ECR 14.1 by Radcliffe Cardiology

European Cardiology Review Volume 14 • Issue 1 • Spring 2019

Volume 14 • Issue 1 • Spring 2019

www.ECRjournal.com

Coronary Artery Spasm and Perivascular Adipose Tissue Inflammation: Insights From Translational Imaging Research Kazuma Ohyama, Yasuharu Matsumoto and Hiroaki Shimokawa

Behind Traditional Semi-quantitative Scores of Myocardial Perfusion Imaging: An Eye on Niche Parameters Carmela Nappi, Valeria Gaudieri and Alberto Cuocolo

Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments Juan Tamargo

ISSN: 1758-3756

DNA strand and Cancer Cell Oncology Research Concept

Extensive Left Ventricular Adrenergic Denervation and Preserved Myocardial Perfusion

Close up of Atherosclerosis

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Volume 14 • Issue 1 • Spring 2019

www.ECRjournal.com Official journal of

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

Senior Associate Editors Pablo Avanzas

Wolfgang Koenig

Mario Marzilli

Richard Conti

Giuseppe Mancia

Hiroaki Shimokawa

University Hospital of Oviedo, Oviedo

Technical University of Munich, Munich

University of Florida, Gainesville

University of Milano-Bicocca, Milan

University of Pisa, Pisa Tohoku University, Sendai

Editorial Board Debasish Banerjee

St George’s University of London, London

Vinayak Bapat

Columbia University Medical Centre, New York

Velislav Batchvarov

Alberto Lorenzatti

Hospital Córdoba, Córdoba

Giuseppe Rosano

Ente Ospedaliero Cantonale, Bellinzona

Robert Gerber

Angela Maas

Magdi Saba

Conquest Hospital, Hastings

Bernard Gersh

St George’s University of London, London

Mayo Clinic, Minnesota

Antoni Bayés-Genís

David Goldsmith

Hospital Germans Trias i Pujol, Barcelona

St George’s University of London, London

John Beltrame

Tommaso Gori

University of Adelaide, Adelaide

Christopher Cannon

Harvard Medical School, Boston

Peter Collins

Imperial College, London

Alberto Cuocolo

University of Naples Federico II, Naples

Gheorghe Andrei Dan

Colentina University Hospital, Bucharest

Ranil de Silva

Johannes Gutenberg University Mainz, Mainz

Kim Greaves

National University of Cordoba, Cordoba

Antoni Martínez-Rubio Noel Bairey Merz

University of Athens, Athens

Danderyd University Hospital, Danderyd

Denis Pellerin

Carlo Di Mario

Rao Kondapally

Royal Liverpool University Hospital, Liverpool

Felipe Martinez

Thomas Kahan

University of Hertfordshire, Hatfield

Michael Fisher

University of Bologna, Bologna

Argyrios Ntalias

Hippokration General Hospital, Athens

King’s College London, London

Olivia Manfrini

Cedars-Sinai Heart Institute, Los Angeles

Mike G Kirby

Albert Ferro

Karolinska Institute, Stockholm

St George’s University of London, London

University of Florida, Florida

Polychronis Dilaveris

University College, London

Aneil Malhotra

Eileen Handberg

Imperial College, London

Perry Elliott

St George’s University of London, London

Sunshine Coast University Hospital, Queensland

Koichi Kaikita

St George’s University of London, London

Patrizio Lancellotti University of Liège, Liège

Amir Lerman Mayo Clinic, Minnesota

José Luis López-Sendón La Paz Hospital, Madrid

IRCCS San Raffaele, Rome

Radboud University Medical Center, Nijmegen

University Hospital of Sabadell, Sabadell

Kumamoto University, Kumamoto

Careggi University Hospital, Florence

Cover image © AdobeStock

Augusto Gallino

St Bartholomew’s Hospital, London

Gianluigi Savarese Roxy Senior

Imperial College, London

Nesan Shanmugam

St George’s University of London, London

Sanjay Sharma

St George’s University of London, London

Rosa Sicari

Italian National Research Council, Rome

Iana Simova

National Cardiology Hospital, Sofia

Juan Tamargo

University Complutense, Madrid

Konstantinos Toutouzas University of Athens, Athens

Carl Pepine

Isabella Tritto

Piotr Ponikowski

Dimitrios Tziakas

Wroclaw Medical University, Wroclaw

Democritus University of Thrace, Xanthi

Eva Prescott

Mauricio Wajngarten

Axel Pries

Hiroshi Watanabe

Charité Universitätsmedizin Berlin

Hamamatsu University School of Medicine, Hamamatsu

Hari Raju

Matthew Wright

University of Florida, Florida

Bispebjerg Hospital, Copenhagen

Macquarie University, Sydney

Robin Ray

St George’s University of London, London

University of Perugia, Perugia

University of São Paulo

St Thomas’ Hospital, London

José Luis Zamorano

Hospital Ramón y Cajal, Madrid

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 1758–3756 • eISSN: 1758–3764

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Established: April 2005 | Frequency: Tri-annual | Current issue: Spring 2019

Aims and Scope

Submissions and Instructions to Authors

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

• Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.ECRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Ashlynne Merrifield ashlynne.merrifield@radcliffe-group.com

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

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

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Open Access, Copyright and Permissions Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/ legalcode). Radcliffe Cardiology retain all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor.

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

Cardiology

Lifelong Learning for Cardiovascular Professionals

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Contents

Foreword Juan Carlos Kaski

DOI: https://doi.org/10.15420/ecr.2019.14.1.F01

Ischaemic Heart Disease Coronary Artery Spasm and Perivascular Adipose Tissue Inflammation: Insights From Translational Imaging Research

Kazuma Ohyama, Yasuharu Matsumoto and Hiroaki Shimokawa DOI: https://doi.org/10.15420/ecr.2019.3.2

Improvement of Fractional Flow Reserve after Percutaneous Coronary Intervention Does Not Necessarily Indicate Increased Coronary Flow

Rikuta Hamaya, Yoshihisa Kanaji, Eisuke Usui, Masahiro Hoshino, Tadashi Murai, Taishi Yonetsu and Tsunekazu Kakuta DOI: https://doi.org/10.15420/ecr.2018.27.2

Behind Traditional Semi-quantitative Scores of Myocardial Perfusion Imaging: An Eye on Niche Parameters

Carmela Nappi, Valeria Gaudieri and Alberto Cuocolo DOI: https://doi.org/10.15420/ecr.2019.5.1

Stable Angina Medical Therapy Management Guidelines: A Critical Review of Guidelines from the European Society of Cardiology and National Institute for Health and Care Excellence

Talla A Rousan and Udho Thadani DOI: https://doi.org/10.15420/ecr.2018.26.1

Heart Failure and Arrhythmias Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments

Juan Tamargo DOI: https://doi.org/10.15420/ecr.2018.34.2

Cardiac Resynchronisation Therapy and Cellular Bioenergetics: Effects Beyond Chamber Mechanics

Christos-Konstantinos Antoniou, Panagiota Manolakou, Nikolaos Magkas, Konstantinos Konstantinou, Christina Chrysohoou, Polychronis Dilaveris, Konstantinos A Gatzoulis and Dimitrios Tousoulis DOI: https://doi.org/10.15420/ecr.2019.2.2

Insights for Stratification of Risk in Brugada Syndrome

Daniel García Iglesias, José Rubín, Diego Pérez, César Morís and David Calvo DOI: https://doi.org/10.15420/ecr.2018.31.2

Risk Factors and Cardiovascular Disease Prevention The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives

Sotirios Tsalamandris, Alexios S. Antonopoulos, Evangelos Oikonomou, George-Aggelos Papamikroulis, Georgia Vogiatzi, Spyridon Papaioannou, Spyros Deftereos and Dimitris Tousoulis DOI: https://doi.org/10.15420/ecr.2018.33.1

Obesity and Cardiovascular Risk After Quitting Smoking: The Latest Evidence

Koji Hasegawa, Maki Komiyama and Yuko Takahashi DOI: https://doi.org/10.15420/ecr.2019.4.2

Pharmacotherapy Cardiovascular Imaging and Theranostics in Cardiovascular Pharmacotherapy

Mattia Cattaneo, Alberto Froio and Augusto Gallino DOI: https://doi.org/10.15420/ecr.2019.6.1

AF in Cancer Patients: A Different Need for Anticoagulation?

Ana Pardo Sanz and José Luis Zamorano Gómez DOI: https://doi.org/10.15420/ecr.2018.32.2

Cardiomasters Featuring: Antonio Bayés de Luna

Antonio Bayés de Luna DOI: https://doi.org/10.154210/ecr.2019.14.1.CM1

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Lugano

Meeting of the 24th Scientific International Society of

Cardiovascular Pharmacotherapy (ISCP) Palazzo dei Congressi, Lugano, Switzerland

May 9thâ&#x20AC;&#x201C;10th

2019

The educational and scientific programme covers a wide spectrum of cardiovascular pharmacotherapy and is addressed to cardiologists as well as general internists.

Accreditation Swiss Society of Cardiology: 14 credits

World epidemics â&#x20AC;&#x201C; Joint session with ESC Working Group on Cardiovascular Pharmacotherapy

The Polypill: A simple, inexpensive approach to reduce mortality and morbidity worldwide

A changing paradigm in management of dyslipidaemia

Atrial fibrillation Chronic heart failure: a paradigm shift

The emerging role of PCSK9 inhibitors after Odyssee

Acute heart failure

Anti-inflammatory treatment

How low to go with glucose, cholesterol and blood pressure in primary prevention of CVD

Medical vs invasive treatment strategies in stable CAD

Diabetes and cardiovascular disease

Emerging indications for new oral anticoagulation in CAD For information about the scientific programme, abstract submission, registration, accommodation and travelling to Lugano, visit

Organized in collaboration with

ISCP-A4_Inserat.indd 1 Untitled-2 1

Working Group on Cardiovascular Pharmacaotherapy (European Society of Cardiology)

Arterial hypertension

www.iscp2019.com Swiss Atherosclerosis www.agla.ch

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Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), UK, Honorary Consultant Cardiologist at St George’s Hospital NHS Trust, London, and immediate past director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Professor Kaski is a Doctor of Science, University of London, an immediate past president of the International Society of Cardiovascular Pharmacotherapy (ISCP), and an editorial board member and associate editor of numerous peer-review journals. He is also fellow of the European Society of Cardiology (ESC), American College of Cardiology (ACC), American Heart Association (AHA), Royal College of Physicians (RCP) and more than 30 other scientific societies worldwide. Professor 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. Professor Kaski has published more than 450 papers in peerreviewed journals, more than 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

t is a great pleasure for me to present a new issue of ECR. This issue has, in addition to our customary article devoted to a ‘Cardio Master’, eleven great papers grouped under four major sections: Ischaemic Heart Disease, Heart Failure and Arrhythmias, Risk Factors and Cardiovascular Disease Prevention and Pharmacotherapy. The latter, guest-edited by the International Society of Cardiovascular Pharmacotherapy (ISCP) presents two important articles, one by Cattaneo et al. focusing on cardiovascular imaging and theranostics and the other, by Sanz et al., discussing anticoagulant therapies in patients with cancer and atrial fibrillation. The Ischaemic Heart Disease section contains a scholarly article by Shimokawa et al. on the links between coronary artery spasm and perivascular fat inflammation, and a provocative paper by Kakuta et al., discussing the implications of an improvement in fractional flow reserve after percutaneous coronary intervention. Morever, this section presents two critical review articles, one by Thadani et al on international guidelines for management of stable angina pectoris and another by Cuoccolo et al. suggesting new scoring systems for the quantification of myocardial perfusion. Under the overarching heading of Heart Failure and Arrhythmias, this section contains three extremely important articles. Juan Tamargo discusses the role of sodium-glucose cotransporter 2 (SGLC-2) inhibitors in heart failure patients, Dilaveris et al. tackle the important issue of cardiac resynchronisation therapy and its effects on cardiac energetics and Calvo et al. review risk stratification in patients with Brugada syndrome. In the section devoted to Risk Factors and Cardiovascular Disease Prevention, Tousoulis et al. and Hasegawa et al. shed light onto the role of inflammation in the genesis of cardiovascular events in patients with diabetes mellitus, and the determinants of coronary artery disease progression after quitting smoking, respectively. In accordance with ECR’s traditional approach, all of the articles in this issue have major importance for patient risk stratification and management. I trust that the information contained in the present issue will assist healthcare practitioners to successfully tackle the continuing challenges posed by patients in clinical practice. Last but not least, the Cardiomasters section in this issue celebrates the achievements of Antoni Bayes de Luna, an outstanding physician and clinical investigator from Catalonia whose discoveries and teachings have inspired several generations of physicians worldwide. Once again, I have enjoyed editing this issue of ECR and hope you will find its content to be of interest and of assistance in your clinical endeavours. I look forward to meeting at least some of you, our over 30,000 readers, in Barcelona at the Radcliffe Cardiology booth during the forthcoming meeting of the European Society of Cardiology.

Best wishes to all and everyone!

DOI: https://doi.org/10.15420/ecr.2019.14.1.F01 © RADCLIFFE CARDIOLOGY 2019

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Ischaemic Heart Disease

Coronary Artery Spasm and Perivascular Adipose Tissue Inflammation: Insights From Translational Imaging Research Kazuma Ohyama, Yasuharu Matsumoto and Hiroaki Shimokawa Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

Abstract Perivascular adipose tissue, which constitutes perivascular components along with the adventitial vasa vasorum, plays an important role as a source of various inflammatory mediators in cardiovascular disease. Inflammatory changes in the coronary adventitia are thought to be involved in the pathogenesis of coronary artery spasm and vasospastic angina. Recent advances in translational research using noninvasive imaging modalities, including 18F-fluorodeoxyglucose PET and cardiac CT, have enabled us to visualise perivascular inflammation in the pathogenesis of coronary artery spasm. These modality approaches appear to be clinically useful as a non-invasive tool for examining the presence and severity of vasospastic angina.

Keywords Coronary spasm, perivascular adipose tissue, coronary adventitia, 18F-fluorodeoxyglucose PET, cardiac CT Disclosure: This work was supported in part by Grants-in-Aid for Scientific Research (18890018, 16K19384) and the Global COE Project (F02); Grants-in-Aid (H22Shinkin-004) from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan; the grant for young investigators of translational research from Tohoku University Hospital; and Grants-in-Aid for Scientific Research (16K19384). Received: 7 January 2019 Accepted: 6 February 2019 Citation: European Cardiology Review 2019;14(1):6–9. DOI: https://doi.org/10.15420/ecr.2019.3.2 Correspondence: Hiroaki Shimokawa, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E: shimo@cardio.med.tohoku.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary Artery Spasm and Adventitial Inflammation Coronary artery spasm plays an important role in the pathogenesis of a wide range of ischaemic heart disease, not only in variant angina, but also in other forms of angina pectoris and myocardial infarction.1,2 Recent studies have demonstrated that coronary spasm is also as frequently noted in European people as in Asian people.3 We have previously demonstrated that activation of Rho kinase, a molecular switch for vascular smooth muscle cell contraction, is a central mechanism of coronary spasm in animals and humans.1,4,5 In addition, we demonstrated that coronary spasm can be induced without endothelial dysfunction in a porcine model with chronic adventitial application of interleukin-1 beta through Rho kinase activation.6 In these studies, we demonstrated that vascular smooth muscle cell hypercontraction induced by adventitial inflammation through Rho kinase activation, rather than endothelial dysfunction, plays a major role in the pathogenesis of coronary spasm.1,4,5

surrounds the media and thus mediates communication with medial vascular smooth muscle cells.1,10 The adventitia also interacts with its adjacent PVAT, which is linked to microvessels and nerves, to regulate vascular physiology, homeostasis and structural remodelling, exerting major influences on the progression or regression of vascular disease.10 Ectopic adipose tissue, defined as the deposition of fat in non-classical locations including the heart and blood vessels, may contribute to the development of cardiovascular disease by exerting a local toxic effect on adjacent vasculature.11–13 One such ectopic adipose tissue is PVAT, which is directly adhered to blood vessels. PVAT, similarly to other adipose tissues, is metabolically active, secreting a wide variety of bioactive substances.14 Indeed, Owen et al. also reported that inflamed PVAT exerts augmented contractile effects through Rho-dependent signalling in pigs ex vivo.15

We also recently demonstrated that optical coherence tomography (OCT) enables us to precisely observe the adventitial vasa vasorum (VV) area, and that adventitial inflammatory changes, including VV formation, play important roles in the pathogenesis of coronary spasm in pigs and humans.7–9

Thus, much attention has been focused on identifying the inflammation and metabolic activity of PVAT in experimental animals and humans.15–18 Indeed, recent advances in translational research using non-invasive imaging modalities, including 18F-fluorodeoxyglucose (18F-FDG) PET and cardiac CT, have enabled us to visualise perivascular inflammation.

Perivascular Adipose Tissue

In this brief review, we provide an overview of the recent progress in imaging for PVAT inflammation, particularly in the field of coronary artery spasm.

The coronary artery consists of the intima, media, adventitia and perivascular adipose tissue (PVAT; Figure 1). The adventitia completely

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Insights From Translational Imaging Research Cardiac CT for Evaluation of Perivascular Adipose Tissue

Figure 1: Coronary Adventitia and Perivascular Adipose Tissue in Patients With Vasospastic Angina

Validation Studies Although it has been considered to be technically difficult to directly detect PVAT or vascular inflammation on cardiac CT, inflammatory changes of PVAT have been emerging as a surrogate marker to detect the changes.16 Antonopoulos et al. reported that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can be monitored using a CT imaging approach.16 They examined human adipose tissue explants and their CT images from patients undergoing cardiac surgery, and developed a new imaging metric, termed as the CT fat attenuation index (FAI), that effectively describes adipocyte lipid content and size. The FAI has excellent sensitivity and specificity for detecting tissue inflammation, as assessed by tissue uptake of 18F-FDG PET. The FAI gradient around human coronary arteries effectively detected early subclinical coronary artery disease in vivo, as well as dynamic changes of PVAT. Indeed, we also demonstrated that adipocyte size significantly differed between the spastic site after drug-eluting stent (DES) implantation and the control site in our experimental study.19

Perivascular adipose tissue

However, our previous findings indicated that local adventitial inflammation including PVAT, but not systemic inflammation, plays important roles in the pathogenesis of coronary spasm.1,7,9 We thus suggested that increased PVAT volume of the spastic coronary segment could result in enhanced overall epicardial adipose tissue volume in the study by Ito et al.24 In addition, in our prospective clinical study, we confirmed that coronary PVAT volume was significantly increased at the spastic left anterior descending (LAD) coronary artery in VSA patients compared with non-VSA patients, although there were no significant differences in bodyweight, body mass index or percentage of body fat between the two groups (Figure 2).25 This finding indicates that coronary PVAT per se, but not bodyweight or other adipose tissue, plays an important role in the pathogenesis of VSA. Importantly, there was a significant positive correlation between the extent of the coronary PVAT volume index and that of coronary vasoconstricting responses to acetylcholine in VSA patients.23 Interestingly, the Cardiovascular Risk Prediction using Computed Tomography (CRIPT-CT) study recently showed that high perivascular FAI values are an indicator of increased cardiac mortality in patients with atherosclerosis by providing a quantitative measure of coronary inflammation.26

F-fluorodeoxyglucose PET for Perivascular Adipose Tissue Inflammation

Validation Studies F-FDG PET has been clinically used to detect inflammation, as it reflects the metabolic activity of glucose, which is known to be enhanced in inflamed tissue.27 Indeed, 18F-FDG PET can non18

EUROPEAN CARDIOLOGY REVIEW

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Adventitial vasa vasorum

The coronary artery consists of the intima, media, adventitia and perivascular adipose tissue. The adventitia also interacts with its adjacent perivascular adipose tissue, which is linked to microvessels and nerves. Perivascular adipose tissue is metabolically active, secreting a wide variety of bioactive substances to regulate vascular physiology, homeostasis and structural remodelling, exerting major influences on the progression or regression of vascular disease. Source: Ohyama et al. 2018.25 Reproduced with permission from Elsevier.

