ECR 10.2 by Radcliffe Cardiology

Volume 10 • Issue 2 • Winter 2015

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A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension Brendan P Madden

Myocardial Infarction With Non-obstructive Coronary Arteries – Diagnosis and Management Sivabaskari Pasupathy, Rosanna Tavella, Simon McRae and John F Beltrame

Home Orthostatic Training in Elderly Patients with Vasovagal Syncope – A Prospective Randomised Controlled Trial Steven Podd, Jacqueline Hunt and Neil Sulke

Takotsubo Syndrome – Stress-induced Heart Failure Syndrome Mary N Sheppard

A Valve histology showing progression of the disease

Disease Standard progression:cuff Age and(industry sex standard) Increased serum lipids Increased blood pressure Diabetes and metabolic syndrome Smoking Artery marking

Initiating factors: Biscuspid valve Generic factors Shear Stress Early lesion T cell Monocyte LDL Aorta

End-stage disease

Endothelium Ca2+ Oxidized LDL Macrophage Ang II

Fibrosa

TGF-β Osteopontin TNF-α Interleukin 1β ViewVentricularis Inflammatory Process Left ventricle

High Power of Myocytes of Calcific Aortic B Aortic-value anatomy Showing Transverse Stenosis Irregular Bands

Fibroblast

Calcification Increased alkaline phosphatase Osteoblast Increased BMP-2 Wrap CuffIncreased osteocalcin

Intelli Technology New Intelli wrap cuff

Artery marking

Normal

Aortic scleroisis

Smaller ‘acceptable range’ of placement versus brachial artery means risk of error if placed outside of range

Artery Phenotypic transformation Wnt3, Lrp5, and β catenin Bladder

Mid-to-moderate Artery aortic stenosis

Acceptable range Longer Servere aorticair bladder = larger scleroisis ‘acceptable range’ of

placement versus brachial artery Radcliffe Cardiology means risk of error if placed

Bladder

Lifelong Learning for outside of range is lower than with

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Volume 10 • Issue 2 • Winter 2015

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

Associate Editor

Velislav Batchvarov

Nesan Shanmugam

St George’s University of London, London, UK

Luigi Paolo Badano

Koichi Kaikita

Sven Plein

Kumamoto University, Kumamoto, Japan

University of Leeds, Leeds, UK

Velislav Batchvarov

Juan Carlos Kaski

St George’s University of London, London, UK

Piotr Ponikowski

Elijah Behr

Sverre Kjeldsen

St George’s University of London, London, UK

University Hospital, Oslo, Norway

John Beltrame

Wolfgang Koenig

University of Adelaide, Adelaide, Australia

University of Ulm, Ulm, Germany

Richard Conti

Steen Dalby Kristensen

University of Padua, Padua, Italy

University of Florida, Florida, US

Aarhus University, Aarhus, Denmark

Martin Cowie

Patrizio Lancellotti

Imperial College London, London, UK

University of Liège, Liège, Belgium

Filippo Crea

Catholic University of the Sacred Heart, Milan, Italy

Alberto Cuocolo

University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan

Colentina University Hospital, Bucharest, Romania

Polychronis Dilaveris

Hippokration General Hospital, Athens, Greece

Kenneth Earle

St George’s University of London, London, UK

Perry Elliott

Gaetano Antonio Lanza Catholic University of the Sacred Heart, Milan, Italy

Giuseppe Mancia University of Milano-Bicocca, Milan, Italy

Antoni Martínez-Rubio University Hospital of Sabadell, Sabadell, Spain

Mario Marzilli University of Pisa, Pisa, Italy

Attilio Maseri Vita-Salute San Raffaele University, Milan, Italy

Noel Bairey Merz

University College London, London

Cedars-Sinai Heart Institute, Los Angeles, US

Albert Ferro

Petros Nihoyannopoulos

King’s College London, London

Imperial College London, London, UK

Wroclaw Medical University, Wroclaw, Poland

Eva Prescott Bispebjerg Hospital, København, Denmark

Fausto Rigo Ospedale dell’Angelo Hospital, Venice, Italy

Giuseppe Rosano IRCCS San Raffaele, Rome, Italy

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

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

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

Hiroaki Shimokawa Tohoku University, Sendai, Japan

Rosa Sicari Italian National Research Council

Iana Simova National Cardiology Hospital, Sofia, Bulgaria

Philippe Gabriel Steg Imperial College London, London, UK

Jun Takata Kochi University, Nankoku, Japan

Augusto Gallino

Argyrios Ntalianis

Dimitris Tousoulis

Xavier Garcia-Moll

National and Kapodistrian University of Athens, Athens, Greece

Autònoma University, Barcelona, Spain

Camici Paolo

Konstantinos Toutouzas

Simon Gibbs

San Raffaele Hospital, Segrate, Italy

University of Athens, Athens, Greece

Imperial College London, London, UK

Zoltan Papp

Dimitrios Tziakas

Tommaso Gori

University of Debrecen, Debrecen, Hungary

Democritus University of Thrace, Xanthi, Greece

Antonio Pelliccia

Hiroshi Watanabe

Technical University of Munich, Munich, Germany

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

Hamamatsu University School of Medicine, Hamamatsu, Japan

Eileen Handberg

Joep Perk

José Luis Zamorano

Linnaeus University, Kalmar, Sweden

University Complutense, Madrid, Spain

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Johannes Gutenberg University Mainz, Mainz, Germany

Martin Halle

University of Florida, Florida, US

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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. © 2015 All rights reserved

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Established: April 2005 Frequency: Bi-annual Current issue: Winter 2015

Aims and Scope

Submissions and Instructions to Authors

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

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

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

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

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RadcliffeCardioAd.indd 194

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Contents

Foreword 73 Juan Carlos Kaski Editorial 74 The Syndrome of Inter-Atrial Conduction Block

Velislav N Batchvarov

76 Stroke Prevention in Atrial Fibrillation – The Use of NOACS in Everyday Clinical Practice

Gheorghe-Andrei Dan and Adrian Catalin Buzea

Angina Pectoris – Myocardial Infarction

79 Myocardial Infarction With Non-obstructive Coronary Arteries – Diagnosis and Management

Sivabaskari Pasupathy, Rosanna Tavella, Simon McRae and John F Beltrame

Cardiomyopathies and Heart Failure

83 Takotsubo Syndrome – Stress-Induced Heart Failure Syndrome Mary N Sheppard

Sleep-disordered Breathing in Heart Failure

Systemic and Pulmonary Hypertension

Simon G Pearse, Martin R Cowie, Rakesh Sharma, Ali Vazir

95 Home Blood Pressure Monitoring Jacob George and Thomas MacDonald

102 A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension

Brendan P Madden

Structural Cardiac and Vascular Disease

108 Calcific Aortic Valve Disease – Molecular Mechanisms and

Therapeutic Approaches

Daniel Alejandro Lerman, Sai Prasad and Nasri Alotti

113 Cardiac Amyloid –

An Update

Jason N Dungu

Syncope and Sudden Cardiac Death

118 Sudden Cardiac Death Risk Stratification –

An Update

Reginald Liew

123 Home Orthostatic Training In Elderly Patients With Vasovagal Syncope A Prospective Randomised Controlled Trial

Steven Podd, Jacqueline Hunt and Neil Sulke

ECR10.2_contents.indd 72

11/12/2015 14:38

Foreword

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

his issue of European Cardiology Review features articles of major practical relevance as well as reviews and expert opinions on topics of pathophysiological importance.

J Dungu reviews diagnostic and prognostic issues regarding cardiac amyloid highlighting the importance of imaging for the diagnosis and management of the condition. M Sheppard gives a pathologist’s perspective on stress cardiomyopathy while D Lerman et al’s manuscript focuses on the clinical implications of aortic calcification. A current issue that is of major interest i.e. sleep-disordered breathing in heart failure, is tackled by SG Pearse et al. One of the sections of the current issue has been devoted to systemic and pulmonary hypertension, featuring important contributions by B Madden on practical diagnostic pathways in pulmonary hypertension and J George et al on the importance of home blood pressure monitoring. The problems of which NOAC to use in clinical practice and the management of anticoagulation in high bleeding risk patients are addressed by G Dan. The myocardial infarction session features a scholarly review on MINOCA by S Pasupathy et al and there are also two other important manuscripts, one authored by R Liew et al on the topic of Sudden Cardiac Death Risk Stratification and the second one by V Batchvarov on Inter-Atrial Conduction Block, a recently reported novel syndrome. Last but not least, an original research article by S Podd et al. on Home Orthostatic Training In Elderly Patients With Vasovagal Syncope closes the current issue, objectively assessing the role of orthostatic training in the elderly for prevention of vasovagal syncope. We hope that this issue of European Cardiology Review will assist the reader in getting insight into the diagnosis and management of frequent and complex conditions affecting the cardiovascular system. n

ECR10.2_foreword.indd 73

07/12/2015 17:10

Editorial

The Syndrome of Inter-atrial Conduction Block Ve l i s l a v N B a t c h v a r o v St George’s University of London, London, United Kingdom

Abstract The formulation of the syndrome of interatrial conduction block is an important step for improved identification of patients at high risk of developing atrial fibrillation (those with advanced, that is, third degree interatrial block, which includes retrograde instead of normal activation of the left atrium). The rationale and potential benefits of prophylactic antiarrhythmic treatment of patients with advanced interatrial block currently seems not sufficiently convincing and requires further study including prospective trials. In addition to the identified future directions for research in this syndrome, it seems important also to explore novel electrocardiogram (ECG) methods (e.g. new electrode positions and ECG leads) for improved characterisation of the atrial electrical events. Oesophageal electrocardiography and vectorcardiography are old, venerable and unjustifiably forgotten ECG techniques: their additional use of for better diagnosis of interatrial conduction block is highly commendable.

Keywords Electrocardiography, P wave, interatrial block, atrial fibrillation, atrial abnormality, oesophageal electrocardiography, vectorcardiography Disclosure: The author has no conflicts of interest to disclose. Received: 28 July 2015 Accepted: 16 August 2015 Citation: European Cardiology Review, 2015;10(2):74–5 Correspondence: Velislav N Batchvarov, Cardiac & Vascular Sciences Research Centre, St George’s University of London, Cranmer Terrace, London SW17 0RE,UK. E: velislav.batchvarov@gmail.com

The two most important, both medically and socially, cardiac arrhythmic problems of our time are sudden cardiac death due to ventricular fibrillation (VF) (mainly in the setting of coronary artery disease) and atrial fibrillation (AF). For both of them, the identification of electrocardiogram (ECG) markers that can reliably predict the occurrence of the arrhythmia is generally an unresolved matter. An important step towards the identification of one such marker of sharply increased risk of occurrence of AF is the formulation of the syndrome of interatrial block (or syndrome of Bayes de Luna, if the medical community will accept the eponym), which needs to be distinguished from the more general (and currently more widely used) term ‘left atrial abnormality’.1 The ECG criteria for third degree (advanced) interatrial block proposed by Bayes de Luna and associates are P wave duration of 120 ms or more and biphasic (plus-minus) P wave in the inferior leads II, III and AVF reflecting delayed and retrograde activation of the left atrium (instead of its normal activation via the Bachman bundle). The late and retrograde activation of the left atrium can be demonstrated more clearly with the simultaneous recording of surface and oesophageal (that is, left atrial) ECG recording and with the abnormal inscription of the second part of the P wave loop on the vectorcardiogram (VCG). Bayes de Luna and associates have investigated the interatrial conduction abnormalities for more than 20 years and have convincingly demonstrated that patients with advanced interatrial block have significantly increased risk of atrial fibrillation compared with those with less-severe forms of interatrial block (e.g. those with first degree block – delayed but still normal and not retrograde infero-superior activation of the left atrium). As is often the case in cardiology, it is less clear what to do with these patients. The rationale and the potential benefits of prophylactic antiarrhythmic treatment of patients with advanced interatrial conduction

Batchvarov_FINAL.indd 74

block for prevention of AF as formulated by de Luna et al.1 does not sound to me sufficiently convincing. The use of Class I medications that will further depress conduction seems counterintuitive and, of course, against our bitter experience with the application of these medications for prevention of VF during the years before the Cardiac Arrhythmia Suppression Trial (CAST) trail.2 On the other hand, current evidence of the effect of various modes of pacing for prevention of AF is not consistent.3 However, the ultimate verdict about the effectiveness (or lack thereof) of such preventive therapy will be given, of course, only by carefully designed prospective trials, as suggested by the authors. The authors have identified important directions for future research on this syndrome, including the creating of international registry to enable follow-up of these patients, ECG-morphological studies to identify the underlying substrate, possible genetic influences and others. To this I would add one more purely electrocardiographic aspect, as described below. The standard 12-lead ECG, at least in its present format and currently available methods for visual and computerised analysis, has important limitations when applied to the study of the atrial electrical events. Its format and method of acquisition (that is, the number and positions of the nine recording electrodes and the specific interelectrode connections for construction of the eight independent leads) has remained virtually unchanged since the late 1940s, that is, decades before the beginning of the modern era of interest in AF. As noted recently, historically this system has been optimised for assessment of ventricular rather than atrial electrical events.4,5 I think it is important to explore alternative chest lead positions and, possibly, alternative lead constructions (such as bi- and multipolar leads) that could probably be more suitable for assessment of atrial abnormalities and conduction defects.

11/12/2015 14:43

The Syndrome of Inter-atrial Conduction Block

To overcome the limitations of the standard 12-lead ECG and better characterise the interatrial conduction delays, Bayes de Luna and colleagues have also applied two old and venerable electrocardiographic methodologies, namely oesophageal ECG recording and VCG. This is highly commendable. Regrettably, both methods are largely unknown to young generations of electrocardiographers. The oesophageal ECG recording provides a high-amplitude, sharply delineated (left atrial) P wave and thus can considerably help the analysis of left atrial activation. The method is easily applicable (think of transesophageal echocardiography), very often even in emergency settings, when the detection and assessment of the P wave can be crucial for ECG rhythm analysis (e.g. during broad QRS complex tachycardia). The normal and abnormal morphology of oesophageal P wave and its temporal relation to the surface ECG, to my knowledge,

1. 2. 3. 4. 5.

have not been sufficiently investigated. Intuitively, the quantitative assessment of the much larger and more clearly delineated (compared with the surface ECG) oesophageal P wave (that is, its duration, amplitude, morphology, notching/fractionations, etc.) especially if the recording is saved in a digital format to enable the application of software programs, could further enhance the assessment of atrial conduction defects. Vectorcardiography is not only a very useful method for morphological ECG analysis, it is also a powerful tool for teaching, comprehension and mental visualisation of the sequence in space of depolarisation and repolarisation. Sadly, several generations of ECG readers have been deprived of the merits of this method during their training. Luckily, in recent years, VCG seems to have undergone a revival due to the effort of some researchers, among them de Luna and his associates. n

Henein MY, Gronlund C, Tossavainen E, et al. Right and left heart dysfunction predict mortality in pulmonary hypertension. Clin Physiol Funct Imaging 2015: epub ahead of press Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321 :406–12. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation 2014;130 :e199–e267. Guillem MS, Climent AM, Bollmann A, et al. Limitations of Dower’s inverse transform for the study of atrial loops during atrial fibrillation. Pacing and Clin Electrophysiol 2009;32 :972–80. Malik M, Broadening the scope of electrocardiography. Pacing and Clin Electrophysiol 2009;32 :969–71.

EUROPEAN CARDIOLOGY REVIEW

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11/12/2015 14:43

Editorial

Stroke Prevention in Atrial Fibrillation – The Use of NOACs in Everyday Clinical Practice Gheorg h e - A n d r e i D a n 1 a n d A d r i a n Ca t a l i n B u z e a 2 1. International Society of Cardiovascular Pharmacotherapy; 2. University of Medicine ‘Carol Davila’ – Colentina University Hospital, Bucharest, Romania

Abstract Non-antivitamin K oral anticoagulants (NOACs) have recently emerged as a new class of antithrombotic drugs. Four large-scale, randomised controlled trials (RCT) accredited dabigatran, rivaroxaban and edoxaban with evident advantages for stroke prevention in atrial fibrillation (AF) compared with warfarin. The superiority concerns not only the manageability but also the antithrombotic efficacy and safety. Aspects of real-life clinical experience with NOAC for stroke prevention in AF are analysed in an attempt to underline some practical differences. If at present the individualisation of the NOAC class drugs is still a subject of debate it is probable that in the near future we will be able to adapt the drug and dosages to individual patient’s profile.

Keywords NOAC (non-antivitamin K oral anticoagulants), oral anticoagulants (OAC), abigatran, ivaroxaban, apixaban, edoxaban, warfarin, darucizumab, atrial fibrillation, stroke prevention Disclosure: Gheorghe-Andrei Dan is a consultant, is on the speakers bureau, an investigator and has received small speaker fees for Boehringer Ingelheim, Bayer, Pfizer and Daiichi-Sankyo, but has nothing linked to this paper. Adrian Catalin Buzea has no conflicts of interests to disclose. Received: 14 October 2015 Accepted: 25 November 2015 Citation: European Cardiology Review, 2015;10(2):76–8 Correspondence: Gheorghe-Andrei Dan, 22 Kiseleff Blvd, 011346 Bucharest, Romania. E: andrei.dan@gadan.ro

Non-antivitamin K oral anticoagulants (NOACs) are no longer ‘new’ drugs: they already are established. Since randomised controlled trials (RCTs) usually enrol highly selected patient populations, the best way to demonstrate new drug efficiency/cost-effectiveness is to use long-term and ‘real-world’ data. In order to understand the NOAC experience in real life properly, one must first understand how the substrate for such therapy was modified, i.e. what is the awareness and attitude towards stroke prevention in atrial fibfrillation (AF) in everyday clinical practice. Several important registries,1–4 with different collection designs, have demonstrated that despite the considerable increase in the awareness of AF-related risk of stroke in the last years, the percentage of undertreated patients remains high. This also includes the AF patients with lower risk (CHA2DS2VASc score of one in men and two in women) who also require anticoagulant therapy.5 There is also a percentage of over-treated patients (CHA2DS2VASc of 0) and an excess of aspirin use despite of the demonstrated lack of preventive effect of this drug in AF6 and increased bleeding risk when associated to oral antivitamin K anticoagulants (AVKs) or NOACs. A third conclusion is that despite an increase of worldwide approval of NOAC they are still underused. RELY-ABLE study was an open-label prolongation of the RE-LY study with a 28-month extension of the parent study follow-up beyond 4 years of ongoing treatment. The results were consistent with those of RE-LY with an impressive low rate of intracerebral bleeding that was sustained throughout the study.7 XANTUS was a prospective, single-arm, observational, non-interventional phase IV study intended to collect real-world data on adverse events in patients with non-valvular AF treated with rivaroxaban and to determine the safety profile of rivaroxaban across the broad range

Dan_FINAL.indd 76

of patient risk profiles encountered in routine clinical practice.8 Again the stroke and bleeding rates were low in patients treated with NOAC. An interesting post-hoc pooled analysis of the RE-LY study according to the European label recommendations failed to demonstrate a difference compared with the original RE-LY study.9 An extensive real-life analysis included 134,414 elderly patients treated with 2 dosages of dabigatran (150 mg and 75 mg – not approved in Europe) and warfarin and collected 2,715 events. The results confirmed global risk benefit observed in RE-LY (20 % reduction in stroke and 66 % reduction in devastating intracerebral haemorrhage compared with warfarin) but also confirmed the slight increase in gastrointestinal haemorrhage. 10 A somewhat similar pharmacovigilance study conducted by the US Department of Defense electronic healthcare records that included 27,467 real-life patients treated with rivaroxaban confirmed the low rate of bleeding observed in ROCKET-AF.11 Adherence to therapy is a very important target in considering NOACs if we need to translate effective therapies in effective disease management in patients and diseases where persistence to warfarin therapy is suboptimal. A once-daily regimen could be an advantage in this regard as demonstrated by several studies,12,13 which highlight the superiority of rivaroxaban compared with warfarin, dabigatran and apixaban. However, in the case of NOAC the rhythmicity of drug administration could have apparent paradoxical implications. The explanation of this paradox is the relatively short half-life of NOAC. When the drug is administered twice daily (bid), the drug concentration inside the therapeutical interval is more constant with lower trough to peak rate than in the once-daily (od) regimen. This implies that missing one dose (which could happen quite often in real life) of an od regimen will

11/12/2015 14:47

Stroke Prevention in Atrial Fibrillation – The Use of NOACs in Everyday Clinical Practice

lead to a similar lowering in plasma drug exposure as missing three consecutive doses in a bid regimen, which is less likely in real life14 (see Figure 1).

Figure 1: Implications for NOAC of the Effect of Nonpersistence in Cases of Once-and Twice-daily Regimen (Modified from Reference 15) Dose delivered OD Dose delivered BID

This apparent paradox caused by a greater continuity of drug action in a bid regimen could be the basis of a greater need of persistence required for the od than for bid regimen.15

but the test is not widely available. The PT has some sensitivity for rivaroxaban but not for apixaban (see Table 1)

Antidote to NOACs The lack of an antidote to NOACs has been a major concern in the debates about their use in clinical practice. Most often, bleeding due to NOAC is mild to moderate and responds to the usual supportive or anti-hemorrhagic management treatment as with warfarin, for which the ‘antidote’ – intravenous vitamin K is far from ideal. Nonetheless, the antidote matter has a clear clinical relevance when dealing with severe haemorrhage or during emergent surgery. A solution to the problem seems to offer the humanised monoclonal antibody fragment (idarucizumab) with has much higher binding affinity to thrombin than dabigatran, no procoagulant or anticoagulant effect and rapid onset of action. The product is already available on the market as dabigatran antidote.20 Other antidotes targeting factor X and/or other coagulation components are under advanced research.

Selecting the right NOAC for each patient Selecting the right NOAC for the each patient is probably one of the most challenging problems of current clinical practice for prevention of embolism in AF. A complicated stochastic multiacceptability criteria evaluation comparing the benefit–risk balance across current antithrombotic therapies in AF patients21 revealed a net favourable profile of NOAC compared with other anti-thrombotic drugs across a wide range of assumptions regarding the relative importance of clinical events. In clinical practice it seems that the preference for one NOAC or another is actually mainly based on the perceived relative importance of clinical profile of the patient. There have been several attempts to individualise NOAC therapy based on pharmacological criteria,22 accumulated real-life experience, RCT results or Summary of Product Characteristics (SmPC) descriptions. However, so far no single approach has been validated for practice and presently the best approach seems to be balanced between current knowledge summarised in the available guidelines,19 doctor’s experience and the clinical profile and preference of the patient.

EUROPEAN CARDIOLOGY REVIEW

Dan_FINAL.indd 77

Concentration

A challenge for future research is that currently there is no approved test to guide therapeutical decisions and the routine coagulation monitoring is not mandatory for NOACs. However, in special circumstances (emergent surgery, thrombolysis indication for stroke, haemorrhagic complications, etc.) the clinician needs an informative test. Currently available tests have variable impact depending on NOAC.16–18 For dabigatran, the prothrombin time (PT) is too insensitive, the thrombin time (TT) is too sensitive and the activated partial thromboplastin time (aPTT) is prolonged under dabigatran, but the relation is curvilinear and reagent-dependent. The diluted thrombin time (Hemoclot) and the ecarin clotting time (ECT) are more suitable but unfortunately with reduced availability. For practical purposes, the most commonly used is the aPTT: a prolonged aPTT indicates that the patient is within therapeutical dabigatran concentration. For rivaroxaban and apixaban the situation is more difficult. The direct anti-Xa activity assay is consistent with plasma concentration,

OD Missed dose

OD regimen BID regimen 5

Day

Table 1: Usefulness of Clotting Tests for Monitoring NOAC Effect Dabigatran

Rivaroxaban Apixaban

Edoxaban

aPTT

⊗

∅

TT, dTT

⊕

∅

ECT

⊕

∅

Anti-FXa assays

∅

⊕

∅

⊗

∅

INR

∅

⊕ = useful; ∅ = not useful; ⊗ = qualitative. aPTT = activated partial thromboplastin time; ECT = ecarin clotting time; dTT = diluted thrombin time; FXa = activated factor X of coagulation; INR = international normalised ratio; PT = prothrombin time; TT = thrombin time. Adapted from reference 19.

Conclusions and Practical Implications NOAC represents one of the most important drug discoveries of the new century. These drugs are the result of a new understanding of the treatment of pathological coagulation because, unlike AVK, they target the critical molecules of the coagulation mechanism and not coagulation as a whole. Their development is a result of both the success as well as the limitations of a half a century of treatment with AVK. As a class, NOAC proved to be superior to warfarin for stroke prevention in AF both as anti-embolic efficacy and safety, mainly in terms of major bleeding and especially intracerebral bleeding. NOACs represent palpable progress in the management of AF patients at risk of stroke and effort should be made to implement this therapy in daily practice. However, it should be emphasised that a ‘class’ is only a necessary simplification in the history of a new drug molecule. The pharmacological profile of molecules is as different as the physiological implication of their specific target. Only a better understanding of both components in relation to the clinical profile of the patient would enable us to pinpoint a specific molecule in a specific dosage for a specific patient. When first introduced in practice, one of the main advantages of NOAC was a simplified therapy with few dosages and no need for coagulation monitoring after the model of ‘one fits all’. Available data do not allow us yet to fully individualise NOAC members and dosages for the vast spectrum of all patients but the expectations are at the horizon. As UK Prime Minister Winston Churchill said: ‘This is not the end. It is not even the beginning of the end. But it is perhaps the end of the beginning.’ n

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Editorial 1.

Lip GY, Laroche C, Dan GA, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace 2014;16 :308–19. Lip GY, Laroche C, Dan GA, et al. ‘Real-World’ Antithrombotic Treatment in Atrial Fibrillation: The EORP-AF Pilot Survey. Am J Med 2014;6 :519–29.e1. Huisman MV, Rothman KJ, Paquette M, et al. Antithrombotic Treatment Patterns in 10,871 Patients with Newly Diagnosed Nonvalvular Atrial Fibrillation: The GLORIA-AF Registry, Phase II. Am J Med 2015;128 :1306–13.e1. Kakkar AK, Mueller I, Bassand JP, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS One 2013;8 :e63479. Lip GY, Skjøth F, Rasmussen LH, Larsen T. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc Score. J Am Coll Cardiol 2015;65 :1385–94. Själander S, Själander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014;16 :631–8. Connolly SJ, Wallentin L, Ezekowitz MD. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study, Circulation . 2013;128 :237–43.

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10.

11.

12.

13.

14.

15.

Camm AJ, Amarenco P, Haas S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2015: epub ahead of print. Lip GY1, Clemens A, Noack H, et al. Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database. Thromb Haemost 2014;111 :933–42. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131 :157–64. Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015;38 :63–8. Laliberté F, Cloutier M, Nelson WW, et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin 2014;30 :1317–25. McHorney CA, Crivera C, Laliberté F, et al. Adherence to nonvitamin-K-antagonist oral anticoagulant medications based on the Pharmacy Quality Alliance measure. Curr Med Res Opin 2015;31 :2167–73. Vrijens B, Claeys MJ, Legrand V, et al. Projected inhibition of platelet aggregation with ticagrelor twice daily vs. clopidogrel once daily based on patient adherence data (the TWICE project). Br J Clin Pharmacol 2014;77 :746–55. Vrijens B, Heidbuchel H. Non-vitamin K antagonist oral

16.

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18.

19.

20. 21.

22.

anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace 2015;17 :514–23. JDouxfils , Mullier F, Loosen C, et al. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature, Thromb Res 2012;130 :956–66. Douxfils J, Chatelain C, Chatelain B, et al. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013;110 :283–94. Douxfils J, Mullier F, Robert S, et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012;107 :985–97. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2015;17 :1467–507. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373 :511–20. Dogliotti A, Giugliano RP. A novel approach indirectly comparing benefit – risk balance across anti-thrombotic therapies in patients with atrial fibrillation. Eur Heart J 2015;1 :15–28. Gong, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 2013;29 :S24–S33.

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Angina Pectoris – Myocardial Infarction

Myocardial Infarction With Non-obstructive Coronary Arteries – Diagnosis and Management Sivabaskari Pasupathy, 1,2 Rosanna Tavella, 1,2 Simon McRae 1,3 and John F Beltrame 1,2 1. University of Adelaide; 2. Central Adelaide Local Health Network; 3. SA Pathology, Adelaide, SA, Australia

Abstract MI with non-obstructive coronary arteries (MINOCA) is an enigma that is being increasingly recognised with the frequent use of angiography following acute MI. To diagnose this condition, it is important to determine the multiple potential underlying mechanisms that may be responsible, many of which require different treatments. This review evaluates the contemporary diagnosis and management of MINOCA.

Keywords Cardiac magnetic resonance imaging, coagulation, coronary angiography, coronary artery disease, diagnosis, MINOCA, myocardial infarction Disclosure: The authors have no conflicts of interest to disclose. Received: 20 October 2015 Accepted: 5 November 2015 Citation: European Cardiology Review, 2015;10(2):79–82 Correspondence: John F Beltrame, Discipline of Medicine, The Queen Elizabeth Hospital/University of Adelaide, 28 Woodville Road, Woodville South, Adelaide, SA, Australia 5011. E: john.beltrame@adelaide.edu.au

Early coronary angiography performed during acute MI (AMI) identifies an occluded vessel in most patients with ST elevation MI (STEMI)1 and less frequently in those with non-STEMI;2 however, ≥90 % of patients with AMI have evidence of obstructive coronary artery disease.3 For these patients with overt coronary artery disease (CAD), the benefits of reperfusion strategies and cardioprotective therapies are well established and appropriate considering the documented atherothrombotic process involved. However, in up to 10 % of patients with clinical diagnostic features of AMI, early angiography does not reveal an occluded vessel or possibly any evidence of CAD.3 These patients constitute an intriguing subgroup referred to as MI with non-obstructive coronary arteries (MINOCA),4 which present a diagnostic and therapeutic conundrum to clinicians as prospective studies evaluating these patients are limited. This review evaluates the contemporary diagnosis and management of MINOCA.

MINOCA Definition The diagnosis of MINOCA requires: (1) clinical documentation of a myocardial infarct, (2) the exclusion of obstructive CAD and (3) no overt cause for the AMI presentation, such as cardiac trauma (Table 1). Accordingly, the diagnosis is usually made following invasive coronary angiography in the evaluation of an apparent AMI. The diagnostic criteria for AMI are universally established and focus on a significant increase in troponin levels associated with clinical markers of ischaemia. 5 Conventionally, obstructive CAD is defined as an epicardial artery stenosis ≥50 % 6 on angiography, thus a stenosis <50 % is required for the diagnosis of MINOCA. Although the diagnostic criteria for MINOCA are specific, it should not be considered a final diagnosis but a ‘working diagnosis’ whose underlying aetiology requires further evaluation. This is similar to the diagnosis of heart failure, where the aetiology

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responsible needs to be determined rather than just demonstration of ventricular dysfunction.

Aetiology The mechanism responsible for AMI involves an interaction between atheroma, thrombosis and vascular dysfunction. Given the limited burden of atherosclerosis in MINOCA, it would be expected that atheroma would play a small role in the pathogenesis of the infarct; hence, the focus should be on other potential mechanisms (Table 2). Previous studies have implicated spasm,7 microvascular dysfunction8 and thrombophilic states (Factor V Leiden,9–11 protein C deficiency12 and malignancy-associated thrombophilia13). DaCosta et al. reported that a third of patients with MINOCA had evidence of coronary spasm or thrombotic disorders.10 Furthermore, non-ischaemic causes of MINOCA must also be considered. Several disorders that result in myocardial injury may mimic ischaemic MI and fulfil the universal criteria for AMI. Acute myocarditis, pulmonary embolism and some cardiomyopathies14,15 are examples of disorders that may mimic AMI. Delineating these aetiologies is paramount since it will impact on the appropriate management of these patients.

Prevalence The reported prevalence of MINOCA varies depending on the data collection methods and definitions used. For example, data from large AMI registries with consecutive patient recruitment report a prevalence of 1–4 % when the definition is restricted to completely normal coronaries (0 % stenosis);13,16 however, if a <50 % stenosis threshold is used, the prevalence has been reported as 5–14 %.3,17,18 A recent systematic review of the published literature using a <50 % stenosis threshold for MINOCA reported a prevalence of 6 % (95 %CI: 5–7 %).4

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Angina Pectoris – Myocardial Infarction Table 1. Definition of MINOCA 1. Acute myocardial infarction (AMI) criteria5 Clinical evidence of AMI including any of the following: • Symptoms – chest pain criteria • ECG – new changes including ST segments, LBBB, pathological Q waves • Myocardial perfusion imaging – new loss of viable myocardium • Left ventricular functional imaging – new regional wall motion abnormality 2. Non-obstructive coronary arteries6 No stenosis ≥50 % on coronary angiography 3. No clinically overt cause for AMI presentation LBBB = left bundle branch block; MINOCA = MI with non-obstructive coronary arteries.

Table 2. Aetiology of MINOCA Mechanism

Clinical disorder

Diagnostic evaluation

Renal impairment

Serum creatinine

Pulmonary embolism

CTPA, CMRI

Cardiomyopathy

Echo, CMRI

Inflammation

Myocarditis

CRP, CMRI

Coronary artery

Vasospastic angina

ACh provocation testing

clearance Increased right heart pressures Cardiac causes Structural myocardial dysfunction

spasm

Drug screen (e.g. cocaine)

Microvascular

Microvascular angina

Coronary flow reserve

dysfunction

Microvascular spasm

ACh provocation testing

Coronary slow flow

TIMI frame count

phenomenon Thrombophilia

Factor V Leiden

Thrombophilia

Protein C and

Disorder screen

S deficiency Ach = Acetylcholine; CMRI = cardiac magnetic resonance imaging; CRP = C-reactive protein; CTPA = computed tomography pulmonary angiogram; Echo = echocardiography; MINOCA = MI with non-obstructive coronary arteries; TIMI = thrombolysis in MI.

Clinical Presentation As the working diagnosis of MINOCA is typically made following coronary angiography, some clinically overt non-ischaemic causes of the apparent AMI presentation will be immediately evident. For example, direct cardiac trauma resulting in myocardial injury with associated ECG changes and increased troponin levels should not be diagnosed as MINOCA if angiography is undertaken to document the underlying coronary anatomy. Similarly, classical apical ballooning on left ventriculography with non-obstructive coronary arteries on angiography should be diagnosed as takotsubo cardiomyopathy rather than MINOCA. This exclusion of patients with overt clinical causes for their AMI presentation is consistent with the principle of MINOCA as a working diagnosis, necessitating the determination of the underlying cause. In patients with clinical markers of an AMI in the absence of obstructive CAD and no overt underlying cause for their presentation (Table 1), a diagnosis of MINOCA should be made and the potential causes (as listed in Table 2) considered. A systematic review of

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Prognosis The prognosis of MINOCA is often considered benign by clinicians given the absence of obstructive CAD. However, contemporary data suggest that the prognosis is more guarded with some large studies reporting an all-cause mortality rate of 1.1–2.6 % at 30 days and 3.3–6.4 % at 12 months.13,19 Furthermore, a Korean AMI registry that evaluated 12-month all-cause mortality rates in 8,510 consecutive AMI patients reported rates of 3.1 % in those with MINOCA and 3.2 % in those with single- or double-vessel obstructive CAD.20

Diagnostic Measures

Non-cardiac causes Reduced troponin

the published literature comparing the clinical characteristics of AMI with and without obstructive CAD revealed that patients with MINOCA (a) tended to be younger, (b) were more frequently women, but (c) had a similar cardiovascular risk profile.4 Thus, distinguishing a patient with MINOCA from those with obstructive CAD on the basis of the clinical presentation and characteristics alone is not possible.

When using the working diagnosis of MINOCA to assess the underlying cause, the first step is to exclude non-cardiac pathology responsible for the raised troponin levels (and thus incidental nonobstructive coronaries). Examples include pulmonary embolism and renal impairment (as discussed below). Thereafter, cardiac causes should be considered, including disorders associated with: (a) structural myocardial dysfunction and (b) ischaemic myocardial damage (Table 2).

Non-cardiac Investigations Acute pulmonary embolism may mimic AMI, presenting with chest pain and the associated acute right heart strain producing ECG changes and an increase in troponin levels. Thus, a diagnosis of acute pulmonary embolism needs to be considered in MINOCA, but the merits of routinely screening for this diagnosis are less clear. Collste et al. performed routine computed tomography pulmonary angiography in 100 consecutive MINOCA patients and did not identify any cases of pulmonary embolism.21 Accordingly, although this diagnosis needs to be considered in MINOCA, pulmonary angiography is not justified as routine assessment tool and should be reserved for clinically suspicious cases. The use of routine D-dimer assessment in patients with MINOCA to exclude pulmonary embolism needs to be evaluated. Renal impairment may be associated with elevated troponin levels due to reduced clearance.22 Thus, the diagnosis of AMI may be difficult in the presence of renal impairment, but should be distinguishable by serial measurements.

Cardiac Investigations Troponin may be released (a) from dysfunctional myocardial cells in disorders associated with structural myocardial dysfunction, and/or (b) during ischaemic myocardial injury arising from coronary artery spasm, coronary microvascular dysfunction or coronary thrombosis associated with a thrombophilic disorder (Table 2). Delineating these aetiologies is important considering the different treatment approaches required for the specific diagnoses.

