ECR 11.2

T1 ↑ ↑

European Cardiology Review Volume 11 • Issue 2 • Winter 2016

3.0T)

Volume 11 • Issue 2 • Winter 2016

www.ECRjournal.com

Fabry (3.0T)

Athlete (3.0T)

Amyloid (1.5T)

Native T1 ↓↓

Native T1 ↓

Native T1 ↑↑

ECV ↔ Flow Reserve Assessment ECV ↓ ECV ↑↑ Fractional of Coronary Artery Stenosis

Serban Balanescu

Role of T1 Mapping in Inherited Cardiomyopathies Peter P Swoboda, Adam K McDiarmid, Stephen P Page, John P Greenwood and Sven Plein

Optical Coherence Tomography For the Detection of the Vulnerable Plaque Konstantinos Toutouzas, Antonios Karanasos and Dimitris Tousoulis

Cardiovascular Management of Adults with Marfan Syndrome

2000

Yukiko Isekame, Sabiha Gati, Jose Antonio Aragon-Martin, Rachel Bastiaenen, Sreenivasa Rao Kondapally Seshasai and Anne Child

1800 1600 1400 1200 1000 800 90 80 70 60 50 40 30 20 10 0

theter (Pa)

Stenosis ISSN: 1758-3756

Pressure ± Doppler guide wireMeasuring FFR

Distal sensor (Pd) Coronary sinus reducer device

Hypertrophic Cardiomyopathy

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Volume 11 • Issue 2 • Winter 2016

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

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

Luigi Paolo Badano

Eileen Handberg

Sven Plein

University of Padua, Padua, Italy

University of Florida, Florida, US

University of Leeds, Leeds, UK

Velislav Batchvarov

Koichi Kaikita

Piotr Ponikowski

Kumamoto University, Kumamoto, Japan

Wroclaw Medical University, Wroclaw, Poland

Sverre Kjeldsen

Eva Prescott

University Hospital, Oslo, Norway

Bispebjerg Hospital, København, Denmark

Wolfgang Koenig

Fausto Rigo

University of Ulm, Ulm, Germany

Ospedale dell’Angelo Hospital, Venice, Italy

Steen Dalby Kristensen

Giuseppe Rosano

Aarhus University, Aarhus, Denmark

IRCCS San Raffaele, Rome, Italy

Patrizio Lancellotti

Magdi Saba

University of Liège, Liège, Belgium

St George’s University of London, London, UK

Gaetano Antonio Lanza

Sanjay Sharma

Catholic University of the Sacred Heart, Milan, Italy

St George’s University of London, London, UK

Giuseppe Mancia

Hiroaki Shimokawa

University of Milano-Bicocca, Milan, Italy

Tohoku University, Sendai, Japan

Antoni Martínez-Rubio

Rosa Sicari

University Hospital of Sabadell, Sabadell, Spain

Italian National Research Council

Hippokration General Hospital, Athens, Greece

Mario Marzilli

Iana Simova

Kenneth Earle

University of Pisa, Pisa, Italy

National Cardiology Hospital, Sofia, Bulgaria

St George’s University of London, London, UK

Attilio Maseri

Philippe Gabriel Steg

Perry Elliott

Vita-Salute San Raffaele University, Milan, Italy

Hospital Bichat Claude Bernard, Paris, France

University College London, London

Noel Bairey Merz

Jun Takata

Albert Ferro

Cedars-Sinai Heart Institute, Los Angeles, US

Kochi University, Nankoku, Japan

King’s College London, London

Petros Nihoyannopoulos

Dimitris Tousoulis

Augusto Gallino

Imperial College London, London, UK

University of Athens Medical School, Athens, Greece

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Camici Paolo

Konstantinos Toutouzas

San Raffaele Hospital, Segrate, Italy

University of Athens, Athens, Greece

Zoltan Papp

Dimitrios Tziakas

University of Debrecen, Debrecen, Hungary

Democritus University of Thrace, Xanthi, Greece

Antonio Pelliccia

Hiroshi Watanabe

Johannes Gutenberg University Mainz, Mainz, Germany

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

Martin Halle

Joep Perk

José Luis Zamorano

Technical University of Munich, Munich, Germany

Linnaeus University, Kalmar, Sweden

University Complutense, Madrid, Spain

St George’s University of London, London, UK

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

John Beltrame University of Adelaide, Adelaide, Australia

Richard Conti University of Florida, Florida, US

Martin Cowie Imperial College London, London, UK

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

Alberto Cuocolo University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan Colentina University Hospital, Bucharest, Romania

Polychronis Dilaveris

Xavier Garcia-Moll Autònoma University, Barcelona, Spain

Simon Gibbs Imperial College London, London, UK

Tommaso Gori

Hamamatsu University School of Medicine, Hamamatsu, Japan

Managing Editor Lindsey Mathews • Production Jennifer Lucy • Senior Designer Tatiana Losinska Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director Mark Watson •

Editorial Contact Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

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

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

Aims and Scope •

•

•

European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiology medicine and practice.

European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

European Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • •

• •

European Cardiology Review is a bi-annual journal comprising review articles, editorials, and case reports.

The structure and degree of coverage assigned to each category of the journal is determined by the Editor-in-Chief, with the support of the 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 European Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Associate Editors and an Editorial Board comprising leading authorities from a variety of related disciplines.

• Invited contributors who are recognised authorities from their respective fields.

• Peer review – conducted by experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

Peer Review • •

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On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion.

The Managing Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind.

Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

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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.

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

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

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Contents

Foreword

68

Juan Carlos Kaski

Ischaemic Heart Disease

69

Management of Refractory Angina Pectoris

77

Fractional Flow Reserve Assessment of Coronary Artery Stenosis

83

Guest Editorial: Controversies in Fractional Flow Reserve

85

Prediction of Post Percutaneous Coronary Intervention Myocardial Ischaemia

90

Optical Coherence Tomography For the Detection of the Vulnerable Plaque

Kevin Cheng, Paul Sainsbury, Michael Fisher and Ranil de Silva

Serban Balanescu

Maria Chiara Scali, Doralisa Morrone and Mario Marzilli

Alda Huqi, Giacinta Guarini, Doralisa Morrone and Mario Marzilli

Konstantinos Toutouzas, Antonios Karanasos and Dimitris Tousoulis

Cardiomyopathy and Inherited Heart Disease

96 102

Role of T1 Mapping in Inherited Cardiomyopathies Peter P Swoboda, Adam K McDiarmid, Stephen P Page, John P Greenwood and Sven Plein

Cardiovascular Management of Adults with Marfan Syndrome Yukiko Isekame, Sabiha Gati, Jose Antonio Aragon-Martin, Rachel Bastiaenen, Sreenivasa Rao Kondapally Seshasai and Anne Child

Stress and Heart Disease

111

Viewpoint: Role of Mind–body Therapies in the Management of Cardiovascular Disorders Kavita Prasad

Cardiovascular Pharmacotherapy

114

ECR–ISCP Partnership Announcement European Cardiology Review partners with the International Society of Cardiovascular Pharmacotherapy Juan Carlos Kaski

115

ISCP Editorial Cardiovascular Pharmacotherapies Focus Antoni Martínez-Rubio and Gheorghe-Andrei Dan

118

Using Direct Oral Anticoagulants in Patients with Atrial Fibrillation: Assessment, Monitoring and Treatment Reversal Antoni Martínez-Rubio, Mario DiazNuila Alcazar, Anna Soria Cadena and Roger Martínez-Torrecilla

Cardiology Masters

123

Featuring: Dr Valentin Fuster

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Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), Honorary Consultant Cardiologist at St George’s Hospital, NHS Trust, London, UK and Director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Prof Kaski is Doctor of Science, University of London, immediate Past-President of ISCP (International Society of Cardiovascular Pharmacotherapy) and editorial board member and associate editor of numerous peer review journals. He is also fellow of the ESC (FESC), the ACC (FACC), the AHA (FAHA), the Royal College of Physicians (FRCP), and over 30 other scientific societies worldwide.

Prof Kaski’s research areas include mechanisms of rapid coronary artery disease progression, inflammatory and immunological mechanisms of atherosclerosis, microvascular angina and biomarkers of cardiovascular risk. Prof Kaski has published over 400 papers in peer-review journals, over 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

W

elcome to a new issue of European Cardiology Review. This, the final issue of 2016, comprises several important review articles, a provocative guest editorial and a new contribution to our Cardiology Masters section that charts the amazing career and achievements of Dr Valentin Fuster, currently

Editor-in-Chief of the Journal of the American College of Cardiology.

Importantly, we are excited to launch a new section: Cardiovascular Pharmacotherapy. We present this section in collaboration with our friends and colleagues at the International Society of Cardiovascular Pharmacotherapy (ISCP). The section will be devoted to highlighting advances in the pharmacological treatment of cardiovascular disease and the development of medical devices. This section will be co-edited by the current President of the International Society of Cardiovascular Pharmacotherapy (ISCP), Professor A Martinez-Rubio and myself.

Cardiovascular Pharmacotherapy represents the starting point of important collaborative work between ECR and ISCP, aimed at promoting rational, evidence-based, patient-centered treatments and independent educational programmes in the field.

I would like to underline the importance of our review articles in this issue. Serban Balanescu discusses fractional flow reserve assessment of coronary artery stenosis and why it is the best available invasive method of physiological testing of focal lesions. Peter P Swoboda and colleagues review a rapidly evolving method for the quantitative assessment of tissue characteristics in inherited cardiomyopathies: T1 mapping. Optical coherence tomography (OCT) for the detection of the vulnerable plaque is reviewed by Konstantinos Toutouzas and colleaugues, who summarise the pathophysiological insights into the formation and rupture of vulnerable plaque that can be obtained with OCT imaging. Anne Child and colleagues provide a useful update on best practice in the cardiovascular management of adults with Marfan syndrome.

I truly hope you enjoy reading this issue of European Cardiology Review and wish you all a peaceful and prosperous 2017. n

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Ischaemic Heart Disease

Management of Refractory Angina Pectoris K ev in C heng , 1 , 2 P au l S a i n s b u r y , 3 M i c h a e l F i s h e r 4 a n d R a n i l d e S i l v a 1 ,5 1. Specialist Angina Service, Royal Brompton and Harefield NHS Foundation Trust, London, UK; 2. Heart Science, National Heart and Lung Institute, Imperial College London, London, UK; 3. Department of Cardiology, Bradford Royal Infirmary, Bradford, UK; 4. Institute for Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital NHS Trust and Royal Liverpool and Broadgreen NHS Trust, Liverpool, UK; 5. Vascular Science, National Heart and Lung Institute, Imperial College London, London, UK

Abstract With improvements in survival from coronary artery disease (CAD) and an ageing population, refractory angina (RA) is becoming an increasingly common clinical problem facing clinicians in routine clinical practice. These patients experience chronic symptoms in the context of CAD, characterised by angina-type pain, which is uncontrolled despite optimal pharmacological, interventional and surgical therapy. Although mortality rates are no worse in this cohort, patients experience a significantly impaired quality of life with disproportionately high utilisation of healthcare services. It has been increasingly recognised that the needs of RA patients are multifactorial and best provided by specialist multi-disciplinary units. In this review, we consider the variety of therapies available to clinicians in the management of RA and discuss the promise of novel treatments.

Keywords Angina pectoris, refractory angina pectoris, chest pain, myocardial ischaemia, external enhanced counterpulsation, coronary sinus reducer, neurological manifestations, spinal cord stimulation, pragmatic rehabilitation, specialist angina services Disclosure: The authors have no conflicts of interest to declare.

Acknowledgement: The authors would like to thank Dr Michael Rubens for assistance with labelling Figure 2c.

Received: 19 October 2016 Accepted: 24 October 2016 Citation: European Cardiology Review 2016;11(2):69–76. DOI: 10.15420/ecr.2016:26:1 Correspondence: Dr Ranil de Silva, Senior Lecturer in Clinical Cardiology, National Heart and Lung Institute, Brompton Campus, Sydney Street, London SW3 6NP, UK. E: r.desilva@imperial.ac.uk

Refractory angina (RA) is conventionally defined as a chronic condition (≥3 months in duration) characterised by angina in the setting of coronary artery disease (CAD), which cannot be controlled by a combination of optimal medical therapy, angioplasty or bypass surgery, and where reversible myocardial ischaemia has been clinically established to be the cause of the symptoms.1 In clinical practice, patients diagnosed with RA are a heterogeneous group; common among them, however, is that they remain significantly limited by persistent debilitating chest discomfort despite optimised conventional therapy. In many cases, functional imaging may not demonstrate myocardial ischaemia. It is important to recognise that irrespective of aetiology, patients with refractory chest discomfort often attribute their symptoms to be cardiac in origin and believe that they may herald a life-threatening cardiac event. This predisposes to a progressive decline in their mental wellbeing and increasing anxiety whereby pain begets pain. Consequently, patients can develop persistent symptoms and pessimistic health beliefs, translating to negative behaviours and an impaired quality of life. In this regard, a shift in our approach of RA to that of managing a ‘chronic chest pain syndrome’ may help us not only to better appreciate the multifactorial aetiologies that are in operation in any given patient but also encourage the use of a holistic approach to manage these patients more effectively.

growing problem.2,3 Variations in definition and clinical heterogeneity of patients labelled with a diagnosis of RA significantly complicate such endeavours. Data from the Canadian Community Health Survey (2000–2001) suggest that ~500,000 Canadians are living with unresolved angina.4 The proportion of these patients with true RA is unknown.5 In the US, it is estimated that between 600,000 and 1.8 million patients have RA, with approximately 75,000 new cases diagnosed each year.5,6 In Europe, the annual incidence of RA is estimated at 30,000–50,000 new cases per year.1,7 Specific figures for the UK are lacking and further work to define the burden of RA in the UK population is needed. However, if the results shown by Williams et al., who found that 6.7 % of patients undergoing angiography in a contemporary cohort had no revascularisation option, are applied to the 247,363 angiograms performed in England in 2014, it can be estimated that ~16,500 new cases of RA may occur in England per year.3,8 Given improvements in CAD-related survival and increasing age of the population, together with an increasing appreciation from the contemporary Outcome of Percutaneous Coronary Intervention for Stent ThrombosIs Multicentre Study (OPTIMIST) registry that the long term prognosis of RA is not as bad as previously thought, the incidence and prevalence of RA is only set to rise.5,6,9,10 Furthermore, it has also been recently shown by Povsic et al. that patients with RA use significant healthcare resources, undergoing frequent hospitalisations, and experience high healthcare costs (~US$10,185 over a 3-year period).11

Epidemiology

Diagnosis

Precise estimates of the prevalence and incidence of RA are not available; however, several sources suggest that this is a large and

Patients with RA are a heterogeneous group that remain significantly limited by persistent debilitating chest discomfort despite optimal

© RADCLIFFE CARDIOLOGY 2016

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Ischaemic Heart Disease Figure 1: Triage of Patients with Chronic Chest Pain Syndrome According to Angina Symptoms and Presence of Epicardial Coronary Artery Disease or Reversible Ischaemia on Functional Testing A

Typical angina

Epicardial CAD

+ve

High probability

Atypical angina

Intermediate probability

Epicardial ± MVD Epicardial ± MVD

–ve

Intermediate probability

Low probability

Epicardial ± MVD Likely non-cardiac

High probability

Low probability

Intermediate probability

Low probability

MVD

Likely non-cardiac

MVD

Likely non-cardiac

+ve

–ve

+ve

–ve

Reversible ischaemia on functional test

B

High probability

Intermediate probability

Low probability

Cardiac and pain-focused pragmatic rehabilitation

Pain-focused pragmatic rehabilitation

Anti-ischaemic therapies

Pain modulating therapies

Pain modulating therapies

A: Stratification of probability of refractory angina into high (red), intermediate (orange) and low (green). Aetiology for each stratification shown (yellow). B: Emphasis of treatment based on stratified probability of refractory angina and likely aetiology. CAD = coronary artery disease; MVD = multivessel disease.

conventional therapy.1 This syndrome characteristically involves angina-type pain usually in the context of epicardial CAD with or without demonstrable ischaemia. Given the heterogeneity in patients complaining of chronic chest pain, appropriate stratification of patients with regard to their risk of RA helps to direct healthcare resources tailored to individual patients’ needs (see Figure 1).

A convincing clinical history of angina, together with circumstantial evidence supporting a diagnosis, should raise clinical suspicion. The coronary anatomy in these patients is highly variable with many having had prior revascularisation (72.4 % by some estimates), and myocardial ischaemia is often difficult to detect using conventional stress imaging protocols.10 The absence of demonstrable myocardial ischaemia in the context of epicardial CAD is not uncommon in patients referred with suspected RA and should in itself not exclude the diagnosis. Interpretation of negative functional tests must therefore consider the caveat of 1) a false negative test result or 2) the degree of ischaemia lies below the detection threshold of the imaging modality employed. Furthermore, it is important to rule out a diagnosis of non-cardiac chest pain with bystander CAD. However, when a patient’s history is suggestive of angina in the absence of any other causative factor (anaemia, dyspepsia, musculoskeletal pain), the lack of demonstrable myocardial ischaemia should not absolutely preclude a diagnosis of RA.

Pharmacological Therapies To date, no pharmacological therapy has been shown in adequatelypowered placebo-controlled randomised clinical trials (RCTs) to significantly improve symptoms and quality of life in patients with RA. However, a significant body of evidence exists in the literature with regard to pharmacological therapy for stable angina (see Table 1).12–30 The choice of additional medication over and above first-line treatment (with either a beta-blocker or calcium channel antagonist) follows

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the rationale for chronic stable angina – i.e. it is considered on an individual patient basis, taking into account age, heart rate, blood pressure, the presence of diabetes mellitus or impaired renal function and tolerability.31,32 Follow-up 2–4 weeks after initiation of a new medication should assess its efficacy and tolerability, and dependent on whether there is any benefit, uptitration to the maximal tolerated dose should occur. If still ineffective, the medication should be stopped and an alternative considered. However, polypharmacy is a significant problem in patients with RA and rationalising medical therapy to ensure optimal benefit, adherence and tolerability is a major clinical challenge.1,33

Coronary Sinus Reducer Preclinical studies have suggested that occlusion of the coronary sinus, the major venous drainage of the left heart, results in preservation of the endocardial to epicardial perfusion ratio and reduction of myocardial infarction size during coronary artery ligation. 34 These data coupled with encouraging early surgical experience motivated the development of a balloon-inflatable coronary sinus reducer device, which can be implanted via a simple trans-jugular approach (see Figure 2).35–37 In normal physiology, exercise induces sympathetic vasoconstriction in the epicardial circulation, which promotes subendocardial perfusion (subendocardial:subepicardial perfusion ratio: ~1.2).38 In the setting of epicardial CAD, this mechanism is thought to become dysfunctional. Myocardial ischaemia induces impaired regional wall motion and increased left ventricular end-diastolic pressure causes compression of the subendocardial capillaries, reducing perfusion (subendocardial:subepicardial perfusion ratio: <0.8).

Following insertion of a reducer, fibrosis occurs around the waist of the hourglass-shaped stent over a period of ~6 weeks, gradually increasing coronary sinus pressure and venous backflow. This results in dilation of venules and capillary recruitment with a reduction of resistance to subendocardial flow, which promotes recruitment of collateral flow from the subepicardium into the ischaemic subendocardium. It has also been suggested that this approach may encourage neovascularisation.37 A randomised, blinded, sham-controlled trial (Coronary Sinus Reducer for Treatment of Refractory Angina [COSIRA]) assessing this device has recently demonstrated significant improvements in angina symptoms and quality of life scores.39 In the treatment group, 35 % of patients had a reduction of ≥2 CCS classes compared to 15 % in the control group (p=0.020). Quality of life, as measured by the Seattle Angina Questionnaire, improved by 17.6 (treatment) versus 7.6 points (control; p=0.030). No major adverse effects were associated with this intervention.37,39–41 However, it is only suitable for patients with leftsided coronary ischaemia. Consideration whether further intervention of the coronary sinus (e.g. cardiac resynchronisation therapy) may be indicated in the near future should be made, although notably, the waist of the reducer device can be dilated to allow such procedures.42 Further results of ongoing studies to evaluate this device are eagerly awaited.43,44

Cell Therapy Cellular therapies have gained major interest as potential novel treatments for RA. Eight RCTs have evaluated unselected bone marrow mononuclear cells (BMCs), adipose-derived regenerative cells, CD34+ (with recently published 2-year follow-up) and CD133+

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Refractory Angina Pectoris

Table 1: Second- and Third-line Anti-anginal Medication (Above Beta-blockers and Calcium Channel Antagonists) Drug Nicorandil

Mechanism of Action KATP - channel opener

Effects • Vasodilator (conductance and

Source IONA Study Group (2002)12

resistance vessels) • Cardioprotection •

LV preload and afterload

• No tolerance Ivabradine

If current inhibition

• Reduced automaticity of sino-atrial nodal cells • Selective slowing of heart rate

Ranolazine

Late INa current inhibition

• Reduced calcium overload and LV wall tension

Fox et al. (2008)13 Tardif et al. (2009)14 Fox et al. (2014)15 Chaitman et al. (2004)16 Wilson et al. (2009)17

• Improved myocardial perfusion

Kosiborod et al. (2013)18

• Partial inhibition of mitochondrial fatty

Ling et al. (2013)19

acid metabolism

Banon et al. (2014)20 Bennett et al. (2014)21

Trimetazidine

Reversible 3-ketoacyl-thiolase inhibition

• Reduced mitochondrial fatty acid-oxidation

Perhexiline

O-palmitoyltransferase 1/2 inhibition

• Reduced free fatty acid

Ciapponi et al. (2005)22 Grabczewska et al. (2008)23

oxidation and transport into

Cole et al. (1990)24 Phan et al. (2009)25

mitochondria Allopurinol

Xanthine oxidase inhibition

Reduces:

Noman et al. (2010)26

• Oxygen wasting • Endothelial dysfunction • Substrate depletion Molsidomine

Nitric oxide donor

• Vasodilatation

Messin et al. (1995)27 Messin et al. (2003)28 Messin et al. (2005)29

Fasudil/hydroxyfasudil

Rho-kinase inhibition

• Maintains coronary vasodilatation

Vicari et al. (2005)30

LV = left ventricular.

progenitor cells in patients with RA.45–54 After delivery, cellular products poorly engraft and are thought to improve ischaemia by promoting neovascularisation through paracrine effects although the precise mechanisms have not been fully elucidated.55–57

Figure 2: The Coronary Sinus Reducer Device

Fischer et al. performed a meta-analysis demonstrating that in patients with ischaemic heart disease unsuitable for revascularisation, BMCs significantly improve Canadian Cardiovascular Society (CCS) class (mean difference −0.55; 95 % confidence interval [CI][−1.00 to −0.10], p<0.020) and reduce frequency of weekly angina episodes (mean difference −5.21; 95 % CI [−7.35 to −3.07]; p<0.00001).58 A more recent meta-analysis by Khan et al. has confirmed these findings, further reporting that cellular therapies significantly improved a composite endpoint of major adverse cardiac events (myocardial infarction, cardiac-related hospitalisation and death) (OR 0.49, 95 % CI [0.25– 0.98]) as well as angina episodes, use of anti-anginal medication, CCS class, exercise tolerance, myocardial perfusion and arrhythmia occurrence.59 Safety has been shown to be good.59,60 While these results are certainly encouraging, such analyses collate data from small clinical trials (phase I–II) and future work should focus on adequately powered, blinded trials with use of a sham control procedure for comparison.61 A number of unresolved issues remain; namely the optimal cell type, preparation, dose and method of delivery. In addition, the effects of cell therapy may be shortlived and recent data from Mann et al. suggest a need for repeated administrations to maintain efficacy.62,63 These issues must be resolved before cellular therapy can enter routine clinical practice.

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A: Angiogram showing the anatomy of the coronary sinus. B: Placement of the reducer device into the coronary sinus and inflation with a balloon (arrow). C: CT showing the correct positioning of the reducer device in the coronary sinus. CSR = coronary sinus reducer; CT = computed tomography; DA = descending aorta; LA = left atrium; LPVC = left pulmonary venous confluence; LV = left ventricle. *Calcified plaque in left circumflex artery.

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Ischaemic Heart Disease Figure 3: Neuromodulation Targets

Stellate ganglion block Spinal Cord Stimulation

TENS SENS

SCS = spinal cord stimulation; SENS = subcutaneous electrical nerve stimulation; STT = spinothalamic tract; TENS = transcutaneous electrical nerve stimulation. Figure adapted from Henry et al. Nat Rev Cardiol 2014;11(2):78–95 with permission from Macmillan Publishers Ltd, copyright (2014).

External Enhanced Counterpulsation Alternative non-invasive therapies have been investigated for patients with angina pectoris, including external enhanced counterpulsation (EECP). This involves a series of 1–2 hour sessions over several weeks (35 hours total), during which external compressive cuffs are placed on the calves, lower and upper thighs that are sequentially inflated from distal to proximal, synchronised to early diastole, and deflated at the onset of systole.5,64 This counterpulsation effect, similar to that of an intra-aortic balloon pump, promotes retrograde aortic flow with concomitant increase in diastolic pressure, increased coronary perfusion, venous return and cardiac output. Rapid deflation of the cuffs reduces systemic vascular resistance and cardiac workload.64 Furthermore, EECP has been associated with improvement in invasive haemodynamic measures of collateral function;65,66 flow-mediated dilatation of large peripheral arteries;67,68 endothelial function;69 and mediators of inflammation and vasoconstriction.70 A number of small studies have suggested potential benefit from EECP, the largest of which is the Multicenter Study of Enhanced External Counterpulsation (MUST-EECP) trial (n=139), which showed a reduction of self-reported angina episodes by ~25 % and time to development of 1 mm ST depression increased by ~15 %.71 Importantly, quality of life was improved. A meta-analysis subsequently suggested that EECP achieved an improvement in angina by at least one CCS class in 86 % of patients with stable angina pectoris, though this analysis was not

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restricted to those patients with RA.72 A more recent meta-analysis has reported similar results.73 However, while this technology has recently received a Class IIa, Level of Evidence B, recommendation in the European Society of Cardiology (ESC) guidelines for the management of stable CAD, a 2009 Health Technology Assessment report and Cochrane systematic review were unable to find clear evidence of clinical or cost-effectiveness.31,74,75 In addition, this therapy has a number of contraindications, notably arrhythmias, peripheral vascular disease, aortic aneurysm and aortic stenosis.5,71 Further adequately-powered, blinded, sham-controlled RCTs specifically in patients with RA are needed.

Extracorporeal Shockwave Myocardial Revascularisation Therapy An investigational non-invasive treatment, extracorporeal shockwave myocardial revascularisation (ESMR) therapy, involves delivering low-energy shockwaves to the border zones of ischaemic myocardium (~10 % of the high-energy counterpart used in the treatment of urolithiasis) in a series of sessions delivered over 4–9 weeks.76,77 Through inducing local vasodilatation and neovascularisation, it is thought to reduce ischaemia and improve left ventricular function.78,79 Two small RCTs in the literature have shown improvements in angina in patients with RA.80,81 More recently, a case-control study of 72 patients (43 cases) not only demonstrated safety but showed ESMR therapy to be associated with modest improvements in the stress

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myocardial perfusion score (p=0.002), CCS class (p=0.0002), use of glyceryl trinitrate (GTN) (p<0.030), exercise tolerance (p<0.002) and hospitalisation for angina (p<0.030).76,82 A subsequent multicentre study has also demonstrated similar results.77 Interestingly, pretreatment with ESMR therapy has been suggested to enhance the beneficial effects of BMCs delivered by intracoronary infusion in patients with ischaemic left ventricular dysfunction.83 The effects were small; however, ESMR + BMCs improved left ventricular ejection fraction by 3.2 % (95 % CI [2.0–4.4]) versus ESMR + placebo infusion 1.0 % (95 % CI [0.3–2.2]; p=0.020). Upregulation of signalling molecules (stromal cell-derived factor 1 [SDF-1] and vascular endothelial growth factor [VEGF]) by ESMR is thought to underlie this phenomenon of target tissue preconditioning that may aid progenitor cell engraftment.84 Further appropriately designed studies are needed to determine the mechanism and role of ESMR in RA.

Neuromodulation The perception of pain from visceral nociceptive stimuli is complex and the severity of symptoms is often disproportionate to the degree of ischaemia. Various approaches to modulate nociceptive signals are used in patients with RA (see Figure 3), of which, implantation of spinal cord stimulation (SCS) has received a Class IIb, Level of Evidence B, recommendation in recent ESC guidelines.6,31,85 This minimally invasive procedure involves the placement of multipolar electrodes into the epidural space to deliver an electrical current to the dorsal columns between C7 and T1.5,86,87 An implanted patientcontrolled pulse generator allows stimulation at the onset of angina, inducing paraesthesia at the location of anginal chest discomfort.

Mechanistically, SCS may result in anti-nociceptive activation of spinal afferent neurons and inhibit sympathetic efferents, attenuating vasoconstriction and reducing ischaemia.88–90 Several small scale clinical trials of SCS have been aggregated in a meta-analysis, showing significantly improved exercise capacity and quality of life with low complication rates (e.g. infection, lead displacement, etc.).91 A recent registry of 235 patients demonstrated reduced angina frequency, sublingual GTN use with SCS and improved CCS class as well as quality of life up to 1-year of follow-up.92 Adequate sham-controlled RCTs to confirm efficacy and cost-effectiveness are needed – pilot studies (e.g.

Refractory Angina Spinal Cord Stimulation and Usual Care [RASCAL] study) are important but highlight the potential challenges, particularly regarding patient recruitment.93

Pragmatic Rehabilitation Pragmatic rehabilitation is an important approach to promote patients to manage their own chest pain. Through learning cognitivebehavioural self-management techniques and challenging negative health beliefs, quality of life and psychological wellbeing can improve substantially. The Angina Plan is one such tool whereby patients’ understanding of angina can be evaluated and misconceptions corrected.94 It provides a structured approach to address maladaptive coping strategies in patients with angina and has been shown to significantly improve psychological wellbeing (anxiety and depression), symptoms (three episodes of angina fewer per week and reduced GTN use) and functional status (reduced physical limitation score and increased daily walking). Furthermore, from our experience, we have found that reassuring patients their symptoms are non-cardiac in origin has as important an impact as successful management of symptoms secondary to ischaemia.

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Figure 4: Schematic Showing the Assessment of the Patient with Refractory Angina in a Specialist Multidisciplinary Team Setting

CLINICAL ASSESSMENT Suspected angina

Non-anginal symptoms

Nurse specialist Reassure, educate, exercise angina plan, cardiac rehabilitation questionnaires (HADS, EQ5, SAQ)

Review and optimise CV medical therapy

Reassure Ix/Rx non-cardiac conditions

Non-invasive/invasive investigations Anatomy, ischaemia, LV function Limiting symptoms persist Multidisciplinary team discussion

Mod/Sev ischaemia

Mild/No ischaemia

PCI (CTO) Redo CABG CS reducer

Specialist pain management: CBT (1:1 or group) Drugs Stellate ganglion block TENS Spinal cord stimulator

EECP Biologics

Symptoms improved

Nurse specialist follow-up (face to face/telephone) Review, refine, reinforce, questionnaires (HADS, EQ5, SAQ), audit

CAGB = coronary artery bypass grafting; CBT = cognitive behavioral therapy; CS = coronary sinus; CTO = chronic total occlusion; CV = cardiovascular; EECP = enhanced external counterpulsation; EQ5 = EuroQol questionnaire; HADS = Hospital Anxiety and Depression Scale; LV = left ventricular; PCI = percutaneous coronary intervention; SAQ = Seattle Angina Questionnaire; TENS = transcutaneous electrical 33 nerve stimulation. Source: Wright and de Silva, 2016. With permission from British Journal of Cardiology © 2016.

For patients with cardiac ischaemia, pragmatic rehabilitation consists of two main components.

The first involves education to correct common misconceptions about angina and developing a basic understanding of the pain pathway. For example, the notion that stable angina in itself is not life-threatening and their pain not always cardiac in origin is emphasised. Underuse of GTN may occur due to perceptions that it may lose its effectiveness – thus such mistaken beliefs are corrected and patients encouraged to use their GTN more often.

Furthermore, it is explained that the heart can ‘adapt’ to having angina through the process of ischaemic conditioning and collateralisation.95,96 The heightened perception of death is also challenged by discussing data from the OPTIMIST Registry (n=1,200) showing that 71.6 % of patients with RA have a 9-year life expectancy.10 Additionally, patient awareness is raised about how their mental state can significantly affect their perception of symptoms.

The second component addresses important lifestyle adaptations that can significantly impact on patients’ symptoms (e.g. learning how to pace oneself, setting realistic goals and deconstructing

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Ischaemic Heart Disease tasks into manageable portions). Furthermore, behaviours to reduce cardiovascular risk (e.g. smoking cessation, weight loss and exercise) are strongly emphasised as is adherence to aggressive primary and secondary prevention.