Figure 2: Coronary Angiograms and CT Images of Coronary Perivascular Adipose Tissue Volume CAG

Clinical Relevance

ACh

ISDN

ACh

ISDN

Non-VSA VSA

There is growing evidence suggesting that epicardial adipose tissue volume measured by cardiac CT is related to the extent of coronary plaque burden,20 and is also significantly associated with cardiovascular events.21 We recently demonstrated for the first time that coronary PVAT volume is increased at the spastic coronary segment of vasospastic angina (VSA) patients, suggesting the involvement of coronary PVAT in the pathogenesis of coronary spasm.22 Subsequently, Ito et al. reported that increased epicardial adipose tissue volume was associated with ergonovine-induced epicardial coronary artery spasm.23

Vasospasm

Diffuse spasm

Coronary angiograms after intracoronary acetylcholine (ACh) and isosorbide dinitrate (ISDN) are shown on the left. Cross-sectional CT images and 3D reconstructed CT images of coronary perivascular adipose tissue at the spastic left anterior descending coronary artery in a nonvasospastic angina (VSA) patient (A, C) and a VSA patient (B, D) are on the right. Coronary perivascular adipose tissue volume of left anterior descending coronary artery was larger in a VSA patient compared with a non-VSA patient. CAG = coronary angiography; ISDN = isosorbide dinitrate. Source: Ohyama et al. 2018.25 Reproduced with permission from Elsevier.

invasively image the metabolic activity in perivascular, visceral and subcutaneous fat tissues, serving as a surrogate marker for fat tissue inflammation.28,29 Indeed, Tarkia et al. demonstrated that, in early coronary atherosclerotic lesions, plaque inflammation with clearly increased uptake of 18F-FDG can be detected in a pig model of diabetes and hypercholesterolaemia.18 We also recently demonstrated that 18F-FDG PET/CT is useful for assessment of coronary PVAT inflammation in pigs in vivo in the pathogenesis of coronary spasm after DES implantation (Figure 3).19 In that experimental study, an everolimus-eluting stent (EES) was randomly implanted in pigs into the LAD or the left circumflex coronary artery, while a non-stented coronary artery was used as a control. At 1 month after EES implantation, coronary vasoconstricting responses to intracoronary serotonin were examined by coronary angiography in pigs in vivo, followed by in vivo and ex vivo 18F-FDG PET/CT imaging. Coronary vasoconstricting responses to serotonin were significantly enhanced at the EES edges compared with the control site. Notably, in vivo and ex vivo 18F-FDG PET/CT imaging and autoradiography showed enhanced 18F-FDG uptake and its accumulation in PVAT at the EES edges compared with the control site, respectively. Furthermore, histological and reverse transcription polymerase chain reaction

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Ischaemic Heart Disease Figure 3: Perivascular Adipose Tissue Inflammation Evaluated by PET/CT at the Spastic Coronary Segment After Drug-Eluting Stent Implantation in Pigs Control CT

DES PET/CT

PET/CT

Stent site

Control site

2.0 mm

F-fluorodeoxyglucose ( F-FDG) PET/CT images of normal (A, B) and drug-eluting stent (DES)implanted coronary arteries at 1 month (E ,F). Magnified images of the control (C, D) and DES-implanted sites at 1 month (G, H). 18F-FDG uptake at the DES-implanted site is shown by yellow arrows (H). 18F-FDG PET/CT imaging showed that as compared with the control site (A–D), 18F-FDG uptake was markedly enhanced at the DES site (E–H) at 1 month after stent implantation. In the magnified images, 18F-FDG uptake extended from the DES implantation site to the proximal and distal edge segments (H). Source: Ohyama et al. 2017.19 Reproduced with permission from the American Heart Association. 18

Figure 4: Coronary Perivascular Fluorodeoxyglucose Uptake Evaluated With PET/CT Imaging in a Vasospastic Angina Patient and a Non-vasospastic Angina Patient 18

F-FDG PET/CT

Non-VSA

Aorta LAD

control site in pigs. This basic research indicates that inflammatory changes of coronary PVAT are associated with DES-induced coronary hyperconstricting responses in pigs in vivo, and that 18F-FDG PET imaging is useful for assessment of coronary PVAT inflammation.

Clinical Relevance Several studies demonstrated that 18F-FDG PET is clinically able to detect PVAT inflammation in patients with coronary atherosclerosis. 16,22,23 Mazurek et al. reported that inflammatory activity of PVAT assessed by 18F-FDG PET was greater in patients with stable coronary artery disease than in non-coronary artery disease controls, and was independently associated with the extent of coronary stenosis.17 Hong et al. also reported that pericardial adipose tissue was significantly associated with vascular inflammation and various cardiometabolic risk profiles.30 Furthermore, based on our experimental validation study, we also recently demonstrated with ECG-gated 18F-FDG PET/CT that coronary artery spasm was associated with perivascular inflammation in patients with VSA (Figure 4).25 In that clinical study, after excluding patients with ≥75% organic stenosis in the LAD artery, we prospectively examined 27 consecutive VSA patients with acetylcholine-induced diffuse spasm in the LAD artery and 13 individuals with suspected angina, but without organic coronary lesions or coronary spasm. ECG-gated 18F-FDG PET/CT was performed to measure coronary perivascular FDG uptake. OCT was also performed to evaluate the VV of the LAD artery. 18F-FDG PET/CT images showed that coronary perivascular FDG uptake was significantly increased at the spastic LAD artery in the VSA group compared with the non-VSA group. OCT examination showed that adventitial VV area density per a crosssectional OCT image at the spastic LAD artery was markedly greater in the VSA group than in the non-VSA group. Importantly, after 23 months’ follow up with medical treatment, coronary perivascular FDG uptake was significantly decreased in the VSA patients. Rho kinase activity in circulating leukocytes increased in the VSA patients, and substantially decreased after medical treatment. Thus, that clinical study demonstrated that coronary spasm is associated with coronary adventitial and PVAT inflammation, where 18F-FDG PET/CT may be useful for disease activity assessment.23 Although we and others previously demonstrated that atherosclerotic changes, such as focal VV formation, may be involved in the focal spasm compared with the diffuse spasm in VSA patients,31,32 further detailed mechanisms of the type and location of coronary spasm remain to be elucidated in future studies.

VSA

Aorta LAD

F-fluorodeoxyglucose (18F-FDG) PET/CT images of a non-vasospastic angina (VSA) patient (A, B) and a VSA patient (C, D). The yellow arrow shows coronary perivascular FDG uptake in the left anterior descending (LAD) artery (D). Coronary perivascular FDG uptake was markedly enhanced at the spastic LAD artery in the VSA group compared with the non-VSA group. Source: Ohyama et al. 2018.25 Reproduced with permission from Elsevier.

analysis showed that inflammatory changes of coronary PVAT were significantly enhanced at the EES edges compared with the control site. Importantly, Rho kinase expressions and Rho kinase activity at the EES edges were significantly enhanced compared with the

ECR_Shimokawa_FINAL.indd 8

Future Perspectives Other perivascular components, such as sympathetic nerve fibres (SNFs) and lymphatic vessels, begin to attract much attention as crucial players regarding perivascular inflammation. We recently demonstrated that after DES implantation in pigs in vivo, adventitial SNFs can be enhanced, and are associated with adventitial VV growth. Catheterbased renal denervation also significantly upregulates the expression of alpha-2 adrenergic receptor-binding sites in the nucleus tractus solitarius, and attenuates adventitial VV enhancement associated with a decrease in SNF.33 We also recently demonstrated that cardiac lymphatic vessels (LVs) play important roles in the regulation of coronary vasomotion after DES implantation in pigs in vivo.34 In that study, after ligation of the proximal

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Insights From Translational Imaging Research LV close to the left main coronary artery, coronary vasoconstricting responses at DES edges were significantly enhanced in the ligation group compared with the sham group. Importantly, LVs have drainage effects of inflammatory substances from PVAT, and thus may be one of the most crucial regulators for PVAT inflammation.35 Thus, the roles of these perivascular components (e.g. SNF and LV) also remain to be fully elucidated in future studies.

products (i.e. 4-hydroxynonenal) that upregulate adiponectin gene expression in PVAT via a peroxisome proliferator-activated receptor gamma-dependent mechanism, which also suggests the importance of inside-out signalling (i.e. from the vessel to surrounding PVAT). Further studies are required to elucidate the roles of inside-out signalling in cardiovascular disease in future studies.

Conclusion Antonopoulos et al. reported that interactions between the vascular wall and PVAT play an important role for adiponectin in the regulation of endothelial nitric oxide synthase function in patients with atherosclerosis.36,37 They introduced the novel concept that increased oxidative stress in the vessel wall leads to the release of peroxidation

10.

11.

12.

13.

himokawa H. 2014 Williams Harvey Lecture: Importance of S coronary vasomotion abnormalities-from bench to bedside. Eur Heart J 2014;35:3180–93. https://doi.org/10.1093/eurheartj/ ehu427; PMID: 25354517. Yasue H, Takizawa A, Nagao M, et al. Long-term prognosis for patients with variant angina and influential factors. Circulation 1988;78:1–9. https://doi.org/10.1161/01.CIR.78.1.1; PMID: 3260150. Ong P, Athanasiadis A, Hill S, et al. Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary artery spasm in patients with acute coronary syndrome) study. J Am Coll Cardiol 2008;52:523–7. https://doi. org/10.1016/j.jacc.2008.04.050; PMID: 18687244. Kandabashi T, Shimokawa H, Miyata K, et al. Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1b. Circulation 2000;101:1319–23. https://doi. org/10.1161/01.CIR.101.11.1319; PMID: 10725293. Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005;25:1767–75. https://doi.org/10.1161/01. ATV.0000176193.83629.c8; PMID: 16002741. Shimokawa H, Ito A, Fukumoto Y, et al. Chronic treatment with interleukin-1b induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of plateletderived growth factor. J Clin Invest 1996;97:769–76. https://doi. org/10.1172/JCI118476; PMID: 8609234. Nishimiya K, Matsumoto Y, Shindo T, et al. Association of adventitial vasa vasorum and inflammation with coronary hyperconstriction after drug-eluting stent implantation in pigs in vivo. Circ J 2015;79:1787–98. https://doi.org/10.1253/circj. CJ-15-0149; PMID: 26027445. Nishimiya K, Matsumoto Y, Takahashi J, et al. In vivo visualization of adventitial vasa vasorum of the human coronary artery on optical frequency domain imaging. Validation study. Circ J 2014;78:2516–8. https://doi. org/10.1253/circj.CJ-14-0485; PMID: 24976390. Nishimiya K, Matsumoto Y, Takahashi J, et al. Enhanced adventitial vasa vasorum formation in patients with vasospastic angina: Assessment with OFDI. J Am Coll Cardiol 2016;67:598–600. https://doi.org/10.1016/j.jacc.2015.11.031; PMID: 26846957. Brown NK, Zhou Z, Zhang J, et al. Perivascular adipose tissue in vascular function and disease: A review of current research and animal models. Arterioscler Thromb Vasc Biol 2014;34:1621– 30. https://doi.org/10.1161/ATVBAHA.114.303029; PMID: 24833795. Lehman SJ, Massaro JM, Schlett CL, et al. Peri-aortic fat, cardiovascular disease risk factors, and aortic calcification: The Framingham Heart Study. Atherosclerosis 2010;210:656–61. https://doi.org/10.1016/j.atherosclerosis.2010.01.007; PMID: 20152980. Montani JP, Carroll JF, Dwyer TM, et al. Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases. Int J Obes Relat Metab Disord 2004;28 Suppl 4:S58–65. https://doi.org/10.1038/sj.ijo.0802858; PMID: 15592488. Rosito GA, Massaro JM, Hoffmann U, et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: The Framingham Heart Study. Circulation 2008;117:605–13.

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14.

15.

16.

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24.

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Recent advances in non-invasive imaging for PVAT inflammation have begun to elucidate the roles of PVAT in the pathogenesis of coronary artery spasm. These imaging approaches for coronary perivascular components will enable us to elucidate the important roles of the coronary adventitia and the pathogenesis of coronary artery disease.

https://doi.org/10.1161/CIRCULATIONAHA.107.743062; PMID: 18212276. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460–6. https://doi.org/10.1161/01. CIR.0000099542.57313.C5; PMID: 14581396. Owen MK, Witzmann FA, McKenney ML, et al. Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: Influence of obesity. Circulation 2013;128:9–18. https://doi.org/10.1161/CIRCULATIONAHA.112.001238; PMID: 23685742. Antonopoulos AS, Sanna F, Sabharwal N, et al. Detecting human coronary inflammation by imaging perivascular fat. Sci Transl Med 2017;398:9. https://doi.org/10.1126/scitranslmed. aal2658; PMID: 28701474. Mazurek T, Kobylecka M, Zielenkiewicz M, et al. PET/CT evaluation of 18F–FDG uptake in pericoronary adipose tissue in patients with stable coronary artery disease: Independent predictor of atherosclerotic lesions’ formation? J Nucl Cardiol 2017;24:1075–84. https://doi.org/10.1007/s12350-015-0370-6; PMID: 26951555. Tarkia M, Saraste A, Stark C, et al. [18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs. PloS One 2015;10:e0131332. https://doi.org/10.1371/journal. pone.0131332; PMID: 26120829. Ohyama K, Matsumoto Y, Amamizu H, et al. Association of coronary perivascular adipose tissue inflammation and drug-eluting stent-induced coronary hyperconstricting responses in pigs: 18F-fluorodeoxyglucose positron emission tomography imaging study. Arterioscler Thromb Vasc Biol 2017;37:1757–64. https://doi.org/10.1161/ ATVBAHA.117.309843; PMID: 28751570. Alexopoulos N, McLean DS, Janik M, et al. Epicardial adipose tissue and coronary artery plaque characteristics. Atherosclerosis 2010;210:150–4. https://doi.org/10.1016/ j.atherosclerosis.2009.11.020; PMID: 20031133. Cheng VY, Dey D, Tamarappoo B, et al. Pericardial fat burden on ECG-gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. JACC Cardiovasc Imaging 2010;3:352–60. https://doi.org/10.1016/ j.jcmg.2009.12.013; PMID: 20394896. Ohyama K, Matsumoto Y, Nishimiya K, et al. Increased coronary perivascular adipose tissue volume in patients with vasospastic angina. Circ J 2016;80:1653–6. https://doi. org/10.1253/circj.CJ-16-0213; PMID: 27194468. Ito T, Fujita H, Ichihashi T, et al. Impact of epicardial adipose tissue volume quantified by non-contrast electrocardiogramgated computed tomography on ergonovine-induced epicardial coronary artery spasm. Int J Cardiol 2016;221:877–80. https://doi. org/10.1016/j.ijcard.2016.07.139; PMID: 27434364. Ohyama K, Matsumoto Y, Shimokawa H. Impact of epicardial adipose tissue volume quantified by noncontrast electrocardiogram-gated computed tomography on ergonovine-induced epicardial coronary artery spasm. (Letter to the Editor) Int J Cardiol 2017;229:40. https://doi. org/10.1016/j.ijcard.2016.10.030; PMID: 27751596. Ohyama K, Matsumoto Y, Takanami K, et al. Coronary adventitial and perivascular adipose tissue inflammation in patients with vasospastic angina. J Am Coll Cardiol 2018;71:414–25. https://doi.org/10.1016/j.jacc.2017.11.046; PMID: 29389358.

26. O ikonomou EK, Marwan M, Desai MY, et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): A post-hoc analysis of prospective outcome data. Lancet 2018;392:929–39. https://doi.org/10.1016/S01406736(18)31114-0; PMID: 30170852. 27. Tawakol A, Migrino RQ, Bashian GG, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 2006;48:1818–24. https://doi.org/10.1016/j.jacc.2006.05.076; PMID: 17084256. 28. Bucerius J, Mani V, Wong S, et al. Arterial and fat tissue inflammation are highly correlated: a prospective 18F-FDG PET/CT study. Eur J Nucl Med Mol Imaging 2014;41:934–45. https:// doi.org/10.1007/s00259-013-2653-y; PMID: 24442596. 29. Christen T, Sheikine Y, Rocha VZ, et al. Increased glucose uptake in visceral versus subcutaneous adipose tissue revealed by PET imaging. JACC Cardiovasc Imaging 2010;3:843–51. https://doi.org/10.1016/j.jcmg.2010.06.004; PMID: 20705265. 30. Hong HC, Hwang SY, Park S, et al. Implications of pericardial, visceral and subcutaneous adipose tissue on vascular inflammation measured using 18FDG-PET/CT. PloS One 2015;10:e0135294. https://doi.org/10.1371/journal. pone.0135294; PMID: 26270050. 31. Nishimiya K, Matsumoto Y, Uzuka H, et al. Focal vasa vasorum formation in patients with focal coronary vasospasm - An optical frequency domain imaging study. Circ J 2016;80: 2252–4. https://doi.org/10.1253/circj.CJ-16-0580; PMID: 27557851. 32. Koyama J, Yamagishi M, Tamai J, et al. Comparison of vessel wall morphologic appearance at sites of focal and diffuse coronary vasospasm by intravascular ultrasound. Am Heart J 1995;130:440–5. https://doi.org/10.1016/00028703(95)90349-6; PMID: 23858100. 33. Uzuka H, Matsumoto Y, Nishimiya K, et al. Renal denervation suppresses coronary hyperconstricting responses after drugeluting stent implantation in pigs in vivo through the kidneybrain-heart axis. Arterioscler Thromb Vasc Biol 2017;37:1869–80. https://doi.org/10.1161/ATVBAHA.117.309777; PMID: 28818859. 34. Amamizu H, Matsumoto Y, Morosawa S, et al. Important roles of cardiac lymphatic vessels in the regulation of coronary vasomotion after DES implantation in pigs in vivo. Eur Heart J 2018;39:ehy565.2435. https://doi.org/10.1093/eurheartj/ ehy565.2435. 35. Arngrim N, Simonsen L, Holst JJ, et al. Reduced adipose tissue lymphatic drainage of macromolecules in obese subjects: A possible link between obesity and local tissue inflammation? Int J Obes (Lond) 2013;37:748–50. https://doi.org/10.1038/ ijo.2012.98; PMID: 22751255. 36. Antonopoulos AS, Margaritis M, Coutinho P, et al. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: The regulatory role of perivascular adipose tissue. Diabetes 2015;64:2207–19. https://doi.org/10.2337/db14-1011; PMID: 25552596. 37. Margaritis M, Antonopoulos AS, Digby J, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation 2013;127:2209–21. https://doi.org/10.1161/ CIRCULATIONAHA.112.001133; PMID: 23625959.

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Ischaemic Heart Disease

Improvement of Fractional Flow Reserve after Percutaneous Coronary Intervention Does Not Necessarily Indicate Increased Coronary Flow Rikuta Hamaya, 1 Yoshihisa Kanaji, 1 Eisuke Usui, 1 Masahiro Hoshino, 1 Tadashi Murai, 1 Taishi Yonetsu 2 and Tsunekazu Kakuta 1 1. Division of Cardiovascular Medicine, Tsuchiura Kyodo General Hospital, Ibaraki, Japan; 2. Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Abstract Coronary flow is expected to increase by epicardial lesion modification after successful percutaneous coronary intervention (PCI) in stable angina. According to the concept of fractional flow reserve (FFR), the improvement in FFR after PCI reflects the extent of coronary flow increase. However, this theory assumes that hyperaemic microvascular resistance does not change after PCI, which is being refuted in recent studies. The authors quantitated regional absolute coronary blood flow (ABF) before and after PCI using a thermodilution method and compared it with FFR in 28 patients with stable coronary artery disease who had undergone successful PCI. Although FFR indicated changes in ABF, with a mean difference of −5.5 ml/min, there was no significant relationship between individual changes in FFR and in ABF (R=0.27, p=0.16). The discrepancy was partly explained by changes in microvascular resistance following PCI. These results suggest that changes in FFR do not necessarily indicate an increase in absolute coronary blood flow following PCI in individual patients, although they could be correlated in a cohort level.

Keywords Fractional flow reserve, coronary blood flow, microvascular resistance, percutaneous coronary intervention, stable angina Disclosure: The authors have no conflict of interests to declare. Received: 23 November 2018 Accepted: 20 March 2019 Citation: European Cardiology Review 2019;14(1):10–2. DOI: https://doi.org/10.15420/ecr.2018.27.2 Correspondence: Tsunekazu Kakuta, Department of Cardiology, Tsuchiura Kyodo General Hospital, 4-4-1 Otsuno, Tsuchiura City, Ibaraki, 300-0028, Japan. E: kaz@joy.email.ne.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Clinical and economic benefits of fractional flow reserve (FFR)-guided revascularisation have been established and the strategy is a class-1 recommendation in current guidelines.1,2 FFR values both before and after percutaneous coronary intervention (PCI) have been reported to provide prognostic information.3–5 Originally, FFR was used as a surrogate measure of impaired coronary flow, and employed to compare flow without epicardial stenosis; the change in coronary flow before and after PCI could be evaluated, and minimum microvascular resistance under drug-induced vasodilation was assumed to remain constant. However, recent data have cast doubt on this presumption and indicate potential limitations of FFR in representing coronary flow change after PCI.6–9 In this article, we present our results about the relationship between changes in FFR and absolute coronary flow volume and discuss other recent studies examining this topic.