Cardiac Magnetic Resonance Imaging Cardiac MRI (CMRI) should be the initial diagnostic investigation for evaluating the cardiac causes of MINOCA. Non-contrast CMRI provides

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Myocardial Infarction With Non-obstructive Coronary Arteries

useful assessment of structural myocardial dysfunction and readily identifies cardiomyopathies, including takotsubo cardiomyopathy. Furthermore, late gadolinium enhancement images provide evidence for the diagnosis of myocarditis and subendocardial MI. In this regard, CMRI has a spatial resolution to detect a myocardial infarct zone with a mass as small as 0.16 grams. The use of this imaging modality in MINOCA is well illustrated by Leurent et al., who performed CMRI in 107 consecutive MINOCA patients at a mean delay of 6.9 days.23 They reported the following findings with CMRI: myocarditis in 60 %, AMI in 16 %, takotsubo cardiomyopathy in 14 %, and normal findings in 10 %. Of note, the diagnostic yield with CMRI is increased when imaging is undertaken within 7 days of presentation, as delayed imaging may result in some features no longer being evident. However, even with early imaging, 10–20 % of CMRI studies failed to identify any abnormalities despite the clinical presentation consistent with an AMI.14,23–25 Whether small infarcts may have been missed by the gadolinium enhancement CMRI remains a possibility.

Provocative Spasm Testing Provocative spasm testing may be considered in patients with MINOCA. Studies have demonstrated a variable prevalence of inducible spasm in such patients (15–95 %).10,26 It appears to be particularly prevalent among Asian patients, with a reported frequency of 81 % in Japanese27 and 61 % in Korean28 patients with MINOCA.

Thrombophilia Disorder Screening Thrombophilia disorder screening has been performed in several MINOCA studies with abnormalities detected in as many as 19 % of patients.11 Hereditary thrombophilia disorders reported in patients with MINOCA include Factor V Leiden, prothrombin variant G20210A, Factor XII deficiency and protein C and S deficiencies. Important acquired hypercoagulable states that may predispose to MINOCA include collagen vascular disorders, systemic vasculitis, systemic lupus, antiphospholipid syndrome, polycythemia vera, thrombocythaemia, and the use of anabolic steroids or oestrogens/progestins.

Therapeutic Measures Identifying treatable causes of MINOCA is fundamental to its clinical assessment as these may have prognostic implications and may impact on its guarded prognosis. For example, coronary artery spasm is effectively treated with nitrates and calcium channel blockers, with use of the latter shown to be a survival determinant in patients with MINOCA.32 In addition, identification of thrombophilia disorders may influence treatment and could impact on the patient’s offspring in the case of hereditary thrombophilia. The management of MINOCA with no specific underlying aetiology identified requires further investigation. There are no prospectively conducted studies to evaluate if conventional treatments used for AMI patients with obstructive CAD are of benefit in MINOCA. Thus, whether aspirin, statins, beta-blockers and/or angiotensinconverting enzyme inhibitors should be routinely used in patients with MINOCA is open to speculation.

Drug Screening Drug screening for sympathomimetic agents may be indicated in some patients, as cocaine29 and methamphetamines30,31 have been associated with MINOCA. These agents may induce coronary artery spasm via their alpha-agonist properties. Thus, evaluating the history for the use of these agents and, where appropriate, urine drug screening should be considered.

DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303 :897–902. DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after non-q-wave myocardial infarction. N Engl J Med 1986;315 :417–23. Hochman JS, Tamis JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global use of strategies to open occluded coronary arteries in acute coronary syndromes iib investigators. N Engl J Med 1999;341 :226–32. Pasupathy S, Air T, Dreyer RP, et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015;131 :861–70. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60 :1581–98. Scanlon PJ, Faxon DP, Audet AM, et al. Acc/aha guidelines for coronary angiography. A report of the american college of cardiology/american heart association task force on practice guidelines (committee on coronary angiography). Developed in collaboration with the society for cardiac angiography and interventions. J Am Coll Cardiol 1999;33 :1756–824. Ong P, Athanasiadis A, Hill S, et al. Coronary artery spasm as a frequent cause of acute coronary syndrome: The caspar (coronary artery spasm in patients with acute coronary syndrome) study. J Am Coll Cardiol 2008;52 :523–27. Diver DJ, Bier JD, Ferreira PE, et al. Clinical and arteriographic characterization of patients with unstable angina without critical coronary arterial narrowing (from the timi-iiia trial). Am J Cardiol 1994;74 :531–7. Mansourati J, Da Costa A, Munier S, et al. Prevalence of factor v leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost 2000;83 :822–5.

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Conclusion MINOCA is identified using a working diagnosis made following coronary angiography in the assessment of patients with an AMI. It is imperative that the underlying aetiology responsible for the condition is closely considered and investigated. In patients in whom no specific cause is found, further studies are warranted to assess the most effective treatment. n

10. Da Costa A, Isaaz K, Faure E, et al. Clinical characteristics, aetiological factors and long-term prognosis of myocardial infarction with an absolutely normal coronary angiogram: A 3-year follow-up study of 91 patients. Eur Heart J 2001;22 :1459–65. 11. Dacosta A, Tardy-Poncet B, Isaaz K, et al. Prevalence of factor v leiden (apcr) and other inherited thrombophilias in young patients with myocardial infarction and normal coronary arteries. Heart 1998;80 :338–40. 12. Lande G, Dantec V, Trossaert M, et al. Do inherited prothrombotic factors have a role in myocardial infarction with normal coronary arteriogram? J Intern Med 1998;244 :543–4. 13. Larsen AI, Galbraith PD, Ghali WA, et al. Characteristics and outcomes of patients with acute myocardial infarction and angiographically normal coronary arteries. Am J Cardiol 2005;95 :261–3. 14. Gerbaud E, Harcaut E, Coste P, et al. Cardiac magnetic resonance imaging for the diagnosis of patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. Int J Cardiovasc Imag 2012;28 :783–94. 15. Agewall S, Giannitsis E, Jernberg T, Katus H. Troponin elevation in coronary vs. non-coronary disease. Eur Heart J 2011;32 :404–11. 16. Sharifi M, Frohlich TG, Silverman IM. Myocardial infarction with angiographically normal coronary arteries. Chest 1995;107 :36–40. 17. Patel MR, Chen AY, Peterson ED, et al. Prevalence, predictors, and outcomes of patients with non-st-segment elevation myocardial infarction and insignificant coronary artery disease: Results from the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the acc/aha guidelines (crusade) initiative. Am Heart J 2006;152 :641–7. 18. Gehrie ER, Reynolds HR, Chen AY, et al. Characterization and outcomes of women and men with non-st-segment elevation myocardial infarction and nonobstructive coronary artery disease: Results from the can rapid risk stratification of

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unstable angina patients suppress adverse outcomes with early implementation of the acc/aha guidelines (crusade) quality improvement initiative. Am Heart J 2009;158 :688–94. Frycz-Kurek AM, Gierlotka M, Gąsior M, et al. Patients with no significant lesions in coronary arteries and st-segment elevation myocardial infarction have worse outcome than patients with non-st-segment elevation myocardial infarction: Analysis from pl-acs registry. Kardiol Pol 2010;68 :1211–7. Kang WY, Jeong MH, Ahn YK, et al. Are patients with angiographically near-normal coronary arteries who present as acute myocardial infarction actually safe? Int J Cardiol 2011;146 :207–12. Collste O, Sorensson P, Frick M, et al. Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: Results from the stockholm myocardial infarction with normal coronaries study. J Int Med 2013;273 :189–96. Aviles RJ, Askari AT, Lindahl B, et al. Troponin t levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med 2002;346 :2047–52. Leurent G, Langella B, Fougerou C, et al. Diagnostic contributions of cardiac magnetic resonance imaging in patients presenting with elevated troponin, acute chest pain syndrome and unobstructed coronary arteries. Arch Cardiovasc Dis 2011;104 :161–70. Baccouche H, Mahrholdt H, Meinhardt G, et al. Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009;30 :2869–79. Habibian M, Luis S, Luis C, et al. Comparison of the utility of transthoracic echocardiographic and cardiac magnetic resonance imaging in patients presenting with troponin positive chest pain with unobstructed coronary arteries. Heart Lung Circ 2011;20 :S165.

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Angina Pectoris – Myocardial Infarction 26. Hung MJ, Kuo LT, Cherng WJ. Amphetamine-related acute myocardial infarction due to coronary artery spasm. Int J Clin Pract 2003;57 :62–4. 27. Fukai T, Koyanagi S, Takeshita A. Role of coronary vasospasm in the pathogenesis of myocardial infarction: Study in patients with no significant coronary stenosis. Am Heart J 1993;126 :1305–11. 28. Kim MH, Park EH, Yang DK, et al. Role of vasospasm in

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acute coronary syndrome - insights from ergonovine stress echocardiography. Circ J 2005;69 :39–43. 29. Minor RL Jr, Scott BD, Brown DD, Winniford MD. Cocaine-induced myocardial infarction in patients with normal coronary arteries. Ann Intern Med 1991;115 :797–806. 30. Chen JP. Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary

arteries: Refractory global coronary microvascular spasm. J Invasive Cardiol 2007;19 :E89–92. 31. Sadeghian S, Darvish S, Shahbazi S, Mahmoodian M. Two ecstasy-induced myocardial infarctions during a three month period in a young man. Arch Iran Med 2007;10 :409–12. 32. Yasue H, Takizawa A, Nagao M, et al. Long-term prognosis for patients with variant angina and influential factors. Circulation 1988;78 :1–9.

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Cardiomyopathies and Heart Failure

Takotsubo Syndrome – Stress-induced Heart Failure Syndrome Mary N Sheppard St George’s University Medical School, London, United Kingdom

Abstract Takotsubo syndrome has been established as an entity in the past 30 years, particularly with the introduction of interventional angiography for investigation of chest pain. Typically, it occurs in middle-aged females as a response to a stressful event, such as bad news, death, accident, natural disaster, etc. but there is not always a specific trigger. Takotsubo mimics acute myocardial infarction with electrocardiogram changes and elevated troponins. On interventional angiography the coronary arteries are normal with typical apical ballooning of the left ventricle. This feature led to its descriptive name, given by Japanese cardiologists, as the left ventricle resembles a lobster trap with a narrow neck extending into a round ventricle. This leads to a reduction in cardiac function. Takotsubo is believed to be a response to catecholamine release following a stressful event resulting in temporary myocardial damage. It usually has a benign course with spontaneous return of cardiac function. However it may recur and in a small percentage of patients can result in sudden cardiac death with arrhythmia, acute myocardial infarction and cardiac rupture. It is usually treated symptomatically depending on the severity of presentation.

Keywords Stress, cardiomyopathy, takotsubo, broken heart, catecholamine, spasm, cardiac failure, cardiogenic shock, cardiac rupture Disclosure: The author has no conflicts of interest to disclose. Received: 25 August 2015 Accepted: 7 October 2015 Citation: European Cardiology Review, 2015;10(2):83–8 Correspondence: Mary Sheppard, Department of Cardiovascular Pathology, Centre for Cardiovascular Sciences Research, Jenner Wing, St. George’s University of London, Cranmer Terrace, London SW17 0RE. E: m.sheppard@sgul.ac.uk

Takotsubo syndrome is an acute reversible heart failure syndrome, which is increasingly recognised by coronary angiography for patients with acute ‘cardiac’ chest pain.1 It is a distinct disease entity from acute coronary syndrome, although the initial presentation has similar features to either ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI). Early access to diagnostic coronary angiography has helped identify the increasing incidence of this condition and over the past 24 years there has been increase in the number of case reports, series and registries reported.2

Nomenclature Various names have been used to describe the appearance now described as Takotsubo cardiomyopathy or Takotsubo syndrome, following the initial label given by Sato and colleagues in 1990, comparing the appearance of the left ventricle at end-systole to the local Japanese fishermen’s octopus pots in the Hiroshima fishing markets.3 Many names have been used for the condition, including stress or stress-induced cardiomyopathy, apical ballooning syndrome,4 ampullary-shaped cardiomyopathy5,6 and ‘broken-heart’ syndrome in the context of bereavement.7 While it is a form of acute heart failure, one of the characteristics contributing to the definition is the recovery of the dysfunctional myocardial segments. The majority of patients recover normal cardiac function and patients have a low risk of major adverse cardiac events. The term cardiomyopathy implies a primary disease of the cardiac muscle, but the full recovery and low major adverse cardiac event rate at follow up show major differences with the primary cardiomyopathies. The consensus is that as the diagnosis of Takotsubo syndrome is currently made based upon clinical observations, it fulfils the definition of a clinical syndrome rather than a cardiomyopathy.

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Definition Takotsubo syndrome and its associated variants constitute a type of acute, reversible heart failure that may represent a form of acute catecholaminergic myocardial stunning in the absence of culprit occlusive coronary artery disease to explain the pattern of temporary left ventricular (LV) dysfunction.8–11 Several diagnostic criteria strategies have been proposed, including those by the Mayo Clinic (modified in 2008), the Japanese Takotsubo Cardiomyopathy Group, the Gothenburg Group and the Takotsubo Italian Network.12–16 The author was part of the working group that developed the new 2014 European Society of Cardiology (ESC) Takotsubo Syndrome Diagnostic Criteria (see below). It is important to note that whilst this condition predominantly affects post-menopausal women (~90 % of all cases reported, particularly in the larger cohorts), men and younger women can also from suffer the condition and therefore demographic features are not a mandatory part of the proposed diagnostic criteria.

Diagnostic criteria 1. Transient regional wall motion abnormalities of the left and/or right ventricular (RV) myocardium, which are frequently, but not always, preceded by a stressful trigger (emotional or physical). 2. Regional wall motion abnormalities usually extending beyond a single epicardial vascular distribution, often resulting in circumferential dysfunction of the ventricular segments involved (apical and/or mid-LV or basal segments). 3. Absence of culprit atherosclerotic coronary artery disease including acute plaque rupture, thrombus formation and coronary dissection or other pathological conditions to explain the pattern of temporary LV dysfunction observed (e.g. hypertrophic cardiomyopathy, viral myocarditis).

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Cardiomyopathies and Heart Failure 4. New and reversible electrocardiogaphy (ECG) abnormalities (ST-segment elevation, ST depression, left bundle branch block, T-wave inversion and/or QTc prolongation) during the acute phase. 5. Significantly elevated serum natriuretic peptide (B-type natriuretic peptide [BNP] or N-terminal pro b-type natriuretic peptide [NTproBNP]) level during the acute phase. 6. Positive but relatively small elevation in cardiac troponin measured using a conventional assay (i.e. disparity between the troponin level and the amount of the dysfunctional myocardium present). 7. Recovery of ventricular systolic function on cardiac imaging at follow up.

Clinical Subtypes – Primary and Secondary Takotsubo Syndrome The medical community has reported a variety of clinical scenarios and contexts in which patients with Takotsubo syndrome present to medical attention. These can be classified into two groups:

Primary Takotsubo Syndrome Primary Takotsubo syndrome occurs in individuals when the specific symptoms described are the primary reason for their acute presentation. These include patients with or without clearly identifiable stress triggers (these are often emotional) and any potential co-existing medical conditions that may serve as predisposing risk factors, but are not the primary cause for the catecholamine rise. These cases can be considered primary Takotsubo syndrome, with clinical management directed to the specific complications.

Secondary Takotsubo Syndrome A significant proportion of cases occur in individuals already hospitalised for other medical, surgical, anaesthetic, obstetric or psychiatric conditions. These individuals have a sudden activation of their sympathetic nervous system and/or a rise in catecholamines and develop an acute Takotsubo syndrome as a complication of their primary condition or its treatment. These should be diagnosed as secondary Takotsubo syndrome, thereby focusing on the management pathway not only for Takotsubo syndrome and its cardiac complications, but also for the primary underlying disease and its treatment that served as the trigger for the secondary Takotsubo syndrome.

Anatomical Variants Primary and secondary Takotsubo syndromes can present with an array of possible anatomical variants.17–19 The initial definition of Takotsubo syndrome described what is now considered the classic pattern of LV regional wall motion abnormalities, with apical and circumferential mid-ventricular hypokinesia and basal hypercontractility. At end-systole the left ventricle has the typical appearance of the Takotsubo with a narrow neck and globular lower portion, giving the appearance of virtual ‘apical ballooning’. This typical Takotsubo syndrome variant with apical dysfunction is present in ~50–80 % cases depending on the various series reported, but a number of other anatomical variants may also occur. The two most common atypical variants are the inverted Takotsubo or basal variant, with circumferential basal hypokinesia and apical hypercontractility – also referred to as the ‘nutmeg’ or ‘artichoke’ heart – and the mid-ventricular variant with circumferential midventricular hypokinesia and both basal and apical hypercontractility.20–22 This has a unique end-systolic appearance which has been likened to either a Greek vase or the ‘ace of spades’, although the basal variant also can have the ace of spades appearance. In both inverted and mid-LV Takotsubo variants, the similar principle exists of reversible

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LV dysfunction affecting more than one coronary territory, usually circumferential pattern, in the absence of culprit coronary artery disease. Other rarer variants have been described, including biventricular apical dysfunction, dysfunction sparing the apical tip (possibly a form of the mid-ventricular Takotsubo variant) and isolated RV Takotsubo syndrome.19,23–25 These different morphological variants may depend upon the timing of early segment recovery and clinical evaluation. Recurrent cases have been described with different anatomical variants in the same individual, suggesting that an individual can be susceptible to more than one subtype.26,27

Epidemiology Several series in Asian and Western, predominantly Caucasian, populations suggest around 1–2 % of patients with suspected acute coronary syndrome (ACS) are eventually diagnosed with Takotsubo syndrome.17,28 With increasing awareness and more widespread access to early coronary angiography, the syndrome is now being recognised and appreciated more frequently. In the first study, Takotsubo syndrome was diagnosed in 0.02 % of all acute hospitalisations (6,837/33,506,402 patients).29 The majority were elderly post-menopausal women (90 %, aged from 66–80 years), a demographic repeated across many published cohorts, with risk factors including smoking, alcohol abuse, anxiety states and hyperlipidaemia. A higher Takotsubo syndrome rate was observed in whites compared with African Americans and Hispanics (67.4 % versus 4.4 % and 4.3 %, respectively).29 The second study and largest cohort to date reported details of 24,701 patients with a discharge code for Takotsubo syndrome. The study found similar demographics with 89 % women, with a mean age of 66.9 ± 30.7 years, and most patients (59.6 %) were ≥65 years old.30

Gender Differences Takotsubo syndrome predominantly affects post-menopausal women. In the German Takotsubo syndrome registry (324 patients; 91 % female and 9 % male with a mean age of 68 ± 12 versus 66 ± 12 years, respectively), both genders showed similar demographic and clinical characteristics.8 Emotional stress or no identifiable trigger were more prevalent in triggering episodes in women. Conversely a physical stress-triggering event, shock and/or resuscitation on presentation and higher levels of cardiac biomarkers (troponin), QT prolongation were more frequent in men. The National Inpatient Sample USA cohort (2008–2009; 24,701 Takotsubo syndrome patients) reports significantly higher mortality rates in male (8.4 % male versus 3.6 % females; p<0.0001), perhaps reflecting the higher frequency of underlying severe critical illness and secondary Takotsubo syndrome (36.6 % in men versus 26.8 % in women; p< 0.0001).30

Age Elderly patients are at higher risk of Takotsubo syndrome and related major complications, whereas fewer than 10 % of patients are below 50 years of age.29,31 In the Takotsubo Italian Network, Takotsubo syndrome patients older than 65 years have greater prevalence of hypertension, cerebrovascular disease, a lower glomerular filtration rate and LVEF at discharge. Older adults (≥75 years) have higher in-hospital complications and in-hospital mortality rates (6.3 % versus 2.8 % of overall in-hospital mortality).9

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Pathophysiology Given the frequently sudden, unexpected stressful precipitant, the signs of sympathetic activation at presentation and the secondary medical triggers that also lead to extreme sympathetic activation, the role of catecholamines appears central to the pathophysiology of Takotsubo cardiomyopathy. Serum catecholamine levels at presentation are significantly elevated compared with both resting levels in the individual patient and to levels in comparable patients with acute heart failure secondary to acute myocardial infarction.32 Several varieties of iatrogenic Takotsubo syndrome cases have been reported after administration of sympathomimetic drugs; for example, dobutamine in stress echocardiography.33 Several hypotheses have been proposed to explain the unique cardiac appearance in Takotsubo syndrome and the cardiac response to severe stress. These can be broadly divided into vascular and myocardial causes.

Acute Multivessel Coronary Spasm The initial cases described in Japan frequently had concomitant vasospasm at diagnostic coronary angiography and it is conceivable that some individuals may be prone to multivessel coronary artery spasm. Some authors propose that Takotsubo syndrome results from multivessel vasospasm and is a form of ischaemic stunning with superimposed catecholamines.34 In some cases vasospasm correlates with the region of dysfunction, but equally in other cases it does not, which goes against vasospasm as the cause of Takotsubo syndrome.35 There are also significant differences in histopathological features when examining endomyocardial biopsies taken from patients with Takotsubo syndrome that show a pattern of myocardial abnormalities not associated with infarcted, stunned or hibernating myocardium, which would not support a primary vascular cause.36 All patients showed the typical contractile pattern of Takotsubo and complete functional recovery within 12 ± 3 days. In ‘acute’ biopsies, many vacuoles of different sizes were found with intracellular accumulation of glycogen. Structural deteriorations characterised by disorganisation of contractile and cytoskeletal proteins could be seen, but evidence of oncotic and apoptotic cell death, as well as infarction, were absent.

Acute Left Ventricular Outflow Tract Obstruction Acute LV outflow tract obstruction (LVOTO) has been proposed as the cause for Takotsubo syndrome. Individuals may develop a dynamic mid-cavity LV obstruction under catecholamine excess. Potentially older women with smaller hearts, who frequently have prominent septal bulges, could be predisposed to acute LVOTO during intense stress and sympathetic activation. This could explain the transient nature of the regional dysfunction as the apical wall stress would subsequently be reduced by the ensuing ischaemia and apical dysfunction, limiting pressure necrosis and infarction. LVOTO was noted in 25 % of cases in the acute phase of Takotsubo syndrome,37 which indicates that it can be a contributory factor in a subset of patients but is unlikely to be the underlying main cause of Takotsubo syndrome.

Direct Catecholamine-mediated Myocardial Stunning A consistent finding across several mammalian species, including humans, is a higher sympathetic nerve density in the basal myocardium compared with the apex. Conversely, there is an apical-basal gradient of β adrenergic receptors (βAR). These opposing sympathetic nerve and βAR gradients allow balanced myocardial responses to sympathetic activation under low and medium levels of activation, but at the highest

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levels epinephrine release from the adrenal glands would perfuse the heart via the circulation and the receptor gradient would determine the response. The second element of the hypothesis proposed is that epinephrine at low and medium doses is a positive inotrope, but at the highest doses it becomes a negative inotrope via the β2AR, by activating a switch from the Guanine Nucleotide binding protein stimulation to the cardioinhibitory Guanine Nucleotide binding protein inhibition (Gi) secondary messenger.38,39 This could explain the transient negative inotropism observed in the apical myocardium after exposure to very high levels of circulating epinephrine, such as those reported in Takotsubo syndrome patients following triggers of extreme stress. Activation of the β2AR-Gi pathway is cardioprotective and may minimise the toxic effects of excessive catecholaminergic stimulation upon the myocardium. This hypothesis was tested in a rodent model in which high-dose epinephrine induced reversible apical hypokinesia and it was found this Takotsubo model could be prevented by prior treatment with pertussis toxin, which deactivates Gi signalling.40 Combinations of these hypotheses form the most likely causes of the cardiac response to severe stress.41

Clinical Presentation and Diagnosis Individuals with Takotsubo syndrome typically present with acute and unstable chest pain of cardiac origin (angina), breathlessness, palpitations due to sinus tachycardia or arrhythmia and in the more severe cases presyncope or syncope secondary to ventricular tachyarrhythmias, severe LVOTO and/or cardiogenic shock. The majority of diagnoses of Takotsubo syndrome are made at cardiac catheterisation when diagnostic coronary angiography demonstrates the absence of culprit coronary artery disease to explain the presenting symptoms, ECG changes and regional wall motion abnormalities. Once the diagnosis of Takotsubo syndrome is confirmed, early cardiac imaging and cardiac biomarkers are helpful to exclude myocardial infarction and to further stratify risk. This strategy is to be recommended to allow patients with a higher-risk phenotype to be kept under observation with appropriate monitoring in a coronary care or highdependency care setting, while those with lower risk can be cared for in a non-specialist ward and discharged once baseline imaging and risk stratification has been completed and the patient is asymptomatic, free of arrhythmias and haemodynamically stable. When the clinical picture is uncertain, cardiac magnetic resonance imaging with late gadolinium enhancement often clarifies the presence or absence of acute myocardial infarction in a typical coronary distribution.18,19

Pathology The majority of Takotsubo syndrome cases survive. The rare cases that have undergone biopsy during the acute phase show contractionband necrosis in myocytes as evidence of catecholamine-triggered cardiomyocyte calcium overload (see Figure 1).42 This can be can be fatal due to the complications of cardiogenic shock, arrhythmia or cardiac rupture and can be readily detected post-mortem in a confirmed case of Takotsubo syndrome. More difficult is the case of sudden cardiac death in the community with a stressful precipitant and a structurally normal heart and coronary arteries.43–45 In addition to inherited arrhythmic sudden death syndromes known to be triggered by stress (e.g. catecholaminergic polymorphic ventricular tachycardia), acute Takotsubo syndrome with ventricular fibrillation or

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Cardiomyopathies and Heart Failure Figure 1: High Power View of Myocytes Showing Transverse Irregular Bands of Hyper Contracted Myofilaments. (Contraction Band Necrosis). Magnification x900.Stain Haematoxylin and Eosin

of patients, often accompanied by mitral regurgitation.28,53,56 A midventricular or LVOTO gradient >25 mmHg is considered haemodynamically significant and ≥40 mmHg is a high-risk factor. Abnormal Q waves in the electrocardiogram, hypotension and cardiogenic shock are more frequent in these patients. Normally, the outflow tract obstruction resolves spontaneously over a few days.

Mitral Regurgitation Acute mitral regurgitation is another potentially serious complication occurring in 14–25 % of patients.57,58 LV ejection fraction is lower and pulmonary artery pressure higher in cases with significant regurgitation and these patients present more frequently with acute heart failure or cardiogenic shock. Two independent mechanisms may cause acute mitral regurgitation: systolic anterior motion of the mitral valve in association with dynamic LV outflow tract obstruction and apical tethering of the subvalvular mitral valve apparatus.59 In most cases the mitral regurgitation improves with normalisation of LV function, which may be delayed compared with patients without acute mitral regurgitation.

Cardiogenic Shock

asystole should be considered if the heart is normal. There may be dilatation or oedema in the distribution characteristic of an anatomical variant of Takotsubo syndrome, but if post-mortem examination is delayed then non-specific contraction may prevent this assessment.46–48 A hypercontracted left ventricle at autopsy, with increased wall thickening, but a normal heart weight has been reported in the context of severe stress (death in systole). Contraction-band necrosis of individual myocytes with interstitial oedema and a mixed inflammatory cell infiltrate are described in this phenomenon.42,49,50 Cases of idiopathic infarction with normal coronary arteries resulting in sudden death may also be due to Takotsubo.51

Complications and Acute Prognosis

Cardiogenic shock, primarily due to acute LV dysfunction, may be aggravated by RV involvement, LV outflow tract obstruction or acute mitral regurgitation. Echocardiography plays an important role in determining the mechanism of cardiogenic shock in order to apply an appropriate therapy. The mortality of cardiogenic shock in Takotsubo syndrome is high (between 17–30 %).8,41,53,55,60

Arrhythmias New onset of atrial fibrillation has been reported in 5–15 % of patients with Takotsubo syndrome.8,55,61,62 During the acute phase of Takotsubo syndrome, ventricular arrhythmias occur in 4–9 % of patients. Resuscitation as a result of cardiac arrest, which may be the initial presenting symptom, has been reported in 4–6 % of cases. Bradycardia due to atrioventricular block and asystole has been described in a limited number of patients (2–5 %).

A variety of complications can occur in ≤52 % of Takotsubo patients.8,52,53

Thrombus formation Right Ventricular Involvement Patients with biventricular involvement generally take a more severe clinical course. RV involvement assessed by ECG or magnetic resonance imaging has been reported in 18–34 % of the patients and is associated with older age, a lower LV ejection fraction, a higher frequency of heart failure, pleural effusion and a longer hospital stay.8,54

Acute Heart Failure Systolic heart failure is the most common complication in the acute phase of Takotsubo syndrome, occurring in 12–45 % of patients.8,16,28,53,55 Independent predictors for the development of acute heart failure are advanced age, low LV ejection fraction on presentation, higher admission and peak troponin levels and a physical stressor preceding the onset of Takotsubo syndrome. In some patients pulmonary oedema due to acute LV dysfunction is aggravated by mitral regurgitation and/or LV outflow tract obstruction.

Left Ventricular Outflow Tract Obstruction As a consequence of myocardial stunning of the apical segments and hypercontraction of the basal LV myocardium, a dynamic intraventricular pressure gradient due to mitral valve systolic anterior motion may develop in the acute phase. Significant LV outflow tract obstruction with gradients ranging from 20–140 mmHg have been observed in 10–25 %

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Thrombus formation may be detected within the akinetic ventricular apex in 2–8 % of Takotsubo syndrome patients, occasionally resulting in stroke or arterial embolism.63

Pericardial Effusion Acute pericarditis with recurrent chest pain, reappearance of ST-segment elevation and a small amount of pericardial effusion has been observed in some patients during the recovery phase of Takotsubo syndrome.64–66

Ventricular Wall rupture Mechanical complications including rupture of the ventricular free wall or perforation of the interventricular septum are seen in less than 1 %.67,68

Mortality Initial small case series have reported mortality rates varying from <1–12 %.17,69 In large studies and registries, in-hospital mortality is lower and has been observed in 2–5 % of the patients with Takotsubo syndrome, mainly caused by refractory cardiogenic shock or ventricular fibrillation.8,53 A recent meta-analysis evaluating 37 studies with 2,120 patients reported an in-hospital mortality of 4.5 %70 and this figure matches the 4.2 % in-hospital mortality reported in the large NISUSA Takotsubo syndrome cohorts in 2008 to 2009.29,30

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Takotsubo Syndrome – Stress-induced Heart Failure Syndrome

Recurrence The reported incidence of recurrence varies between 3.5–22 % of cases from different series.13,16,41,55 If a patient has a recurrent episode of Takotsubo syndrome, they are once more at risk of complications. Prognosis should be individualised considering the likelihood of recurrence, triggering event and co-existing medical conditions. If an individual has a recurrent episode then long-term clinical follow up should be considered.

or inappropriate sinus tachycardia (continuous or paroxysmal) and 24-hour ambulatory blood pressure monitors may be helpful for detecting transient and inappropriate hypertensive episodes. Persisting ECG changes and sometimes other evidence of autonomic disturbance can provide objective evidence and exclude non-cardiac explanations for ongoing symptoms.

Clinical Management General Considerations

Long-term Prognosis Data regarding long-term prognosis of patients with Takotsubo syndrome are limited, but initial reports from limited cohorts suggest prognosis may be similar to acute myocardial infarction, but driven by non-cardiovascular causes and higher than the healthy agematched population. Most patients settle rapidly following the acute episode and become asymptomatic. There is increasing evidence of physiological abnormalities persisting beyond the timeframe when resting contractile abnormalities have normalised macroscopically. There is also growing recognition of a subgroup of patients with persistent cardiac symptoms following the acute episode.71 These include angina, exertional breathlessness, palpitation and/or a tremulous anxiety state, reflecting heightened sympathetic tone. Although the coronary arteries are unobstructed and ventricular function has recovered macroscopically, it is helpful to document objective evidence of ongoing cardiac abnormalities to reassure the patient and to guide treatment. Twenty-four-hour Holter ECG monitors to assess for atrial arrhythmias

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Akashi Y, Sakakibara M, Sasaki E, et al. Takotsubo cardiomyopathy with pneumothorax. Nihon Naika Gakkai Zasshi 2001;90 :23014. Shao Y, Redfors B, Lyon AR, et al. Trends in publications on stress-induced cardiomyopathy. Int J Cardiol 2012;157 :435–6. Sato T, Hagiwara K, Nishikido A, et al. Takotsubo (ampullashaped) cardiomyopathy associated with microscopic polyangiitis. Intern Med 2005;44 :251–5. Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. J Am Coll Cardiol 2001;38 :11–8. Kawai S, Suzuki H, Yamaguchi H, et al. Ampulla cardiomyopathy (‘Takotusbo’ cardiomyopathy) – reversible left ventricular dysfunction: with ST segment elevation. Jpn Circ J 2000;64 :156–9. Owa M, Aizawa K, Urasawa N, et al. Emotional stressinduced ‘ampulla cardiomyopathy’: discrepancy between the metabolic and sympathetic innervation imaging performed during the recovery course. Jpn Circ J 2001;65 :349–52. Mukherjee A, Sunkel-Laing B, Dewhurst N. ‘Broken Heart’ syndrome in Scotland: a case of Takotsubo cardiomyopathy in a recently widowed lady. Scott Med J 2013;58 :e15–9. Schneider B, Athanasiadis A, Stollberger C, et al. Gender differences in the manifestation of tako-tsubo cardiomyopathy. Int J Cardiol 2013;166 :584–8. Citro R, Rigo F, Previtali M, et al. Differences in clinical features and in-hospital outcomes of older adults with takotsubo cardiomyopathy. J Am Geriatr Soc 2012;60 :93–8. Bellandi B, Salvadori C, Parodi G, et al. Epidemiology of Takotsubo cardiomyopathy: the Tuscany Registry for Tako-tsubo Cardiomyopathy. G Ital Cardiol (Rome) 2012;13 :59–66. Delgado GA, Truesdell AG, Kirchner RM, et al. An angiographic and intravascular ultrasound study of the left anterior descending coronary artery in takotsubo cardiomyopathy. Am J Cardiol 2011;108 :888–91. Omerovic E. How to think about stress-induced cardiomyopathy? Think “out of the box”! Scand Cardiovasc J 2011;45 :67–71. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155 :408–17. Kawai S, Kitabatake A, Tomoike H, et al. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J 2007;71 :990–2. Parodi G, Citro R, Bellandi B, et al. Revised clinical diagnostic criteria for Takotsubo syndrome: the Takotsubo Italian Network proposal. Int J Cardiol 2014;172 :282–3. Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics

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One of the most important criteria for the diagnosis of Takotsubo syndrome is eventual spontaneous restoration of normal cardiac function. The major objective of in-hospital treatment should be supportive care to sustain life and to minimise complications during recovery. In mild cases, either no treatment or a short course of limited medical therapy may be sufficient. In severe cases complicated by progressive circulatory failure and cardiogenic shock, the patient should be considered for early mechanical support as a ‘bridge-to-recovery’.

Conclusion and Future Directions Takotsubo syndrome is a fascinating acute heart failure syndrome increasingly recognised by the medical community. Many facets of this condition are incompletely understood and current knowledge to guide optimal clinical management is limited. The increasing incidence and the high frequency of complications during the acute phase underpin the need to improve care pathways for individuals with Takotsubo syndrome with establishment of national and international registries. n

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63. Korosoglou G, Haars A, Kuecherer H, et al. Prompt resolution of an apical left ventricular thrombus in a patient with takotsubo cardiomyopathy. Int J Cardiol 2007;116 :e88–e91. 64. Guevara R, Aguinaga-Meza M, Hazin MI, et al. Takotsubo cardiomyopathy complicated with acute pericarditis and cardiogenic shock. J Natl Med Assoc 2007;99 :281–3. 65. Kim J, Laird-Fick HS, Alsara O, et al. Pericarditis in takotsubo cardiomyopathy: a case report and review of the literature. Case Rep Cardiol 2013;2013 :917851. 66. Omar HR. Takotsubo-pericarditis association. Am J Emerg Med 2012;30 :382–3. 67. Izumi K, Tada S, Yamada T. A case of Takotsubo cardiomyopathy complicated by ventricular septal perforation. Circ J 2008;72 :1540–3. 68. Sakai K, Ochiai H, Katayama N, et al. Ventricular septal perforation in a patient with takotsubo cardiomyopathy. Circ J 2005;69 :365–7. 69. Vidi V, Rajesh V, Singh PP, et al. Clinical characteristics of tako-tsubo cardiomyopathy. Am J Cardiol 2009;104 :578–82. 70. Singh K, Carson K, Shah R, et al. Meta-analysis of clinical correlates of acute mortality in takotsubo cardiomyopathy. Am J Cardiol 2014;113 :1420–8. 71. Elesber AA, Prasad A, Lennon RJ, et al. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol 2007;50 :448–52.

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Cardiomyopathies and Heart Failure

LE ATION.