Pragmatic rehabilitation is typically delivered by a nurse specialist and a clinical psychologist via a series of group-based education sessions where patients are taught self-management techniques.97 This facilitates an improvement in their quality of life whilst reducing dependency on resource-limited medical services.98 Potential avenues to develop the mode of delivery may include the use of technology such as smartphone apps. Novel technological methods to deliver such therapies have been increasingly investigated, and their benefit has been recognised for chronic conditions, including cardiovascular disease, since they can effectively complement rehabilitation as well as improve adherence to medication.99,100 The efficacy of psychoeducational interventions in patients with chronic stable angina, including RA, has been investigated in a number of small studies, which have been analysed in a meta-analysis by McGillion et al.101 Seven RCTs (total n=949) of self-management programmes were assessed, most of which studied the intervention delivered in small groups of 6–15 patients. It revealed that psychoeducational intervention resulted in significantly less angina (~3 fewer episodes per week; −2.85, 95 % CI [−4.04 to −1.66]) and reduced nitrate consumption (~4 times less per week; −3.69, 95 % CI [−5.50 to −1.89]) at 3–6 months follow-up.101 Importantly, statistically significant improvements in quality of life (as per the Seattle Angina Questionnaire) were observed for physical limitation and disease perception. More recent data from refractory angina services in the UK have reported encouraging

1.

Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 2002;23 :355–70. DOI: 10.1053/euhj.2001.2706; PMID: 11846493 2. Jolicoeur EM, Granger CB, Henry TD, et al. Clinical and research issues regarding chronic advanced coronary artery disease: part I: Contemporary and emerging therapies. Am Heart J 2008;155 :418–34. DOI: 10.1016/j.ahj.2007.12.004; PMID: 18294474 3. Williams B, Menon M, Satran D, et al. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality. Catheter Cardiovasc Interv 2010;75 :886–91. DOI: 10.1002/ccd.22431; PMID: 20432394 4. Statistics Canada. Canadian Community Health Survey (CCHS). 2002. Available at: www23.statcan.gc.ca/imdb/p2SV. pl?Function=getSurvey&Id=3359 (Accessed 15 October 2016).

5. McGillion M, Arthur HM, Cook A, et al. Management of patients with refractory angina: Canadian Cardiovascular Society/Canadian Pain Society joint guidelines. Can J Cardiol 2012;28 (2 Suppl):S20-41. DOI: 10.1016/j.cjca.2011.07.007; PMID: 22424281 6. Bhatt AB, Stone PH. Current strategies for the prevention of angina in patients with stable coronary artery disease.

Curr Opin Cardiol 2006;21 :492–502. DOI: 10.1097/01. hco.0000240588.22086.43; PMID: 16900014 7. Thadani U. Recurrent and refractory angina following revascularization procedures in patients with stable angina pectoris. Coron Artery Dis 2004;15 :S1-4. DOI: 10.1097/01. mca.0000129883.86374.6c; PMID: 15179121 8. British Cardiovascular Intervention Society Audit 2014.

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9. Chow CM, Donovan L, Manuel D, et al. Canadian Cardiovascular Outcomes Research Team. Regional variation in self-reported heart disease prevalence in Canada. Can J Cardiol 2005;21 :1265–71. PMID: 16341294 10. Henry TD, Satran D, Hodges JS, et al. Long-term survival in patients with refractory angina. Eur Heart J 2013;34 :2683–8.

DOI: 10.1093/eurheartj/eht165; PMID: 23671156 11. Povsic TJ, Broderick S, Anstrom KJ, et al. Predictors of long-term clinical endpoints in patients with refractory angina. J Am Heart Assoc 2015;4 :e001287. DOI: 10.1161/ JAHA.114.001287; PMID: 25637344; PMCID: PMC4345862 12. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 2002;359 :1269–75.

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results.97,102,103 A short psychological intervention consisting of four 2-hour sessions based on an angina programme combined with a course of cognitive behaviour therapy has been shown to significantly improve quality of life whilst reducing anxiety and depression.97 Selfreported scores of 1) restriction from and 2) control over angina also significantly improved. Impressively, these results were maintained in the long term (3-year follow-up).102

A Dedicated Multidisciplinary Service Almost by definition, the management of these ‘no option’ patients with RA is challenging. Their needs are best met via integrated care delivered by specialist multidisciplinary teams in dedicated specialist services (see Figure 4). Such a framework enables addressing the issues of this heterogeneous patient cohort in a bespoke way, and allows the full spectrum of clinical management including investigative and novel treatments for appropriately selected patients.33 Through such a combination approach involving selection from the spectrum of therapies mentioned above, management can be individually tailored to meet patients’ needs. Although such resources are scarce, the recognition of the importance of multidisciplinary teams in this unique subset of patients will hopefully encourage further provision of services.

Conclusion Whilst novel therapeutic approaches to managing these patients are welcome, evaluation of their efficacy through robust clinical data must be rigorously pursued. The development of clinical guidelines specific to RA should also be encouraged. Finally, further studies should investigate the effect of novel therapies on reducing healthcare utilisation and demonstrate cost-effectiveness in patients with RA. n

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DOI: 10.1161/CIRCRESAHA.116.308409; PMID: 26987911 62. Mann I, Rodrigo SF, van Ramshorst J, et al. Repeated Intramyocardial Bone Marrow Cell Injection in Previously Responding Patients With Refractory Angina Again Improves Myocardial Perfusion, Anginal Complaints, and Quality of Life. Circ Cardiovasc Interv 2015;8 :e002740. DOI: 10.1161/ CIRCINTERVENTIONS.115.002740; PMID: 26259770 63. Henry TD, Povsic TJ. Repeat Cell Therapy for Refractory Angina: Déjà vu All Over Again? Circ Cardiovasc Interv 2015;8 :e003049. DOI: 10.1161/ CIRCINTERVENTIONS.115.003049; PMID: 26259771 64. Manchanda A, Soran O. Enhanced external counterpulsation and future directions: step beyond medical management for patients with angina and heart failure. J Am Coll Cardiol 2007;50 :1523–31. DOI: 10.1016/j.jacc.2007.07.024; PMID: 17936150 65. Buschmann EE, Utz W, Pagonas N, et al. Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial). Eur J Clin Invest 2009;39 :866–75. DOI: 10.1111/j.1365-2362.2009.02192.x; PMID: 19572918 66. Gloekler S, Meier P, de Marchi SF, et al. Coronary collateral growth by external counterpulsation: a randomised controlled trial. Heart 2010;96 :202–7. DOI: 10.1136/ hrt.2009.184507; PMID: 19897461 67. Braith RW, Conti CR, Nichols WW, et al. Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study. Circulation 2010;122 :1612–20. DOI: 10.1161/CIRCULATIONAHA.109.923482; PMID: 20921442; PMCID:PMC2963100 68. Levenson J, Simon A, Megnien JL, et al. Effects of enhanced external counterpulsation on carotid circulation in patients with coronary artery disease. Cardiology 2007;108 :104–10.

DOI: 10.1159/000095949; PMID: 17008798 69. Levenson J, Pernollet MG, Iliou MC, et al. Cyclic GMP release by acute enhanced external counterpulsation. Am J Hypertens 2006;19 :867–72. DOI: 10.1016/j.amjhyper.2006.01.003; PMID: 16876689 70. Casey DP, Conti CR, Nichols WW, et al. Effect of enhanced external counterpulsation on inflammatory cytokines and adhesion molecules in patients with angina pectoris and angiographic coronary artery disease. Am J Cardiol 2008;101 :300–2. DOI: 10.1016/j.amjcard.2007.08.031; PMID: 18237588 71. Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999;33 :1833–40. PMID: 10362181 72. Shah SA, Shapiro RJ, Mehta R, Snyder JA. Impact of enhanced external counterpulsation on Canadian Cardiovascular Society angina class in patients with chronic stable angina: a meta-analysis. Pharmacotherapy 2010;30 :639–45. DOI: 10.1592/phco.30.7.639; PMID: 20575628 73. Zhang C, Liu X, Wang X, et al. Efficacy of Enhanced External Counterpulsation in Patients With Chronic Refractory Angina on Canadian Cardiovascular Society (CCS) Angina Class: An Updated Meta-Analysis. Medicine (Baltimore) 2015;94 :e2002.

DOI: 10.1097/MD.0000000000002002; PMID: 26632696 74. McKenna C, McDaid C, Suekarran S, et al. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

Health Technol Assess 2009;13 :iii–iv, ix–xi, 1-90. DOI: 10.3310/ hta13240; PMID: 19409154 75. Amin F, Al Hajeri A, Civelek B, et al. Enhanced external counterpulsation for chronic angina pectoris. Cochrane

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CD007219.pub2; PMID: 20166092 Alunni G, Marra S, Meynet I, et al. The beneficial effect of extracorporeal shockwave myocardial revascularization in patients with refractory angina. Cardiovasc Revasc Med 2015; 16:6–11. DOI: 10.1016/j.carrev.2014.10.011; PMID: 25555620 Prasad M, Wan Ahmad WA, Sukmawan R, et al.

Extracorporeal shockwave myocardial therapy is efficacious in improving symptoms in patients with refractory angina pectoris–a multicenter study. Coron Artery Dis 2015;26 :194– 200. DOI: 10.1097/MCA.0000000000000218; PMID: 25734606 Song J, Qi M, Kaul S, Price RJ. Stimulation of arteriogenesis in skeletal muscle by microbubble destruction with ultrasound. Circulation 2002;106 :1550–5. PMID: 12234963 Nishida T, Shimokawa H, Oi K, et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation 2004;110 :3055–61. DOI: 10.1161/01.

CIR.0000148849.51177.97; PMID: 15520304 Fukumoto Y, Ito A, Uwatoku T, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006;17 :63–70. PMID: 16374144 Yang P, Guo T, Wang W, et al. Randomized and double-blind controlled clinical trial of extracorporeal cardiac shock wave therapy for coronary heart disease. Heart Vessels 2013;28 :284–91. DOI: 10.1007/s00380-012-0244-7; PMID: 22457097 Slavich M, Ancona F, Margonato A. Extracorporeal shockwave myocardial revascularization therapy in refractory angina patients. Int J Cardiol 2015;194 :93. DOI: 10.1016/ j.ijcard.2015.05.067; PMID: 26011274 Assmus B, Walter DH, Seeger FH, et al. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA 2013;309 :1622–31. DOI: 10.1001/jama.2013.3527; PMID: 23592107 Aicher A, Heeschen C, Sasaki K, et al. Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation 2006;114 :2823–30.

DOI: 10.1161/CIRCULATIONAHA.106.628623; PMID: 17145991 Rosen SD. From heart to brain: the genesis and processing of cardiac pain. Can J Cardiol 2012;28(2 Suppl) :S7–19.

DOI: 10.1016/j.cjca.2011.09.010; PMID: 22424286 TenVaarwerk I, Jessurun G, DeJongste M, et al. Clinical outcome of patients treated with spinal cord stimulation for therapeutically refractory angina pectoris. The Working Group on Neurocardiology. Heart 1999;82 :82–8. PMID: 10377314 Ekre O, Eliasson T, Norrsell H, et al. Long-term effects of spinal cord stimulation and coronary artery bypass grafting on quality of life and survival in the ESBY study. Eur Heart J 2002;23 :1938–45. PMID: 12473256 de Jongste MJ, Haaksma J, Hautvast RW, et al. Effects of spinal cord stimulation on myocardial ischaemia during daily life in patients with severe coronary artery disease. A prospective ambulatory electrocardiographic study. Br Heart J 1994;71 :413–8. PMID: 8011403 Hautvast RW, Blanksma PK, DeJongste MJ, et al. Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am J Cardiol 1996;77 :462–7. PMID: 8629585 Prager JP. What does the mechanism of spinal cord stimulation tell us about complex regional pain syndrome?

Pain Med 2010;11 :1278–83. DOI: 10.1111/j.15264637.2010.00915.x; PMID: 20704677 Taylor RS, De Vries J, Buchser E, Dejongste MJ. Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.

BMC Cardiovasc Disord 2009;9 :13. DOI: 10.1186/1471-2261-913; PMID: 19320999 Andréll P, Yu W, Gersbach P, et al. Long-term effects of spinal cord stimulation on angina symptoms and quality of life in patients with refractory angina pectoris--results from the European Angina Registry Link Study (EARL).

Heart 2010;96 :1132–6. DOI: 10.1136/hrt.2009.177188; PMID: 20483898 Eldabe S, Thomson S, Duarte R, et al. The Effectiveness and Cost-Effectiveness of Spinal Cord Stimulation for Refractory Angina (RASCAL Study): A Pilot Randomized Controlled Trial.

Neuromodulation 2016;19 :60–70. DOI: 10.1111/ner.12349; PMID: 26387883 Lewin RJ, Furze G, Robinson J, et al. A randomised controlled trial of a self-management plan for patients with newly diagnosed angina. Br J Gen Pract 2002;52 :194–6, 199–201. PMCID: PMC1314238; PMID: 12030661 Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation 1995;91 :37–45. PMID: 7805217 Koerselman J, van der Graaf Y, de Jaegere PPT, Grobbee DE. Coronary collaterals: an important and underexposed aspect of coronary artery disease. Circulation 2003;107 :2507–11.

DOI: 10.1161/01.CIR.0000065118.99409.5F; PMID: 12756191 Khan M, Thappar S, Taylor S, Sainsbury P. The impact of a short psychological intervention on quality of life and angina control in patients with chronic refractory angina. Eur Heart J

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Ischaemic Heart Disease 2013;34 :P2265. DOI: http://dx.doi.org/10.1093/eurheartj/ eht308.P2265 98. Moore RK, Groves D, Bateson S, et al. Health related quality of life of patients with refractory angina before and one year after enrolment onto a refractory angina program.

Eur J Pain 2005;9 :305–10. DOI: 10.1016/j.ejpain.2004.07.013; PMID: 15862480 99. Neubeck L, Lowres N, Benjamin EJ, et al. The mobile revolution--using smartphone apps to prevent cardiovascular disease. Nat Rev Cardiol 2015;12 :350–60.

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DOI: 10.1038/nrcardio.2015.34; PMID: 25801714 100. Cheng K, Ingram N, Keenan J, Choudhury RP. Evidence of poor adherence to secondary prevention after acute coronary syndromes: possible remedies through the application of new technologies. Open Heart 2015;2 :e000166.

DOI: 10.1136/openhrt-2014-000166; PMID: 25713726 101. McGillion M, Arthur H, Victor JC, et al. Effectiveness of Psychoeducational Interventions for Improving Symptoms, Health-Related Quality of Life, and Psychological well Being in Patients with Stable Angina. Curr Cardiol Rev 2008;4 :1–11.

DOI: 10.2174/157340308783565393; PMID: 19924272; PMCID:PMC2774580 102. Patel PA, Khan M, Thapar S, et al. The short- and long-term impact of psychotherapy in patients with chronic, refractory angina. Br J Cardiol 2016;23 :57–60.

DOI:10.5837/bjc.2016.019 103. Tinson D, Swartzman S, Lang K, et al. Clinical and psychological outcomes of an angina management programme. Br J Cardiol 2016;23 :61–4. DOI:10.5837/ bjc.2016.020

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Ischaemic Heart Disease

Fractional Flow Reserve Assessment of Coronary Artery Stenosis Serban Balanescu Cardiology Department, Elias University Hospital, Bucharest, Romania

Abstract Objective proof of focal lesions is mandatory, and the best invasive method of physiological testing is fractional flow r eserve (FFR). The increased trans-stenotic gradient is measured via the guiding catheter and pressure transducer on a 0.014” coronary wire at maximal hyperaemia induced by adenosine. Patients with a FFR of less than 0.8 should undergo myocardial revascularisation by percutaneous coronary intervention or coronary artery bypass graft, particularly if the proximal and middle segments of the main coronary arteries and large side-branches are affected; there is no prognostic revascularisation benefit in patients with moderate stenoses and FFR greater than 0.80. FFR assessment of coronary lesions is superior to other invasive morphological studies, such as intracoronary ultrasound or optical coherence tomography. Its use in non-culprit vessels in acute coronary syndromes is currently under scrutiny. Recent advances in computed tomographic technique allow non-invasive assessment of FFR, but clinical validation has yet to be obtained.

Keywords Coronary artery disease, fractional flow reserve, revascularisation Disclosure: The author has no conflicts of interest to declare.

Received: 21 August 2016 Accepted: 8 November 2016 Citation: European Cardiology Review 2016;11(2):77–82; DOI: 10.15420/ecr/2016:24:2 Correspondence: Associate Professor Serban Balanescu, Cardiology Department, Elias University Hospital, 17, Marasti Blvd, Sector 1, 011461, Bucharest, Romania.

E: smbala99@hotmail.com

Coronary artery disease (CAD) due to atherosclerosis is a major cause of morbidity and mortality. Early prevention of atherothrombotic disease with a healthy lifestyle (diet, exercise, optimal body weight and no smoking) is considered the best method of “treating” CAD, although increasing age remains associated with significant cardiovascular events.

When coronary atherothrombotic disease becomes clinically significant, it can evolve into stable ischaemic heart disease or an acute coronary syndrome (ACS). In ST-elevation ACS, an invasive approach with early coronary angiography and revascularisation of the culprit lesions can reduce mortality and promptly alleviate symptoms. Recent studies advocate early complete revascularisation of all coronary stenoses greater than 50 % in ACS, although this still remains a matter of debate.1 It is presumed that in unstable clinical conditions full revascularisation is warranted, irrespective of the real ischaemic significance of a coronary stenosis.2

Identification of Atherosclerotic Coronary Lesions on Angiography Current indications for coronary angiography in patients with stable ischaemic heart disease are limited to high-risk clinical conditions determined by non-invasive testing. Some patient subsets have a mortality risk greater than 3 % per year.3,4 Patients who have survived an episode of sudden cardiac arrest, have high-risk spontaneous ventricular arrhythmias, who develop unexplained heart failure or who have high-risk criteria at non-invasive stress testing should undergo coronary angiography3,4 as it allows the assessment of coronary anatomy and may be the deciding factor in whether a patient should undergo revascularisation.

In stable CAD revascularisation is a much more debatable issue due to the lack its effect on the hard endpoints of unselective intervention based only on the angiographic severity of a coronary stenosis.

Revascularisation should be reserved for patients who have both coronary artery stenoses at angiography and myocardial ischaemia due to significant flow reduction.

It is currently accepted that revascularisation by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) should be performed when: a stenosis >50 % is observed during angiography of the left main (LM) stem or proximal left anterior descending (LAD) coronary artery; the patient has a single remaining patent vessel; or suffers from two- or three-vessel disease with a left ventricular ejection fraction <40 %.5 Another indication for revascularisation resulted from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial: any coronary stenosis >50 % that can produce myocardial ischaemia in >10 % of the left ventricular myocardium.5,6

This review supports the use of objective proof of inducible myocardial ischaemia prior to deciding whether a patient with stable CAD and moderate stenoses should undergo revascularisation.

Many lesions of the coronary arteries fall outside these clearcut situations. Some patients have critical coronary stenoses in vessels that have no distal run-off or irrigate non-viable myocardium.

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Ischaemic Heart Disease Figure 1: Schematic of the Method Used to Measure Fractional Flow Reserve in the Catheterisation Laboratory

Guiding catheter (Pa)

Stenosis Pressure ± Doppler guide wire

Distal sensor (Pd)

Concomitant measurement of aortic pressure (Pa) and coronary pressure (Pd) across a coronary stenosis is performed at rest and maximal vasodilatation obtained by the administration of different drugs (e.g. adenosine/ATP [intravenous: 140 µg/kg/min; intracoronary: 50–150 µg]; papaverine [right coronary artery: 12–6 mg; left coronary artery: 16–20 mg]; nitroprusside [intracoronary bolus: 0.6 µg/kg]) to establish fractional flow reserve in the catheter laboratory. Normal fractional flow reserve is Pd/Pa greater than 0.75 at maximal hyperaemia.

Other patients have moderate coronary lesions with between 50 and 70 % stenosis with no clinical proof of myocardial ischaemia, and the decision whether or not to revascularise them is made by the interventional cardiologist based on this “occulo-stenotic reflex”.

Others have diffuse plaque burden and negative remodelling with no critical stenoses, but have significant inducible myocardial ischaemia.

A recent review of all randomised trials in this patient category demonstrated that the worst prognosis was observed in patients with both focal stenoses and global diffuse disease, followed by those with diffuse disease and no focal stenoses; patients with focal stenoses, but no diffuse disease had also better long-term outcomes.7 Currently 20–30 % of all coronary revascularisation procedures are performed in patients with stable CAD, raising the issue of how appropriate these procedures are in individuals with moderate coronary artery stenosis.8 Revascularisation of the “intermediate coronary lesions” with stenoses of between 50 and 70 % should be based on accurate physiological measurements of impaired epicardial blood flow obtained in the catheterisation laboratory (cath-lab) by measures of intracoronary pressure (the fractional flow reserve, FFR) or coronary flow (coronary flow reserve, CFR) by intracoronary Doppler.9 Recent advances in non-invasive angio-computed tomography (CT) allow indirect assessment of FFR by computation from static coronary CT images using computational fluid dynamics (CT-derived computed FFR or FFRCT).10,11 Multiple clinical trials have proven the value of the physiological assessment of coronary atherosclerosis determined either by FFR or non-invasive CFR for assessing prognosis in stable CAD.12,13

Physiologically Assessing Coronary Stenosis in the Catheterisation Laboratory Intermediate coronary stenoses of between 50 and 70 % induce myocardial ischaemia in 35 % of cases; of lesions with 71–90 % stenoses, some 80 % are functionally significant; and lesions with between 91 and 99 % stenoses induce myocardial ischaemia in 96 % of cases.14 Appropriate identification of ischaemia-inducing lesions is thus mandatory.

FFR is the ratio between pressure distal to a coronary stenosis and aortic pressure at maximum vasodilatation induced by a potent coronary vasodilator, usually adenosine.15 Different doses are given in the left and right coronary arteries (100–200 μg and 50–100 μg,

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respectively); a continuous intravenous adenosine infusion may be used instead of direct intracoronary administration at a rate of 140 μg/kg/min. Alternative agents include intracoronary nitroprusside, papaverine or nicorandil and intravenous regadenoson (an A2A receptor blocker), but the standard FFR drug is adenosine.

Aortic pressure is measured at the tip of a guiding catheter placed adjacent to the coronary ostium, and distal coronary pressure is recorded by a 0.014” guide-wire equipped with a pressure sensor 3 cm from its tip (see Figure 1). Some pressure-wires also have miniature intravascular ultrasound (IVUS) or Doppler probes and can be used to invasively measure CFR or provide anatomical information about the vessel wall by IVUS at the maximum vasodilation induced by adenosine.16 The most recent systems employ wireless technology and fibre-optic wires or catheters to improve pressure signal detection.

A synopsis of the different FFR measurement systems available is provided in Table 1. Normal coronary physiology is associated with a FFR value of 1, while myocardial ischaemia occurs at a FFR of less than 0.75 with a diagnostic accuracy of 90 %.15 FFR is the gold standard method for detecting myocardial ischaemia in the cath-lab and should be performed routinely in intermediate coronary stenoses between 50 and 70 %. Its main advantages are: • It has a well-defined cut-off point of 0.75 and a very narrow “grey zone” of between 0.75 and 0.80 • It is not influenced by systemic haemodynamic factors (such as blood pressure, heart rate and contractility) • In chronic stable ischaemic heart disease it does not depend on the status of microcirculation, as opposed to CFR; acute impairment by microemboli, spasm, compressing myocardial oedema or leukocyte margination in ACSs may be associated with false-negative (normal) FFR values • It is influenced by the collateral flow, which may sometimes bring a significant blood supply to the distal myocardium, depending on a main narrowed epicardial vessel (see Figure 2) • It is highly reproducible and easily obtainable after coronary angiography • It has high spatial resolution in the case of multiple stenotic segments in the same vessel.

Current indications for FFR assessment when intermediate coronary stenoses are not present are related to the accurate identification of significant lesions in multivessel CAD, differentiation between the functional significance of focal and diffuse coronary atherosclerosis, establishment of the presence of a significant lesion in multiple consecutive stenoses in the same vessel, and finally assessment of the efficiency of collateral circulation. A FFR of less than 0.75 is superior in its detection of myocardial ischaemia to other tests used in practice (such as exercise testing, thallium perfusion scans and stress echocardiography), with a specificity of 100 %, sensitivity of 88 % and accuracy of 93 %.15 Recently an adenosine-independent technique was developed by a FFR system manufacturer and tested as a possible substitute for classic techniques that use maximal pharmacological hyperaemia.

This technique is called the instantaneous wave-free pressure ratio (iFR). It has been determined that a wave-free period between the pressure wave in the aorta and distal microcirculatory pressure meets the criteria for FFR assessment. This occurs at 75 % in diastole 5 msec prior to the occurrence of the R wave. When compared to FFR, an

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Assessment of Coronary Artery Stenosis

Table 1: Currently-available Fractional Flow Reserve Systems Approved by Both the US Food and Drug Administration and European Medicines Agency (CE Mark) for the Clinical Assessment of Flow-limiting Stenoses in the Coronary or Peripheral Arteries Volcano System

Core®

ACIST Medical Systems

Boston Scientific

Opsens Inc

Core®

Quantien™

St Jude Pressure

RXi® Rapid Exchange

iLab POLARIS™

OptoWire®;

Mobile

Integrated

Wire™

FFR System (Navvus®

Imaging System

OptoMonitor®

FFR System

Receiver

Microcatheter)

(FFR-capable)

(FFR module)

CE mark year

2012

2013

2012

2008

2013

2014

2014

Indications

Coronary

Coronary

Coronary

Coronary

Coronary

Coronary

Coronary

and

and

artery

artery

and

artery

artery

peripheral

peripheral

arteries

arteries

Mean time for

Boot-time

Boot-time

FFR in a single

2 min;

2 min;

iFR

iFR

measurement

measurement

5 sec

5 sec

No

Virtual histology Need for adenosine

peripheral arteries NA

NA

~ 5 min

NA

NA

No

Yes

Yes

No

Yes

No

Yes

Yes

No

No

No

No

No

No (for iFR

No (for iFR

Yes

Yes

Yes

Yes

Yes

and FFR)

and FFR) NA

NA

NA

lesion

Wireless data transmission

administration Integrated

IVUS with

IVUS with

imaging

ChromaFlo®,

ChromaFlo®,

modalities

Virtual

Virtual

Histology

Histology

(VH®)

(VH®)

Acquired

FFR, iFR,

FFR, iFR,

physiological

Pd/Pa

Pd/Pa

FFR

FFR

No (high-definition IVUS:

IVUS (with Opticross™

HDi® since 2014)

catheter)

FFR, Pd/Pa

FFR

FFR

data FFR = fractional flow reserve; iFR = instantaneous wave-free pressure ratio; IVUS = intravascular ultrasound; NA = not applicable; Pd/Pa = coronary pressure/aortic pressure.

iFR value of less than 0.89 correlated with an FFR of less than 0.80 in correctly identifying 83 % of significant coronary stenoses in the ADVANCE II study.17 There are some limitations of FFR measurements in lesions of intermediate severity, but they are relatively uncommon. Pressure damping by placing the pressure transducer on the wire too distally with no surrounding flow produces false-negative results (high or normal FFR). An inadequate dose of adenosine may also produce false-negative results.

Figure 2: The Main Haemodynamic Factors Determining Fractional Flow Reserve with Maximum Hyperaemia Microcirculation Epicardial system (adenosine responsive)

+/- Collateral Intra-myocardial microcirculation capillaries

Central venous system

Pa (Ao) Pv

In ACSs, FFR may also show normal values due to diffuse microcirculation impairment (or obstruction) in the distal myocardium.

This generally improves over time, and when FFR is measured again the same vessel may prove to be significantly ischaemic with myocardial flow improvement.

Use of FFR to Determine Revascularisation in Stable CAD Multiple clinical trials have demonstrated that revascularisation should only be performed on intermediate lesions in stable CAD if myocardial ischaemia can be documented by a FFR value of less than 0.75. It was also proven in the DEFERral of percutaneous coronary intervention (DEFER) trial that performing PCI on coronary lesions with a FFR greater than 0.75 leads to the same 5-year prognosis and chest pain prevalence as medical treatment.18 Patients with physiologically-

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Epicardial coronary artery resistance

Right Atrium

Pd

Microvascular resistance (collateral vessels included)

Epicardial vessel resistance FFR

Venous resistance

IMR CFR

Ao = aorta; CFR = coronary flow reserve; FFR = fractional flow reserve; IMR = index for microcirculatory resistance; Pa = aortic pressure; Pd = coronary pressure; Pv = venous pressure. Adapted from Berry et al., 2015.44

significant lesions with a FFR of less than 0.75 had the worst prognosis irrespective of revascularisation by PCI.18 Previous studies showed that the risk of a major adverse cardiac event at 1 year is 27 % when

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Ischaemic Heart Disease FFR is less than 0.75 compared to 9 % with a FFR greater than 0.75 in patients with multivessel CAD and intermediate stenosis.19 The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2 (FAME 2) trial was stopped early by the Data and Safety Monitoring Board following the randomisation of only 888 patients (54 % of the planned enrolment group) after a mean follow-up of 7 months rather than 2 years because of a highly statistically significant reduction in the primary endpoint in the PCI group, due to a higher need for urgent revascularisation.20 In this trial, patients with stable CAD, intermediate coronary artery stenoses and at least one stenosis with a FFR of less than 0.8 were randomised to PCI with drug eluting stents plus optimal medical therapy versus optimal medical therapy alone. The primary endpoint was a composite of death, myocardial infarction and urgent revascularisation at 2 years. The composite endpoint was observed in 4.3 % of patients enrolled in the PCI group versus 12.7 % in the medical therapy group. The conclusion of the study was that FFR-guided PCI offers the best outcome when associated with best medical therapy in stable CAD patients.

The decision to prematurely stop the trial was highly criticised, however, as there was no significant difference in the hard endpoints (death and myocardial infarction) between the groups. A second publication by the study investigators with complete 2-year follow-up showed a sustained 77 % reduction in the need for urgent revascularisation in the PCI group, but no difference in mortality or myocardial infarction.21 When all patients with periprocedural myocardial infarctions were excluded, statistical analysis showed a lower incidence of death or myocardial infarction in the PCI group (4.6 % versus 8 %; p=0.04).

Stable CAD patients with the worst prognosis are those with concomitant focal stenoses and diffuse disease sometimes combined in very long lesions with negative remodelling of the vessel.7 These are usually patients with long-standing diabetes or severe risk factors for CAD (i.e. familial hypercholesterolaemia). Physiological assessment in these vessels may be useful when deciding whether focal treatment is necessary, usually by PCI. Continuous pull-back of the pressure wire is performed by the operator while observing the FFR measurement at maximal hyperaemia; PCI and focal treatment is necessary if a sudden normalisation of pressure gradient is observed along the pull-back manoeuver along the diseased vessel.22 Continuous decrease in the pressure gradient along the investigated vessel is an indication for conservative treatment, although the prognosis remains reserved due to the severity of atherosclerotic disease.

One of the most useful indications for FFR measurement in stable CAD is multivessel disease. In the FAME trial, 1,005 patients with multivessel CAD were randomised to an angiography-based revascularisation strategy of all stenosis >50 % or a FFR of less than 0.8based strategy for performing PCI.23 FFR-guided PCI was associated with a lower rate of total mortality, non-fatal myocardial infarction and repeat revascularisation (13.2 % versus 18.3 %, p=0.02). The incidence of angina was the same in both groups, however, with 80 % of patients being angina-free. Better resource use was observed in the FFR group, with a lower use of coronary stents. The mortality advantage was maintained at 2-year follow-up, with an 8.4 % prevalence of angina in the FFR group versus 12.9 % in the angiography-alone group.24 Another angiographical challenge that may be settled by the use of FFR is the use of revascularisation in patients with LM or right coronary artery ostial stenosis with downstream disease. When measuring FFR in these conditions, the operator needs to take extra care to avoid

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pressure damping by selectively engaging the vessel with the catheter tip, while using a continuous intravenous infusion of adenosine rather than an intracoronary bolus. FFR should be measured in both the LAD and circumflex (Cx) arteries by selective positioning of the pressure wire in the distal vessels. A FFR greater than 0.80 in 50 % LM artery stenosis was considered an indication for medical therapy alone, while in patients with the same angiographical stenosis of the LM artery and FFR of less than 0.80 CABG was performed.25 Only 23 % of the lesions with >50 % stenosis at angiography had a FFR of less than 0.80. Estimated survival rates at 5 years were the same in the non-physiologically-significant lesions of the LM artery (FFR greater than 0.80) as those with physiologically-significant lesions who were revascularised by CABG (89.8 % versus 85.4 %).

LM lesions with associated distal disease of the LAD and/or Cx arteries are more difficult to assess, as distal disease may influence the FFR of the LM artery stenosis. To appropriately assess the physiological significance of a LM stenosis, the pressure wire should be positioned in the non-diseased artery, either the LAD or the Cx. When both LAD and Cx arteries have atherosclerotic disease, a false-negative FFR measurement may be recorded. In these cases an observed FFR of between 0.81 and 0.85 corresponds to a real FFR of less than 0.80, and the artery requires revascularisation.26

Can Atherosclerotic Plaque Morphology Determine FFR in Stable CAD? FFR differentiates between significant haemodynamic stenoses and non-ischaemia inducing lesions. It is less clear whether it can predict prognosis in patients with lipid-rich, large necrotic core plaques (thin cap fibroatheroma, TCFA) and allow treatment prior to the occurrence of an ACS. Some recent trials correlating FFR measurement with imaging studies of the vessel walls have demonstrated that only vulnerable, lipid-rich atherosclerotic plaques are associated with reduced FFR independent of the degree of luminal stenosis.27–29 In a study performed with both IVUS and FFR measurement in moderate coronary stenoses (between 50 and 70 %), only TCFA plaques were correlated with low FFR; larger, lipid-rich necrotic cores were correlated with lower FFR values.30 A normal FFR denotes a low likelihood of the presence of unstable, vulnerable plaques. It has been postulated that a normal FFR excludes not only haemodynamic impairment due to significant mechanical flow obstruction, but also unstable plaques with large necrotic cores, demonstrating that medical treatment alone is safe in all these cases.27 The COMBINEd Optical Coherence Tomography Morphologic and Fractional Flow Reserve (COMBINE (OCT-FFR)) is currently enrolling patients. It is a prospective trial comparing the outcomes in patients with diabetes mellitus and FFR-negative values in intermediate coronary artery stenoses with or without TCFA against FFR-positive patients treated with PCI.31 The trial’s primary endpoints are cardiac death, myocardial infarction, and clinically-driven target lesion revascularisation or hospitalisation for unstable angina at 18-months in non-TCFA patients versus TCFA patients both with normal FFR values. Secondary endpoints compare FFR-negative TCFA-positive patients with PCI-treated FFR-positive patients.