Methods The present analyses were based on data from a recent report by our group. Changes in absolute coronary blood flow (ABF) and hyperaemic microvascular resistance (MR) after PCI were assessed using the thermodilution method.6 In brief, a small infusion catheter with a distal end-hole (3.9 Fr, Kiwami) was advanced over a pressure-temperature

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sensor-tipped guidewire, placed in the proximal portion of the coronary artery, and saline was continuously infused through the catheter. Pressure and temperature were continuously recorded using the guidewire, which was pulled back from distal segment into the infusion catheter. ABF and MR were calculated as follows: ABF (ml/min) = 1 .08 × (distal temperature)/(infused saline temperature) × (infusion rate of saline, 20 ml/h) Hyperaemic MR = distal coronary pressure/ABF (dyne∙s∙cm−5) Moreover, on the basis of FFR theory in which MR is constant during PCI procedure, we calculated the theoretically expected post-PCI ABF as follows: Expected post-PCI ABF (ml/min) = pre-PCI ABF × p ost-PCI FFR/ pre-PCI FFR Delta ABF and FFR were defined as the post-PCI value minus the prePCI value. We recruited 28 patients with stable angina who underwent PCI and ABF/FFR assessment both before and after PCI. Successful PCI was performed in all the patients and no periprocedural MI

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Percutaneous Coronary Intervention Figure 1: Changes after Percutaneous Coronary Intervention

Table 1: Baseline Characteristics Patient characteristics

200

Age (years)

150

Delta ABF

100 50 0 –50 –100 0.1

0.2

0.3

25 (89.3)

BMI (kg/m2)

24.6±3.3

Hypertension

22 (78.6)

Hyperlipidaemia

20 (71.4)

Diabetes

7 (25.0)

Smoking

20 (71.4)

Left ventricular ejection fraction (%)

63 (57–68)

Vessel characteristics

R=0.27, p=0.16

67.6±11.8

Male

0.4

0.5

Delta FFR

Pre-PCI FFR

0.70 (0.65–0.75)

Post-PCI FFR

0.88 (0.84–0.95)

Delta FFR

0.16 (0.11–0.30)

Pre-PCI ABF (ml/min)

137.8 (86.2–183.3)

Post-PCI ABF (ml/min)

173.3 (137.5–234.4)

Delta ABF (ml/min)

300

52.8 (8.4–84.5)

Pre-PCI hyperaemic MR (10

3dyne·s/cm5)

Difference: measured ABF-expected ABF

Post-PCI hyperaemic MR (103dyne·s/cm5) 3

Delta hyperaemic MR (10 dyne·s/cm )

200

32.0 (24.2–45.6) 36.8 (27.6–44.6) 3.2 (–5.6–10.6)

Values are mean±SD, median (IQR) or n (%). ABF = absolute coronary blood flow; FFR = fractional flow reserve; MR = microvascular resistance; PCI = percutaneous coronary intervention.

100

was documented. FFR was improved following PCI in every patient. We examined the association between: delta ABF and delta FFR; expected and measured post-PCI ABF and the difference between ‘expected and measured post-PCI ABF’; and changes in hyperaemic MR following PCI. The associations were measured by scatter plots and Pearson correlation coefficient using JMP 11.2.0 (SAS Institute).

–100

–200

Results The present cohort had lesions and a median FFR of 0.70 (IQR 0.65–0.75). The mean age of the patients was 67.6 years (SD 11.8 years) and 89.3% (25/28) were male. Baseline characteristics are summarised in Table 1.

–300 0

100

200

300

400

500

Mean: (measured ABF + expected ABF)/2

Difference between expected ABF and actual ABF

150

At cohort level, ABF significantly increased following PCI from a median 137.8 ml/min before to 173.3 ml/min after the procedure. However, at an individual level, six patients (21.4%) showed a decrease in ABF after PCI. The relationship between delta ABF and delta FFR was not significant (R=0.27, p=0.16) (Figure 1A). Delta ABF was widely distributed for lesions with delta FFR <0.2, which suggests that PCI might not necessarily improve coronary flow.

150 50 0 –50 –100 –150 –200 –250

R=0.72, p<0.001

–300 –30,000

–20,000

–10,000

10,000

20,000

30,000

Changes in microvascular resistance following percutaneous coronary intervention Scatter plots showing linear correlations (A and C) and a Blant-Altman plot showing the differences in measured and expected post-PCI absolute coronary flow (ABF) (B). Scatter plots show the association between delta absolute coronary flow (ABF) and delta fractional flow reserve (FFR) (A), and the difference between expected and actual post-PCI ABF and change of microvascular resistance (MR) following PCI (C).

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Figure 1B shows a Bland-Altman plot for measured and expected postPCI ABF. Although the mean difference was −5.5 ml/min (measured ABF: 185.0 ml/min; expected ABF: 190.5 ml/min), the difference values varied greatly between individuals, and the 95% CI was relatively wide (−35.6–24.6 ml/min). Changes in FFR reflected changes in coronary flow well at a cohort level but poorly at an individual level. Finally, we calculated the difference between expected and measured post-PCI ABF and compared the values with changes in hyperaemic MR following PCI (Figure 1C). The linear association was strong and robust (R=0.72, p<0.001). The results imply that coronary flow might decrease when hyperaemic MR increases following PCI.

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Ischaemic Heart Disease Discussion The present study provides evidence of the limitations of FFR in predicting absolute changes in coronary flow following PCI. Changes in MR might play a role in the discrepancy between changes in FFR and in absolute coronary flow. Driessen et al. demonstrated a strong linear relationship between an improvement in FFR and an increase in myocardial blood flow, measured by serial PET examinations, following PCI.9 Their data are consistent with our study because strong relationships were observed especially in cases demonstrating high FFR improvement were likely to be associated with high myocardial blood flow improvement, and because changes in myocardial blood flow varied when the FFR was close to the grey zone. Another study investigating PCI-related changes in myocardial flow, which used phase-contrast cine cardiac MRI, also supports this observation.8 Importantly, these reports consistently demonstrate the phenomenon that PCI could result in a decrease in global myocardial blood flow. These data suggest an important limitation of FFR as a surrogate measure for coronary blood flow, counterarguing the assumption that microvascular resistance under drug-induced vasodilation is constant from pre-PCI to post-PCI. Under the assumption, Ohm’s law suggests that the absolute blood flow should increase in all cases after PCI, since PCI increases distal coronary pressure as well as FFR value in almost all cases. The cases in which a decrease in coronary flow was documented imply that PCI that could potentially lead to an increase in microvascular resistance. The present study directly demonstrates this hypothesis by showing the relationship between the difference between the expected and actual post-PCI ABF and the change in microvascular resistance following PCI. Change in evaluating shown the strategy. 10

coronary blood flow may be an important marker for the benefit of PCI. Several large randomised trials have non-inferiority of optimal medical therapy to an invasive

A double-blinded randomised trial demonstrated a non-significant efficacy of PCI in relieving patients’ symptoms. 11

Z immermann FM, Omerovic E, Fournier S, et al. Fractional flow reserve-guided percutaneous coronary intervention vs medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data. Eur Heart J 2019;40:180–6. https://doi.org/10.1093/eurheartj/ehy812; PMID: 30596995. FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med 2018;379:250–9. https://doi.org/10.1056/NEJMoa1803538; PMID: 29785878. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year followup of the DEFER trial. Eur Heart J 2015;36:3182–8. https://doi. org/10.1093/eurheartj/ehv452; PMID: 26400825. Rimac G, Fearon WF, De Bruyne B, et al. Clinical value of postpercutaneous coronary intervention fractional flow reserve

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However, these studies did not evaluate PCI-related flow changes, and it is possible that the majority of these PCIs might not have resulted in coronary flow improvement. A recent meta-analysis showed an efficacy of FFR-guided PCI in reducing cardiovascular events. 1 The result might be interpreted as evidence that the prePCI flow conditions were associated with the potential of flow improvement by PCI. Further studies are warranted to clarify the association between flow improvement and clinical outcomes. Pre- or post-PCI FFR value in a continuous fashion is certainly one of the most important physiological markers. Changes in FFR can be correlated with coronary flow change in a cohort level; however, FFR alone could not accurately predict PCI-related flow change in individual patient levels. An observational study suggested the potential utility of flow evaluation of another physiological index, coronary flow capacity, in addition to FFR.12 FFR is without doubt a clinically useful marker, but we need to recognise its limitations and explore other markers to support FFR in the prediction of individualised coronary flow improvement following PCI, and its relationship with the incidence of future cardiac events.

Limitations This study prospectively, but not consecutively, included subjects from a single centre, making selection bias unavoidable. The current method for measuring ABF might not add any clinical value over FFR. Furthermore, it is difficult to determine coronary flow reserve by this method because direct saline infusion induces suboptimal hyperaemia. The reproducibility and inter/intra-observer variability of ABF or MR were not assessed. Other limitations are listed in our previous article.6

Conclusion Changes in FFR following PCI do not necessarily indicate an increase in absolute coronary blood flow in individual patients, although they could be correlated at cohort level. This discrepancy might be explained by a change in microvascular resistance.

value: a systematic review and meta-analysis. Am Heart J 2017;183:1–9. https://doi.org/10.1016/j.ahj.2016.10.005; PMID: 27979031. Kanaji Y, Murai T, Yonetsu T, et al. Effect of elective percutaneous coronary intervention on hyperemic absolute coronary blood flow volume and microvascular resistance. Circ Cardiovasc Interv 2017;10:e005073. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005073; PMID: 29038224. Hamaya R, Sugano A, Kanaji Y, et al. Absolute myocardial blood flow after elective percutaneous coronary intervention evaluated on phase-contrast cine cardiovascular magnetic resonance imaging. Circ J 2018;82:1858–65. https://doi. org/10.1253/circj.CJ-17-1449; PMID: 29643278. Kanaji Y, Yonetsu T, Hamaya R, et al. Impact of elective percutaneous coronary intervention on global absolute coronary flow and flow reserve evaluated by phasecontrast cine-magnetic resonance imaging in relation to regional invasive physiological indices. Circ Cardiovasc Interv 2018;11:e006676. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.006676; PMID: 30006332.

riessen RS, Danad I, Stuijfzand WJ et al. Impact of D revascularization on absolute myocardial blood flow as assessed by serial [15O]H2O positron emission tomography imaging: a comparison with fractional flow reserve. Circ Cardiovasc Imaging 2018;11:e007417. https://doi.org/10.1161/ CIRCIMAGING.117.007417; PMID: 29703779. 10. Bangalore S. Applicability of the COURAGE, BARI 2D, and FREEDOM trials to contemporary practice. J Am Coll Cardiol 2016;68(10):996–8. https://doi.org/10.1016/j.jacc.2016.06.020; PMID: 27585502. 11. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2018;391:31–40. https://doi.org/10.1016/S0140-6736(17)32714-9. PMID: 29103656. 12. Hamaya R, Yonetsu T, Kanaji Y et al. Diagnostic and prognostic efficacy of coronary flow capacity obtained using pressuretemperature sensor-tipped wire-derived physiological indices. JACC Cardiovasc Interv 2018;11:728–37. https://doi.org/10.1016/j. jcin.2018.01.249; PMID: 29605243.

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Ischaemic Heart Disease

Behind Traditional Semi-quantitative Scores of Myocardial Perfusion Imaging: An Eye on Niche Parameters Carmela Nappi, Valeria Gaudieri and Alberto Cuocolo Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy

Abstract The evaluation of stress-induced myocardial perfusion defects by non-invasive myocardial perfusion imaging (MPI) modalities has a leading role in the identification of coronary artery disease, and has excellent diagnostic and prognostic value. Non-invasive MPI can be performed using conventional and novel gamma cameras or by PET/CT. New software has allowed novel parameters that may have a role in the identification of early marks of cardiac impairment to be evaluated. We aim to give an overview of niche parameters obtainable by single photon emission CT (SPECT) and PET/CT MPI that may help practitioners to detect initial signs of cardiac damage and identify new therapy targets. In particular, we summarise the role of left ventricular geometry indices for remodelling, phase analysis parameters to evaluate mechanical dyssynchrony, the concept of relative flow reserve in the evaluation of flow-limiting epicardial stenosis, vascular age and epicardial adipose tissue as early markers of atherosclerotic burden, and emerging parameters for the evaluation of myocardial innervation, such as the total defect score.

Keywords Shape index, phase analysis, relative flow reserve, vascular age, epicardial adipose tissue Disclosure: The authors have no conflicts of interest to declare. Received: 7 January 2019 Accepted: 26 February 2019 Citation: European Cardiology Review 2019;14(1):13–7. DOI: https://doi.org/10.15420/ecr.2019.5.1 Correspondence: Carmela Nappi, Department of Advanced Biomedical Sciences, University Federico II, Via Pansini 5, 80131 Naples, Italy. E: c.nappi@unina.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Evaluating stress-induced myocardial perfusion defects by noninvasive myocardial perfusion imaging (MPI) modalities has taken a leading role in the identification of flow-limiting epicardial coronary artery disease (CAD); it has excellent diagnostic and prognostic value. Non-invasive MPI can be performed using conventional and novel gamma cameras or PET/CT.1 A range of imaging techniques has become available and more sophisticated reconstruction algorithms have improved the accuracy of each method, with the crucial benefit of dose reduction.2–4 In addition, the possibility of obtaining a variety of perfusion and functional parameters by using semi-quantitative scores has given a good insight into cardiac function.

the assessment of early stages of atherosclerosis or microvascular dysfunction and the identification of balanced ischaemia with reduction of MBF in all three major coronary arteries.7 Integrating functional data with information derived from coronary CT provides incremental information about coronary artery morphology and coronary calcium burden. 8–10 New software has allowed novel parameters that may have a role in the identification of early marks of cardiac impairment to be evaluated. We aim to give an overview on niche parameters obtainable by SPECT and PET/CT MPI that may help clinicians to detect the initial signs of cardiac damage and new therapy targets.

MPI Niche Parameters

The latest single photon emission CT (SPECT) MPI guidelines recommend reporting the extent, severity and reversibility of perfusion defect, ventricular dilatation and transient ischaemic dilation (TID).5 In particular, the TID ratio adds value to clinical and perfusion data to identify the presence of severe CAD in patients with suspected or known CAD, especially in those with diabetes.6 When ECG-gated CT is performed, it is necessary to evaluate regional wall motion and thickening and to report the ejection fraction after stress and/or at rest.

Left ventricle (LV) geometry changes in response to exposure to cardiovascular risk factors. This is significant, given that LV remodelling is associated with poorer outcomes.11 The LV can change its structure considerably in relatively short periods of time, with the potential for pathological remodelling to be reversed to some degree.12 Previous studies have examined the relationship between cardiac volumes, ejection fraction and remodelling.13

Non-invasive quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR) by PET/CT increase the scope of conventional SPECT MPI from the evaluation of advanced CAD to

Several non-invasive imaging techniques can be used to evaluate different structural modifications in myocardial tissue. Ultrasound and MRI studies take a two-dimensional approach to evaluate LV geometry

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Left Ventricular Geometry

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Ischaemic Heart Disease Figure 1: Examples of Abnormal and Normal Geometry A

The closer the dimensions of the axes are, the more the ellipsoid takes the shape of a sphere (Figure 1). These parameters are highly repeatable and have been shown to have clinical utility in identifying not only patients with an exacerbation of cardiac heart failure but also early LV remodelling in patients with diabetes, demonstrating a prognostic value, even in the presence of normal myocardial perfusion.18–20 However, no studies to examine the role of these indices in the evaluation of reverse remodelling have yet been conducted.

Phase Analysis B

A: Patient with heart failure and abnormal geometry indices (end-diastolic LVSI: 0.91 and endsystolic LVSI 0.84). B: Patient with atypical angina and suspected CAD and normal geometry indices (end-diastolic LVSI: 0.64 and end-systolic LVSI 0.42). ANT = anterior; INF = inferior; LVSI = left ventricular shape index; SEPT = septum.

Figure 2: Cardiac CT Images of Two Patients with Different Epicardial Adipose Tissue Values

Cardiac CT images of two patients of similar age with suspected coronary artery disease and different epicardial adipose tissue (EAT) values. A: EAT volume 20.2 cm3. B: EAT volume 260.65 cm3. .

by manual measurements obtained from perpendicular views.14–15 However, these techniques are subject to variability and depend on the experience of the operator.

Speckle-tracking echocardiography, cardiac MRI and nuclear imaging have allowed LV mechanical dyssynchrony to be evaluated, providing quantitative measurements of mechanical delay.21 Phase analysis by gated SPECT evaluates temporal sequence of contraction, using continuous Fourier harmonic functions, to analyse LV synchronic contraction. Phase analysis parameters of gated SPECT at rest can be calculated using dedicated software and provides five quantitative indices (P, SD, B, S, and K) from the phase histogram to describe the phase histogram’s characteristics (time of onset, dispersion, symmetry and envelope) of the LV regional onset of mechanical contraction to quantify dyssynchrony. P is the most frequent phase (the phase corresponding to the peak of the phase histogram). SD is the standard deviation of the phase distribution. B includes 95% of the elements in the phase distribution. S indicates the symmetry of the histogram (positive S indicates the histogram skewed to the right with a longer tail to the right of the peak phase). K (kurtosis) indicates the degree to which the histogram has peaked; a histogram with a higher peak within a narrower band has higher kurtosis.22 Recently, cut-off values for SD, bandwidth (BW), skewness (S) and kurtosis (K) obtained from gated SPECT that show a good discriminatory capacity between healthy patients and those with varying degrees of cardiac mechanical dyssynchrony were suggested.23 Evaluation of mechanical dyssynchrony predicts response to resynchronisation therapy with long-term prognostic value.24–25 A method that automatically integrates the myocardial viability polar map and the polar map of LV regional contraction synchronicity from gated SPECT could be used to detect the latest contracting viable left ventricular segments and help guide resynchronization therapy.26 In a small population of patients with acute MI and multivessel disease who had undergone successful revascularisation of the culprit arteries, stress phase SD and stress histogram BW were independent predictors of events, which suggests an intriguing application of phase analysis.27 In the light of high prognostic value of such parameters, standardised cut-off values could potentially help cardiologists to interpret imaging to provide more tailored therapeutic strategies.

Relative Flow Reserve Quantitative gated SPECT allows 2D and 3D LV geometry to be evaluated, providing remodelling parameters, such as eccentricity and the end-diastolic and end-systolic LV shape index (LVSI), which are automatically generated by QGS software (QGIS Development Team).16 Specifically, eccentricity is a measure of the elongation of the LV, and varies from 0 (sphere) to 1 (line); it is calculated from the major and the minor axes of the ellipsoid that best fits the mid-myocardial surface, while LVSI is calculated as the ratio of the maximum 3D short- and long-axis LV dimension, at end-diastole and at end-systole by applying the algorithm proposed by Abidov et al.17

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Alongside widely validated quantitative parameters derived from PET, such as MBF and CFR, the concept of relative flow reserve (RFR) has been proposed; this is defined as the ratio of hyperaemic MBF in a stenotic area to hyperaemic MBF in a normally perfused area.28 The increasing interest on this new variable originates from the need to find an accurate, noninvasive indicator of flow-limiting coronary stenosis. The literature has reported discrepancies regarding the relationship between conventional PET-derived measurements and invasive index significant epicardial stenosis. For example, fractional flow reserve

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Myocardial Perfusion Imaging (FFR) has a well-established inverse relationship with outcomes; lesions with lower FFR values receive greater absolute benefits from revascularisation.29,30

Figure 3: Patient with Heart Failure and Reduced Early and Late Heart:Mediastinum Ratios

Even if hyperaemic MBF had a better correlation with FFR than CFR, the parameters look at different pathophysiological processes: hyperaemic MBF not only measures the entire single coronary vascular bed affected by an epicardial stenosis but also indicates microvascular resistance. Therefore, a reduced hyperaemic MBF may be an epiphenomenon of two different kind of coronary vascular damage and it cannot separate the effects of a specific lesion from those of microvascular dysfunction. RFR shows a linear correspondence with FFR and it has been reported that RFR of 0.70–0.80 predicts FFR ≤0.8 with good diagnostic performance.31 A recent study used PET-derived CFR and RFR as references to compare the diagnostic performance between FFR and resting indices in predicting ischaemia.32 However, prognostic data are needed to validate this new variable.