Sleep-disordered Breathing in Heart Failure Simon G P ea rse, M a r t i n R Co w i e, Ra k e s h S h a r m a a n d A l i Va z i r Royal Brompton and Harefield NHS Trust and Imperial College London, London, United Kingdom

Abstract Sleep-disordered breathing affects over half of patients with heart failure (HF) and is associated with a poor prognosis. It is an under-diagnosed condition and may be a missed therapeutic target. Obstructive sleep apnoea is caused by collapse of the pharynx, exacerbated by rostral fluid shift during sleep. The consequent negative intrathoracic pressure, hypoxaemia, sympathetic nervous system activation and arousals have deleterious cardiovascular effects. Treatment with continuous positive airway pressure may confer symptomatic and prognostic benefit in this group. In central sleep apnoea, the abnormality is with regulation of breathing in the brainstem, often causing a waxing-waning Cheyne Stokes respiration pattern. Non-invasive ventilation has not been shown to improve prognosis in these patients and the recently published SERVE-HF trial found increased mortality in those treated with adaptive servoventilation. The management of sleep-disordered breathing in patients with HF is evolving rapidly with significant implications for clinicians involved in their care.

Keywords Sleep-disordered breathing, heart failure, sleep apnoea, CPAP, ASV Disclosure: Simon G Pearse has received a research grant from Boston Scientific. Martin R Cowie provides consultancy advice to several companies developing or producing diagnostics, devices or drugs for heart failure. Rakesh Sharma has received research grants, speaker honoraria and travel funding from Boston Scientific, Medtronic, Servier and St Jude. Ali Vazir has received a research grant from Boston Scientific. Received: 21 October 2015 Accepted: 3 November 2015 Citation: European Cardiology Review, 2015;10(2):89–94 Correspondence: Simon G Pearse, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. E: s.pearse@rbht.nhs.uk

Despite advances in therapy, heart failure (HF) continues to be a leading cause of hospitalisation in those over 65.1 Around 2 % of people in Europe live with HF and as many as 10 % of those over 75 years are affected.2 Prognosis continues to be poor, with approximately half of patients dying within 5 years of first hospitalisation,3 a more severe prognosis than many malignancies.4 Sleep-disordered breathing (SDB) may comprise obstructive sleep apnoea (OSA) or central sleep apnoea (CSA), although many patients have a mixed pattern that may change during the course of a night.5 SDB is common in HF with either reduced or preserved ejection fraction (EF) – around 50 % of patients are affected compared with less than 10 % of the general population.6,7 SDB is associated with an increased morbidity and mortality in patients with HF and there is some evidence that it is not merely a marker of poor prognosis, but may be a process with independent pathophysiological consequences that may accelerate the natural history of HF. It remains under-diagnosed and may be a therapeutic target in some patients. This article reviews the aetiology and mechanisms of SDB and the current evidence for the investigation and management of this condition in patients with HF. The SERVE-HF randomised outcome trial8 has recently reported some unexpected results that have changed our view of CSA and this will be discussed.

Aetiology and Classification of Sleep-disordered Breathing in Heart Failure SDB describes a range of conditions in which there is an abnormality of the breathing pattern during sleep. By definition, a cessation of

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oro-nasal airflow for over 10 seconds is termed an apnoea, while a reduction in airflow amplitude by 30 % or more for 10 seconds associated with a desaturation of 3 % or more is a hypopnoea.9 Events are further classified into obstructive, central or mixed depending on the presence, absence or characteristics of thoraco-abdominal movement during the episode. The number of events per hour of sleep is the apnoea–hypopnoea index (AHI). Up to 5 events per hour is considered normal, 5–15/hour mild, 15–30/hour moderate and over 30 events/hour severe SDB.9 Although OSA and CSA have different underlying mechanisms, they are both driven by the internal pathophysiological environment found in HF. In OSA, the interruption of airflow is caused by collapse of the airway at the pharynx during inspiration. Pharyngeal muscle tone is decreased during sleep and, in HF, rostral shift of fluid from oedematous extremities to the pharynx may exacerbate this tendency. Research has demonstrated a significant increase in neck circumference overnight associated with a decrease in leg circumference in those with HF and OSA.10 Obesity and retrognaithism also predispose to this condition, although patients with HF and OSA are more frequently nonobese compared with patients with normal cardiac function.11 OSA is characterised by abrupt cessation of breathing as the airway occludes, accompanied by respiratory muscle effort and often snoring, followed by compensatory hyperventilation to restore arterial partial pressure of carbon dioxide (PaCO2) (see Figure 1). In CSA, the abnormal breathing pattern is mediated by dysregulation in the respiratory centres of the brainstem. While the mechanisms of CSA are not fully understood and may vary between individuals, the following processes are likely to contribute. In normal physiology,

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Cardiomyopathies and Heart Failure Figure 1: Obstructive Sleep Apnoea on Sleep Polygraphy

Pathophysiological Effects of Sleep-disordered Breathing Although OSA is traditionally thought to accelerate cardiovascular deterioration, whereas CSA is predominantly a marker of severity of HF, both types of SDB share common deleterious pathophysiological consequences. However, there is evidence that CSA may in some cases be adaptive in HF.

Note the persistence of thoraco-abdominal movement during episodes of airflow cessation (apnoea), the presence of snoring and marked swings in oxygen saturation and heart rate.

Figure 2: Central Sleep Apnoea on Sleep Polygraphy

In OSA, apnoea is accompanied by negative intrathoracic pressure as the respiratory muscles attempt to inspire against a collapsed airway. This enhances venous return to the right heart, increasing pre-load, which increases the work of the failing heart and pushes the septum to the left, further embarrassing LV function. In addition, negative intrathoracic pressure opposes contraction of the ventricular free wall, effectively increasing afterload. Recurrent episodes of apnoea and hypopnoea lead to arousals and sympathetic nervous system stimulation, known to be maladaptive in HF, and swings in heart rate and blood pressure.13 High concentrations of urinary catecholamines are found in patients with OSA14 and sleep quality is disrupted, often resulting in day-time somnolence and increased risk of road traffic accidents.15 In patients with OSA there is evidence of abnormal endothelial function – the vasodilatory response to nitric oxide is blunted and expression of the vasoconstrictors endothelin-1 and angiotensin II increased.14,16 OSA is associated with hypertension, coronary artery disease, stroke and arrhythmias, probably due to both shared risk factor profiles and the mechanisms described. These maladaptive mechanisms affect both systolic and diastolic cardiovascular function. Perhaps unsurprisingly, patients with OSA and HF have a significantly increased mortality compared with those without OSA, particularly with co-existent ischaemic heart disease.17 In the Sleep Heart Health

Note the absence of thoraco-abdominal movement during apnoea, the absence of snoring and the swings in oxygen saturation and heart rate.

depth and frequency of breathing (and hence minute ventilation) is driven by PaCO2 sensed by the chemoreceptors in the carotid bodies, aortic arch and brainstem. Small rises in PaCO2 result in a transient increase in ventilation that restores the PaCO2 to within the narrow normal physiological range. In patients with CSA, there is an exaggerated hypercapnic ventilatory response, so that small rises in PaCO2 result in inappropriate hyperventilation, which drives the PaCO2 down. If the PaCO2 falls to below the ‘apnoeic threshold’ the neural drive becomes insufficient to stimulate a breath and an apnoea occurs. Lesser reductions in neural drive result in hypopnoea. The PaCO2 subsequently rises again and the cycle repeats.12 Exaggerated sympathetic nervous activity in HF is thought to underlie this excessive response and patients with CSA and HF have a low resting PaCO2.5 In addition, prolonged circulation time in HF results in a lag between the PaCO2 sensed in the brainstem and that at the alveoli, which exacerbates an overshoot of the feedback loop. Oedema and congestion in the lungs, which may progress during the night, stimulates pulmonary J receptors resulting in a reflex hyperventilation. A characteristic crescendo-decrescendo pattern of breathing in CSA is termed ‘Cheyne-Stokes respiration’ (see Figure 2).

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Study, a large community-based cohort observational study, the presence of severe OSA was associated with more than twice the all-cause mortality risk over 8 years of follow-up.18 OSA was also associated with a 58 % increase in risk of developing HF de novo.19 Patients with OSA and HF have an increased risk of sudden cardiac death, malignant arrhythmia and the need for implantable defibrillator therapy, particularly during the night; in patients with HF and either CSA or no SDB, malignant arrhythmias and defibrillator therapies occur predominantly during the day.20,21 CSA is also associated with a worsened prognosis in HF. In one study, the presence of any CSA (including mild disease) was associated with a significantly shorter mean survival in patients with EF <45 %: 45 months versus 90 months. 22 This has traditionally been attributed to CSA being a marker of more severe cardiac dysfunction. However, there are reasons to believe that CSA itself may accelerate HF. Patients with CSA experience episodes of hypoxaemia and swings in heart rate and blood pressure, in a similar way to OSA (see Figure 2). CSA is associated with higher sympathetic nervous system activity, known to be maladaptive in HF, 23 although there is debate as to whether this is due to the CSA itself or the underlying HF. 24,25 A possible role for CSA in driving enhanced sympathetic activity is suggested by the finding that administered oxygen and continuous positive airway pressure (CPAP) both ameliorate sympathetic tone.26 The episodes of hyperventilation in CSA may also increase demands on the failing heart. However, in contrast to OSA, there is no marked negative intrathoracic pressure during apnoeas and hypopnoeas, as the respiratory muscles are not

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stimulated, so many of the haemodynamic effects of this (such as changes in ventricular pre- and after-load) are absent. This view of CSA has been challenged recently by the unexpected findings of the SERVE-HF trial.8 In this randomised study, treatment of patients with HF and predominant CSA with adaptive servoventilation (a non-invasive ventilation technique known to ameliorate the peaks and troughs of ventilation in CSA very effectively) had no impact on the primary combined endpoint of time to death, lifesaving cardiovascular intervention or unplanned HF hospitalisation, but did increase the risk of all-cause and cardiovascular mortality compared with controls (hazard ratio for death from any cause, 1.28, 95 % confidence interval [CI] 1.06–1.55; p=0.01). This surprising result raises the possibility that CSA may in fact be protective in HF and there are possible explanations for this, as described by Naughton in 2012.27 Indeed, in patients without cardiovascular disease, the Sleep Heart Health Study found that CSA was not associated with increased mortality.18 The increased mortality seen in patients with HF and CSA may be partly related to the difficulty in identifying an appropriate control group (as those with CSA tend to have more severe cardiac dysfunction even within the inclusion criteria of the studies). There are several proposed mechanisms for the potential cardioprotective effects of CSA. The episodes of hyperventilation lead to end-tidal volume increases of 400 ml on average.28 This increases oxygen storage in the lung, reduces hypoxaemia in the presence of pulmonary oedema and impaired gas exchange and improves lung compliance in a similar way to CPAP therapy. The hyperventilation phase of CSA has been shown to reduce sympathetic and increase vagal tone, and the elevated sympathetic tone seen in those with HF and CSA relates more closely to the severity of HF than of CSA.25 Importantly, the episodes of hyperventilation induce a respiratory alkalosis. Hypocapnia has been shown to preserve myocardial function in the presence of hypoxia in dogs 29 and alkalosis results in better myocardial performance during hypoxia in vitro.30 Hypocapnia and alkalosis also increases the oxygencarrying capacity of haemoglobin, according to the Bohr and Haldane effects. As hypercapnia and acidosis are a frequent finding in acute decompensated HF, this may have a protective role. Swings in intrathoracic pressure with hyperventilation may also augment cardiac output via pump-like variations in pre- and after-load. In addition, hyperventilation is thought to reverse oedema-induced bronchoconstriction.31 During apnoeic episodes in CSA there is also slightly elevated intrathoracic pressure, which may prevent alveolar collapse.32 Furthermore, recurrent episodes of hypoxaemia may stimulate erythropoiesis and it is postulated that alternating high and low workload may reduce respiratory muscle fatigue and improve oxygenation compared with constant effort.33 The effect of adaptive servo-ventilation (ASV) on these protective mechanisms may, at least in part, explain the surprising increase in cardiovascular mortality found in the SERVE-HF trial.

Investigation of Sleep-disordered Breathing Given the prevalence of SDB inpatients with HF, a high index of suspicion is appropriate. In the general population, questionnaires designed to screen for daytime somnolence, such as the Epworth sleepiness questionnaire are frequently used. However, patients with HF tend to report low daytime somnolence even in the presence of significant SDB,11 possibly due to increased sympathetic nervous activity. It is therefore usually necessary to take a confirmatory history

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from a partner where possible or to proceed to formal investigation where SDB is suspected. However, those with SDB do have increased measures of sleepiness when assessed objectively.34 Simple screening for SDB may be performed by overnight pulse oximetry. Using desaturations of ≥3 % at a cut off of 12.5 events/ hour for significant SDB, Ward et al. reported a sensitivity of 93 % and specificity of 77 % compared with formal polysomnography.35 With this approach, few patients with SDB would be missed, but pulse oximetry alone is unable to differentiate between OSA and CSA and further investigation is mandatory in patients with a high desaturation index or anyone in whom suspicion remains high despite a negative test. Several non-contact bedside monitors are available which use ultralow power radiowaves to detect respiratory movement during sleep. These can diagnose significant SDB with a sensitivity and specificity of around 90 %,36 but are not yet common in clinical practice. The gold-standard test for SDB remains in-hospital polysomnography. This involves the patient spending a night in a monitored sleep laboratory while the equipment monitors the respiratory pattern, oxygen saturation, electrocardiogram, electroencephalogram and, in some cases, electromyogram and oculogram. This test provides unparalleled detail on the severity and type of SDB, as well as phases and architecture of sleep. It is, however, relatively expensive and laborious and therefore SDB is commonly diagnosed by more limited sleep polygraphy in the patient’s home. This test usually incorporates elastic effort straps around the chest and abdomen, a finger saturation probe and tubing under the nostrils to measure airflow. A thermistor may be included to estimate oral airflow and a snore sensor is also available. This is easily portable and can be fitted by the patient; it may provide more useful data in that sleep is less likely to be disrupted by the hospital environment and the data are relatively simple to interpret. Research has shown that polygraphy correlates well with polysomnography for the diagnosis of SDB in HF. 37 Over the past 10 years, there has been interest in whether pacemaker respiratory sensors can be used to accurately diagnose and monitor SDB. Both simple and complex devices are now available that incorporate algorithms that use changes in transthoracic impedance with ventilation to give a respiratory disturbance index, akin to the AHI. In one study, a commercially available pacemaker algorithm showed a sensitivity of 88.9 % and a specificity of 84.6 % for the diagnosis of severe SDB.38 Evaluation of the accuracy of other available algorithms is currently underway (NCT02204865). At pacemaker download, up to 3 months of data on AHI are available and, with remote monitoring, changes in AHI could be a useful early indicator of HF decompensation. Further research is required.

Treatment of Sleep-disordered Breathing in Heart Failure Optimal pharmacological therapy of HF, including careful attention to maintaining euvolaemia, would be expected to improve SDB of both sorts by reducing pharyngeal oedema, sympathetic drive and pulmonary congestion, although specific data are lacking. While OSA and CSA share many pathophysiological mechanisms and may co-exist in the same patient to varying degrees, the role of noninvasive ventilation (NIV) and some novel therapies are very different between the two.

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Cardiomyopathies and Heart Failure Figure 3: The Effect of Different Modes of Non-invasive Ventilation on Severity of Central Sleep Apnoea in Heart Failure

Events/hour

There are conflicting reports regarding the impact of cardiac resynchronisation therapy (CRT) on OSA.47,48 The majority of research has demonstrated no significant improvement in AHI with CRT, in contrast to those with CSA. In some patients with retrognathism or tongue enlargement, mandibular advancement devices have been shown to be effective.49 Hypoglossal nerve stimulation is a novel technique aimed at maintaining pharyngeal tone during sleep. A non-controlled study of 126 general OSA patients demonstrated a 68 % reduction in AHI with this technique, but the role in patients with HF is not known.50

Central apnoea index

and that this reduction is ameliorated by CPAP therapy.45 Measures of cardiac sympathetic tone are also reduced by CPAP in those with OSA.46

Central Sleep Apnoea 0 Versus control

Control

Oxygen P<0.001

CPAP P<0.001

Bilevel P<0.001

Versus ASV

P<0.001

P<0.02

ASV P<0.001

ASV = adaptive servo-ventilation; CPAP = continuous positive airway pressure. Reproduced with permission from: Teschler et al., 2014.53 Reprinted with permission of the American Thoracic Society. Copyright © 2015 American Thoracic Society. Cite: Teschler H, Döhring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: A novel treatment for Cheyne-Stokes respiration in heart failure. Am J Resp Crit Care Med. 2001;164:614–9. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Obstructive Sleep Apnoea The approach to patients with OSA and HF includes advice regarding weight loss and sleep hygiene, including avoidance of excess alcohol or other sedatives as appropriate.39,40 This is relatively less useful in the HF population as OSA is less frequently associated with these factors than in the general population, but should be considered on an individual patient basis. Non-invasive ventilation, particularly with CPAP, is well-established in current guidelines for non-HF patients with moderate to severe OSA and daytime somnolence (40). In this population, CPAP significantly improves the AHI and Epworth sleepiness score, but has not been consistently shown to improve hypertension, mortality or quality of life measures.40,41 The evidence for CPAP use in the HF population is based on fewer and smaller studies than the general population. In a randomised controlled trial of 24 patients with HF and OSA, Kaneko et al.42 found that 1 month of CPAP therapy improved left ventricular EF (LVEF) from 25.0 ± 2.8 % to 33.8 ± 2.4 % (p<0.001), reduced LV end systolic diameter from 54.5 ± 1.8 mm to 51.7 ± 1.2 mm (p=0.009) and reduced heart rate and blood pressure in parallel with a significant decrease in AHI (37.1 ± 6.4/hour to 8.3 ± 2.8/hour; p<0.001). There was no significant change in these parameters in the control group. Mansfield et al. randomised 55 patients with HF and OSA to CPAP for 3 months or control. Those receiving CPAP had a greater improvement in LVEF (5.0 ± 1.0 % versus 1.5 ± 1.4 %; p=0.04), reduced urinary noradrenaline and improved quality of life scores.43 In a larger non-randomised trial, Kasai et al. followed 88 patients with HF and moderate to severe OSA for around 2 years.44 They demonstrated that those not treated with CPAP had a significantly higher risk of death or hospitalisation (HR 2.03, 95 % CI 1.07–3.68; p=0.030) than those receiving CPAP. Those with poor CPAP compliance also had significantly worse outcomes. Physiologically, OSA has been shown to acutely reduce stroke volume and cardiac output overnight

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Following successful trials of CPAP in OSA and HF, the CANPAP trial sought to evaluate its use in those with CSA.51 This study randomised 258 patients with HF and CSA to CPAP or optimal medical therapy only with a mean follow up of 2 years. CPAP was effective at improving AHI (–21 ± 16 versus –2 ± 18 per hour; p<0.001) and nocturnal oxygen saturation, as well as plasma noradrenaline concentration, LVEF and 6-minute walk distance. However, CPAP had no overall influence on rates of hospitalisation and death compared with controls. A posthoc analysis did demonstrate a survival advantage in those treated with CPAP in whom AHI was supressed to below 15/hour, raising the possibility that more efficacious ventilatory techniques may provide survival benefit to the wider population with HF and CSA.52 A more complex non-invasive ventilatory modality is ASV. In this mode, the ventilator automatically adjusts the degree of respiratory support such that more inspiratory positive airway pressure (IPAP) is provided during episodes of hypopnoea and apnoea and less during hyperpnoea. It also provides positive end expiratory pressure (PEEP) as in CPAP and mandatory breaths during apnoeas. It is therefore potentially effective in both CSA and OSA. Several studies have demonstrated benefits of ASV on surrogate endpoints in CSA and HF. Teschler and colleagues showed that ASV was significantly more efficacious at suppressing CSA than CPAP, bi-level positive airway pressure (BiPAP) or oxygen therapy (see Figure 3).53 In an observational study, Oldenburg and colleagues found that 6 months of ASV therapy in those with HF and CSA almost eradicated CSA, from 37.4 ± 9.4/h to 3.9 ± 4.1/h (p=0.001) and was associated with markedly improved cardiopulmonary exercise test parameters, increased LVEF (28.2 ± 7 % to 35.2 ± 11 %; p=0.001) and reduced N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) concentration.54 These results were largely replicated by Hastings et al.55 Similar improvements were found in those with HF with preserved EF (HFPEF).56 Reductions in sympathetic nervous activity have also been demonstrated with ASV therapy.57 Furthermore, registry data have revealed a significantly longer time to first implantable cardioverter defibrillator (ICD) therapy or ventricular arrhythmia in patients with HF, CSA and an ICD treated with ASV compared with those not treated58. Meta-analysis of trials suggested an overall reduction in AHI, improved exercise capacity, LVEF and quality of life measures with ASV treatment compared with controls.59 However, these trials were not powered to detect changes in harder clinical endpoints. SERVE-HF is the first large-scale and longer-term randomised trial to report the effect of ASV on clinical outcomes.8 This multi-centre trial enrolled 1,325 patients who were randomised to ASV in addition to optimal medical therapy or optimal medical therapy only for

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a median of 31 months. The trial was powered for the combined endpoint of all-cause death, unplanned hospitalisation for worsening HF, heart transplantation, cardiac arrest or appropriate ICD therapy. As discussed above, ASV did not influence the primary end-point but was associated with a significant increase in both all-cause and cardiovascular mortality. Most of the excess mortality related to sudden death, presumably from cardiac arrhythmia, and not only during the night. Based on this study, the largest of its kind in HF and SDB, and despite the beneficial effects demonstrated previously, ASV cannot be recommended for those with CSA and HF.

A novel therapy for CSA is phrenic nerve stimulation. This involves the implantation of a pacemaker-like device with a lead that communicates with the phrenic nerve via the left pericardiophrenic or right brachiocephalic vein. The device stimulates the phrenic nerve when no intrinsic impulse is detected for a specified time period and this stimulates a breath, preventing the hypercapnia, which triggers the cycles of Cheyne-Stokes respiration. Early research suggests a significant improvement in AHI, oxygenation and arousals, but the impact on prognosis is unknown.63 Further research is underway.

Conclusion In the randomised CHF-HOT study of 97 patients with CSA and HF, overnight oxygen therapy reduced AHI and improved LVEF and New York Heart Association (NYHA) grades,60 but the effect on clinical outcomes is unknown. Inhaled carbon dioxide is also effective at reducing AHI, but not arousals or sympathetic nervous activity.61 CRT produces a significant reduction in AHI in appropriately selected patients,62 presumably due to improved cardiac output, reduced pulmonary congestion and ameliorated sympathetic tone. Research is underway to determine whether improvement in CSA with CRT is associated with normalisation of the hypercapnic ventilatory response (NCT02203383). It is unknown whether the presence of CSA should be a factor when considering a patient for CRT.

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SDB in HF is common, frequently undiagnosed and associated with a poor prognosis. The use of sleepiness questionnaires is not useful in HF. While polysomnography remains the gold standard test, simple screening may be performed with overnight pulse oximetry. Home polygraphy is simple to use and interpret with adequate diagnostic power in most patients. In parallel with optimal HF treatment, therapy with CPAP is likely to be of benefit for those with HF and OSA. The role of positive pressure support in CSA is unclear. ASV has many advantages in CSA and HF but this does not appear to translate in to improved clinical endpoints and it increases mortality. The long-term results of novel therapies such as phrenic nerve stimulation are awaited. Our understanding of SDB continues to evolve rapidly and there are likely to be major changes in our approach to the condition in the coming years. n

17. Yumino D, Wang H, Floras JS, et al., Relationship between sleep apnoea and mortality in patients with ischaemic heart failure, Heart , 2009;95 :819–24. 18. Punjabi NM, Caffo BS, Goodwin JL, et al., Sleep-disordered breathing and mortality: A prospective cohort study, PLoS Med , 2009;6 :1–9. 19. Gottlieb DJ, Yenokyan G, Newman AB, et al., Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: The sleep heart health study, Circulation , 2010;122 :352–60. 20. Gami AS, Olson EJ, Shen WK, et al., Obstructive sleep apnea and the risk of sudden cardiac death: A longitudinal study of 10,701 adults, J Am Coll Cardiol , 2013;62 :610–6. 21. Bitter T, Fox H, Dimitriadis Z, et al., Circadian variation of defibrillator shocks in patients with chronic heart failure: The impact of Cheyne-Stokes respiration and obstructive sleep apnea, Int J Cardiol , 2014;176 :1033–5. 22. Javaheri S, Shukla R, Zeigler H, Wexler L, Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure, J Am Coll Cardiol , 2007;49 :2028–34. 23. Solin P, Bergin P, Richardson M, et al., Influence of pulmonary capillary wedge pressure on central apnea in heart failure, Circulation , 1999;99 :1574–9. 24. Spaak J, Egri ZJ, Kubo T, et al., Muscle sympathetic nerve activity during wakefulness in heart failure patients with and without sleep apnea, Hypertension , 2005;46 :1327–32. 25. Mansfield D, Kaye DM, La Rocca HB, et al., Raised sympathetic nerve activity in heart failure and central sleep apnea is due to heart failure severity, Circulation , 2003;107 :1396–400. 26. Naughton MT, Benard DC, Liu PP, et al., Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea, Am J Respir Crit Care Med , 1995;152 :473–9. 27. Naughton MT. Cheyne-Stokes respiration: friend or foe? Thorax , 2012;67 :357–60. 28. Brack T, Jubran A, Laghi F, Tobin MJ, Fluctuations in endexpiratory lung volume during Cheyne-Stokes respiration, Am J Respir Crit Care Med , 2005;171 :1408–13. 29. Wexels JC, Mjøs OD, Effects of carbon dioxide and pH on myocardial function in dogs with acute left ventricular failure, Crit Care Med , 1987;15 :1116–20. 30. Bing OH, Brooks WW, Messer JV, Heart muscle viability following hypoxia: protective effect of acidosis, Science , 1973;180 :1297–8. 31. Chapman DG, Berend N, King GG, et al., Deep inspirations protect against airway closure in nonasthmatic subjects, J Appl Physiol , 2009;107 :564–9. 32. Christie RV, Meakins JC, The intrapleural pressure in congestive heart failure and its clinical significance, J Clin Invest, 1934;13 :323–45. 33. Levine M, Cleave JP, Dodds C, Can periodic breathing have

advantages for oxygenation? J Theor Biol , 1995;172 :355–68. 34. Hastings P, Vazir A, O’Driscoll D, et al., Symptom burden of sleep-disordered breathing in mild-to-moderate congestive heart failure patients, Eur Respir J , 2006;27 :748–55. 35. Ward NR, Cowie MR, Rosen SD, et al. Utility of overnight pulse oximetry and heart rate variability analysis to screen for sleep-disordered breathing in chronic heart failure, Thorax , 2012;67 :1000–5. 36. Zaffaroni A, Kent B, O’Hare E, et al., Assessment of sleepdisordered breathing using a non-contact bio-motion sensor, J Sleep Res , 2013;24 :231–6. 37. Quintana-Gallego E, Villa-Gil M, Carmona-Bernal C, et al., Home respiratory polygraphy for diagnosis of sleep-disordered breathing in heart failure, Eur Respir J , 2004;24 :443–8. 38. Defaye P, de la Cruz I, Martí-Almor J, et al., A pacemaker transthoracic impedance sensor with an advanced algorithm to identify severe sleep apnea: The DREAM European study, Heart Rhythm , 2014;11 :842–8. 39. Araghi MH, Chen Y-F, Jagielski A, et al., Effectiveness of lifestyle interventions on obstructive sleep apnea (OSA): systematic review and meta-analysis, Sleep , 2013;36 :1553–62, 40. Qaseem A, Holty JC, Owens DK, et al., Clinical Guideline Management of Obstructive Sleep Apnea in Adults‚ÄØ: A Clinical Practice Guideline From the American College of Physicians, Ann Intern Med , 2013;159 :471–83. 41. Simon S, Collop N, Latest advances in sleep medicine: obstructive sleep apnea, Chest , 2012;142 :1645–51. 42. Kaneko Y, Floras JS, Usui K, et al., Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea, N Engl J Med , 2003;348 :1233–41. 43. Mansfield DR, Gollogly NC, Kaye DM, et al., Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure, Am J Respir Crit Care Med , 2004;169 :361–6. 44. Kasai T, Narui K, Dohi T, et al., Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure, Chest , 2008;133 :690–6. 45. Kasai T, Yumino D, Redolfi S, et al., Overnight Effects of Obstructive Sleep Apnea and Its Treatment on Stroke Volume in Patients With Heart Failure, Can J Cardiol , 2015;31 :831–8. 46. Hall AB, Ziadi MC, Leech JA, et al., Effects of short-term continuous positive airway pressure on myocardial sympathetic nerve function and energetics in patients with heart failure and obstructive sleep apnea, Circulation , 2014;130 :892–901. 47. Oldenburg O, Faber L, Vogt J, et al., Influence of cardiac resynchronisation therapy on different types of sleep disordered breathing, Eur J Heart Fail , 2007;9 :820–6. 48. Stanchina ML, Ellison K, Malhotra A, et al., The Impact of Cardiac Resynchronization Therapy on Obstructive Sleep Apnea in Heart Failure Patients, Chest , 2008;132 (2):433–9.

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Cardiomyopathies and Heart Failure 49. Leite FGJ, Rodrigues RCS, Ribeiro RF, et al., The use of a mandibular repositioning device for obstructive sleep apnea, Eur Arch Oto-Rhino-Laryngology , 2013;1–7. 50. Strollo PJ, Soose RJ, Maurer JT, et al., Upper-airway stimulation for obstructive sleep apnea, N Engl J Med , 2014;370 :139–49. 51. Bradley TD, Logan AG, Kimoff RJ, et al., Continuous positive airway pressure for central sleep apnea and heart failure, N Engl J Med , 2005;353 :2025–33. 52. Arzt M, Floras JS, Logan A, et al., Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: A post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure Trial, Circulation , 2007;115 :3173–80. 53. Teschler H, D√∂hring J, Wang YM, Berthon-Jones M, Adaptive pressure support servo-ventilation: A novel treatment for Cheyne-Stokes respiration in heart failure, Am J Respir Crit

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Care Med , 2001;164 :614–9. 54. Oldenburg O, Schmidt A, Lamp B, Bitter T, Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne – Stokes respiration, Eur J Hear Fail , 2008;10 :581–6. 55. Hastings PC, Vazir A, Meadows GE, et al., Adaptive servoventilation in heart failure patients with sleep apnea: a real world study, Int J Cardiol , 2010;139 :17–24. 56. Bitter T, Westerheide N, Faber L, et al., Adaptive servoventilation in diastolic heart failure and Cheyne-Stokes respiration, Eur Respir J , 2010;36 :385–92. 57. Koyama T, Watanabe H, Tamura Y, et al., Adaptive servoventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure, Eur J Heart Fail , 2013;15 :902–9. 58. Bitter T, Gutleben K-J, Nölker G, et al., Treatment of CheyneStokes Respiration reduces arrhythmic events in chronic heart failure, J Cardiovasc Electrophysiol , 2013;24 :1132–40.

59. Sharma BK, Bakker JP, McSharry DG, et al., Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis, Chest , 2012;142 :1211–21. 60. Nakao YM, Ueshima K, Yasuno S, Sasayama S, Effects of nocturnal oxygen therapy in patients with chronic heart failure and central sleep apnea: CHF-HOT study, Heart Vessels , 2014: epub ahead of print. 61. Szollosi I, Jones M, Morrella MJ, et al., Effect of CO2 inhalation on central sleep apnea and arousals from sleep, Respiration , 2004;71 :493–8. 62. Sinha A-M, Skobel EC, Breithardt O-A, et al., Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure, J Am Coll Cardiol , 2004;44 :68–71. 63. Ponikowski P, Javaheri S, Michalkiewicz D, et al., Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure, Eur Heart J , 2012;33 :889–94.

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Systemic and Pulmonary Hypertension

Home Blood Pressure Monitoring Ja c o b G e o r g e 1 a n d Th o m a s M a c D o n a l d 2 1. Senior Clinical Lecturer, Honorary Consultant Physician, Clinical Pharmacology/Acute Medicine, University of Dundee Medical School/NHS Tayside, Dundee, Scotland; 2. Professor of Clinical Pharmacology, Medicines Monitoring Unit and Hypertension Research Centre, Division of Medical Sciences, University of Dundee, Ninewells Hospital & Medical School, Dundee, Scotland

Abstract Hypertension is the most common preventable cause of cardiovascular disease. Home blood pressure monitoring (HBPM) is a selfmonitoring tool that can be incorporated into the care for patients with hypertension and is recommended by major guidelines. A growing body of evidence supports the benefits of patient HBPM compared with office-based monitoring: these include improved control of BP, diagnosis of white-coat hypertension and prediction of cardiovascular risk. Furthermore, HBPM is cheaper and easier to perform than 24-hour ambulatory BP monitoring (ABPM). All HBPM devices require validation, however, as inaccurate readings have been found in a high proportion of monitors. New technology features a longer inflatable area within the cuff that wraps all the way round the arm, increasing the ‘acceptable range’ of placement and thus reducing the impact of cuff placement on reading accuracy, thereby overcoming the limitations of current devices.

Keywords Home blood pressure monitoring, hypertension Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the authors, funded by Omron Healthcare. Received: 29 June 2015 Accepted: 4 October 2015 Citation: European Cardiology Review, 2015;10(2):95–101 Correspondence: Thomas MacDonald, Medicines Monitoring Unit and Hypertension Research Centre, Division of Medical Sciences, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK. E: tom@memo.dundee.ac.uk

Hypertension increases the risk of heart attack, stroke, kidney disease, and heart failure1 and is the leading preventable risk factor for global cardiovascular (CV) disease burden worldwide.2 At ages 40–69 years, each increase of 20 mmHg in systolic blood pressure (BP) is associated with more than a doubling of the baseline mortality rate from cardiovascular disease (CVD).3 However, despite the fact that the impact of BP on CV risk is supported by one of the greatest bodies of clinical trial data in medicine, few clinical studies have been devoted to the issue of BP measurement and its validity. Studies also lack consistency in the reporting of BP measurements and some do not even provide details on how BP monitoring was performed.4 This article aims to discuss the advantages and disadvantages of home BP monitoring (HBPM) and examines new technology aimed at improving its accuracy.

The Use of Home Blood Pressure Monitoring Office BP measurement is associated with several disadvantages. Large variability in office BP readings have been reported, both in clinical trials5 and in the primary care setting.6 A study in which repeated BP measurements were made over a 2-week period under research study conditions found variations of as much as 30 mmHg with no treatment changes.7 A recent observational study required primary care physicians (PCPs) to measure BP on 10 volunteers. Two trained research assistants repeated the measures immediately after the PCPs. The PCPs were then randomised to receive detailed training documentation on standardised BP measurement (group 1) or information about high BP (group 2). The BP measurements were repeated a few weeks later and the PCPs’ measurements compared with the average value of four measurements by the research

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assistants (gold standard). At baseline, the mean BP differences between PCPs and the gold standard were 23.0 mmHg for systolic and 15.3 mmHg for diastolic BP. Following PCP training, the mean difference remained high (group 1: 22.3 mmHg and 14.4 mmHg; group 2: 25.3 mmHg and 17.0 mmHg). As a result of the inaccuracy of the BP measurement, 24–32 % of volunteers were misdiagnosed as having systolic hypertension and 15–21 % as having diastolic hypertension.6 Two alternative technologies are available for measuring out-of-office BP. Ambulatory BP monitoring (ABPM) devices are worn by patients over a 24-hour period with multiple measurements and are considered the gold standard for BP measurement.8 The average of multiple measurements at home tends to be lower compared with the measurements in a surgery5 and is more reproducible than clinic measurements.5 It also has the advantage of measuring nocturnal BP and therefore allowing the detection of an attenuated dip during the night. However, ABPM monitors are expensive and, while cost-effective for the diagnosis of hypertension, are not practical for the long-term monitoring of BP. In the past decade, HBPM has emerged as an effective and convenient means of screening for hypertension, 4,9 as well as being costeffective.10 Methods for non-invasive BP measurement include auscultatory, oscillometric, tonometry and pulse wave record and analysis. HBPM uses the same technology as ABPM monitors, but allows patients to monitor BP as often as they wish. The advantages and disadvantages of HBPM are summarised in Table 1. While ABPM provides BP information at many timepoints on a particular day during unrestricted routine daily activities, HBPM provides BP information

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Systemic and Pulmonary Hypertension Table 1: Advantages and Limitations of Home Blood Pressure Monitoring Advantages

Limitations

• Can take multiple readings over

• Some devices have been found

an extended period of time

to be inaccurate

• Avoids white-coat reaction to

• Cuff placement can affect accuracy

BP measurement

• May induce anxiety and excessive

• Reproducible

monitoring

• Predicts CV morbidity and

• Risk of treatment change by

mortality better than office BP

patients based on casual home

• Can diagnose white-coat and

measurements without doctors’

masked hypertension

guidance

• Allows patients to better understand hypertension management

• Lack of nocturnal recording • Not yet reimbursed by insurance

• Telemonitoring allows remote

companies in many countries

monitoring by healthcare professionals

(mercury, aneroid or other) is not recommended for HBPM.15 Monitors that use the oscillometric method are accurate, reliable, easy to use and relatively inexpensive.16 Recommendations are in place to ensure the accuracy of monitoring devices:17–19 in the UK and Ireland the Dabl Educational Trust20 and the British Hypertension Society have produced lists of validated devices.21 The European Society of Hypertension Working Group on Blood Pressure Monitoring has produced a detailed consensus document on guidelines for HBPM.15 It recommends semiautomated (manual cuff inflation) or automated electronic devices that measure BP at the upper arm as the preferred option for HBPM. Such devices are easier to use and avoid observer bias. Monitors equipped with an automated memory should prevent patients from misreporting their BP measurements. Finger and wrist devices are less accurate and are not recommended, unless brachial measurements are difficult or impossible to obtain (for example, in subjects with very large arm circumference or extreme obesity).