The Future of Coronary Physiological Measures in the Cath-lab There is an intense debate about the use of physiological measurements in ACSs to guide non-culprit lesion revascularisation.

Culprit lesion revascularisation without physiological assessment

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Assessment of Coronary Artery Stenosis

Table 2: Actual Diagnostic Performance of Fractional Flow Reserve (FFR) Computed Tomography when Compared with Invasive FFR in Physiologically-significant Lesions that Need Revascularisation (FFR <0.80) Clinical trial

Patients

Sensitivity

Specificity

Positive predictive

Negative predictive

(n)

(%)

(%)

value (%)

value (%)

(%)

DeFACTO45

252

90

54

67

84

73

DISCOVER-FLOW42

103

93

82

85

91

87

NXT

251

86

79

65

92

81

606

90

72

72

89

80

41

Accuracy

DeFACTO = Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography; DISCOVER-FLOW = Diagnosis of ISChaemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve; NXT = Analysis of Coronary Angiography: Next Steps. Adapted from Nørgaard et al., 2014,41 Koo et al., 201142 and Leipsic et al., 2014.45

improves prognosis by reducing the risks of recurrent myocardial infarction and mortality.32 The long-term outcome for ACS patients is a return to the baseline risk of any CAD patient.

Coronary physiological assessment may eventually be used in ACS patients with no obvious culprit lesion at diagnostic angiography.

This is not a common clinical situation as angiography identifies at least one culprit lesion in most ACS patients. When no obvious culprit lesion is identified, FFR measurements even in mild CAD may be useful, although the cause–effect relationship may be very difficult to prove and the decision to revascularise is debatable.

In ACS patients with clear culprit lesions, coronary physiology measurements of the culprit vessel may demonstrate serial improvement of blood flow due to progressive improvement of the resistance of the distal capillary bed (or index for microcirculatory resistance, see Figure 2).33 In these culprit vessels, blood flow measurements (using Doppler flow velocity or bolus thermodilution) after primary PCI are associated with clinical outcome.34,35 No clinical trials have yet demonstrated the prognostic value of flow measures after revascularisation for ACS; consequently, culprit vessel flow measurements provide some prognostic insights after an ACS, but their clinical use is still under debate.

Two small randomised studies have used FFR in non-culprit lesions to decide whether or not to revascularise ACS patients. The Fractal Flow Reserve Versus Angiography Guided Management to Optimise Outcomes in Unstable Coronary Syndromes (FAMOUS-NSTEMI) trial randomised 350 patients with at least one 30 % non-culprit stenosis to FFR (less than 0.8) or angiography to determine whether revascularisation by PCI or CABG was required. At 1-year follow-up, prognosis was the same for both groups, despite higher rates of revascularisation in the angiography-alone subgroup.36 In the Third DANish Study of Optimal Acute Treatment of Patients With STEMI: PRImary PCI in MULTIvessel Disease (DANAMI-3 – PRIMULTI) study, 627 patients with STEMI were randomised to FFR- or angiography-based revascularisation assessment in lesions with at least 50 % luminal stenosis in non-culprit vessels.37 All STEMI lesions were previously treated by PCI. Total mortality and non-fatal myocardial infarction levels were no different between the two groups at 1-year follow-up. There was a significant reduction in the revascularisation rate in the FFR-guided group at 1 year.

Whether or not to use FFR-based assessment of the need for revascularisation of non-culprit lesions in STEMI patients will be answered when results from the large-scale randomised COMPLETE trial are published in 2018.38 The trial will enrol 3,900 patients. Inclusion criteria will be related to a >70 % lesion or a 50–70 % stenosis with a FFR of less than 0.8 in a non-culprit lesion. The primary endpoint

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will be cardiovascular death and nonfatal myocardial infarction.

Studies like COMPLETE with hard endpoints will be necessary in the near future to determine the value of FFR in deciding whether to revascularise non-culprit lesions in ACS. Finally, the significance of medium-size jailed side branches when implanting stents in main coronary arteries can also be determined

by FFR measurement. When an ostial side branch stenosis >50 % occurred after stenting the main vessel, the mean FFR in the side branch was 0.85±0.11 in vessels greater than 2 mm. One-third of lesions angiographically found to have stenosis more severe than 75 % were found to be physiologically significant by FFR.39

A New Non-invasive Option to Assess the Physiological Significance of CAD New angio-CT techniques mean that FFR at maximum hyperaemia can now be non-invasively assessed using computational fluid dynamics.40 This method depends heavily on image acquisition and image-processing algorithms. It was even proposed that coronary angioCT coupled with FFR-CT be used to decide which patients with 30–70 % stenoses should go to the cath-lab, even when their Agatston calcium score was >400.41 The functional significance of coronary atherosclerosis could be obtained by a single non-invasive method; however, the results of the first three randomised trials comparing FFR-CT with FFR measured in the cath-lab using a pressure wire were not convincing.41–43 The non-invasive method is plagued by a low average diagnostic accuracy of about 80 % and it has been assessed in a rather low number of patients (see Table 2).

It has been proposed that the diagnostic accuracy of a non-invasive FFR-CT test should be compared with that of other non-invasive tests alone. There is hope that, with continuous improvement in technology and standardisation of the technique, FFR-CT will become a useful clinical tool.

Conclusion CAD in stable patients is frequently associated with moderate coronary stenoses of between 50 and 70 %. The functional significance of these lesions should be assessed by FFR, and myocardial ischaemia should be demonstrated. FFR-guided PCI should always be used in stable CAD patients with moderate coronary stenoses as it is the best current therapy in these cases. Revascularisation is warranted in patients with stable CAD and a FFR of less than 0.75–0.80, either

by PCI or CABG. Due to its functional significance, FFR is superior to other invasive anatomical investigation methods, such as IVUS or optical coherence tomography. When used concomitantly with FFR, it

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Ischaemic Heart Disease was demonstrated that low FFR values are obtained from moderate coronary artery stenoses that most frequently have large lipid-rich necrotic cores. The use of FFR is futile in stable ischaemic patients who have concordant high-risk stress tests and an angiogram showing

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DOI: 10.1016/j.jacc.2013.12.014 Johnson N, Tóth G, Lai D, et al. Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes. J Am Coll Cardiol 2014;64 :1641–54. DOI: 10.1016/ j.jacc.2014.07.973; PMID: 25323250 Herzog B, Husmann L, Valenta I, et al. Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol 2009;54 :150–6. DOI: 10.1016/j.jacc.2009.02.069; PMID: 19573732 Tonino P, Fearon W, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;25 :2816–21.

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a high-risk coronary anatomy (i.e. 50 % stenosis of the proximal LAD).

There are great expectations that refinements to CT-angiography will enable the accurate determination of FFR and predict the need for revascularisation in stable CAD patients. n

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Prospective assessment of the diagnostic accuracy of instantaneous wave-free ratio to assess coronary stenosis relevance: Results of ADVISE II International, Multicenter Study (ADenosine Vasodilator Independent Stenosis Evaluation II). JACC Cardiovasc Interv 2015;8 :824–33.

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Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49 :2105–11. DOI: 10.1016/ j.jacc.2007.01.087; PMID: 17531660 19. Chamuleau S, Meuwissen M, Koch K, et al. Usefulness of fractional flow reserve for risk stratification of patients with multivessel coronary artery disease and an intermediate stenosis. Am J Cardiol 2002;89 :377–80. PMID: 11835914 20. De Bruyne B, Pijls N, Kalesan B, et al.; FAME 2 Trial Investigators. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367 :991–1001. DOI: 10.1056/ NEJMoa1408758; PMID: 25176289 21. De Bruyne B, Fearon W, Pijls N, et al. Fractional flow reserveguided PCI for stable coronary artery disease. N Engl J Med 2014;371 :1208–17. DOI: 10.1056/NEJMoa1408758 22. Pijls N, De Bruyne B, Bech G, et al. Coronary pressure measurement to assess the hemodynamic significance of serial stenoses within one coronary artery: validation in humans. Circulation 2000;102 :2371–7. PMID: 11067791 23. Tonino P, De Bruyne B, Pijls N, et al.; FAME Study Investigators.

Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360: 13–24. DOI: 10.1056/NEJMoa0807611; PMID: 19144937 24. Pijls N, Fearon W, Tonino P, et al.; FAME Study Investigators.

Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56 : 177–84. DOI: 10.1016/j.jacc.2010.04.012; PMID: 20537493 25. Hamilos M, Muller O, Cuisset T, et al. Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation 2009;120 :1505–12. DOI: 10.1161/ CIRCULATIONAHA.109.850073; PMID: 19786633 26. Fearon W, Yong A, Lenders G, et al. The impact of downstream coronary stenosis on fractional flow reserve assessment of intermediate left main coronary artery disease: human validation. JACC Cardiovasc Interv 2015;8 : 398–403. DOI: 10.1016/j.jcin.2014.09.027; PMID: 25790763 27. Ahmadi A, Stone G, Leipsic J, et al. Association of coronary stenosis and plaque morphology with fractional flow reserve and outcomes. JAMA Cardiol 2016;3 :350–7. DOI: 10.1001/ jamacardio.2016.0263; PMID: 27438119 28. Park H, Heo R, ó Hartaigh B, et al. Atherosclerotic plaque characteristics by CT angiography identify coronary lesions that cause ischemia: a direct comparison to fractional flow reserve. JACC Cardiovasc Imaging 2015;8 :1–10. DOI: 10.1016/ j.jcmg.2014.11.002; PMID: 25592691 29. Gaur S, Øvrehus K, Dey D, et al. Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemiacausing lesions. Eur Heart J 2016;37 :1220–7. DOI: 10.1093/ eurheartj/ehv690; PMID: 26763790 30. Tanaka S, Noda T, Segawa T, et al. Relation between functional stenosis and tissue characterization of intermediate coronary plaques in patients with stable coronary heart disease. J Cardiol 2010;55 :296–302.

DOI: 10.1016/j.jjcc.2009.12.001 31. Kennedy M, Fabris E, Ijsselmuiden A, et al. Combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of nonculprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT–FFR) prospective study. Rationale and design. Cardiovasc Diabetol 2016;15 :144–50. DOI: 10.1186/ s12933-016-0464-8; PMID: 27724869 32. Fox K, Clayton T, Damman P, et al.; FIR Collaboration.

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J Am Coll Cardiol 2014;64 :1894–904. DOI: 10.1016/ j.jacc.2014.07.987; PMID: 25444143 Kitabata H, Kubo T, Ishibashi K, et al. Prognostic value of microvascular resistance index immediately after primary percutaneous coronary intervention on left ventricular remodeling in patients with reperfused anterior acute ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2013;6 :1046–54. DOI: 10.1016/j.jcin.2013.05.014; PMID: 24156965 Hennigan B, Layland J, Fearon W, Oldroyd K. Fractional flow reserve and the index of microvascular resistance in patients with acute coronary syndromes. EuroIntervention 2014;10 : T55-63. DOI: 10.4244/EIJV10STA10; PMID: 25256535 Layland J, Oldroyd K, Curzen N, et al. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial. Eur Heart J 2015;36 :100–11. DOI: 10.1093/eurheartj/ ehu338; PMID: 25179764 Engstrøm T, Kelbæk H, Helqvist S, et al.; DANAMI-3 – PRIMULTI Investigators. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386 :665–71. PMID: 26347918 Complete vs culprit only revascularization to treat multivessel disease after primary PCI for STEMI (COMPLETE). Population Health Research Institute. 2015. Available at: https:// clinicaltrials.gov/ct2/show/NCT01740479 (accessed 23 November 2016) Koo B, Kang H, Youn T, et al. Physiologic assessment of jailed side branch lesions using fractional flow reserve. J Am Coll Cardiol 2005;46 :633–7. DOI: 10.1016/j.jacc.2005.04.054; PMID: 16098427 Taylor C, Fonte T, Min J. Computational fluid dynamics applied to cardiac computed tomography for noninvasive quantification of fractional flow reserve: scientific basis. J Am Coll Cardiol 2013;61 :2233–41. DOI: 10.1016/j.jacc.2012.11.083; PMID: 23562923 Nørgaard B, Leipsic J, Gaur S, et al.; NXT Trial Study Group Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol 2014;63 :1145–55. DOI: 10.1016/ j.jacc.2013.11.043; PMID: 24486266 Koo B, Erglis A, Doh J, et al. Diagnosis of ischemia-causing coronary stenoses by non-invasive fractional flow reserve computed from coronary computed tomographic angiograms.

Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study.

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JAMA 2012;308 :1237–45. DOI: 10.1001/2012.jama.11274; PMID: 22922562 Berry C, Corcoran D, Hennigan B, et al. Fractional flow reserve-guided management in stable coronary disease and acute myocardial infarction: recent developments. Eur Heart J 2015;36 :3155–64. DOI: 10.1093/eurheartj/ehv206; PMID: 26038588 Leipsic J, Yang T, Thompson A, et al. CT angiography (CTA) and diagnostic performance of noninvasive fractional flow reserve: results from the Determination of Fractional Flow Reserve by Anatomic CTA (DeFACTO) study. AJR Am J Roentgenol 2014;202 :989–94. DOI: 10.2214/AJR.13.11441; PMID: 24758651

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Ischaemic Heart Disease

Guest Editorial Controversies in Fractional Flow Reserve Ma ria C hia ra S c a l i , 1 D o r a l i s a M o r r o n e 2 a n d M a r i o M a r z i l l i 2 1. Cardiovascular Medicine Division, United Hospitals of Valdichiana, Montepulciano, Italy; 2. Cardiovascular Medicine Division, Cardio-Thoracic & Vascular Department, University of Pisa, Pisa, Italy

Abstract Fractional flow reserve (FFR) has been identified as the optimal diagnostic tool to identify significant coronary lesion. However, current evidence does not support this role. The optimal diagnostic strategy should give highly sensitive and specific results with lowest cost and accomplishing this task has been made more difficult in the era following the COURAGE trial.

Keywords Fractional flow reserve, diagnostic tool, COURAGE trial Disclosure: The authors have no conflict of interest to declare.

Acknowledgement(s): (NOTE TO DESIGN: delete this line if not provided in Word doc) Citation: European Cardiology Review, 2016;11(2):83–4 DOI: 10.15420/ecr.11.2:ED3 Correspondence: Professor Mario Marzilli, Cardiovascular Medicine Division, Cardio-Thoracic & Vascular Department, University of Pisa, Via Paradisa, 2, 56100, Pisa, Italy. E: mario.marzilli@med.unipi.it

As coronary angiography is of limited value in defining the functional significance of a stenosis, the timely article by Balanescu in this issue of European Cardiology Review rationally proposes to integrate the anatomic information with a functional assessment, either by measuring coronary flow reserve (CFR) or intracoronary artery pressure with fractional flow reserve (FFR). CFR measurements depend on the status of the microcirculation, as well as on the severity of the lesion in the epicardial vessel.1 Nowadays, FFR is considered to be the ‘gold standard’ for invasive assessment of stenosis haemodynamic impact and a useful tool for decision-making in coronary revascularisation. FFR is calculated as the ratio of distal coronary pressure to aortic pressure measured during maximal hyperaemia. A normal value for FFR is 1.0, regardless of the microcirculation status; stenoses with an FFR >0.80 are rarely associated with exercise-induced ischaemia. This provides guidance for the clinician in situations when it is not clear if a lesion of intermediate angiographic severity is the cause of ischaemia. The use of FFR was upgraded to a Class IA classification in multivessel percutaneous coronary intervention (PCI) in the European Society of Cardiology (ESC) guidelines on coronary revascularisation.2 At present, FFR is recommended as for use where noninvasive stress imaging is contraindicated, discordant, nondiagnostic or unavailable in stable ischaemic heart disease. In these conditions, FFR should be used to assess the functional significance of intermediate coronary stenosis (50–70 %) and more severe stenoses (< 90 %).3 There are, however, major pathophysiological, practical and prognostic limitations to the extensive use of FFR in the cardiac catheterisation laboratory.

• FFR determines the physiological significance of coronary stenosis, but fails to identify what is present upstream, within and downstream the stenosis, such as vulnerable blood, vulnerable plaque, coronary

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vasomotion or anatomic or dynamic microcirculation dysfunction.

All of these variables can determine myocardial ischaemia and catastrophic cardiovascular events, yet are ignored by a merely stenocentric approach.4 • The second limitation relates to the additional cost (~US$1000)5 and radiation exposure (~5 mSv, corresponding to 250 chest X-rays, in addition to the 7 mSv of a coronary angiography) associated with FFR performed in the catheterisation laboratory.6 • Findings on the prognostic impact of FFR are limited.7,8 Its impact is greater than that of assessment of coronary stenosis, but smaller than that of CFR. Concordance between FFR and CFR is low; in more than 25 % of patients, FFR and CFR do not point in the same diagnostic direction. Whereas a combination of abnormal CFR/ normal FFR values is indicative of microvascular disease, a normal CFR/abnormal FFR combination has been shown to be associated with a good prognosis.9 At present, a stenocentric approach to ischaemic heart disease is not supported by convincing data. Randomised trials, such as Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) 17 and FAME 2,8 which are often quoted to promote the use of FFR to guide revascularisation, are conspicuously lacking for CFR; those that have been completed only show, at best, some benefit for weak and soft endpoints.

Evidences are considerably weaker when hard endpoints are considered. In the FAME 1 trial, the entire difference in MI rate was attributable to events occurring during the first few days after randomisation (i.e. at the time of the initial revascularisation procedure).9 The difference in adverse events is entirely explained by fewer revascularisation procedures occurring in the FFR-guided

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Ischaemic Heart Disease arm compared with the angiography arm. In the FAME 2 trial, patient selection was based on clinical presentation of stable angina pectoris.4 One-third of included patients had no ‘significant’ (FFR <0.80) stenosis at angiography. This observation strongly challenges the association between stable angina and significant stenosis.4 The FAME 2 trial was prematurely interrupted due to excess benefit in the PCI arm. However, an unbiased evaluation of the data reveals that hard events, including death and non-fatal MI, occurred at a similar frequency across the three patient groups (no significant stenosis, significant stenosis on medical therapy and significant stenosis on medical therapy plus PCI),4 thus supporting a speculation of futility for FFR-guided PCI. In a head-to-head assessment, coronary flow velocity reserve (a prognostically efficient surrogate of CFR) showed greater prognostic value compared with FFR, thus indicating a greater importance of coronary flow than coronary pressure for prognosis.10 It is tempting to shift the focus of diagnostic evaluation upstream to the cardiac catheterisation laboratories, where in the stress echocardiography laboratory information can be obtained on regional wall motion, coronary flow velocity reserve,11 left ventricular contractility (with simple assessment of elastance reserve), patient symptoms, ECG changes and extravascular lung water (with B-lines during stress).12,13 More variables than merely coronary stenosis are involved in the determination of myocardial ischaemia, and our diagnostic protocols should be changed accordingly.4

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Montalescot G, Sechtem U, Achenbach S, for the Task Force Members. 2013 ESC guidelines on the management of stable coronary artery disease-addenda: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.

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DOI: 10.1002/ccd.25222; PMID: 24227282.

Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link!

J Am Coll Cardiol 2012;60:951–6. DOI: 10.1016/j.jacc.2012.02.082; PMID: 22954239.

Fearon WF, Bornschein B, Tonino PA, et al. Economic

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So, is there no room left in 2016 for FFR in the management of ischaemic patients? The main benefit of FFR, as consistently shown in many studies, is to avoid useless procedures. The second contribution of FFR studies is reassurance that deferring elective procedures does not expose patients to excess risk. Thus, according to current guidelines on coronary revascularisation (ESC 2013 guidance), revascularisation should be considered if a patient has intolerable angina despite optimal medical therapy.2 Under these circumstances, when patients present with an intermediate lesion in the culprit vessel, FFR may help in deciding if it is worth treating. This recommendation is consistent with the observations that no prospective randomised trial or metanalysis has shown a mortality/morbidity benefit following elective revascularisation procedures, and that FFR was not useful in predicting adverse events in one of the initial validation studies.14 In conclusion, FFR can identify a ‘haemodynamically significant’ stenosis, but this does not imply that the stenosis causes myocardial ischaemia. It has been conclusively demonstrated that the majority of patients with ischaemic heart disease do not have a signifcant stenosis and conversely, that the majority of patients with a significant stenosis do not have ischaemic heart disease. Therefore, any technique aimed at diagnosing myocardial ischaemia that focuses on the atherosclerotic obstructions and does not consider the role of functional mechanisms, microvascular dysfunction, platelet dysfunction, etc, is bound to be disappointing and misleading, including FFR. n

evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 2010;122 :2545–50.

DOI: 10.1161/CIRCULATIONAHA.109.925396; PMID: 21126973.

Ntalianis A, Trana C, Muller O, et al. Effective radiation dose, time, and contrast medium to measure fractional flow reserve. JACC Cardiovasc Interv 2010;3 :821–7. DOI: 10.1016/j. jcin.2010.06.006; PMID: 20723854.

Tonino PA, De Bruyne B, Pijls NH, for the FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360 :213–24. DOI: 10.1056/NEJMoa0807611; PMID: 19144937.

De Bruyne B, Pijls NH, Kalesan B, for the FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367 :991–1001. DOI: 10.1056/NEJMoa1205361; PMID: 22924638.

Arbad-Zadeh A. Fractional flow reserve-guided percutaneous coronary intervention is not a valid concept. Circulation 2014;129 :1871–8. DOI: 10.1161/ CIRCULATIONAHA.113.003583; PMID: 24799503.

10. van de Hoef TP, van Lavieren MA, Damman P, et al.

Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity.Circ Cardiovasc Interv 2014;7 :301–11. DOI: 10.1161/ CIRCINTERVENTIONS.113.001049; PMID: 24782198.

11. Nijjer SS, de Waard GA, van de Hoef TP, et al. Coronary pressure and flow relationships in humans: phasic analysis of normal and pathological vessels and the implications for stenosis assessment: a report from the Iberian-Dutch-English (IDEAL) collaborators. Eur Heart J 2016;37 :2069–80. DOI: 10.1093/eurheartj/ehv626. PMID: 26612582.

12. Cortigiani L, Rigo F, Gherardi S, et al. Coronary flow reserve during dipyridamole stress echocardiography predicts mortality. JACC Cardiovasc Imaging 2011;5 :1079–85. DOI: 10.1016/j.jcmg.2012.08.007; PMID: 23153906.

13. Picano E, Pellikka PA. Stress echo applications beyond coronary artery disease. Eur Heart J 2014;35 :1033–40. DOI: 10.1093/eurheartj/eht350; PMID: 24126880.

14. Chamuleau S, Meuwissen M, Koch K, et al. Usefulness of fractional flow reserve for risk stratification of patients with multivessel coronary artery disease and an intermediate stenosis. Am J Cardiol 2002;89 :377–80. PMID: 11835914.

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Ischaemic Heart Disease

Prediction of Post Percutaneous Coronary Intervention Myocardial Ischaemia Alda Huqi, Gia c i n t a G u a r i n i , D o r a l i s a M o r r o n e a n d M a r i o M a r z i l l i Cardiac Care Unit, Santa Maria Maddalena Hospital, Pisa, Italy

Abstract Following revascularisation the majority of patients obtain symptom relief and improved quality of life. However, myocardial ischaemia may recur or persist in a significant patient subset. Symptom recurrence is usually attributed to inaccurate evaluation of epicardial stenosis, incomplete revascularisation or stent failure and disease progression. However, technological advances with modern imaging and/or physiological evaluation of epicardial plaques have not solved this issue. Conversely, recent clinical studies have shown that abnormal coronary vasomotion and increased myocardial resistance are frequent determinants of post-percutaneous coronary intervention (PCI) myocardial ischaemia. Strategies to enhance prediction of post-PCI angina include proper selection of patients undergoing revascularisation, construction of clinical prediction models, and further invasive evaluation at the time of coronary angiography in those with high likelihood.

Keywords Persistent angina, percutaneous coronary intervention, ischaemic heart disease, coronary artery disease, microvascular dysfunction Disclosure: The authors have no conflicts of interest to declare.

Received: 17 October 2016 Accepted: 19 November 2016 Citation: European Cardiology Review 2016;11(2):85–9; DOI: 10.15420/ecr.2016:27:2 Correspondence: Dr Alda Huqi, Cardiac Care Unit, Santa Maria Maddalena Hospital, Borgo San Lazzero n. 5, Volterra, Pisa, Italy. E: al.huqi@gmail.com

Myocardial revascularisation in patients with stable chronic angina is performed with the aim of reducing cardiovascular death, reducing myocardial infarction (MI) and relieving angina symptoms. However, contrary to expectations, modern therapy with percutaneous coronary intervention (PCI) has not had a significant impact on hard outcomes.1–5 Indeed, as also summarised in a recently published meta-analysis,6 PCI in stable angina patients does not reduce cardiovascular death or MI. Therefore, symptom relief remains the final rationale for suggesting our chronic angina patients undergo PCI. Major international guidelines for the management of chronic stable angina recommend a revascularisation procedure in patients with obstructive coronary artery disease (CAD), high risk features at noninvasive evaluation, and lack of symptom control under maximally tolerated medical therapy.7,8 Following revascularisation the majority of patients obtain symptom relief and improved quality of life.

Nonetheless, angina symptoms and/or ischaemia may recur or persist in a significant patient subset.9,10 The reported rate for post-PCI angina and/or ischaemia is variable, and ranges from 15 % to more than 50 %.2–4,11–15 These findings have also been confirmed in more recently published studies that adopted modern therapeutic strategies (see Table 1). 5,16,17 Besides reduced quality of life, symptom and/or ischaemia recurrence is associated with adverse cardiovascular events and increased healthcare costs.18,19 Therefore, identification and treatment of this patient population is warranted.

In this paper, we discuss potential pathophysiological mechanisms underlying post-PCI myocardial ischaemia and propose strategies to enhance their identification prior to the revascularisation procedure.

© RADCLIFFE CARDIOLOGY 2016

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Pathophysiological Basis of Post-percutaneous Coronary Intervention Angina and Ischaemia The traditional understanding of stable CAD is that of a disease causing exercise- and/or stress-related symptoms due to narrowing of ≥50 % in the left main coronary artery and/or of ≥70 % in ≥1 of the major arteries.7 For this reason, symptom recurrence following identification and removal of the coronary stenosis is regarded with great suspect. Indeed, post-PCI symptoms are frequently considered as either non-cardiac (i.e. of gastrointestinal or skeletal origin) or as non-ischaemic (i.e. stretch pain). Conversely, once the ischaemic nature is documented, it is attributed to a combination of procedurerelated factors (i.e. restenosis, incomplete revascularisation, atherosclerotic disease progression, epicardial coronary spasm, etc.), patient-related factors (left ventricular hypertrophy, aortic valve disease, etc.) or factors related to the methodology used to investigate persistent angina and/or ischaemia.20–23 However, in most series, the reported restenosis rate after stent implantation is <10 % and usually occurs 2–3 months after index PCI.24,25 Similarly, the extent to which incomplete revascularisation and disease progression contribute to persistent angina is much lower than the rate of persistent angina reported in the literature. In a registry study of 1,755 consecutive patients undergoing PCI, 26 % reported angina at 1-year follow-up. Patients with incomplete revascularisation reported a slightly higher angina rate (32 %). However, angina also recurred in 23 % of patients with complete revascularisation. 26 In addition, following revascularisation, the rate of altered results at non-invasive testing despite no epicardial obstructions at coronary angiography is higher than in patients with initial angina diagnosis.27–29 Unfortunately, these data have not generated scientific curiosity. On the contrary, positive non-invasive test results are often considered

Access at: www.ECRjournal.com

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Ischaemic Heart Disease Table 1: Principal Clinical Trials on Patients with Ischaemic Heart Disease Study

Follow-up

Type of

Patients with

Duration (years)

Intervention

Angina (%)

RITA-2

1

PCI, GDMT

38 PCI, 57 GDMT

MASS-II

1

CABG, PCI, GDMT

12 CABG, 21 PCI,

BARI

1

CABG, PCI

10 CABG, 30 PCI

COURAGE

5

PCI, GDMT

26 PCI, 28 GDMT

FAME

2

Angiography-

24 angiography-

guided PCI,

guided PCI,

FFR-guided PCI

20 FFR-guided PCI

stress distal to the stenosis, with decreased nitric oxide activity37 or a low perfusion pressure that negatively influences microvascular remodelling and the capacity of maximal vasodilation after restoration of a normal basal coronary blood flow can also be the cause of persistent symptoms.38,39 Indeed, as documented in the study by Li and colleagues, a PCI-specific effect cannot fully explain the findings also observed in the reference vessels.16

54 GDMT

Patients with symptom persistence/recurrence in main clinical trials, expressed in percentage. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; COURAGE = Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; FAME = Fractional Flow Reserve Versus Angiography for Multivessel Evaluation; FFR = fractional flow reserve; GDMT = guideline-directed medical therapy; MASS-II = Medicine, Angioplasty, or Surgery Study; PCI = percutaneous coronary intervention; RITA-2 = Randomized Intervention Treatment of Angina-2.

’false positive‘ and, for this reason, routine clinical assessment by means of non-invasive testing is not recommended within 2 years from index PCI and within 5 years from coronary bypass surgery in some countries.27,28,30–33 In order to control for all these confounding factors, we conducted an observational study on a highly selected, chronic angina patient population, undergoing complete PCI. 17 Patients with valvular dysfunction, primary cardiomyopathy, or other conditions known to interfere with electrocardiographic interpretation, were excluded.

We adopted an identical and serially repeated clinical evaluation with exercise stress testing and quality of life questionnaire at baseline and at early (1 month), medium (6 months) and long-term (12 months) time points after index PCI, thereby increasing the probability of obtaining highly reproducible and reliable stress test outcomes. Yet, of the 198 patients enrolled in the study, about one-third suffered angina with impaired quality of life and had a positive result at control followup visits with stress testing.

Microvascular Dysfunction as a Cause of Persistent Angina Li et al. went a step further and hypothesised that microvascular dysfunction was the cause of post-PCI angina and/or ischaemia.16 They measured thermodilution-derived coronary flow reserve (CFR) and hyperaemic index of myocardial resistance (IMR) in 39 subjects with chest pain and 12 control subjects who were asymptomatic after PCI with angioplasty and stenting. Measurements were taken in the culprit vessel and in a non-culprit reference artery. No restenosis was documented in the study participants. Compared with the control group, patients with persistent symptoms had a higher resting IMR in both culprit and reference arteries. Persistent angina patients also had a higher hyperaemic IMR and a lower CFR, with 54 % of them displaying a CFR of <2.5. The authors concluded that coronary microvascular dysfunction was responsible for the post-PCI myocardial ischaemia in a significant part of these patients. The effect that PCI with stenting exerts on microvascular function is supported by conflicting evidence.16,34,35 Revascularisation is associated with microembolism and/or activation of platelets or microparticles, ischaemia-reperfusion injury, and exaggerated liberation of reactive oxygen species that lead to functional and/or structural dysfunction, and thus has been hypothesised to induce microvascular dysfunction.36 On the other hand, chronic low shear

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Abnormal Coronary Vasomotion as a Cause of Persistent Angina In another study, Ong and colleagues sought to determine the rate of abnormal coronary vasomotion to intracoronary acetylcholine (ACH) administration in 104 consecutive patients with persistent angina despite successful PCI.34 Focal or diffuse epicardial coronary diameter reduction of >75 % in any epicardial coronary artery segment and/or reproduction of patient’s symptoms/ electrocardiogram (EKG) abnormalities (microvascular spasm) were considered positive.

Abnormal coronary vasomotion in response to ACH was found in 66 % of study participants, with 73 % of them displaying enhanced epicardial coronary vasomotion and 27 % displaying microvascular spasm.

Other Causes of Persistent Angina Thus, when further investigated, an alternative cause for myocardial ischaemia (i.e. microvascular dysfunction, vasospasm) is identified in the majority of patients with post-PCI myocardial ischaemia. However, going back to the study by Li et al., only slightly more than 50 % of subjects with persistent symptoms had invasive measurements that would reach criteria for abnormal microcirculation, whereas the cause of persistent angina in the remaining patients remains undetermined.16 Similarly, only 66 % of patients displayed abnormal coronary vasomotion in the study by Ong et al.34 Other causes of persistent angina include incomplete revascularisation, endothelial dysfunction, inflammation, platelet dysfunction, coagulation abnormalities, and various combinations of them.40,41 All these factors are in line with the proposed multifactorial model for stable ischaemic heart disease (IHD), where obstructive CAD constitutes only one among a myriad of other factors.42 In line with considerations, the latest major international guidelines recognise that factors such as microvascular dysfunction and vasospasm can all induce myocardial ischaemia. However, according to the same guidelines, these factors are to be investigated only when obstructive CAD is excluded, as if epicardial stenosis conferred immunity versus the other mechanisms.