Early H/M = 1.52

Vascular Age From hybrid techniques for MPI, such as PET/CT, some parameters have emerged as additional, earlier marks of cardiovascular impairment. Vascular age, for example, is a novel variable based on the logarithmic transformation of the coronary artery calcium (CAC) score measured in Agatston units into a theoretical age in years that better identifies degeneration in the vascular system than chronological age due to calcium deposit.33 Calculating the CAC score already has a primary role in atherosclerosis evaluation. Clinical practice guidelines in the US and Europe consider CAC scoring could improve cardiovascular risk assessment in asymptomatic people and guide preventive therapies.34,35 Of note, it has been widely demonstrated that patients with suspected CAD without evidence of coronary calcium do not need further cardiac imaging investigations.36–39 This emerging concept of assigning a vascular age to patients undergoing coronary CT is based on evidence that plaques in elderly patients are more calcified than those in younger patients. The findings of large-scale studies, including the Multi-Ethnic Study of Atherosclerosis (MESA) and the St Francis Heart Study, demonstrate that vascular age is better for risk assessment because it is a much stronger predictor of cardiovascular events than chronological age.40,41 Recently, we demonstrated that coronary vascular age, assessed using CAC score, is associated with stress-induced myocardial ischaemia in patients with suspected CAD and this marker appears to be more accurate than chronological age in predicting ischaemia.42 Therefore, vascular age has a better clinical utility when making decisions on therapies and healthier lifestyles.

Epicardial Adipose Tissue Epicardial adipose tissue (EAT) is the heart’s fat storehouse. It is located between the myocardium and pericardium, sharing the same perfusion of the heart with no barrier.43 It produces different bioactive substances that can affect cardiac function.44 It is increasingly thought that the traditional anthropometric indices of pathological obesity such as BMI and body surface area may not identify obese patients who have an increased risk of cardiovascular events.45,46 EAT can be measured using different modalities and indicators. While echocardiography allows the evaluation of EAT thickness with good reproducibility, it does not provide an estimation of the total epicardial

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Late H/M = 1.55 123

I-MIBG findings with D-single photon emission CT planogram in a patient with heart failure and reduced early and late heart:mediastinum ratios. H/M = heart:mediastinum ratio.

fat amount; however, cardiac CT (Figure 2) and MRI give detailed volumetric quantification of fat load with high reproducibility.47 It has been recently observed that increased EAT volume is associated with coronary calcium burden, inﬂammatory markers and poorer outcomes; it also associated with cardiac sympathetic denervation, which can lead to catecholamine production in a cardiac response to sympathetic stimuli.48,49 Therefore, EAT evaluation could play a part in the atherosclerosis development and may be considered a marker and a therapeutic target at the same time.

Behind and Beyond Myocardial Perfusion Imaging: Myocardial Innervation Both myocardial perfusion and innervation can be studied by conventional and novel gamma cameras. Cardiac neuronal function is compromised in a number of cardiac diseases. Therefore, the evaluation of functional and electrophysiological properties of the autonomic nervous system at cardiac level has become a focus of interest in the field of cardiovascular imaging.50 A number of radiopharmaceuticals are used to investigate autonomic neuronal functions.51 It has been widely demonstrated that the status of catecholamine storage at the level of the myocardial sympathetic presynaptic fibres can be assessed with 123I-labelled meta-iodobenzylguanidine (123I-MIBG).52–54 In addition to the traditional evaluation of heart:mediastinum (H:M) ratios obtained by early and late planar acquisitions, the innervation defect size can be measured by performing supplementary tomographic imaging. From SPECT images, tracer uptake can be assessed semiquantitatively using the 17-segment model and a 5-point scale: 0 = normal uptake; 1 = mildly reduced uptake; 2 = moderately reduced uptake; 3 = severely reduced uptake; and 4 = no uptake.

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Ischaemic Heart Disease Figure 4: Extensive Left Ventricular Adrenergic Denervation and Preserved Myocardial Perfusion

The addition of SPECT method on 123I-MIBG imaging overcomes the limitations in the interpretation of planar acquisition, such as the superposition of noncardiac structures and lack of segmental analysis, and improves the clinical utility of this technique for diagnosis and prognosis. However, visual scoring of 123I-MIBG SPECT images is challenging and they need to be compared to normal data files. Moreover, SPECT requires longer acquisition time so can be performed only in fully collaborative patients.

Future directions The recent introduction of solid-state cardiac cameras with cadmiumzinc-telluride (CZT) detectors, which have higher photon sensitivity and spatial resolution than standard cameras, may allow parameters obtained by 123I-MIBG SPECT imaging to be used to gain a more accurate evaluation of cardiac adrenergic activity (Figure 3). Moreover, the possibility of obtaining both planar equivalent images and SPECT data during the same acquisition, thanks to the advanced geometry of these cameras, makes the examination shorter and more comfortable.

These dual isotope 99mTc sestamibi/123I MIBG images, obtained simultaneously using a cadmium zinc telluride camera, show extensive left ventricular adrenergic denervation (upper slices) involving the inferior and lateral walls and preserved myocardial perfusion in the same territories (lower slices) with innervation/perfusion mismatch.

The total defect score (TDS) can be calculated on the polar maps by the sum of the 17 segmental tracer uptake scores. Therefore, the innervation defect size can be expressed as percentage of the total enervated myocardium (% LV) using the formula: TDS/68 × 100, where 68 is the maximum TDS in the 17-segment model. Defect severity, as defined by TSD on 123I-MIBG SPECT using a conventional Anger camera, is significantly associated with inducible ventricular tachyarrhythmia in patients with left ventricular dysfunction and previous MI.56 Imbriaco et al. recently showed that sympathetic neuronal damage evaluated by TDS obtained from 123I-MIBG imaging might detect cardiac involvement at an early stage in patients with Anderson-Fabry disease, leading to straight therapeutic strategies in patients prone to LV fibrosis development.57

1. 2.

Gibbons RJ. Myocardial perfusion imaging. Heart 2000;83:355– 60. https://doi.org/10.1136/heart.83.3.355; PMID: 10677421. Schaefferkoetter J, Ouyang J, Rakvongthai Y, et al. Effect of time-of-flight and point spread function modeling on detectability of myocardial defects in PET. Med Phys 2014;41:062502. https://doi.org/10.1118/1.4875725; PMID: 24877836. Nappi C, Acampa W, Nicolai E, et al. Long-term prognostic value of low-dose normal stress-only myocardial perfusion imaging by wide beam reconstruction: a competing risk analysis. J Nucl Cardiol 2018. https://doi.org/10.1007/s12350018-1373-x; PMID: 30027504; epub ahead of press. Brambilla M, Lecchi M, Matheoud R, et al. Comparative analysis of iterative reconstruction algorithms with resolution recovery and new solid state cameras dedicated to myocardial perfusion imaging. Phys Med 2017;41:109–16. https://doi.org/10.1016/j.ejmp.2017.03.008; PMID: 28343906. Dorbala S, Ananthasubramaniam K, Armstrong IS, et al. Single photon emission computed tomography (SPECT) myocardial perfusion imaging guidelines: instrumentation, acquisition, processing, and interpretation. J Nucl Cardiol 2018;25:1784–846. https://doi.org/10.1007/s12350-018-1283-y; PMID: 29802599. Petretta M, Acampa W, Daniele S, et al. Transient ischemic dilation in SPECT myocardial perfusion imaging for prediction

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Furthermore, the narrower energy windows and better photon energy discrimination of CZT technology allow simultaneous 99mTcsestamibi/123I-MIBG dual isotope imaging with a significant reduction in down-scatter of the two isotopes’ photopeaks.58–61 From this perspective, the possibility of viewing myocardial perfusion and innervation in one imaging session (Figure 4), combined with the opportunity to obtain more accurate parameters for innervation evaluation such as TSD, offers significant potential. The extensive pool of available data has prepared the ground for the challenge of the future that is the use of machine learning and artificial intelligence for clinical applications. Machine learning is the area of computer science that exploit available information to produce reliable and repeatable choices to guide clinical decision-making. This approach seems very promising in the era of personalised medicine.62–64 The integration of information derived from traditional and novel parameters with data obtained from demographics may have a role in driving diagnostic work-up in individual patients, making medical care more personalised. However, this requires a great deal of measurement and evaluation, from image acquisition, through imaging parameters generation and developing decision-making algorithms before a critical clinical choice therapy based on human critical thinking rather than choice generated by machine algorithm can be made.

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atherosclerosis, inflammation and major adverse cardiac events in asymptomatic subjects. J Cardiovasc Comput Tomogr 2018;12:67–73. https://doi.org/10.1016/j.jcct.2017.11.007; PMID: 29233634. Parisi V, Rengo G, Perrone-Filardi P, et al. Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure. Circ Res 2016;118:1244–53. https://doi.org/10.1161/ CIRCRESAHA.115.307765; PMID: 26926470. Rengo G, Pagano G, Vitale DF, et al. Impact of aging on cardiac sympathetic innervation measured by 123I-mIBG imaging in patients with systolic heart failure. Eur J Nucl Med Mol Imaging 2016;43:2392–400. https://doi.org/10.1007/s00259-016-34323; PMID: 27287990. Nappi C, Acampa W, Pellegrino T, et al. Beyond ultrasound: advances in multimodality cardiac imaging. Intern Emerg Med 2015;10:9–20. https://doi.org/10.1007/s11739-014-1106-3; PMID: 25037458. Tamaki N, Kuge Y, Yoshinaga K. Molecular imaging in heart failure patients. Clin Transl Imaging 2013;1:341–51. https://doi. org/10.1007/s40336-013-0034-y; PMID: 24765617. Perrone-Filardi P, Paolillo S, Dellegrottaglie S, et al. Assessment of cardiac sympathetic activity by MIBG imaging in patients with heart failure: a clinical appraisal. Heart 2011;97:1828–33. https://doi.org/10.1136/ heartjnl-2011-300343; PMID: 21917663. De Lucia C, Gambino G, Petraglia L, et al. Long-term caloric restriction improves cardiac function, remodeling, adrenergic responsiveness, and sympathetic innervation in a model of postischemic heart failure. Circ Heart Fail 2018;11:e004153. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004153; PMID: 29535114. Flotats A, Carrió I, Agostini D, et al. Proposal for standardization of 123I-metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging 2010;37:1802–12. https://doi.org/10.1007/s00259-010-1491-4; PMID: 20577740. Bax JJ, Kraft OR, Buxton AE, et al. 123 I-mIBG scintigraphy to predict inducibility of ventricular arrhythmias on cardiac electrophysiology testing: a prospective multicenter pilot study. Circ Cardiovasc Imaging 2008;1:131–40. https://doi. org/10.1161/CIRCIMAGING.108.782433; PMID: 19808530. Imbriaco M, Pellegrino T, Piscopo V, et al. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease. Eur J Nucl Med Mol Imaging 2017;44:2266–73. https://doi.org/10.1007/s00259–017-3778-1; PMID: 28733764. Blaire T, Bailliez A, Ben Bouallegue F, et al. First assessment of simultaneous dual isotope (123I/99mTc) cardiac SPECT on two different CZT cameras: a phantom study. J Nucl Cardiol 2018;25:1692–704. https://doi.org/10.1007/s12350-0170841-z; PMID: 28275896. Blaire T, Bailliez A, Ben Bouallegue F, et al. Determination of the heart-to-mediastinum ratio of 123I-MIBG uptake using dualisotope (123I-MIBG/99mTc-tetrofosmin) multipinhole cadmiumzinc-telluride SPECT in patients with heart failure. J Nucl Med 2018;59:251–8. https://doi.org/10.2967/jnumed.117.194373; PMID: 28646015. Zampella E, Nappi C, Acampa W. Simultaneous dual isotope 201 Tl/99mTc myocardial perfusion imaging using CZT cameras: clinical utility or technical challenge? J Nucl Cardiol 2018. https://doi.org/10.1007/s12350-018-01522-w; PMID: 30478659; epub ahead of press. Juarez-Orozco LE, Knol RJJ, Sanchez-Catasus CA, et al. Machine learning in the integration of simple variables for identifying patients with myocardial ischemia. J Nucl Cardiol 2018. https://doi.org/10.1007/s12350-018-1304-x; PMID: 29790017; epub ahead of press. Gomez J, Doukky R, Germano G, Slomka P. New trends in quantitative nuclear cardiology methods. Curr Cardiovasc Imaging Rep 2018;11:1. https://doi.org/10.1007/s12410-018-9443-7; PMID: 30294409. Nappi C, Cuocolo A. The machine learning approach: artificial intelligence is coming to support critical clinical thinking. J Nucl Cardiol 2018. https://doi.org/10.1007/s12350-018-1344-2; PMID: 29923100; epub ahead of press.

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Ischaemic Heart Disease

Stable Angina Medical Therapy Management Guidelines: A Critical Review of Guidelines from the European Society of Cardiology and National Institute for Health and Care Excellence Talla A Rousan and Udho Thadani University of Oklahoma Health Sciences Center and Veteran Affairs Medical Center, Oklahoma City, Oklahoma, US

Abstract Most patients with stable angina can be managed with lifestyle changes, especially smoking cessation and regular exercise, along with taking antianginal drugs. Randomised controlled trials show that antianginal drugs are equally effective and none of them reduced mortality or the risk of MI, yet guidelines prefer the use of beta-blockers and calcium channel blockers as a first-line treatment. The European Society of Cardiology guidelines for the management of stable coronary artery disease provide classes of recommendation with levels of evidence that are well defined. The National Institute for Health and Care Excellence (NICE) guidelines for the management of stable angina provide guidelines based on cost and effectiveness using the terms first-line and second-line therapy. Both guidelines recommend using low-dose aspirin and statins as disease-modifying agents. The aim of this article is to critically appraise the guidelines’ pharmacological recommendations for managing patients with stable angina.

Keywords Antianginals, ESC, guidelines, NICE, pharmacotherapy, stable angina Disclosure: UT received honoraria for consulting from Clovis pharmaceuticals and Gilead sciences; from the speakers’ bureau of Gilead sciences and Amgen, and received research grants and is the local principal investigator for NIH and VA Coop studies and for multicenter trials with AstraZeneca and Novartis. TR has no conflicts of interest to declare. Received: 31 October 2018 Accepted: 21 December 2018 Citation: European Cardiology Review 2019;14(1):18–22. DOI: https://doi.org/10.15420/ecr.2018.26.1 Correspondence: Udho Thadani, University of Oklahoma Health Sciences Center and VA Medical Center, 800 Stanton L Young Blvd, COM 5400, Oklahoma City, OK 73104, US. E: udho-thadani@ouhsc.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background

Prognosis for Patients with Stable Angina

Definition of Stable Angina

The prognosis for patients with stable angina varies, but there is an annual mortality rate of up to 3.2%. Long-term prognosis is influenced by left ventricular systolic function, extent of coronary artery disease (CAD), exercise duration or effort tolerance, and comorbid conditions.3 The published data does not account for medical interventions, such as statins and aspirin, which reduce mortality and morbidity in coronary artery disease, and it is likely that the prognosis of stable angina without medical therapy may be very different.4

Angina pectoris was first defined by William Heberden in 1768. He described it as a smothering sensation or tightness across the front of the chest which may radiate to the left arm or to both arms as well as the jaw or back. It is usually triggered by exercise or emotional stress and it may be aggravated by the ingestion of a heavy meal.1 The pain usually resolves by stopping exercise or with sublingual nitroglycerin. Angina is arbitrarily defined as stable when the angina episodes are stable over a period of 3–6 months.2,3 Atypical features, such as shortness of breath during exercise in the absence of pulmonary disease or extreme fatigue during exertion, have been considered as angina equivalents.4 These atypical presentations in the absence of chest pain are often found in women, older people and people with diabetes.

Causes of Stable Angina The exact aetiology of stable angina is not well defined; however, it is thought to be secondary to a mismatch between myocardial supply and demand.5 The majority of patients with angina have significant narrowing of one or more epicardial coronary arteries. It is also recognised that many patients with stable angina have non-obstructive or even normal coronary arteries.

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Pharmaceutical Therapy Nitrates, Beta-blockers and Calcium Channel Blockers Nitrates are available in different formulations and both shortand long-acting organic nitrates have been shown to be effective in treating angina when used appropriately to avoid nitrate tolerance.3,6,7 Nitrates are as effective as beta-blockers (BB) and calcium channel blockers (CCB).8 Sublingual nitroglycerin tablets and oral nitroglycerin spray are rapidly absorbed and when taken prophylactically can improve exercise tolerance and reduce the incidence of MI.9,10 One of the major side-effects of nitrate use is headaches that may be severe enough to necessitate discontinuation of the therapy.11 Tachyphylaxis, or tolerance to continuous use of nitrates is another limiting factor, but can be avoided by allowing

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Stable Angina Medical Therapy prolonged nitrate-free intervals for nitrate levels to decline before the next dose.6,7,9,12 Long-acting nitrates have been downgraded to second-line therapy in guidelines because of their side-effects and the incidence of tachyphylaxis. The first reported use of BBs to treat hypertension and angina was in the 1970s in the UK.13,14 BBs are an effective therapy in the management of stable angina.14–17 Many BB are available for clinical use. They have the common property of blocking beta-adrenergic receptors and selective and non-selective BB can be chosen for their different properties. Although BB can reduce mortality and morbidity in patients with heart failure with reduced ejection fraction and in patients with recent MI, these agents have a limited effect on mortality and the incidence of MI when used in patients with stable angina.18–26 CCBs, both dihydropyridine (DHP) agents and non-DHP agents, have been used for more than five decades, and are very effective for the treatment of stable angina. They significantly reduce the episodes of angina, increase exercise duration and decrease the frequency of nitroglycerin use.27–30 When combined with BB, they have been shown to significantly delay the onset of ST-segment depression using an exercise treadmill test.31 Patients with asthma or chronic obstructive pulmonary disease (COPD) are good candidates for treatment with CCB, given the risk of bronchospasm in these patients when taking BB.32 A combination of BB and non-DHP CCB should be avoided due to the risk of symptomatic bradycardia and atrioventricular block.33

Nicorandil, Ranolazine, Trimetazidine, Ivabradine and Allopurinol Nicorandil, which is a nitrate-moiety nicotinamide ester and adenosine-sensitive potassium channel opener, increases coronary blood flow and prevents coronary artery spasm.34 It has been approved for clinical use in Japan and many European countries on the basis of small trials in patients with stable angina.35,36 This medication is not used in the US because placebo-controlled studies from Australia and the US failed to confirm antianginal efficacy of nicorandil compared with placebo.37 In Europe, it has been used instead of nitrates or in combination with other antianginals.37 Sideeffects of gastrointestinal ulcerations and headache limit the longterm use of nicorandil in patients with stable angina.38,39

Table 1: Chronic Stable Angina Pharmacotherapy: Comparison of Guideline Recommendations

Antianginal Drug

European Society of Cardiology

National Institute for Health and Care Excellence

First-line therapy Sublingual nitroglycerin

Short-acting nitrates

First-line treatment

Long-acting nitrates

IIaB

Second-line treatment

Beta-blockers

Uncomplicated patient: IA Previous MI: IB Reduced LVEF (<40%): IB

First-line treatment*

Calcium channel blockers:

Non-dihydropyridines: IA Dihydropyridines: IA

First-line treatment* Avoid nondihydropyridines with BB or ivabradine

Second- and third-line therapy Ranolazine

IIaB

Second-line treatment†,c,d

Ivabridine

IIaB Use when beta-blockers are contraindicated

Second-line treatment†,c,d

Nicorandil

IIaB Preferred to nitrates

Second-line treatment†,c,d

Trimetazidine

IIbB

Allopurinol

Second- or third-line agent for symptom control

Interventions for secondary prevention of cardiovascular disease Abstain from smoking

Assess the need for lifestyle advice, including smoking cessation

Aspirin

I 75–150 mg daily (consider clopidogrel if aspirin intolerance)

75 mg. Take into account the risk of bleeding

Statin

I Target dose to achieve LDL level <1.8 mmol/l or >50% reduction

Offer statin in line with lipid modification guidelines (atorvastatin 80 mg to achieve non-HDL cholesterol reduction >40%)

ACE inhibitor or ARB

II: normal LVEF I: with hypertension and/or diabetes

Consider ACE inhibitor for patients with diabetes

Ranolazine is an orally active piperazine derivative. 40 The exact mechanism its antianginal action is unknown, but animal studies have shown that it inhibits late sodium inward current during periods of ischaemia, reducing intracellular calcium overload.41,42 Ranolazine is an effective antianginal and anti-ischaemic agent compared with placebo and is as equally effective as atenolol.43,44 Extended-release ranolazine compared with placebo, as monotherapy or in combination with other antianginals, has been shown to significantly increased total exercise time by 116 seconds and 23.7 seconds, respectively.43,44 It also increased treadmill walking time for people with angina and delayed the onset of exercise-induced MI.43,45,46 Ranolazine has been shown to be ineffective in the treatment of women with microvascular angina compared with placebo.47

Allopurinol is a pyrazolopyrimidine and an analogue of hypoxanthine.51,52

Trimetazidine is available in Europe and several countries in Asia as an adjunct therapy for angina, but it is not used in the US.4,35,48 In patients who remain symptomatic despite treatment with first-line therapy drugs, trimetazidine decreases angina frequency without exerting any effects on heart rate or blood pressure, as shown in the TRIMetazidine in POLand (TRIMPOL) trials I and II.49,50

It has been demonstrated that high-dose allopurinol is associated with a significant improvement in endothelium-dependent vasodilation and exercise tolerance. The effects of high-dose allopurinol (600 mg daily) have been shown to be similar to conventional antianginal medications. 53 While recommended in the European Society of Cardiology (ESC) guidelines as a second- or third-line agent for symptom control, allopurinol is not endorsed in the National Institute

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*Interchangeable.