• Detects increased BP variability

Advantages of Home Blood Pressure Monitoring

BP = blood pressure; CV = cardiovascular. Adapted from Parati, 2010.15

Reproducibility and Accuracy Figure 1: Accuracy of Home Blood Pressure Monitors in the Measurement of Systolic Blood Pressure 40 30

Difference: Home SBP mercury SBP

20 10 0 -10 -20 -30 -40

100

120

140

160

180

200

220

Mean: (Home BP + mercury SBP)/2

It has been found that HBPM readings are often lower than readings taken in the office and closer to the average BP recorded during 24-hour ABPM.22 HBPM allows increased numbers of readings, achieves more reproducible readings than office readings and provides improved correlations with measures of target organ damage.16,23–26 A randomised controlled trial (n=555) compared manual BP measurement and automated measurement in an office setting and concluded that the quality and accuracy of automated office BP measurement was significantly higher compared with manual office BP measurement.27 A retrospective analysis of a clinical trial (n=163) compared the withinpatient variability of the different methods of BP measurement for at least 6 weeks and found coefficients of variation of 8.6 %, 5.5 %; and 4.2 % for office BPM, ABPM and HPBM, respectively. The study concluded that a week of self-monitoring was the most accurate method of measuring BP.28 Another study (n=133) found that HBP has superior reproducibility compared with both office BPM and ABPM.29

White-coat Effect and Masked Hypertension

• for each BP recording, two consecutive measurements are taken, at least 1 minute apart with the person seated; • BP is recorded twice daily, ideally in the morning and evening; and • BP recording continues for at least 4 days, ideally for 7 days.

White-coat effect, defined as elevated office and low ambulatory or home BP, can manifest with very high clinic readings. The use of automated BP measurements have significantly reduced this effect in primary care settings.27 The reverse phenomenon – i.e. normal clinic BP and elevated out-of-clinic BP – is termed masked hypertension and is associated with increased CV risk.30,31 Some studies have found that HBPM is as effective as and more convenient than ABPM in the diagnosis of this phenomenon,32,33 but others suggest that ABPM has greater sensitivity.34 A recent meta-analysis found that HPBM is particularly useful in risk stratification in masked hypertension.31 Both phenomena are relatively common, occurring in 10–15 % of patients with hypertension, but diagnosis requires physicians to be alert to the possibility, particularly with regard to masked hypertension.30,35 The European Society of Hypertension has recommended that both white-coat and masked hypertension can be diagnosed using ambulatory or home BP measurements.17

Measurements taken on the first day should be discarded and the average value of the remaining days after day one is discarded be used.

Prediction of Cardiovascular and Stroke Morbidity and Mortality

Except for special cases (for example, patients with arrhythmias trained in auscultatory BP measurement), the use of auscultatory devices

Many,24,26,36–39 but not all,40,41 prospective studies have found that HBPM predicts CV and stroke42 morbidity and mortality more accurately than office BP; the major studies are summarised in Table 2. A meta-

BP = blood pressure; SBP = systolic blood pressure. Source: Hiremath, 2014.75

obtained under fixed times and conditions over a long period; thus, HBPM gives stable readings with high reproducibility and has been shown to be as reliable as ABPM.11–13

Recommendations for the Use of Home Blood Pressure Monitoring National Institute for Clinical Excellence (NICE) guidelines14 for HBPM recommend that when using HBPM to confirm a diagnosis of hypertension it is necessary to ensure that:

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Home Blood Pressure Monitoring

Table 2: Prospective Studies Comparing HBPM and Office BPM in Terms of Stroke and Cardiovascular Risk Study Type

Study Population Findings

Reference

Prospective cohort study,

Age ≥40 years

Average of multiple (taken more than three times) home SBP but not screening

Ohkubo et al.,

values was significantly and strongly related to the CV mortality risk according to

199838

n=1,769, mean 6.6 years

Cox model Longitudinal study, n=209

Age 31–86

Prospective cohort study,

Age 70 ± 6.5 years For BP self-measurement at home, each 10 mmHg increase in SBP increased the risk

n=4,939, mean 3.2 years

Correlation between LVMI, HBP and OBP was closer for HPB of a cardiovascular event by 17.2 % (95 % CI 11.0 %–23.8 %); each 5 mmHg increase in

Tsuonda, 200226 Bobrie et al., 200436

diastolic BP increased that risk by 11.7 % (95 % CI 5.7 %-18.1 %). The same increase in BP observed using office measurement was not associated with a significant increase in the risk of a cardiovascular event Prospective cohort study,

Age ≥40 years

n=1,702, mean 11 years Prospective cohort study,

Age 25–74 years

n=2,051, mean 131 months

The JNC-7 classification had a stronger predictive power of stroke using

Asayama et al.,

HBP-based classification compared with CBP-based classification

200442

Office, home and ambulatory BP values showed a significant exponential direct

Sega, 200540

relationship with risk of CV or all-cause death, greater for systolic than for diastolic BP and for night than for day BP, but not better for home or ambulatory than for office BP. The slope of the relationship, however, was progressively greater from office to home and ambulatory BP

Prospective cohort study,

Age 71 ± 9 years;

n=391, median 10.9 years

Incidence of major CV events (cardiovascular death, MI and stroke) was related

Fagard et al.,

to the BPs by use of multivariate Cox regression analysis. Prognostic value of home

200537

BP was better than that of office BP Prospective cohort study,

Age 53.9 ± 14.5

In a multivariate regression analysis in which age, sex, body mass index, OBP,

Shimbo et al.,

n=163, compared OBPM,

years

awake ABP and HBPM were included, only age, sex and HBP were significant

200724

ABPM and HPBM

predictors of LVMI

Cross-sectional study,

Mean age

HBPM and office BPM were both significant predictors of cardiovascular risk

Stergiou et al.,

n=662, compared OBPM and HPBM

54.1 ± 17.6 years

but there was no significant prognostic superiority of HBPM over office BPM

200741

Prospective cohort study,

Age 45–74 years

HBPM (HR 1.22/1.15, 95 % CI 1.09 to 1.37/1.05 to 1.26), but not office BP

Niiranen et al.,

(HR 1.01/1.06, 95 % CI 0.92 to 1.12/0.97 to 1.16), was predictive of

201039

n=2,081, median 6.8 years

cardiovascular events. Systolic home BP was the sole predictor of total mortality (HR 1.11; 95 % CI 1.01/1.23) Meta-analysis, n=5,008,

Mean age

HBPM substantially refines risk stratification at office BPM levels assumed to carry

Asayama et al.,

median 8.3 years

57.1 years

no or only mildly increased risk, in particular in the presence of masked hypertension

201431

RCT, n=778 Intervention = usual

Aged 25–75 years

Group 1: non-significant increase in controlled BP 36 % [95 % CI 58, 30 %–42 %]

Green et al.,

care (control), HBPM monitoring

with uncontrolled

versus 31 % (95 % CI 25 %–37 %); 0 = 0.21).

200857

+ website training (group 1), or

hypertension

Group 2: controlled BP in 56 %; 95 % CI 49 %–62% (p0<0.001) SBP decreased

HBPM + website training plus

stepwise from control to group 1 to group 2. DBP decreased only group 2

pharmacist care management delivered through website (group 2). 2 x 2 RCT, n=636 intervention =

Mean age was 61

Improvements in BP control in 4.3 % (95 % CI -4.5 % to 12.9 %) of group 1, 7.6 %

Bosworth et al.,

usual care, behavioural intervention years, 49 % were

(CI -1.9 % to 17.0 %) of group 2, and 11.0 % (CI 1.9 %, 19.8 %) in group 3. Change

200958

(group 1), HBPM (group 2) or HPPM + African American,

in SBP was -0.6 mmHg (CI -2.2 to 3.4 mmHg) in group 1, -0.6 mmHg (CI -3.6 to

behavioural intervention (group 3),

and 19 % reported 2.3 mmHg) in group 2, and -3.9 mmHg (CI -6.9 to -0.9 mmHg) in group 3; patterns

24 months

having inadequate were similar for DBP incomes

Cochrane review of interventions to

Mixed

control BP in hypertension, 72 RCT

HBPM was associated with reduction in SBP (-2.5 mmHg, 95 % CI -3.7 to

Glynn et al.,

-1.3 mmHg) and DBP (-1.8 mmHg, 95 % CI: -2.4 to -1.2 mmHg)

201051

RCT, n=527, 12 month

Aged 35–85

Mean SBP decreased by 12.9 mmHg (95 % CI 10.4–15.5) at 6 month in

McManus et al.,

Intervention = HBPM +

years, BP >140/90

self-management group and by 9.2 mmHg (6.7–11.8) in control group (p=0.013).

201061

telemonitoring

mmHg despite

At 12 months, SBP decreased by 17.6 mmHg (14.9-20.3) in self-management group

antihypertensive

and by 12.2 mmHg (9.5-14.9) in control group (p=0.0004)

treatment Meta analysis, 25 RCTs,

Mixed

HBPM was associated with reduction of SBP of -3.82 mmHg (95% confidence

Bray et al.,

interval -5.61 to -2.03), and DBP -1.45 mmHg (-1.95 to -0.94). Self-monitoring

201049

increased the chance of meeting office BP targets RR = 1.09 (1.02 to 1.16)). Significant heterogeneity was observed between studies Meta analysis, 37 RCTs, n=9449

Mixed

HPBM was associated with reductions in SBP (-2.63 mmHg; 95% CI -4.24, -1.02),

Agarwal et al.,

DBP (-1.68 mmHg; 95% CI -2.58, -0.79 reductions in antihypertensive medication

201150

(RR 2.02 [95% CI 1.32 to 3.11]) and less therapeutic inertia defined as unchanged medication despite elevated BP (RR for unchanged medication, 0.82 [95% CI 0.68 to 0.99])

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Systemic and Pulmonary Hypertension Table 2: Cont. Study Type

Study Population Findings

Reference

Cluster randomised trial, n=450,

Uncontrolled BP,

BP was controlled at 6 and 12 month in 57.2 % (95 % CI 44.8 % to 68.7 %) of

Margolis et al.,

12 month intervention and

mean age

intervention group versus 30.0 % (95 % CI 23.2 % to 37.8 %) of usual care (p = 0.001).

201362

6-month post-intervention follow

61.1±14 years

At 18 mo, BP was controlled in 71.8 % (95 % CI 65.0 % to 77.8 %) of intervention group

up. Intervention = HBPM +

versus 57.1 % (95 % CI 51.5% to 62.6%) of usual care group (p = 0.003). SBP decreased

telemonitoring

more in intervention group at 6 months (-10.7 mmHg [95 % CI -14.3 to -7.3 mmHg]; p<.001), at 12 months (-9.7 mmHg [95 % CI -13.4 to -6.0 mmHg]; p<0.001), and at 18 months (-6.6 mmHg [95% CI -10.7 to -2.5 mmHg]; p=0.004). DBP decreased at 6 months (-6.0 mmHg [95 % CI -8.6 to -3.4 mmHg]; p<0.001), at 12 months (-5.1 mmHg [95 % CI -7.4 to -2.8 mmHg]; p<0.001), and at 18 months (-3.0 mmHg [95 % CI -6.3 to 0.3 mmHg]; p =0 .07)

Prospective cohort study.

Predominantly

53 % of the patients had controlled hypertension at follow-up. Systolic and DBP

Angell et al.,

9 months

black and

decreased by 18.7 mmHg and 8.5 mmHg, respectively, at follow-up

201352

Hispanic adults with uncontrolled hypertentsion from clinics in lowincome, medically underserved communities Randomised controlled trial,

History of stroke,

Mean SBP decreased by 9.2 mmHg (95 % CI 5.7-12.7) in systolic and

McManus et al.,

n=552, 12 months

coronary heart

diastolic by 3.4 mmHg (95 % CI 1.8-5.0)

201454

Yi et al., 201553

disease, diabetes, or CKD and with baseline blood pressure of at least 130/80 mmHg Randomised controlled trial,

Predominantly

SBP decreased (intervention, 14.7 mmHg; control, 14.1 mmHg; p=0.70).

n=900, 9 months

black and

Control was achieved in 38.9 % of intervention and 39.1% of control

Hispanic adults

participants at the end of follow-up. No significant difference between groups

with uncontrolled hypertension from clinics in lowincome, medically underserved communities CI = confidence interval; CKD = chronic kidney disease; DBP = diastolic blood pressure; HBPM = home blood pressure monitoring; HR = hazard ratio; JNC-7 = Joint National Committee 7; LVMI = left ventricular mass index; RCT = randomised controlled trial; RR = relative risk; SBP = systolic blood pressure.

analysis included 5,008 people who had home and conventional BP measurements and were not being treated with antihypertensive medication that would influence the prognostic outcome. Participants were stratified into five categories of BP: optimal, 120/80 mmHg; normal, 120–129/80–84 mmHg; high–normal, 130–139/85–89 mmHg; mild hypertension, 140–159/90–99 mmHg; and severe hypertension, ≥160/≥100 mmHg. At every level of BP below severe hypertension, the additional measurements obtained from HBPM improved risk stratification, supporting the use of HBPM in routine assessment of risk.31 This finding could refine risk stratification in people with optimal, normal or high-normal BP, who are not conventionally treated. A recent systematic review (19 studies) compared HBPM with ABPM in terms of outcomes including heart attack, stroke, kidney failure and/or all-cause mortality and concluded that HBPM encourages patient-centred care and improves BP control and patient outcomes.43 Large-scale studies are now investigating the optimum use of HBPM in prevention of CV outcomes. The multicentre Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP; 2001–2010) trial (n=3,518) proved the feasibility

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of adjusting antihypertensive drug treatment via a computer algorithm that automatically generated treatment recommendations based on HBP and suggested that a systolic HBP level of 130 mmHg should be an achievable and safe target.44 The Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study (n=21,591), found that morning HBP should be controlled to <145 mmHg.45

Other Advantages Different methods of measuring BP response might clinically influence treatment decisions. A meta-analysis of more than 6,000 patients found that antihypertensive response to therapy measured by HBPM was 20 % less than office measurements.46 In addition, a clinical study found that HBPM was similar to 24-hour ABPM in assessing BP response to the antihypertensive agents atenolol and hydrochlorothiazide.47 Office BP measurements overestimated BP response compared with HBPM, with an average 4.6 mmHg greater reduction in SBP (p<0.0001) and 2.1 mmHg greater reduction in diastolic BP (p<0.0001) across all therapies.47 These findings indicate that HBPM can influence management decisions in hypertension, particularly given the relative ease of incorporating HBPM into daily activities.

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Compliance and Improvement of Blood Pressure Control Incorporation of HBPM into routine management of patients with uncontrolled hypertension may improve BP control. Several metaanalyses have shown that compared with usual care, the use of HBPM is associated with significant reductions in systolic and diastolic BP,48–51 as well as reductions in antihypertensive medication and therapeutic inertia, defined as unchanged medication despite elevated BP.50 While most studies have focused on white populations, some studies have looked at ethnically diverse adults with uncontrolled BP52,53 and highrisk patients (i.e. history of stroke, coronary heart disease, diabetes or chronic kidney disease (CKD) and with baseline BP of at least 130/80 mmHg) from clinics in low-income, medically underserved communities.54 Studies are also ongoing in stroke and at-risk groups.55 HBPM is most effective when accompanied by input from a healthcare professional, e.g. telemonitoring, whereby readings made at home are instantly relayed to a primary healthcare professional who can guide treatment along a predetermined algorithm in such a way that treatment is effected by readings obtained in a more direct manner.56–60 Numerous studies support the use of HBPM and telemonitoring,61–63 and other studies are planned.64 The use of telemonitoring avoids travel for the patient and saves time for the healthcare team. It has also been hypothesised that if patients can understand their own BP measurements and appreciate the impact of treatment, then they may be more likely to comply with medical therapy in the longer term, even if the treatment does not appear to be making them feel better.4 There is a need for clinical trial data to confirm this hypothesis. Some studies suggest that HBPM may contribute towards medication adherence in hypertensive patients,65,66 although others have not reached this conclusion.67 NICE guidelines still recommend ABPM where possible.

Cost-effectiveness of Home Blood Pressure Monitoring A recent cost-benefit analysis found that HBPM is more effective than conventional clinic BP monitoring in the diagnosis and management of hypertension, is easier to implement and requires less labour and capital investment than ABPM.10,68 As a result of these findings, the American Heart Association, the American Society of Hypertension and the Preventive Cardiovascular Nurses’ Association have released a statement suggesting that HBPM be incorporated into usual care.16 European guidelines also support the use of HBPM as an adjunct to conventional office management.15,69

Limitations of Home Blood Pressure Monitoring Patient Groups Further research is required in the clinical application of HBPM in certain patient groups; this includes children and adolescents. A systematic review of 27 studies found that HBPM has similar diagnostic value in children as in adults and appears to be a reliable alternative to ABPM monitoring in the detection of white-coat hypertension. However, systolic daytime BP readings in children was found to be lower when measured with than daytime ABPM, whereas no such difference exists in adults.70 In patients with CKD, preliminary data suggest that HBPM outperforms office BP monitoring in predicting progression to end-stage renal disease or death.71 When combined with additional support such as telemonitoring, medication titration or behavioural therapy, HBPM results in a sustained

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Figure 2: Intelli Wrap Cuff Technology Standard cuff (industry standard) Acceptable range

Artery marking

Smaller ‘acceptable range’ of placement versus brachial artery means risk of error if placed outside of range

Artery Bladder

New Intelli wrap cuff Acceptable range

Artery marking Artery Bladder

Longer air bladder = larger ‘acceptable range’ of placement versus brachial artery means risk of error if placed outside of range is lower than with standard cuff

improvement in BP control. However, HBPM does not provide nocturnal recordings and therefore cannot give information on diurnal patterns in BP, which are more prevalent in the CKD population and are important CV risk factors.71 Finally, caution should be exercised in the use of HBPM in the elderly. In a comparison of Korotkoff (K-BP, the traditional means of BP measurement employed in HBPM and office methods) and Strain-Gauge-Finger-Plethysmography (SG-BP) methods, K-BP underestimated BP in 46 % of subjects with SG-BP ≥140 mmHg at age 81.72

Accuracy of Home Blood Pressure Monitors Accuracy of devices remains a limiting factor associated with HBPM. In a 2009 study to determine the accuracy of 554 automated HBPM devices, only 30 % of the devices were found to have acceptable validation, while 72 % of the automated monitors were inaccurate. The frequency of accuracy was higher among validated devices compared with non-validated devices.73 In a 2011 study, only 30 % of the 382 devices studied had been acceptably validated and 24 % of the devices were inaccurate. Upper arm devices were more accurate than wrist devices. The categorisation of upper arm devices into validated and ‘others’ showed that the validated devices were more accurate than the ‘others’.74 A recent retrospective review analysed ‘real use’ data from 210 patients attending hypertension clinics and found that 30 % of HBPM readings were >5 mmHg different and 8 % were >10 mmHg different from mercury systolic BP measurement taken in the clinic (see Figure 1). For diastolic BP, the proportions were 32 % and 9 %, respectively.75 In addition, a 2005 analysis of 30 studies found that the accuracy of most devices tends to decrease at higher BP levels.76 However, the study’s author suggested that the reported decrease in accuracy might be explained by the fact that BP is more variable at higher levels and by the use of sequential measurements. The match between upper arm circumference and cuff size is essential to the accuracy of HBPM monitors; inappropriate cuff size has been associated with inaccuracy; studies have suggested that different cuffs should be used for BP measurement in child, adult and obese patients.77,78 The inflatable bladder of the cuff should cover 80–100 % of the individual’s arm circumference.15 The use of too small a cuff

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Systemic and Pulmonary Hypertension for the size of the arm can result in overestimation of BP, whereas a too large one results in an underestimation. Although standard cuffs are appropriate for most patients, in those with small (<24 cm) or large (>32 cm) arm circumference only the devices equipped with appropriate sized cuffs should be used.15 A study of six cuffs of various lengths and widths concluded a single long bladder cuff can measure BP with comparable accuracy both in subjects with large arms and in subjects with normal sized arms.79

New Technology to Improve Reading Accuracy of Home Blood Pressure Monitoring In order to measure BP accurately, the cuff must be wrapped correctly and proper posture of the patient during the measurement is essential. Users can find it difficult to wrap the cuff in the correct position, especially if they are inexperienced. If the cuff is wrapped incorrectly then the result is less accurate. In addition, irregular pulses due to arrhythmias lead to inaccurate BP readings. Home monitoring devices equipped with automated cuff wrapping and a display indicating correct positioning have been introduced.80 These devices can detect irregular pulses that cause inaccurate BP readings. Moreover, they detect noises and wave pulses within the cuff that are caused by arm movements. These device functions may help provide more accurate BP readings.80 The latest development in HPBM technology is Intelli wrap cuff technology. This features a longer inflatable area within the cuff that wraps all the way round the arm. This reduces pressure loss on the brachial artery, increasing the ‘acceptable range’ of placement and thus reducing the impact of cuff placement on accuracy (see Figure 2). It is also pre-formed, enabling it to be easily fitted with one hand.

4. 5.

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Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report, JAMA 2003;289 :2560–72. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010, Lancet 2012;380 :2224–60. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies, Lancet 2002;360 :1903–13. Padfield PL, The case for home monitoring in hypertension, BMC Med 2010;8 :55. Benediktsson R, Padfield PL, Maximising the benefit of treatment in mild hypertension:three simple steps to improve diagnostic accuracy, QJM 2004;97 :15–20. Sebo P, Pechere-Bertschi A, Herrmann FR, et al. Blood pressure measurements are unreliable to diagnose hypertension in primary care. J Hypertens, 2014;32:509–17. Padfield PL, Self-monitored blood pressure: a role in clinical practice?, Blood Press Monit 2002;7 :41–4. Little P, Barnett J, Barnsley L, et al. Comparison of agreement between different measures of blood pressure in primary care and daytime ambulatory blood pressure. BMJ 2002;325 :254. Imai Y, Obara T, Asamaya K, et al. The reason why home blood pressure measurements are preferred over clinic or ambulatory blood pressure in Japan. Hypertens Res 2013;36:661–72. Arrieta A, Woods JR, Qiao N, et al. Cost-benefit analysis of home blood pressure monitoring in hypertension diagnosis and treatment: an insurer perspective, Hypertension 2014;64 :891–6. Appel LJ, Stason WB. Ambulatory blood pressure monitoring and blood pressure self-measurement in the diagnosis and management of hypertension, Ann Intern Med 1993;118 :867–82. Jula A, Puukka P, Karanko H. Multiple clinic and home blood pressure measurements versus ambulatory blood pressure monitoring. Hypertension 1999;34 :261–6. Ntineri A, Nasothimiou E, Kollias A, et al. 3c.05: Diagnostic agreement of the European Society of Hypertension Home Blood Monitoring Schedule with ambulatory blood pressure monitoring in untreated and treated subjects. J Hypertens 2015;33 Suppl 1:e38.

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An ongoing study evaluated a validated oscillometric device (Omron M6-Comfort; HEM-7321-E) coupled with the Intelli wrap cuff in subjects (planned n=50) aged 50.7 ± 16.0 years with arm circumference 33.3 ± 4.4cm, body mass index 32.8 ± 7.9 kg/m2 and in stable clinical condition. Interim data from this study has recently been presented and shows that incorrect positioning of a conventional cuff significantly affects BP measurement results, with the greatest overestimation of BP when the bladder centre is displaced by 90° laterally or by 180° compared with the correct position. When the Intelli Wrap cuff was used, there was no significant effect resulting from cuff position. BP values obtained with the oscillometric device tended to be lower than those obtained by reference method because of relative undercuffing with the mercury device equipped with standard size cuff in subjects with a large arm circumference.81

Summary and Conclusion The growing burden of hypertension has seen an increase in the use and availability of HBPM devices. HBPM provides extensive BP information obtained under fixed timeframes and conditions over a long period; thus, the mean values of HBP are stable and the reproducibility are high. The use of HBPM devices is cost-effective and has stronger prognostic value in terms of CV risk when compared with clinic BP measurement. HBPM is easy to incorporate into normal daily routines, can accurately assess response to hypertensive therapy and enables remote consultations by use of telemonitoring. HBPM also appears to be valuable in assessing patients at risk who would not usually be considered as potentially benefitting from treatment. However, recent data suggest that around a third of HBPM devices are inaccurate.75 The Intelli Wrap cuff technology may reduce the impact of cuff placement and arm movements on accuracy, although further studies are required to confirm this. n

14. NICE. Hypertension: Clinical management of primary hypertension in adults. Available at: https://www.nice.org.uk/ guidance/cg127 (accessed 29 June 2015). 15. Parati G, Stergiou GS, Asmar R, et al. European Society of Hypertension practice guidelines for home blood pressure monitoring. J Hum Hypertens 2010;24 :779–85. 16. Pickering TG, Miller NH, Ogedegbe G, et al. Call to action on use and reimbursement for home blood pressure monitoring: executive summary: a joint scientific statement from the American Heart Association, American Society Of Hypertension and Preventive Cardiovascular Nurses Association. Hypertension 2008;52:1–9. 17. O’Brien E, Waeber B, Parati G, et al. Blood pressure measuring devices: recommendations of the European Society of Hypertension. BMJ 2001;322 :531–6. 18. O’Brien E, Petrie J, Littler W, et al. An outline of the revised British Hypertension Society protocol for the evaluation of blood pressure measuring devices, J Hypertens 1993;11 :677–9. 19. Association for the Advancement of Medical Instrumentation. American National Standard. Electronic or automated sphygmomanometers. ANSI/AAMI SP 10–1992. Arlington, VA: AAMI; 1993;40. 20. dabl Educational Trust. Sphygmomanometers for Selfmeasurement of Blood Pressure (SBPM). Available at: http://www.dableducational.org/sphygmomanometers/ recommended_cat.html (accessed 28 April 2015). 21. British Hypertension Society. Blood pressure monitors validated for home use. www.bhsoc.org//index.php?cID=246 (accessed 28 April 2015). 22. McGowan N, Padfield PL. Self blood pressure monitoring: a worthy substitute for ambulatory blood pressure? J Hum Hypertens 2010;24 :801–6. 23. Gaborieau V, Delarche N, Gosse P. Ambulatory blood pressure monitoring versus self-measurement of blood pressure at home: correlation with target organ damage. J Hypertens 2008;26 :1919–27. 24. Shimbo D, Pickering TG, Spruill TM, et al. Relative utility of home, ambulatory, and office blood pressures in the prediction of end-organ damage, Am J Hypertens 2007;20 :476–82. 25. Mule G, Caimi G, Cottone S, et al. Value of home blood pressures as predictor of target organ damage in mild arterial hypertension. J Cardiovasc Risk 2002;9 :123–9. 26. Tsunoda S, Kawano Y, Horio T, et al. Relationship between home blood pressure and longitudinal changes in target organ damage in treated hypertensive patients. Hypertens Res 2002;25 :167–73.

27. Myers MG, Godwin M, Dawes M, et al. Conventional versus automated measurement of blood pressure in primary care patients with systolic hypertension: randomised parallel design controlled trial, BMJ 2011;342 :d286. 28. Warren RE, Marshall T, Padfield PL, et al. Variability of office, 24-hour ambulatory, and self-monitored blood pressure measurements. Br J Gen Pract 2010;60 :675–80. 29. Stergiou GS, Baibas NM, Gantzarou AP, et al. Reproducibility of home, ambulatory, and clinic blood pressure: implications for the design of trials for the assessment of antihypertensive drug efficacy. Am J Hypertens 2002;15 :101–4. 30. Stergiou GS, Asayama K, Thijs L, et al. Prognosis of whitecoat and masked hypertension: International Database of HOme blood pressure in relation to Cardiovascular Outcome. Hypertension 2014;63 :675–82. 31. Asayama K, Thijs L, Brguljan-Hitij J, et al. Risk stratification by self-measured home blood pressure across categories of conventional blood pressure: a participant-level metaanalysis. PLoS Med 2014;11 :e1001591. 32. Stergiou GS, Salgami EV, Tzamouranis DG, et al. Masked hypertension assessed by ambulatory blood pressure versus home blood pressure monitoring: is it the same phenomenon? Am J Hypertens 2005;18 :772–8. 33. Mancia G, Bombelli M, Brambilla G, et al. Long-term prognostic value of white-coat hypertension: an insight from diagnostic use of both ambulatory and home blood pressure measurements. Hypertension 2013;62 :168–74. 34. Kang YY, Li Y, Huang QF, et al. Accuracy of home versus ambulatory blood pressure monitoring in the diagnosis of white-coat and masked hypertension. J Hypertens 2015;33 :1580–7. 35. Hansen TW, Kikuya M, Thijs L, et al. Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7,030 individuals. J Hypertens 2007;25 :1554–64. 36. Bobrie G, Chatellier G, Genes N, et al. Cardiovascular prognosis of “masked hypertension” detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA 2004;291 :1342–9. 37. Fagard RH, Van Den Broeke C, De Cort P. Prognostic significance of blood pressure measured in the office, at home and during ambulatory monitoring in older patients in general practice. J Hum Hypertens 2005;19 :801–7. 38. Ohkubo T, Imai Y, Tsuji I, et al. Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a

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population-based observation in Ohasama, Japan. J Hypertens 1998;16 :971–5. Niiranen TJ, Hanninen MR, Johansson J, et al. Home-measured blood pressure is a stronger predictor of cardiovascular risk than office blood pressure: the Finn-Home study. Hypertension 2010;55 :1346–51. Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005;111 :1777–83. Stergiou GS, Baibas NM, Kalogeropoulos PG. Cardiovascular risk prediction based on home blood pressure measurement: the Didima study. J Hypertens 2007;25 :1590–6. Asayama K, Ohkubo T, Kikuya M, et al. Prediction of stroke by self-measurement of blood pressure at home versus casual screening blood pressure measurement in relation to the Joint National Committee 7 classification: the Ohasama study. Stroke 2004;35 :2356–61. Breaux-Shropshire TL, Judd E, Vucovich LA, et al. Does home blood pressure monitoring improve patient outcomes? A systematic review comparing home and ambulatory blood pressure monitoring on blood pressure control and patient outcomes. Integr Blood Press Control 2015;8 :43–9. Asayama K, Ohkubo T, Metoki H, et al. Cardiovascular outcomes in the first trial of antihypertensive therapy guided by selfmeasured home blood pressure. Hypertens Res 2012;35 :1102–10. Kario K, Saito I, Kushiro T, et al. Home blood pressure and cardiovascular outcomes in patients during antihypertensive therapy: primary results of HONEST, a large-scale prospective, real-world observational study. Hypertension 2014;64 :989–96. Ishikawa J, Carroll DJ, Kuruvilla S, et al. Changes in home versus clinic blood pressure with antihypertensive treatments: a meta-analysis. Hypertension 2008;52 :856–64. Beitelshees AL, Gong Y, Bailey KR, et al. Comparison of office, ambulatory, and home blood pressure antihypertensive response to atenolol and hydrochlorthiazide. J Clin Hypertens (Greenwich), 2010;12 :14–21. Cappuccio FP, Kerry SM, Forbes L, et al. Blood pressure control by home monitoring: meta-analysis of randomised trials. BMJ 2004;329 :145. Bray EP, Holder R, Mant J, et al. Does self-monitoring reduce blood pressure? Meta-analysis with meta-regression of randomized controlled trials. Ann Med 2010;42 :371–86. Agarwal R, Bills JE, Hecht TJ, et al. Role of home blood pressure monitoring in overcoming therapeutic inertia and improving hypertension control: a systematic review and meta-analysis. Hypertension 2011;57 :29–38. Glynn LG, Murphy AW, Smith SM, et al. Interventions used to improve control of blood pressure in patients with hypertension. Cochrane Database Syst Rev 2010;CD005182. Angell S, Guthartz S, Dalal M, et al. Integrating self-blood pressure monitoring into the routine management of uncontrolled hypertension: translating evidence to practice. J Clin Hypertens (Greenwich), 2013;15 :180–5.

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53. Yi SS, Tabaei BP, Angell SY, et al. Self-blood pressure monitoring in an urban, ethnically diverse population: a randomized clinical trial utilizing the electronic health record. Circ Cardiovasc Qual Outcomes 2015;8 :138–45. 54. McManus RJ, Mant J, Haque MS, et al. Effect of selfmonitoring and medication self-titration on systolic blood pressure in hypertensive patients at high risk of cardiovascular disease: the TASMIN-SR randomized clinical trial. JAMA 2014;312 :799–808. 55. O’Brien C, Bray EP, Bryan S, et al. Targets and selfmanagement for the control of blood pressure in stroke and at-risk groups (TASMIN-SR): protocol for a randomised controlled trial. BMC Cardiovasc Disord 2013;13 :21. 56. Rogers MA, Small D, Buchan DA, et al. Home monitoring service improves mean arterial pressure in patients with essential hypertension. A randomized, controlled trial. Ann Intern Med 2001;134 :1024–32. 57. Green BB, Cook AJ, Ralston JD, et al. Effectiveness of home blood pressure monitoring, web communication, and pharmacist care on hypertension control: a randomized controlled trial. JAMA 2008;299 :2857–67. 58. Bosworth HB, Olsen MK, Grubber JM, et al. Two selfmanagement interventions to improve hypertension control: a randomized trial. Ann Intern Med 2009;151 :687–95. 59. Wang V, Smith VA, Bosworth HB, et al. Economic evaluation of telephone self-management interventions for blood pressure control. Am Heart J 2012;163 :980–6. 60. Magid DJ, Ho PM, Olson KL, et al. A multimodal blood pressure control intervention in 3 healthcare systems. Am J Manag Care 2011;17 :e96–103. 61. McManus RJ, Mant J, Bray EP, et al. Telemonitoring and selfmanagement in the control of hypertension (TASMINH2): a randomised controlled trial. Lancet 2010;376 :163–72. 62. Margolis KL, Asche SE, Bergdall AR, et al. Effect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. JAMA 2013;310 :46–56. 63. Mengden T, Ewald S, Kaufmann S, et al. Telemonitoring of blood pressure self measurement in the OLMETEL study. Blood Press Monit 2004;9 :321–5. 64. Spruill TM, Williams O, Teresi JA, et al. Comparative effectiveness of home blood pressure telemonitoring (HBPTM) plus nurse case management versus HBPTM alone among black and Hispanic stroke survivors: study protocol for a randomized controlled trial. Trials 2015;16 :97. 65. Fletcher BR, Hartmann-Boyce J, Hinton L, McManus RJ. The effect of self-monitoring of blood pressure on medication adherence and lifestyle factors: a systematic review and meta-analysis. Am J Hypertens 2015;28:1209–21. 66. Ogedegbe G, Schoenthaler A. A systematic review of the effects of home blood pressure monitoring on medication adherence. J Clin Hypertens (Greenwich), 2006;8 :174–80. 67. Hosseininasab M, Jahangard-Rafsanjani Z, Mohagheghi A, et al. Self-monitoring of blood pressure for improving adherence to antihypertensive medicines and blood pressure

control: a randomized controlled trial. Am J Hypertens 2014;27 :1339–45. 68. Lovibond K, Jowett S, Barton P, et al. Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modelling study. Lancet 2011;378 :1219–30. 69. Parati G, Stergiou GS, Asmar R, et al. European Society of Hypertension guidelines for blood pressure monitoring at home: a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring. J Hypertens 2008;26 :1505–26. 70. Stergiou GS, Karpettas N, Kapoyiannis A, et al. Home blood pressure monitoring in children and adolescents: a systematic review. J Hypertens 2009;27 :1941–7. 71. Sanghavi S, Vassalotti JA. Practical use of home blood pressure monitoring in chronic kidney disease. Cardiorenal Med 2014;4 :113–22. 72. Siennicki-Lantz A, Elmstahl S. Phenomenon of declining blood pressure in elderly-high systolic levels are undervalued with Korotkoff method. BMC Geriatr 2011;11 :57. 73. Akpolat T, Dilek M, Aydogdu T, et al. Home sphygmomanometers: validation versus accuracy. Blood Press Monit 2009;14 :26–31. 74. Akpolat T, Aydogdu T, Erdem E, et al. Inaccuracy of home sphygmomanometers: a perspective from clinical practice. Blood Press Monit 2011;16 :168–71. 75. Hiremath Sea, Are Home Blood Pressure Monitors Accurate Compared to Validated Devices? Presented at the American Society of Nephrology Kidney Week, 11–16 November 2014, Philadelphie, PA. Abstract no SA-PO187, 2014. 76. Braam RL, Thien T. Is the accuracy of blood pressure measuring devices underestimated at increasing blood pressure levels? Blood Press Monit 2005;10 :283–9. 77. Bur A, Herkner H, Vlcek M, et al., Factors influencing the accuracy of oscillometric blood pressure measurement in critically ill patients, Crit Care Med 2003;31 :793–9. 78. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension 2005;45 :142–61. 79. van Montfrans GA, van der Hoeven GM, Karemaker JM, et al. Accuracy of auscultatory blood pressure measurement with a long cuff. Br Med J (Clin Res Ed) 1987;295 :354–5. 80. Takahashi H, Yoshika M, Yokoi T. Validation of two automatic devices for the self-measurement of blood pressure according to the ANSI/AAMI/ISO81060–2:2009 guidelines: the Omron BP765 (HEM-7311-ZSA) and the Omron BP760N (HEM7320-Z). Vasc Health Risk Manag 2015;11 :49–53. 81. Bilo G, Sala O, Perego C, et al. Incorrect positioning of cuff for blood pressure measurement – clinical relevance and usefulness of novel cuff design, Presented at the 25th European Meeting on Hypertension and Cardiovascular Protection, Milan, 12–15 June 2015.