In fact, the lack of benefit of PCI continues to be related to the inaccurate assessment of epicardial coronary obstructions.43 As such, imaging modalities that assess epicardial coronary plaques have gained increasing relevance.

Fractional flow reserve (FFR) is the most popular modality used to assess the physiological effects of epicardial plaques. The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation-2 (FAME-2) trial reported on the efficacy of FFR-guided PCI versus medical therapy in stable coronary disease.44 Patients with a coronary stenosis that produced a significant drop in pressure (FFR of 0.80 or less) in a major coronary artery were included in the study. Similar to the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial,14 the rate of revascularisation was the only outcome that significantly differed between treatment groups. In a

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Post Percutaneous Coronary Intervention Myocardial Infarction

registry-based study involving more than 7,000 patients referred for coronary angiography, those undergoing FFR measurements tended to have lower rates of death/MI (hazard ratio [HR]: 0.85, 95 % confidential interval [CI] [0.71–1.01]; p<0.060). However, among those patients undergoing FFR, the rate of MI was lower in those whom PCI was deferred. In particular, deferral of PCI guided by FFR was associated with a reduced rate of MI (HR: 0.46, 95 % CI [0.26–0.82]; P<0.008).

Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are two other imaging techniques that have been used to guide and optimise PCI. These modalities provide complementary tomographic imaging of the vessel wall and allow for quantification of atheroma burden and assessment of arterial remodelling. However, by improving anatomic assessment, such modalities have further evidenced the lack of a direct relationship between stenosis severity and myocardial perfusion.45–47 Indeed, hybrid imaging physiological studies have reinforced the concept that stenosis severity does not reliably predict the effects on myocardial blood flow48–51 and that factors other than stenosis severity are better predictors of adverse events.52,53 Indeed, in contrast with the linear model originally proposed by Gould et al.,54 when tested in the clinical settings, the relationship between stenosis severity and the impact on coronary myocardial blood flow is characterised by large scatter.45,46 Actually, while many patients with angina do not display obstructive CAD, stable coronary plaques may also be completely clinically silent.18,42,55 In a large registry study of 15,888 patients referred for coronary angiography between 1996 and 2010, the highest rate of obstructive CAD was distributed amongst patients with typical angina. However, obstructive CAD was also identified in 30–50 % of patients with no angina. Therefore, what is the reason to believe that all symptoms in those with typical angina were provoked by obstructive CAD.56 Similarly, it is conceivable that not all patients with epicardial obstructions will benefit from stenosis removal. Indeed, patients with post-PCI angina suffer myocardial ischaemia that is independent from stenosis removal. Despite evidence of an obstructive CAD, alternative mechanisms were responsible for myocardial ischaemia in this patient subset. While obstructive CAD did not prevent their occurrence, its removal enhanced their discovery.

Predicting Post-percutaneous Coronary Intervention Myocardial Ischaemia As mentioned, patients with persistent angina constitute a significant, although variable, patient population subset. Their recognition is further acknowledged by the conduction of studies that have aimed to determine the underlying mechanisms. However, at the current state of knowledge, we are not able to predict which patients will or will not benefit from revascularisation, thereby constituting the next big challenge.

According to the new paradigm for stable IHD, myocardial ischaemia should be considered a multifactorial disease. These factors appear neither necessary nor sufficient to induce myocardial ischaemia. This is the reason why unifactorial disease-centred care (i.e. search for and removal of obstructive CAD) has been shown to be ineffective in some patients with suspected IHD. Indeed, PCI in stable angina is a ’one-size-fits-all’ approach, useful for patients for whom epicardial stenosis is the cause of symptoms but not helpful for those in whom it is an innocent bystander. Major international guidelines state that revascularisation should be performed in patients with persistent symptoms despite guideline-directed medical therapy (GDMT). 57

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Figure 1: Management Pathway of Angina Patients Including Strategies for Early Identification of Probable Persistent Ischaemia Implement and titrate GDMT for an adequate period of time

continue GDMT only Treatment success

All patients with angina at initial evaluation Treatment failure

collect outcomes for constructing clinical prediction models proceed to catheterisation

Patients with known predictors of persistent angina

Patients with unknown predictors of persistent angina

assess baseline vasomotion and/or microcirculation

proceed to PCI as necessary

GDMT = guideline-directed medical therapy; PCI = percutaneous coronary intervention.

However, revascularisation is often pursued without attempting implementation and/or titration of adequate medical therapy. In a CathPCI Registry® study including 467,211 patients with stable CAD undergoing PCI, less than half were receiving GDMT before PCI and approximately two-thirds were receiving GDMT at discharge following PCI.58 Factors favouring an initial revascularisation strategy include referral bias, financial gain, poor understanding of pathophysiological mechanisms, individual physician belief of what might benefit the patient, and patient perception of the potential benefit of the procedure.59 PCI in stable angina does not prevent death or MI, does not make the asymptomatic patient feel better and has rare but potentially dangerous complications.6 However, most patients undergoing PCI believe that it will reduce the risk of MI and death,60 and cardiologists continue to perform PCI in patients with minimal or no angina.61 Overrated use with improper selection of patients that may benefit from revascularisation may have contributed to the lack of full-scale beneficial effects of angioplasty. We believe that a more comprehensive utilisation of medical therapy would help understand and predict the effects that a treatment strategy incurs.

In addition, population based studies could be used to construct clinical prediction models for persistent angina. For instance, baseline angina frequency has been shown to be a strong predictor of recurrent angina despite medical treatment or revascularisation. 9 Smoking status,62 younger age, and more progressive and severe symptoms prior to revascularisation are other determinants of persistent angina.19 Finally, early identification of patients who are more likely to have persistent angina could be attempted at the time of coronary angiography (i.e. assessment of baseline coronary vasomotor response to ACH or baseline coronary microvascular resistance) (see Figure 1).

In a prospective study of 55 patients undergoing PCI for stable angina, resting status of the coronary microcirculation was the strongest independent predictor of post-PCI microvascular resistance.63

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Ischaemic Heart Disease Conclusion Although revascularisation can improve ischaemic symptoms, its effects are not unconditional and currently predictable. These findings are in line with the multidimensional model for IHD, with obstructive CAD constituting only one among other determinants. Therefore, evidence of an obstructive coronary plaque should not be automatically

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DOI: 10.1016/j.jacc.2007.05.003; PMID: 17616306 Mancini GB, Gosselin G, Chow B, et al. Canadian Cardiovascular Society guidelines for the diagnosis and management of stable ischemic heart disease. Can J Cardiol 2014;30 :837–49. DOI: 10.1016/j.cjca.2014.05.013; PMID: 25064578 Ong P, Athanasiadis A, Perne A, et al. Coronary vasomotor abnormalities in patients with stable angina after successful stent implantation but without in-stent restenosis. Clin Res Cardiol 2014;103 :11–9. DOI: 10.1007/s00392-013-0615-9; PMID: 23995322 De Maria GL, Cuculi F, Patel N, et al. How does coronary stent implantation impact on the status of the microcirculation during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction? Eur Heart J 2015;36 :3165–77. DOI: 10.1093/ eurheartj/ehv353; PMID: 26254178; PMCID: PMC4664836 Niccoli G, Scalone G, Lerman A, Crea F. Coronary microvascular obstruction in acute myocardial infarction.

Eur Heart J 2016;37 :1024–33. DOI: 10.1093/eurheartj/ehv484; PMID: 26364289 Anderson TJ. Chest Pain After Percutaneous Coronary Intervention: More Than Meets the Eye. Can J Cardiol 2015;31 :960–2. DOI: 10.1016/j.cjca.2015.04.010; PMID: 26100215 Piek JJ, Boersma E, Voskuil M, et al. The immediate and longterm effect of optimal balloon angioplasty on the absolute coronary blood flow velocity reserve. A subanalysis of the DEBATE study. Doppler Endpoints Balloon Angioplasty Trial Europe. Eur Heart J 2001;22 :1725–32. DOI: 10.1053/ euhj.2000.2587; PMID: 11511122 van Liebergen RA, Piek JJ, Koch KT, et al. Immediate and long-term effect of balloon angioplasty or stent implantation on the absolute and relative coronary blood flow velocity reserve. Circulation 1998;98 :2133–40. PMID: 9815867 el-Tamimi H, Davies GJ, Sritara P, et al. Inappropriate constriction of small coronary vessels as a possible cause of a positive exercise test early after successful coronary angioplasty. Circulation 1991;84 :2307–12. PMID: 1959186 Hofma SH, van der Giessen WJ, van Dalen BM, et al.

Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J 2006;27 : 166–70. DOI: 10.1093/eurheartj/ehi571; PMID: 16249221 Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol 2012;60 :951–6. DOI: 10.1016/ j.jacc.2012.02.082; PMID: 22954239 Tonino PA, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55 :2816–21.

DOI: 10.1016/j.jacc.2009.11.096; PMID: 20579537 De Bruyne B, Pijls NH, Kalesan B, et al. Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease. N Engl J Med 2012;367 :991–1001.

DOI: 10.1056/NEJMoa1205361; PMID: 22924638 Uren NG, Melin JA, De Bruyne B, et al. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med 1994;330 :1782–8. DOI: 10.1056/ NEJM199406233302503; PMID: 8190154 Uren NG, Marraccini P, Gistri R, et al. Altered coronary vasodilator reserve and metabolism in myocardium subtended by normal arteries in patients with coronary artery disease. J Am Coll Cardiol 1993;22 :650–8. PMID: 8354794 Ahmadi A, Stone GW, Leipsic J, et al. Association of Coronary Stenosis and Plaque Morphology With Fractional Flow Reserve and Outcomes. JAMA Cardiol 2016;1 :350–7. DOI: 10.1001/jamacardio.2016.0263; PMID: 27438119 Naya M, Murthy VL, Blankstein R, et al. Quantitative relationship between the extent and morphology of coronary atherosclerotic plaque and downstream myocardial perfusion. J Am Coll Cardiol 2011;58 :1807–16. DOI: 10.1016/ j.jacc.2011.06.051; PMID: 21996395; PMCID: PMC3951833 Kang SJ, Lee JY, Ahn JM, et al. Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity.

Circ Cardiovasc Interv 2011;4 :65–71. DOI: 10.1161/ CIRCINTERVENTIONS.110.959148; PMID: 21266708 Waksman R, Legutko J, Singh J, et al. FIRST: Fractional Flow Reserve and Intravascular Ultrasound Relationship Study. J Am Coll Cardiol 2013;61 :917–23. DOI: 10.1016/ j.jacc.2012.12.012; PMID: 23352786 Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemiacausing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter

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perfusion. J Am Coll Cardiol 2011;58 :1807–16. DOI: 10.1016/ j.jacc.2011.06.051; PMID: 21996395; PMCID: PMC3951833 56. Vavalle JP, Shen L, Broderick S, et al. Effect of the Presence and Type of Angina on Cardiovascular Events in Patients Without Known Coronary Artery Disease Referred for Elective Coronary Angiography. JAMA Cardiol 2016;1 :232–4. DOI: 10.1001/jamacardio.2016.0076; PMID: 27437900 57. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27 :1341–81. DOI: 10.1093/eurheartj/ehl001; PMID: 16735367 58. Borden WB, Redberg RF, Mushlin AI, et al. Patterns and intensity of medical therapy in patients undergoing percutaneous coronary intervention. JAMA 2011;305 :1882–9.

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PMID: 27019878 60. Kureshi F, Jones PG, Buchanan DM, et al. Variation in patients’ perceptions of elective percutaneous coronary intervention in stable coronary artery disease: cross sectional study. BMJ 2014;349 :g5309. DOI: 10.1136/bmj.g5309; PMID: 25200209; PMCID: PMC4157615 61. Rothberg MB, Sivalingam SK, Ashraf J, et al. Patients’ and cardiologists’ perceptions of the benefits of percutaneous coronary intervention for stable coronary disease. Ann Intern Med 2010;153 :307–13. DOI: 10.7326/0003-4819-1535-201009070-00005; PMID: 20820040 62. Jang JS, Buchanan DM, Gosch KL, et al. Association of smoking status with health-related outcomes after percutaneous coronary intervention. Circ Cardiovasc Interv 2015;8 .pii: e002226. DOI: 10.1161/ CIRCINTERVENTIONS.114.002226; PMID: 25969546; PMCID: PMC4435805 63. Layland J, Judkins C, Palmer S, et al. The resting status of the coronary microcirculation is a predictor of microcirculatory function following elective PCI for stable angina. Int J Cardiol 2013;169 :121–5. DOI: 10.1016/j.ijcard.2013.08.092; PMID: 24095159

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Optical Coherence Tomography For the Detection of the Vulnerable Plaque Konstantinos Toutouzas, Antonios Karanasos and Dimitris Tousoulis Athens Medical School, Hippokration Hospital, Athens, Greece

Abstract Morphological characteristics of the atheromatous plaque have been associated with the development of plaque rupture and the pathogenesis of acute coronary syndromes (ACS). Plaques with a specific morphological phenotype that are at high risk of causing ACS are called vulnerable plaques, and can be identified in vivo through the use of intracoronary imaging. Optical coherence tomography (OCT) is a high-resolution intravascular imaging modality that enables detailed visualization of atheromatous plaques. Consequently, OCT is a valuable research tool for examining the role of morphological characteristics of atheromatous plaques in the progression of coronary artery disease and plaque destabilisation, which leads to the clinical manifestation of ACS. This article summarises the pathophysiological insights obtained by OCT imaging in the formation and rupture of the vulnerable plaque.

Keywords optical coherence tomography, intravascular ultrasound, intravascular imaging, vulnerable plaque, plaque rupture, percutaneous coronary intervention, acute myocardial infarction, acute coronary syndrome Disclosure: AK has received research support from St. Jude Medical. KT and DT have no conflicts of interest to declare.

Received: 23 October 2016 Accepted: 21 November 2016 Citation: European Cardiology Review 2016;11(2):90–5; DOI: 10.15420/ecr.2016:29:2 Correspondence: Konstantinos Toutouzas, Hippokration Hospital, 114, Vas.Sofias Avenue, 11528, Athens, Greece. E: ktoutouz@gmail.com

Acute coronary syndromes (ACS) comprise a major cause of morbidity and mortality. The almost-exclusive cause of ACS, including unstable angina, acute myocardial infarction (AMI) with or without ST-segment elevation, and sudden cardiac death, is atherothrombosis. Pilot pathological studies have identified the pathophysiological processes implicated in the destabilisation and thrombosis of atheromatous plaques.1–3 According to the current understanding of ACS, plaques with specific morphological characteristics are more prone to rupture and development of thrombosis, which subsequently leads to the clinical manifestation of ACS. However, pathological studies are limited by their cross-sectional and teleological nature, thus imaging tools have been developed that can assess such morphological characteristics in vivo. Intracoronary imaging techniques can assess coronary plaques beyond luminal assessment (i.e. coronary angiography) and can visualise atheromatous plaques in vivo.4 Among these techniques, due to its high resolution (~15 µm) optical coherence tomography (OCT) can identify the majority of the morphological characteristics of stable and complicated atheromatous plaques, including precise measurement of the thickness of the overlying fibrous plaque and a high sensitivity for thrombus detection.5 Thus, OCT offers a valuable tool for obtaining in vivo insights into the pathomechanisms of ACS.6

erosion is defined as the presence of thrombosis in the absence of plaque thrombosis, often with absence of an endothelial layer at the thrombosed sites.2 Calcified nodules is a less common cause of coronary thrombosis, characterised by thrombus formation over nodular calcification protruding into the lumen through a disrupted thin fibrous cap.

Plaques that are at high risk of undergoing acute thrombosis are called vulnerable plaques and bear morphological resemblance to the aforementioned plaques.7 Nevertheless, eroded plaques do not have specific distinct morphological characteristics; therefore, the identification of erosion-prone plaques is challenging. In contrast to eroded plaques, plaques undergoing rupture have distinct morphological characteristics, including a large necrotic core, a thin (<65 µm in pathology series) and inflamed fibrous cap, high plaque burden, intimal vascularisation, inflammatory cell infiltration and spotty calcification.8 These characteristics are also observed in another type of plaque, called thin cap fibroatheroma (TCFA), which is considered the precursor of the ruptured plaque, and thus the main morphological subtype of vulnerable plaques.8

Pathological Paradigm of the Vulnerable Plaque

Optical Coherence Tomography Features of Stable Coronary Plaques

Post-mortem studies of sudden cardiac death victims have shown that the major pathological substrates of coronary thrombosis are plaque rupture in 60–70 % of cases, plaque erosion in 20–30 % and thrombosis triggered by calcified nodules in 2–5 %.1–3 Plaque rupture, the most frequent mechanism of coronary thrombosis, involves disruption of a thin fibrous cap that overlies a large necrotic core, causing the thrombogenic contents of the necrotic core to come into contact with the bloodstream and trigger thrombus formation. Plaque

Post-mortem OCT studies have defined the optical appearance and morphological characterisation of the plaque,9–14 showing an overall good agreement with histology and high reproducibility (see Table 1).

OCT can identify normal wall segments and early atherosclerotic lesions,15,16 and also perform tissue characterisation in advanced atherosclerotic lesions (see Table 2).5 The major plaque types identified

by OCT are fibrous plaques, appearing as a signal-rich, homogeneous region with low signal attenuation; fibrocalcific plaques, appearing

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Table 1: Sensitivity and Specificity of Optical Coherence Tomography For Detection of Different Plaque Types in Pathological Studies Fibrous plaque (%)

Fibroatheroma (%)

Fibrocalcific plaque (%)

Sensitivity

Specificity

Sensitivity

Specificity

Sensitivity

Specificity

Yabushita et al.9

71–79

97–98

90–94

90–92

95–96

97

Manfrini et al.11

83

82

45

83

68

76

Kawasaki et al.

98

94

95

98

100

100

Rieber et al.10

64

88

77

94

67

97

Kume et al.13

79

99

85

94

96

88

Brown et al.14

N/A

N/A

82

93

63

98

12

N/A = not applicable.

as a signal-poor heterogeneous region, with sharp borders and low signal attenuation; and necrotic core, which appears as a signal-poor region, with diffuse borders and high signal attenuation within a lesion that is covered by a fibrous cap.5,9 Fibroatheroma has been defined as a plaque with a necrotic core and a fibrous cap. Importantly, the thickness of the fibrous cap can be precisely measured by OCT.17,18 A thin-cap fibroatheroma identified by OCT is defined as a fibroatheroma covered by a thin fibrous cap; the current threshold of thin cap is the extrapolated by histology value of 65 µm, although the in vivo optimal threshold is controversial. Mixed plaques identified by OCT are those with more than one plaque morphology within a single cross-sectional frame. Additional tissue components that can be identified by OCT include macrophages that are characterised by bright reflectance and high signal attenuation, and intimal vasculature that appears as sharply delineated signal-poor voids within the intima.5,19 Figure 1

Table 2: Stable and Unstable Plaque Morphology by Optical Coherence Tomography

demonstrates the main plaque types by OCT and a comparison of OCT with other invasive imaging modalities is presented in Table 3.

Unstable plaque

Stable plaque Fibrous plaque

Signal-rich, homogeneous region with low signal attenuation

Fibrocalcific plaque

Signal-poor heterogeneous region, with sharp borders and low signal attenuation

Fibroatheroma

Plaque with necrotic core, defined as a signalpoor region, with diffuse borders and high signal attenuation, and a fibrous cap

Thin-cap fibroatheroma

Fibroatheroma covered by a thin fibrous cap (<65 µm)

Macrophages

Bright reflectance and high signal attenuation

Intimal vasculature

Sharply delineated signal-poor voids within the intima

Thrombus

Intraluminal mass attached to luminal surface or floating within the lumen with high (red thrombus)

Optical Coherence Tomography Features of Unstable Coronary Plaques Importantly, OCT can also be used for tissue characterisation in thrombosed plaques by imaging thrombus as an intraluminal mass attached to the luminal surface or floating within the lumen.20 Plaque rupture can be identified by OCT as a fibroatheroma with fibrous cap disruption over necrotic core, with or without cavity formation.5 While plaque erosion is defined as a plaque with thrombus and no evidence of rupture in multiple adjacent frames, although due to the presence of red thrombus, plaque rupture can be obscured, which can lead to an underestimation of its incidence in lesions with red thrombus.

Thrombosis of calcified nodules can be identified as evidence of thrombus in conjunction with calcium protruding into the lumen, frequently forming sharp, jutting angles.21

or low (white thrombus) signal attenuation Rupture

Fibroatheroma with fibrous cap disruption over necrotic core, with or without cavity formation

Erosion

Plaque with thrombus and no evidence of rupture in multiple adjacent frames

Calcified nodules

Thrombus in conjunction with calcium protruding into the lumen, frequently forming sharp, jutting angles

Figure 1: Plaque Morphology By Optical Coherence Tomography

Plaque Morphology and Clinical Presentation As OCT can accurately image thrombosed plaques, a number of OCT studies have focused on examining pathophysiological aspects of vulnerable plaques, including mechanisms of plaque formation, progression and destabilisation. It has been shown by OCT that vulnerable plaque morphology with thin fibrous cap and OCT-detected TCFA is more frequent in unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI) compared with stable angina.22,23 Moreover, OCT can more accurately assess complicated plaque morphology and thrombus in ACS compared with intravascular ultrasound (IVUS) or coronary angioscopy,24 enabling the evaluation of the incidence of pathomechanisms of ACS in an in vivo setting.25 In an in vivo OCT study of ACS, plaque rupture was identified in the culprit lesion of 44 % of

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A: Normal vessel; B: Fibrous plaque; C: Fibroatheroma (minimum fibrous cap thickness: 180 μm); D: Thin-cap fibroatheroma (minimum fibrous cap thickness: 60 mm); E: Fibrocalcific plaque; F: Mixed plaque with necrotic core and calcification. Ca = calcifications; NC = necrotic core.

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Ischaemic Heart Disease Table 3: Comparison of OCT with Other Modalities For Detection and Quantification of Vulnerable and Unstable Plaque Components Plaque

Expansive

Necrotic

Fibrous

burden

remodelling

core

cap

Greyscale IVUS

+++

+++

±

–

OCT

+

+

++

IVUS-NIRS

+++

+++

+++

Macrophages

Intimal

Spotty

vasculature

calcification

–

–

++

+++

+

+

±

–

–

Thrombus

Plaque

Calcified

rupture

nodules

+

++

+

+++

+++

+++

+++

++

+

++

+

IVUS = intravascular ultrasound; IVUS-NIRS = combined intravascular ultrasound and near-infrared spectroscopy; OCT = optical coherence tomography.

the patients, erosion in 31 %, thrombosis of calcified nodules in 8 %, and other causes (including subocclusive stenosis, dissection and coronary spasm) in 17 %,26 showing a discordance with post-mortem studies. Of note, plaque rupture was more common in STEMI, in contrast to erosion, which was more common in patients with non-ST elevation ACS and calcified nodules that were exclusively observed in non-ST elevation ACS. Differences in morphological characteristics of the ruptured plaque also translate into differences in clinical presentation. Ruptured plaques of patients with STEMI are associated with a greater extent of cap disruption and a smaller minimal lumen area compared with ruptured plaques of patients with NSTEMI.27,28 Similarly, ruptured culprit plaques of ACS had a lower lumen area in comparison with non-culprit plaques in the same patients who had undergone silent rupture.29 Moreover, asymptomatic patients with silent plaque rupture on OCT examination had a higher minimal lumen area than patients with non-ST-segment elevation ACS with culprit lesion plaque rupture.30 Collectively, these studies provide indirect evidence that the pre-existing lumen narrowing might also contribute to the clinical manifestation following plaque rupture. Morphological differences in ruptured plaques have also been found between ruptured culprit plaques of patients with exercise-triggered ACS and ruptured culprit plaques of patients with rest-onset ACS, where patients with exercisetriggered ACS had a higher cap thickness and higher incidence of rupture at the shoulder of the plaque.31 Finally, the presence of culprit lesion rupture in patients with ACS has been associated with lower incidence of prodromal symptoms compared with patients without evidence of culprit plaque rupture.32

Morphology of the Vulnerable Plaque: In Vivo Measurement of Fibrous Cap OCT has shown an association of positive remodelling of the culprit lesion with TCFA morphology and inflammation,33,34 both being important features of the vulnerable plaque as shown in pathological and in vivo IVUS studies.8,35 Furthermore, OCT has been used for identifying a critical value of cap thickness that characterises ruptureprone plaques in vivo. Although autopsy series have shown that ruptured caps have a mean thickness of 23 ± 19 µm, with 95 % being thinner than 64 µm,1 the overestimation of cap thickness by OCT in comparison with histology17 and the effect of anisotropic tissue shrinkage in histology18,36 indicate that these thresholds might not be applicable in an in vivo setting. OCT studies of ruptured plaques have shown that cap thickness in ruptured plaques can be as high as 160 µm,27,31 and it is consistently thinner in the rupture site compared with the minimal lumen area site.27 The current consensus for defining thin cap by OCT is using the histology-derived threshold of 65 µm.

However, it has been shown that a fibrous cap thickness of 67 µm has only 83 % sensitivity and 77 % specificity for discriminating between ruptured and non-ruptured plaques in vivo.37 Therefore, not only

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fibroatheromas with cap thickness <65 µm, but also those with cap thickness ≤100 µm, could be prone to rupture.

Localisation of Vulnerable Plaques Knowledge of spatial distribution of vulnerable plaques may lead to more effective screening of these plaques. Angiographic studies have shown that most STEMI events tend to cluster within the proximal portion of coronary artery,38 matching the distribution of coronary atherosclerosis.39 Similarly, thin-cap fibroatheromas and ruptured plaques are localised in focal spots within the proximal third of coronary art, as shown in pathological studies.40,41 OCT studies have also tried to assess plaque morphology in relation to plaque localisation. OCT can be used for assessment of plaque morphology in all coronary vessels including left main lesions,42 although imaging of true ostial lesions (i.e. ostial left main and ostial right coronary artery) might be more challenging and require more imaging attempts also with withdrawal of the guiding catheter to the aorta.43–46 Preliminary OCT studies have also demonstrated a localisation of TCFAs at the proximal segment of coronary arteries,31,47 while our group has further demonstrated that culprit lesions of patients with ACS located in the proximal 30 mm of coronary arteries were more often associated with rupture and TCFA morphology compared with the more distal lesions, indicating that plaque rupture is the main pathomechanism for ACS in these proximal lesions.48 This knowledge of the spatial distribution of the high-risk plaques can be potentially useful in the future for the development of preventive treatment strategies.49–51

Multiple Coronary Lesion Instability in Acute Coronary Syndromes Although ACS are in principle focal manifestations arising from a single lesion, multiple lesion instability is commonly observed in atherothrombosis.52–54 Thus, non-culprit lesions of patients with MI have a more complex angiographic morphology and are associated with rapid lesion progression and increased event rates at follow-up.55,56 In addition, patients with STEMI undergoing primary percutaneous coronary intervention of the culprit lesion with additional prophylactic revascularisation of non-culprit lesion with >50 % stenosis had fewer events than patients with culprit-only treatment.57 Based on these observations, it has been hypothesised that non-culprit lesions of patients with ACS have more unstable plaque morphology than lesions of stable patients. OCT studies have further shown increased incidence of non-culprit lesion TCFA and thrombus, and a higher incidence of multiple TCFA lesions in non-culprit lesions of patients with AMI compared with non-culprit lesions of patients with stable angina.23,58 Furthermore, non-culprit lesions of patients with AMI have a higher lipid content, a thinner fibrous cap and a higher incidence of macrophage infiltration and thrombus, in conjunction with higher incidence of TCFA.59 This is mainly observed in patients with rupture of the culprit plaque as pathomechanism for the ACS,60 and is more pronounced in patients with diabetes, in whom the incidence

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of non-culprit lesion TCFA and rupture is higher than in those without diabetes.61

Figure 2: Features of Non-culprit Plaque Vulnerability by Optical Coherence Tomography

Vulnerable Plaques and Thrombolytic Therapy In OCT studies, vulnerable plaque morphology has also been associated with impaired flow after thrombolytic therapy administration, where increased lipid content, thinner fibrous cap and plaque rupture were more common among patients without complete flow restoration compared with those with complete flow restoration. Although the reason behind this observation is not entirely clear, increased thrombogenicity of vulnerable plaques due to an exaggerated inflammatory reaction has been speculated to play an important role.62 Furthermore, in patients with STEMI with a ruptured culprit lesion, the residual thrombus burden by OCT 1 day after fibrinolysis was higher than in patients with erosion of the culprit lesion, with the presence of white thrombus at the site of the rupture,63 thus underscoring the importance of the underlying plaque morphology in STEMI as a major determinant of the response to thrombolytic therapy.

Neoatherosclerosis and the Vulnerable Plaque The long-term follow-up of both bare metal and drug-eluting stents has demonstrated that these devices are subject to failure, and have long intervals after implantation (up to 15–20 years).64–66 Pathological studies together with in vivo OCT observations have demonstrated a variety in the neointimal patterns observed at follow-up after stent implantation, which resemble components of native atherosclerosis, and imply the atherosclerotic change of the neointimal tissue.67–71 Neoatherosclerosis has been defined by pathological studies as the presence of clusters of lipid-laden foamy macrophages with or without necrotic core formation, and/or calcification within the neointimal tissue of stented segments.68,72 Several OCT studies have demonstrated the association of neoatherosclerosis development with late stent failure.72 The role of neointimal disruption, analogue to plaque rupture in native atherosclerosis, to very late stent thrombosis is under investigation.64 Neointimal rupture has been shown to be a very prevalent mechanism in very late bare metal stent thrombosis, especially a long time after implantation,73 and is one of the most common causes of late and very late drug-eluting stent thrombosis.66,74 Neointimal rupture is a mechanism occurring mainly at longer intervals following stent implantation,75 in regions with high necrotic core content and thin fibrous cap76 (similarly to what is observed with vulnerable plaques in native atherosclerosis) and a high incidence of macrophage infiltration.76 These features are being identified mainly by OCT.72

A: Angiogram of a non-culprit right coronary artery lesion (fractional flow reserve: 0.95; minimal lumen area: 3.55 mm2) in a patient with stable angina; B–D: Optical coherence tomography cross-sections demonstrating several features of vulnerability in three locations across the length of the artery (noted with black lines), including: (B’) a protruding calcified nodule (Ca), (B”) intimal microvessels (white arrowheads), (C’) macrophage infiltration (yellow arrowheads), and (D’) cholesterol crystals (arrow) with (D”) adventitial vasa vasorum (white arrowheads) at the site of a thick-cap fibroatheroma (L). Reproduced with permission from Toutouzas, et al., 2015.81

Figure 3: Assessment of Plaque Rupture by PolarisationSensitive Optical Coherence Tomography

Shortcomings of Current Vulnerable Plaque Detection Strategies: New Targets For Imaging Although vulnerable plaque morphology has been prospectively associated with adverse outcomes in studies of IVUS with virtual histology and near-infrared spectroscopy, the predictive value of plaque morphology is poor, due to a high prevalence of these findings and a relatively low event rate.77–80 Consequently, despite the prognostic value of TCFA, the need to identify patients who are at high risk of cardiovascular events remains unmet.81 Therefore, new imaging targets that can enhance the prognostic potential of invasive imaging for lesion-level future events need to be identified. The identification by OCT of new imaging targets such as calcified nodules, intimal vasculature, macrophages and cholesterol crystals can offer additional information over the vulnerability of atheromatous plaques

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A: Culprit lesion angiogram. Structure images showed a thin-cap fibroatheroma (Panel B1; arrow) with plaque rupture (Panel C1; white arrow) and thrombus (Panels C1–D1). Inspection of birefringence images revealed the presence of low birefringence (yellow colour) in the fibrous cap region both at the rupture site and proximally, suggesting the absence of thick collagen fibres (Panels B2–C2; white arrow). The intracoronary thrombus had predominantly low birefringence, consistent with the unorganised architecture of acute thrombus (Panel D2), but also featured areas of intermediate-to-high birefringence, suggesting a higher degree of organisation (Panel C2; black arrow). Reproduced with permission from van der Sijde, et al., 2016.91

(see Figure 2). Moreover, the combination of anatomical assessment

by OCT and biomechanical assessment of endothelial shear stress could give further insight into high-risk plaques.82–84

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Ischaemic Heart Disease Future Developments Technological advances include improved plaque characterisation using the current technology and the development of new technologies based on OCT imaging. Algorithms for the automated measurement of cap thickness are already available that can provide a fast and objective measure of this critical component of plaque vulnerability, while simultaneously increasing reproducibility of such measurements.85,86 Systems for automated tissue characterisation in atherosclerotic plaques can be used for a faster, more objective evaluation of plaque morphology. 87,88 The development of ultra-high-speed OCT imaging systems will allow the complete high-resolution assessment of long arterial segments within a heartbeat, 89 enabling a more accurate biomechanical assessment of the haemodynamic environment in the coronary arteries. The development of technologies such as polarisation-sensitive OCT that can measure the collagen content of atherosclerotic plaques90 will perhaps better redefine fibrous caps at a high risk of rupture (see Figure 3).91 Furthermore, new imaging systems with resolution comparable to electronic microscopy able to identify (sub-)cellular structures, 92 and hybrid systems incorporating the ability for

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detection of molecules targeted with probes simultaneously with plaque imaging,93 are currently under development; these systems may enhance the prognostic potential of OCT imaging for vulnerable plaque identification.