If symptoms not controlled switch to other option or use both. Avoid the combination of BB and non-dihydropyridine CCB. †Use as monotherapy if first-line agents (BB and/or CCB) are not tolerated or contraindicated. Use as addition to BB or CCB if one of these is not tolerated or contraindicated. Do not routinely combine these antianginals in addition to dual therapy with BB and CCB except in patients awaiting revascularisation consideration or when revascularisation is inappropriate. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BB = beta-blocker; CCB = calcium channel blocker; LVEF = left ventricular ejection fraction; NA = not applicable.

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Ischaemic Heart Disease for Health and Care Excellence (NICE) guidelines.35,54,55 Allopurinol is not approved by the Food and Drug Administration to treat angina in the US. Ivabradine lowers heart rate and inhibits the primary sinoatrial node current.56 It is use-dependent, meaning that its effect is the highest in high heart rate and vice versa; bradycardia is less commonly encountered in patients on ivabradine because its effect is ameliorated at lower heart rates.57 Studies have shown that ivabradine as an add-on therapy to atenolol significantly increased exercise time and reduces the number of angina attacks compared with atenolol alone or other BB and it did not cause significant bradycardia.58–61 However, symptomatic bradycardia remains a concern when using combination therapy, and it may adversely affect outcome in severely symptomatic patients.33 In patients with stable angina without heart failure, ivabradine added to background therapy was shown not to decrease the incidence of death from cardiovascular causes or non-fatal MI, but in a subgroup of patients with severe angina, ivabradine performed worse than placebo with regards to hard endpoints.62

Combination Antianginal Therapy Monotherapy in optimal doses,is often as effective as combination therapy using two or more agents.3,4,35,63,64 There is a lack of welldesigned studies showing that treatment with more than one class of drug is superior to combination treatment with a different class of antianginal drugs.65,66 Adding either a long-acting nitrate or a CCB to BB therapy is often useful and reduces angina frequency, improves exercise tolerance and reduces MI.63,65 A combination of BB and ivabradine has been shown to be effective in patients with a heart rate greater than 60 BPM, but safety concerns have been raised.62,67 As discussed earlier, extended release ranolazine monotherapy, or in combination with BB or CCB, is effective.43,45,46 Trimetazidine as an addon to older antianginal drugs has also been shown to be effective.44,45 None of the trials involving a combination of antianginal drugs have been adequately blinded to make firm conclusions regarding the superiority of a combination of two antianginal drugs to doses of monotherapy. Data on the efficacy of triple therapy with three different classes of antianginal drugs are not available.

Guidelines for Stable Angina There are published guidelines for the management of patients with stable ischaemic heart disease and stable angina. The ESC and NICE guidelines have been updated regularly to provide a clear set of guidelines for management for healthcare professionals in the UK and Europe.35,54,55 ESC guidelines (Table 1) provide recommendations divided into classes: • Class I where the evidence and/or general agreement that a given treatment or procedure is beneficial, useful and effective. • Class IIa where the weight of evidence or opinion is in favour of usefulness/efficacy. • Class IIb where usefulness/efficacy is less well established by evidence or opinion. • Class III where there is evidence or general agreement that the given treatment or procedure is not useful/effective and in some cases may be harmful.35

• Level of evidence A denotes that data were derived from multiple randomised clinical trials or meta-analyses. • Level of evidence B indicates that data were derived from a single randomised clinical trial or large non-randomised studies. • Level of evidence C is where a consensus of opinion of the experts and/or small studies, retrospective studies or registries were available.35 NICE guidelines (Table 1) are based on extensive reviews of published data and take into consideration cost-effectiveness and the adverse effects of medications. The terms first-line treatment and second-line treatment are used and guidance is given on the most appropriate use of antianginal therapy, taking co-morbidities into consideration when selecting therapy.54,55

Guidelines for Antianginal Therapy A previously published article compared the American and Canadian guidelines.65 This article compares the recommendations for antianginal therapy in ESC and NICE guidelines (Table 1). Both sets of guidelines agree that optimal medical therapy includes antianginal therapy and medications to prevent MI and stroke, including aspirin and statins. They both favour the use of sublingual short-acting nitrates for the relief of an established attack of angina or for prophylaxis. Both guidelines recommend the use of BB or CCB as first-line therapy with the notion that non-DHP CCB should not be combined with ivabradine or BB. NICE guidelines recommend a trial of a maximally tolerated dose of either a BB or a CCB as initial therapy. If there are contraindications to one class of drugs or no response, switching to a CCB from a BB and vice versa should be considered. If the response to one class of these antianginal drugs is sub-optimal, NICE recommends a combination of a BB with a DHP-CCB as preferred combination therapy. Use of secondline drugs (long-acting nitrates, nicorandil, ranolazine or ivabradine) as monotherapy or in combination therapy is only recommended when there are contraindications to first-line drugs. Triple therapy is only recommended when patients are being considered for possible revascularisation and remain symptomatic despite treatment with firstline agents. ESC guidelines are more liberal on the use of combination therapy with two or more agents. ESC guidelines specify certain subsets of patients who would benefit from BB (patients with previous MI and patients with reduced left ventricular ejection fraction), while NICE guidelines do not have any specific patient subgroups. Ranolazine, ivabradine, and nicorandil are considered to be second-line treatments based on both guideline documents. While trimetazidine and allopurinol are recommended as second- or third- line therapy in the ESC guidelines, NICE guidelines do not endorse the use of those medications for patients with stable angina.

Co-morbidities and Stable Angina Both guidelines recommend use of specific antianginal medications, taking into consideration the presence or absence of comorbidities such as COPD, hypertension, peripheral vascular disease and diabetes, despite the lack of randomised controlled trials to support this.64,65,68

Guidelines to Reduce MI and Sudden Cardiac Death Lifestyle Changes

In addition, for each class of recommendation, a level of evidence is included:

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Smoking cessation or abstinence reduces the risk of CAD mortality by 50% in 1 year and after 5–15 years the coronary mortality risk reaches

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Stable Angina Medical Therapy that of non-smokers.69 In addition to decreasing cardiovascular mortality and morbidity, stopping smoking in patients with angina also increases exercise performance.64 Although based on small observational studies, exercise training was shown to have favourable outcomes in patients with stable angina.70 Both guidelines emphasise the importance of smoking cessation and regular exercise. NICE guidelines do not specify any special diets, while ESC guidelines recommend a Mediterranean diet. Cardiac rehabilitation is recommended in ESC guidelines, but not in NICE guidelines.

Antiplatelet Therapy Both guidelines recommend daily use of low-dose aspirin because it has been shown to reduce the incidence of acute MI and sudden death in patients with known CAD.71 This has only been shown to be effective for patients with stable angina in a small study.72 The use of aspirin in patients with stable angina in the absence of CAD is uncertain.65 In patients who are allergic to aspirin, clopidogrel may be used instead according to ESC guidelines, but is not evidence-based; although routine combination of aspirin and a P2Y12 inhibitor is not recommended due to an excessive risk of bleeding.73

or angiotensin receptor blockers (ARB) for patients with stable angina who have diabetes.

Concomitant Management of Patients with Angina and Heart Failure With Reduced Ejection Fraction There are no randomised controlled trials that have studied patients with stable angina and heart failure with reduced ejection fraction. Based on the available outcome trials showing survival benefit, the use of BB and angiotensin-converting enzyme inhibitors or ARB is recommended in patients with reduced left ventricular ejection fraction <40% and concomitant angina.4,19,79–82

Treatment of Patients with Stable Angina and Normal Coronary Arteries or Microvascular Angina NICE does not make any specific pharmacotherapy recommendations for patients with stable angina and normal coronary arteries or microvascular angina, while ESC guidelines recommend a trial of antianginal drugs. There are no efficacy trials regarding hard outcomes in patients with stable angina who have normal coronary arteries.65 Current evidence does not support the routine use of aspirin or statins in patients with microvascular angina who have normal coronary arteries.

Treatment of Dyslipidaemia There are no specific trials of statins in patients with stable angina, however this class of drugs reduce all-cause mortality, acute coronary events, and the need for revascularisation in patients with CAD and in those at high risk of CAD.74,75 ESC guidelines recommend the use of statins to achieve the ideal low-density lipoprotein goal (<1.8 mmol/l), while NICE guidelines recommend the use of high-dose statins, such as 80 mg atorvastatin (Table 1).

Control of Hypertension There are no specific trials of antihypertensive medications in patients with stable angina who also have hypertension. But given the documented beneficial effects of controlling blood pressure on hard outcomes, especially stroke and heart failure, both guidelines recommend optimal control of blood pressure in patients with stable angina to reduce the incidence of stroke and MI. The blood pressure goal is <140 mmHg for systolic, however recent data suggest that lowering systolic blood pressure to 120 mmHg may be a desirable option if tolerated by the patient.76,77

Management of Diabetes Diabetes is commonly found in patients with stable angina. Control of diabetes reduces micro- as well as macrovascular complications. Based on the Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) trial, an HbA1C level <7% is desirable.78 Both guidelines recommend routine use of angiotensin-converting enzyme inhibitors

1. 2.

Heberden W. Some account of a disorder of the breast. Medical Transactions 1772;2:59–67. Abrams J, Thadani U. Therapy of stable angina pectoris: the uncomplicated patient. Circulation 2005;112: e255–9. https:// doi.org/10.1161/CIRCULATIONAHA.104.526699; PMID: 16216965. Thadani U. Current medical management of chronic stable angina. J Cardiovasc Pharmacol Ther 2004;9(Suppl 1):S11–29. PMID: 15378129. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/ AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart diseases. J Am Coll Cardiol 2012; 60:e44–e164. https://doi.org/10.1016/j. jacc.2012.07.013; PMID: 23182125. Opie LH. Angina pectoris: the evolution of concepts. J Cardiovasc Pharmacol Ther 2004;9:S3–9. https://doi. org/10.1177/107424840400900102; PMID: 15378128. Thadani U, Lipicky RJ. Short and long-acting oral nitrates for stable angina pectoris. Cardiovasc Drugs Ther 1994;8:611–23.

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Identification of High-Risk Patients with Left main or Severe Triple Vessel Coronary Artery Disease Updated NICE guidelines recommend use of coronary CT angiography for an initial investigation for all patients with typical and atypical angina to define coronary anatomy non-invasively, even if the patients are adequately treated with pharmacotherapy.83 This is based on available data showing that coronary artery bypass surgery is superior to medical treatment in this group of patients. ESC guidelines, on the other hand, use non-invasive stress testing to define a high-risk group.83

Conclusion The current guidelines are largely based on expert opinion and consensus rather than high-quality randomised controlled trials. The two documents discussed in this article make different recommendations for first-line treatment, as well as add-on treatment with two or three antianginal drugs, without objective data. Secondary prevention strategies vary; however, the use of low-dose aspirin and statin therapy seem to be justified based on the available data. The management of patients with microvascular disease or normal coronary arteries and angina remains uncertain especially in the absence of randomised controlled trials. The guideline recommendations rely mostly on assumptions and extrapolations and expert opinion based on the available data regarding patients with obstructive CAD.

https://doi.org/10.1007/BF00877415; PMID: 7848896. Thadani U, Lipicky RJ. Ointments and transdermal nitroglycerin patches for stable angina pectoris. Cardiovasc Drugs Ther 1994;8:625–33. https://doi.org/10.1007/BF00877416; PMID: 7848897. 8. Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA 1999;281:1927–36. https://doi. org/10.1001/jama.281.20.1927; PMID: 10349897. 9. Thadani U. Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance. Am J Cardiovasc Drugs 2014;14:287–301. https://doi.org/10.1007/ s40256-014-0072-5; PMID: 24664980. 10. Thadani U, Wittig T. A randomized, double-blind, placebocontrolled, crossover, dose-ranging multicenter study to determine the effect of sublingual nitroglycerin spray on exercise capacity in patients with chronic stable angina. Clin Med Insights Cardiol 2012;6:87–95. https://doi.org/10.4137/CMC. S9132; PMID: 22566749.

11. Thadani U, Rodgers T. Side effects of using nitrates to treat angina. Expert Opin Drug Saf 2006;5:667–74. https://doi. org/10.1517/14740338.5.5.667; PMID: 16907656. 12. Steering Committee, Transdermal Nitroglycerin Cooperative Study. Acute and chronic antianginal efficacy of continuous twenty-four-hour application of transdermal nitroglycerin. Am J Cardiol 1991;68:1263–73. https://doi.org/10.1016/00029149(91)90229-E; PMID: 1951111. 13. Prichard BN, Owens CW. Mode of action of beta-adrenergic blocking drugs in hypertension. Clin Physiol Biochem 1990;8:1– 10. PMID: 1982756. 14. Prichard BN. Beta-adrenergic receptor blocking drugs in angina pectoris. Drugs 1974;7:55–84. https://doi. org/10.2165/00003495-197407010-00005; PMID: 4151695. 15. Thadani U, Davidson C, Singleton W, Taylor SH. Comparison of the immediate effects of five beta-adrenoreceptorblocking drugs with different ancillary properties in angina pectoris. N Engl J Med 1979;300:750–5. https://doi.org/10.1056/ NEJM197904053001402; PMID: 581782.

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Ischaemic Heart Disease 16. Thadani U, Davidson C, Singleton W, Taylor SH. Comparison of five beta-adrenoreceptor antagonists with different ancillary properties during sustained twice daily therapy in angina pectoris. Am J Med 1980;68:243–50. https://doi. org/10.1016/0002-9343(80)90361-7; PMID: 6101934. 17. Thadani U, Sharma B, Meeran MK, et al. Comparison of adrenergic beta-receptor antagonists in angina pectoris. Br Med J 1973;1:138–42. https://doi.org/10.1136/bmj.1.5846.138; PMID: 4145234. 18. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. https://doi.org/10.1016/S01406736(98)11181-9; PMID: 10023943. 19. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001– 7. https://doi.org/10.1016/S0140-6736(99)04440-2; PMID: 10376614. 20. Packer M, Bristow MR, Cohn JN, et al. 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angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol 1992;20:131–8. PMID: 1383622. 41. Thadani U. Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal. Expert Opin Pharmacother 2012;13:2555–63. https://doi.org/10.1517/14656566.2012.740 458; PMID: 23121448. 42. Codolosa JN, Acharjee S, Figueredo VM. Update on ranolazine in the management of angina. Vasc Health Risk Manag 2014;10:353–62. https://doi.org/10.1517/14656566.201 2.740458; PMID: 25028555. 43. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375–82. https://doi.org/10.1016/ j.jacc.2003.11.045; PMID: 15093870. 44. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309–16. https://doi.org/10.1001/jama.291.3.309; PMID: 14734593. 45. Stone PH, Gratsiansky NA, Blokhin A, et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566–75. https://doi. org/10.1016/j.jacc.2006.05.044; PMID: 16875985. 46. Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol 2013;61:2038–45. https://doi.org/10.1016/j.jacc.2013.02.011; PMID: 23500237. 47. Bairey Merz CN, Handberg EM, Shufelt CL, et al. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J 2016;37:1504–13. https://doi.org/10.1093/ eurheartj/ehv647; PMID: 26614823. 48. Gupta AK, Winchester D, Pepine CJ. Antagonist molecules in the treatment of angina. Expert Opin Pharmacother 2013;14:2323–42. https://doi.org/10.1517/14656566.2013.834 329; PMID: 24047238. 49. Thadani U. Modified-release formulation of trimetazidine for exceptional control of angina pectoris: fact or fiction. Am J Cardiovasc Drugs 2005;5:331–4. https://doi. org/10.2165/00129784-200505050-00006; PMID: 16156689. 50. Szwed H, Sadowski Z, Elikowski W, et al. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J 2001;22:2267–74. https://doi.org/10.1053/ euhj.2001.2896; PMID: 11728147. 51. Kelkar A, Kuo A, Frishman WH. Allopurinol as a cardiovascular drug. Cardiol Rev 2011; 19:265–71. https://doi. org/10.1097/CRD.0b013e318229a908; PMID: 21983313. 52. Day RO, Graham GG, Hicks M, et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet 2007;46:623–44. https://doi. org/10.2165/00003088-200746080-00001; PMID: 17655371. 53. Noman A, Ang DS, Ogston S, et al. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet 2010;375:2161–7. https://doi.org/10.1016/S01406736(10)60391-1; PMID: 20542554. 54. O’Flynn N, Timmis A, Henderson R, et al. Management of stable angina: summary of NICE guidance. BMJ 2011;343:d4147. https://doi.org/10.1136/bmj.d4147; PMID: 21821647. 55. National Institute for Health and Care Excellence. Stable Angina: Management. London: NICE, 2011. Available at: https:// www.nice.org.uk/guidance/cg126 (accessed 23 February 2019). 56. 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EUROPEAN CARDIOLOGY REVIEW

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Heart Failure and Arrhythmias

Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments Juan Tamargo Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, CIBERCV, Madrid, Spain

Abstract Heart failure is a common complication in patients with diabetes, and people with both conditions present a worse prognosis. Sodium– glucose cotransporter 2 inhibitors (SGLT2Is) increase urinary glucose excretion, improving glycaemic control. In type 2 diabetes (T2D), some SGLT2Is reduce major cardiovascular events, heart failure hospitalisations and worsening of kidney function independent of glycaemic control. Multiple mechanisms (haemodynamic, metabolic, hormonal and direct cardiac/renal effects) have been proposed to explain these cardiorenal benefits. SGLT2Is are generally well tolerated, but can produce rare serious adverse effects, and the benefit/risk ratio differs between SGLT2Is. This article analyses the mechanisms underlying the cardiorenal benefits and adverse effects of SGLT2Is in patients with T2D and heart failure and outlines some questions to be answered in the near future.