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LE ATION.

A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension Brendan P Madden St Georges Hospital, London, United Kingdom

Abstract Pulmonary hypertension is defined by a mean pulmonary artery pressure of >25 mmHg at rest or 30 mmHg during exercise. There are many causes and currently diseases causing the condition are classified into five groups. The greatest elevation in pulmonary arterial pressure is found among those disorders in group 1 (known as pulmonary arterial hypertension [PAH]) and research and targeted therapy has focused on this group in particular, although patients in group 4 (chronic thromboembolic PH [CTEPH]) also receive advanced pulmonary vasodilator therapy. The symptoms of PH are often vague and the diagnosis is frequently missed or delayed. Efforts are therefore being made to improve awareness of PH among clinicians to enable prompt referral to a PH unit to confirm the diagnosis and instigate appropriate therapy. Multi-disciplinary team (MDT) discussion is necessary if patients with PH require surgical intervention or become pregnant. For patients in the other PH groups, treatment is usually concentrated on the primary disorder. A small number of patients with PAH will respond to calcium-channel-blocking agents. Specific targeted therapy is often given in combination depending on the patients functional performance status. Available agents include phosphodiesterase type V inhibitors, endothelin receptor antagonists, prostglandin analogues and nitric oxide. Many novel agents are under review. For carefully selected patients surgical options, include lung transplantation, pulmonary thromboendarterectomy and atrial septostomy.

Keywords Pulmonary hypertension, echocardiography, radiological imaging, right heart catheterisation, treatment Disclosure: Fifty per cent of the funding for our pulmonary hypertension nurse was provided by Actelion Pharmaceuticals. Received: 7 October 2015 Accepted: 1 November 2015 Citation: European Cardiology Review, 2015;10(2):102â&#x20AC;&#x201C;7 Correspondence: Brendan P Madden, Professor of Cardiothoracic Medicine, Cardiothoracic Unit, St Georges Hospital, Tooting, London, SW17 0QT, London, UK. E: brendan.madden@stgeorges.nhs.uk

Pulmonary hypertension (PH) is said to occur when the mean pulmonary arterial pressure (mPAP) exceeds 25 mmHg at rest or 30 mmHg during exercise. There are many diverse causes of this condition but the term pulmonary arterial hypertension (PAH) is used to describe a rare group of diseases that share histopathological similarities in the small muscularised pulmonary arterioles leading to vascular remodelling known as plexogenic pulmonary arteriopathy (PPA). As a consequence, there is a progressive elevation in the pulmonary vascular resistance (PVR) that, if untreated, leads to death as a consequence of progressive right heart failure. Currently, there is no effective cure for PAH and the majority of treatments available either stabilise the condition or slow the rate of progression.1,2 Unfortunately, PH is often not considered or misdiagnosed and a median time of 14 months from symptom onset to diagnosis has been reported.3 It is essential that there is an improvement in the awareness of PH among health care professionals and that clinicians managing these complex patients know how to correctly interpret the investigations necessary to reach the diagnosis. Furthermore once the diagnosis has been made, patients should be referred to a specialist PH centre to enable appropriate therapeutic intervention to be made as soon as is possible.4

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Classification Although many conditions are associated with the development of PH, the PAH group is associated with the greatest elevation in PAP. Over the past 15 years a number of efforts have been made to classify conditions into groups according to common pathological and clinical features.5,6 These are outlined in Table 1.6 The PAH disorders are in group 1. At the present time, specific targeted therapy for PH is reserved for patients in groups 1 and 4. Group 1 patients share the histopathological entity known as PPA.7 In this condition, smooth muscle cells from the inner aspect of the media of muscularised pulmonary arterioles migrate though the intima into the lumen and proliferate. Once inside the lumen they differentiate into myofibroblasts, which are capable of laying down either fibrous tissue or smooth muscle tissue. The vascular proliferation develops in a concentric fashion so that on section the vessel has the appearance of an onion. Therefore, this type of proliferation is often referred to as onion skin proliferation. As the radius of the vessel gets less, the flow is reduced in proportion to the fourth power of the radius in accordance with Poiseuileâ&#x20AC;&#x2122;s Law. The pressure progressively rises and at points of proximal weakness where blood vessels branch, the wall gets progressively thinner and ultimately ruptures. Primitive blood vessels then grow into this area in a haphazard (plexiform) fashion giving rise to a plexiform lesion. The combination of concentric

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A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension

laminar (or onion skin) proliferation and plexiform lesions is known as PPA. Why this only occurs in those disorders listed in group 1 is far from clear although there are many theories relating to genetic predisposition, infection, autoimmunity and the role of pulmonary endocrine cells.1,4,7 Pulmonary thromboembolic disease can have many potential underlying causes including malignancy and thrombophillia abnormalities. Chronic thrombolembolic PH (CTEPH) is also an indication for advanced pulmonary vaso dilator therapy and for selected patients surgery in the form of pulmonary thromboendarterectomy may be an option.4 The pulmonary vasculature is normally a low-pressure low-resistance system with high distensibility as the resistance vessels normally possess only a small amount of smooth muscle relative to their systemic counterparts.7 This enables the right ventricle to deliver the same stroke volume as the left ventricle with 1/6 of the stroke work.8 However, as vascular remodelling occurs and vascular obstruction develops the resistance to flow increases. The PVR is calculated by the following equation:

Table 1: The Current Classification of Pulmonary Hypertension as per the European Respiratory and Cardiology Society Guidelines 2009 Divided into Five Separate Groups 6 1. PAH 1.1 Idiopathic 1.2 Heritable 1.2.1 BMPR2 1.2.2 ALK 1, endoglin (± hereditary haemorrhagic telangiectasia) 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with PAH 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.4.6 Chronic haemolytic anaemia 1.5 Persistent pulmonary hypertension of the newborn 1’. Pulmonary veno-occlusive disease and/or pulmonary capillary

mPAP – mean pulmonary capillary wedge pressure (mPCWP) PVR = Cardiac output (CO) As the PVR progressively increases in patients with PH, the right ventricle is susceptible to pressure overload and the response of the right ventricle to this increased after load determines the patient’s exercise capacity, symptoms and outcome.9,10 Ultimately patients die from right ventricular failure. Over 90 % of patients do not fall within group 1 and left heart disease is one of the most common causes of PH in general.11,12 The functional class of patients can be determined using the New York Heart Association (NYHA) criteria and this can be used to help determine disease severity and prognosis.

Symptomatology The diagnosis of PH is frequently missed. When it is associated with other comorbidities e.g. lung or heart diseases failure of the primary disease to respond to conventional therapies should lead one to suspect a possible association with PH in addition which warrants diagnosis, classification and potential therapeutic intervention. For many patients symptoms develop late in the course of the disease and they are often non-specific. As a consequence, delay or failure of diagnosis is still far too common. Symptoms that are associated with PH include dyspnoea with exertion, which may progress and subsequently occur with minimal exertion, or may occur at rest as the PVR rises. Palpitations are often due to right atrial stretch and underlying atrial arrhythmias. Haemoptysis may reflect vessel rupture as elevation in PAP progresses or indeed can be associated with pulmonary thromboembolic disease. Pre-syncope and syncope are common as the PVR progressively rises. Certain conditions including hypoxia or general anaesthesia can lead to an acute elevation in PVR over a short period of time resulting in compromised left heart filling with low cardiac output and profound hypotension or even death. This is termed a PH crisis. Chest pain is often attributed to right ventricular angina as the right ventricle hypertrophies.

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haemangiomatosis 2. PH due to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3. PH due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities 4. CTEPH 5. PH with unclear and/or multi-factorial mechanisms 5.1 Haematological dirsorders: myeloproliferate disorders, splenectomy 5.2 S ystemic disorders: sarcoidosis, pulmonary Langerhan’s cells histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 M etabolic disorders: glycogen storage disease, Gaucher’s disease, thyroid disorders 5.4 O thers: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis ALK 1 = activin receptor-like kinase 1 gene; BMPR2 = bone mophogenetic protein receptor, type 2; CTEPH = chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension.

In addition to the NYHA classification of dyspnoea, an unencouraged 6-minute walk test is a useful benchmark and can be used to monitor a patient’s progression.

History and Examination It is important to consider the diagnosis of PH and to take a careful history e.g. a familial background of PH, history of connective tissue disease or of thrombophilia abnormalities, alcohol consumption, etc. Physical examination may reveal evidence of other pathologies e.g. left heart failure, underlying lung disease, deep venous thrombosis, connective tissue disease or malignancy.

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Systemic and Pulmonary Hypertension Table 2: New York Heart Association Pulmonary Hypertension Functional Class Based on Symptoms 6 Functional Description Class I

Patients with PH but without resulting limitation of PA. Ordinary PA does not cause undue dyspnoea or fatigue, chest pain or near syncope

Patients with PH resulting in slight limitation of PA. They are comfortable at rest. Ordinary PA causes undue dyspnoea or fatigue, chest pain or near syncope

III

Patients with PH resulting in marked limitation of PA. They are comfortable at rest. Less than ordinary activity causes under dyspnoea or fatigue, chest pain or near syncope

Patients with PH with inability to carry out any PA without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any PA

PA = physical activity; PH = pulmonary hypertension.

The clinical signs associated with PH include: 1. A prominent a wave reflecting high right ventricular filling pressures in the jugular venous pressure. 2. An accentuated V wave suggesting tricuspid regurgitation in the jugular venous pressure. 3. A loud pulmonary component of the second heart sound as a consequence of forceful valve closure from raised PAP. 4. A left parasternal lift as a consequence of right ventricular hypertrophy (a right ventricular heave). 5. A right ventricular gallop rhythm (third and or forth heart sound). 6. Signs of right ventricular failure.

Investigations Blood Tests Routine haematological and biochemical parameters are performed including autoimmune profile, HIV serology and thrombophilia screen (if pulmonary embolism is suspected). Genetic studies are important if familial PAH is being considered. B-type natriuretic peptide (BNP) or N-terminal pro b-type natriuretic peptide (NT-proBNP) can be elevated in PH and mainly in the absence of left heart disease may suggest the diagnosis or be used to monitor right ventricular dysfunction.1,2,4,13 Both are unhelpful in the diagnosis of early disease before there is significant cardiac dysfunction. BNP also rises in response to left ventricular failure and so it is not specific for the right heart.

Chest Radiology Chest radiography has low sensitivity and specificity for the evaluation of PH, but does provide a useful, rapid and repeatable overview of cardio-pulmonary status. It may of course suggest that a lung pathology is causative.1

Electrocardiogram Right atrial and right ventricular overload may be identified on a twelve-lead electrocardiogram (ECG), P wave amplitude can be assessed and abnormal QRS features may be noted however a normal resting ECG does not exclude PH. Arrhythmias may also be present particularly if there is right atrial stretch and 24-hour Holter monitor may be indicated if confirmation of underlying cardiac arrhythmia is necessary.1,4

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Echocardiography Echocardiography is a useful investigation in the initial diagnosis of PH and helps to risk stratify patients and monitor progress. It is also helpful in assessing right and left heart interaction and other potential causes of PH such as intracardiac shunting, valvular heart disease or primary myocardial disease.1,4,14 The commonest method of assessing pulmonary artery pressure is the use of Doppler echocardiography. This determines right ventricular systolic pressure, which is equivalent to pulmonary artery systolic pressure if there is no obstruction to the right ventricular outflow tract. The right ventricular systolic pressure is calculated by measuring the maximum tricuspid regurgitant jet velocity and then the modified Bernoulli equation is applied to give the trans-tricuspid valve pressure gradient. The right atrial pressure is added to the transtricuspid valve pressure gradient to calculate right ventricular systolic pressure. However an estimate of pulmonary artery systolic pressure should always be interpreted alongside an assessment of right ventricular size and function (e.g. using the tricuspid annular plane systolic excursion [TAPSE]) and within the clinical context. Even in experienced hands echocardiography can be unreliable in diagnosing or excluding PH and often the derived pressure measurements do not correlate well with measurements subsequently obtained at right heart catheterisation. Furthermore, it is possible for patients to have PH in the absence of significant tricuspid regurgitation, which can render assessment of pulmonary haemodynamics difficult. Therefore, current guidelines support determining only a probability of PH from echocardiographic evaluation. This study however does play a central role in disease surveillance evaluating how the right ventricle adapts over time and also enabling us to monitor response to treatment.

Lung Function Tests and Arterial Blood Gas Analysis Pulmonary function testing is useful in diagnosing and assessing the contribution of underlying lung disease in patients with PH. In PAH the carbon monoxide diffusion as a percentage of predicted (diffusing capacity for carbon monoxide [DLCO] percentage) is usually impaired, independent of lung disease.1,4,6 It is important to bear in mind that patients who have unexplained dyspnoea with a low carbon monoxide diffusion capacity for which there is no obvious cause may have underlying pulmonary thromboembolism. Overall, there is no convincing correlation between lung function tests and pulmonary haemodynamics and therefore pulmonary function tests are not a reliable screen for patients with PH. They are of course important for patients who have primary lung diseases with PH resulting as a secondary phenomenon. There is some evidence that patients with scleroderma who have a reduced diffusion capacity for carbon monoxide are more likely to develop PH.15 Arterial blood gas analysis may be normal in patients with PH particularly those with PAH.

The Unencouraged 6-minute Walk Test The unencouraged 6-minute walk test is a reproducible measure of peak oxygen consumption, is easily performed, is inexpensive and results correlate well with functional status and are an independent prognostic marker.16,17 A value below 300 metres may suggest a worse prognosis and mandate a review to change or initiate treatment,13 although it is not a reliable marker of pulmonary vascular disease progression.18 Cardiopulmonary exercise testing may also be used to functionally evaluate patients with PH and may also assist with prognosis and response to treatment.19,20

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A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension

Other Radiological Imaging Other radiological imaging includes ventilation perfusion (VQ) scanning, which is usually applied to investigate patients with PH potentially associated with pulmonary thromboembolism,21,22 but abnormalities are not usually helpful in confirming the diagnosis of PAH.21 However, the historical importance of VQ studies in distinguishing CTEPH from non-CTEPH causes of PH is diminishing with the use of multi-detector computed tomography (CT) (MDCT) scanning1,23 and in its greater resolution and disease-discriminating capacity. In terms of CT scanning, VQ imaging retains a radiation dose advantage and is a pure functional technique. Catheter pulmonary angiography was once considered the gold standard for the determination or exclusion of CTEPH in PH,24 but this is rarely performed now. It is usually limited to occasional cases where further delineation of complex congenital anatomy is required or where there is a concomitant need to perform an image-guided interventional procedure, such as mechanical clot disruption or biopsy of an indeterminate and potentially neoplastic intravascular lesion.1 Computed tomographic pulmonary angiography (CTPA) is the predominant current radiological imaging strategy for the evaluation of patients with suspected PH.25,26 MDCTPA provides the best temporal and spatial resolution providing a high-resolution comprehensive vascular and pulmonary evaluation in less than 5 seconds. Magnetic resonance imaging (MRI) imaging is complex, has limited availability and is associated with poor pulmonary parenchymal evaluation. Therefore, in the near future, this is not likely to replace CT evaluation.1

Right Heart Catheterisation The gold standard investigation for diagnosing PH is right heart catheterisation.27–29 The procedure is usually performed via the right internal jugular vein although the femoral or subclavian veins are suitable alternatives. A balloon-tipped, triple-lumen Swan-Ganz catheter is connected to a pressure transducer and inserted through the venous sheath. Pressure measurements are then taken in the right atrium, right ventricle and pulmonary artery and the catheter is then advanced carefully with the balloon inflated and wedged in a more distal aspect of the pulmonary artery and the pulmonary capillary wedge pressure is measured. The balloon is then deflated and cardiac output measurements are made using the Fick method or more commonly an indicator dilution method.1 At least three readings of cardiac output should be obtained and the mean value is used to ensure accuracy. It is also routine to measure pulmonary artery oxygen saturation (Sv02) and when intracardiac shunting is suspected oxygen saturations are also measured in the right ventricle, at different points in the right atrium and in the vena cavae. The PVR is calculated as described above and the normal value is less than 2 Wood units (1 Wood unit is 1 mmHg per litre per minute and equates to 80 dynes. second.CM−5). Assessment of PVR is more helpful than mPAP alone when documenting the severity and pathophysiology of PH. As the disease progresses the cardiac output through the lungs falls and this is reflected in a lower pulmonary artery pressure value than is predicted by the patient’s clinical presentation. However when the PVR is calculated it may be demonstrated that the unexpectedly low pulmonary artery pressure is falsely misleading. This has important implications if surgical intervention is being considered for other co-morbidities in these patients.4 Cardiac index (litres per minute per body surface area squared) or PVR index can be calculated by adjusting for body surface. The body surface area is approximated from formulae, such as the Dubois

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formula, which incorporates height and weight.30 Vaso reactivity testing can be performed during right heart catheter to demonstrate a reduction in mPAP or PVR with an improvement in cardiac output. For some patients with PAH (usually less than 10 %) vaso reactivity testing may indicate a likelihood to respond to long-term calcium channel blockers and these patients may have a better prognosis.31 Those who have a positive response will demonstrate reversibility in mPAP by greater than 10 mmHg to achieve an absolute value of less than 40 mmHg with an unchanged or increased cardiac output during right heart catheterisation when they are given nitric oxide, prostacyclin or adenosine.1 Vaso reactivity testing is not reliable to predict response to treatment for patients who are classified in the other PH groups. It should only be performed by experienced operators cautiously with graded dosing in medically stabilised patients. It should not be performed in patients suspected of having pulmonary veno-occlusive disease as life-threatening pulmonary oedema may be precipitated.13 Most right heart catheter procedures are performed quickly (less than 30 minutes), are well tolerated and have a low complication rate.27 In our unit we also have a special protocol adopted to perform right heart catheter in patients with sickle cell disease.1

Pathophysiology Our understanding of the molecular biology of the pathobiology of PAH has improved in recent years and this in turn has helped to develop new therapeutic agents against a variety of potential molecular targets. It is possible that vascular injury can occur in patients with PAH who have a genetic pre-disposition e.g. those with bone morphogenetic protein receptor 2 (BMPR2) mutations. Should these mutations occur there may be a loss of the inhibitory (regulatory) action of BMP on vascular smooth muscle growth. Should a subsequent insult occur e.g. as a consequence of autoimmune disease, drugs, HIV infection or toxins (which are not metabolised in patients with liver disease) vascular injury can occur. This may lead to endothelial cell dysfunction with, for example, abnormal production of nitric oxide, prostaglandins, endothelin 1, etc. Smooth muscle cell dysfunction and migration and proliferation due to abnormalities in the production of calcitonin and gastrin-releasing peptide or 5 hydroxytryptamine can follow,5 and lead to inflammation facilitated by a variety of interleukin, chemokines, fract alkaline and many others, which ultimately give rise to vascular remodelling and PPA.4

Disease Progression As PH progresses the PVR rises and cardiac output falls. Initially dyspnoea may occur with exertion and subsequently at rest. Chest pain, palpitations, pre syncope, syncope or haemoptysis may be reported and ultimately the signs and symptoms of right heart failure develop. A median survival of 2.8 years has been reported for untreated patients in NYHA class 3 or 4.3,5,6 PH crises are acute elevations in PVR and are potentially life threatening as a consequence of acute reduction in left heart filling with profound systemic hypotension. This can occur during general anaesthetic induction (e.g. when the systolic vascular resistance falls) and is one of the reasons that patients with PAH need careful preoperative evaluation prior to surgical intervention.

Surgical Intervention Pre-operative close communication between the PH team, surgeons and anaesthetists is essential when patients with PH require surgical intervention. The patient may require deployment of a PA flotation catheter perioperatively, advice may be required on fluid replacement,

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Systemic and Pulmonary Hypertension optimal haemoglobin values inotropic and vasoactive support and how baseline therapy will be given if patients are intolerant of oral drugs post op. It is important that the patient is managed in an appropriate environment e.g. for some patients post-operative management in intensive care may be appropriate and that appropriate work up and treatment strategies are defined. A joint discussion regarding the most appropriate approach to surgical intervention e.g. open versus laproscopic should take place. For example, laparoscopic abdominal surgery may require intra-abdominal gas inflation and this may compromise venous return, which in turn may be poorly tolerated. Additionally, pre-operative close communication and assessment will ensure that if a pulmonary hypertensive crisis develops, appropriate information will have been given to staff who will have management strategies in place. Whenever possible, patients with congenital heart disease should be managed in a congenital heart disease centre. Pregnant women with PAH should always be supervised closely by a PH centre and delivery should ideally be made at a specialist centre or have a PH specialist as part of the multi-disciplinary team in attendance.32 Depending on the underlying cause of PH and the kind of surgery proposed, mortality rates between 7 % and 24 % have been reported especially in cases of emergency interventions.32–35 It is clear that PH must be diagnosed, classified and treated pre-operatively and that there is pre-operative multi-disciplinary input. The necessity for surgery must be scrutinised bearing in mind the potential risks attendant on the proposed procedure for the patient and their median-term outcome on the basis of their PH alone independent of intervention. Pre-operative optimisation includes identifying and addressing conditions contributing to PH and assessing whether peri- and postoperative pulmonary vaso dilators are necessary. It is important that PH specialists are involved in the pre-operative treatment strategy.

Treatment If patients have PH occurring in association with other disease processes their primary disorder should be optimised in the first instance. Strategies for the treatment of PAH vary around the world and typically advanced pulmonary vasodilator therapy is given to those patients who are in groups 1 and 4 and those who are in renal failure on dialysis. It is customary for advanced pulmonary vaso dilator therapy to be prescribed if the mPAP exceeds 25 mmHg at rest and the mean pulmonary capillary wedge pressure is less than 15 mmHg. Usually patients who receive specific targeted therapy are in World Health Organization (WHO) functional class 2, 3 or 4.1,2,4,36 There is insufficient evidence to justify the use of specific targeted therapy to treat patients whose PH occurs in association with lung disease. Furthermore, there is concern that should patients have PH in association with cardiac disease with left atrial filling pressure above 15 mmHg, specific targeted therapy may lead to increased venous return that, in turn, can exacerbate or produce acute left heart failure. Patients with obstructive sleep apnoea should have appropriate treatment e.g. lifestyle advice, nocturnal nasal continuous positive airway pressure in the first instance and only have consideration given to advanced pulmonary vasodilator therapy should PH persist after standard therapies for sleep-disordered breathing have been prescribed.1,4 For the majority of patients who develop PAH there is no effective cure, but the use of specific targeted therapeutic agents have been shown to improve exercise capacity, WHO functional class, haemodynamic parameters and time-to-clinical worsening. Recent evidence suggests

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that one of the newer endothilin receptor antagonists (ERA), macitentan, may be associated with improved survival, although further studies are required to support this.37 Usually ERAs are prescribed as second-line therapy after patients have been started on either a calcium channel blocker or much more commonly a phosphodiesterase type 5 inhibitor. ERAs are contraindicated in pregnancy because of concerns relating to teratogenicity. A small number of PAH patients may respond to calcium channel blockers; however, calcium channel blockers are not effective for the vast majority of patients with PAH. They should only be prescribed either by or in conjunction with PH specialists and should not be given as an alternative to recommended therapies. Sildenafil and tadalifil are phosphodiesterase type V inhibitors acting on the nitric oxide pathway promoting vaso dilatation. Sildenafil may also possess anti-proliferative effects on vascular smooth muscle.37–39 Soluble guanylate cyclise stimulators (e.g. riociguat) reduce intracellular calcium in a nitric oxide dependent and independent fashion and have been used to treat patients with PAH and those whose PH is associated with CTEPH.40 Usually patients are started on a phosphodiesterase V inhibitor and then either an ERA is added or replaces the initial agent. There are different ERAs available that can block either the endothelin A or A and B receptors and these antagonise vaso contriction and vascular remodelling promoted by the excessive endothelin release known to occur in patients with PAH.1,2,4,6,36–39 As a consequence of other endothelial factors that are absent or deficient in patients with PAH some patients, usually those in WHO class 3 who are unresponsive to combination therapy or in class 4 can be given intravenous continuous prostacyclin therapy, although this agent can also be prescribed by regular inhalation of subcutaneous injection.4 A newer oral formulation is expected to be available for clinical use within the next 2 years. However, the precise role of combination therapies for patients with PAH is receiving constant evaluation. There are a variety of other agents being studied, which include anti-inflammatory drugs, monoclonal antibodies, anti-platelet agents and lipid-lowering compounds.4,36 For some patients in class 4 disease, atrial septostomy is available to offload the right ventricle as a bridge to transplantation.40 Pulmonary thromboendarterctomy is available for selected patients with CTEPH although this is a major operation with a complication rate approximating 50 %. It should be performed in specialised centres.4,36 Lung transplantation (single or more usually bilateral) is an option for carefully selected patients, but limited donor organ availability and the complication of obliterative bronchiolitis remain major problems to be addressed.

Conclusion It is hoped that further improvement of our understanding of the pathophysiological mechanisms involved in the development of PAH will be accompanied by the development of more effective treatments and that the role of combination therapy will be defined. However, PAH remains a progressive lethal disease that is frequently not diagnosed because initial symptoms are non-specific. Improved awareness is therefore necessary to ensure that patients with PAH receive earlier

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A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension

diagnosis and are referred to an appropriate specialist centre to have the condition characterised and to receive appropriate therapeutic intervention as soon as possible. It is widely held that patients with PAH should be managed in a PH centre where there are specialist clinicians and nurses trained in the assessment and management of these challenging patients. Often this model occurs in a combination or shared cared arrangement with one or more satellite hospitals who have agreed shared protocols, joint MDT meetings and clinics. This

2. 3.

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Bacon JL, Peerbhoy MS, Wong E, et al. Current diagnostic investigation in pulmonary hypertension. Current Respiratory Medicine Reviews 2013;9 :79–100. Madden BP, Pulmonary hypertension, European Cardiology Review , 2015;10 :1–3. Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTPEH): results from an international prospective registry, Circulation 2011;124:1973–81. Madden B (editor): Treatment of Pulmonary Hypertension – Current Cardiovascular Therapy, Cham, Switzerland: Springer International Publishing, 2015. Simonneau H, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 2009;54 (Suppl. 1):S43–54. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30 :2493–537. Madden BP, Gosney J, Coghlan JG, et al. Pretransplant clinicopathological correlation in end-stage primary pulmonary hypertension. Eur Respir J 1994;7 :672–8. Di Salvo TG. Pulmonary hypertension and right ventricular failure in left ventricular systolic dysfunction. Curr Opin Cardiol 2012;27 :262–72. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 2009;135 :794–804. Howard LS, Grapsa J, Dawson D, et al. Echocardiographic assessment of pulmonary hypertension: Standard operating procedure. Eur Respir Rev 2012;21 :239–48. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicans: new concepts and experimental therapies. Circulation 2010;121 :2045–66. Strange G, Playford D, Stewart S, et al. Pulmonary hypertension: Prevalence and mortality in the Armadale echocardiography cohort. Heart 2012;98 :1805–11. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34 :1219–63. Forfia PR, Vachiery JL. Echocardiography in pulmonary arterial hypertension. Am J Cardiol 2012;110 (Suppl. 6):16S–24S.

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offers convenience for the patients and should they develop problems locally they can attend their local hospital and have appropriate advice and treatment given. If necessary, support can be sought from the primary specialist centre. Patients who are pregnant require careful MDT assessment and regular antenatal and perinatal input from the PH team. Likewise patients with PH who are referred for surgical intervention require close communication between anaesthetists, surgeons and the PH team. n

15. Steen V, Medsger TA, Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited curaneous involvement. Arthritis Rheum 2003;48 :516–22. 16. Lourenco AP, Fontoura D, Henriques-Coelho T, Leite-Moreira AF. Current pathophysiological concepts and management of pulmonary hypertension. Int J Cardiol 2012;155 :350–61. 17. Mclaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54 (Suppl. 1):S97–107. 18. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert consensus Documents and the American Heart Association developed in collaboration with American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53 :1573–619. 19. Schwaiblmair M, Faul C, Von Scheidt W, Berghaus TM. Ventilatory efficiency testing as prognostice value in patients with pulmonary hypertension. BMC Pulm Med 2012;12 :23. 20. Wensel R, Opitz CR, Ankler SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 2002;106 :319–24. 21. Worsley DF, Palevsky HI, Alavi A. Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med 1994;35 :793–6. 22. Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension, J Nucl Med 2007;48:680–4. 23. Soler X, Hoh CK, Test VJ, et al. Single photon emission computed tomography in chronic thromboembolic pulmonary hypertension. Respirology 2011;16 :131–7. 24. Auger WR, Fedullo PF, Moser KM, et al. Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology 1992;182 :393–8. 25. Tsai IC, Tsai WL, Wang KY, et al. Comprehensive MDCT evaluation of patients with pulmonary hypertension: diagnosing underlying causes with the updated Dana Point 2008 classification. AJR Am J Roentgenol 2011;197 :W471–81. 26. Devaraj A, Wells AU, Meister MG, et al. The effect of diffuse pulmonary fibrosis on the reliability of CT signs of pulmonary hypertension. Radiology 2008;249 :1042–9.

27. Ranu H, Smith K, Nimako K, et al. A retrospective review to evaluate the safety of right heart catheterization via the internal jugular vein in the assessment of pulmonary hypertension. Clin Cardiol 2010;33 :303–6. 28. Paul R, Bacon J, Anwar M, et al. Right heart catheterization: Emerging indications and applications in the optimal management of left heart disease. Am J Respir Crit Care Med 2013;187 :10.1164/ajrccm-conference. 2013.187.1_ MeetingAbstracts.A4686. 29. Holden EL, Daniel S, Ranu H, Madden BP. Right heart catheterisation in patients with chronic lung disease. Am J Respir Crit Care Med 2011 Thoracic Society International Conference, ATS; Conference: Ameran. 30. Baim D, Grossman W, (Eds). Cardiac catheterisation, Angiography, and intervention. 5th ed. Baltimore: Williams and Wilkins; 1996. 31. Papierniak ES, Lowenthal DT, Mubarak K. Pulmonary arterial hypertension: Classification and therapy with a focus on prostaglandin analogs. Am J Ther 2012;19 :300–14. 32. Madden BP, Pulmonary hypertension and pregnancy. Int J Obstet Anesth 2009;18 :156–64. 33. Rinne T, Zwissler B. Intraperative anesthetic management in patients with pulmonary hypertension. Intensiv- und Notfallbehandlung 2004;29 :4–13. 34. Fischer LG, Van Aken H, Burkle H. Management of pulmonary hypertension: Physiological and pharmacological considerations for anesthesiologists. Anesth Analg 2003;96 :1603–16. 35. McGlothlin D, Ivascu N, Heerdt PM. Anesthesia and pulmonary hypertension. Prog Cardiovasc Dis 2012;55 :199–217. 36. Pulmonary hypertension in UK clinical practice: an update. Br J Cardiol 2015;22 (Suppl. 1):S2–S15. 37. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369 :809–18. 38. Humbert M, Lau EMT, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014;130 :2189–208. 39. Madden BP, Sheth A, Ho T, Kanagasabay R. A potential role for sildenafil in the management of perioperative pulmonary hypertension and right ventricular dysfunction following cardiac surgry. Br J Anaesth 2004;93 :155–6. 40. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Eng J Med 2013;369 :330–40.

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Structural Cardiac and Vascular Disease

LE ATION.

Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches Da niel Alejan d r o L e r m a n , 1 S a i P ra s a d 1 a n d N a s r i A l o t t i 2 1. Royal Infirmary Hospital of Edinburgh (NHS Lothian), The University of Edinburgh, United Kingdom; 2. Zala County Hospital, Pécs University, Hungary

Abstract Calcification occurs in atherosclerotic vascular lesions and in the aortic valve. Calcific aortic valve disease (CAVD) is a slow, progressive disorder that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, termed aortic stenosis. In the past, this process was thought to be ‘degenerative’ because of time-dependent wear and tear of the leaflets, with passive calcium deposition. The presence of osteoblasts in atherosclerotic vascular lesions and in CAVD implies that calcification is an active, regulated process akin to atherosclerosis, with lipoprotein deposition and chronic inflammation. If calcification is active, via pro-osteogenic pathways, one might expect that development and progression of calcification could be inhibited. The overlap in the clinical factors associated with calcific valve disease and atherosclerosis provides further support for a shared disease mechanism. In our recent research we used an in vitro porcine valve interstitial cell model to study spontaneous calcification and potential promoters and inhibitors. Using this model, we found that denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand may, at a working concentration of 50 μg/mL, inhibit induced calcium deposition to basal levels.