Conclusion Introduction of OCT in clinical practice has provided useful insights into the pathomechanisms of vulnerable plaque. These insights have enhanced our understanding of ACS, and have provided a knowledge base to use for clinical purposes. However, identification of the vulnerable plaque is not yet ready for clinical application, as the prognostic significance of a vulnerable plaque phenotype is poor, and a clinical benefit from interventions targeting vulnerable plaques is yet to be proven. Therefore, a better identification process needs to be implemented that can increase the prognostic significance of the findings in a way that it will be meaningful for the development and testing of local strategies targeting the vulnerable plaque. Future developments in the field will be aimed at early identification of highrisk plaques and timely intervention that could potentially result in a reduction of the mortality rates of patients with ACS. n

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Cardiomyopathy and Inherited Heart Disease

Role of T1 Mapping in Inherited Cardiomyopathies P eter P Swoboda , 1 Ada m K Mc D i a r m i d , 2 S t e p h e n P Pa g e, 3 J o h n P G r e e n w o o d 1 a n d S v e n Ple in 1 1. Multidisciplinary Cardiovascular Research Centre and Division of Biomedical Imaging, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK; 2. Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3. Inherited Cardiac Conditions Service, Leeds General Infirmary, Leeds, UK

Abstract T1 mapping by cardiovascular magnetic resonance is a rapidly evolving method for the quantitative assessment of tissue characteristics in cardiac disease. The myocardial T1 time can be measured without contrast (native T1) or following the administration of intravenous gadolinium-based contrast agent (post-contrast T1). By combining both of these measures, the myocardial extracellular volume fraction can be approximated. This value has been validated histologically in various inherited cardiomyopathies. Due to overlapping phenotypes, the diagnosis of inherited cardiomyopathy can at times be challenging. In this article we discuss when T1 mapping may be a useful tool in the differential diagnosis of cardiomyopathy. We also present evidence of when T1 mapping provides incremental risk stratification over other biomarkers.

Keywords T1 mapping, extracellular volume, cardiovascular magnetic resonance, cardiomyopathy Disclosure: The authors have no conflicts of interest to declare.

Received: 14 October 2016 Accepted: 18 November 2016 Citation: European Cardiology Review 2016;11(2):96–101; DOI: 10.15420/ecr/2016:28:2 Correspondence: Peter P Swoboda, NIHR Clinical Lecturer, Multidisciplinary Cardiovascular Research Centre and Division of Biomedical Imaging, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK. E: p.swoboda@leeds.ac.uk

Inherited cardiomyopathies are primary disorders of the heart muscle that have a genetic basis. On long-term follow-up they are associated with adverse outcomes, particularly sudden death, arrhythmia and heart failure.1 The diagnosis is made on the basis of clinical, cardiac imaging (primarily with transthoracic echocardiography) and genetic features,2 ideally by a tertiary inherited cardiac conditions service that involves both cardiologists and clinical geneticists.3 Inherited cardiomyopathies are typically defined according to their imaging findings rather than their genetic basis4,5 and include hypertrophic, dilated, right ventricular, restrictive and unclassified phenotypes (see Figure 1).

cardiomyopathy. With echocardiography it is possible to make an accurate assessment of cardiac morphology and function, which is necessary to make a diagnosis of an inherited cardiomyopathy.

Echocardiography may be suboptimal in certain individuals, however, due to body habitus or hyperinflation of the lungs; in these individuals cardiovascular magnetic resonance (CMR) is recommended as an alternative.8 CMR is also recommended for assessment of the right ventricle (which can be difficult to assess in its entirety by echocardiography) and in certain cardiomyopathies such as left ventricular non-compaction and amyloidosis.8

The pathways that lead from genetic mutation to individual phenotypes of various cardiomyopathies have been studied for the past three decades. In broad terms, alterations within specific components of the cardiac architecture are associated with different cardiomyopathies, for example abnormal function of contractile proteins within the sarcomere is associated with hypertrophic cardiomyopathy (HCM), dysfunction of the link between the sarcomere and cytoskeleton is associated with dilated cardiomyopathy (DCM), and abnormal desmosome function is associated with arrhythmogenic right ventricular cardiomyopathy (ARVC).6 The expressed phenotype can vary dramatically between individuals, however, and mutations within the same gene can lead to different phenotypes. For example, different mutations in the beta-myosin heavy chain can lead to either HCM or DCM.7 Genetic testing should not therefore be used in isolation in the diagnosis of inherited cardiomyopathy and needs to be combined with clinical evaluation and cardiac imaging.

A unique property of CMR is that it allows the interrogation of specific myocardial tissue characteristics, particularly the distribution of scar tissue. The presence of focal scarring is most widely assessed by the presence of late gadolinium enhancement (LGE). LGE imaging relies upon the administration of an exclusively extracellular gadoliniumbased contrast agent, which passively accumulates in damaged cells with a leaky cell membrane or areas of extracellular matrix expansion.

The pattern of enhancement can aid in the diagnosis of the aetiology of cardiomyopathy as LGE has a characteristic appearance in many conditions.9 For example subendocardial or transmural LGE are seen in ischaemic cardiomyopathy, mid-wall LGE in DCM, patchy LGE in areas of hypertrophy in HCM, and global subendocardial LGE in amyloid cardiomyopathy (see Figure 2).

Due to its wide availability and safety, echocardiography forms the cornerstone of cardiac imaging in the diagnosis of inherited

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Extracellular fibrosis is a common pathological finding in many inherited cardiomyopathies. CMR to assess LGE is a well-established method by which to assess and quantify the extent of discrete areas of fibrosis. This process relies on the contrast between normal and abnormal myocardium, and a qualitative comparison of

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enhancement. When the myocardium is diffusely diseased, the LGE technique is limited and qualitative assessment can be insufficient to make a diagnosis. For such diffuse processes, quantitative tissue characterisation methods are available that measure the T1,10 T211 or T2* relaxation times of the myocardium.

Native tissue maps alone can be used for tissue characterisation. T1 mapping is often performed before and after the administration of a T1-shortening gadolinium-based contrast agent using techniques such as modified look-locker inversion recovery (MOLLI), shortened modified look-locker inversion recovery (ShMOLLI) and saturationrecovery single-shot acquisition (SASHA), which all have inherent strengths and weaknesses.12 Tissues with an expanded extracellular space due to fibrosis, infiltration or scarring have a larger distribution volume for the extracellular contrast agent, and consequently the reduction in T1 relaxation time is more pronounced than in normal tissue. Post-contrast myocardial T1 has been shown to significantly correlate with histological areas of fibrosis.13 From pre- and post-contrast T1 maps, the extracellular volume (ECV) fraction may be calculated as: ECV = (1 – Hct )

Inherited Cardiomyopathy

HCM

Native T1 mapping and ECV mapping both provide non-invasive assessments of tissue characteristics and can be used in conjunction with each other. ECV detects focal and diffuse extracellular fibrosis, however it requires intravenous cannulation for the administration of the contrast agent and measurement of haematocrit from a venous blood sample. Measurement of native T1 is not hampered by these issues, but in addition to extracellular fibrosis is also influenced by intracellular water, iron and fat, giving a weaker histological correlation with extracellular fibrosis than ECV.15 Furthermore, native T1 varies significantly depending on the field strengths, scanner vendor and technique used to measure it,16 and in clinical practice requires validation for the specific pulse sequence and field strength used.17

T1 Mapping in the Diagnosis of Cardiomyopathy Extracellular matrix expansion and fibrosis are common pathological findings in many inherited cardiomyopathies.2 The non-invasive assessment of extracellular fibrosis by T1 mapping is therefore a potentially promising tool, in addition to conventional CMR including LGE, in the diagnosis of suspected cardiomyopathy.

Hypertrophic Cardiomyopathy HCM is the most common inherited cardiomyopathy, affecting between two and 20 adults per 1,000.18 HCM is commonly defined as a disease of the cardiac muscle characterised by hypertrophy of the left ventricle in the absence of another cardiac or systemic cause.19 It is typically caused by autosomaldominant mutations of genes encoding contractile sarcomeric proteins and myofilament elements. 20 These mutations lead to micro- and macroscopic changes within the heart, including cellular disarray, hypertrophy and interstitial fibrosis. These changes lead to hypertrophy that can affect the heart in a variety of patterns, and

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ARVC = arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LVNC = left ventricular non-compaction cardiomyopathy; RCM = restrictive cardiomyopathy. Adapted from Elliot et al.5

Figure 2: Typical Cine and Late Gadolinium Enhancement Imaging in Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy and Arrhythmogenic Right Ventricular Cardiomyopathy

R1( myo pre contrast ) – R1( myo post contrast ) blood pre contrast ) – R1( blood post contrast ) R1(b

where ECV is the extracellular volume, Hct is haematocrit and R1=1/T1. ECV fraction has a significant correlation with the histological degree of fibrosis and volume of collagen in the myocardium.14

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Figure 1: Classification of Inherited Cardiomyopathy According to Morphological Features

HCM

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ARVC = arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; ECV = extracellular volume fraction; HCM = hypertrophic cardiomyopathy; LGE = late gadolinium enhancement.

may affect any segment of the left ventricle.21 Although hypertrophy can be widespread, phenotypic expression within the same heart can be variable.22 At present the diagnosis of HCM is primarily made by the identification of one or more hypertrophied segments by a cardiac imaging modality.18,19 In the majority of cases this involves identification of a ≥15 mm segment by echocardiography. CMR cine imaging enables accurate and reproducible assessment of the extent and location of hypertrophy when considering a diagnosis of HCM. It is reported that CMR detects hypertrophy in around 12 % of patients with HCM in whom it was not detected by echocardiography.22 LGE is seen in approximately two-thirds of patients with HCM and is typically found in areas of hypertrophy in a mid-wall pattern and at the right ventricular septal insertion points.23 The presence of LGE in HCM is suggestive of replacement fibrosis, and on necropsy there is a strong linear correlation between the extent of LGE within a particular segment and the amount of collagen measured histologically.24

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Cardiomyopathy and Inherited Heart Disease Figure 3: Typical T1 Mapping and Late Gadolinium Enhancement Findings in Hypertrophic Cardiomyopathy and Differential Diagnoses of Left Ventricular Hypertrophy

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The normal ranges from our institution are native T1 of 895–1,035 ms for 1.5T and 960–1,180 ms for 3.0T and ECV of 24–30 % for both 1.5T and 3.0T. From left: HCM: discrete regions of replacement fibrosis on LGE imaging with increased native T1 time and ECV, particularly in regions of hypertrophy; Anderson-Fabry Disease: low native T1 time with no replacement fibrosis on LGE imaging and ECV in the normal range; athlete: no replacement fibrosis, low native T1 time and low ECV (19.8 %); cardiac amyloidosis: diffuse enhancement on LGE imaging, globallyincreased native T1 time and ECV (60 %). ECV = extracellular volume; LGE = late gadolinium enhancement; HCM = hypertrophic cardiomyopathy.

With T1 and ECV mapping the extent of diffuse fibrosis in HCM can be quantified. Extracellular matrix expansion is one of the histological hallmarks of the disease process, and can be detected using quantitative T1 and ECV mapping techniques. Results demonstrate a good correlation with histological fibrosis quantification from specimens taken at the time of surgical myomectomy.14 One study has reported a correlation between post-contrast T1 time and histological degree of fibrosis in HCM hearts explanted at the time of transplant.25 However, in this study ECV (which is better validated than post-contrast T1 time) was not calculated, the sample size was small (four HCM necropsy specimens) and there was a long interval between the CMR and surgical explant.

Several studies have shown that both native T1 values26,27 and ECV14,28,29 are elevated in HCM. ECV is highest in regions with replacement fibrosis detected on LGE imaging. Native T1 value and ECV also appear to be elevated in regions without overt LGE,29,30 suggesting that they are able to detect more diffuse fibrosis not seen on LGE imaging.

Several groups have also shown that both native T1 value and ECV are elevated in subjects with a mutation known to cause HCM without sufficient phenotypic expression to diagnose the disease on current imaging criteria.29,31,32

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Differential Diagnosis of Hypertrophic Cardiomyopathy Excluding alternative causes of hypertrophy of the left ventricle is fundamental to making a diagnosis of HCM and is often clinically challenging. Several of these “phenocopies” have a particular pattern on T1 mapping that could be clinically useful in differentiating them from HCM (see Figure 3).

Cardiac Amyloidosis Cardiac amyloidosis is associated with progressive infiltration of the heart by extracellular amyloid protein resulting in hypertrophy of the left and right ventricles, interatrial septum and the atrioventricular valves. Given that this disease process involves pathological expansion of the extracellular space by amyloid protein, it is logical that both the native T1 value and ECV can be substantially raised in this condition.33–35 Patients with the highest native T1 value and ECV appear to have the greatest cardiac involvement and worst clinical outcomes.36 The typically very high native T1 value and ECV contributes to the differentiation of amyloidosis from HCM. In addition, the hypertrophy and fibrosis are more global in cardiac amyloidosis compared with the usually more regional hypertrophy in HCM.

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Anderson-Fabry Disease Anderson-Fabry disease is an inherited metabolic disorder associated with alpha-galactosidase deficiency and intracardiac glycolipid accumulation. The typical cardiac manifestation includes concentric biventricular hypertrophy, thickening of the atrioventricular valves and an inferolateral pattern of LGE. The disease process involves intramyocyte accumulation of lipids, which can shorten native T1 time. The extracellular matrix is not altered, however, and therefore recognition of a shortened native T1 value but normal ECV may aid in the diagnosis of Anderson-Fabry disease.37,38

Athlete’s Heart Physical training leads to an increase in left ventricular mass and cavity size, and in certain situations this can be difficult to differentiate from HCM. HCM is the leading cause of sudden death in athletes and early identification is important so that abstinence from intense exercise can be advised.39 With T1 mapping it has been shown that as fitness increases in athletes there is an increase in myocyte mass with a relatively constant extracellular mass.40 As hypertrophy of the left ventricle increases in athletes there is therefore a decrease in ECV, whereas in HCM there is an increase in ECV. Based on this divergent principle, T1 mapping can be used to differentiate athletic remodelling of the left ventricle from HCM.41

Hypertension Systemic hypertension can lead to concentric hypertrophy of the left ventricle and it is important that hypertensive heart disease is excluded before a diagnosis of HCM is made. It has been shown that in hypertensive patients regions of myocardial hypertrophy have increased native T1 values and ECV,42,43 albeit to a lesser extent than in HCM. These indices may therefore contribute to the differentiation of hypertensive heart disease from HCM.29 It should be noted, however, that in both HCM and hypertension as hypertrophy increases there is an associated increase in T1 indices, suggesting that the diagnostic utility may be lower in subjects with borderline hypertrophy. This is illustrated by the fact that both ECV and native T1 values are similar in subjects with hypertensive disease and in patients with a gene mutation known to cause HCM who do not yet have overt hypertrophy.29

Dilated Cardiomyopathy DCM involves pathological dilatation and impairment of the left ventricle in the absence of abnormal loading conditions or ischaemic heart disease. A causative mutation can be found in around a third of patients with familial DCM.2 More than 40 causative genes, many of which relate to the cytoskeleton, have been identified.2 Mutation of these genes leads to loss of cardiomyocyte contractility, ultimately with the common pathophysiological end-point of cell death and fibrotic replacement.

The diagnosis of DCM is typically made after clinical examination and echocardiography. Fibrosis is a pathological feature of DCM and the CMR assessment of diffuse fibrosis by LGE and T1 mapping is increasingly being used in this situation. DCM is associated with a mid-wall pattern of fibrosis on LGE imaging, which when present confers an adverse prognosis.44 Mid-wall fibrosis is only present in around one-third of subjects with DCM, however, and T1 mapping may be a useful additional diagnostic tool in patients without overt changes on LGE.45 It has been demonstrated that both native T1 value and ECV are elevated in patients with DCM, even in regions without replacement fibrosis seen on LGE imaging.26,27,45 The native T1 value and

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ECV have been validated histologically in DCM against whole hearts explanted at the time of transplant15 and endomyocardial biopsy.46 One of the most common mutations in familial DCM is in the LMNA gene, which codes lamin A/C. In one study of seven families affected by a mutation in this gene it was shown that elevated ECV could be detected in gene carriers without overt left ventricular dysfunction.31 Part of the diagnosis of DCM involves the exclusion of alternative causes of cardiac dysfunction and dilatation, such as valvular or ischaemic heart disease. T1 mapping may have a role in the exclusion of other dilated phenotypes too, such as iron overload cardiomyopathy which has low native T1 value secondary to cardiac iron,47 and athletic ventricular dilation which has normal native T1 value and ECV.48 Elevated ECV has been shown to be an adverse prognostic marker in a mixed cohort of patients (including those with DCM but not HCM) and is associated with heart failure outcomes and mortality.49

Arrhythmogenic Right Ventricular Cardiomyopathy ARVC is characterised by fibrofatty replacement of the right and sometimes left ventricles, which predisposes individuals to ventricular arrhythmia. Around half of ARVC cases are familial and the condition is typically caused by mutations affecting the desmosome.2 The diagnosis of ARVC is made by a combination of clinical, electrocardiographic, histological and imaging features.50 The diagnostic imaging features are regional right ventricular akinesia, dyskinesia or dyssynchrony in addition to dilation or impairment of function. In theory it might be possible to diagnose the fibrofatty replacement that is characteristic of ARVC as a shortened native T1 time; however the thin wall of the right ventricle poses important challenges and makes T1 mapping more susceptible to partial volume effects.

Other Inherited Cardiomyopathies Familial restrictive cardiomyopathy is rare and is defined by a restrictive filling pattern on echocardiography. This phenotype may be caused by end-stage HCM or DCM, or can be caused by systemic diseases such as amyloidosis, sarcoidosis, carcinoid heart disease or scleroderma. T1 mapping could potentially be used as outlined previously to exclude alternative causes of left ventricular hypertrophy.

Left ventricular non-compaction cardiomyopathy (LVNC) is characterised by abnormal trabeculation, most commonly at the apex, and is often associated with ventricular hypertrophy, dilation or impairment of function. The molecular mechanisms of LVNC are not yet fully understood but genetic inheritance is reported in 30–50 % of patients.51 On CMR, a non-compacted to compacted myocardium ratio of >2.3 has been proposed as a diagnostic criterion for LVNC.52 As with ARVC, measuring T1 indices in the thinned compact layer of the myocardium is challenging and vulnerable to partial volume effects.

One study has reported elevated native T1 values in a series of 31 patients with LVNC, even in areas without LGE.53 Takotsubo cardiomyopathy is characterised by acute transient apical ballooning of the left ventricle in the absence of obstructive coronary artery disease, often in the setting of psychological stress. The pathological processes are complex and likely involve catecholamine pathways, with some studies suggesting a genetic predisposition too.54,55 The transient myocardial dysfunction in Takotsubo cardiomyopathy appears to be mediated by myocardial

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Cardiomyopathy and Inherited Heart Disease oedema, which can be detected by a lengthened native T1 value in regions with oedema and dysfunction.56

Conclusion T1 mapping is evolving as a useful clinical tool in the identification and diagnosis of inherited cardiomyopathy and it may have a future role in establishing the natural history of fibrosis progression in inherited cardiomyopathies and the timing of appropriate interventions. It is becoming particularly well established in the investigation of patients with unexplained left ventricular hypertrophy.

The optimal pulse sequence for T1 mapping is yet to be established, and standardisation remains an important aim. Standardised acquisition

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would also facilitate the publication of generally applicable normal ranges to facilitate more widespread use of T1 mapping in clinical practice and research. In the future, CMR sequences with shortened breath-holds or free breathing acquisition will be available to improve utility in patients with symptoms of dyspnoea. Sequences with improved spatial resolution will also aid in the investigation of T1 indices in thinned regions of myocardium, as in cases of ARVC and LVNC. The prognostic importance of T1 indices over more commonly used imaging parameters such as wall thickness in HCM or ejection fraction in DCM remains to be established. Large prospective multicentre registries and trials are required to answer these questions and are awaited in the coming years. n

mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Magn Reson 2013;15 :92.

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Circ Cardiovasc Imaging 2012;5 :726–33. DOI: 10.1161/ CIRCIMAGING.112.976738; PMID: 23071146 Kellman P, Wilson JR, Xue H, et al. Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience. J Cardiovasc Magn Reson 2012;14 :64. DOI: 10.1186/1532-429X-14-64 Hinojar R, Varma N, Child N, et al. T1 mapping in discrimination of hypertrophic phenotypes: hypertensive heart disease and hypertrophic cardiomyopathy: findings from the International T1 Multicenter Cardiovascular Magnetic Resonance Study. Circ Cardiovasc Imaging 2015;8 :e003285. DOI: 10.1161/CIRCIMAGING.115.003285; PMID: 26659373 Kato S, Nakamori S, Bellm S, et al. Myocardial native T1 time in patients with hypertrophic cardiomyopathy. Am J Cardiol 2016;118 :1057–62. DOI: 10.1016/j.amjcard.2016.07.010; PMID: 27567135 Fontana M, Barison A, Botto N, et al. CMR-verified interstitial myocardial fibrosis as a marker of subclinical cardiac involvement in LMNA mutation carriers. JACC Cardiovasc Imaging 2013;6 :124–6. DOI: 10.1016/j.jcmg.2012.06.013;

PMID: 23328570 32. Ho CY, Abbasi SA, Neilan TG, et al. T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. Circ Cardiovasc Imaging 2013;6 :415–22. DOI: 10.1161/CIRCIMAGING.112.000333; PMID: 23549607 33. Fontana M, Banypersad SM, Treibel TA, et al. Native T1 mapping in transthyretin amyloidosis. JACC Cardiovasc Imaging 2014;7 :157–65. DOI: 10.1016/j.jcmg.2013.10.008; PMID: 24412190 34. Banypersad SM, Sado DM, Flett AS, et al. Quantification of myocardial extracellular volume fraction in systemic AL amyloidosis: an equilibrium contrast cardiovascular magnetic resonance study. Circ Cardiovasc Imaging 2013;6 :34–9.

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Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 2013;6 :488–97.

DOI: 10.1016/j.jcmg.2012.11.013; PMID: 23498672 36. Banypersad SM, Fontana M, Maestrini V, et al. T1 mapping and survival in systemic light-chain amyloidosis. Eur Heart J 2015;36 :244–51. DOI: 10.1093/eurheartj/ehu444; PMID: 25411195 37. Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping.

Circ Cardiovasc Imaging 2013;6 :392–8. DOI: 10.1161/ CIRCIMAGING.112.000070; PMID: 23564562 38. Pica S, Sado DM, Maestrini V, et al. Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2014;16 :99. DOI: 10.1186/s12968-014-0099-4; PMID: 25475749 39. Finocchiaro G, Papadakis M, Robertus JL, et al. Etiology of sudden death in sports: insights from a United Kingdom regional registry. J Am Coll Cardiol 2016;67 :2108–15.

DOI: 10.1016/j.jacc.2016.02.062; PMID: 27151341 40. McDiarmid AK, Swoboda PP, Erhayiem B, et al. Athletic cardiac adaptation in males is a consequence of elevated myocyte mass. Circ Cardiovasc Imaging 2016;9 :e003579.

DOI: 10.1161/CIRCIMAGING.115.003579; PMID: 27033835 41. Swoboda PP, McDiarmid AK, Erhayiem B, et al. Assessing myocardial extracellular volume by T1 mapping to distinguish hypertrophic cardiomyopathy from athlete’s heart. J Am Coll Cardiol 2016;67 :2189–90. DOI: 10.1016/j.jacc.2016.02.054 42. Kuruvilla S, Janardhanan R, Antkowiak P, et al. Increased extracellular volume and altered mechanics are associated with LVH in hypertensive heart disease, not hypertension alone. JACC Cardiovasc Imaging 2015;8 :172–80. DOI: 10.1016/ j.jcmg.2014.09.020; PMID: 25577446 43. Treibel TA, Zemrak F, Sado DM, et al. Extracellular volume quantification in isolated hypertension – changes at the detectable limits? J Cardiovasc Magn Reson 2015;17 :74.

DOI: 10.1186/s12968-015-0176-3; PMID: 26264919 44. Gulati A, Jabbour A, Ismail TF, et al. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 2013;309 : 896–908. DOI: 10.1001/jama.2013.1363; PMID: 23462786 45. Ugander M, Oki AJ, Hsu LY, et al. Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J 2012;33 :1268–78. DOI: 10.1093/eurheartj/ehr481; PMID: 22279111 46. aus dem Siepen F, Buss SJ, Messroghli D, et al. T1 mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and comparison with endomyocardial biopsy. Eur Heart J Cardiovasc Imaging 2015;16 :210–6. DOI: 10.1093/ehjci/jeu183; PMID: 25246502 47. Sado DM, Maestrini V, Piechnik SK, et al. Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload. J Magn Reson Imaging 2015;41 :1505–11. DOI: 10.1002/jmri.24727; PMID: 25104503 48. Mordi I, Carrick D, Bezerra H, et al. T1 and T2 mapping for early diagnosis of dilated non-ischaemic cardiomyopathy in

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middle-aged patients and differentiation from normal physiological adaptation. Eur Heart J Cardiovasc Imaging 2016;17 :797–803. DOI: 10.1093/ehjci/jev216; PMID: 26358692 49. Wong TC, Piehler K, Meier CG, et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality. Circulation 2012;126 :1206–16. DOI: 10.1161/ CIRCULATIONAHA.111.089409; PMID: 22851543 50. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31 :806–14. DOI: 10.1093/eurheartj/ehq025; PMID: 20172912

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51. Towbin JA, Lorts A, Jefferies JL. Left ventricular noncompaction cardiomyopathy. Lancet 2015;386 :813–25.

DOI: 10.1016/S0140-6736(14)61282-4; PMID: 25865865 52. Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005;46 :101–5.

DOI: 10.1016/j.jacc.2005.03.045; PMID: 15992642 53. Zhou H, Lin X, Fang L, et al. Characterization of compacted myocardial abnormalities by cardiac magnetic resonance with native T1 mapping in left ventricular non-compaction patients – a comparison with late gadolinium enhancement.

Circ J 2016;80 :1210–6. DOI: 10.1253/circj.CJ-15-1269; PMID: 27010628 54. Spinelli L, Trimarco V, Di Marino S, et al. L41Q polymorphism

of the G protein coupled receptor kinase 5 is associated with left ventricular apical ballooning syndrome. Eur J Heart Fail 2010;12 :13–6. DOI: 10.1093/eurjhf/hfp173; PMID: 20023040 55. Figtree GA, Bagnall RD, Abdulla I, et al. No association of G-protein-coupled receptor kinase 5 or beta-adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort. Eur J Heart Fail 2013;15 :730–3.

DOI: 10.1093/eurjhf/hft040; PMID: 23794609 56. Ferreira VM, Piechnik SK, Dall’Armellina E, et al. Noncontrast T1-mapping detects acute myocardial edema with high diagnostic accuracy: a comparison to T2-weighted cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2012;14 :42. DOI: 10.1186/1532-429X-14-42

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Cardiomyopathy and Inherited Heart Disease

Cardiovascular Management of Adults with Marfan Syndrome Yukiko Isekame, Sabiha Gati, Jose Antonio Aragon-Martin, Rachel Bastiaenen, Sreenivasa Rao Kondapally Seshasai and Anne Child Cardiovascular and Cell Sciences Research Institute, St. George’s, University of London, London, UK

Abstract Marfan syndrome (MFS) is a disease in which connective tissue becomes weak secondary to fibrillin-1 mutations, resulting in aortic dilatation, aneurysm formation, aortic dissection, aortic regurgitation and mitral valve prolapse. This autosomal dominantly inherited condition, which was first reported in 1895 and was more fully described in 1931, is characterised by abnormal Fibrillin-1 protein (FBN1) (discovered in 1990), which is encoded by the FBN1 gene (reported in 1991). In the 1970s, the life expectancy of people with MFS was 40–50 years, mainly due to increased risk of aortic dissection or heart failure from aortic or mitral regurgitation. However, due to advances in medical and surgical therapy, life expectancy has improved dramatically and is now comparable to that of the general population. We discuss the cardiac manifestations of MFS, the incidence of arrhythmia in this population, the standard of medical care for arrhythmia and valve insufficiency, and a new use of preventive medication to preserve the integrity of the aortic wall in patients with MFS.

Keywords Marfan syndrome, management, aortic root, aortic aneurysm, mitral valve, arrhythmia Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: This work was supported by Marfan Trust and St George’s, University of London.

Received: 16 June 2016 Accepted: 14 September 2016 Citation: European Cardiology Review 2016;11(2):102–10. DOI: 10.15420/ecr/2016:19:2 Correspondence: Anne Child, St. George’s, University of London, Cranmer Terrace, London SW17 0RE, UK. E: achild@sgul.ac.uk

Marfan syndrome (MFS) is a disease in which connective tissue becomes weak secondary to fibrillin-1 mutations, resulting in aortic dilatation, aneurysm formation, aortic dissection, aortic regurgitation and mitral valve prolapse (MVP; see Table 1).

normal and when the ECM is damaged due to the force of the blood flow ejected from the heart, the mesenchymal cells promote active TGF-beta to restore the ECM. This results in excessive TGF-beta signalling, causing ECM degradation, apoptosis and an inflammatory state, leading to aneurysm formation or dissection (see Figure 1).6,7

Epidemiology MFS is an autosomal dominant condition: 75 % of all patients inherit the condition from one affected parent and 25 % are affected as the result of a new mutation. The population incidence is 2–3 per 10,000.1 The autosomal dominant inheritance of this disorder was described in 1934,2 and has been ascribed to abnormalities in fibrillin-1 protein (discovered in 1990),3 which is encoded by the FBN1 gene (reported in 1991).4 The most common causes of death in MFS are cardiovascular, especially aortic dissection and rupture. According to a Taiwanese study, aortic dissection is the most serious complication, occurring in 9.7 % of individuals with MFS (nearly 61 % of these patients are male) and carrying an average mortality of approximately 10.6 %.5

Cardiovascular Manifestations In MFS, the main cardiovascular manifestations are aortic dilatation and MVP. Tricuspid regurgitation (TR), pulmonary artery (PA) dilatation, ventricular arrhythmia and dilated cardiomyopathy also occur.

Pro-transforming growth factor-beta (TGF-beta) binds to the latent TGF-beta binding protein-1 (LTBP-1) and forms the latency-associated peptide (LAP), followed by a complex termed the large latent TGF-beta complex (LLC). This is secreted and sequestered in the extracellular matrix (ECM). FBN1 is a matrix glycoprotein and the major constituent of ECM microfibrils comprising elastic fibres. In MFS, the ECM is not

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At present, more than 3,000 FBN1 mutations have been discovered.

Almost all of them develop similar manifestations such as heart, eye and skeletal problems, and are related to excessive TGF-beta signalling via integrin, which provides a common mechanism by promoting latent TGF-beta and expressing TGF-beta.6 Endothelial cells, smooth muscle cells and fibroblasts sense and respond to blood flow and blood pressure. Increasing or decreasing blood pressure increases or decreases wall stress. Cells sense and regulate the ECM through integrins and cytoskeletal components.

Sensing high versus low stress causes different cell signalling.

Misperception of high stress as low stress can cause maladaptive remodelling by activating the pathways observed in thoracic aortic aneurysms and aortic dissections (TAAD).8

The Aorta In MFS, aortic dilatation and aneurysm formation are caused by cystic medial necrosis, in which the medial layer of the aorta demonstrates fewer cells and a lacunar appearance. Most aortic dilatation starts in the sinuses of Valsalva. A reduced content of elastic fibres (including fibrillin-1) associated with continual force from left ventricular (LV) cyclic torsion applied to the aortic root are thought to be the main reasons why dilatation starts at the aortic sinus.9 Aortic root dilatation

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is the most common cardiovascular manifestation occurring in 60–80 % of MFS patients,9 and aortic sinus enlargement causing aortic aneurysm occurs in 50–60 % of adult patients and 50 % of paediatric patients.10 Syndromic thoracic aortic aneurysm (TAA) growth rate is variable in each TAA subtype. The average rate of TAA growth in MFS patients is 0.5–1.0 mm per year.11 Ascending aortic dilatation increases with age and 96 % of patients have ascending aortic dilatation by 60 years.12 In comparison, the average rate of TAA growth in patients with Loeys–Dietz syndrome, a similar but more serious cardiovascular disorder, is more than 0.5–1.0 mm per year.13,14 Figure 2 depicts the normal dimensions of the ascending and descending aorta in healthy individuals.15,16 Aortic size is strongly influenced by body surface area (BSA), weight, age and sex.17 When the aorta dilates, the risk of aortic dissection/rupture becomes higher. In MFS, aortic diameter is used for monitoring, but its significance is influenced by BSA, so the Z-score, which is adjusted to BSA and age, is used.18,19 In MFS, the average speed of aneurysm growth in the ascending aorta is 0.5–1.0 mm per year and after aortic root replacement for aortic dissection, is 0.58 ± 0.5 mm per year in the distal descending aorta.20 The distal aorta can be the first site of dissection or prophylactic surgery in up to 18 % of patients with MFS.21

Table 1: Criteria for Marfan Syndrome Diagnosis from Revised Ghent Criteria In the absence of family history: (1) Ao (Z ≥2) AND EL=MFS (2) Ao (Z ≥2) AND FBN1=MFS (3) Ao (Z ≥2) AND Syst (≥7 pts)=MFS (4) EL AND FBN1 with known Ao=MFS EL with or without Syst AND with a FBN1 not known with Ao or no FBN1=ELS Ao (Z <2) AND Syst (≥5 with at least one skeletal feature) without EL=MASS MVP AND Ao (Z <2) AND Syst (<5) without EL=MVPS In the presence of family history: (5) EL AND FH of MFS (as defined above)=MFS (6) Syst (≥7 pts) AND FH of MFS (as defined above)=MFS (7) Ao (Z ≥2 above 20 years old, ≥3 below 20 years) + FH of MFS=MFS Ao = aortic diameter at the sinuses of Valsalva above indicated Z-score or aortic root dissection; EL = ectopia lentis; ELS = ectopia lentis syndrome; FBN1 = fibrillin-1 mutation, FH = family history; MASS = mitral valve prolapse, borderline (Z <2) aortic root dilatation, striae, skeletal findings phenotype; MFS = Marfan syndrome; MVPS = mitral valve prolapse 18 syndrome; Syst = systemic score; Z = Z-score. Source: Loeys et al., 2010. Reproduced with permission from BMJ Publishing Group © 2010.