Keywords Type 2 diabetes, heart failure, sodium–glucose cotransporter, sodium-glucose cotransporter inhibitors, cardiovascular outcome trials, safety profile Disclosure: JT received no direct or indirect compensation related to the development of the manuscript. This work was supported by grants from the Instituto de Salud Carlos III [PI16/00398 and CIBER-Cardiovascular (CB16/11/00303)] and Comunidad de Madrid (B2017/BMD-3738). Received: 26 December 2018 Accepted: 26 February 2019 Citation: European Cardiology Review 2019;14(1):23-32 DOI: https://doi.org/10.15420/ecr.2018.34.2 Correspondence: Juan Tamargo, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, CIBERCV, Madrid, 28040, Spain. E: jtamargo@med.ucm.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Type 2 diabetes (T2D) remains a major cardiovascular (CV) risk factor1–5 and it confers an approximately two- to threefold fold excess risk for coronary heart disease, including MI, stroke and heart failure (HF) in patients with and in patients without established cardiovascular disease (CVD).1,6–8 The prevalence of T2D among patients with HF is as high as 40–45% and that of HF in patients with T2D is reported to be 10–23%.8 Patients with both conditions – regardless of ejection fraction – present a higher risk of hospitalisation for HF (HHF), all-cause and CV mortality, irrespective of ischaemic/non-ischaemic aetiology.8–10 The risk is further increased in the presence of diabetic nephropathy. Therefore, new therapeutic strategies that improve symptoms and reduce mortality and hospitalisations are needed for patients with T2D, HF and renal impairment. For decades, it was hypothesised that glucose-lowering drugs (using HbA1c as a surrogate marker) might improve CV outcomes. However, this glucocentric approach was proved incorrect because firstly, some glucose-lowering drugs (muraglitazar, rosiglitazone) decreased HbA1c levels but worsened CV outcomes, and secondly, the results of the post-trial follow-up of the UK Prospective Diabetes Study (UKPDS),and of a meta-analysis of large glucose-lowering outcome trials,suggested an approximately 15% cardiovascular risk reduction (RR) per 1% decrement in HbA1c.11,12 The UKPDS recruited low-risk patients with newly diagnosed T2D (only 7.5% had CVD at baseline). During the interventional phase of the study, intensive glucose control

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using metformin and sulphonylurea-insulin reduced HbA1c by 0.9% for a median of 10 years, but not the risk of death, MI, HF, stroke, or amputations.11 However, in the 10-year post-trial follow-up, patients originally randomised to intensive therapy achieved a significant reduction in MI (15%) and all-cause mortality (13%) despite an early loss of glycaemic differences between the intensive and conventional therapy groups.13 These findings suggested that early and intensive glucose control in newly diagnosed T2D patients could have long-term benefits (‘legacy effect’), irrespective of treatment modality. However, the metaanalysis of randomised controlled trials (RCTs) of more- versus lessintensive glycaemic control in patients with long-standing T2D (8–12 years) and either known CV disease or other risk factors showed that more-intensive glycaemic control (difference in HbA1c 0.9%) was associated with a significant 9% RR for the composite of major adverse cardiovascular events (MACE; CV death, nonfatal stroke or nonfatal MI) during an average follow-up of 4.4 years. This reduction was driven primarily by a 15% RR in MI. However, intensive glucose lowering did not reduce the risk of fatal/nonfatal stroke, peripheral artery disease, hospitalised or fatal HF or CV and all-cause mortality, but increased the risk of severe hypoglycaemia.12,14 The differences in outcomes among these studies and the long-term ‘legacy effect’ observed in the UKPDS could be related to important

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Heart Failure and Arrhythmias differences in the study populations, HbA1c reduction from baseline, speed of HbA1c lowering, duration of follow-up and background therapies. Because of the concerns regarding adverse cardiovascular outcomes with antidiabetic agents, in 2008 the US Food and Drug Administration (FDA) mandated sponsors to conduct long-term cardiovascular outcome trials (CVOTs) for ensuring the cardiovascular safety of all new glucose-lowering drugs, with a focus on MACE.15 Surprisingly, HF was not included as a component of composite endpoints. Recent CVOTs performed with three sodium–glucose cotransporter 2 inhibitors (SGLT2Is; canagliflozin, empagliflozin and dapagliflozin) demonstrated noninferiority compared with placebo in the MACE primary composite end point and that they reduced the risk of HHF and of progression of renal disease, regardless of the presence of atherosclerotic CVD or HF at baseline.16 These findings represent a clinical breakthrough in treating T2D as compared with classical glucoselowering drugs. This article analyses the effects of SGLT2Is in CVOTs, the mechanisms underlying their cardiorenal benefits and their safety profile, together with questions that should be answered in the near future.

SGLT2 Inhibitors Sodium-dependent glucose cotransporters (SGLTs) are responsible for tissular glucose translocation. SGLT1 is widely expressed in numerous organs (the distal S3 segment of the proximal renal tubule, intestines, heart and skeletal muscles), while SGLT2 is expressed in the luminal surface of the S1 segment of the proximal tubule and alfa-pancreatic cells.17–19 The active transport of glucose via SGLT2 is linked to Na+ transport maintained by its active extrusion via the Na+/K+ ATPase of the basolateral membrane into the intracellular fluid. Under normal conditions, glucose is freely filtered into the urine at the glomerulus (180 g/day) and reabsorbed in the proximal tubuli by SGLT2 (90%) and SGLT1 (10%).20 The plasma glucose concentration above which urinary glucose excretion occurs is approximately 180–200 mg/dl, but under diabetic conditions increases up to 300 mg/dl because of the increased activity of SGLT2. SGLT2Is (canagliflozin, dapagliflozin, empagliflozin and ertugliflozin) shift the renal tubular threshold for glycosuria to 50 mg/dl, reduce the reabsorption of filtered glucose (30–50%) and increase glycosuria, decreasing plasma glucose and HbA1c levels independent of insulin.17 Because glycosuria occurs only in the presence of hyperglycaemia, the risk of hypoglycaemia with SGLT2Is is low. Additionally, because Na+ is co-transported with glucose, SGLT2Is cause an osmotic diuresis (increased urine output 107–450 ml/day) and a small natriuresis.21

Cardiovascular Outcomes Trials with SGLT2Is Cardioprotective Effects The effects of empagliflozin, canagliflozin and dapagliflozin were analysed in three CVOTs: EMPAgliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients – Removing Excess Glucose (EMPA-REG OUTCOME), the CANagliflozin cardioVascular Assessment Study (CANVAS) Program and Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) respectively (Table 1).22–24 The EMPA-REG OUTCOME trial recruited patients with T2D and established CVD (secondary prevention).22 Empagliflozin (pooled data of 10 and 25 mg doses) reduced the primary MACE outcome, an effect driven by a marked risk reduction in CV death (38%), without significant effects on atherosclerotic ischaemic events (nonfatal MI and nonfatal

ECR_Tamargo_FINAL.indd 24

stroke). Additionally, empagliflozin significantly reduced all-cause, sudden and HHF. The reduction in HHF was observed in patients with and without documented HF at baseline and was associated to a reduction in the introduction of loop diuretics.22,25 The benefits were consistent among subgroups defined by baseline characteristics, including age, HbA1c levels, BMI, estimated glomerular filtration rate (eGFR) or patients with versus without HF and across categories of medications to treat diabetes and/or HF.22,25–27 The CANVAS Program integrated 2 trials (CANVAS and CANVAS-Renal) recruiting participants with T2D and established CVD (65.6%) or at risk for CV events (primary prevention).23 Canagliflozin significantly decreased MACE and HHF to a similar extent to empagliflozin. However, none of the three individual components of MACE, nor all-cause mortality, were significantly reduced by canagliflozin.23 Thus, it is difficult to understand what drives the superiority of canagliflozin for MACE over placebo. The benefit for the primary outcome was abrogated in patients without established CVD, suggesting that the benefit may be mostly in secondary prevention, while the point estimate for HHF was similar in both cohorts, suggesting that this cardiac benefit may extended to diabetic individuals without overt CVD. Interestingly, the benefit on CV death or HHF may be greater in patients with a history of HF at baseline.28,29 The DECLARE-TIMI 58 trial recruited patients (40.6%) with established atherosclerotic CVD and with multiple risk factors for atherosclerotic CVD (59.4%).24 Dapagliflozin met the pre-specified primary safety endpoint of noninferiority for MACE, but in the two primary efficacy analyses, it did not result in a significantly lower rate of MACE than placebo. However, dapagliflozin resulted in a lower rate of the other pre-specified primary efficacy outcome (the composite of CV death or HHF), which reflected a lower rate oh HHF, regardless of a history of atherosclerotic cardiovascular disease or HF. Thus, SGLT2Is reduce HHF and exert cardioprotective effects in T2D patients, but there were important differences between the CVOTs (Table 1). First, almost all patients in the EMPA-REG OUTCOME trial received secondary prevention of CVD, while the CANVAS Program and DECLARE-TIMI 58 trial included patients who had or were at risk for atherosclerotic CVD (i.e. both primary and secondary prevention). Second, HHF and mortality outcome curves begin to separate within the first 3 months in the EMPA-REG study but later in other CVOTs, i.e. earlier than would be expected from any decrease in atherothrombotic events.22-24,30,31 Third, only empagliflozin reduced both CV and all-cause mortality, probably because EMPA-REG OUTCOME was a secondary prevention trial and it is presumed that the higher the baseline risk for CV events the better the CV protection, while patients without CVD might require longer drug exposure to observe the benefits.22 Finally, canagliflozin reduced the risk of nonfatal stroke, while a trend for an increased risk of stroke was observed with empagliflozin, which might be related to the higher CV risk of the population enrolled in EMPAREG, including more patients with prior stroke (23% versus 19.3%).32 In a post hoc analysis, this difference was attributed to events occurring >90 days after the last intake of study drug and driven by nonfatal ischaemic stroke, but there were no differences in the risk of recurrent, fatal, or disabling strokes, or transient ischaemic attacks, between empagliflozin and placebo.32

Renoprotective Effects Chronic kidney disease (CKD) affects up to 40% of patients with T2D and increases mortality and morbidity.33,34 In the CVOTs, mean baseline eGFR

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Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure Table 1: Characteristics of Cardiovascular Outcomes Trials Completed with Sodium–glucose Cotransporter 2 Inhibitors Parameters

EMPA-REG OUTCOME22

CANVAS Program23 †

DECLARE-TIMI 5824

Drug

Empagliflozin

Canagliflozin

Dapagliflozin

Number of patients/mean age (years)

7,020/63.1

10,142/63.3

17,160/63.9

Women (%)

28.5

35.8

37.4

White/Asian/black

72.6/21.5/5.1

78.3/12.7/3.3

79.4/13.5/3.6

Diabetes duration (years)

57% >10

13.5

10.5

HbA1c (%)

8.0

8.2

8.3

BMI (kg/m2)

30.7

Established CV disease (%)

99.5

65.6

40.6

Coronary artery disease (%) MI (%) Stroke (%) Heart failure (%) Peripheral artery disease (%)

76 47 23.5 10.1 21

57 – 19.3 14.4 20.8

33.0 – 7.6 10.0 6.0

Median follow-up time (years)

3.1

2.4

4.2

eGFR (ml/min/1.73 m2)

83.1

76.5

85.2

eGFR <60 ml/min/1.73 m2 (%)

25.9

20.1

7.4

Microalbuminuria (%)

10.9

22.6

Macroalbuminuria (%)

28.5

7.6

Prior history of amputations (%)

–

2.3

–

Primary endpoint

MACE (1)

MACE (2); a composite of CVD or HHF

Three-point MACE: CV death, nonfatal MI, or nonfatal stroke

0.86 (0.74–0.99) NI, p<0.001 Superiority, p=0.04

0.86 (0.75–0.97) NI, p<0.001 Superiority, p=0.02

0.93 (0.84–1.03) NI, p<0.001 Superiority, p=0.17

CV death

0.62 (0.49–0.77)*

0.87 (0.72–1.06)

0.98 (0.81–1.17)

CV death or hospitalisation for HF

0.66 (0.55–0.79)*

0.78 (0.67–0.91)*

0.83 (0.73–0.95)*

All-cause mortality

0.68 (0.57–0.82)*

0.87 (0.74–1.01)

0.93 (0.82–1.04)

Hospitalisation for HF

0.65 (0.50–0.85)*

0.67 (0.52–0.87)*

0.73 (0.61–0.88)*

MI (fatal or nonfatal)

0.87 (0.70–1.09)

0.89 (0.73–1.09)

0.89 (0.77–1.01)

Stroke (fatal or nonfatal)

1.18 (0.89–1.56)

0.87 (0.69–1.09)

1.01 (0.84–1.21)

Fatal or hospitalisation for HF

0.65 (0.50–0.85)*

0.67 (0.52–0.87)*

0.83 (0.73−0.95)*

Worsening of nephropathy‡

0.61 (0.53–0.70)*

0.60 (0.47–0.77)*

0.76 (0.67−0.87)*

Progression of albuminuria

0.62 (0.54–0.72)*

0.73 (0.67–0.79)*

Dose (mg)

10 and 25

100 and 300

Approved clinical indication

As an adjunct to diet and exercise to improve glycaemic control in adults with T2D Reduce the risk of CV death in adult patients with T2D and established CVD

Reduce the risk of MACE in adults with T2D and established CVD

Outcomes reported as HR (95% CI). * Significant. †Pooled data from CANVAS and CANVAS-R. MACE(1): death from cardiovascular causes, nonfatal MI, or nonfatal stroke. MACE(2): CV death, MI, or ischaemic stroke. ‡Worsening nephropathy was defined as doubling of the serum creatinine level and an eGFR of ≤45 ml/min/1.73m2, the need for continuous renal-replacement therapy, or death due to renal events in EMPA-REG OUTCOME; 40% reduction in eGFR, renal-replacement therapy, or death from renal causes in CANVAS; sustained decrease of ≥40% in eGFR to <60 ml/min/1.73m2, new end-stage renal disease, or death from any cause in DECLARE-TIMI 58. CANVAS = CANagliflozin cardioVascular Assessment Study; CV = cardiovascular; CVD = cardiovascular disease; DECLARE-TIMI 58 = Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis in Myocardial Infarction 58; eGFR = estimated glomerular filtration rate; EMPA-REG = EMPAgliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients – Removing Excess Glucose; HF = heart failure; MACE = major adverse cardiovascular events; NI = noninferiority; SGLT2I = sodium–glucose cotransporter 2 inhibitor; T2D = type 2 diabetes.

ranged between 76 and 85 ml/min/1.73m2 but there were important differences in the percentage of patients with an eGFR <60 ml/min/ 1.73 m2 or with macro/microalbuminuria (Table 1). Canagliflozin, dapagliflozin and empagliflozin showed a favourable effect on renal outcomes and slowed the progression of albuminuria and new onset or worsening nephropathy, even when the components of renal outcomes differ between CVOTs (Table 1).16,22–24,30,31 In the EMPA-REG OUTCOME trial, where 25.9% of the population had CKD, the relative reductions in the risk of MACE, CV death, allcause mortality, and HHF were independent of eGFR down to 30 ml/ min/1.73m2 or albuminuria status at baseline and similar across the

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two doses of empagliflozin versus placebo.27 Similarly, in the CANVAS Program (20.1% of patients had CKD), the effects of canagliflozin on MACE, HHF and progression of kidney disease appeared similar across different levels of kidney function down to eGFR levels of 30 ml/ min/1.73m2.35 These findings require further confirmation in specific, powered trials in patients with diabetic kidney disease. Interestingly, the curves of renal outcomes start to separate within the first months and were maintained for >3 years, and the renal benefits were observed in patients on renin–angiotensin–aldosterone system (RAAS) inhibitors and with an eGFR >30 ml/min/1.73 m2, despite the attenuated HbA1c-lowering effects in this setting.22-24,30,31,36

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Heart Failure and Arrhythmias Figure 1: Potential Mechanisms Involved in the Cardioprotective and Renoprotective Effects of Sodium–glucose Cotransporter 2 Inhibitors SGLT2 inhibition

Metabolic responses

Direct cardiac effects

Metabolic shift

Osmotic diuresis and natriuresis

glucagon erythropoietin

Inhibits NHE1 activity FA oxidation glucose oxidation BHOB oxidation P/O ratio cardiac hypertrophy, fibrosis and remodelling

Positive inotropism

Direct renal effects

glucosuria HbA1c glucotoxicity insulin resistance bodyweight and visceral adiposity uricosuria oxidative stress inflammation markers vascular dysfunction

cardiac efficiency

haemoglobin and haematocrit

plasma volume interstitial fluid blood pressure vascular stiffness pre-load/-afterload congestion cardiac wall stress

tissular O2 delivery

cardiac efficiency

MACE HHF and improved HF outcomes

glomerular pressure albuminuria renal growth and inflammation Restores TG feedback Inhibits NHE3 activity

Preservation of renal function progression of albuminuria worsening of nephropathy

RENOPROTECTION

CARDIOPROTECTION BHOB = 3-beta-hydroxybutyrate; FA = fatty acid; HHF = hospitalisations for HF; MACE = major adverse cardiovascular events; NHE = Na+-H+ exchanger; P/O = ATP yield per oxygen atom consumed of oxidative phosphorylation; SGLT2 = sodium-glucose cotransporter 2; TG = tubuloglomerular.

Because patients with lower eGFR at baseline are at an increased risk of HHF, the renoprotective effects of SGLT2Is may contribute to improved HF outcomes.30,31,36,37

Mechanisms of Action Multiple mechanisms are proposed to explain the early cardiorenal benefits of SGLT2Is17–20,22,36–73 (Figure 1 and Table 2). The early benefits observed in EMPA-REG OUTCOME and CANVAS Program cannot be explained by the modest changes in HbA1c, blood pressure (BP), weight, visceral adiposity, uricaemia or haematocrit, alone or in combination, suggesting that other glucose-independent mechanisms may contribute to the cardiorenal protective effects of SGLT2Is.19,30,36,37,41,55 In fact, the reduction in CV events related to glucose control appears only after many years of follow-up17,37 and in T2D patients antihypertensive therapy takes years to reduce major CV events, including nonfatal stroke and MI which remain unaltered with SGLT2Is.17,43,44,74 Three hypotheses have been proposed to explain the beneficial CV effects of SGLT2Is – the diuretic hypotheses, the thrifty substrate hypothesis and the NHE (Na+-H+ exchanger) hypothesis.

be an important mechanism.30,75–77 Indeed, an exploratory analysis of the EMPA-REG OUTCOME trial showed that changes in markers of plasma volume were the most important mediators of the reduction in the risk of CV death with empagliflozin versus placebo.75 However, the diuretic effects of SGLT2Is are quite different from those observed with thiazide or loop diuretics.77 The first reason for this is that SGLT2Is act in the proximal tubule, where they inhibit glucose and Na+ reabsorption resulting in osmotic diuresis. However, compared with osmotic diuretics, SGLT2Is do not affect plasma osmolarity. Second, because SGLT2Is work in the proximal tubule, they increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback, an effect that is not achieved by loop and thiazide diuretics because they reduce Na+ flux to the macula densa.17,69 Third, compared with loop diuretics, SGLT2Is produce a greater fluid clearance from the interstitial fluid space than from the circulation, potentially resulting in better congestion relief with minimal impact on BP, arterial filling and organ perfusion or inducing a neurohumoral activation.78

The Diuretic Hypotheses The early (<3 months) and significant reduction in HHF and CV mortality produced by empagliflozin in the absence of significant changes in the incidence of MI or stroke suggests that the predominant mechanism may relate to its haemodynamic effects. It has been hypothesised that the reduction in Na+ and water retention, leading to reduced ventricular filling pressure and cardiac workload, could

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Furthermore, SGLT2Is produce greater electrolyte-free water clearance than loop or thiazide diuretics acting at different sites of the nephron and producing more potent diuresis and natriuresis.17,20 Finally, loop diuretics reduce HHF but not CV mortality69 and their long-term use reduces the risk of stroke but can worsen renal function renal function – effects that are not observed with SGLT2Is.33,69,70,77 Because

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Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure Table 2: Mechanisms of Action Underlying the Beneficial Effects of Sodium–glucose Cotransporter 2 Inhibitors on Cardiovascular and Renal Outcomes Pharmacological Effect

Cardiovascular and Renal Benefits of SGLT2Is

Glycosuria17–19,36–38

• Reduce glucose and Na+ reabsorption in the proximal tubule • Urinary glucose excretion (60–100 g/day) decreases fasting plasma glucose (−0.73 mmol/l) and HbA1c levels (0.4–1.1%) • Increase loss of calories and decrease body weight • Decrease serum uric acid levels • Reduce the cardiac effects of glucotoxicity

Osmotic diuresis and natriuresis17–19,22,39–41

• Decrease plasma volume (cardiac preload) and total Na+ tissue content • SGLT2Is produce a greater fluid clearance from the interstitial space than from the circulation, resulting in better control of congestion without reducing arterial filling and tissue perfusion • Decrease ventricular preload and wall tension and elevated filling pressures • Counteract insulin-related fluid retention • These effects would reduce congestion, clinical decompensation and the risk of HHF

BP reduction19,39,42–44

• D ue to osmotic diuresis and natriuresis and a reduction in intravascular volume and vascular stiffness, reduce BP (3.4–5.4/1.5–2.2 mmHg). • Reduce afterload, intracardiac filling pressures and wall stress and may prevent clinical decompensation • Do not produce a reflex sympathetic activation

Decrease arterial stiffness and PVR40,42,45

• Arterial stiffness is a well-recognised predictor of CV morbidity and mortality • Due to weight loss, circulating volume contraction and vascular smooth muscle relaxation through a negative Na+ balance • Reduce PVR, BP and afterload, improve subendocardial blood flow and may contribute to reduce HHF

Decrease body weight and visceral adiposity17–19,36,37,46

• Glycosuria results in caloric loss (240–400 Kcal/day) and body weight reduction (1.8–2.7 kg) • Visceral adiposity is associated with adverse left ventricular remodelling, lower cardiac output and increased PVR

Increase in haemoglobin and haematocrit levels19,39,47

• Due to due osmotic diuresis and a transient increase in erythropoietin secretion • Improve myocardial/tissular oxygen delivery

Anti-inflammatory and antioxidant effects48,49

• R educe oxidative stress, pro-inflammatory and pro-oxidant biomarkers, decrease the formation of advanced glycation end products and improve endothelial function

A shift in cardiac and renal fuel energetics41,50–55 • - - - -

Shift fuel energetics from FFA and glucose toward ketone bodies Produce ATP energy more efficiently Decrease myocardial and renal O2 consumption Reduce hypoxic stress on the diabetic heart and kidney Increase cardiac work efficiency and function