Keywords Aortic valve calcification disease, aortic valve interstitial cells, markers of calcification, gene regulation, aortic porcine model, denosumab, atorvastatin Disclosure: The authors have no conflicts of interest to disclose. Acknowledgement: We wish to give thanks for all the support of Dr Neil Mackenzie, who unfortunately passed away after a fall while ice climbing in Canada (RIP). Received: 22 September 2015 Accepted: 28 October 2015 Citation: European Cardiology Review, 2015;10(2):108–12 Correspondence: Daniel Lerman, Royal Infirmary Hospital of Edinburgh (NHS Lothian), The University of Edinburgh, Scotland. E: s0978484@staffmail.ed.ac.uk

Progressive thickening of the aortic valve leaflets and narrowing of the aortic annulus leads to increased mechanical stress on the left ventricle and reduces cardiac output, resulting in further complications.1–3 The proportion of the population affected increases as the median age of a country or region rises. Approximately 2–4 % of people aged over 65 will develop calcific aortic stenosis, with 25 % of people in this age group presenting with signs of the disease, leading to a 50 % increased risk of cardiovascular related events. Furthermore, there is an associated risk of 80 % over 5 years of progression to heart failure, aortic valve replacement or death.4

Anatomy and Histology The normal aortic valve maintains unidirectional blood flow from the left ventricle into the aorta. It is a supple membrane that opens and closes with each heartbeat more than 100,000 times a day. The healthy aortic valve comprises three leaflets and is located at the junction between the left ventricular outflow tract and the aortic root. The internal collagen framework of the leaflets is arranged in three distinct layers, which – from the aortic to ventricular surface – are the fibrosa, spongiosa, and ventricularis (see Figure 1). This leaflet structure is covered on both the ventricular and aortic surfaces by

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endothelium in continuity with both the ventricular endocardium and the aortic endothelium. Each layer of the aortic valve has a distinct structure and function. The fibrosa, with its dense connective tissue, contains circumferentially oriented collagen fibres that provide most of the strength of the leaflets. The spongiosa is found at the bases of the leaflets. It contains a loose matrix of mucopolysaccharides, and provides a cushion to resist compressive forces and facilitate movements between the fibrosa and ventricularis during leaflet motion. The ventricularis layer contains radially oriented elastin and contributes to flexibility, allowing for changes in leaflet shape during opening and closing. Under normal conditions, all three layers are avascular with no cellular infiltrates and are innervated by adrenergic and cholinergic neural networks.5–7 To remain pliable, the aortic valve must undergo continuous repair throughout life. Accumulation of fibrotic tissue and calcium in a valve leads to decreased pliability and narrowing of the valve orifice.8,9 Valve interstitial cells (VICs) are found in each of these layers, and have distinct sub-populations that regulate homeostasis within the valve leaflets.10–12 In addition to the common tricuspid anatomy of the aortic valve, a congenital bicuspid valve is found in 0.5–1.4 % of the general population, giving rise to differential biomechanical forces – both on the valve and the aortic wall.13–15

Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches

Pathophysiology and Mechanism of Calcification Over the past several decades, the aetiology of calcific aortic valve disease (CAVD) has changed considerably. The lower prevalence of rheumatic heart disease and increased longevity in industrialised countries has resulted in a pattern shift from rheumatic to degenerative calcification as the most common cause of CAVD and subsequent calcific aortic stenosis.16–18 CAVD is the third most common heart disease in the western world,19 following coronary heart disease and hypertension. Its prevalence in the elderly (≥65 years of age) ranges from 2–4 % when considering only severe aortic stenosis, increasing to 25 % when aortic sclerosis is included.9 However, a relative minority of elderly individuals develop aortic valve calcification, suggesting pathological influences other than age play a role. Calcific aortic stenosis is the second most prevalent cause for heart surgery and is responsible for approximately 15,000 deaths annually in North America.18 Calcific aortic stenosis is a well-known disease entity and we are able to assess numerous haemodynamic parameters using cardiac catheterisation or ultrasonography as well as cardiac computed tomography and cardiac magnetic resonance imaging.20 In CAVD, calcified nodules are initially observed at the base of the cusps and their presence gradually extends towards the orifice. All three cusps are usually usually affected, but one or more may be dominant. When blood flow through the stenotic aortic orifice becomes significantly restricted, haemodynamic impairment associated with serious symptoms of congestive heart failure and sudden cardiac death may occur. Severe symptomatic aortic stenosis is a Class I indication for surgical valve replacement according to the American Heart Association and American College of Cardiology guidelines for valvular heart disease.21 CAVD is currently considered as an actively regulated and progressive disease, characterised by a cascade of cellular changes that initially cause fibrotic thickening, followed by extensive calcification of the aortic valve leaflets. This in turn leads to significant aortic valve stenosis and eventual left ventricular outflow obstruction (see Figure 2),10,22 for which surgical replacement remains the only viable treatment option. Currently there is no approved pharmacological treatment to stop the progression of CAVD.23 Descriptive studies using human specimens have demonstrated the hallmark features of this disease, including early atherosclerosis, cell proliferation and osteoblast expression. 24–26

CAVD and Traditional Risk Factors for Atherosclerosis Aortic valve stenosis was first described by Lazare Riviere in 1663.27 In the early 1900s, eminent pathologists such as Monckeberg, described CAVD as a passive degenerative process associated with rheumatic fever or aging, during which serum calcium attaches to the valve surface and binds to the leaflet to form nodules.28 In more recent decades, several studies have implicated the traditional risk factors for cardiovascular atherosclerosis in the development of CAVD. Atherosclerosis is a complex and multifactorial process that produces a lesion composed of lipids,29,30 macrophages,31 proliferating smooth muscle cells32 and apoptosis.33 It is regulated by endothelial nitric oxide synthase,34–38 and over time causes occlusion of the vessel diameter. Total cholesterol, increased low-density lipoprotein (LDL) cholesterol, increased lipoprotein(a), increased triglycerides, decreased high-density lipoprotein cholesterol, male sex, cigarette smoking, hypertension, and diabetes mellitus have been reported to

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Figure 1: Cellular Architecture of the Aortic Valve Aorta

VECs VICs

Fibrosa

Collagen VICs

Spongiosa

GAGs VICs

Ventricularis

Elastin VECs

Valve endothelial cells (VECs) line the outer surface of the valve and function as a barrier to limit inflammatory cell infiltration and lipid accumulation. The three middle layers of the valve are the fibrosa, spongiosa, and ventricularis. These layers contain valve interstitial cells (VICs) as the predominant cell type. The fibrosa is nearest the aortic side of the valve, contains Type I and Type III fibrillar collagen, and serves a load-bearing function. The spongiosa contains glycosaminoglycans (GAGs) that lubricate the fibrosa and ventricularis layers as they shear and deform during the cardiac cycle. The ventricularis contains elastin fibres to decrease radial strain. Source: Rajamannan, 2011.10

Figure 2: Inflammatory Process of Calcific Aortic Stenosis A Valve histology showing progression of the disease Initiating factors: Biscuspid valve Generic factors Shear Stress Early lesion T cell Monocyte LDL

Disease progression: Age and sex Increased serum lipids Increased blood pressure Diabetes and metabolic syndrome Smoking

End-stage disease

Aorta Endothelium Ca2+ Oxidized LDL Macrophage Ang II

Fibrosa

TGF-β TNF-α Ventricularis Interleukin 1β Left ventricle

Osteopontin

Phenotypic transformation Wnt3, Lrp5, and β catenin

Fibroblast

Calcification Increased alkaline phosphatase Osteoblast Increased BMP-2 Increased osteocalcin

B Aortic-value anatomy

Normal

Aortic scleroisis

Mid-to-moderate aortic stenosis

Servere aortic scleroisis

A: Progression of histological changes during the process of calcific aortic stenosis. B: Tricuspid aortic valve, showing increasing deposition of calcium and reduction of the aortic annulus. BMP = bone morphogenetic protein; LDL = low-density lipoprotein; TNF = tumour necrosis factor; TGF = transforming growth factor. Source: Otto, 2008.22

increase the incidence of aortic stenosis, and are likely contribute to endothelial dysfunction and leaflet damage.2,3,39–43 The presence of LDL and atherosclerosis in calcified valves in surgical pathological studies supports the hypothesis of a common cellular mechanism.44,45 Furthermore, patients with familial hypercholesterolaemia develop aggressive peripheral vascular disease, coronary artery disease and aortic valve lesions, which calcify with age.39,46–48 Oxidised LDL (oxLDL) is implicated in vascular calcification associated with atherosclerosis.49,50 Elevated blood levels of oxLDL correlate with aortic valve calcification and fibrosis,51 and oxLDL accumulation in calcific, stenotic aortic valves is well described.52–56 Metabolic bone diseases – including Paget’s disease, secondary hyperparathyroidism and renal disease – as well as increased serum creatinine and calcium are also linked to progression of valve calcification, but include only a relative minority of patients who have aortic stenosis.57–59 Understanding of these clinical risk factors provides the foundation for cellular studies and the potential for targeted medical therapies for this disease, similar to vascular atherosclerosis. However, the overall evidence indicated by the presence of atherosclerotic risk factors may partly explain why

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Structural Cardiac and Vascular Disease some patients who have congenitally abnormal valves develop aortic stenosis and require valve replacement sooner than those without risk factors. If atherosclerotic risk factors are important in the development of valvular heart disease, then experimental models of atherosclerosis are important in the understanding of this process. Studies in mice and rabbits have confirmed that experimental hypercholesterolaemia causes both atherosclerosis and calcification in the aortic valves.60–64 Two months of cholesterol diet treatment in an experimental rabbit model induced marked thickening and complex calcification in the aortic valve leaflets. The model was extended to test the pharmacological effect of atorvastatin and angiotensin receptor antagonists on the inhibition of atherosclerosis pathways and calcification.65–69 Other pathways, such as Wnt signalling and increased calcium concentration via kallikrein-kinin signalling, are involved in CAVD. Wnt proteins interact with trans-membrane receptors, in particular LDL receptors, and inhibit the effect of the degradation of the intracellular protein β catenin. In turn, β catenins mediate osteoblastic transformation of VICs and bone production. In vitro, atorvastatin – an inhibitor of LDL-cholesterol in blood – can neutralise this signal pathway in mice models.66,70–72 The molecular and cellular processes that contribute to aortic valve stenosis are not fully characterised, but could provide insights into the development of new therapeutic approaches. Heart valves comprise a heterogeneous population of valvular endothelial cells and VICs, which maintain valve homeostasis and structural leaflet integrity. VICs, the most abundant cell type in the heart valve, play a key role in CAVD progression. 73 Various VIC phenotypes have been identified in diseased human heart valves,74 including quiescent fibroblast-like VICs, which upon pathological cues can differentiate into activated myofibroblast-like VICs; and osteoblastlike VICs, which are responsible for the active deposition of calcium in CAVD.53,62,74 Additionally, several studies have demonstrated the ability of VICs to undergo osteogenic differentiation.26,67,75

TGF-β1 and TGF-β1 activation. This in turn may lead to progressive valve narrowing and fibrosis, and thus even greater shear stress. Calcifying valves initially have macrophage and T-cell infiltrates as a result of endothelial injury.74 Bone morphogenetic protein (BMP)-2 and BMP-4 are then expressed by myofibroblasts and preosteoblasts adjacent to these lymphocytic infiltrates.74 Furthermore, cardiac valves express markers of osteoblastic differentiation, including core-binding factor alpha 1 and osteocalcin.26 These valves also calcify in a manner similar to osteogenesis, with lamellar bone evident in the majority of pathological specimens examined.85 Congenitally bicuspid aortic valves uniformly show signs of calcification by the time individuals reach age 30,86 which may, in part, be attributable to the particular mechanical stressors to which these valves are subjected.87 Recently, the molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2).88 Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor-κB (RANK). 89

Regulatory Pathways There is increasing evidence that regulatory pathways that control heart valve development also are active with valve pathogenesis later in life. CAVD includes the activation of VICs in addition to increased expression of transcription factors that regulate the earliest events of valvulogenesis in the developing embryo.90 In addition to valve developmental pathways, regulatory proteins that promote the development of cartilage and bone lineages also are active in diseased valves.91 Thus, knowledge of the molecular regulatory pathways that control valve development will likely be informative in determining the molecular mechanisms of valve pathogenesis.

CAVD and Shear Stress Although atherosclerotic coronary artery disease and CAVD share common features, they do have differences in rheology. This difference may provide at least a partial explanation for the differences in pathophysiology and response to therapy.76–80 CAVD is characterised by pulsatile shear stress on the ventricular side and low and reciprocating shear stress on the aortic side,81 whereas the coronary artery is exposed to sustained laminar blood flow under normal circumstances.82 As stenosis progresses, wall shear stress across the aortic valve dramatically increases.76 Ahamed and colleagues have demonstrated that in vitro shear stress can activate latent transforming growth factor (TGF)-β1,82 a critical pro-fibrotic growth factor that can induce fibrosis and calcification.83 They also showed that active TGF-β1 could be eluted from thrombi formed in response to vascular injury in the carotid artery of mice where partial occlusion may have led to high local shear stress.82 Subsequently, Albro et al. independently confirmed that shear stress can activate latent TGF-β1 in synovial fluid.83 These data raise the possibility of an association between the activation of circulating latent TGF-β1 under high shear stress and the development of CAVD. Because platelets contribute ~45 % of the baseline circulating TGF-β1 level84 and have 40–100 times more latent TGF-β1 than any other cells,85 it is possible that shear stress has two separate effects – inducing release of latent TGF-β1 from platelets and activating the released latent TGF-β1. This mechanism may contribute to the progression of CAVD, because aortic valve narrowing increases shear stress resulting in greater release of platelet

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Aetiology CAVD has multifactorial aetiology. Many factors are centered on an inflammatory process affecting the valve and leading to calcification,74,85 including deposition of LDLs,44,45 osteoblastic transformation with bone formation of valvular interstitial cells, connective tissue synthesis and tissue remodelling. On a microscopic level, the aortic leaflets contain disorganised collagen fibres, chronic inflammatory cells, extracellular bone matrix proteins, lipidic proteins and bone minerals.5 Calcification of the valve occurs following trans-differentiation of the VICs through a myofibroblast stage and into osteoblast cells.71,92 Half of adults undergoing aortic valve replacement have a bicuspid aortic valve associated, and nearly all of them will need to have a new valve inserted.93 Shear stress occurring with each cardiac systole is greater in a bicuspid valve than in a tri leaflet structure and these valves calcify earlier.93 Interestingly, the expression of RANK ligand (RANKL) by osteoblast cells will be actively involved in the activation and differentiation of osteoclast cells.89 RANKL levels normally rise with age and can predict cardiovascular events in humans, while osteoprotegerin (a physiological inhibitor of RANK) deficit can lead to vascular calcification in animal models.94,95 This study highlights an in vitro model to assess the mechanisms of aortic valve calcification.95

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Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches

Molecular Mechanisms of Calcification The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology.2 Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells). These cells produce cytokines, including TGF-β, which regulates cell proliferation and differentiation; tumour necrosis factor-α, whose primary function is the regulation of the immune cells; and interleukin 2, which is produced by activated T lymphocytes with growth factor activity.1 VICs activated by the inflammatory process are designated myofibroblasts.5 These cells will develop angiogenic activity and produce matrix metalloproteinases, proteins that are involved in tissue remodelling and support VIC activation and transformation.96,97 During this process activated VICs differentiate into osteoblasts.

Our recent unpublished studies demonstrated the upregulation of key molecules during the spontaneous calcification of porcine VICs with an increase of calcium, collagen and alkaline phosphatase (ALP) activity. In vitro calcification was determined using standard staining and enzyme activity assays. Calcification in pig VICs was induced with sodium phosphate. The cells expressed markers for both vascular smooth muscle cells and osteoblasts, suggesting a transdifferentiation of the phenotype. Upregulation of α-actin, RUNX2, TGF-β and RhoA and downregulation of calponin were noted, with no changes seen in RANKL expression. Sodium phosphate increased nodular formation by day 7 and ALP activity of porcine VICs by day 14. The findings suggest that porcine VICs may be a good model to study the process of CAVD.100

Denosumab as a Potential Inhibitor of VIC Calcification In Vitro

In Vitro Studies

Denosumab is a human IgG2 monoclonal antibody designed to target RANKL,101 which is expressed on the membrane of the osteoblasts and osteoclasts. Denosumab is used in the treatment of osteoporosis. Additionally, owing to its mechanism that blocks the receptor RANKL, it neutralises the activation of RANK receptors on the membrane of pre-osteoclast cells.More research is needed to address the interaction between RANK receptor and denosumab in porcine VICs.

Initial studies in our laboratory have involved the establishment and validation of porcine VIC isolation, culture and calcification

Our recent unpublished studies showed that 50 µg/mL denosumab

procedures and the effect of denosumab on in vitro calcification. During the characterisation of porcine VICs, the first objective was to determine the expression level of a common marker of myofibroblast phenotype, α-actin, to demonstrate that active VICs were present in the samples. The expression of RUNX2, a major regulator of osteoblast differentiation, was analysed to corroborate that CardiologyCardiology the effect of the complete transdifferentiation of VICs had taken place and that the osteoblast phenotype was present. Furthermore, changes in the expression of TGF-β (a promoter of osteogenesis), were detected and recorded. Additionally, RhoA, a regulator of nodule formation in myofibroblasts, was analysed, followed by examining changes in the expression of RANKL, a key regulator of bone metabolism. Finally, calponin, a protein with potential capability to inhibit bone formation, was measured to complete the genetic studies. TGF-β can increase calcium and collagen deposition.98 It is known that TGF-β can also stimulate the expression of RANK on pre-osteoclastic cells, and in this way increase osteoclastic sensitivity to RANKL.99 RANKL is expressed in the membrane of osteoblasts and monocytes. As yet there is still no evidence that TGF-β promotes calcification in porcine VICs by increasing RANK expression levels.

inhibited induced calcium deposition to basal levels in porcine VIC culture.100 Although associated with bone loss and shown to reduce vascular calcification, the effect of denosumab on calcification of human VICs is unknown. Recently, denosumab has been shown to reduce calcium deposition in the aorta, although the mechanisms by which it affects ectopic calcification are poorly understood.102 Furthermore, osteoprotegerin (a signalling protein receptor and a member of the tumour necrosis factor receptor family) has been shown to stop ectopic calcification in vitro via a similar mechanism to denosumab, but there is still not enough evidence of any effect in reverting the process of calcification. Osteprotegerin’s mechanism of action is to block RANKL-RANK receptor interaction.94,95 A fuller understanding of the mechanisms of action of denosumab may identify a novel therapeutic approach for clinical treatment, supplementing the current surgical approach. It should be noted that extrapolation of the results obtained in an in vitro porcine model to humans should be cautious, as species variations are likely to exist. Although it is not possible to include all mechanisms involved in CAVD in a single model, experimental models can contribute towards identifying the role several factors may play in the development of CAVD. n

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Atherosclerosis, 2006;185 :219–26. 50. Doherty TM, Fitzpatrick LA, Inoue D, et al., Molecular, endocrine, and genetic mechanisms of arterial calcification, Endocr Rev, 2004;25:629–72. 51. Côté C, Pibarot P, Després JP, Mohty D, Cartier A, Arsenault BJ, Couture C, Mathieu P, Association between circulating oxidised lowdensity lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis, Heart , 2008; 94 :1175–80. 52. Derbali H, Bossé Y, Côté N, et al., Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via Toll-like receptor 2, Am J Pathol , 2010;176 :2638–45. 53. Otto CM, Kuusisto J, Reichenbach DD, et al., Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies, Circulation , 1994;90 :844–53. 54. Mehrabi MR, Sinzinger H, Ekmekcioglu C, et al., Accumulation of oxidized LDL in human semilunar valves correlates with coronary atherosclerosis, Cardiovasc Res , 2000; 45 :874–82. 55. Mohty D, Pibarot P, Després JP, et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis, Arterioscler Thromb Vasc Biol, 2008;28:187–93. 56. Côté N, Pibarot P, Pépin A, et al., Oxidized lowdensity lipoprotein, angiotensin II and increased waist cirumference are associated with valve inflammation in prehypertensive patients with aortic stenosis, Int J Cardiol , 2010; 145 :444–9. 57. Strickberger SA, Schulman SP, Hutchins GM, Association of Paget’s disease of bone with calcific aortic valve disease, Am J Med , 1987;82 :953–6. 58. Maher ER, Pazianas M, Curtis JR, Calcific aortic stenosis: A complication of chronic uraemia. Nephron 1987;47:119‚Äì22. 59. Palta S, Pai AM, Gill KS, Pai RG, New insights into the progression of aortic stenosis : implications for secondary prevention, Circulation , 2000;101 :2497–502. 60. Rajamannan NM, Sangiorgi G, Springett M, et al., Experimental hypercholesterolemia induces apoptosis in the aortic valve, J Heart Valve Dis , 2001;10 :371–4. 61. Drolet MC, Arsenault M, Couet J, Experimental aortic valve stenosis in rabbits, J Am Coll Cardiol , 2003;41 :1211–7. 62. Weiss RM, Ohashi M, Miller JD, et al., Calcific aortic valve stenosis in old hypercholesterolemic mice, Circulation , 2006;114 :2065–9. 63. Aikawa E, Nahrendorf M, Sosnovik D, et al., Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease, Circulation, 2007;115:377–86. 64. Drolet MC, Roussel E, Deshaies Y, et al., A high fat/high carbohydrate diet induces aortic valve disease in C57BL/6J mice, J Am Coll Cardiol , 2006;47 :850–5. 65. Rajamannan NM, Subramaniam M, Springett M, et al., Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve, Circulation , 2002;105 :2260–5. 66. Rajamannan NM, Subramaniam M, Caira F, et al., Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway, Circulation , 2005;112 (Suppl 9):I229–34. 67. Osman L, Yacoub MH, Latif N, et al., Role of human valve interstitial cells in valve calcification and their response to atorvastatin, Circulation , 2006;114 (Suppl 1):I547–52. 68. Osman L, Chester AH, Amrani M, et al., A novel role of extracellular nucleotides in valve calcification: a potential target for atorvastatin, Circulation, 2006;114(Suppl 1):I566–72 69. Arishiro K, Hoshiga M, Negoro N, et al., Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits, J Am Coll Cardiol , 2007; 49 :1482–9. 70. Caira FC, Stock SR, Gleason TG, et al., Human degenerative valve disease is associated with upregulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation, J Am Coll Cardiol, 2006;47:1707–12. 71. Akat K, Borggrefe M, Kaden JJ, Aortic valve calcification: basic science to clinical practice. Heart 2009;95:616‚Äì23. 72. Salas MJ, Santana O, Escolar E, Lamas GA, Medical therapy for calcific aortic stenosis, 2012;17 :133–8. 73. Liu AC, Joag VR, Gotlieb AI, The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology, Am J Pathol , 2007;171 :1407–18. 74. Peacock JD, Levay AK, Gillaspie DB, et al. Reduced sox9 function promotes heart valve calcification phenotypes in vivo, Circ Res , 2010;106 :712–9. 75. Gould ST, Srigunapalan S, Simmons CA, Anseth KS,

Hemodynamic and cellular response feedback in calcific aortic valve disease, Circ Res , 2013;113 :186–97. 76. Sun L, Rajamannan NM, Sucosky P, Design and validation of a novel bioreactor to subject aortic valve leaflets to sidespecific shear stress, Ann Biomed Eng, 2011;39:2174–85. 77. Sucosky P, Balachandran K, Elhammali A, et al., Altered shear stress stimulates upregulation of endothelial vcam-1 and icam-1 in a bmp-4- and tgf-beta1-dependent pathway, Arterioscler Thromb Vasc Biol , 2009;29 :254–60. 78. Sun L, Chandra S, Sucosky P, Ex vivo evidence for the contribution of hemodynamic shear stress abnormalities to the early pathogenesis of calcific bicuspid aortic valve disease, PLoS One , 2012;7 :e48843. 79. Sun L, Rajamannan NM, Sucosky P, Defining the role of fluid shear stress in the expression of early signaling markers for calcific aortic valve disease, PLoS One , 2013;8 :e84433. 80. Chandra S, Rajamannan NM, Sucosky P, Computational assessment of bicuspid aortic valve wallshear stress: Implications for calcific aortic valve disease, Biomech Model Mechanobiol , 2012;11 :1085–96. 81. Chiu JJ, Chien S, Effects of disturbed flow on vascular endothelium: Pathophysiological basis and clinical perspectives, Physiol Rev , 2011;91 :327–87. 82. Ahamed J, Burg N, Yoshinaga K, et al., In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-beta1, Blood , 2008;112 :3650–60. 83. Albro MB, Cigan AD, Nims RJ, et al., Shearing of synovial fluid activates latent tgf-beta, Osteoarthritis Cartilage , 2012;20 :1374–82. 84. Assoian RK, Komoriya A, Meyers CA, et al., Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization, J Biol Chem, 1983;258 :7155–60. 85. Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, et al., Bone formation and inflammation in cardiac valves, Circulation , 2001;103 :1522–8. 86. Yener N, Oktar GL, Erer D, et al., Bicuspid aortic valve, Ann Thorac Cardiovasc Surg , 2002;8 :264–7. 87. Robicsek F, Thubrikar MJ, Cook JW, Fowler B, The congenitally bicuspid aortic valve: how does it function? Why does it fail? Ann Thorac Surg, 2004;77 :177–85. 88. Garg V, Muth AN, Ransom JF et al., Mutations in NOTCH1 cause aortic valve disease, Nature , 2005;437 :270–4. 89. Kaden JJ , Bickelhaupt S, Grobholz R, Receptor activator of nuclear factor Kappab ligand and osteoprotegerin regulate aortic valve calcification, J Mol Cell Cardiol, 2004;36:57–66. 90. Combs MD, Yutzey KE, Heart valve development: Regulatory networks in development and disease, Circ Res , 2009; 105 :408–21. 91. Wirrig EE, Hinton RB, Yutzey KE, Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves, J Mol Cell Cardiol , 2011;50 :561–9. 92. Cohn H. Cardiac surgery in the adult, Third edition. Copyright 2009, 2003, 1997. Mc Graw-Hill.Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin, Circulation Research , 2004; 95 :1046–57. 93. Nalini M Rajamannan, Frank J Evans, Calcific aortic valve disease: not simply a degenerative process, Circulation , 2011;124 :1783–91. 94. Min H, Morony S, Sarosi I, Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis, J Exp Med , 2000;192 :463–74. 95. Price PA, June HH, Buckley JR. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D, Arterioscler Thromb Vasc Biol , 2001;21 :1610–6. 96. Soiny Y, Satta J, Maata M, Expression of MMP2, MMP9, MT1MMP, TIMP1 and TIMP2 m RNA in valvular lesions of the heart, J Pathol , 2001;194 :225–31. 97. Kaden JJ, Demflie CE, Grobholz R, Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis, Cardiovasc Pathol , 2005;14 :80–7. 98. Roman-Blas JA, Stokes DG, Jimenez SA, Modulation of TGF-β signaling by proinflammatory cytokines in articular chondrocytes, Osteoarthritis and Cartilage , 2007;5 :1367–77. 99. Khosla S, Mini-review: The OPG/RANKL/RANK System, Endocrinology , 2001;142 :5050–5. 100. Lerman D. Msc Thesis, Inhibitors and promoters of calcific aortic stenosis. University of Edinburgh. Edinburgh, 2012. 101. Baron R, Ferrari, Graham R, Russell G, Denosumab and biphosphonates: Different mechanisms of action and effects, Bone , 2011;48 :677–92. 102. Receptor Activator of NF-κB Ligand by Denosumab Attenuates Vascular Calcium Deposition in Mice, Am J Pathol , 2009;175 :473–8.

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Cardiac Amyloid – An Update Ja s o n N D u n g u Essex Cardiothoracic Centre, Basildon University Hospital, Basildon, United Kingdom

Abstract Cardiac amyloidosis is a condition characterised by rapidly progressive heart failure and poor prognosis. The two main subtypes, immunoglobulin light chains (AL) and transthyretin (ATTR), have been investigated extensively in recent years. Cardiac imaging has advanced with the widespread use of cardiac MRI with late gadolinium enhancement imaging and newer techniques including T1 mapping to quantify amyloid burden. Nuclear imaging has developed as a highly accurate method to confirm cardiac amyloid deposits noninvasively with very high sensitivity in ATTR amyloidosis. Despite advances in imaging, cardiac biopsy remains the gold standard diagnostic test to confirm and type amyloidosis. Hereditary ATTR amyloidosis of V122I type has been the focus of important studies in the past year, due to the high prevalence of the amyloidogenic allele in patients of African descent. Recent research concluded a significant number of Afro-Caribbean heart failure patients are likely to have undiagnosed cardiac amyloidosis. Misdiagnosis may lead to inappropriate treatment with potentially harmful ‘standard’ heart failure medications with no evidence base in amyloidosis. Treatment options have, until recently, been limited but cardiac amyloidosis is the focus of novel therapeutic regimes. New insights into the pathophysiological mechanisms resulting in disease have suggested exciting targets for drug therapy.

Keywords Cardiac amyloidosis, heart failure, cardiomyopathy, diastolic dysfunction, cardiac MRI, echocardiography, nuclear imaging, prognosis Disclosure: The author has no conflicts of interest to disclose. Received: 4 October 2015 Accepted: 1 November 2015 Citation: European Cardiology Review, 2015;10(2):113–7 Correspondence: Jason Dungu, The Essex Cardiothoracic Centre, Basildon and Thurrock University Hospitals NHS Foundation Trust, Nethermayne, Basildon, Essex SS16 5NL, UK. E: j.dungu@nhs.net

Amyloidosis is a condition characterised by accumulation of pathologic fibrillar proteins in organs causing dysfunction.1 Several protein precursors have been shown to cause amyloidosis.2 Cardiac amyloidosis, when waxy, starch-like deposits infiltrate the heart, is most commonly secondary to the accumulation of amyloid fibrils derived from immunoglobulin light chains (AL) or transthyretin (ATTR). Most of the early literature regarding cardiac amyloidosis investigated the AL type, which is often associated with extra-cardiac manifestations with multi-organ involvement. The Mayo staging criteria, as reported by Dispenzeiri et al., are used to grade systemic AL amyloidosis associated with plasma cell dyscrasias. Prognosis in AL amyloidosis correlates with cardiac biomarkers troponin and brain natriuretic peptide (BNP), regardless of confirmed cardiac involvement by routine assessment.3 Cardiac AL amyloidosis has poor prognosis, with most studies reporting median survival of 6–12 months from the date of diagnosis.4,5 More recently, the ATTR subtype has been identified as an important cause of cardiac amyloidosis.6 ATTR amyloidosis is further subdivided into senile cardiac amyloidosis, due to amyloid fibrils composed of wild-type non-mutant transthyretin (ATTRwt), and hereditary forms caused by gene mutations in the transthyretin gene on chromosome 18 (ATTRm). Overall prognosis for cardiac ATTR amyloidosis is better than for the AL type, with median survival typically 2–6 years.7–9 Amyloidosis remains a histological diagnosis, with confirmation requiring microscopic examination of amorphous material in affected tissue

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in which Congo red displays apple-green birefringence when viewed under high-intensity cross-polarised light.10 Immunohistochemical staining of the amyloid deposits is performed using the peroxidise anti-peroxidase method to confirm the amyloid fibril type, using purified immunoglobulin G (IgG) fractions of monospecific antibodies reactive with serum amyloid A protein (SAA), transthyretin (TTR) and with kappa and lambda immunoglobulin light chains.11 Laser microdissection and proteomic analysis using mass spectrometry is now considered the gold standard test to identify the amyloid type but is not widely available.12 A summary of useful investigations in patients with presumed cardiac amyloidosis can be found in Table 1 with further explanation throughout the text.

Pathophysiology There are data to suggest prognosis in AL amyloidosis is poor due to myocardial light chain toxicity.13 Pathophysiology due to ATTR amyloidosis is probably related to infiltration alone, with concomitant cell hypertrophy contributing to increased wall thickening.14 New insights into the pathogenic processes involved in ATTR amyloidosis have been reported. Transthyretin, a transporter protein for thyroxine and retinol in the blood, is formed from four subunits.15 Instability of the tetrameric transthyretin protein has been shown to increase the likelihood of forming amyloid fibrils.16 Proteostasis in all ATTR types may be as important as the point mutations causing ATTRm, as evidenced by overexpression of extracellular chaperones in ATTR patients.17 Proteolytic cleavage has been identified as an important step in destabilisation of the TTR tetramer. The mechano-enzymatic

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Structural Cardiac and Vascular Disease Table 1: Investigation of Presumed Cardiac Amyloidosis Bloods* Elevated troponin and BNP Serum paraprotein† (AL) Elevated serum free light chains (AL) Urine* Bence Jones protein (AL) ECG* Low-voltage complexes Normal complexes in the context of severe LVH Imaging Echocardiography* Concentric LVH, speckled myocardium, diastolic dysfunction, valvular thickening, pericardial effusion, impaired longitudinal strain with apical sparing CMR* Concentric LVH, pleural and pericardial effusions, diffuse late gadolinium enhancement, high native T1 values Tc-DPD** Myocardial uptake SAP Scintigraphy** Extra-cardiac deposits (AL, unable to image the heart) Genetic Testing** TTR gene mutation present (ATTRm) TTR gene mutation absent (ATTRwt or AL) Non-cardiac Biopsy* Congo red staining to confirm systemic amyloidosis (fat pad, rectal, flexor retinaculum from carpal tunnel decompression surgery) Endomyocardial Biopsy* Congo red staining to confirm cardiac involvement Typing** Immunohistochemistry Mass spectrometry *Available in all cardiac centres; **Specialist amyloid centres only; †Note false positive monoclonal gammopathy undetermined significance (MGUS) present in 5 % of over 70s. AL = immunoglobulin light chains amyloidosis; ATTRm = mutations in the transthyretin gene on chromosome 18; ATTRwt = wild-type transthyretin amyloidosis; BNP = brain natriuretic peptide; LVH = left ventricular hypertrophy; TTR = transthyretin.

mechanism described by Marcoux et al. is common to several amyloidogenic variants and is particularly important in the heart where shear stress, a process increasing susceptibility to proteolytic cleavage, is greatest.18 The findings are encouraging for the development of therapies targeting inhibition of transthyretin amyloidogenesis.

The Importance of ATTR Cardiac Amyloidosis Two separate post-mortem series reported a high incidence (25 %) of transthyretin amyloid deposits in the myocardium of elderly subjects at the time of death.19,20 It is not yet known whether the presence of transthyretin amyloid in the heart of very elderly subjects is part of a general aging process or represents under-diagnosis of the clinical phenotype pre-mortem. ATTRwt is associated with an isolated cardiac phenotype, presenting as diastolic heart failure in the eighth decade, with approximately 9:1 male:female ratio.7 Wildtype ATTR amyloidosis is increasingly recognised as an important, yet often unrecognised, cause of heart failure with preserved ejection fraction (HFpEF), a likely heterogeneous group with differing aetiologies. Nuclear imaging with technetium-99m-labelled (99mTc) 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) was used to screen 120 HFpEF patients and 16 patients (13.3 %) showed significant cardiac uptake, later confirmed as ATTRwt following genetic testing and endomyocardial biopsy.21 Unlike the vast majority

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of studies on ATTRwt, there was no difference in sex in the HFpEF patients with cardiac amyloidosis, suggesting the diagnosis by other methods is often missed in women.22 Undiagnosed ATTRwt has been suggested as a possible cause of poor outcomes in patients undergoing transcutaneous aortic valve replacement (TAVR).23 Coexistent degenerative aortic stenosis and ATTRwt has been reported in a small series of 5/43 patients undergoing aortic valve replacement, with confirmed wild-type TTR on endomyocardial biopsy.24 The authors propose larger prospective studies to determine the role of screening for cardiac amyloidosis with Tc-DPD to aid risk stratification in patients being selected for aortic valve interventions. Over 100 TTR gene mutations have been associated with systemic amyloidosis, a condition with autosomal dominant inheritance.25 The V122I variant, in which valine is substituted for isoleucine at position 122, has been the focus of significant interest in recent years. V122I amyloidosis was first reported in 1989 and the clinical phenotype is identical to ATTRwt, with isolated cardiac involvement.26,27 V122I allele frequency was first reported as 3.9 % in African Americans in 1996 and has more recently been re-calculated in a study analysing DNA from 1688 New York State African American newborns.28,29 TTR V122I was detected in 65/3376 alleles and, through expansion of the analysis to include samples from a ‘wellness’ study in San Diego, the authors calculated 3.43 % of African Americans under 65 carry at least one copy of the amyloidogenic allele. Disease onset is reported from 65 years and thus, with the aging population, and improving detection techniques, ATTR V122I is expected to be confirmed as the cause of heart failure in increasing numbers of elderly black patients. In January 2015, it was reported by Quarta et al. in The New England Journal of Medicine that there was no significant difference in mortality for V122I carriers and the prevalence of overt cardiac abnormalities was low, following an interim analysis of the Atherosclerosis Risk in the Communities (ARIC) study.30 Final follow-up, totalling 21.5 years, took place before the median age of presentation with ATTR V122I.31,32 As a result, the authors may have underestimated the true burden of cardiac amyloidosis due to ATTR V122I.33

Imaging Echocardiography Echocardiography is generally the first imaging modality in the investigation of cardiac disease; it is widely available and can be performed at the bedside. Echocardiography is well established in the diagnosis of cardiac amyloidosis with characteristic features. Increased, often concentric, wall thickening with a bright ‘speckled’ appearance of the myocardium is a characteristic finding, often misinterpreted as left ventricular ‘hypertrophy’ despite a different underlying process to hypertrophic cardiomyopathy or hypertensive heart disease. Valvular thickening, diastolic and systolic dysfunction, abnormal strain with typical apical-sparing and pericardial effusion are features suggesting amyloid infiltration.9,34–36 Most studies report increased wall thickening in ATTR compared with AL amyloidosis but longitudinal strain impairment is similar and does have adequate sensitivity or specificity to distinguish between types. A recent small study found no statistically significant echocardiographic differences between cardiac AL and ATTR amyloidosis when comparing systolic and diastolic function but distinguished the types using a ratio of BNP and left ventricular mass index that was higher in AL patients.37 Echocardiography has been used in combination with ECG to detect early cardiac involvement in ATTR amyloidosis. Low-voltage ECG complexes are frequently seen in AL (71 %) and ATTR (56 %) but with

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poor sensitivity.38,39 The combination of low-voltage ECG and septal wall thickness >14 mm can help to identify early cardiac amyloidosis in subjects with transthyretin gene mutations,40 but nuclear imaging is now considered the gold standard for preemptive screening.

Cardiovascular Magnetic Resonance Cardiovascular magnetic resonance (CMR) produces high-resolution images of the heart through complex physics and computational algorithms by using the magnetising properties of atomic nuclei in tissues. Delayed images are routinely acquired after gadolinium infusion, an intravascular contrast agent known to accumulate in regions of extracellular expansion. Several studies have shown the high sensitivity of late gadolinium imaging in cardiac amyloidosis and the findings have been correlated with histological examination of explanted tissue.41–43 More recently, novel T1 mapping techniques to interrogate the native tissue characteristics and quantify the extracellular volume have been deployed in the investigation of cardiac amyloidosis.44,45 A relatively large study of the prognostic value of late gadolinium enhancement (LGE) CMR has been published recently by Fontana et al.46 The authors highlight the additional benefit of phase sensitive inversion recovery (PSIR) imaging to eliminate potential operator-dependent errors relating to the abnormal gadolinium kinetics observed in cardiac amyloidosis41 and no difference in the pattern of LGE was found between the amyloid subtypes. There are conflicting reports in the literature regarding the differentiation of amyloid types by deposition patterns, including a study by the present author.47 A recent histological study of postmortem specimens found diffuse pericellular deposits suggesting AL and nodular deposits more commonly observed in ATTR, from which it can be inferred that morphological differences may be observed according to amyloid fibril composition.48

Nuclear Imaging Nuclear cardiac imaging has emerged as an imaging modality with high sensitivity in the detection of cardiac amyloid deposits, particularly the ATTR subtype.49 Several phosphonate-based tracers, including 99mTcpyrophosphate (Tc-PYP) and Tc-DPD, have been reported to localise amyloid in the heart as a separate property to their original use in bone scintigraphy.50 There are no reports of false negative Tc-DPD scans in patients with confirmed cardiac ATTR amyloidosis and more than half of patients with cardiac AL type have positive scans.51 Tc-DPD is being considered as a screening investigation to rule out cardiac involvement in carriers of ATTR mutations since positive results may occur before abnormalities on echocardiogram.52 Nuclear imaging can be performed in patients who have contraindications to cardiac MRI, such as non-compatible pacing devices or implantable cardioverter defibrillators (ICDs).