Figure 1: A Potential Molecular Pathway of Dysregulation of Transforming Growth Factor-beta Leading to Aneurysms and Dissections N

If a tear forms within the intima of the dilated aorta, aortic dissection may occur. Aortic dissection is defined as disruption of the medial aortic layer provoked by intramural bleeding, resulting in separation of the aortic wall layers and subsequent formation of a false lumen with or without communication with the true lumen.13 If dissection involves a coronary artery, myocardial infarction may also occur.

Ischaemia of the mesenteric and femoral arteries has also been described in association with abdominal aortic dissection.10 The location of pain usually correlates with the location of the dissection; involvement of the ascending aorta causes anterior chest pain, of the descending aorta causes back pain and of the abdominal aorta causes abdominal pain. In MFS patients, dissection is most commonly Stanford type A involving the ascending aorta (see Figure 3).13 Aortic dilatation/dissection are major criteria for MFS diagnosis in the revised Ghent criteria, while MVP is included as a diagnostic systemic feature.18 Data from Januzzi et al.22 has demonstrated that 5 % of all patients with aortic dissection have a diagnosis of MFS. In comparing aortic dissection in patients with MFS and without MFS, type A dissection was more prevalent (76 versus 62 %; p=0.04) and intramural haematoma was less prevalent (2 versus 11 %; p=0.03) in MFS. Patients with aortic dissection and MFS were younger than those without MFS (35 ± 12 versus 64 ± 13; p<0.001), and less likely to have a history of hypertension (27 versus 74 %; p<0.001) or atherosclerosis (0 versus 32 %; p<0.001).12 In patients under forty years of age aortic dissection was less common (7 % of all patients with dissections), but a greater proportion of aortic dissections occurred in patients with MFS who were under forty.23 In the International Registry of Acute Aortic Dissection, 50 % of patients under 40 years with aortic dissection had MFS and 2 % of patients over 40 years with aortic dissection had MFS.23 Risk factors for aortic dissection in MFS are as follows: aortic diameter >5 cm, progressive aortic dilatation extending beyond the sinus of Valsalva, rapid aortic growth rate (>5 % per year or >2 mm per year in adults) and family history of aortic dissection.10

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LAP

C Fibrillin-1

LLC

N LTBP-1

inactive TGFβ

active TGFβ

C

TGFBR2

TGFBR1

P P Smad2/3

P

Increased Smad 2/3 phosphorylation?

Smad4 Increased Smad nuclear localization Aortic smooth muscle cell

P

ECM degradation

P

Altered TGFβ responsive gene expression?

P

Apoptosis Inflammation

Aneurysms/Dissections

A potential molecular pathway of dysregulation of transforming growth factor-beta (TGF-beta) leading to aneurysms and dissections. TGF-beta is secreted in a biologically inactive form and stored in the extracellular matrix in a complex termed the large latent TGF-beta complex (LLC), consisting of a TGF-beta homodimer associated with the latency-associated peptide (LAP) and the latent TGF-beta binding protein-1 (LTBP-1). Dysregulated TGF-beta signalling results from mutations in fibrillin-1, TGFBR1 or TGFBR2, leading to altered transcription of TGF-beta-responsive genes, and ultimately resulting in degenerative changes in the vessel 7 wall leading to aneurysms and dissections. Source: Adapted from Pannu H et al., 2005.

Reproduced with permission from John Wiley & Sons © 2005.

Sudden death from aortic dissection is decreasing due to improved aortic monitoring and elective aortic root surgery. However, after elective aortic root surgery, dilatation of the distal aorta is even more common,21 and careful monitoring of the entire aorta is important even though the aortic root has been repaired. Some patients will require surgery for distal aorta after aortic root surgery.20 In addition, pulse wave velocity (PWV) is higher in MFS patients and PWV of the whole aorta increases with age,24 indicating age-related aortic stiffening in MFS patients, with PWV a sensitive marker of aortic condition.

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Cardiomyopathy and Inherited Heart Disease Figure 2: Diagram of Ascending and Descending Aorta with Expected Diameters in Healthy Adults Left common carotid artery

Innominate artery

Ascending aorta

Aortic arch 22-36 mm

Left subclavian artery

Tubular ascending aorta 22-36 mm (15+2 mm/m2)

PA

Ligamentum arteriosum

Descending aorta 20-30 mm

Sinotubular junction 22-36 mm (15+1 mm/m2) Sinuses of Valsalva 24-40 mm (18+2 mm/m2) Aortic annulus 20-31 mm (13+1 mm/m2)

Diaphragm

There are normal ranges for the diameter of each section of aorta. The aorta is divided into thoracic aorta and abdominal aorta. Thoracic aorta consists of ascending aorta, aortic arch and descending aorta. The ascending aorta includes the aortic annulus, sinuses of Valsalva, sinotubular junction and proximal ascending aorta. The aortic arch extends from the brachiocephalic (innominate) artery to the arterial ligament. The descending aorta extends from the arterial ligament to the level of the diaphragm. The abdominal aorta is below 15,16 the level of the diaphragm. ECM = extracellular matrix. Source: Evangelista et al., 2010.

Reproduced with permission from Oxford University Press © 2010.

Figure 3: The Classification of Aortic Dissection De Bakey

Type I

Type II

Type III

Stanford

Type A

Type A

Type B

and the left atrium enlarges, reflecting the increased end-diastolic LV pressure and left atrial pressure. The LV ejection fraction does not decrease due to compensatory increases in ventricular contraction.

Over time, chronic volume overload may result in myocardial damage and failure of the compensatory mechanisms such that cardiac output cannot be maintained. Myocardial damage affects the entire left ventricle and causes global hypokinesis.26

Mitral Valve MFS patients have elongated and thickened mitral valve (MV) leaflets.

This appears to be due to defective connective tissue and myxomatous degeneration secondary to increased TGF-beta signalling (see Figure 1).27 Ng et al.28 studied mice with FBN1 mutations to determine whether elongation and thickening of the MV leaflets was caused by increased activation and signalling of TGF-beta. They found that treating the mice with a TGF-beta neutralising antibody resulted in regression of the elongation and thickening of the leaflets, which returned to normal.

In the general population, the prevalence of isolated MVP is 2–3 %.29 In MFS the prevalence of MVP is 40 % and the prevalence of severe mitral regurgitation (MR) is 12 %.30 Anterior leaflet prolapse is more common than posterior leaflet or bileaflet prolapse, and prolapse of the posterior leaflet can predict severe MR.29 In contrast, another study reports that MVP is seen in 77 % of MFS patients carrying a FBN1 mutation.12 MVP carries a risk of developing MR, heart failure and infective endocarditis. Kühne et al. studied MFS patients with causative FBN1 mutations and moderate MR. Twenty-six percent of the group had progressive MR, associated with posterior leaflet prolapse and/or thickening, decreased LV ejection fraction, an increased indexed end-diastolic LV diameter, increased indexed left atrial diameter and tricuspid valve prolapse.31 When MR occurs, the left ventricle and left atrium become volume-overloaded, and heart failure may therefore occur in the decompensated phase.

Shows the classification of aortic dissection. De Bakey classification is according to entry level and dissection. De Bakey type 1 involves entry in ascending aorta and dissection extends to abdominal aorta. De Bakey type 2 involves dissection only of ascending aorta.

De Bakey type 3 involves entry in descending aorta. De Bakey type 3 has subtypes 3A and 3B. Type 3A dissection does not extend to the abdominal aorta and type 3B extends to the abdominal aorta. Stanford classification is according to the level of dissection. Stanford type A dissection occurs in the ascending aorta. Stanford type B dissection does not relate to the 13 ascending aorta. Source: Erbel et al., 2014. Reproduced with permission from the author and the European Society of Cardiology © 2014.

Aortic Valve Aortic root dilatation causes aortic regurgitation (AR) with a central jet secondary to annular dilatation and/or myxomatous valvular degeneration.25 Patients usually have no symptoms during early stages. The severity of AR is evaluated by morphological features, Doppler index (including colour Doppler) and quantitative assessment using echocardiography. As the regurgitant volume increases, so does the volume of blood ejected with each LV contraction. Thus the end-diastolic LV volume becomes larger to maintain cardiac output,

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Calcification of the MV annulus has been reported to occur at a greater rate in MFS than in normal individuals, and it is included in the diagnostic minor criteria in the cardiovascular system for MFS published in 1996.32 However, De Backer has studied some of the cardiovascular findings required in the criteria in 2009 and reported that calcification of MV annulus is not common nor practical for inclusion in MFS criteria.33 The severity of MR is variable. Some paediatric MFS patients have early onset and severe symptoms. In infancy, MR may cause congestive heart failure, pulmonary hypertension and death. More than 25 % of MFS patients have progressed from MVP to MR by adulthood, and twice as many women as men develop progressive mitral dysfunction.34 In 2011, Von Kodolitsch et al. reported that in MFS, the prevalence of MVP was 40 %, of severe MR was 12 % and of infective endocarditis was 2.5 %.29 More severe myxomatous MV thickening with prolapse occurred in 25 % of MFS patients.27 The reported outcomes of MVP and MVP-related events in 112 patients with MFS were as follows: bileaflet MVP affected 62 %, with anterior MVP occurring more often than posterior MVP. MR progression (related to a floppy MV and increased end-systolic LV dimensions) was seen in 37 %. MV infective endocarditis, heart failure and the need for MV replacement

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and repair were seen in 28 % (predicted by floppy MV and mild or moderate MR). Aortic dilatation, dural ectasia and ectopia lentis were not related to the outcome of MVP. Neither blood pressure nor medication (beta-blocker and angiotensin receptor blockers) had any effect on MV-related outcomes.29

can therefore improve cardiovascular function when congestive failure is present.48 It has been reported that 2.9 % of MFS patients without significant valvular disease experience heart failure.41 In MFS with end-stage heart failure, orthotopic transplantation is effective.49 In addition in MFS, acute onset heart failure may be caused by aortic dissection with aortic valve insufficiency.1

Tricuspid Valve and the Pulmonary Artery Tricuspid valve thickening, prolapse and regurgitation are common findings in MFS patients.1 These may occur due to degeneration of the tricuspid valve. In the study of Gu et al.,25 tricuspid valve involvement was seen in 12 % of MFS patients who underwent valvular or aortic surgery, severe tricuspid valve regurgitation was seen in 3 % of them and required valve repair. Moreover, tricuspid valve involvement sometimes occurred with MV involvement.

PA dilatation is also a minor criterion for MFS,32 usually occurring at the level of the root.35 In a cross-sectional study of adult MFS patients, computed tomography (CT) or magnetic resonance imaging (MRI) was performed to evaluate the PA.36 In normal subjects, the mean PA diameter was 24.0 ± 2.0 to 27.2 ± 3.0 mm. In MFS patients, the mean PA root diameter was 35 mm and mean PA trunk diameter was 29.8 mm. There was a correlation between PA dilatation and severity of ascending aortic disease. PA dilatation (>30 mm) was found in 54.0 % of patients with MFS, and 34.5 % of patients with MFS undergoing ascending aortic surgery. Both PA and trunk diameters were larger in patients who underwent ascending aortic surgery than in patients who did not (p=0.041).36 Another study published in 2014 also examined PA dilatation in MFS.37 It was reported that PA dilatation (upper normal limit set as 26 mm in this study) was seen significantly more often in MFS patients than in normal controls, 69.4 % and 4.9 %, respectively. They also reported that PA aneurysm existed in 15.3 % of MFS patients.37 Pulmonary hypertension can be the result.38,39

Left Ventricular Dilatation and Dysfunction LV dimensions and configuration are normal in most MFS patients.40 A proportion (up to 7 %) have LV dilatation without other features of idiopathic dilated cardiomyopathy.40 In MFS patients with significant mitral, aortic or TR, LV dilatation and dysfunction may occur due to volume-overload. MVP may cause significant MR and heart failure, and 5 % of MFS patients with MVP develop heart failure.29 However, some MFS patients appear to develop ventricular dysfunction independently, in the absence of significant valvular regurgitation. Approximately 25 % of MFS patients have mild (<10 %), asymptomatic reduction in LV ejection fraction, suggesting impaired systolic function and underlying cardiomyopathy.41 In this group, 25.0 % have increased indexed left ventricular end-diastolic volume (LVEDV) and 30.9 % have increased left ventricular end-systolic volume (LVESV).41 Some of these patients also have right ventricular (RV) systolic dysfunction.41 LV ejection fraction and RV ejection fraction are strongly correlated.42 De Backer et al. reported some MFS patients have mild but significant LV systolic and diastolic dysfunction.43 To detect or predict changes of cardiac deformation or function, strain rate imaging may be useful for unoperated adults with MFS.44,45

Arrhythmia and Sudden Cardiac Death In 1997, Savolainen et al. investigated 45 adult patients with MFS50 and found the prevalence of cardiac arrhythmias, prolonged atrioventricular conduction, ST segment depression and ventricular repolarisation abnormalities such as QT interval prolongation, was higher than in the general population.50 Patients with MFS had more frequent atrial arrhythmias >1 extra premature beat/hour, ventricular arrhythmias >1 beat/hour, ventricular arrhythmias >10 beats/hour, ventricular salvos of >3 beats and R on T phenomenon. The most common arrhythmias were premature atrial or ventricular beats.

This was not related to aortic root dilatation, left atrial dilatation, LV dilatation or function. It was presumed that deficiency of fibrillin-1 in patients with MFS, which causes microfibril abnormality in the matrix of the myocardium, affects conduction of impulses.50 Most arrhythmia does not lead to life threatening complications in patients with MFS; however, ventricular arrhythmia may occur in patients with repolarisation abnormality.50,51 Yetman et al. reported that ventricular arrhythmia was seen in 21 % of MFS patients and 4 % died from arrhythmia.51 Aydin et al.52 reported that in MFS, ventricular couplets and non-sustained ventricular tachycardia (VT) were seen in 40 % and premature ventricular contractions (PVCs) >10 beats/ hour were seen in 35 % of patients. PVCs, couplets, non-sustained VT and ventricular arrhythmias were related to N-terminal pro-brain natriuretic peptide (NT-proBNP) level elevation, left atrial dilatation, end-systolic LV dilatation, moderate MR and prolonged corrected QT (QTc). LV dysfunction and exon 24–32 mutations in the FBN1 gene also increased the risk of ventricular arrhythmia. In this cohort, the incidence of ventricular arrhythmias was 48 % and the incidence of ventricular arrhythmic event was 12 % including 4 % of SCD. The prevalence of ventricular arrhythmic events including SCD was 8 %, higher than in the general population.52 PVCs appear to be an independent risk factor for sudden death. Hoffmann et al. reported that 2.1 % of their MFS patients experienced SCD and 6.5 % had sustained VT. In this cohort, NT-proBNP levels ≥214.3 pg/ml carried a significant risk of SCD.46 These patients had a higher New York Heart Association (NYHA) classification and decreased LV function. Impaired LV function was also a risk factor for SCD. Overall the incidence of SCD in MFS is thought to be 0.92 per 1,000-person-years and in those with MFS aged 18–50 years is thought to be 0.09 per 1,000-personyears. Currently it is not possible to predict SCD by FBN1 mutation type.46 Abnormal heart rate turbulence parameters due to imbalanced autonomic dysfunction appears to be a risk factor for ventricular arrhythmia and SCD in patients with MFS.53

Investigations Echocardiogram

Impaired LV ejection fraction is a key factor for sudden cardiac death (SCD).46 Although de Witte et al. reported that there were no correlations between aortic elasticity and LV ejection fraction, 47 increases in LV afterload caused by aortic root stiffness48 as well as ECM remodelling and abnormal TGF-beta due to fibrillin deficiency, may contribute to impaired LV function.46 Afterload reducing agents

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Echocardiography is widely used for evaluation of cardiac valves and the aortic root, as it is convenient and non-invasive, and can be used in case of emergency. Following initial diagnosis, a second echocardiogram (ECG) should be performed after 6 months to assess the growth of aortic diameter and decide the interval for follow-up.54 Thereafter, echocardiography should be performed at least once a

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Cardiomyopathy and Inherited Heart Disease year in adults, unless aortic diameter is 4.5 cm or over, or there is recent major change in the aorta, when echocardiography should be performed twice a year.10 The incidence of aortic dissection is increased in those patients with more rapid increase in aortic diameter compared with those with a slower rate of growth.

Measurements of the aortic diameter are made in the parasternal long axis view at end-diastole using the leading-edge to leading-edge convention parallel to the aortic annular plane.55 In order to measure the maximum aortic diameter, the apical long axis view of the aorta is also helpful. Aortic diameter should be checked at the annulus, sinuses of Valsalva, ST junction, ascending aorta, descending aorta and abdominal aorta. The annulus is measured during mid-systole and other measurements are made at end-diastole.56 As mentioned before, aortic diameter depends on age, height and gender.19 Women have smaller aortas by 5 mm on average.57,58 Devereux et al. studied aortic root diameters in normal subjects and found that men had larger aortic diameters and so did people with a larger BSA.19 They devised the Z-score, calculated using height as shown below:19 Predicted aortic root (cm) for length = 1.519 + (age × 0.010) – (sex [male = 1; female = 2] × 0.247) Z-score = (Measured diameter – predicted aortic root) / SD [model SD = 0.215 cm, with a SD of 0.125 cm] In case of large BSA patients, it is suggested that this equation be used, as aortic diameter more than 40 mm should always be considered as dilated.56

Computed Tomography or Magnetic Resonance Imaging CT, MRI and transoesophageal echocardiography all have high sensitivity and specificity for diagnosis of aortic dissection.10 CT is used for evaluation of the aorta and coronary arteries, and diagnosis of aortic dissection. MRI allows detailed assessment of the aorta, valve disease and ventricular size. If patients have chest deformities, the MRI is a good tool for evaluation. Evaluation of this systemic condition including whole aorta is possible by MRI without radiation.

Two types of measurement of the aortic root are used: cusp– commissure and cusp–cusp. It is said that the aortic root diameter measured from cusp–commissure in diastole by non-contrast MRI is similar to the aortic diameter measured using inner edge–inner edge by echocardiography.59 For patients who have had surgery to replace their aortic root, CT or MRI should be done before discharge to evaluate structures beyond the aortic root, i.e. the aortic arch, descending aorta and the abdominal aorta.54 This should be repeated every 6 months until the aortic diameter has been stable, as some patients who have had aortic surgery will develop distal aortic dilatation.9

leads to impaired conduction.50 Repolarisation abnormalities are thought to be related to LV dilatation51 and PQ interval duration is thought to be associated with heart structure.50 The European Society of Cardiology guidelines suggest that patients who have cardiac symptoms should have a 24-hour ECG, as ventricular arrhythmia, conduction disorder and SCD may occur in this group.58

Prevention and Treatment Daily Life In the 1970s, the life expectancy of people with MFS was 40–50 years with death occurring due to aortic dissection, or heart failure from aortic or MR.60 Due to progression of medical and surgical therapy, life expectancy has vastly improved and now approaches that of the general population.61,62 MFS patients require appropriate exercise, isometric and isokinetic exertion at less than maximal effort. However, to avoid severe cardiovascular complications they should avoid contact sports, which may cause chest trauma, and also ocular complications such as ectopia lentis. Sports such as rugby and heavy weightlifting cause straining, which may produce Valsalva strain (breath-holding).

Valsalva manoeuvres result in sudden increases in heart rate and blood pressure. 63 Increasing intrathoracic pressure results in decreasing venous return, leading to systolic pressure and heart rate decrease. Due to baroreceptor reflex, heart rate and peripheral blood pressure increase. In general, patients with MFS are recommended to perform low- to moderate-intensity exercise.

They should also have regular blood pressure checks and, according to European guidelines, blood pressure should be kept under 120/80 mmHg. If aortic dissection occurs, the target systolic blood pressure is lower still at 110 mmHg.58 Risk factors that accelerate expansion of the aortic wall should be addressed and modified. Smokers have a higher aortic dilatation expansion rate and higher occurrence of dissection than nonsmokers. Smoking should therefore be avoided by patients with MFS as it is related to vascular complications.64 About 30 % of patients with MFS have obstructive sleep apnoea (OSA) or central sleep apnoea (CSA).65 The reasons for OSA might be upper airway collapsibility, high nasal airway resistance and craniofacial abnormalities. There is an association of severity of sleep apnoea with aortic dilatation or dissection. It is thought to be related to progression of aortic dilatation, as this increases pleural pressure during sleep. As continuous positive airway pressure (CPAP) may stop aortic diameter progression, patients who have OSA should be treated with CPAP. Sleep apnoea is also an independent risk factor for reduced LV ejection fraction and increased NT-proBNP. Elevation of NT-proBNP is caused by both systolic and diastolic dysfunction. MFS patients with decreased ejection fraction have diastolic dysfunction before systolic dysfunction occurs.65,66

Medical Treatment Beta-blockers

Electrocardiogram and 24-hour Electrocardiogram The ECG in MFS sometimes demonstrates abnormal findings, including atrioventricular conduction delay, QT interval prolongation and ST depression. These findings do not appear to be related to aortic root diameter, but rather to cardiac structure and function and valve condition. As mentioned before, it is thought that fibrillin-1 deficiency causes microfibrillar abnormality in the myocardium, which in turn

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Beta-blockers are currently used to reduce the progression of aortic root dilatation. Frequency of aortic dissection and rupture is higher among hypertensive patients, and beta-blockers are therefore used to reduce these adverse aortic events in MFS. The target heart rate is under 60–70 beats per minute at rest and up to 100 beats per minute during exercise.10 Beta-blockers inhibit adrenergic betaactivation that occurs when adrenaline is released into the blood

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from sympathetic nerves and the adrenal gland. In the heart, betareceptor stimulation increases heart rate and cardiac contraction, and excitation conduction in the atrioventricular node. Thus beta-blocker therapy decreases heart rate, cardiac contraction and myocardial oxygen consumption. Some studies have shown that beta-blocker reduces blood pressure and heart rate, and thus reduces progression of aortic root size.67,68,69 Aortic stiffness is also reduced and aortic distensibility increased by beta-blockers.10 However, there are no reports which indicate that aortic dissection or prophylactic surgery can be completely avoided by beta-blockers.54 Beta-blockers are more effective in patients with less severe aortic dilatation, <4.0 cm.67 beta-blockers are recommended for use in the early stages regardless of aortic dilatation because the aorta dilates most between the ages of 6â&#x20AC;&#x201C;14 years old.68 The main side effects of beta-blockers are bronchospasm, hypotension and bradycardia, and these should be monitored. Beta-blockers also affect glucose and lipid metabolism, and in patients with diabetes may mask the symptoms of hypoglycaemia, for example palpitations, tremor and hunger. In children, sleep disturbances are common side effects.70

beta-blocker demonstrated slower aortic dilatation progression than those on beta-blocker alone.74 However, these effects may not apply to children and adolescents. In 2014, Dietz et al. compared the effect of losartan versus atenolol over 3 years in 608 children and young adults with MFS who were 6 months to 25 years old. They found no significant difference in the rate of aortic root dilatation, aortic surgery, aortic dissection and death between the two regimens.75 Subsequently, a Spanish trial compared losartan versus placebo in 140 patients and aortic root progression rate was not different, although blood pressure was significantly decreased in the losartan group.76 Moreover, a French trial called Marfan Sartan also resulted in no significant difference in aortic root dilatation between the losartan and the placebo group.77 Considering these results, losartan might be effective for reducing the rate of aortic root dilatation and can be administered when patients are intolerant of beta-blocker; however, the effect of losartan reducing aortic root dilatation is not superior to that of beta-blocker. Hence, beta-blocker remains the first choice for treatment of MFS patients. Two further trials are ongoing in Italy and the UK at present. The Italian trial compares losartan versus nebivolol versus both, and the UK trial compares irbesartan versus placebo; these results are awaited.78,79

Angiotensin Convering Enzyme Inhibitors Angiotensin Receptor Blocker TGF-beta is produced when angiotensin II (AngII) combines with angiotensin II type 1 receptor (AT1R). As explained previously, TGF-beta signalling is excessive in MFS due to abnormal fibrillin-1. Increased activation and signalling of TGF-beta causes aneurysm formation and dissections due to ECM degradation, and consequent apoptosis and inflammation. As activation and signalling of TGF-beta are increased in MFS patients, inhibiting these pathways is felt to be effective therapy.7 Indeed, when mice with FBN1 mutations were treated with TGF-beta antibody, myxomatous degeneration of aortic and MVs was prevented.

Use of AT1R antagonists (losartan) produced similar effects.71 Losartan is an angiotensin receptor blocker (ARB) used to control blood pressure. ARBs act on the renin-angiotensin pathway.72

Yetman et al. compared ACE inhibitor (enalapril) versus beta-blocker (atenolol or propranolol). 80 Aortic distensibility was increased and aortic stiffness index was reduced in MFS patients. Aortic root diameter increase was equally likely in the two medication groups. ACE inhibitor reduces central arterial pressure and arterial stiffness. 81 Activation of AT2R promotes apoptosis of vascular smooth muscle cells and cystic medial degeneration. ACE inhibitors can prevent cystic medial degeneration and apoptosis of vascular smooth muscle cells. 82 However, if patients suffer from dry cough because of bradykinin-mediated side effects, taking this drug should be avoided.

Calcium Channel Blockers The glomerulus in the kidney senses blood pressure. If blood pressure is low, renin is secreted, and if blood pressure is high, renin secretion decreases and renin concentrations affect those of angiotensinogen and angiotensin I (AngI). AngI is converted to AngII by angiotensin converting enzyme (ACE). AngII combines with the angiotensin II receptor; when it combines with AT1R in vascular smooth muscle, vasocontraction occurs, and when it combines with angiotensin II receptor type 2 (AT2R) in adrenal cortex, secretion of aldosterone is stimulated and causes increased blood pressure. ARBs inhibit AngII binding to AT1R, and ARBs reduce AngII action at the AT1R and AT2R. ARBs block AT2R producing antihypertensive effects and block the AT1R reducing endothelial production of TGF-beta. Additionally, AT2R inhibits AT1R, which inhibits ECM degradation, apoptosis and inflammation, thus delaying aneurysm formation.7,72

Calcium channel blockers (CCBs) are sometimes used when the patient cannot take beta-blockers, for example because of asthma.

However, no comparisons between CCBs and beta-blockers have been reported.83 One study comparing CCBs versus placebo in wild type mice and MFS mice was reported. According to this study, CCBs might increase the risk of aortic events such as aortic dissection or aortic surgery.84

Nitrates Nitrates have the effect of venodilatation. These agents reduce pulse wave reflection from arterial branches, resulting in decreased central aortic pressure. This may decrease the rate of aortic dilatation progression and the tendency to dissect.83

Doxycycline There are trials, some already reported and others ongoing, to evaluate the effect of losartan in MFS. According to a prospective, randomised controlled trial published in the Netherlands, losartan use reduced aortic root dilatation rate in adult patients with MFS.73 This study also showed that the reduction of aortic root dilatation rate was irrespective of age, sex, blood pressure, aortic root size, presence of FBN1 mutation and concomitant beta-blocker use. Another small trial in Taiwan also showed patients treated with losartan and

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In 2008, it was shown that administration of the antibiotic doxycycline (a member of the tetracycline family) to mice, inhibited the expression of matrix metalloproteinase 2 and 9 (MMP-2 and -9) (both type 4 collagenases) and delayed elastic fibre disruption and aortic rupture.85 When doxycycline was compared with atenolol in the MFS animal model, animals administered doxycycline did not develop aortic aneurysms. 86 Doxycycline is thought to affect endothelial function, elastic fibres86 and the structure of the aortic

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Cardiomyopathy and Inherited Heart Disease wall. However, as doxycycline has not been tested in patients with MFS, we do not yet have strong evidence to use this drug for inhibiting aortic dilatation.54

Management of Ventricular Arrhythmias Patients with MFS should be carefully monitored for early detection of arrhythmia with resting and/or stress ECGs and periodic 24 hour ECG recordings.87 As arrhythmias may be secondary to other cardiac conditions, it is essential to also treat coexisting cardiac disorders. LV dilatation is associated with ventricular arrhythmias in MFS patients; this should be routinely measured and monitored through echocardiography. Beta-blockers, primarily used to prevent aortic dilatation, are thought to provide a parallel protection against arrhythmias. Sometimes atrial fibrillation and ventricular arrhythmia are related to the renin-angiotensin system (RAS), especially in the case of heart failure and myocardial hypertrophy. Agents like ARBs and ACE inhibitors are likely to play a role in reducing the incidence of arrhythmias indirectly by decreasing the primary cardiac disorder, and directly by modulating alterations in ion channels in RAS.87 However, further research is necessary to elucidate the potential role of RAS inhibitors in the prevention of cardiac arrhythmias in MFS patients.

Hoffmann et al.46 demonstrated NT-proBNP to be an independent predictor of adverse arrhythmias in patients with MFS, and this new finding might help in selecting patients who are at risk of developing life threatening arrhythmias. Myocardial dysfunction may occur in patients with MFS and may lead to malignant arrhythmia such as ventricular fibrillation. In one case report, a MFS patient with impaired LV function received a cardiac resynchronisation therapy-defibrillator (CRT-D) and experienced improvement through reduced morbidity and less frequent hospitalisation for heart failure.88 Patients at high risk of developing malignant arrhythmias are referred for either an implantable cardiac defibrillator (ICD) or pacemaker.

Surgical Treatment Prophylactic aortic replacement may be undertaken to avoid aortic dissection. European guidelines suggest that when the aortic root diameter reaches 5.0 cm, MFS patients should undergo surgery. 58 At 4.5 cm, MFS patients are recommended to undergo surgery if they have risk factors for dissection, i.e. a family history of dissection, rate of growth >2 mm per year, severe AR or MR, or desire for pregnancy. 58,89 However, as the routine cut-off measurement of 5.0 cm may be too late from a logistics perspective (due to constraints such as waiting time). A more realistic value of 4.8 cm is thought to be appropriate for referral. In cases of Stanford type A dissection, patients should be offered emergency surgery, because the mortality within a 48 hour period is 50 % (notwithstanding a perioperative mortality of 25 % and risk of complications).13 Surgery reduces 1 month mortality from 90 to 30 %, including dissection patients without MFS.13 Aortic root surgery is becoming safer. The mortality of elective surgery is 1.5 % compared to that of emergency surgery (11.7 %), survival rate at 5 years is 84 % and at 10 years is 75 %. However, MFS patients have a higher recurrence risk of dissection and aneurysm than in other aortic diseases.90 In Stanford type B dissection, which is seen in 10 % of all aortic dissection in patients with MFS,18 medical treatment is recommended unless there are complications requiring surgery. In all forms of acute aortic dissection, careful pain and blood pressure control is paramount.

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Stent Graft In aortic dissection type B with complications, for example ischaemia of the lower body or impending aortic rupture, surgery has a higher risk and a stent graft may be used to prevent false lumen enlargement.

A stent graft may also be used for patients in whom open surgery is contraindicated.91,92 However, a systematic review reported that although MFS patients with dissection who have had stent graft had 1.9 % mortality, 21.6 % of patients had about 2â&#x20AC;&#x201C;3 times the incidence of periprocedural endoleaks compared with non-MFS patients. The problem of endoleaks persisted at an average follow-up of 2.5 years and the final mortality was 12 %.93 For these reasons, stent graft for patients with MFS is not recommended.

Endocarditis Infective endocarditis can be difficult to prevent as it may occur from such activities as brushing teeth, chewing or flossing.58 According to the National Institute for Health and Care Excellence (NICE) guidelines, patients with acquired valvular heart disease with regurgitation, previous infectious endocarditis or valve replacement are at risk of infectious endocarditis and are recommended prophylactic antibiotics.94 These guidelines do not recommend antibiotics for patients undergoing dental procedures, upper and lower gastrointestinal tract, genitourinary tract and upper and lower respiratory tract procedures.94 However, according to guidelines of the American Heart Association, some patients with MVP, surgical prosthetic material or a history of endocarditis should take prophylactic antibiotics when undergoing dental procedures or minor surgery.10.95 In the general population, endocarditis developed in only 0.48 % with asymptomatic MVP.96 On the other hand, in a cohort study, MVP and endocarditis were found in 40.0 % and 2.5 % of classic MFS patients, respectively,30 and it was reported that the chance of MFS patients developing MV endocarditis was 0.92 % at 30 years increasing to 13.42 % at 60 years of age.30 Another cohort study investigating classic MFS patients who had MVP with mild to moderate MR reported 6 % of patients developed MV endocarditis. MV-related events including MVP were supposed to be predicted by flail mitral leaflet and mild to moderate MR.29 MFS patients with MVP might have a higher risk of endocarditis.

