125(25):3191–200. 26. Slaughter MS, Implantation of the HeartWare left ventricular assist device, Semin Thorac Cardiovasc Surg, 2011;23:245–7. 27. Haberl T, Riebandt J, Mahr S, et al., Viennese approach to minimize the invasiveness of ventricular assist device implantation, Eur J Cardiothorac Surg, 2014 [Epub ahead of print]. 28. Bourque K, Gernes DB, Loree HM 2nd, et al., HeartMate III: pump design for a centrifugal LVAD with a magnetically levitated rotor, ASAIO J, 2001;47:401–5. 29. Loree HM, Bourque K, Gernes DB, et al., The Heartmate III: design and in vivo studies of a maglev centrifugal left ventricular assist device, Artif Organs, 2001;25:386–91. 30. Farrar DJ, Bourque K, Dague CP, et al., Design features, developmental status, and experimental results with the Heartmate III centrifugal left ventricular assist system with a magnetically levitated rotor, ASAIO J, 2007;53:310–5. 31. McGee E Jr, Chorpenning K, Brown MC, et al., In vivo evaluation of the HeartWare MVAD Pump, J Heart Lung Transplant, 2014;33:366–71. 32. Tamez D, LaRose JA, Shambaugh C, et al., Early feasibility testing and engineering development of the transapical approach for the HeartWare MVAD ventricular assist system, ASAIO J, 2014;60:170–7.

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