Metabolic effects19,36,37,54–56

• Decrease excess glucose uptake by the heart • Release glucagon which increases hepatic ketogenesis and exerts positive cardiac inotropic and chronotropic effects • Produce an uricosuric effect via the glucose transporter member 9 (GLUT9) and decrease uric acid levels • Increase LDL-/HDL-cholesterol and reduce triglyceride plasma levels

Cardioprotective effects

• Inhibit NHE3 • Reduce intracellular Na+ and Ca2+ load and increase mitochondrial Ca2+ levels in failing cardiac myocytes and in the diabetic kidney • Restore mitochondrial function, activate ATP production and improve systolic function in the failing heart • Slow the progression of LV hypertrophy in diabetic patients • In animal models, reduce myocardial fibrosis, hypertrophy and remodelling, decrease cardiac macrophage infiltration and improve systolic/diastolic function

19,36,37,41,50,55–66

Renoprotective effects18–20,67–71

• Decrease hyperglycaemia and BP • Inhibit NHE1 and 3 • Restore tubuloglomerular feedback, produce afferent vasoconstriction and decrease intraglomerular pressure and hyperfiltration • Reduce the progression of renal disease • Renoprotective effects may contribute to the reduction in HHF

BP = blood pressure; FFA = free fatty acids; HHF = hospitalisation for heart failure; LV = left ventricular; NHE = Na+-H+ exchanger; PVR = peripheral vascular resistances; SBP/DBP = systolic/ diastolic BP; SGLT2I = sodium-glucose cotransporter 2 inhibitor.

of these important differences, it is unlikely that SGLT2Is prevent HHF by acting simply as diuretics.20,37,39

The Thrifty Substrate Hypothesis A shift in cardiorenal fuel energetics (the ‘thrifty substrate’ hypothesis). Under physiological conditions, nearly 95% of cardiac energy is derived from mitochondrial oxidative metabolism and fuel is derived from free fatty acids (FAs; 60–70%), glucose (30%)

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and – to a lesser degree – lactate, ketones and amino acids.79 In T2D, glucose utilisation decreases while oxidation of FAs markedly increases because of peripheral insulin resistance and inability of insulin to suppress lipolysis.37,80,81 These changes decrease cardiac efficiency/function because excessive FA oxidation is energetically less efficient, increases oxidative stress and cardiac lipotoxicity and impairs LVF.37,50,80,81 SGLT2Is increase the hepatic synthesis and decrease the urinary excretion of ketones producing a mild,

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Heart Failure and Arrhythmias but persistent, hyperketonaemia.51 Under these conditions betahydroxybutyrate (BHOB) is freely taken up by the heart and kidney and oxidised in preference to FAs and glucose, producing ATP more efficiently. In fact, ATP production/O2 consumption ratio (P/O) favours BHOB (2.50) over FA (2.33), and even when the P/O ratio of BHOD and pyruvate are similar, the combustion of BHOB liberates 31% more calories.50–53,82 In rat hearts, BHOB increases external cardiac work and reduces oxygen consumption, thereby improving cardiac efficiency in the diabetic heart.48–53,82 Thus, it has been hypothesised that the cardiorenal benefits of SGLT2Is might be related to a shift in cardiorenal metabolism away from FAs and glucose oxidation toward ketone bodies, a more energy-efficient fuel, which improves cardiac and renal work efficiency/function, reduces oxygen consumption and exhibits antioxidative and antiarrhythmic properties.41,50–53 The utilisation of ketones together with an increased oxygen delivery from SGLT2Iinduced haemoconcentration and a reduced cardiac load resulting from decreases in intravascular volume and BP could be involved in the early benefits observed in CVOTs.

The NHE Hypothesis A reduction in intracellular sodium ([Na+]i) by inhibiting the sarcolemmal Na+-H+ exchanger (NHE; the NHE hypothesis).19,50,55,72 NHE1 is the predominant isoform in the heart and vasculature, while NHE3 is expressed at the apical surface of renal epithelial cells where it co-localises and functionally interacts with SGLT2.55 In patients with T2D and HF, the activity of NHE1/3 is markedly enhanced. This increase facilitates the accumulation of intracellular Na+ ([Na+] + 2+ exchanger i), which stimulates the reverse activity of the Na /Ca 2+ (NCX) leading to an increase in [Ca ]i and cardiomyocyte injury, facilitates mitochondrial Ca2+ extrusion to the cytoplasm and decreases mitochondrial Ca2+ ([Ca2+]m).55,58–62,83 The reduction in [Ca2+]m impairs Ca2+-induced stimulation of Krebs cycle dehydrogenases and reduces ATP production and mitochondrial antioxidative capacity.54,55,58,60–63,71 Even when SGLT2 is not expressed in the heart, SGLT2Is can inhibit cardiac NHE1, possibly through a binding site for SGLT2 on NHE1.55 The inhibition of NHE1 reduces intracellular Na+ and Ca2+ concentrations and increases [Ca2+]m, which restores mitochondrial function and redox state, activates ATP production in the failing heart and improves systolic function.55,62 In animal models, SGLT2Is via the inhibition of NHE1 reduce cardiac hypertrophy and fibrosis and ventricular arrhythmias, slow the progression of left ventricular (LV) remodelling and diabetic cardiomyopathy and improve systolic/diastolic function.55,57–68 In normotensive patients with T2D and established coronary artery disease, but without HF, empagliflozin significantly reduces LV mass and slows the progression of LV hypertrophy versus placebo.84 This finding suggests that empagliflozin promotes a reverse remodelling, which may contribute to the early cardiovascular and HF benefits observed in the EMPA-REG OUTCOME trial. However, several questions remain unanswered, including the mechanism underlying the increase in BHOB, the time course of the hyperketonaemia, the relationship between the dose, hyperketonaemia and improvement in cardiac function, or whether hyperketonaemia might increase the risk of diabetic ketoacidosis (DKA).59,79,83,84 Additionally, an increase in metabolic efficiency and/or NHE inhibition should prove beneficial in myocardial ischaemia and HHF, but in CVOTs these two endpoints were differentially affected by SGLT2Is.50,79

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Thus, at the present time, the ‘thrifty substrate’ hypothesis needs to be demonstrated.83

Renal Effects In patients with T2D, glucose and Na+ reabsorption increases in the proximal tubule via SGLT2 and Na+ delivery to the macula densa decreases, which stimulates renin release by the juxtaglomerular cells and activates the RAAS. This causes, via tubuloglomerular feedback, an afferent arteriolar vasodilation that increases the GFR (‘hyperfiltration’) and contributes to diabetic nephropathy. SGLT2Is reduce Na+ reabsorption in the proximal tubule and increase its delivery to the macula densa.19,20,69,73,85 This inhibits renin release, activates tubuloglomerular feedback, produces an afferent arteriolar vasoconstriction, normalises the GFR and reduces intraglomerular pressure counteracting hyperglycaemia-induced hyperfiltration – an effect that would be expected to slow the progression of diabetic nephropathy.17–20,69,70,73,85 However, afferent arteriolar vasoconstriction is present in patients with HF and an enhancement of such vasoconstriction would not be expected to produce favourable renal effects in non-diabetic patients with HF.55 SGLTIs initially reduce eGFR (~5 ml/min/1.73m2) and albuminuria (30–40%), but eGFR recovers baseline values after 6–12 months, reflecting a haemodynamic alteration rather than a glomerular damage. 31,84 Additionally, the renoprotective effects of SGLT2Is have been related to a decrease in hyperglycaemia, BP, glomerular capillary pressure and glomerular hyperfiltration, and direct effects on mesangial expansion, tubular growth, and inflammation.18–20,69,70,85

Adverse Events SGLT2Is are generally well tolerated and adverse events (AEs) are considered mild-to-moderate in severity. 18–20,22-24,36,37,83,86–101 However, some serious AEs have been reported in postmarketing surveillance programs (Table 3). In the CANVAS Program, canagliflozin significantly increased the risk of fractures and below-knee lower extremity amputations.23,95 In the EMPA-REG trial, amputations and fractures were not mentioned in the study protocol, but a post-hoc analysis reported a similar rate of both AEs with empagliflozin or placebo.26,55 However, EMPA-REG and CANVAS were not powerful enough to detect significant differences in either amputation or fracture among the studied population. Recently, several real-world studies have led to contradictory conclusions on the risk of amputations90–92,94 and a meta-analysis failed to demonstrate an increase in fracture events with SGLT2Is.96 Therefore, it remains unclear whether the risk of these AEs extends across the drug class. Early trials raised the concern that SGLT2Is may increase the risk of bladder and breast cancer, and a meta-analysis suggested an increased risk of bladder cancer with empagliflozin.100 However, given the short-term follow-up and uncertainty of evidence, future long-term prospective studies and postmarketing surveillance studies are warranted.

Unresolved Issues Many questions remain to answered in future preclinical studies and carefully designed controlled trials (Table 4). What are the mechanisms underlying the early cardiorenal benefits of SGLT2Is? CVOTs were designed to test the safety of SGLT2Is but not the mechanism of action. Therefore, the mechanisms underlying the early separation of the curves of CV mortality, HHF and progression of renal disease and the long-term sustained benefits of SGLT2Is are yet to be elucidated. It is possible that haemodynamic, metabolic,

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Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure Table 3. Adverse Effects of Sodium–glucose Cotransporter 2 Inhibitors Adverse Effect

Risk Factors and Recommendations*

Infections

• • • •

22–24,36,37,83,86

• • • •

Related to glycosuria Genital mycotic infections: balanitis and vulvovaginitis UTIs: rare cases of pyelonephritis and urosepsis, sometimes requiring hospitalisation Necrotising fasciitis of the perineum (Fournier’s gangrene). Discontinue SGLT2Is and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary Risk factors: women, previous genital fungal infections, uncircumcised males Monitor and treat infections as appropriate Avoid SGLT2Is in patients with previous history of complicated UTIs, indwelling urinary catheter and recurrent genital mycotic infections SGLT2Is may decrease quality of life in men with prostatic hypertrophy and women with urinary incontinence

Volume depletion

• R isk factors: elderly, patients with dehydration, hypovolaemia, renal impairment, low BP or taking diuretics or nephrotoxic drugs • Assess volume status and BP before initiating treatment - SGLT2Is should be used with caution or discontinued in the presence of hypovolaemia to avoid worsening of renal function - Delay SGLT2I therapy in hypovolaemic or hypotensive individuals until fluid status and BP are corrected • When SGLT2Is are combined with vasodilators or thiazide diuretics it may be necessary to reduce dose by 50%

Hypoglycaemia

• G lucose is not being filtered in the glomerulus when glycaemia is normal; thus, the risk of hypoglycaemia with SGLT2Is is low • Risk of hypoglycaemia when combined with insulin or sulfonylureas

Hypotension

• I n combination with hypovolaemia can cause dizziness and orthostatic hypotension and may increase the risk of falls and fractures • The risk of symptomatic hypotension increases in the elderly, patients with renal impairment, low BP or treated with antihypertensives, diuretics or vasodilators • Monitor for signs and symptoms of hypotension

Acute kidney injury17,36,37,101

• • • •

Diabetic ketoacidosis19,36,37,87–89

• Appears with mildly elevated glucose levels (<13.9 mmol/L) which can delay diagnosis and therapy • Osmotic diuresis may worsen the hypovolaemic state of DKA, particularly in patients with nausea and decreased oral intake • Risk factors: hypovolaemia, acute illness or surgery, alcohol abuse, carbohydrate restriction, low insulin secretory capacity, increased glucagon secretion, previous episodes of ketosis, latent autoimmune diabetes in adults and T1D (SGLT2 are not approved for use) • SGLT2Is should be stopped during acute illness and at least 48 h before any planned surgical procedure • SGLT2Is are contraindicated in patients with DKA

Lower-limb amputations23,28,29,90–94

• Canagliflozin may increase the risk of lower limb (toe or metatarsal) amputations. • SGLT2Is produce haemoconcentration and volume depletion and decrease in BP, effects that may reduce limb perfusion and produce tissue ischaemia. Canagliflozin activates AMP kinase, which inhibits complex I of the respiratory chain and favours tissue ischaemia • Risk factors: men, prior history of lower-limb amputation, advanced peripheral vascular disease, peripheral neuropathy, and diabetic foot ulcers. • EMA recommends careful monitoring of all patients receiving SGLT2Is, emphasising foot care. Consider stopping treatment if patients develop lower-extremity infections, new pain or tenderness, sores, ulcers, infection, osteomyelitis, or gangrene. • Avoid canagliflozin (all SGLT2Is) in patients at the highest amputation risk until more safety data are accumulated

Bone fractures95–99

• C anagliflozin (not empagliflozin or dapagliflozin) increases the rate of all-bone and low-trauma fractures within the first weeks of treatment • Independent of changes in bone mineral density or alterations in calcium homeostasis • Fractures possibly related to: increased parathyroid hormone and FGF23 excretion and orthostatic hypotension and postural falls due to volume depletion • Canagliflozin (possibly all SGLT2Is) should be used with caution in patients with fragility fractures or established osteoporosis, or at risk of falling

Appears within 1 month of starting therapy with canagliflozin and dapagliflozin Risk factors: volume depletion, hypotension, diuretics, ACE inhibitors, ARBs, NSAIDs, or nephrotoxic drugs Monitor for signs and symptoms of acute kidney injury SGLT2Is are contraindicated in patients with eGFR <45 ml/min/1.73 m2 (dapagliflozin when <60 ml/min/1.73 m2), severe renal impairment, end-stage renal disease, or dialysis

Increase of LDL cholesterol levels54,57 • The clinical meaning is uncertain. Monitor and treat as appropriate T2D and established CVD Cancer100

• Avoid dapagliflozin in patients with active bladder cancer (and empagliflozin)?

*Recommendations according to the FDA and/or EMA. ACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; BP = blood pressure; CVD = cardiovascular disease; DKA = diabetic ketoacidosis; eGFR = estimated glomerular filtration rate; EMA = European Medicines Agency; FDA = Food and Drug Administration; FGF = fibroblast growth factor; NSAIDs = non-steroidal anti-inflammatory drugs; SGLT2I = sodium– glucose cotransporter 2 inhibitor; T1D = type 1 diabetes; T2D = type 2 diabetes; UTI = urinary tract infection.

hormonal and direct cardiac and renal mechanisms, possibly unrelated to SGLT2 inhibition, and with different roles over time and in different populations might be involved. So, are the same mechanisms involved

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in the cardiovascular and renal benefits? A better understanding of the mechanisms of action is the first step to identify the patients who could benefit most from the use of SGLT2Is.

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Heart Failure and Arrhythmias Table 4: Questions to Address in Future Preclinical and Clinical Research with SGLT2Is 1. What are the mechanisms underlying the early and long-term sustained benefits of SGLT2Is on cardiorenal outcomes? • Are the same mechanisms involved in the beneficial effects on cardiovascular and renal outcomes? • Where is SGLT2 expressed in the heart, vessels, kidney and peripheral and central nervous system controlling cardiovascular functions? • The putative mechanisms of action of SGLT2Is should be validated in in vivo models and patients with and without T2D, and in those with HF with reduced or preserved ejection fraction. • Are the mechanisms of action comparable across SGLT2Is or specific to individual compounds? • Are there ethnic variations in the response to SGLT2Is? 2. Is the cardiovascular and renal benefit a class effect? • Head-to-head comparisons among SGLT2Is are needed, but they will probably never be performed. 3. How can the marked differences observed in CVOTs among SGLT2Is be explained? 4. What is the benefit of SGLT2Is in patients with HF? • Can the benefits on HF be extended across the left ventricular ejection fraction spectrum in patients with and without T2D? • Can SGLT2Is improve cardiovascular and renal outcomes in patients with T2D but without established CVD? • Can SGLT2Is improve cardiovascular and renal outcomes in patients with CVD but without T2D? • Can the cardiovascular and renal benefits be extended to patients without established CVD or T2D? • What is the beneficial effect of SGLT2Is observed in individuals with newly diagnosed T2D without CVD or nephropathy? • Can SGLT2Is reduce the likelihood of developing CVD in lower-risk patients who have not yet manifested CVD? 5. Can the cardiovascular and renal protection observed in CVOTs be extrapolated to the real world? • Can the results be extrapolated to patients with T2D with or without established CVD? 6. What is the risk:benefit ratio of SGLT2Is in HF patients without T2D in the real world? • Can peripheral hypoperfusion present in HF patients increase the amputation risk? • Are lower-limb extremity amputations and fractures a class effect? • It is critical to clarify the association between SGLT2Is and risk of cancer. CVD = cardiovascular disease; CVOT = cardiovascular outcome trials; HF = heart failure; SGLT2I = sodium-glucose cotransporter 2 inhibitor; T2D = type 2 diabetes.

Is the cardiorenal benefit a class effect? A class effect would not be expected if the underlying mechanisms are unrelated to SGLT2 inhibition. There are differences among SGLT2Is in their SGLT2/SGLT1 selectivity (>2,500 for empagliflozin, 1,116 for dapagliflozin, 250 for canagliflozin), pharmacokinetic properties and – possibly – pharmacodynamic offtarget properties17–19,36,37,102 Thus, there is no evidence that the benefits can be a ‘class effect’. Indeed, the FDA and European Medicines Agency approved all SGLT2Is for glycaemic control in adults with T2D. Additionally, empagliflozin is also approved to reduce the risk of CV death in adults with T2D and established CVD, and canagliflozin to reduce the risk of MACE in adults with T2D and established CVD. How can the marked differences observed in CVOTs among SGLT2Is be explained? Table 1 shows that there are important differences between CVOTs in clinical outcomes related to differences in the recruited population, trial design, concurrent use of cardioprotective drugs, adjudication of CV events or statistical analysis.20–22 In a recent meta-analysis of 13 clinical trials recruiting 34,533 diabetic patients (60.2% with established atherosclerotic CVD), the most consistent effect of SGLT2Is was to reduce HHF (31%) and progression of renal disease (45%), with a modest reduction in MACE (11%).14 The reduction in MACE was apparent only in patients with established atherosclerotic CVD, while the reduction in HHF or progression of renal disease was observed regardless of the presence of atherosclerotic CVD, a previous a history of HF and across different levels of kidney function down to eGFR levels of 30 ml/min/1.73 m2. Are ethnic differences implicated in the response to SGLT2Is? Asian participants (who account for almost half of the world’s population with diabetes)1 and white participants had better CV benefits than black participants in the EMPA-REG study, whereas canagliflozin was superior in black and white participants.22,23 These findings suggest that the benefits of SGLT2Is may depend on the population in which they are used. What is the real benefit of SGLT2Is in patients with HF? CVOTs were not designed to assess the efficacy of SGLT2Is in patients with HF. Indeed,

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<15% of the patients had HF at baseline, HF phenotyping – including echocardiography or biomarkers (B-type natriuretic peptide, troponin T) – was not performed, and effects of SGLT2Is on LV structure and function or haemodynamics remain to be determined. The significant reduction in HHF observed even in patients without atherosclerotic CVD or a history of HF raises the possibility of using SGLT2Is not only in the primary prevention but also for the treatment of HF patients with reduced and/or preserved ejection fraction. Can the cardiovascular and renal protection observed in CVOTs be extrapolated to the real world? The observational Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors (CVD-REAL) and CVD-REAL Nordic trials suggested that initiation of SGLT2Is versus other glucose-lowering drugs was associated with a lower risk of HHF and death regardless of preexisting CVD, and with reduced CV mortality in patients with T2D and a broad cardiovascular risk profile.103–106 Therefore, the benefits observed with empagliflozin and canagliflozin may be a class effect applicable to a broad population of patients with T2D in real-world practice, including in primary prevention. However, because of the observational design, short follow-up and immortal time and time-lag biases, the >50% lower rates of all-cause mortality associated with the use of SGLT2Is in these trials are more likely exaggerated.107 Additionally, in these trials only 25% of patients presented established CVD, most were treated with canagliflozin and dapagliflozin (not with empagliflozin) and drug safety was not reported. Thus, at the present time there is not enough evidence to extrapolate the data from the CVOTs to the real-world setting.107 What is the risk/benefit ratio of SGLT2Is in the real world? Optimal prescription of SGLT2Is requires the understanding of their risk/benefit ratio, but AEs should not overshadow their cardiorenal protective effects. Some serious AEs were not observed in CVOTs, possibly because of the short follow-up and the selection and strict supervision