The Marfan Foundation also recommends prophylaxis of endocarditis for MFS patients who have valvular regurgitation, because although other guidelines do not recommend prophylaxis of endocarditis for patients with valvular regurgitation without personal endocarditis history, there is no risk stratification of endocarditis in the case of patients with systemic connective tissue disorder.97

Conclusion Treatment strategies for cardiac manifestations including betablockers, elective aortic root replacement and MV repair surgery have improved the life expectancy of people with MFS. Despite this improvement, cardiac morbidity remains a major concern among individuals with MFS. Newer approaches, such as the use of ARBs are believed to partly exert their beneficial effects by reducing TGFbeta activity, which has been recognised to play a pivotal role in the pathogenesis of the cardiac manifestations in MFS. However, ARBs have important limitations, and therefore further studies need to be performed to develop therapies that are specifically aimed at reducing TGF-beta activity. n

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Aortic root growth in men and women with the Marfan’s syndrome. Am J Cardiol 2005;96 :1441–4. DOI: 10.1016/j. amjcard.2005.06.094; PMID: 16275195 58. Baumgartner H, Bonhoeffer P, De Groot NM, et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31 :2915–57. DOI: 10.1093/eurheartj/ehq249; PMID: 20801927 59. Burman ED, Keegan J, Kilner PJ. Aortic root measurement by cardiovascular magnetic resonance: specification of planes and lines of measurement and corresponding normal values. Circ Cardiovasc Imaging 2008;1 :104–13. DOI: 10.1161/ CIRCIMAGING.108.768911; PMID: 19808527 60. Pyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart 2009;95 :173–5. DOI: 10.1136/hrt.2008.160515; PMID: 19001001 61. Finkbohner R, Johnston D, Crawford ES, et al. Marfan Syndrome: Long-term survival and complications after Aortic aneurysm repair. Circulation 1995;91 :728–33. PMID: 7828300 62. Silverman DI, Burton KJ, Gray J, et al. Life expectancy in the Marfan syndrome. Am J Cardiol 1995;75:157–60. PMID: 7810492 63. Palatini P. Exercise haemodynamics: field activities versus laboratory tests. Blood Press Monit 1997;2 :133–7. PMID: 10234106 64. Boodhwani M, Andelfinger G, Leipsic J, et al. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol 2014;30 :577–89. DOI: 10.1016/j.cjca.2014.02.018; PMID: 24882528 65. Rybczynski M, Koschyk D, Karmeier A, et al. Frequency of sleep apnea in adults with the marfan syndrome. Am J Cardiol 2010;105 :1836–41. DOI: 10.1016/j.amjcard.2010.01.369; PMID: 20538140 66. Rybczynski M, Koschyk DH, Aydin MA, et al. Tissue Doppler imaging identifies myocardial dysfunction in adults with Marfan syndrome. Clin Cardiol 2007;30 :19–24. DOI: 10.1002/ clc.3; PMID: 17262773 67. Rios AS, Silber EN, Bavishi N, et al. Effect of long-term betablockade on aortic root compliance in patients with Marfan syndrome. Am Heart J 1999;137 :1057–61. PMID: 10347331 68. Salim MA, Alpert BS, Ward JC, Pyeritz RE. Effect of betaadrenergic blockade on aortic root rate of dilation in the Marfan syndrome. Am J Cardiol 1994;74 :629–33. PMID 7915491 69. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994;330 :1335– 41. DOI: 10.1056/NEJM199405123301902; PMID: 8152445 70. Gersony DR, McClaughlin MA, Jin Z, Gersony WM. The effect of beta-blocker therapy on clinical outcome in patients with Marfan’s syndrome: a meta-analysis. Int J Cardiol 2007;114 :303–8. DOI: 10.1016/j.ijcard.2005.11.116; PMID: 16831475 71. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312 :117–21. DOI: 10.1126/ science.1124287; PMID: 16601194; PMCID: PMC1482474 72. Cook JR, Carta L, Galatioto J, Ramirez F. Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes. Clin Genet 2015;87 :11–20. DOI: 10.1111/cge.12436; PMID: 24867163 73. Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013;34 :3491–500.

DOI: 10.1093/eurheartj/eht334; PMID: 23999449 74. Chiu HH, Wu MH, Wang JK, et al. Losartan added to -blockade therapy for aortic root dilation in Marfan syndrome: a randomized, open-label pilot study. Mayo Clin Proc 2013;88 :271–6. DOI: 10.1016/j.mayocp.2012.11.005; PMID: 23321647 75. Lacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med 2014;371 :2061–71. DOI: 10.1056/NEJMoa1404731; PMID: 25405392; PMCID: PMC4386623 76. Forteza A, Evangelista A, Sánchez V, et al. Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. Eur Heart J 2016;37 :978– 85. DOI: 10.1093/eurheartj/ehv575; PMID: 26518245

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Cardiomyopathy and Inherited Heart Disease 77. Milleron O, Arnoult F, Ropers J, et al. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J 2015;36 :2160–6. DOI: 10.1093/eurheartj/ehv151; PMID: 25935877 78. Franken R, Mulder BJM. Aortic disease: Losartan versus atenolol in the Marfan aorta—how to treat? Nat Rev Cardiol 2015;12 :447–8. DOI: 10.1038/nrcardio.2015.95; PMID: 26076947 79. Pitcher A, Emberson J, Lacro RV, et al. Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists’ Collaboration. Am Heart J 2015;169 :605–12. DOI: 10.1016/j .ahj.2015.01.011; PMID: 25965707; PMCID: PMC4441104 80. Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol 2005;95 :1125–7. DOI: 10.1016/j.amjcard.2005.01.032; PMID: 15842990 81. Asmar RG, London GM, O’Rourke ME, et al. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001;38 :922–6. PMID: 11641310 82. Nagashima H, Uto K, Sakomura Y, et al. An angiotensinconverting enzyme inhibitor, not an angiotensin II type1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. J Vasc Surg 2002;36 :818–23. PMID: 12368744 83. Williams A, Davies S, Stuart AG, et al. Medical treatment of Marfan syndrome: a time for change. Heart 2008;94 :414–21.

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Stress and Heart Disease

Viewpoint: Role of Mind–body Therapies in the Management of Cardiovascular Disorders Kavita Prasad St George’s, University of London, London, UK; Mayo Clinic College of Medicine, Mayo Clinic, Rochester, USA

Abstract Cardiovascular disorders (CVD) are the leading cause of death across the globe. The estimated cost to the National Health Service and UK economy is £30 billion. These costs continue to escalate despite major advances in pharmacotherapy and devices, which, in part, is due to improved survival, but also greater resource utilisation per patient. Hence, there is a need to develop cost-effective adjunctive therapies beyond conventional strategies. Mind-body therapies– including mindfulness and meditation, emotional regulation, practicing ‘heartfelt’ emotions including gratitude and compassion– may be novel low-cost approaches to reduce morbidity and mortality in CVD.

Keywords Mental stress, mindfulness, cardiovascular disorders Disclosure: The author has no conflicts of interest to declare.

Submitted: 17 May 2016 Accepted: 12 July 2016 Citation: European Cardiology Review, 2016;11(2):111–3 DOI: 10.15420/ecr.2016:17:2 Correspondence: Dr Kavita Prasad BSc Hons, MBBS, FACP, Consultant in Integrative Medicine and Honorary Senior Lecturer, St George’s, University of London, Blackshaw Road, London, SW17 0QT, UK. E: kprasad@sgul.ac.uk

Role of Mental Stress in Cardiovascular Disease The pathophysiology of how mental stress affects and modulates the cardiovascular system is incompletely understood. Chronic stress has long been suspected to be a risk factor for cardiovascular disorders (CVD), either through direct or indirect mechanisms.1,2 Stress is known to activate two biological systems: the hypothalamic-pituitary-adrenal axis as well as the sympathetic nervous system, leading to increases in noradrenaline, adrenaline, cortisol, blood pressure, inflammatory activity as well as altered glucose metabolism.3–7 The association between acute mental stress as a trigger for an acute cardiac event (e.g. angina, myocardial infarction, arrhythmias) or rarely sudden cardiac death is established.8–11 Epidemiological studies have demonstrated that the incidence of acute coronary syndromes increases immediately following natural disasters such as hurricanes, earthquakes and tsunamis. Common emotional stressors leading to anger or conflict, and sometimes happy events, have also been implicated as potential triggers.12 The relatively recent description of apical ballooning (Takotsubo) syndrome provides a very clear example of this relationship.13,14 Approximately one-third of patients presenting with this intriguing condition have an antecedent emotional stressor.15 Possible pathophysiological mechanisms for the impact of acute stress include sympathetic system mediated coronary artery vasoconstriction, tachycardia and hypertension leading to an acute mismatch of myocardial oxygen demand and supply. This is supported by evidence linking mental stress to endothelial dysfunction, exaggerated peripheral microvascular tone, including vasoconstriction of normal coronary artery segments.16,17 Mental stress may also promote cardiac electrical instability. Thus, the autonomic nervous system forms a key component of the mind–heart connection by linking our thoughts and emotions with the heart.

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The mechanism by which chronic stress influences CVD is less clear.

Animal models have suggested a myriad of potential mechanisms but their clinical significance remains to be determined.18 Potential mediators may include an altered diurnal pattern or blunting of stress hormones release, endothelial dysfunction, epigenetics and a proinflammatory response.18,19 Epidemiological studies have suggested that chronic mental stress, such as excessive work demands, may be harmful. In a recent meta-analysis, comprising data from 603,838 individuals who worked ‘long hours’ (≥55 h per week), there was an association with an increased risk of incident coronary heart disease (CHD).20 Stress-related psychological dispositions such as anxiety, depression and anger/hostility have also been linked to CHD.12,21,22 The INTERHEART study demonstrated a doubling in the incidence of myocardial infarction in individuals with chronic stressors, even after adjustment for conventional cardiovascular risk factors.23 Stress was defined as feeling irritable, filled with anxiety, or as having sleeping difficulties as a result of conditions at work or at home.

Stress is also associated with unhealthy lifestyle behaviours, such as smoking and alcohol consumption.24 Thus, further investigation is required to determine whether chronic stress is a marker or mediator of adverse cardiovascular health outcomes.

Neuroscience of Stress We recognise a close connection between mental stress and the brain; however, the exact mechanism by which stress affects the brain is incompletely understood. A possible pathophysiological mechanism by which the brain may respond to stress is outlined below. It is understood that the brain is both the mediator and target of the stress response with the deep limbic system and the prefrontal cortex modulating the stress response.3 Sensory inputs are processed via the thalamus into these two regions. The instinctive stress response

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Stress and Heart Disease operates via fast subcortical signalling directly to the lateral amygdala from dorsal thalamic nucleus. The lateral amygdala projects to the hypothalamus and the brain stem. The primary effectors of the stress response are the paraventricular nucleus of the hypothalamus and the anterior pituitary. A rationalised response is mediated via a slower cortical route via somatosensory and prefrontal cortex.

Chronic stress may potentially impair brain circuitry through the effects of glucocorticoids.25,26 In animal studies, repeated stress causes shortening of dendrites in the prefrontal cortex and increases dendritic growth in the amygdala. Stress also increases spine synapses in the amygdala. These changes are accompanied by impairment in tests of cognitive flexibility and attention switching.

The default mode network (DMN) appears to be central to modulating the long-term effects of stress, potentially through active recollection of past experiences and anticipation of future events during the stressfree periods.27,28 In an experimental model of stress in 51 healthy young men, functional magnetic resonance imaging was performed prior to stress, immediately following, and 2 hours later. A stress-induced rise in amygdala–hippocampal connectivity, a marker of the DMN, was documented, which was sustained for as long as 2 hours. The sustained limbic system activity was inversely correlated with impaired stress-induced cortisol response. There is some evidence to suggest that cortisol may regulate the activity of the amygdala and other brain regions involved in the stress response via a feedback loop.

and promote patient wellbeing. MBTs include mindfulness-based stress reduction (MBSR), meditation, guided imagery, progressive muscle relaxation, deep breathing exercises, yoga, tai chi, qigong, biofeedback as well as hypnosis. Meditation has been shown to have a beneficial effect on CVD risk factors such as hypertension, insulin resistance and myocardial ischaemia. In patients with CHD, meditation has been shown to reduce clinical events in conjunction with anger scores, potentially with a dose–response effect.31,32 MBTs also improve components of the metabolic syndrome, an important risk factor for cardiovascular disease.33–35 Prior studies have documented the efficacy of both mindfulness and concentrative meditation for decreasing symptoms of stress and anxiety.36–42 A recent review and meta-analysis showed a significant reduction in stress levels in addition to an improvement in spirituality levels in participants who attended the MBSR programmes compared with control subjects.43,44 As a result, MBT is gaining increasing attention from doctors and patients as a potential adjunct to promote chronic disease management (for example, see the US National Center for Complementary and Integrative Health's web page on mind and body practices [nccih.nih.gov/health/mindbody]).

The Mayo Clinic Stress Management and Resiliency Training (SMART) programme is another evidence-based intervention that uses attention training, mindfulness and paced breathing to facilitate recovery from stressful experiences and develop skills to deal with adversity.45,46

Mind-body Therapies as Adjunctive Therapies

Conclusion

Mind-body therapies (MBTs) might improve health via impacting some or all of these mechanisms.29 Mind-body medicine is a branch of integrative medicine gaining growing attention in clinical practice and public health circles as a critical tool to promote chronic disease management and enhance wellbeing and resilience.30

There is a need for innovative strategies to assist patients with CVD in reducing the impact of mental stress. Such initiatives will not only be a step in the right direction for disease management, but will also promote insights into the pathophysiological role of stress in CVD.

There have been few large-scale efforts to date to identify effective MBTs for stress management in patients with CVD. However, there is an emerging body of evidence to suggest that MBTs that reduce stress or enhance stress coping skills have beneficial effects in CVD

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DOI: 10.1207/s15327558ijbm1204_9; PMID: 16262547 38. Walton KG, Fields JZ, Levitsky DK, et al. Lowering cortisol and CVD risk in postmenopausal women: a pilot study using the Transcendental Meditation program. Ann N Y Acad Sci 2004;1032 :211–5. DOI: 10.1196/annals.1314.023; PMID: 15677413 39. Tacón AM, McComb J, Caldera Y, Randolph P. Mindfulness meditation, anxiety reduction, and heart disease: a pilot study. Fam Community Health 2003;26(1):25–33. PMID: 12802125 40. Speca M, Carlson LE, Goodey E, Angen M. A randomized, wait-list controlled clinical trial: the effect of a mindfulness

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meditation-based stress reduction program on mood and symptoms of stress in cancer outpatients. Psychosom Med 2000;62 (5):613–22. PMID: 11020090 Kabat-Zinn J, Massion AO, Kristeller J, et al. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry 1992;149 (7):936–43. DOI: 10.1176/ajp.149.7.936; PMID: 1609875 Miller JJ, Fletcher K, Kabat-Zinn J. Three-year follow-up and clinical implications of a mindfulness meditation-based stress reduction intervention in the treatment of anxiety disorders. Gen Hosp Psychiatry 1995;17 (3):192–200.

PMID: 7649463 Chiesa A, Serretti A. A systematic review of neurobiological and clinical features of mindfulness meditations. Psychol Med 2010:40 :1239–52. DOI: 10.1017/S0033291709991747; PMID: 19941676 Chiesa A, Serretti A. Mindfulness-based stress reduction for stress management in healthy people: a review and meta-analysis. J Altern Complement Med 2009; 15 (5):593–600. DOI: 10.1089/acm.2008.0495; PMID: 19432513 Sood A, Sharma V, Schroeder DR, Gorman B. Stress Management and Resiliency Training (SMART) program among Department of Radiology faculty: a pilot randomized clinical trial. Explore (NY) 2014;10 (6):358–63. DOI: 10.1016/ j.explore.2014.08.002; PMID: 25443423 Loprinzi CE, Prasad K, Schroeder DR, Sood A. Stress Management and Resilience Training (SMART) program to decrease stress and enhance resilience among breast cancer survivors: a pilot randomized clinical trial. Clin Breast Cancer 2011;11 (6):364–8. DOI: 10.1016/j.clbc.2011.06.008; PMID: 21831722

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Cardiovascular Pharmacotherapy ECR–ISCP Partnership Announcement

European Cardiology Review partners with the International Society of Cardiovascular Pharmacotherapy

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 Editor-in-Chief of European Cardiology Review.

I

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

The mission of the ISCP – an associate member of the World Heart Federation – is to foster research initiatives and develop educational programmes on topics related to cardiovascular pharmacology and pharmacotherapy. With representatives from over 35 countries worldwide in its ranks, the ISCP represents an important forum for vital discussions on cardiovascular pharmacotherapy. Among many educational activities, the ISCP supports two major initiatives, namely the Cardiovascular Pharmacotherapy Book Series, with the publication of an average of six volumes on the treatment of cardiovascular conditions per year, and the ISCP Annual Scientific Sessions, which attract a large audience of medical practitioners and healthcare professionals from the world over. The ISCP holds approximately 12 regional meetings annually, aimed at discussing novel issues in the field of cardiovascular and pharmacology and therapy.

Starting in this issue, each volume of ECR will contain a Cardiovascular Pharmacotherapy section that will be jointly edited by the president of the ISCP and myself. This section will publish review articles as well as original systematic reviews and meta-analyses on the most important developments in cardiovascular pharmacotherapy.

Recent outstanding clinical trials, with the potential to change clinical practice, will be presented and discussed by international experts in the field. We also plan to include editorial articles written by the president of the ISCP that will highlight important developments in the field and their potential impact on clinical practice. In addition, we will publish ‘expert opinion’ articles, which will be accompanied by brief scholarly comments by other experts and online interviews with key scientists and opinion leaders.

This is an exciting project that both ECR and ISCP are embracing with optimism, determination and great enthusiasm. We hope that our readers will find this new initiative valuable for their day-to-day practice as well as a means to gain insight into the new developments in the field of cardiovascular pharmacotherapy. n

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Cardiovascular Pharmacotherapy ISCP Editorial

Cardiovascular Pharmacotherapies Focus Are low doses of direct-acting oral anticoagulants justified and appropriate in patients with nonvalvular atrial fibrillation?

Antoni Martínez-Rubio President Elect of the International Society of Cardiovascular Pharmacotherapy, based at the Department of Cardiology, University Hospital of Sabadell and the Autonomous University of Barcelona, Barcelona, Spain

Gheorghe-Andrei Dan Past President of the International Society of Cardiovascular Pharmacotherapy, based at the Department of Cardiology, Colentina University Hospital, Faculty of Medicine, University of Bucharest, Bucharest, Romania

Disclosure: AMR has participated in scientific advisory boards or activities for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Daiichii Sankyo and has received research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer. GAD has received small speaker’s fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer, and research grants from the same companies.

Citation: European Cardiology Review, 2016;11(2):115–7. DOI: 10.15420/ecr.2016:11.2:ED2

The novel direct-acting oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban and rivaroxaban overcome most drawbacks of vitamin K antagonists and have proven efficacious and safe in well-designed multicentre randomised clinical trials.1–4 Furthermore, the advantages of NOACs over vitamin K antagonists have been demonstrated in several specific groups of patients with atrial fibrillation (AF).5 Various cardiology societies now therefore recommend NOACs as first-choice oral anticoagulants in patients with nonvalvular AF.6–8 The four pivotal NOAC trials in patients with AF had very important differences in design, doses, population and results (see Table 1).

Importantly, in the three trials comparing rivaroxaban (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation: ROCKET-AF), apixaban (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation: ARISTOTLE) and edoxaban (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation: ENGAGE-AF) with warfarin, different subgroups of patients received reduced doses of NOACs. In ROCKET-AF, the dose of rivaroxaban was reduced from 20 mg/d to 15 mg/d (a 25 % reduction) in patients with low creatinine clearance (30–49 mL/min).2 In ARISTOTLE, the dose of apixaban was reduced from 5 mg/12h to 2.5 mg/12h (a 50 % reduction) in patients with two or more of the following risk factors: age >80 years, weight <60 kg and serum creatinine >1.5 mg/ dL.3 ENGAGE-AF had three treatment arms: patients were randomised to receive warfarin or 60 mg/d edoxaban or 30 mg/d edoxaban, but the doses of NOAC were halved in patients with low creatinine clearance (30–50 mL/min), weight <60 kg or concomitant use of verapamil, quinidine or dronedarone, and the dose reduction could be reverted if its cause was transitory.4 Thus, except in ENGAGE-AF, the doses of

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NOACs were adjusted at baseline in relation to patient characteristics and could not be modified thereafter.

Unlike these three trials that compared the overall results of NOACs versus warfarin in mixed populations receiving full or reduced (between 25 % and 50 % reduction) NOAC doses, the Randomised Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial established three arms of similar size (each containing >6,000 patients) with enough statistical power to evaluate the noninferiority of each dose of dabigatran (150 mg/12h or 110 mg/12h) versus warfarin for preventing stroke and systemic embolism in nonvalvular AF.1 In this trial, the doses of dabigatran were maintained during the follow-up period. Thus, in the RE-LY trial all patients randomised to either dose of dabigatran received the full dose, whereas in the ROCKET-AF, ARISTOTLE and ENGAGE-AF trials, the dose of the NOAC was reduced at baseline (after randomisation) in 20.7 %, 4.7 % and 25.4 % of patients, respectively.

Since their approval, the NOACs’ advantages over warfarin have been reaffirmed in clinical praxis in diverse populations where confounding factors (e.g. concomitant drugs or diseases) may be present or patients might not follow the prescribed treatment.9–11 Subgroup analyses of lowdose regimens in the pivotal studies of NOACs in nonvalvular AF revealed no alert signs (clear differences in thromboembolic risk) versus the higher dose (non-significant interaction p-value).1–4 Nevertheless, physicians should be aware that only limited numbers of patients received the reduced doses of rivaroxaban, apixaban and edoxaban in the pivotal studies, and there was not enough statistical power to specifically compare the low doses against warfarin. Thus, the benefits of a very conservative approach with a low-dose NOAC to avoid bleeding must be carefully weighed against the risk of the thromboembolic complications

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Cardiovascular Pharmacotherapy ISCP Editorial Table 1: Overview of the Designs, Populations and Outcomes of the Four Pivotal Studies Comparing Novel Oral Anticoagulants (NOACs) with Warfarin

A

RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE-AF

Study design

Randomised, open-label with blinded events adjudication

Randomised, double blind

Randomised, double blind

Randomised, double blind

Number of patients

18,113

14,264

18,201

21,105

Intervention

3 parallel groups: – dabigatran E 110 mg twice daily – dabigatran E 150 mg twice daily – warfarin (INR 2–3) per day

2 parallel groups: – rivaroxaban 20 mg once daily (15 mg once daily if CrCl 30–49 ml/min) – warfarin (INR 2–3) per day

2 parallel groups: – apixaban 5 mg twice daily (2.5 mg twice daily if at least two risk factors: age >80 years, weight <60 kg or creatinine >1.5 mg/dL) – warfarin (INR 2–3) per day

3 parallel groups: – edoxaban 60 mg once daily – edoxaban 30 mg once daily (half doses if CrCl 30–50 ml/min or weight <60 kg or concomitant use of verapamil or quinidine or dronedarone) – warfarin (INR 2–3) per day

Follow-up

Minimum 12 months Median: 2 years Lost: 0.1%

Until 405 events Median: 1.94 years Lost: 0.2%

Until 448 events Median: 1.8 years Lost: 0.4%

Until 672 events Median: 2.8 years Lost: 0.5%

B

RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE-AF

Patients

18,113

14,264

18,201

21,105

Age (years, median)

71

73

70

72

Males (%)

63.6

60.3

64.5

61.9

CHADS2 score (mean, %) 0–1 (%) 2 (%) 3+ (%)

2.1 32 35 33

3.5 0 14 86

2.1 34 35.8 30.2

2.8

Stroke/TIA/ previous embolism (%)

20

55

20

28

Paroxysmal atrial fibrillation (%)

33

17

15

25

Heart failure (%)

32

63

36

57

77/23*

AAS at start of study (%)

39

36

39

29

Without previous OAC experience (%)

50

38

43

41

C

RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE-AF

Time in therapeutic range (warfarin group)

64.4%

55%

62.2%

64.9%

Stroke/systemic embolism (relative risk reduction)

Dabigatran 150 mg: -35% (p<0.001) Dabigatran 110 mg: n.s.

-12% IT (n.s.)

-21% OT (p<0.02)

-21% (p=0.011)

Edoxaban 60 mg IT: n.s.

Edoxaban 30 mg IT: n.s.

Edoxaban 60 mg OT: -21% (p<0.001) Edoxaban 30 mg OT: +7% (p<0.005)

Ischaemic stroke (relative risk reduction)

Dabigatran 150 mg: -24% (p=0.03) Dabigatran 110 mg: n.s

n.s.

n.s.

Edoxaban 60 mg: n.s.

Edoxaban 30 mg: +41% (p<0.001)

Haemorrhagic stroke (relative risk reduction)

Dabigatran 150 mg -74% (p<0.001) Dabigatran 110 mg: -69% (p<0.001)

-41% (p<0.03)

-49% (p<0.001)

Edoxaban 60 mg: -46% (p<0.001) Edoxaban 30 mg: -67% (p<0.001)

Major bleeding (relative risk reduction)

Dabigatran 150 mg: n.s.

Dabigatran 110 mg: -20% (p=0.003)

n.s.

-21% (p<0.001)

Edoxaban 60 mg: -20% (p<0.001) Edoxaban 30 mg: -53% (p<0.001)

Intracranial bleeding (relative risk reduction)

Dabigatran 150 mg: -60% (p<0.001) Dabigatran 110 mg: -69% (p<0.001)

-33%

-49%

Edoxaban 60 mg: -53% (p<0.001) Edoxaban 30 mg: -70% (p<0.001)

Total mortality (relative risk reduction)

Dabigatran 150 mg: -12% (p=0.051) Dabigatran 110 mg: n.s.

n.s.

-11% (p=0.047)

Edoxaban 60 mg: n.s.

Edoxaban 30 mg: -13% (p<0.006)

Cardiovascular mortality (relative risk reduction)

Dabigatran 150 mg: -15% (p=0.04) Dabigatran 110 mg: n.s.

n.s.

Not available

Edoxaban 60 mg: -14% (p<0.014) Edoxaban 30 mg: -15% (p<0.008)

Panel A: Comparison of the design, intervention, and follow-up in the four pivotal studies with NOACs in AF. Panel B: Differences in the populations included in the four pivotal studies with NOAC in AF. *In this study an analysis of the groups of patients with CHADS <3 versus CHADS 4–6 was prespecified, and the numbers (77 % and 23 %) correspond to these groups. Panel C: Differences in outcome obtained with a NOAC versus warfarin in the four pivotal trials in atrial fibrillation. AAS = aspirin; AF = atrial fibrillation; ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CHADS2 = Congestive heart failure (or left ventricular systolic dysfunction, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischaemic attack or thromboembolism; CrCl = creatinine clearance; ENGAGE-AF = Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation; INR = international normalised ratio; IT = intention-to-treat analysis; OAC = oral anticoagulation; OT = on-treatment analysis; n.s. = non-significant; RE-LY = Randomised Evaluation of Long Term Anticoagulant Therapy; ROCKET-AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA = transient ischaemic attack.

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Oral Anticoagulants

of AF posed by inappropriately reduced doses of the NOAC. Reduced doses of NOACs are often prescribed in patients who do not meet the recommended criteria for dose adjustment.12 In addition to this, “good” renal function (creatinine clearance >80 mL/min) might decrease the efficacy of apixaban and edoxaban (but not rivaroxaban or dabigatran) in preventing a first ischaemic stroke (US Food and Drug Administration communication).13 Paradoxically, oral anticoagulants are particularly underused in patients with a high risk of stroke.14 Recently, Fay et al.15 presented data on the dosing patterns of NOACs for AF from more than 4,600 physicians’ prescriptions in France, Germany and the UK between January 2015 and November 2015. They reported that whereas only 4.7 % of the patients in the ARISTOTLE trial received the low dose of apixaban, in clinical practice 44 % of patients received the low dose. Similarly, whereas 49.7 % of the patients randomised to dabigatran in the RE-LY trial received only 110 mg dabigatran twice daily, in clinical practice 59.8 % received this dose and 2.9 % received only 75 mg twice daily; and whereas 20.7 % of patients in the ROCKET-AF trial received 15 mg/d of rivaroxaban, in clinical practice 32.4 % received this dose and 4 % received only 10 mg/d. These data point to the danger that the NOACs’ excellent results in preventing thromboembolic and haemorrhagic complications in nonvalvular AF observed during the pivotal studies1–4 could be distorted in clinical 1.

2.

3.

4.

5.

6.

7.

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. DOI: 10.1056/NEJMoa0905561; PMID: 19717844 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. DOI: 10.1056/NEJMoa1009638; PMID: 21830957 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. DOI: 10.1056/NEJMoa1107039; PMID: 21870978 Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. DOI: 10.1056/NEJMoa1310907; PMID: 24251359 Martínez-Rubio A, Martínez-Torrecilla R. Current evidence for new oral anticoagulants in the treatment of nonvalvular atrial fibrillation: comparison of substudies. Rev Esp Cardiol 2015;68:185–9. DOI: 10.1016/j.rec.2014.07.016; PMID: 25449814 January CT, Wann LS, Alpert JS, et al.; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American college of Cardiology/American heart association task force on practice guidelines and the heart rhythm society. J Am Coll Cardiol 2014;64:e1–76. DOI: 10.1161/CIR.0000000000000040; PMID: 24682348 Verma A, Cairns JA, Mitchell LB, et al.; CCS Atrial Fibrillation Guidelines Committee. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014;30:1114–30. DOI: 10.1016/j.

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8.

9.

10.

11.

12.

13.

praxis if the doses are too low. This seems particularly important with apixaban and edoxaban, because the recommended reduced dose is only 50 % of the standard dose. Specific reversal agents for dabigatran16 and for anti-Xa anticoagulants (apixaban, edoxaban, and rivaroxaban)17 have been clinically evaluated, and the reversal agent for dabigatran (idarucizumab) is available in some countries.16 Although it is crucial to avoid bleeding complications – and low-dose anticoagulant regimens might very well achieve this objective – it is also crucial to avoid thromboembolic events, and the risks and benefits of using low doses must be carefully counterweighed in each individual patient.18–20 In summary, low-dose NOACs are justified in patients who present a high risk of bleeding for any reason. However, the reduction in haemorrhagic risk comes at the cost of lower antithrombotic protection. Moreover, strong evidence for a low fixed dose of NOAC only exists for dabigatran (110 mg twice daily). Patients must therefore be carefully evaluated before being prescribed low-dose NOACs and re-evaluated during the follow-up. Inappropriate application of low-dose NOAC regimens will probably lead to worse thromboembolic results than those observed in the large randomised clinical trials and will likely compromise patient safety. As is true for all drug classes, clinicians need to be educated in all aspects of NOAC treatment, from choosing the most appropriate drug and dose to managing possible complications. n

cjca.2014.08.001; PMID: 25262857 Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; DOI: 10.1093/ eurheartj/ehw210; PMID: 27567408; epub ahead of press.

Tamayo S, Frank Peacock W, 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. DOI: 10.1002/clc.22373; PMID: 25588595 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. DOI: 10.1161/ CIRCULATIONAHA.114.012061; PMID: 25359164 Larsen TB, Skjøth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189. DOI: 10.1136/bmj.i3189; PMID: 27312796 Cardiovascular and Renal Drugs Advisory Committee, Edoxaban NDA 206316. Statistical Considerations, ENGAGE AF Trial. US Food and Drug Administration, 2014. Available at: www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials / Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ UCM421612.pdf (accessed 22.11.2016) Alamneh EA, Chalmers L, Berznicki LR. Suboptimal use oral anticoagulants in atrial fibrillation: has the introduction of direct oral anticoagulants improved prescribing practices?

Am J Cardiovasc Drugs 2016;16:183–200. DOI: 10.1007/s40256016-0161-8; PMID: 26862063

14. Barra ME, Fanikos J, Connors JM, et al. Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med 2016;129:1198–204. DOI: 10.1016/j.amjmed.2016.05.041; PMID: 27341955 15. Fay MR, Martins JL, Czekay B. Oral anticoagulant prescribing patterns for stroke prevention in atrial fibrillation among general practitioners and cardiologists in three European countries. Poster 2597 presented at the European Society of Cardiology Congress 2016, 27–31 August 2016.

16. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20.

DOI: 10.1056/NEJMoa1502000 17. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of Factor Xa inhibitor activity. N Engl J Med 2015;373:2413–24. DOI: 10.1586/17474086.2016.1135046; PMID: 26686866 18. Lip GYH, Frison L, Halperin JL, et al. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41:2731–8.