Cardiac Computed Tomography Extracellular volume quantification is well established in the assessment of cardiac amyloidosis by cardiac MRI techniques (equilibrium contrast CMR [EQ-CMR]). A recent study has reported equilibrium cardiac computed tomography (CT) using pre- and postcontrast calculation of myocardial volume, with good correlation compared with EQ-CMR and using a shorter protocol.53 Cardiac CT may be a useful alternative to CMR for patients with contraindications in whom quantification of amyloid burden is important for serial monitoring. Ionising radiation is unlikely to be a major concern in the more elderly patients, particularly in the context of a condition with relatively poor prognosis, and doses are lower than in conventionally used bone tracer scintigraphy.

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Treatments Correct diagnosis of cardiac amyloidosis is important to identify patients requiring specialist treatments that are not widely available, and to avoid potentially harmful but otherwise routine heart failure treatments. Cardiac amyloidosis patients are often unresponsive to diuretics at normal dosage and there are no data to support the prognostic benefit of angiotensin converter enzyme (ACE) inhibitors. Calcium-channel blockers and digoxin are potentially toxic.6 The high incidence of progressive heart block in some amyloid subtypes suggests a relative contraindication to beta-blocker use, at least in the absence of regular ECG monitoring.39

Chemotherapy Chemotherapy is not indicated in ATTR amyloidosis and correct identification of amyloid type is necessary to prevent inappropriate chemotherapy for presumed systemic AL amyloidosis. Lachmann et al. investigated 350 patients with a diagnosis of apparent AL amyloidosis and found an alternative genetic cause in 9.7 %, including about 5 % patients with hereditary ATTR amyloidosis.54 The presence of a monoclonal gammopathy had often been misleading in this series, suggesting AL amyloidosis, but it is important to appreciate that incidental monoclonal gammopathy undetermined significance (MGUS) occurs in over 5% of persons aged over 70 years.55 Chemotherapy regimes in cardiac AL amyloidosis aim to suppress the production of amyloidogenic immunoglobulin light chains produced by plasma cell clones in the bone marrow. Combination therapy including an alkylating agent, such as melphalan or cyclophosphamide, and a steroid is the backbone of systemic AL amyloidosis treatment.56 The proteasome inhibitor bortezomib (Velcade®) has advanced the treatment options and when used in combination with cyclophosphamide and dexamethasone (CVD) resulted in good haematological response rates of 81 % in a study of AL patients of whom 74 % had cardiac involvement.57 CVD is not well tolerated in advanced cardiac amyloidosis and patients must be monitored closely during the first cycles, when cardiac decompensation may occur. Patients with good early response, identified by a rapid reduction in serum free light chains, troponin and BNP, have the best outcomes.56

Transplantation Organ transplantation is a potential cure for amyloidosis. Availability of donor hearts is low in the UK; advanced age and multi-organ failure further precludes cardiac transplantation in many patients. Autologous stem cell transplantation in AL amyloidosis is recommended following cardiac transplantation to remove the pathological plasma cells, adding to overall risk, with mortality 2–10 % in patients with cardiac or multiorgan involvement.56 The liver produces 95 % of serum TTR and thus liver transplantation may be necessary in addition to cardiac transplantation in ATTRm but is not indicated in ATTRwt given the on-going production of non-mutant TTR. Progression of cardiac amyloidosis following orthotopic liver transplantation has occurred in all patients with the T60A variant treated at the National Amyloidosis Centre.8 A recent single-centre study reported the results of cardiac transplantation in nine patients with AL amyloidosis and 10 patients with ATTR amyloidosis.58 The median age of patients was 59 years and there were two deaths over 380-day follow-up. One-year survival was 100 % for AL patients and 74 % for ATTR patients. The authors attribute the good outcome in AL patients to aggressive control of light chains; eight out of nine patients received chemotherapy prior to transplantation and five patients underwent autologous stem cell transplantation.

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Structural Cardiac and Vascular Disease Novel TTR Treatments ATTR amyloidosis has emerged as an exciting area of therapeutic development.59 Treatment strategies target three areas: inhibition of hepatic TTR production; TTR stabilisation; and increased clearance of TTR amyloid fibrils.60

has been assessed in a single-arm study involving a small number of cardiac ATTR amyloidosis patients (n=13) in whom tolerability was confirmed but the drug has not been investigated in a randomised trial.64 The use of diflunisal remains an off-label indication in the UK and should only be prescribed in specialist amyloidosis centres with the relevant licence.

TTR Inhibition One hypothesis is reducing TTR production will ultimately lead to less amyloid deposition, allowing the normal turnover to exceed accumulation of amyloids in organs and tissues. The small interfering RNAs (siRNAs) that are bound to RNA-inducing silencing complexes mediate cleavage of target messenger RNA (mRNA). The siRNA agent ALN-TTRSC (Alnylam Pharmaceuticals, Cambridge, MA) has been shown to markedly suppress TTR production in ATTR patients and healthy volunteers61 and a phase III clinical trial in familial amyloid cardiomyopathy is in progress. Antisense oligonucleotides (ASOs) are synthetic single-stranded oligomers designed to bind to specific regions of target mRNA. A phase III study of the ASO agent targeted to TTR mRNA, ISIS-TTRRx (Isis Pharmaceuticals, Carlsbad, CA), is in progress in patients with familial amyloid polyneuropathy (FAP).

TTR Stabilisers Tafamadis (Vyndaqel®) is a small molecule that selectively binds to the thyroxine binding site of TTR in plasma and stabilises the tetrameric protein in vitro.62 Tafamadis has been shown to reduce the rate of change in peripheral neuropathy scores in FAP and the encouraging results have prompted a phase III clinical trial in ATTR cardiomyopathy. Diflunisal is a non-steroidal anti-inflammatory drug that binds to the thyroxine binding sites on the TTR tetramer.16 Diflunisal is associated with the typical non-steroidal anti-inflammatory (NSAID) related adverse events, including gastrointestinal bleeding, renal dysfunction and worsening congestive heart failure, all of which may have devastating consequences in patients with amyloidosis. The results of a randomised, double-blind placebo-controlled trial to assess diflunisal in peripheral and autonomic neuropathy showed a reduction in the rate of progression of neuropathy compared with the placebo.63 Diflunisal

Selvanayagam JB, Hawkins PN, Paul B, et al. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol 2007;50 :2101–10. 2. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart 2011;97 :75–84. 3. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22 :3751–7. 4. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32 :45–59. 5. Lebovic D, Hoffman J, Levine BM, et al. Predictors of survival in patients with systemic light-chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone. Br J Haematol 2008;143 :369–73. 6. Dungu JN, Anderson LJ, Whelan CJ, et al. Cardiac transthyretin amyloidosis. Heart 2012;98 :1546–54. 7. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013;2 :e000098. 8. Sattianayagam PT, Hahn AF, Whelan CJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J 2012;33 :1120–7. 9. Quarta CC, Solomon SD, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus lightchain cardiac amyloidosis. Circulation 2014;129 :1840–9. 10. Puchtler H, Sweat F, Levine M. On the binding of Congo red by amyloid. J Histochem Cytochem 1962;10 :355. 11. Tennent GA. Isolation and characterization of amyloid fibrils from tissue. Methods Enzymol 1999;309 :26–47. 12. Vrana J a, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009;114 :4957–9.

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Increased Clearance of TTR Amyloid Fibrils The antibiotic doxycycline has been shown to disrupt amyloid fibrils in a transgenic mouse model.60 A phase II open label study investigating doxycycline in 20 FAP patients over 12 months showed no clinical progression of cardiac involvement and stable neuropathy scoring.65 Further investigation of doxycycline in ATTR amyloidosis is needed to assess the role in the wider patient population. Serum amyloid P component (SAP) is present in all types of amyloid. The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine2-carboxylic acid (CPHPC) is a novel small molecule drug that crosslinks SAP in the plasma, triggering hepatic depletion.66 The combination of CPHPC and anti-SAP antibodies has been shown to eliminate visceral amyloid deposits in mice.67 This immunotherapeutic approach to treatment has been confirmed as safe in man with a recently reported phase 1 trial involving 15 patients with systemic amyloidosis.68 Further studies are needed to confirm the role of the potential cure for systemic amyloidosis in patients with cardiac involvement.

Conclusion Cardiac amyloidosis, previously considered a rare condition, is becoming an increasingly important cause of heart failure. Progressive imaging techniques have markedly increased detection rates. The ATTR type in particular is likely underdiagnosed in elderly and Afro-Caribbean populations. Treatment options have been limited until recently but several therapeutic strategies are currently undergoing phase III clinical trial assessment. Many more patients with cardiac amyloidosis will be identified with increased awareness and should be referred to specialist centres for further characterisation, implementation of an appropriate management plan and allowed access to novel drugs. n

13. McWilliams-Koeppen HP, Foster JS, Hackenbrack N, et al. Light chain amyloid fibrils cause metabolic dysfunction in human cardiomyocytes. PLoS One 2015;10 :e0137716. 14. Fontana M, Banypersad SM, Treibel TA, et al. Differential myocyte responses in patients with cardiac transthyretin amyloidosis and light-chain amyloidosis: a cardiac mr imaging study. Radiology 2015;277 :388–97. 15. Johnson SM, Connelly S, Fearns C, et al. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agencyapproved drug. J Mol Biol 2012;421 :185–203. 16. Sacchettini JC, Kelly JW. Therapeutic strategies for human amyloid diseases. Nat Rev Drug Discov 2002;1 :267–75. 17. Da Costa G, Ribeiro-Silva C, Ribeiro R, et al. Transthyretin amyloidosis: chaperone concentration changes and increased proteolysis in the pathway to disease. PLoS One 10 :e0125392. 18. Marcoux J, Mangione PP, Porcari R, et al. A novel mechanoenzymatic cleavage mechanism underlies transthyretin amyloidogenesis. EMBO Mol Med 2015;7 :1337–49. 19. Cornwell GG, Murdoch WL, Kyle RA, et al. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med 1983;75 :618–23. 20. Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008;40 :232–9. 21. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015;36 :2585–94. 22. Bokhari S, Maurer MS, Castan A. Unveiling wild-type transthyretin cardiac amyloidosis as a significant and potentially modifiable cause of heart failure with preserved ejection fraction. Eur Heart J 2015;36 :2595–7. 23. Castaño A, Bokhari S, Maurer MS. Could late enhancement

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and need for permanent pacemaker implantation in patients undergoing TAVR be explained by undiagnosed transthyretin cardiac amyloidosis? J Am Coll Cardiol 2015;65 :311–2. Longhi S, Lorenzini M, Gagliardi C, et al. Coexistence of degenerative aortic stenosis and wild-type transthyretinrelated cardiac amyloidosis. JACC Cardiovasc Imaging 2015: epub ahead of press. Connors LH, Lim A, Prokaeva T, et al. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10 :160–84. Gorevic PD, Prelli FC, Wright J, et al. Systemic senile amyloidosis. Identification of a new prealbumin (transthyretin) variant in cardiac tissue: immunologic and biochemical similarity to one form of familial amyloidotic polyneuropathy. J Clin Invest 1989;83 :836–43. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variantsequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336 :466–73. Jacobson DR, Pastore R, Pool S, et al. Revised transthyretin Ile 122 allele frequency in African-Americans. Hum Genet 1996;98 :236–8. Jacobson DR, Alexander AA, Tagoe C, et al. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid 2015;22 :171–4. Quarta CC, Buxbaum JN, Shah AM, et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med 2015;372 :21–9. Jacobson D, Tagoe C, Schwartzbard A, et al. Relation of clinical, echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of the transthyretin V122I allele in older African-American men. Am J Cardiol 2011;108 :440–4. Ruberg FL, Maurer MS, Judge DP, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J 2012;164:222–8.e1.

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33. Gillmore JD, Hawkins PN. V122I transthyretin variant in elderly black Americans. N Engl J Med 2015;372 :1768–9. 34. Phelan D, Collier P, Thavendiranathan P, et al. Relative “apical sparing” of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart 2012;98 :1442–8. 35. Koyama J, Falk RH. Prognostic significance of strain Doppler imaging in light-chain amyloidosis. JACC Cardiovasc Imaging 2010;3 :333–42. 36. Falk RH, Uk M, Plehn JF, et al. Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. Am J Cardiol 1987;59 :418–22. 37. Mori M, An Y, Katayama O, et al. Clinical and echocardiographic characteristics for differentiating between transthyretinrelated and light-chain cardiac amyloidoses. Ann Hematol 2015;94 :1885–90. 38. Dubrey S, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998;91 :141–57. 39. Dungu J, Sattianayagam PT, Whelan CJ, et al. The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin Isoleucine 122 (V122I) type in Afro-Caribbean patients. Am Heart J 2012;164 :72–9. 40. Di Bella G, Minutoli F, Piaggi P, et al. Usefulness of combining electrocardiographic and echocardiographic findings and brain natriuretic peptide in early detection of cardiac amyloidosis in subjects with transthyretin gene mutation. Am J Cardiol 2015;116 :1122–7. 41. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111 :186–93. 42. Vogelsberg H, Mahrholdt H, Deluigi CC, et al. Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol 2008;51 :1022–30. 43. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging 2010;3 :155–64.

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44. Banypersad SM, Fontana M, Maestrini V, et al. T1 mapping and survival in systemic light-chain amyloidosis. Eur Heart J 2015;36 :244–51. 45. Fontana M, Banypersad SM, Treibel TA, et al. Native T1 Mapping in transthyretin amyloidosis. JACC Cardiovasc Imaging 2014;7 :157–65. 46. Fontana M, Pica S, Reant P, et al. Prognostic value of late gadolinium enhancement cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2015;132 :1570–9. 47. Dungu JN, Valencia O, Pinney JH, et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC Cardiovasc Imaging 2014;7 :133–42. 48. Larsen BT, Mereuta OM, Dasari S, et al. Correlation of histomorphologic pattern of cardiac amyloid deposition with amyloid type: a histologic and proteomic analysis of 108 cases. Histopathology 2015: epub ahead of press. 49. Maurer MS. Non-invasive identification of ATTRwt cardiac amyloid: the re-emergence of nuclear cardiology. Am J Med 2015: epub ahead of press. 50. Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46 :1076–84. 51. Quarta CC, Guidalotti PL, Longhi S, et al. Defining the diagnosis in echocardiographically suspected senile systemic amyloidosis. JACC Cardiovasc Imaging 2012;5 :755–8. 52. Hutt DF, Quigley A-M, Page J, et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging 2014;15 :1289–98. 53. Treibel TA, Bandula S, Fontana M, et al. Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis. J Cardiovasc Comput Tomogr 2015. 54. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346 :1786–91. 55. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance.

N Engl J Med 2006;354 :1362–9. 56. Mahmood S, Palladini G, Sanchorawala V, et al. Update on treatment of light chain amyloidosis. Haematologica 2014;99 :209–21. 57. Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 2012;119 :4387–90. 58. Davis MK, Kale P, Liedtke M, et al. Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. Am J Transplant 2015;15 :650–8. 59. Lachmann HJ. A new era in the treatment of amyloidosis? N Engl J Med 2013;369 :866–8. 60. Hanna M. Novel drugs targeting transthyretin amyloidosis. Curr Heart Fail Rep 2014;11 :50–7. 61. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013;369 :819–29. 62. Coelho T, Maia LF, da Silva AM, et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 2013;260 :2802–14. 63. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013;310 :2658–67. 64. Castaño A, Helmke S, Alvarez J, et al. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail 2012;18 :315–9. 65. Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 2012;19 (Suppl 1):34–6 66. Pepys MB, Herbert J, Hutchinson WL, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002;417 :254–9. 67. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 2010;468 :93–7. 68. Richards DB, Cookson LM, Berges AC, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med 2015;373 :1106–14.

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Syncope and Sudden Cardiac Death

LE ATION.

Sudden Cardiac Death Risk Stratification – An Update Reginald Liew Gleneagles Hospital Singapore, Duke-NUS Graduate Medical School, Singapore

Abstract Sudden cardiac death (SCD) remains a major public health problem worldwide, yet current methods to identify those at greatest risk are inadequate. High-risk individuals may benefit from potentially life-saving treatment, such as insertion of an implantable-cardioverter defibrillator (ICD). However, such treatments are expensive and have their own associated risks. Furthermore, most cases of SCD occur in the general adult population who may be relatively asymptomatic but yet have an underlying predisposition to SCD. Hence, there is great interest and clinical need in improving methods for risk stratification of SCD to identify those at greatest risk and implement the most appropriate treatment. This review provides an update on current risk-stratification methods for SCD in high-risk groups, in particular patients with reduced left ventricular function following acute myocardial infarction and those with non-ischaemic dilated cardiomyopathy, and highlights some novel methods that may have a role to play in future risk-stratification schemes. Approaches and challenges for SCD risk stratification among the general public are also discussed.

Keywords Sudden cardiac death, risk stratification, ventricular fibrillation, implantable cardioverter defibrillator, early repolarisation syndrome, ischaemic cardiomyopathy, non-ischaemic dilated cardiomyopathy, signal averaged ECG Disclosure: The author has no conflicts of interest to disclose. Received: 5 July 2015 Accepted: 28 October 2015 Citation: European Cardiology Review, 2015;10(2):118–22 Correspondence: Reginald Liew, Gleneagles Hospital, 6A Napier Road, Singapore 258500. E: reginald.liew@gmail.com

Sudden cardiac death (SCD) can be defined as unexpected death that occurs within one hour of the onset of symptoms or during sleep in a person who was previously stable. The mode of death, which may be due to an arrhythmic or non-arrhythmic cause, depends on the underlying cardiovascular abnormality (mechanical or electrical substrate). SCD remains a major public health problem worldwide and is estimated to account for 15–20 % of all deaths.1 Those deemed to be at highest risk of SCD may benefit from potentially life-saving treatment, such as insertion of an implantable-cardioverter defibrillator (ICD). However, such treatments are expensive and have their own associated risks, such as the risk of long-term infection and need for repeated surgeries and regular check-up. Hence, there is great interest and clinical need in improving methods for risk stratification of SCD to identify those at greatest risk. Several factors make research into SCD risk stratification difficult and challenging. First, current guidelines and most international randomised studies on SCD have focused on specific high-risk groups – in particular, patients with reduced (below 30–35 %) left ventricular ejection fraction (LVEF) – with the aim of identifying those patients who would benefit most from an ICD. The latest European Society of Cardiology guidelines on ventricular arrhythmias and SCD recommend ICD therapy in patients with symptomatic heart failure (New York Heart Association [NYHA] class II–III) and LVEF ≤35 % after ≥3 months of optimal medical therapy who are expected to survive for at least 1 year with good functional status.2 Similarly, the American College of Cardiology and American Heart Association guidelines recommend ICD therapy in patients with LVEF ≤35 % due to prior myocardial infarction (MI), at least 40 days post MI, or non-ischaemic

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dilated cardiomyopathy and NYHA class II or III.3 Although low LVEF identifies patients at increased risk for cardiac arrest, the majority of sudden deaths occur in patients with LVEF greater than 30 %.4,5 Indeed, most cases of SCD occur in the general adult population, in people who may be relatively asymptomatic but have an underlying predisposition to SCD. Current guidelines on SCD risk stratification do not adequately cover this general population pool, as acknowledged in the latest European guidelines,2 yet from a population health perspective, this is the group that should be targeted if healthcare providers are to make any meaningful impact on lowering the incidence of SCD worldwide. Second, the mechanisms leading to SCD are complex and multifactorial, making the development of SCD risk scores and algorithms challenging. Even in those at highest risk of SCD, patient factors, comorbidities and underlying cardiovascular substrate abnormalities that predispose to SCD may change over time. Accurate methods for SCD risk stratification should take into account the changing and heterogeneous risk in each individual over time so that the risk is continually revisited and refined. In view of the wide and varying mechanisms and cardiovascular abnormalities underlying SCD, current methods for SCD risk stratification encompass a variety of modalities, which include imaging techniques to look for underlying mechanical or structural abnormalities, assessment for electrical substrate abnormalities and autonomic dysfunction and genetic analyses (see Figure 1). This review will give an update of current methods and strategies for SCD risk stratification in high-risk individuals (namely patients with ischaemic and non-ischaemic dilated cardiomyopathy) and in the general public. Discussion of SCD in patients with inherited

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cardiomyopathies, primary arrhythmogenic diseases and genetic determinants of risk is beyond the scope of this review.

Figure 1: Methods for Risk Stratification of Sudden Cardiac Death

Risk Stratification in Patients with Ischaemic Cardiomyopathy

Genetic testing Analysis of known mutations that increase risk of SCD

Imaging Techniques The formation of myocardial scarring and left ventricle (LV) dysfunction following acute myocardial infarction (AMI) can result in areas of heterogeneous electrical conduction and abnormal electrical circuits within the diseased myocardium, which can predispose patients to the later development of ventricular tachycardia/ ventricular fibrillation (VT/VF) and SCD.6,7 Hence, imaging modalities demonstrating the presence of large areas of myocardial scarring or severe LV dysfunction may provide some indication of SCD risk. Measurement of LVEF is a crude indicator of the degree of myocardial damage and can be easily done using transthoracic echocardiography. The link between a low LVEF and risk of SCD has been well established.8 Consequently, LVEF was an important parameter measured in many of the early landmark randomised ICD trials and remains an integral component of current international guidelines on the indications for ICD implantation in patients following AMI for both primary and secondary prevention. However, a major limitation of the use of LVEF as a risk-stratification tool for determining which patients would benefit most from an ICD is that it is a good predictor of overall mortality but less accurate in predicting the development of VT/VF.9,10 More sophisticated imaging modalities for assessment of myocardial scarring have been found to be better predictors of the development of ventricular arrhythmias in patients with ischaemic cardiomyopathy. For example, strain imaging echocardiography appears to provide better prediction of VT/VF and SCD than LVEF alone, particularly in patients with LVEF > 35 %, in patients >40 days post AMI.11 Single photo emission computed tomography (SPECT) and positron emission tomography (PET) have also been shown to identify myocardial scarring and have a value in prediction of arrhythmic events in patients post AMI.12 The use of cardiac magnetic resonance (CMR) in assessing myocardial scar burden among AMI survivors and predicting mortality and arrhythmic events has been well explored and found to be of benefit by several investigators.13–16 The advantage of CMR over SPECT or PET imaging is that it has a much greater spatial resolution and is not dependent on vascular perfusion, so can also be used to identify scarring in non-ischaemic cardiomyopathies. Furthermore, CMR not only provides information on the overall scar burden and distribution, but also differentiates between different types of scarring, which provides further information on the underlying electrophysiological substrate abnormality. Quantification of the peri-infarct zone using contrast-enhanced CMR was shown to be an independent predictor of mortality following AMI in early studies.13 Other investigators have demonstrated that tissue heterogeneity in the peri-infarct zone, as detected by contrast-enhanced CMR, is likely to signify a pro-arrhythmic substrate and is one of the strongest predictors of ventricular arrhythmias and appropriate ICD therapies. 14–16 Studies correlating myocardial scarring on CMR with invasive electrophysiological (EP) data from VT studies have shown that areas of heterogeneous scarring are more arrhythmogenic than areas of dense scarring and an independent predictor of VT/VF.17,18 More recently, investigators have shown that the extent of peri-infarct zone detected by CMR post AMI correlated with increased ventricular inducibility, even in patients with relatively preserved LVEF.19

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ECG-based parameters • QT interval • QRS duarion • Fragmented QRS complexes • Signal-averaged ECG

Autonomic function tests • Heart rate variability • Heart rate turbulence

Genetic predisposition

Arrhythmogenic substrate

Screening for ventricular arrhythmias • Ambulatory monitoring for VT • Programmed ventricular stimulation

Myocardial imaging • Echo to access LV systolic function • SPECT/PET • CRM to assess myocardial scar

SCD risk

Other cardiovascular parameters

Anatomical substrate Population risk assesment • Risk scores • Serum biomarkers • ECG-based parameters • Imaging techniques

CMR = cardiac magnetic resonance imaging, LV = left ventricle, PET= positron emission tomography, SCD = sudden cardiac death, SPECT= single photo emission computed tomography, VT = ventricular tachycardia

ECG-based Parameters for Risk Assessment Several ECG-based parameters, including QRS duration, fragmented ECG complexes and signal-averaged ECG (SAECG), have been widely studied in the context of prediction of ventricular arrhythmias in patients with ischaemic cardiomyopathy.20 Although a number of studies have shown some value in these tests, their overall positive predictive accuracy has been insufficient to allow them to be used solely as a risk-stratification tool. The presence of fragmented QRS complexes (fQRS) on the routine 12-lead ECG has been described as a marker of abnormal ventricular depolarisation and demonstrated to be a predictor of mortality and sudden cardiac death.21,22 fQRS is a simple, inexpensive and easily accessible ECG sign that may be of value in determining the risk for SCD and guiding prophylactic ICD insertion in AMI survivors. In a recent meta-analysis of 12 studies involving 5009 patients, the presence of fQRS complexes was associated with all-cause mortality and SCD.23 Hence, fQRS complexes appear to be a useful marker of increased SCD risk. However, a greater understanding of the significance of this non-specific finding and future prospective, multicentre data is required before it can routinely be adopted into clinical practice. The prognostic value of SAECG in predicting mortality among AMI survivors has been examined in multiple studies over the past few decades.24,25 The sensitivity of SAECG to predict arrhythmic events has been very variable from these studies, ranging from 15 % to 75 %, with follow-up of between 6 and 24 months. The main value of the SAECG appears to be its use in identifying low-risk patients in view of its high negative predictive value (over 90 %). However, its positive predictive accuracy is much lower, thus decreasing its usefulness as a single variable to identify high-risk patients.24 The coronary artery bypass grafting (CABG) Patch Trial was an important negative study in which SAECG appeared to be unhelpful in identifying a high-risk group of patients.10 With the increasing use of primary percutaneous coronary intervention (PCI) in the treatment of AMI, the prognostic value of the SAECG has become less clear. Bauer et al. performed SAECGs in 968 patients following AMI, 91 % of whom underwent PCI, and found that the presence of ventricular late potentials (VLPs) was not significantly associated with cardiac death or a serious arrhythmic event during a median follow up of 34 months.26 Ikeda et al. also found that VLPs had no significant prognostic role in predicting the primary outcome

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Syncope and Sudden Cardiac Death of death or resuscitated cardiac arrest when measured in 627 patients post AMI (82 % underwent PCI).27 The value of the SAECG in arrhythmic risk prediction among post-AMI survivors may be increased when it is used in combination with other tests to further refine risk in patients already deemed to be at higher risk, such as those with decreased LVEF. Gomes et al. demonstrated that the combination of an abnormal SAECG and LVEF<30 % in 1268 patients with coronary artery disease and nonsustained VT identified a particularly high-risk subset of patients that represented 21 % of the total population.28 In this group, 36 % and 44 % succumbed to arrhythmic and cardiac death, respectively. Microvolt T-wave alternans (MTWA) has also been found to be a powerful predictor of life-threatening arrhythmias and SCD in patients post AMI, both with and without decreased LVEF.27,29,30 MTWA appears to be a better risk predictor when compared with SAECG31 and may be even more powerful when combined with LVEF and invasive electrophysiological (EP) testing.32 In a prospective multicentre study involving 575 patients, Chow et al. found that MTWA testing in patients with ischaemic heart disease and LVEF<30 % who already qualified for an ICD did not predict subsequent ventricular arrhythmic events, although MTWA non-negative patients (i.e. positive and indeterminate MTWA results) had significantly higher mortality compared with MTWA negative patients.33 The value of MTWA in risk stratification may actually be in deciding which patients are least likely to benefit from ICD insertion, as suggested by the ABCD (Alternans Before Cardioverter Defibillator) trial.34 This prospective, multicentre study was the first to use MTWA to guide prophylactic ICD insertion. The investigators demonstrated that MTWA achieved one-year positive and negative predictive values of 9 % and 95 %, respectively, and that its use in risk stratification was comparable to invasive EP study at one year and complementary when applied in combination.

Autonomic Function Tests Autonomic function tests, such as heart rate variability (HRV) and heart rate turbulence (HRT), have also been extensively studied because autonomic dysfunction can increase the risk of ventricular arrhythmias, especially in patients post AMI. Evidence suggests that decreased HRV is associated with increased ventricular arrhythmias and mortality.35,36 In the Multicenter Postinfarction Study (MPS), which involved 808 patients, a strong correlation was found between reduced HRV and total mortality following AMI.37 However, HRV does not appear to fare as well as other markers of autonomic dysfunction when directly compared. In the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) study, which involved 1284 patients with a recent (<28 days) MI, baroreceptor sensitivity (calculated from measuring the rate‚Äìpressure response to intravenous phenylephrine) was a better predictor of mortality, particularly in patients with LVEF<35 %.36 Several large-scale prospective studies have provided strong evidence that HRT is a powerful independent predictor of risk following AMI.38–40 In the REFINE study, autonomic function tests, including measurements of HRT, were conducted in 322 patients with LVEF <50 % post AMI. The investigators found that these tests could reliably identify those at high risk of serious cardiac events.39 Another prospective6 study involving 2343 survivors of AMI found that the combination of HRT and deceleration capacity could be used together to identify a high-risk group equivalent in size and mortality to patients with LVEF<30 %.40

Role of Invasive Electrophysiological Testing Early studies on the use of invasive EP testing to risk-stratify patients at increased risk of malignant ventricular arrhythmias were performed

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in AMI survivors – reports from these studies were conflicting, with nearly half of all studies finding that the inducibility of sustained VT was unhelpful in predicting later mortality or arrhythmic events.41,42 The apparent confusion in the literature is probably related to differences in patient population, stimulation protocols and time intervals between AMI and EP testing.41,42 In addition to the invasive nature of the test and need for specialist equipment and personnel, another limitation to the routine use of EP testing in risk prediction includes the wide range of reported sensitivities (between 28 % and 80 %). The future role of this invasive test in risk prediction may lie in its combined use with other non-invasive tests, such as MTWA and HRV, to further refine the selection of potential ICD recipients.34,43,44

Risk Stratification in Patients with Non-ischaemic Dilated Cardiomyopathy Risk stratification of SCD in patients with non-ischaemic dilated cardiomyopathy (NIDCM) has been less studied than in patients with ischaemic heart disease and depressed LVEF. There is as great a need for accurate and reliable risk stratification in NIDCM patients because they tend to be younger and have a better prognosis and therefore may receive less overall benefit from an ICD than patients with ischaemic cardiomyopathy.45 The pathophysiology of VT/VF in patients with NIDCM is less understood and is likely to be due to a variety of mechanisms, including myocardial fibrosis, left ventricular dilatation and autonomic dysfunction. Consequently, despite the plethora of tests available for SCD risk stratification, there is currently no definite test or recommendation for this population other than using the LVEF, which is a crude estimate of VT/VF risk. Unlike the potential value of autonomic function tests in SCD risk stratification in patients post AMI, these tests do not appear to be useful in patients with NIDCM. In a recent study of 60 patients with NIDCM and LVEF≤50%, Pezawas et al. demonstrated that a variety of non-invasive tests (including pharmacological baroreflex testing, short-term spectral analysis of HRV, long-term time domain analysis, exercise MTWA, SAECG, and corrected QT-time) could not reliably identify patients at risk of fatal ventricular arrhythmias.46 In a meta-analysis of 45 studies involving non-invasive tests to predict the risk of arrhythmic events in 6088 patients with NIDCM, Goldberger et al. found that fragmented QRS complexes and T-wave alternans (TWA) had the best odds ratios, whereas none of the autonomic tests (HRV, HRT and baroreflex sensitivity) were significant predictors.47 In view of the heterogeneous nature of NIDCM and the multiple mechanisms that underlie the pathophysiology of VT/VF, a different strategy and combination of tests is probably required to optimise risk stratification in this patient population.

Risk Stratification in the General Population From a population perspective, reliable identification of people in the general public a t highest risk of malignant ventricular arrhythmias would provide the greatest impact on decreasing the incidence of SCD. Since a major cause of SCD is in the context of an acute coronary syndrome or myocardial infarction, identification of those at risk of an acute atherosclerotic event and subsequent VT/VF may be a useful avenue to pursue. Although risk stratification for coronary artery disease is well established in clinical practice, there are currently no accurate methods available to identify individuals at risk of plaque rupture and the development of VT/VF. Epidemiological studies on certain serum biomarkers, such as N-Terminal pro-B type natriuretic peptide, non-esterified fatty acids, interleukin-6 and circulating antibodies, appear to show some potential in helping to identify those in the general public at risk of acute plaque rupture

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Sudden Cardiac Death Risk Stratification – An Update

and sudden VT/VF,48–51 although more data is required before such biomarkers can be used clinically. Advances in cardiac CT technology have allowed the characterisation of atherosclerotic plaque features that can provide additional information on the risk of plaque rupture and subsequent SCD.52–54 However, this imaging modality would not be suitable for mass screening on a population level. Other imaging modalities, such as echocardiography, may have a role to play in SCD risk assessment in the general population. For example, echocardiographic measurements of left ventricular mass and diameter have been shown to be associated with an increased risk of sudden death among the general public.55,56 A more practical method to assess SCD risk in the general population is to use ECG-based parameters and large-scale screening. A Finnish cohort of over 10,000 middle-aged subjects has helped provide some of the most useful data on ECG-based risk of SCD to date.57–60 In this cohort, QRS prolongation of ≥110 ms, intraventricular conduction delay (but not bundle branch block), and early repolarisation of at least 0.2 mV, were all independent predictors of arrhythmic death. However, the low prevalence of each of these markers may limit their utility in large-scale screening. The clinical significance of early repolarisation on the surface ECG has gained increasing interest following two seminal studies demonstrating a link between early repolarisation syndrome (ERS) and idiopathic VF/sudden death.60,61 Investigators have since compared ERS in cardiac arrest survivors with preserved ejection fraction,62 in families with sudden arrhythmic death syndrome63 and other families with an early repolarisation pattern on the ECG64 and in Asian populations.65 ERS in the inferior leads, especially in cases without other QRS complex abnormalities, appears to predict the occurrence of VT/VF but not non-arrhythmic cardiac events, suggesting that early repolarisation is a specific sign of increased vulnerability to ventricular arrhythmias.66 Programmed ventricular stimulation was not found to enhance risk stratification in patients with ERS, even among those at highest risk who survived a cardiac arrest.67 Despite the increasing body of evidence in this area, controversy still remains on the exact clinical significance, implications and optimal management in patients with ERS on the surface ECG.68,69 Other novel ECG-based parameters may also be potentially useful in population screening for SCD. In a recent study of 14,024 participants without left ventricular hypertrophy in the Atherosclerosis Risk in

1. Hayashi M, Shimizu W, Albert CM, The spectrum of epidemiology underlying sudden cardiac death, Circ Res , 2015;116 :1887–906. 2. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al., 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), Eur Heart J , 2015;. 3. Tracy CM, Epstein AE, Darbar D, et al., 2012 ACCF/AHA/ HRS Focused Update Incorporated Into the ACCF/AHA/ HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society, J Am Coll Cardiol , 2013;61 :e6–e75. 4. Gorgels APM, Gijsbers C, de Vreede-Swagemakers J, et al., Out-of-hospital cardiac arrest-the relevance of heart failure. The Maastricht Circulatory Arrest Registry, Eur Heart J , 2003;24 :1204–9. 5. Stecker EC, Vickers C, Waltz J, et al., Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study, J Am Coll Cardiol ,

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Communities (ARIC) study, beat-to-beat spatiotemporal variability in the T-vector on standard 12-lead ECGs was found to be associated with SCD over a median follow-up of 14 years.70 In another large, retrospective population-based cohort study using the ARIC database, ECG-deep terminal negativity of the P-wave in V1 was also found to be associated with an increased risk of SCD.71

Conclusion It is clear that current methods for SCD risk stratification are inadequate, both in high-risk groups such as patients with reduced LVEF post AMI, patients with NIDCM and among the general public. Several novel risk-stratification techniques, including imaging, ECGbased methods and serum biomarkers, have shown considerable promise in refining SCD risk on top of conventional methods. However, such data has been derived from single-centre studies or studies involving a small number of centres, rather than large international randomised clinical trials. Hence, their clinical utility, effect on outcomes and cost-effectiveness require further evaluation and, consequently, these novel risk-stratification techniques have not yet been incorporated into current international guidelines on ICD therapy. Different approaches may be required for risk stratification of different populations. In high-risk groups, a combination of risk-stratification tests involving imaging and ECG-based techniques, in addition to conventional transthoracic echo to assess LVEF, is likely to be needed. Specific combinations may be required for patients with ischaemic and non-ischaemic cardiomyopathy, which will need to be validated prospectively. Repeat risk assessments may be appropriate in patients who are not deemed to be at high risk at baseline as the risk may change over time; hence, non-invasive tests may be more practical than invasive investigations such as EP testing. The approach to SCD risk stratification and reduction of risk in the general public will require a different angle because it is not possible or economically viable to perform sophisticated and expensive tests on a population level. The future in this area will probably lie in the use of improved clinical risk scores, possibly in combination with simple, inexpensive tests (ECGbased or serum biomarkers). These risk-stratification methods may be applied to certain subsets of the public who may be at increased risk, e.g. in males above the age of 40 and post-menopausal women, or those with other cardiovascular risk factors such as hypertension or diabetes. As it would not be practical to perform conventional randomised‚ controlled trials on a population level, validation of such an approach would require international epidemiological studies and good registry data. n

2006;47 :1161–6. 6. Stevenson WG, Brugada P, Waldecker B, et al., Clinical, angiographic, and electrophysiologic findings in patients with aborted sudden death as compared with patients with sustained ventricular tachycardia after myocardial infarction, Circulation , 1985;71 :1146–52. 7. Yalin K, Golcuk E, Buyukbayrak H, et al., Infarct characteristics by CMR identifies substrate for monomorphic VT in post-MI patients with relatively preserved systolic function and ns-VT, Pacing Clin Electrophysiol , 2014;37 :447–53. 8. Bigger JT, Jr., Fleiss JL, Kleiger R, et al., The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction, Circulation , 1984;69 :250–8. 9. Hohnloser SH, Kuck KH, Dorian P, et al., Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction, N Engl J Med , 2004;351 :2481–8. 10. Bigger JT, Jr, Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators, N Engl J Med , 1997;337 :1569–75. 11. Haugaa KH, Grenne BL, Eek CH, et al., Strain echocardiography improves risk prediction of ventricular arrhythmias after myocardial infarction, JACC Cardiovasc Imaging , 2013;6 :841–50.

12. Dorbala S, Hachamovitch R, Curillova Z, et al., Incremental prognostic value of gated Rb-82 positron emission tomography myocardial perfusion imaging over clinical variables and rest LVEF, JACC Cardiovasc Imaging, 2009;2:846–54. 13. Yan AT, Shayne AJ, Brown KA, et al., Characterization of the peri-infarct zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality, Circulation , 2006;114 :32–9. 14. Schmidt A, Azevedo CF, Cheng A, et al., Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction, Circulation , 2007;115 :2006–14. 15. Roes SD, Borleffs CJ, van der Geest RJ, et al., Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillator, Circ Cardiovasc Imaging , 2009;2 :183–90. 16. Gouda S, Abdelwahab A, Salem M, et al., Scar characteristics for prediction of ventricular arrhythmia in ischemic cardiomyopathy, Pacing Clin Electrophysiol , 2015;38 :311–8. 17. Perez-David E, Arenal A, Rubio-Guivernau JL, et al., Noninvasive identification of ventricular tachycardia-related conducting channels using contrast-enhanced magnetic resonance imaging in patients with chronic myocardial infarction: comparison of signal intensity scar mapping and endocardial voltage mapping, J Am Coll Cardiol, 2011;57:184–94.

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Syncope and Sudden Cardiac Death 18. Roes SD, Borleffs CJ, van der Geest RJ, et al., Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverterdefibrillator, Circ Cardiovasc Imaging , 2009;2 :183–90. 19. Yalin K, Golcuk E, Buyukbayrak H, et al., Infarct characteristics by CMR identifies substrate for monomorphic VT in post-MI patients with relatively preserved systolic function and ns-VT, Pacing Clin Electrophysiol , 2014;37 :447–53. 20. Liew R, Prediction of sudden arrhythmic death following acute myocardial infarction, Heart , 2010;96 :1086–94. 21. Das MK, Zipes DP, Fragmented QRS: a predictor of mortality and sudden cardiac death, Heart Rhythm , 2009;6 (3 Suppl):S8–14. 22. Pei J, Li N, Gao Y, et al., The J wave and fragmented QRS complexes in inferior leads associated with sudden cardiac death in patients with chronic heart failure, Europace , 2012;14 :1180–7. 23. Rosengarten JA, Scott PA, Morgan JM, Fragmented QRS for the prediction of sudden cardiac death: a meta-analysis, Europace , 2015;17:969–77. 24. Kuchar DL, Thorburn CW, Sammel NL, Late potentials detected after myocardial infarction: natural history and prognostic significance, Circulation , 1986;74 :1280–9. 25. Hartikainen JEK, Malik M, Staunton A, et al., Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signalaveraged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction, J Am Coll Cardiol, 1996;28:296–304. 26. Bauer A, Guzik P, Barthel P, et al., Reduced prognostic power of ventricular late potentials in post-infarction patients of the reperfusion era, Eur Heart J , 2005;26 :755–61. 27. Ikeda T, Saito H, Tanno K, et al., T-wave alternans as a predictor for sudden cardiac death after myocardial infarction, Am J Cardiol , 2002;89 :79–82. 28. Gomes JA, Cain ME, Buxton AE, et al., Prediction of longterm outcomes by signal-averaged electrocardiography in patients with unsustained ventricular tachycardia, coronary artery disease, and left ventricular dysfunction, Circulation , 2001;104 :436–41. 29. Bloomfield DM, Steinman RC, Namerow PB, et al., Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II conundrum, Circulation , 2004;110 :1885–9. 30. Chow T, Kereiakes DJ, Bartone C, et al., Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy, J Am Coll Cardiol, 2006;47:1820–7. 31. Armoundas AA, Rosenbaum DS, Ruskin JN, et al., Prognostic significance of electrical alternans versus signal averaged electrocardiography in predicting the outcome of electrophysiological testing and arrhythmia-free survival, Heart , 1998;80 :251–6. 32. Rashba EJ, Osman AF, Macmurdy K, et al., Enhanced detection of arrhythmia vulnerability using T wave alternans, left ventricular ejection fraction, and programmed ventricular stimulation: a prospective study in subjects with chronic ischemic heart disease, J Cardiovasc Electrophysiol, 2004;15:170–6. 33. Chow T, Kereiakes DJ, Onufer J, et al., Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial, J Am Coll Cardiol , 2008;52 :1607–15. 34. Costantini O, Hohnloser SH, Kirk MM, et al., The ABCD (Alternans Before Cardioverter Defibrillator) Trial: strategies using T-wave alternans to improve efficiency of sudden

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cardiac death prevention, J Am Coll Cardiol , 2009;53 :471–9. 35. Farrell TG, Paul V, Cripps TR, et al., Baroreflex sensitivity and electrophysiological correlates in patients after acute myocardial infarction, Circulation , 1991;83 :945–52. 36. La Rovere MT, Bigger JT, Jr., Marcus FI, et al., Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators, Lancet , 1998;351 :478–84. 37. Kleiger RE, Miller JP, Bigger JT, Jr., et al., Decreased heart rate variability and its association with increased mortality after acute myocardial infarction, Am J Cardiol , 1987;59 :256–62. 38. Makikallio TH, Barthel P, Schneider R, et al., Prediction of sudden cardiac death after acute myocardial infarction: role of Holter monitoring in the modern treatment era, Eur Heart J , 2005;26 :762–9. 39. Exner DV, Kavanagh KM, Slawnych MP, et al., Noninvasive risk assessment early after a myocardial infarction: The REFINE Study, J Am Coll Cardiol , 2007;50 :2275–84. 40. Bauer A, Barthel P, Schneider R, et al., Improved stratification of autonomic regulation for risk prediction in post-infarction patients with preserved left ventricular function (ISAR-Risk), Eur Heart J , 2009;30 :576–83. 41. Bourke JP, Richards DA, Ross DL, et al., Does the induction of ventricular flutter or fibrillation at electrophysiologic testing after myocardial infarction have any prognostic significance? Am J Cardiol , 1995;75 :431–5. 42. Roy D, Marchand E, Theroux P, et al., Programmed ventricular stimulation in survivors of an acute myocardial infarction, Circulation , 1985;72 :487–94. 43. Bailey JJ, Berson AS, Handelsman H, et al., Utility of current risk stratification tests for predicting major arrhythmic events after myocardial infarction, J Am Coll Cardiol , 2001;38 :1902–11. 44. Huikuri HV, Raatikainen MJP, Moerch-Joergensen R, et al., Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction, Eur Heart J , 2009;30 :689–98. 45. Desai AS, Fang JC, Maisel WH, et al., Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials, JAMA , 2004;292 :2874–9. 46. Pezawas T, Diedrich A, Winker R, et al., Multiple autonomic and repolarization investigation of sudden cardiac death in dilated cardiomyopathy and controls, Circ Arrhythm Electrophysiol , 2014;7 :1101–8. 47. Goldberger JJ, Subacius H, Patel T, et al., Sudden cardiac death risk stratification in patients with nonischemic dilated cardiomyopathy, J Am Coll Cardiol , 2014;63 :1879–89. 48. Patton KK, Sotoodehnia N, DeFilippi C, et al., N-terminal proB-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study, Heart Rhythm , 2011;8 :228–33. 49. Jouven X, Charles MA, Desnos M, et al., Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population, Circulation , 2001;104 :756–61. 50. Empana JP, Jouven X, Canoui-Poitrine F, et al., C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the PRIME study, Arterioscler Thromb Vasc Biol , 2010;30 :2047–52. 51. Loupy A, Vernerey D, Viglietti D, et al., Determinants and Outcomes of Accelerated Arteriosclerosis: Major Impact of Circulating Antibodies, Circ Res , 2015;117 :470–82. 52. Kristensen TS, Kofoed KF, Kuhl JT, et al., Prognostic implications of nonobstructive coronary plaques in patients with non-ST-segment elevation myocardial infarction: a multidetector computed tomography study, J Am Coll Cardiol , 2011;58 :502–9.

53. Motoyama S, Sarai M, Harigaya H, et al., Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome, J Am Coll Cardiol, 2009;54 :49–57. 54. Ozaki Y, Okumura M, Ismail TF, et al., Coronary CT angiographic characteristics of culprit lesions in acute coronary syndromes not related to plaque rupture as defined by optical coherence tomography and angioscopy, Eur Heart J , 2011;32 :2814–23. 55. Laukkanen JA, Khan H, Kurl S, et al., Left ventricular mass and the risk of sudden cardiac death: a population-based study, J Am Heart Assoc , 2014;3 :e001285. 56. Narayanan K, Reinier K, Teodorescu C, et al., Left ventricular diameter and risk stratification for sudden cardiac death, J Am Heart Assoc , 2014;3 :e001193. 57. Aro AL, Anttonen O, Tikkanen JT, et al., Intraventricular conduction delay in a standard 12-lead electrocardiogram as a predictor of mortality in the general population, Circ Arrhythm Electrophysiol , 2011;4 :704–10. 58. Aro AL, Huikuri HV, Tikkanen JT, et al., QRS-T angle as a predictor of sudden cardiac death in a middle-aged general population, Europace , 2012;14 :872–6. 59. Aro AL, Eranti A, Anttonen O, et al., Delayed QRS transition in the precordial leads of an electrocardiogram as a predictor of sudden cardiac death in the general population, Heart Rhythm , 2014;11 :2254–60. 60. Tikkanen JT, Anttonen O, Junttila MJ, et al., Long-term outcome associated with early repolarization on electrocardiography, N Engl J Med , 2009;361 :2529–37. 61. Haissaguerre M, Derval N, Sacher F, et al., Sudden cardiac arrest associated with early repolarization, N Engl J Med , 2008;358 :2016–23. 62. Derval N, Simpson CS, Birnie DH, et al., Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry, J Am Coll Cardiol, 2011;58 :722–8. 63. Nunn LM, Bhar-Amato J, Lowe MD, et al., Prevalence of J-point elevation in sudden arrhythmic death syndrome families, J Am Coll Cardiol , 2011;58 :286–90. 64. Gourraud JB, Le Scouarnec S, Sacher F, et al., Identification of large families in early repolarization syndrome, J Am Coll Cardiol , 2013;61 :164–72. 65. Haruta D, Matsuo K, Tsuneto A, et al., Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram, Circulation , 2011;123 :2931–7. 66. Junttila MJ, Tikkanen JT, Kentta T, et al., Early repolarization as a predictor of arrhythmic and nonarrhythmic cardiac events in middle-aged subjects, Heart Rhythm , 2014;11 :1701–6. 67. Mahida S, Derval N, Sacher F, et al., Role of electrophysiological studies in predicting risk of ventricular arrhythmia in early repolarization syndrome, J Am Coll Cardiol, 2015;65:151–9. 68. Junttila MJ, Sager SJ, Tikkanen JT, et al., Clinical significance of variants of J-points and J-waves: early repolarization patterns and risk, Eur Heart J , 2012;33 :2639–43. 69. Antzelevitch C, Yan GX, J-wave syndromes: Brugada and early repolarization syndromes, Heart Rhythm, 2015;12:1852– 66. 70 . Waks JW, Soliman EZ, Henrikson CA, et al., Beat-to-beat spatiotemporal variability in the T vector is associated with sudden cardiac death in participants without left ventricular hypertrophy: the Atherosclerosis Risk in Communities (ARIC) Study, J Am Heart Assoc , 2015;4 :e001357. 71. Tereshchenko LG, Henrikson CA, Sotoodehnia N, et al., Electrocardiographic deep terminal negativity of the P wave in V(1) and risk of sudden cardiac death: the Atherosclerosis Risk in Communities (ARIC) study, J Am Heart Assoc , 2014;3 :e001387.

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Home Orthostatic Training in Elderly Patients with Vasovagal Syncope – A Prospective Randomised Controlled Trial St ev en P o d d , Ja c q u e l i n e H u n t a n d N e i l S u l k e Eastbourne District General Hospital, East Sussex, United Kingdom

Abstract Aim: The aim of this study was to assess the effect of home orthostatic training (HOT) on autonomic reflexes in elderly patients with vasovagal syncope (VVS). Methods: Design and Setting: A single-blind randomised control trial was conducted at Eastbourne District General Hospital, East Sussex NHS Trust. Patients: Individuals with recurrent syncope underwent tilt-table testing between August 2007 and October 2009.Those with at least two syncopal episodes and tilt-test proven VVS were recruited. Participants were divided into those aged >65 years (O65) and those aged <65 years (U65). Interventions: Patients in the O65 group were randomised 1:1 to receive active HOT (O65+) or sham HOT (O65−). The U65 group received active HOT. Participants performed HOT/sham HOT and recorded their training and symptoms. Patients had a repeat tilt test at 3 months. Outcome Measures: Time to syncope at repeat tilt-table testing, low-frequency heart rate variability (LF-HRV), high-frequency heart rate variability (HF-HRV), mean upslope baroreflex sensitivity (BRS) and mean downslope BRS were assessed. Results: A total of 106 patients with recurrent syncope underwent tilt-table testing. Of these, 45 consecutive patients (30 in the O65 group and 15 in the U65 group) were recruited. Two, one and three patients withdrew or were lost-to-follow-up in the O65+, O65−, and U65 groups, respectively. Symptomatic benefit occurred in four (31 %) of the O65+, four (29 %) of the O65−, and six (50 %) of the U65. None of the autonomic measures changed significantly in any group. No difference was seen with HF-HRV, LF-HRV mean upslope BRS and mean downslope BRS. Fifty per-cent of the O65+ group stopped training because of back pain. Time constraint (25 %) was the most common reason for cessation in the U65 group. Conclusions: Despite good tilt training compliance, no improvement in autonomic measures in any group was shown. The most common reason for cessation of training was back pain in the elderly groups. This study does not support the use of HOT in elderly patients.

Keywords Vasovagal syncope, home orthostatic training, elderly, randomised controlled trial, tilt-table testing Disclosure: The author has no conflicts of interest to disclose. Acknowledgement(s): The Eastbourne Syncope Assessment Tilt Training Trial (EaSy As II T3) sub-study was supported by a research grant from the Eastbourne Cardiology Charitable Research Fund. Trial registration: Clinicaltrials.gov: NCT00517023. Received: 14 October 2015 Accepted: 1 November 2015 Citation: European Cardiology Review, 2015;10(2):123–7 Correspondence: Steven Podd, Cardiology Research department, Eastbourne District General Hospital, East Sussex NHS Trust, Eastbourne, Kings Drive, East Sussex, BN21 2UD, United Kingdom. E: steven.podd@esht.nhs.uk

Vasovagal syncope (VVS) is most common cause of syncope,1 with 37 % of the population suffering at least one attack during their life time.2 Head up tilt-table testing (HUTT) was first evaluated and used for the diagnosis of VVS in 1986.3–4 Prior to this, diagnosis relied purely on the clinical history and exclusion of other conditions. With almost 40 % of patients with VVS experiencing no prodrome5 prior to syncope, and the general acceptance that it was a condition of the young, VVS was significantly undiagnosed – particularly in the elderly.4,6–7 The exact mechanism of VVS is complex. It involves several autonomic reflexes, of which some are exaggerated (parasympathetic) and others depressed (sympathetic), resulting in a reduction in blood pressure and/or pulse rate and subsequent cerebral hypoperfusion and syncope.8–10 The mechanism can differ with subsequent attacks and from patient-to-patient. Most patients respond to the European Society of Cardiology (ESC) recommendation11 of lifestyle modification and withdrawal of vasoactive medications; however, a significant number of patients continue to have repeated syncopal and pre-syncopal attacks. There is no associated increase in mortality, so the condition is often referred to as benign. Despite this, in patients with refractory VVS the condition can be frightening, disabling

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and have significant impact on quality of life12 and there is an urgent need for an effective treatment option in these refractory patients. Permanent pacemakers13 and drug treatment, in particular beta-blockers14, selective serotonin reuptake inhibitors, fludrocortisone15 and midodrine,16 have not been proven or not adequately assessed to be beneficial in VVS and are therefore not routinely used. Home orthostatic training (HOT) has been shown to improve autonomic measures after repeat assessments in non-age selected cohorts.17–19 However, HOT has not been tested in an exclusively elderly population. Therefore the aim of this study was to evaluate the effect of HOT on autonomic reflexes in elderly patients with VVS. Our research questions were: • Are there different mechanisms of vasovagal syncope in elderly and young populations? • What therapies are efficacious in vasovagal syncope? • Are autonomic measurements useful in the assessment of vasovagal syncope?

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Figure 1: Study Protocol and Baseline Characteristics of Participants

Patients

106 patients underwent tilt table testing 61 participants had negative tilt table tests 45 patients with positive tilt table tests recruited 15 participants under 65, 30 participants over 65 Over 65s randomised 1:1

U65 3 patients moved area O65+ 2 patients withdrew

15 patients under 65

15 patients over 65

HOT

Sham HOT

U65

O65+

O65-

39 participants underwent a repeat tilt table test

O65- 1 patient withdrew

Consecutive patients with positive HUTT were invited to participate in the study. All participants were aged >16 and had had at least two syncopal episodes in the previous 12 months and a positive HUTT. A positive HUTT was defined as a reduction in blood pressure associated with syncope. Exclusion criteria included the following: (i) inability to provide informed consent; (ii) physical or mental inability to perform HOT as determined by the investigators; and (iii) pregnancy.

Interventions The local research ethics committee approved the study and written informed consent was obtained from all participants. All patients received normal clinical care in accordance with ESC guidelines for VVS. Subjects were divided into two cohorts: those aged >65 years (O65) and those aged <65 years (U65). The O65 group was randomised to receive either active HOT (O65+) or sham training (O65−). The U65 cohort were all actively trained and acted as an additional control group. Randomisation was performed by an independent clinician using computer-generated random numbers. Active or sham training was taught to the participant during a one-to-one training session. A written crib sheet of the training technique and regime was also provided. Participants and their clinicians not involved in the trial were

Characteristics

Participants – Participants – Participants – U65 (n=12)

O65+ (n=13) O65- (n=14)

Female [n (%)]

8 (66)

10 (77)

10 (71)

Age [years, mean (SD)]

44.6 (17.0)

77.8 (6.4)

76.1 (7.8)

2 (15.4)

2 (14.3)

blinded to the treatment group. Training was undertaken for a total of 3 months before a repeat HUTT was performed (Figure 1).

Active HOT

Any occlusive vascular disease 0 (0) [n (%)] Hypertension [n (%)]

1 (8.3)

6 (46.2)

7 (50.0)

Smoker [n (%)]

2 (16.7)

0 (0)

Diabetes [n (%)]

0 (0)

2 (15.4)

2 (14.3)

Vasoactive drugs [n (%)]

1 (0.0)

6 (46.2)

7 (50.0)

Participants in the U65 and O65+ groups were asked to stand with their backs against a wall supported by their head and shoulders and to move their feet 20 cm from the base of the wall. They were asked to hold this position for 30 minutes or until pre-syncopal symptoms occurred. Participants were warned to prepare the training area so that a prone position could be achieved quickly if symptoms occurred suddenly.

U65 = patients aged <65 years who received home orthostatic training (HOT); O65+ = patients aged >65 years who received HOT; O65− = patients aged >65 years who received sham HOT.

Figure 2: HRV and BRS in the Three Groups.

Sham Training

Mean ratio logged pre training: logged post training values

p=0.33

}

p=0.46

p=0.85

p=0.37

}

p=0.79

p=0.21

}

p=0.69

p=0.24

}

p=0.67

}

p=0.97

}

p=0.99

}

1.5

p=0.79

}

p=0.40

}

p=0.29

}

p=0.66

}

2.5

}

p=0.56

}

3.5

Participants in the O65− group were asked to stand with their backs against a wall supported by their head and shoulders but move their feet just 5 cm from the base of the wall. They were asked to hold this position for 5 minutes or until pre-syncopal symptoms occurred. As with the active group, participants were warned to prepare the training area so that a prone position could be achieved quickly if symptoms occurred suddenly.

Measurements

0.5 U65 O65+ O65-

HF-HRV Post-GTN Phase

U65 O65+ O65-

U65 O65+ O65HF-HRV Pre-GTN Phase

U65 O65+ O65-

LF-HRV Post-GTN Phase

U65 O65+ O65-

LF-HRV Pre-GTN Phase

U65 O65+ O65-

HUTT U65 O65+ O65-

BRS Up Pre-GTN Phase

BRS Up Post-GTN Phase

BRS Down Pre-GTN Phase

Values were recorded from the pre- glyceryl trinitrate (GTN) phase of the head-up tilt-table test (HUTT) and the post GTN phase of the HUTT. All values were initially logged to ensure normal distribution of the data. The difference between the logged pre- and post-training values were anti-logged (elog difference) to give a ratio. Numbers >1 represent an increase in the autonomic parameter and numbers <1 represent a decrease in the autonomic parameter. The paired t-test showed no significant change in any group between logged pre- and post-training values. Independent t-tests showed no significant difference between the control group (U65 and O65−) elog difference and that of the test group (O65+) for each autonomic parameter. P values shown represent the independent t-test between each control group (U65, O65−) and the O65+ group. U65 = patients aged <65 years who received home orthostatic training (HOT); O65+ = patients aged >65 years who received HOT; O65− = patients aged >65 years who received sham HOT; LF-HRV = low frequency (0.04–0.15 Hz) heart rate variability, HF-HRV = high frequency (0.15–0.4 Hz) heart rate variability; BRS Up = baroreflex sensitivity upslope, BRS Down = baroreflex sensitivity downslope.

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A baseline and 3-month HUTT were performed. Participants were asked to fast for no longer than 2 hours prior to the test. All drugs affecting the validity of the HUTT were stopped at least five half-lives prior to testing. Participants were prepared with continuous ECG monitoring, a non-invasive blood pressure cuff, a digital non-invasive beat-to-beat blood pressure monitor and patches for impedance monitoring using the Task Force® Monitor system (CNSystems, Graz, Austria). The tilt-testing laboratory is temperature controlled, quiet and the test was performed under low lighting levels. Participants were laid in a supine position for 10 minutes to allow haemodynamic measures to stabilise before being tilted to 70°. This was maintained for 20 minutes, when 200 μg of sub-lingual glyceryl trinitrate was administered. A further 20 minutes of recording was performed. The

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Home Orthostatic Training in Elderly Patients with Vasovagal Syncope

test was terminated if syncope occurred. Time to syncope during the HUTT was recorded in seconds.

Heart Rate Variability (HRV) The autoregressive method for HRV was used to calculate the low-frequency (LF) 0.04–0.15 Hz and high-frequency (HF) 0.15–0.4 Hz spectral densities from the continuous ECG recording for each HUTT phase. Automated software eliminated ectopic beats and artefactual recordings.

Table 1: Training and Symptom Diaries Group

U65

Average

Patients

Reasons for

percentage completing with

termination/premature

trained

52 %

50 % of

subjective

cessation of training

training

benefit

[n (%)]

7 (58)

6 (50)

Time constraints, 3 (25) Pre-syncopal symptoms, 3 (25); Back pain, 1 (8)

Baroreflex Sensitivity (BRS) For each phase of HUTT the BRS was calculated using the sequence method. The slope regression was determined for increases in systolic blood pressure (SBP) accompanied by lengthening of the R-R interval (RRI) (up sequences) and decreases in SBP associated with shortening of the RRI (down sequences) for three or more consecutive R-waves. The blood pressure sequences were paired with the RRI at which the changes occurred.

Symptom and Training Diaries Participants were asked to record their daily training regime and document reasons for failure or premature termination of training on each and every occasion. Any pre-syncopal symptoms or syncopal attacks were also documented.

Statistical Analysis All continuous variables were reported as mean with SD for normally distributed data and median with interquartile range for nonnormally distributed data. For the haemodynamic variables, LF-HRV, HF-HRV, upslope BRS, downslope BRS, the values were initially logged to ensure normal distribution. The paired student’s t-test was used for within-group comparisons of pre- and post-training logged haemodynamic data and time to syncope. For comparison of haemodynamic measures between groups, the log differences were calculated and then the elog differences were compared using the unpaired student’s t-test. Log ratios of pre- and post-haemodynamic values were recorded. A value of 1 indicated no change, <1 indicated a reduction in the haemodynamic measure and >1 indicated an improvement. A two-tailed P-value of <0.05 was considered statistically significant. PASW Statistics 18.0™ for Windows® was used for all data analysis.

Results Overall, 106 participants with recurrent syncope underwent HUTT. Of these, 45 had a positive HUTT response and were diagnosed with VVS. The first 30 participants aged >65 years and the first 15 participants aged <65 years who met the study criteria were recruited. Fifteen participants in the O65 group were randomised to active HOT. Two participants in the O65+ group declined the repeat tilt-table testing and their data were not used in the analysis. No reason was given. One participant in the O65− group suffered a hip fracture not related to the study. Three participants from the U65 group moved out of area and were lost to follow-up. Baseline characteristics were similar in the two O65 groups (Figure 1).

HRV No significant difference was seen between pre- and post-training in any of the groups in any phase of HUTT (P=NS). Comparison of the

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O65+

28 %

5 (38)

4 (31)

Back pain, 7 (50) Pre-syncopal symptoms, 3 (15)

O65−

75 %

10 (71)

4 (29)

Pre-syncopal symptoms, 2 (14); Back pain, 1 (7)

U65 = patients aged <65 years who received home orthostatic training (HOT); O65+ = patients aged >65 years who received HOT; O65− = patients aged >65 years who received sham HOT. Symptomatic benefit was seen in just less than a third of the older cohort (regardless of active HOT) and 50 % of the U65 cohort.

elog difference of the pre- and post-training values for the U65 and O65− groups to the O65+ group showed no significant difference (see Figure 2).

BRS No significant improvement from HOT was seen in any of the treatment groups or between any treatment group (Figure 2).

Time to syncope on HUTT All except two participants (one in the O65+ group and one in the U65 group) had a positive HUTT on repeat testing. HOT did not significantly influence the time to syncope during HUTT (from 1473 seconds ± 336 to 1386 seconds ± 698 [P=0.67] in the U65 group; from 1574 seconds ± 278 to 1532 seconds ± 623 [P=0.80] in the O65+ group; and from 1454 seconds ± 332 to 1435 seconds ± 286 [P=0.84] in the O65− group).

Subjective Data All participants in the analysis returned satisfactory training and symptom diaries, which were used in the subjective analysis. The most common cause of premature termination of training was back pain in the O65+ group (seven patients in the O65+ group [50 %], one patient in the O65− group [7 %] and one patient in the U65 group [8 %]). Time constraint was the reason for withdrawal in three patients in the U65 group (25 %) but none in either O65 group. Pre-syncopal symptoms were the reason for withdrawal in three patients in the O65+ group (15 %), two in the O65− group (14 %) and three in the U65 group (25 %). (Table 1). Comparison of the autonomic parameters pre- and posttraining in those participants that experienced symptomatic benefit as opposed to those who did not revealed no significant differences.

Discussion This prospective single-blind randomised trial is the first to assess HOT in an exclusively elderly population with VVS. Furthermore, with the exception of one study,19 all other randomised controlled trials20–21 examining the role of HOT have compared active orthostatic training to conventional therapy. The presence of the sham-training group in this study allows patient blinding to therapy and hence greatly strengthens the overall power. Unlike previous studies,19-20,22 no improvement in any autonomic cardiovascular reflex was observed in any of the study groups.

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Syncope and Sudden Cardiac Death Early studies have assessed the changes in simple measures such as blood pressure, heart rate, time to first syncope and tilt-table result.17,21,23 These parameters have poor reproducibility24 and unless autonomic function is grossly altered, any subtle change will be lost in background noise. BRS and HRV spectral densities are being increasingly utilised as a sensitive research tool when looking at autonomic responses. The high sensitivity is in part because of the exponential changes in these values as opposed to linear changes in the traditionally-measured parameters. HRV spectral density plots show two regions of interest when considering the activity of the autonomic system. LF-HRV changes during respiration and is thought to reflect sympathetic activity, whilst HF-HRV is thought to represent parasympathetic activity.25 Tilt-table testing in patients with VVS has shown a reduced BRS at rest and an exaggerated drop in BRS during HUTT.26 Changes in HRV have been less consistent in patients with VVS with the exception of LF-HRV response, which is diminished.27 The aim of orthostatic training is to modify these autonomic responses in patients to induce a normalised response to orthostatic stress and therefore preventing the symptoms of VVS. The expected benefit in our actively-trained elderly group was not observed. One reason that might account for this is that VVS has been shown to be bi-modally distributed across the population, with peaks between20–29 years and an older cohort aged >70 years.17 This suggests that the VVS mechanism in these two groups may have some important differences that may explain the lack of efficacy of HOT seen in this trial. It is well-documented that autonomic responses are blunted in an elderly population.28 This depression of the autonomic response may account for the observed HUTT differences, with younger patients having a more pronounced and rapid-onset bradycardia with hypotension (classical response), whilst the elderly population tends to have a slower, asymptomatic onset of hypotension with a less pronounced bradycardia (dysautonomic response),29 as observed in our study cohorts. Younger patients also exhibit the classical warning signs of an exaggerated autonomic response of pallor, sweatiness, abdominal discomfort and lightheadedness whilst the older population do not. 4 It is therefore conceivable that orthostatic training in an elderly population may not enhance an age-related degenerated autonomic system whereas in a younger group, HOT may be able to ‘retrain’ an exaggerated or inappropriate autonomic response.

Soteriades ES, Evans JC, Larson MG, et al. Incidence and Prognosis of Syncope. N Engl J Med 2002;347 :878–85. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J 2006;27 :1965–70. 3. Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: A useful test for investigating unexplained syncope. Lancet 1986 Jun 14;327 :1352–5. 4. Tan MP, Parry SW. Vasovagal syncope in the older patient. J Am Coll Cardiol 2008;51 ;599–606. 5. Grubb B, Samoil D. Neurocardiogenic syncope. In: Kenny RA (ed). Syncope in the older patient: Causes, investigations and consequences of syncope and falls. London: Chapman & Hall, 1996;91–106. 6. Day S, Cook E, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med 1982;73 :15–23. 7. Kapoor W, Snustad D, Peterson J, et al. Syncope in the elderly. Am J Med 1986;80 :419–28. 8. Grassi G. Vasovagal syncope, sympathetic mechanisms and prognosis: the shape of things to come. Eur Heart J 2010;31:1951–3. 9. Glick G, Yu P. Hemodynamic changes during spontaneous vasovagal reactions. Am J Med 1963;34 :42–51. 10. Béchir M, Binggeli C, Corti R, et al. Dysfunctional baroreflex regulation of sympathetic nerve activity in patients with 2.

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However our results show little effect of HOT in the younger control patients. The explanation for this lack of response is not clear. Previous studies have shown that the mechanism of VVS may begin to change from a predominately exaggerated autonomic response to a depressed autonomic response in patients in their forties.19 Almost two thirds of the younger cohort were aged >50 years, which may have resulted in a HOT response similar to that in the O65 activelytrained cohort. All previous studies have shown benefit from HOT in younger patients (mean ages 16.0 years,17 45.0 years,19 31.0 years22 and 19.4 years.21) Most participants had no symptoms for the duration of the study. It has been shown that the autonomic improvements provoked by orthostatic training can be observed within 1 week of training initiation19 and that HUTT maybe rendered negative within 24 hours of in-hospital training.22 It is possible that these autonomic benefits may be lost at a similar rate on cessation of training. With a low symptom burden the participants training regime may not have been adhered to as strictly as reported. Back pain was the most commonly reported cause of lack of HOT compliance. This was worse in the elderly cohort. In the younger group, lack of time and pre-syncopal symptoms were the most common causes of failed compliance. Overall compliance was comparable with previous studies demonstrating autonomic improvements from HOT.19

Study limitations Participant record of compliance could not be verified beyond self-reporting, and records may be an overestimation of actual time trained. Despite this, even participants who reported great symptomatic benefit from the training showed no change in objectively assessed autonomic measures.

Conclusion This randomised placebo-controlled study is the first to assess HOT in patients aged >65 years with VVS using serial autonomic cardiovascular reflex measures. There were no improvements in these autonomic measures in any of our study groups. The lack of efficacy in the elderly population may relate to the degeneration of the autonomic nervous system not responding to physical countermeasures. These findings do not support the use of HOT in the elderly population. n

vasovagal syncope. Circulation 2003;107:1620–5. 11. Krediet CT, van Dijk N, Linzer M, et al. Management of vasovagal syncope: Controlling or aborting faints by leg crossing and muscle tensing. Circulation 2002;106:1684–9. 12. van Dijk N, Sprangers M, Colman N, et al. Clinical factors associated with quality of life in patients with transient loss of consciousness. J Cardiovasc Electrophysiol 2006;17:998–1003. 13. Connolly SJ, Sheldon R, Thorpe KE, et al. Pacemaker Therapy for Prevention of Syncope in Patients With Recurrent Severe Vasovagal Syncope. JAMA 2003;289 :2224–9. 14. Sheldon R, Rose S, Connolly S, et al. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006;113:1164–70. 15. Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: A doubleblind, placebo-controlled, randomized trial. J Am Coll Cardiol 2005;45 :484–8. 16. Raviele A, Brignole M, Sutton R, et al. Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: A double-blind, randomized, placebo-controlled trial. Circulation 1999;99 :1452–7. 17. Di Girolamo E, Di Iorio C, Leonzio L, et al. Usefulness of a tilt training program for the prevention of refractory

neurocardiogenic syncope in adolescents: A controlled study. Circulation 1999;100 :1798–801. 18. Reybrouck T, Heidbuchel H, Van de Werf F, Ector H. Long-term follow-up results of tilt training therapy in patients with recurrent neurocardiogenic syncope. Pacing Clin Electrophysiol 2002;25 :1441–6. 19. 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 :240–6. 20. Di Girolamo E, Di Iorio C, Leonzio L, et al. Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents: A controlled study. Circulation 1999;100 :1798–801. 21. Gurevitz O, Barshesheta A, Bar-Lev D, et al. Tilt Training: Does It Have a Role in Preventing Vasovagal Syncope? Pacing Clin Electrophysiol 2007;30 :1499–505. 22. Verheyden B, Ector H, Aubert AE, Reybrouck T, et al. Tilt training increases the vasoconstrictor reserve in patients with neurally mediated syncope evoked by head-up tilt testing. Eur Heart J 2008;29 :1523–30. 23. Duygu H, Z M, Turk U, Ozerkan F, et al. The role of tilt training in preventing recurrent syncope in patients with vasovagal syncope: A prospective and randomized study. Pacing Clin Electrophysiol 2008;31 :592–6.

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24. Sagristà-Sauleda J, Romero B, Permanyer-Miralda G, et al. Reproducibility of sequential head-up tilt testing in patients with recent syncope, normal ECG and no structural heart disease. Eur Heart J 2002;23 :1706–13. 25. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation

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1996;93 :1043–65. 26. Furlan R, Perego F, Colombo S. Baroreflex regulation of sympathetic nerve activity in patients with vasovagal syncope. Circulation 2004;109 :e171. 27. Piccirillo G, Naso C, Moise A, et al. Heart rate and blood pressure variability in subjects with vasovagal syncope. Clin Sci 2004;107 :55–61. 28. Kaijser L, Sachs C. Autonomic cardiovascular responses in

old age. Clin Physiol 1985;5 :347–57. 29. Verheyden B, Gisolf J, Beckers F, et al. Impact of age on the vasovagal response provoked by sublingual nitroglycerine in routine tilt testing. Clin Sci 2007;113 :329–37. 30. Kochiadakis GE, Papadimitriou EA, Marketou ME, et al. Autonomic Nervous System Changes in Vasovagal Syncope. Pacing Clin Electrophysiol 2004;27 :1371–7.

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