DOI: 10.1161/STROKEAHA.110.590257; PMID: 20966417 19. Olesen JB, Lip GYH, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. DOI: 10.1136/bmj.d124; PMID: 21282258 20. Friberg L, Rosenqvist M, Lip GYH. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012;33:1500–10. DOI: 10.1093/eurheartj/ehr488; PMID: 22246443

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Using Direct Oral Anticoagulants in Patients with Atrial Fibrillation: Assessment, Monitoring and Treatment Reversal Antoni Ma rt ínez- R ubio, Ma rio Diaz N u i l a A l c a z a r, A n n a S o r i a Ca d e n a a n d R o g e r M a r t í n e z - To r re cilla Department of Cardiology, University Hospital Sabadell, Autonomous University of Barcelona, Barcelona, Spain and the International Society of Cardiovascular Pharmacotherapy

Abstract It is essential to prevent thromboembolic events in atrial fibrillation. The risks of thromboembolic and haemorrhagic events must be carefully assessed and weighed against one another, both in routine situations and in relation to invasive procedures. Vitamin K antagonists, until recently the first-line treatment for prophylaxis against thromboembolic events in patients with atrial fibrillation, have various drawbacks. Direct-acting oral anticoagulants overcome these limitations and are efficacious and safe. The recent developments of tests to monitor anticoagulant levels, and of target-specific reversal agents for these newer drugs, has facilitated their use in several situations, including emergencies. For these reasons, the European Society of Cardiology and other scientific societies now recommend direct-acting oral anticoagulants as first-line treatment for preventing thromboembolic events in atrial fibrillation.

Keywords Atrial fibrillation, coagulation monitoring, direct-acting oral anticoagulants, periprocedural management, reversal agents, risk stratification Disclosure: AMR has participated in activities and been a member of scientific advisory boards for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo and Pfizer, and has received research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer.

Received: 24 April 2016 Accepted: 27 October 2016 Citation: European Cardiology Review 2016;11(2):118–22; DOI: 10.15420/ecr.2016:30:1 Correspondence: Antoni Martínez-Rubio, University Hospital Sabadell, Department of Cardiology, Autonomous University of Barcelona, Parc Taulí 1, E-08208 Sabadell, Barcelona, Spain. E: amartinezrubio@icloud.com

Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice in Western countries. The prevalence of AF depends on the population studied1 and especially on age.2–9 It is affected by increasing longevity and is modulated by the prevalence of cardiovascular risk factors, especially arterial hypertension and related habits. In Spain, for example, the prevalence of AF among people >40 years of age is about 4.4 %,9 rising to 8.5 % among those >60 years and reaching 16.5 % among those >85 years.4 The prevalence of AF is expected to double in the next 50 years.10,11

efforts to correct and/or control it are required; however, for various reasons these efforts often fall short. The efficacy of antiarrhythmic drugs is unpredictable, depending mainly on the duration of AF and the patient’s underlying heart disease. Moreover, antiarrhythmic drug treatment can cause proarrhythmia. AF can also recur after catheter ablation. Given the uncertain success of attempts to directly treat AF, it is therefore important to manage the attendant increased risk of thromboembolic events; most patients with AF will eventually need anticoagulant therapy to prevent thromboembolism.21,23,24

AF is characterised by the anarchic (fast and disorganised) and unpredictable contraction of atrial muscle fibres. This arrhythmia is appears on an electrocardiogram as an absence of P-waves and irregular R-R intervals. It is usually associated with tachycardia. The resulting asynchrony leads to ineffective contraction, decreased ventricular ejection fraction and blood pooling, predisposing to coagulation inside the atrium and increasing the risk of thromboembolic events.

During the past 50 years, vitamin K antagonists (VKAs) have become the first-line oral anticoagulant treatment of choice for preventing thromboembolic events.25 Although VKAs improve prognosis by reducing thromboembolic events, they have diverse clinical limitations (see Figure 1).1 VKAs significantly increase the risk of minor and major bleeding complications, of which intracranial haemorrhage is particularly harmful. They can interact with many drugs and foods, and their effects are also influenced by hepatic metabolism. Regular monitoring and dose adjustments are thus essential to keep patients within the narrow therapeutic range throughout VKA treatment.

AF increases the risk of mortality and morbidity, resulting in high healthcare costs. It increases the probability of stroke by two- to sixfold and the probability of death by 1.5-fold to 2.2-fold.12–18 Moreover, the risk of stroke recurrence is higher in patients with AF than in those without. AF has been also associated with cognitive dysfunction, diminished quality of life and diminished functional capacity.19–22 The prevention and treatment of AF is important for both patients and healthcare systems. The complexity of the mechanisms involved calls for a multidimensional approach. Since AF is potentially dangerous,

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The novel direct-acting oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban and edoxaban have been developed to overcome the limitations of VKAs and are now considered a valid alternative.21 Compared to VKAs, DOACs are at least as effective in reducing stroke and systemic embolism and are associated with a lower risk of haemorrhage.26–29 Another benefit is their predictable, dose-related effects that do not require close monitoring.26–30 The

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beneficial effects of DOACs over VKAs have been documented in several subsets of patients with AF including patients with diabetes mellitus, with heart failure and with previous stroke.31 Until recently, the main drawback of novel anticoagulants was the lack of an agent to reverse their effects. Now, however, various clinically-effective antidotes have been developed.32–35 Another factor against the use of DOACs is their cost. Although they are more expensive than VKAs, comparisons of the overall costs of the two treatment strategies in various contexts have demonstrated that DOACs can be a cost-effective alternative to dose-adjusted warfarin for stroke prevention in AF in most patients.36–41 For these reasons, the European Society of Cardiology and several other scientific societies now recommend using DOACs as first-line therapy.23,42,43 This review presents the current recommendations for the use of DOACs in patients with nonvalvular AF at high risk of bleeding.

Stratifying the Risk of Thromboembolism and Bleeding in AF All anticoagulants increase the risk of bleeding. The benefits of decreasing the risk of thromboembolism must be weighed against the potential harm of increasing the risk of bleeding. Several scores have been proposed to assess these risks. Currently, the most widely recommended and used scores are the CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack, Vascular disease, Age 65–74 years, Sex category) for thromboembolism and the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history of/predisposition, Labile international normalised ratio (INR), Elderly, Drug therapy/alcohol intake) for bleeding. These scores have been validated in very broad populations.44–48 The European Society of Cardiology has proposed an algorithm for managing thromboembolic and haemorrhagic risk in patients with AF.23 Other strategies for reducing thromboembolic risk include aspirin and antiplatelet drugs; however, compared to anticoagulation alone, aspirin alone provokes similar indexes of intracranial bleeding and higher rates of other major bleeding events.47 There is thus no argument for using aspirin instead of anticoagulation because of bleeding risk.49 Aspirin plus antiplatelet therapy or, less effectively, aspirin alone may, however, be considered in patients who refuse oral anticoagulant treatment.

Importantly, the HAS-BLED score should not be used to exclude patients from treatment; rather it should be used to correct potentially reversible risk factors and to determine whether selected patients with the highest risk of bleeding could benefit from low doses of DOACs. Chao et al. recently analysed the risk of stroke in 186,570 patients with AF not using antiplatelet or anticoagulant agents to determine whether patients with a single risk factor (apart from sex) should receive oral anticoagulation.50 Analysing the impact of the components of the CHA2DS2-VASc score, they found that the weight of the components differed; the risk of stroke was highest for age, followed by the presence of diabetes mellitus. Thus, given the high risk of ischaemic stroke, oral anticoagulation is recommended in all patients with CHA2DS2-VASc scores greater than two and in most patients with CHA2DS2-VASc scores of one, unless the only risk factor is female sex.49,50

Results of Pivotal Clinical Trials Using DOACs To date, four extensive randomised clinical trials comparing four DOACs (dabigatran, rivaroxaban, apixaban and edoxaban) with warfarin in

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Figure 1: Limitations of Treatment with Vitamin K Antagonists

Genetic variants

Multiple interactions (food & drugs)

Unpredictable response

Slow beginning & stopping of action

Narrow therapeutic range (INR 2-3)

Dosage adjustments Routine monitoring Costs & Time & Efforts Drawbacks of vitamin K antagonists include the slow onset and offset of anticoagulation and a narrow therapeutic range. Genetic variants and multiple interactions with other drugs and food mean that patients’ responses are unpredictable, making routine monitoring and dose adjustments essential. Abbreviations: INR = international normalised ratio; VKA = vitamin K antagonists. Source: adapted from Martínez-Rubio et al.1 With the permission from Spanish Society of Cardiology and Elsevier España S.L., © 2013, all rights reserved.

different cohorts of patients with nonvalvular AF have been published.26–29 Table 1 summarises the results of these trials, which have led to the authorisation of these DOACs for clinical use in AF in several countries.

Since the publication of these trials, the results of two large observational studies that equalled or surpassed the clinical results obtained in the clinical trials have been published, further supporting the use of DOACs.51,52 The efficacy and safety of DOACs can thus be considered as good as or possibly better than those of VKAs,26–29,53 and DOACs have the additional advantage that their effects are dose-dependent and predictable. Furthermore, the advantages of DOACs over VKAs have been demonstrated in several specific groups of patients with AF (e.g. patients of both genders or with comorbidities such as heart failure, arterial hypertension, diabetes mellitus and previous stroke).31

Monitoring of DOACs Although routine monitoring of coagulation levels is not necessary in patients on DOACs, simple and widely-available tests (see Table 2) help measure their anticoagulant effects if unexpected situations, such as urgent surgery, haemorrhagic events, overdose or acute renal failure, require it.

Dabigatran prolongs the activated partial thromboplastin time (aPTT), but this effect is not linear and the sensitivity of aPTT reagents varies greatly. A trough aPTT (>12 hours after the most recent dose) >80 seconds or two- to three-times higher than the baseline value is associated with a higher risk of bleeding, whereas a normal aPTT indicates that dabigatran has no clinically-significant anticoagulant effect.54 A normal thrombin time (TT) is an indicator of a drug concentration outside the clinically-relevant range.55 The ecarin clotting time (ECT) measures dabigatran activity and the diluted thrombin time with an appropriate dabigatran calibrator (Hemoclot® thrombin inhibitor assay) measures dabigatran concentration.

Dabigatran plasma concentration >200 ng/ml or an ECT three to four times the baseline value or >65 seconds at trough is associated with increased bleeding risk.54 Prothrombin time (PT) and INR are not useful for measuring dabigatran’s effects.56 PT is of limited value for monitoring the anti-Xa anticoagulants rivaroxaban, apixaban and edoxaban. Rivaroxaban and apixaban may prolong PT, but PT is highly dependent on the reagent used in

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Cardiovascular Pharmacotherapy Table 1: Percentage Relative Risk Reduction for Major Events Determined by the Pivotal Clinical Trials of Direct-acting Oral Anticoagulants versus Warfarin Variable

Dabigatran

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Edoxaban

150 mg twice

110 mg twice

20 mg once

5 mg twice

60 mg once

30 mg once

daily (%)

daily (%)

daily (%)

daily (%)

daily (%)

daily (%)

Stroke and systemic embolism 35

n.s.

n.s.

21

n.s.

n.s.

Ischaemic stroke

24

n.s.

n.s.

n.s.

n.s.

↑ 41

Haemorrhagic stroke

74

69

41

49

46

67

Intracranial bleeding

59

70

33

58

53

70

Total mortality

n.s.

n.s.

n.s.

11

n.s.

13

Vascular mortality

15

n.s.

n.s.

n.s.

14

15

Data taken from Connolly et al., 2009,26 Patel et al., 2011,27 Granger et al., 201128 and Giugliano et al., 2013.29 n.s. = non-significant.

Table 2: Measurement of the Anticoagulant Effects of Direct Oral Anticoagulants using Specific and Non-specific Assays

Specific

Test Drug

Dabigatran Hemoclot and

assay

specific

ecarin clotting-

Rivaroxaban Anti-Xa

Apixaban Anti-Xa

time aPTT

↑↑↑

↑

↑

PT

↑

↑↑

↑↑

TT

↑↑↑↑

No effect

No effect

Nonspecific assays

Based on Huisman et al., 201554 and Cuker et al., 2014.55

Table 3: Agents that Reverse the Effects of Direct-acting Anticoagulants

Structure

Idaraucizumab Humanised Fab

Andexanet alpha Human

Cirapantag Synthetic

fragment

rXa variant

water-soluble

Dabigatran

FXa inhibitors

molecule Target

Factor Xa and factor lla as well as heparin-based anticoagulants

Administration

Bolus

Bolus and infusion

Bolus

Clinical

Rapid, complete

Rapid, complete

Rapid, complete

studies

reversal

reversal

reversal

Based on Pollack et al., 2015,32 Siegal et al., 2015,35 Das and Liu, 201560 and Gomez-Outes et al., 2014.61

the assay.55–57 A normal PT, however, indicates that these drugs are not having a clinically-significant effect. PT, aPTT and INR should not be used to measure edoxaban’s effects due to this lack of evidence, presumed insensitivity, the significant variation between reagents and lack of standardisation, which also effect the measurements of other direct anti-Xa inhibitors.56 Anti-factor Xa assays using rivaroxaban, apixaban and edoxaban standards do, however, provide accurate information and seem the best approach to quantifying the anticoagulant effects of these drugs.55,57

Reversal of DOAC effects To reverse the effects of a DOAC, it is essential to know the type of DOAC administered, the dosing regimen, the time since the last dose was administered and factors influencing plasma concentration, e.g.

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renal failure. Time reduces the effects of anticoagulants. Currentlyavailable DOACs have short half-lives (about 12–15 hours), and their effects would be expected to completely disappear by four drug half-lives (after about 48–60 hours). 58 DOACs are absorbed and have an anticoagulant effect 1–4 hours after consumption, so early gastric lavage can be considered if little time has elapsed since the last dose. The administration of oral activated charcoal is useful within 2 hours of dabigatran intake and within 6 hours of apixaban intake.58 The clearance of all DOACs depends to varying extents on renal function, so adequate hydration and diuresis are essential.

Haemodialysis can be used for the emergency elimination of dabigatran; however, the risk of bleeding at puncture sites for dialysis needs to be carefully balanced against the risk of waiting. Nonspecific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used to treat serious bleeding, but the results are controversial.58,59 The recent advent of target-specific reversal agents that enable the effects of DOACs to be reversed within a few minutes (Table 3) represents a major safety advance in urgent situations.32–35,60 One such agent, idarucizumab, is a humanised monoclonal antibody fragment with 350 times higher affinity for dabigatran than thrombin but lacks thrombin-like enzymatic activity and does not bind thrombin substrates.60 It is easily administered intravenously (5 g as two 50-ml bolus infusions, no more than 15 minutes apart) and specifically and completely reverses the anticoagulant effects of dabigatran in few minutes. Ex vivo studies in rats have shown that steady-state dabigatran levels of 200 ng are completely reversed within 1 minute after the administration of an intravenous bolus of idarucizumab.60 The safety and efficacy of idarucizumab have also been demonstrated in patients requiring urgent procedures or presenting with severe bleeding.32 This drug is available for clinical use in some countries, obviating the need for dialysis in emergencies.32,33 Another target-specific reversal agent, andexanet alfa, has been designed specifically to reverse the anticoagulant effects of factor Xa inhibitors.34,35,60 Andexanet alfa is a recombinant modified decoy of factor Xa. Its efficacy has been demonstrated in healthy volunteers treated with apixaban or rivaroxaban; it reverts anticoagulant activity within minutes after administration and for the duration of infusion.35 In these healthy volunteers, transient increases in D-dimer and prothrombin fragments 1 and 2 without clinical thrombotic events have been observed. The dose of andexanet alfa depends on the DOAC. Whereas a 400-mg intravenous bolus followed by a continuous infusion of 4 mg/min for 120 minutes reverses the effects of 5 mg of apixaban twice daily, reversing the effects of 20 mg of rivaroxaban

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once daily requires 800 mg as an intravenous bolus (30 mg/min) followed by continuous infusion of 8 mg/min for 120 minutes.35 PER977, also called aripizine or ciraparantag, can also reverse the effects of factor Xa inhibitors. This small, synthetic, water-soluble molecule binds to direct inhibitors of factor Xa and factor IIa as well as to heparin-based anticoagulants. It antagonises the effects of all anticoagulants except VKAs and argatroban within 30 minutes after intravenous administration, and has a clearance half-life of about 1.5 hours.60,61 To date, however, very few clinical data have been published62 and the drug is not yet clinically and commercially available.

Periprocedural Management of Patients Treated with DOACs One of the most important issues related to DOACs in daily clinical practice is appropriate periprocedural management to reduce the risk of bleeding events and the inherent risk of thromboembolic events. This challenge encompasses a wide range of clinical scenarios, including elective and urgent surgery as well as circumstances involving the risk of fatal haemorrhage, such as multiple traumas.

The first step in the periprocedural management of a patient on a DOAC is to determine the risks of thromboembolism with the CHADS-VASc score and bleeding with the HAS-BLED score.23,24 Next, the inherent risk

1.

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of bleeding associated with the invasive procedure to be undertaken must be determined and weighed against the benefit of remaining on anticoagulants on a case-by-case basis. Clinical guidelines detailing the risks involved in different invasive procedures and recommendations to minimise them63,64 have proven very useful in clinical practice.65 The decision to continue or to pause anticoagulant treatment should be based on pharmacokinetic principles and the estimated thromboembolic and bleeding risks. Interestingly, accumulating evidence is leading to a consensus that bridging with heparin is unnecessary in patients treated with a DOAC64–66 and that the availability of fast-acting reversal agents minimises anticoagulant-related bleeding during urgent or emergent interventions.

Conclusion AF is very common and is associated with increased morbidity, mortality and healthcare costs. Appropriate clinical management, including the prevention of thromboembolic events, is thus crucial.

Preventing thromboembolic events with VKAs has various clinical limitations; DOACs overcome these limitations and have proven efficacious and safe. The recent developments of tests that allow the monitoring of anticoagulant levels and of target-specific reversal agents for DOACs have facilitated the use of these drugs in several situations, including emergencies. n

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j.jacc.2015.01.044; PMID: 25770314 50. Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65 :635–42. DOI: 10.1016/j.jacc.2014.11.046; PMID: 25677422 51. 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. DOI: 10.1002/clc.22373; PMID: 25588595 52. 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. DOI: 10.1161/ CIRCULATIONAHA.114.012061; PMID: 25359164 53. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383 :955–62. DOI: 10.1016/ S0140-6736(13)62343-0; PMID: 24315724 54. Huisman MV, Lip GYH, Diener HC, et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost 2012;107(5):838–47 55. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64 :1128–39. DOI: 10.1160/TH11-10-0718; PMID: 22318514 56. Nutescu EA, Burnett A, Fanikos J, et al. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41 :15–31.

DOI: 10.1007/s11239-015-1314-3; PMID: 26780737 57. Nagakari K, Emmi M, Iba T. Prothrombin time tests for the monitoring of direct oral anticoagulants and their evaluation as indicators of the reversal effect. Clin Appl Thromb Hemost 2016; DOI: 10.1177/1076029616638506: epub ahead of press 58. Sartori MT, Prandoni P. How to effectively manage

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DOI: 10.1586/17474086.2016.1112733; PMID: 26573697 Franchini M, Bonfanti C, Mannucci PM. Management of bleeding associated with new oral anticoagulants. Semin Thromb Hemost 2015;41 :788–801. DOI: 10.1055/s-00351556046; PMID: 26408923 Das A, Liu D. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol 2015;4:25. DOI: 10.1186/ s40164-015-0020-3; PMID: 26380149 Gomez-Outes A, Suarez-Gea ML, Lecumberri R, et al.

Specific antidotes in development for reversal of novel anticoagulants: a review. Recent Pat Cardiovasc Drug Discov 2014;9 :2–10. PMID: 25494843 Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371 :2141–42. DOI: 10.1056/NEJMc1411800; PMID: 25371966 Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014;130 :e278–333. DOI: 10.1161/CIR.0000000000000106; PMID: PMID: 25085961 Kristensen SD, Knuuti J. New ESC/ESA guidelines on non-cardiac surgery: Cardiovascular assessment and management. Eur Heart J 2014;35 :2344–5. DOI: 10.1093/ eurheartj/ehu285; PMID: 25104785 Schulman S, Carrier M, Lee AYY, et al. Perioperative management of dabigatran: a prospective cohort study. Circulation 2015;132 :167–73. DOI: 10.1161/ CIRCULATIONAHA.115.015688 Healey JS, Eikelboom J, Douketis J, et al.

Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation 2012;126 : 343–8. DOI: 10.1161/CIRCULATIONAHA.111.090464; PMID: 22700854

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Cardiology Masters

In the Cardiology Masters section of European Cardiology Review we bring you an insight into the career of a key contributor to the field of cardiology.

In this edition, we feature Dr Valentin Fuster, Mount Sinai Hospital, New York, USA

Dr Valentín Fuster is Physician-in-Chief at the Mount Sinai Medical Hospital and Director of Mount Sinai Heart, the Zena and Michael A Wiener Cardiovascular Institute and the Marie-Josée and Henry R Kravis Center for Cardiovascular Health. He also holds the Richard Gorlin, MD/Heart Research Foundation Professorship at Icahn School of Medicine, Mount Sinai, and is the General Director of the Spanish National Centre for Cardiovascular Research (Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC) in Madrid, Spain.

Dr Fuster is the only cardiologist to have received the highest awards for research from the four leading cardiovascular organisations: the American Heart Association, the American College of Cardiology, the European Society of Cardiology and the Inter-American Society of Cardiology.

Other key positions Dr Fuster has held include President of the American Heart Association, President of the World Heart Federation, member of the US National Academy of Medicine (where he chaired the Committee on Preventing the Global Epidemic of Cardiovascular Disease: Meeting the Challenges in Developing Countries, which produced the document Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health), member of the US National Heart, Lung and Blood Institute and President of the training programme of the American College of Cardiology.

Dr Fuster has been named doctor honoris causa by 33 universities around the world. He is an author of more than 1000 scientific articles in international medical journals, and lead editor of two books on clinical cardiology and research: The Heart and Atherothrombosis and Coronary Artery Disease and Hurst’s The Heart. He was also Editor-in-Chief of the prestigious journal Nature Reviews in Cardiology. In 2014, Dr Fuster was appointed Editor-in-Chief of the Journal of the American College of Cardiology, the American College of Cardiology’s (ACC) flagship publication and the main American source of clinical information on cardiovascular medicine Dr Fuster has received many prestigious awards including the Prince of Asturias Award for Technical and Scientific Research for his research into the origin of cardiovascular events in 1996, the Kurt Polzer from the European Academy of Science and Arts (2008), the international Arrigo Recordati prize for his contribution to advances in the area of cardiovascular imaging (2009) and the Grand Prix Scientifique of the Institute of France for his translational research into atherothrombotic disease (2011).

In 2012, Dr Fuster was named by the ACC as one of the Living Legends in Cardiology Medicine, and was awarded the Research Achievement Award, the highest award given by the American Heart Association. In 2013, Dr Fuster was awarded the Ron Haddock International Impact Award by the American Heart Association and the American Stroke Association in recognition of his global leadership. In May 2014, King Juan Carlos I of Spain granted Dr Fuster the title of marquis for his “outstanding and unceasing research efforts and his educational outreach work”.

In addition to his dedication to research, Dr Fuster is strongly committed to communicating to the public which has led to an upcoming documentary, the publication of seven books and the launch of the Science, Health and Education Foundation (SHE), of which Dr Fuster is President, directed at improving public health, especially in the young.

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rowing up in a family of doctors – my dad was a psychiatrist, my grandfather was a general physician and my maternal grandfather was President of the University of Barcelona and medical school – you’d be forgiven for thinking that becoming a doctor was a natural progression for me. Actually I was more interested in the environment and researching plants. I wanted to study agriculture, but this wasn’t an option at the university in my hometown of Barcelona, and the tendency was to stay with your family.

of recommendation describing me as an investigator of the future and a sportsman. My tutor also advised me to move to the University of Edinburgh in Scotland, which then had one of the first coronary care units in the world. He also felt that because it was relatively small I wouldn’t get lost in a sea of people. The unit was led by Michael Oliver, a consultant of cardiology at the Royal Infirmary, and Desmond Julian, another consultant and head of the coronary care unit. It was here that I completed my thesis.

I also had a passion for tennis and played at a national level, practicing 3–4 hours each day; it wasn’t until I was beaten in a tournament that I realised my future lay elsewhere and I stopped playing. Little did I know then that tennis would serve as a stepping-stone in my career on more than one occasion.

Move across the Atlantic

It was at a tennis club that I met Spain’s leading physician at that time, Pedro Farreras, who was author of the standard Spanish textbook of medicine. It was Dr Farreras who told me that I’d make a great doctor, so not knowing what I should do with my life I trusted him and followed his advice.

Move to the UK Dr Farreras became my mentor, and it was when he had a heart attack in his 40s that he told me I should become a cardiologist; it was an area in which Dr Farreras felt he was weak. He then encouraged me to go to England to study pathology. He felt that to go to a small country would help to build my self-esteem as a professional. I ended up doing this for two summers. During the first summer I studied pathology specimens at the Middlesex Hospital in London, and I spent the second summer in Liverpool with a fantastic pathologist called Harold Sheehan, professor and head of pathology at the university, looking at slides from autopsies and biopsies.

The first day I worked with Professor Sheehan he showed me a slide that was a blood clot full of platelets; it was from a patient who had died of a heart attack. I asked what a blood clot had to do with a heart attack, and he said he didn’t know if it was the cause or the consequence. This was around 1963. Professor Sheehan suggested I investigate it for my thesis, so this is exactly what I did; I investigated the function of platelets to understand how heart attacks occurred.

I was Professor Julian’s right-hand man on clinical matters and I stayed in Edinburgh for 3 years. I was curious about the United States, so I applied to San Diego to work with Eugene Braunwald and was accepted; however, at the last minute there was a problem with my visa. To cut a long story short, a friend contacted the Mayo Clinic where I didn’t need a green card and I got a job there that lasted 12 years! It was a great experience and I became involved with some great people including Dwight Mgoon, a cardiac surgeon who was a tremendous mentor to me and Bob (Robert) Frye and who was loved by us all.

Once I’d finished my training programme at the Mayo Clinic and become a member of staff, I wanted to carry out research and was fortunate to receive a National Institutes of Health grant. I began to work with people with Von Willebrand disease and this is where I learnt that platelets were important in vascular health because this patient group didn’t develop vascular disease.

Climb to Mount Sinai My career really began to take off, which made it difficult to go back to Spain, and then one day I received a phone call from Dr Richard Gorlin, who was Chairman of Medicine at Mount Sinai Medical Center in New York. He wanted to recruit me as head of cardiology. I said no at first, but then my wife said the move would enable her to study art history at Columbia University, so I reconsidered. Finally we moved to New York and I spent 10 years at Mount Sinai before being recruited as Head of Cardiology at Massachusetts General Hospital. In 1995 I returned to New York to head the new Cardiovascular Institute at Mount Sinai, a unique venture for the United States, with all the specialties in cardiovascular disease pulled together under a single umbrella.

Proudest achievements This led me to investigate atherosclerotic disease of the vessel wall, and then visual imaging. It was at this time that we conducted the first randomised study with aspirin.1 We knew that aspirin was important in blood clots but this was a study about aspirin in the prevention of blood clots with saphenous vein bypass graft, which led to many other studies with aspirin and cardiac and arterial conditions.

In terms of my academic achievements, I think the highlights so far have been understanding the closure of vein grafts and the use of aspirin, understanding how a plaque ruptures leading to a heart attack, and using MRI for the first time to address the arterial system; my team and I were pioneers in imaging and developed the technique to see how plaques that are not obstructed can rupture.

I guess my tendency has always been to get to the root of the problem and it all started with that slide. I realise that a change in society’s lifestyle is key to most of our health problems, which is why I’m passionate about global health and why I have created SHE, a nonprofit foundation that, while focused on basic and clinical research (Science), is aimed at promoting healthy habits (Health) through communication and Education of the population.

Then, through MRI, we learnt about the use of rapamycin in the prevention of restenosis following angioplasty. Rapamycin is the drug that has been used for drug-eluting stents and this led to the FREEDOM [Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease] trial that aimed to define the optimal revascularisation strategy for diabetic patients with multivessel coronary disease;2 it has had a significant impact in diabetic patients with coronary artery disease, which is why I’m very proud to have led the trial.

Edinburgh Feeling unnoticed in Liverpool, I decided to enter another tennis tournament. I hadn’t picked up a racket for about 6 years. I won and became a hero overnight! After this, Professor Sheehan wrote letters

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A more recent development I feel proud about is developing the polypill for heart attacks. It has been approved in 35 countries. Adherence to medication is much better as a result, and this highlights the

EUROPEAN CARDIOLOGY REVIEW

Cardiology Masters: Dr Valentín Fuster

importance of understanding human behaviour and psychology. In fact, acknowledging this has enabled me to make progress in global health.

Motivating people to manage their health is possible, especially if you involve the wider community. I’ve been involved in a couple of projects that demonstrate this. One is in Kenya with Dr Rajesh Vedantan, where we are working in a poor area where people develop high blood pressure due to consuming food with too much salt. What we are doing is distributing automatic blood pressure machines to the communities and we’ve seen how this has motivated people to take their blood pressure and encourage their neighbours to do the same. Now we probably have one of the best registries of blood pressure we’ve ever seen in Africa.

It’s all about motivating a community about a risk factor, in this case hypertension. We are replicating this psychology in a community in Catalonia, where my wife grew up, and in seven other communites. This time, we’ve divided people into groups of 10 and they help each other on exercise, obesity, smoking cessation and blood pressure. The groups meet every 2 months. The results are fascinating and demonstrate that between ages 25 and 50 there is no question that people in the community are motivating each other to change their behaviour.

Sesame Street I also work as an international advisor on Sesame Workshop’s Global Health Initiative. The goal of the initiative is to measure health improvements in children and build global partnerships to address critical health issues.

I first joined forces with the Sesame Workshop in 2006 to collaborate with Plaza Sésamo, the Latin American version of Sesame Street, to promote cardiovascular health and well being in Colombia. The series there encourages children, parents, teachers and caregivers to make informed nutritional and lifestyle decisions based on educational television content, community outreach and evidence-based research.

I was the inspiration for a Muppet doctor on Barrio Sésamo: Monstrous Supersanos, and my character Dr Valentín Ruster is helping to educate children to lead healthier lifestyles through exercise and healthy diet. This Spanish version of Sesame Street has just debuted on Spain’s Antena 3.

I’m helping them to extend this initiative in the United States.

What we learnt through Sesame Street is that our behaviour develops by and large through our exposure to society aged between 3 and 5.

We therefore used this window of opportunity to make health a priority with these children. Follow up after 9 years shows that it is really working. It will be interesting to see whether this intervention has an impact on the behaviour of the 75,000 children we are studying as they reach the age of 20.

from treating to promoting health. It’s an economic decision: the cost of treating cardiovascular disease in the United States last year was $300 billion, and this is increasing. The way science is advancing is fantastic but healthcare is becoming very expensive; we’re prolonging life at a tremendous expense and it’s impossible to continue like this.

Preventing disease is much less expensive and I’m proud to have been involved in so many projects that have looked at behaviour in children and in middle age, degenerative brain disease in later life, and how these health issues can be prevented and health promoted. We haven’t left science but are studying genetics and using imaging to help move the pendulum from treating disease too late to promoting health as early as possible; trying to see if we can change the behaviour of people we identify with disease.

I think the future of cardiology will continue to evolve scientifically but there will be a big driving force to understand disease before it evolves and to try to prevent it. The polypill to me is cosmetic. The answer to health isn’t to have a polypill after you’ve had a heart attack; the answer is to prevent a heart attack. We need to use technology to see who is at risk. If you look at the technology and apps from the likes of Google and Apple, for example, they are all trying to predict who might be at risk of disease and to act earlier. That said, I don’t think they’re paying enough attention to how we can help children.

Ten years ago our cardiologists-in-training didn’t think about promotional health and prevention at all; now the tide is turning and out of the 18 fellows that we are working with, six of them want to work in global health to make the world better. This is a huge change and I feel quite optimistic about it.

Motivating the young Although I’ve been lucky enough to have witnessed and been involved in so many important developments in cardiology, I think one of the highlights for me has been the motivation of young people. Just as I have been mentored, now and in the past, I spend a lot of time trying to mentor young people and it’s a privilege. The world is becoming more complex and so it’s important to have more people around you.

Young people sometimes have a hard time accepting this.

Young people need to ask themselves what they are good at, be it seeing patients or working with imaging technology, for example.

Once they understand who they are, then they can put passion into it and push themselves, bearing in mind that there will always be ups and downs along the way. Life isn’t straightforward and as long as we acknowledge that, we can mentally prepare ourselves for the ride and exercise resilience.

Prevention I think the culmination of these projects and my work understanding human behaviour amongst the different age groups has led to my new appointment as Co-chair of the Consensus Committee on Global Health and the Future of the United States. The Committee will advise the next presidential administration on the role of the United States in the future of global health and I’m proud to be part of it. I cannot comment on what we’re working on now but I can say there is a tremendous drive

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It’s a bit like biking: as anyone who has experienced any of the world’s great mountain biking challenges such as the Giro d’Italia or the Tour de France will know, each mountain is different and needs to be tackled as a challenge in its own right. The same goes for each new path we take or corner we turn in life. We must face it head on, enjoy the journey, embrace the challenge and, hopefully, make a difference along the way. n

Chesebro JH, Fuster V, Elveback LR, et al. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 1984;310:209–14. DOI: 10.1056/NEJM198401263100401 Farkouh ME, Domanski M, Fuster V et al; FREEDOM Trial Investigators. Strategies for multivessel revascularisation in patients with diabetes. N Engl J Med 2012;367 :2375–84.

DOI: 10.1056/NEJMoa1211585; PMID: 23121323

Written by Harriett Seager, based on an interview with Dr Valentin Fuster, available online at www.radcliffecardiology.com EUROPEAN CARDIOLOGY REVIEW

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

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