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Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure of patients, but they were reported in postmarketing surveillance studies and some of these AEs were unexpected. Are bone fractures and amputations a class effect? What are the mechanisms involved in bone fractures and amputations? What is the clinical meaning of the trend in stroke in the EMPA-REG OUTCOME trial? Further research is needed to identify the risk factors for the development of serious AEs, including infections, Fournier’s gangrene, acute kidney injury, DKA, amputations and bone factures in patients treated with the different SGLT2Is in daily clinical practice. Furthermore, there is little information on drug interactions between SGLT2Is and other treatments prescribed in patients with T2D and HF. In the EMPA-REG OUTCOME trial, the effect

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Heart Failure and Arrhythmias 52. S ato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 1995;9:651–8. PMID: 7768357. 53. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPAREG OUTCOME trial: a ‘thrifty substrate’ hypothesis. Diabetes Care 2016;39:1108–14. https://doi.org/10.2337/dc16-0330; PMID: 27289126. 54. Briand F, Mayoux E, Brousseau E, et al. Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism. Diabetes 2016;65:2032–8. https://doi.org/10.2337/ db16-0049; PMID: 27207551. 55. Packer M, Anker SD, Butler J, et al. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017;2:1025–9. https://doi.org/10.1001/ jamacardio.2017.2275; PMID: 28768320. 56. Cheeseman C. Solute carrier family 2, member 9 and uric acid homeostasis. Curr Opin Nephrol Hypertens 2009;18:428–32. https://doi.org/10.1097/MNH.0b013e32832ee3de; PMID: 19593129. 57. Bays HE, Sartipy P, Xu J, et al. Dapagliflozin in patients with type II diabetes mellitus, with and without elevated triglyceride and reduced high-density lipoprotein cholesterol levels. J Clin Lipidol 2017;11:450 e1–458 e1. https://doi.org/ 10.1016/j.jacl.2017.01.018; PMID: 28502502. 58. Pessoa TD, Campos LC, Carraro-Lacroix L, et al. Functional role of glucose metabolism, osmotic stress, and sodiumglucose cotransporter isoform-mediated transport on Na+/ H+ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol 2014;25:2028–39. https://doi.org/10.1681/ ASN.2013060588; PMID: 24652792. 59. Lopaschuk GD, Verma S. Empagliflozin’s fuel hypothesis: not so soon. Cell Metab 2016;24:200–2. https://doi.org/10.1016/j. cmet.2016.07.018; PMID: 27508868. 60. Kohlhaas M, Maack C. Adverse bioenergetic consequences of Na+-Ca2+ exchanger-mediated Ca2+ influx in cardiac myocytes. Circulation 2010;122:2273–80. https://doi.org/10.1161/ CIRCULATIONAHA.110.968057; PMID: 21098439. 61. Baartscheer A, Schumacher CA, van Borren MM, et al. Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res 2003;57:1015–24; PMID: 12650879. 62. Baartscheer A, Schumacher CA, Wust RC, et al.Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 2017;60:568–73. https://doi.org/10.1007/s00125-016-4134-x; PMID: 27752710. 63. Liu T, Takimoto E, Dimaano VL, et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a guinea pig model of heart failure. Circ Res 2014;115:44–54. https://doi. org/10.1161/CIRCRESAHA.115.303062; PMID: 24780171. 64. Nakamura TY, Iwata Y, Arai Y, et al. Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res 2008;103:891–9. https://doi.org/10.1161/CIRCRESAHA.108.175141; PMID: 18776042. 65. Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 2014;13:148. https:// doi.org/10.1186/s12933-014-0148-1; PMID: 25344694. 66. de Leeuw AE, de Boer RA. Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects. Eur Heart J Cardiovasc Pharmacother 2016;2:244–55. https://doi.org/10.1093/ehjcvp/pvw009; PMID:27533948. 67. Joubert M, Jagu B, Montaigne D, et al. The sodiumglucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes 2017;66:1030–40. https://doi.org/10.2337/db16-0733; PMID: 28052965. 68. Habibi J, Aroor AR, Sowers JR, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol 2017;16:9. https://doi.org/10.1186/ s12933-016-0489-z; PMID: 28086951. 69. Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyperfiltration: is there a role for SGLT2 inhibitors in diabetic kidney disease? Circulation 2014;129:542– 4. https://doi. 10.1161/CIRCULATIONAHA.113.007071; PMID: 24334174. 70. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Cardiol 2017;120(1S):S28–36. https://doi.org/10.1016/j. amjcard.2017.05.013; PMID: 28606341.

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71. L ayton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule. Am J Physiol Renal Physiol 2015;308:F134357. https://doi.org/10.1152/ajprenal.00007.2015; PMID: 25855513. 72. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587–97. https://doi.org/10.1161/ CIRCULATIONAHA.113.005081; PMID: 24334175. 73. Ghezzi C, Loo DDF, Wright EM. Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia 2018;61:2087–97. https://doi:10.1007/s00125-018-4656-5; PMID: 30132032. 74. Sciarretta S, Palano F, Tocci Get al. Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk. Arch Intern Med 2011;171:384–94. https://doi.org/10.1001/ archinternmed.2010.427; PMID: 21059964. 75. McMurray J. EMPA-REG - the “diuretic hypothesis”. J Diabetes Complications 2016;30:3-4. https://doi.org/10.1016/j. jdiacomp.2015.10.012; PMID: 26597600. 76. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2018;41:356–63. doi: 10.2337/dc17-1096; PMID: 29203583. 77. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab 2016;42:224–33. https://doi. org/10.1016/j.diabet.2016.05.006; PMID: 27291329. 78. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obesity Metab 2018;20:479–87. https://doi.org/10.1111/dom.13126; PMID: 29024278. 79. Lopaschuk GD, Ussher JR, Folmes CDL, et al. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90:207–58. https://doi.org/10.1152/physrev.00015.2009; PMID: 20086077. 80. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 2014;171:2080-90. https://doi.org/10.1111/bph.12475; PMID: PMC3976623. 81. Riggs K, Ali H, Taegtmeyer H, et al. The use of SGLT-2 inhibitors in type 2 diabetes and heart failure. Metab Syndr Relat Disord 2015;13:292–7. https://doi.org/10.1089/met.2015.0038; PMID: 26125313. 82. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004;70:309–19. https://doi.org/10.1016/j.plefa.2003.09.007; PMID: 14769489. 83. Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia 2018;61:2118–25. https://doi.org/10.1007/s00125-018-4663-6; PMID: 30132031. 84. Verma S, Mazer CD, Yan AT, et al. EMPA-HEART CardioLink-6 trial: a randomized trial of empagliflozin on left ventricular structure, function, and biomarkers in people with type 2 diabetes and coronary heart disease. Presented at: AHA 2018, Chicago, IL, 11 November 2018. 85. Wanner C. EMPA-REG OUTCOME: the nephrologist’s point of view. Am J Cardiol 2017;120(Suppl 1):S59–67. https://doi. org/10.1016/j.amjcard.2017.05.012; PMID: 28606346. 86. Thong KY, Yadagiri M, Barnes DJ, et al. Clinical risk factors predicting genital fungal infections with sodium-glucose cotransporter 2 inhibitor treatment: the ABCD nationwide dapagliflozin audit. Prim Care Diabetes 2018;12:45–50. https:// doi.org/10.1016/j.pcd.2017.06.004; PMID: 28669625. 87. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638–42. https:// doi.org/10.2337/dc15-1380; PMID: 26294774. 88. Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med 2017;376:2300–2. https://doi.org/10.1056/NEJMc1701990; PMID: 28591538. 89. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia 2017;60:1385–9. https://doi. org/10.1007/s00125-017-4301-8; PMID:28500396. 90. Khouri C, Cracowski JL, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect? Diabetes Obes Metab 2018;20:1531–4. https://doi.org/10.1111/ dom.13255; PMID: 29430814

91. S cheen AJ. Does lower-limb amputation concern all SGLT-2 inhibitors? Nature Rev Endocrinol 2018;18:326-8. https://doi. 10.1038/s41574-018-0001-9; PMID: 29626204. 92. Fadini GP, Avogaro A. SGLT2 inhibitors and amputations in the US FDA adverse events reporting system. Lancet Diabetes Endocrinol 2017;5:680–1. https://doi.org/10.1016/S22138587(17)30257-7; PMID: 28733172. 93. Udell JA, Yuan Z, Rush T, et al. Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World). Circulation 2018;137:1450–9. https://doi.org/10.1161/ CIRCULATIONAHA.117.031227; PMID: 29133607. 94. Yuan Z, DeFalco FJ, Ryan PB, et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab 2018;20:582–9. https://doi.org/10.1111/dom.13115; PMID: 28898514. 95. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016;101:157–66. https://doi.org/10.1210/ jc.2015-3167; PMID: 26580237. 96. Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016;18:1199–206. https://doi.org/10.1111/ dom.12742; PMID: 27407013. 97. Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone markers in patients with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitors. J Clin Endocrinol Metab 2016;101:44– 51. https://doi.org/10.1210/jc.2015-1860; PMID: 26580234. 98. Bays HE, Weinstein R, Law G, et al. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring) 2014;22:1042–9. https://doi.org/10.1002/ oby.20663; PMID: 24227660. 99. Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 2015;3:8–10. https://doi.org/10.1016/S2213-8587(14)70227-X; PMID: 25523498. 100. Tang H, Dai Q, Shi W, et al. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia 2017;60:1862–72. https://doi.org/10.1007/s00125-017-4370-8. PMID: 28725912. 101. Singh M, Kumar A. Risks Associated with SGLT2 Inhibitors: An Overview. Curr Drug Saf. 2018;13:84–91. https://doi.org/10.2174/ 1574886313666180226103408. PMID: 29485006. 102. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterization and comparison with other SGLT2 inhibitors. Diabetes Obes Metab 2012;14:83–90. https://doi. org/10.1111/j.1463-1326.2011.01517.x; PMID: 21985634. 103. Kosiborod M, Birkeland KI, Cavender MA, et al.; CVDREALInvestigators and Study Group. Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: Results from the CVD-REAL study. Diabetes Obes Metab 2018;20:1983–7. https://doi.org/10.1111/ dom.13299; PMID: 29569378. 104. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017;136:249–59. https://doi.org/10.1161/CIRCULATIONAHA.117.029190; PMID: 28522450. 105. Birkeland KI, Jorgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol 2017;5:709–17. https://doi.org/10.1016/S22138587(17)30258-9; PMID: 28781064. 106. Persson F, Nyström T, Jørgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and allcause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab 2018;20:344–51. https://doi.org/10.1111/dom.13077; PMID: 28771923. 107. Suissa S. Lower risk of death with SGLT2 inhibitors in observational studies: real or bias? Diabetes Care 2018;41:6–10. https://doi.org/10.2337/dc17-1223; PMID: 29263192.

EUROPEAN CARDIOLOGY REVIEW

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Heart Failure and Arrhythmias

Cardiac Resynchronisation Therapy and Cellular Bioenergetics: Effects Beyond Chamber Mechanics Christos-Konstantinos Antoniou, Panagiota Manolakou, Nikolaos Magkas, Konstantinos Konstantinou, Christina Chrysohoou, Polychronis Dilaveris, Konstantinos A Gatzoulis and Dimitrios Tousoulis First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

Abstract Cardiac resynchronisation therapy is a cornerstone in the treatment of advanced dyssynchronous heart failure. However, despite its widespread clinical application, precise mechanisms through which it exerts its beneficial effects remain elusive. Several studies have pointed to a metabolic component suggesting that, both in concert with alterations in chamber mechanics and independently of them, resynchronisation reverses detrimental changes to cellular metabolism, increasing energy efficiency and metabolic reserve. These actions could partially account for the existence of responders that improve functionally but not echocardiographically. This article will attempt to summarise key components of cardiomyocyte metabolism in health and heart failure, with a focus on the dyssynchronous variant. Both chamber mechanics-related and -unrelated pathways of resynchronisation effects on bioenergetics – stemming from the ultramicroscopic level – and a possible common underlying mechanism relating mechanosensing to metabolism through the cytoskeleton will be presented. Improved insights regarding the cellular and molecular effects of resynchronisation on bioenergetics will promote our understanding of non-response, optimal device programming and lead to better patient care.

Keywords Dyssynchronous heart failure; cardiac resynchronisation therapy; bioenergetics; metabolism; chamber mechanics; mitochondria Disclosure: The authors have no conflicts of interest to declare. Received: 2 January 2019 Accepted: 15 March 2019 Citation: European Cardiology Review 2019;14(1):33–44. DOI: https://doi.org/10.15420/ecr.2019.2.2 Correspondence: Polychronis Dilaveris, National and Kapodistrian University of Athens, 22 Miltiadou St, 155 61 Athens, Greece. E: hrodil1@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiac resynchronisation therapy (CRT) has been a cornerstone in the treatment of select advanced heart failure cases since its introduction to our armamentarium in the early 2000s.1 Indeed, 30–60% of advanced heart failure patients exhibit evidence of dyssynchrony, when defined electrocardiographically or mechanically.2–4 The latter is a consequence of the former. CRT has several unique features, summarised in Table 1. Although the main mechanisms through which CRT is thought to act are improvements in chamber mechanics, a more subtle effect has been recognised, linking resynchronisation to cellular metabolism and energy efficiency. Full comprehension of this connection could help us to interpret nonresponse and lead to more sophisticated criteria for CRT use, help detect concealed responders – patients who do not have increases in mechanical output but do have improvements in bioenergetics and may have improved functional reserve – and alter CRT programming approach. This article will present cellular bioenergetics in myocardial cells and subsequent alterations in heart failure. Cellular and molecular aspects of CRT effects on bioenergetics will be discussed, along with their potential implications for clinical practice.

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Cardiomyocyte Metabolism in Health and Heart Failure Normal Conditions The human heart has been called a metabolic omnivore because of its ability to use all common oxidative substrates. Under normal conditions, 60–90% of adenosine triphosphate (ATP) produced is a product of fatty acid oxidation with the rest attributed to glucose oxidation.5 Notably, these metabolic pathways are mutually inhibitory (the Randle cycle) and the relative flow is determined by the fed or fasted state of the cell; fed leading to preferential use of glucose and fasted to fatty acid oxidation.6 Given the much higher efficiency of aerobic oxidation compared with anaerobic metabolism, the heart predictably uses the former (it accounts for 90% of energy production).7,8 Oxidative metabolism begins in the sarcoplasm but continues in the mitochondria, which occupy 30% of cardiomyocyte volume, strategically placed near myofibrils and sarcoplasmic reticulum (SR) to minimise the diffusion distance of the high-energy bondcontaining molecules from production to consumption sites.8 This highlights the crucial dependency of cellular function on mitochondrial integrity, placement and output. The burden of cardiac work is such that there is no energy production reserve. At maximal exercise the heart is operating at >90% of

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Heart Failure and Arrhythmias Table 1: Unique Features in Development, Effect and Implementation of Cardiac Resynchronisation Therapy • H istorically, CRT has followed the opposite course to normal, i.e. it was first successfully tried clinically and then had its results and mechanism elucidated, with fewer than 0.5% of relevant studies focusing on basic mechanisms.145 • CRT is unique among all heart failure therapeutic interventions because it simultaneously improves both heart contractility/output and survival, in contrast to beta-blockers and inotropes.81 It should be noted that betablockade effects rely significantly on drug exposure and reduced resting heart rates.81,145,192,193 • A sizeable portion (30–40%) of patients allocated a CRT device do not respond – even unfavourably – to the intervention, without any of the proposed criteria having been able to predict the outcome and improve patient selection.68,69,194–203 • CRT is an example of personalised medicine, it has to be finely tailored to each recipient to exert its beneficial effects. Failure to adjust or optimise CRT could lead to loss of benefit or even harm. CRT = cardiac resynchronisation therapy.

for this role inasmuch as they participate in both actin-myosin crosstalk regulation and in activation of major mitochondrial complexes (Table 2) and ATP synthase.10–12 One of the key aspects of cellular bioenergetics lies in the recognition that the sarcoplasm is not a homogeneous solution of molecules; rather, local concentrations of metabolites are essential in determining metabolic efficiency, as dictated by the laws of thermodynamics.7 More specifically, the energy yield from ATP dissociation is determined by the equation: G=

G0 + RT ln

[ADP] × [P]i [ATP]

Where ΔG denotes change in Gibbs free energy, a measure of the energy yield and so of the spontaneous nature of a reaction, combining both enthalpy (thermal output) and entropy (measure of randomness) through the equation: G ≡ H − TS

Table 2: Complexes of the Mitochondrial Respiratory (Electron Transport) Chain and Their Functions • C omplex I (NADH dehydrogenase) removes two electrons from NADH and transfers them to ubiquinone, a soluble carrier, while pumping four protons across the inner mitochondrial membrane. Electron leakage to molecular oxygen is highly probable and so this is one of the main sites of superoxide production.204 • Complex II (succinate dehydrogenase) performs a triple role, acting as an intermediate carrier of electrons from complex I, inserting electrons from flavin adenine dinucleotide (in the hydrogenated form of FADH2) into the electron transport chain and as a catalyst for the conversion of succinate to fumarate, where FADH2 is formed from FAD before relinquishing its hydrogen atoms to the complex. Notably, no proton pumping occurs in this complex and so all electrons entering the transport chain at this level ultimately yield lower proton electrochemical gradient. Furthermore, although cytoplasmic NADH is converted into FADH2 in most tissues, because of an ineffective shuttling system to the mitochondria, this is optimised in cardiac tissue, yielding mitochondrial NADH entering the chain at the complex I level, so maintaining a higher overall efficiency of the oxidative process. • Complex III (cytochrome bc1 complex) removes two electrons from the quinone pool, relinquishes them to the notorious cytochrome c (another lipid-soluble electron carrier) and pumps four protons across the inner mitochondrial membrane. When electron transfer is reduced – as in the case of reduced activity of complex IV, the downstream electron acceptor – electron leakage may occur, leading to superoxide formation.186,187 • Complex IV (cytochrome oxidase) transfers four electrons from the cytochrome c pool to molecular oxygen, while eight protons are removed from the mitochondrial matrix. Four protons are pumped across the membrane and four are combined with oxygen radicals to form water, contributing to the electrochemical gradient, albeit indirectly and to a lesser extent than complexes I and III. • Complex V (ATP synthase) consists of two main units further divided into subunits. F0 constitutes an ion channel allowing for the backflow of protons to the matrix, while causing a rotation of the unit (one full rotation per eight protons channelled), leading to conformational changes that yield free energy, allowing the catalytic F1 unit to convert ADP to ATP and partially convert free energy into chemical energy. ADP = adenosine diphosphate; ATP = adenosine triphosphate; FAD = flavin adenine dinucleotide; FADH2 = reduced flavin adenine dinucleotide; NADH = reduced nicotinamide adenine dinucleotide.

maximum oxidative capacity and recycles an amount of ATP (6 kg) more than 20 times its weight.6,9 As such, establishing effective coupling between energy producing and consuming organelles is crucial. Calcium ions are a strong candidate

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With H denoting enthalpy, T absolute temperature and S entropy. ΔG0 is the standard free energy change at a temperature of 25°C (298 K), R is the universal gas constant in J mol-1 K-1, ln(X) is the natural logarithm of X and [Y] denotes the local concentration – allowed to freely diffuse in the vicinity without barriers such as membranes – of substance Y. Consequently, the free energy yield (ΔG) is critically dependent on local concentrations of products and reactants and fast regeneration of ATP, along with rapid removal of adenosine diphosphate (ADP) from the vicinity to ensure optimal energy output. Simply put, the same intracellular task may require more ATP as a result of lower energy from every ATP dissociation owing to the mismanagement of reactants. Reduced yield may cause reactivation of the foetal myosin isoform (beta-myosin), producing less shortening per power stroke, but requiring less energy to undergo conformational changes than the adult one (alpha-myosin).13 In addition to the electron transport chain/ATP synthase proximity in mitochondria, all the enzymes of glycolysis are organised in complexes attached to energy-consuming structures (SR/ myofibrils). Phosphocreatine (PCr) kinase also exhibits high concentrations near myosin head regions, SR calcium transport ATPase (SERCA) pumps and ADP/ATP mitochondrial antiporter, where it ensures rapid ATP regeneration and – in the latter case – rapid ATP shuttling to the sarcoplasm, maintaining optimal yield from ATP dissociation.14–17 Prerequisites for optimal and efficient cellular bioenergetics are listed in Table 3.

Alterations in Heart Failure In heart failure, the heart switches from an omnivore to preferentially using glucose oxidation for energy production, initially by increasing glucose consumption and ultimately by decreasing fatty acid oxidation.18–20 In the short term, glucose and fatty acids compete with each other for use as substrates for energy production (the Randle cycle).21 In the fasted state, beta-oxidation of the relatively abundant fatty acids – released by the liver – causes an increase in the mitochondrial ratios of acetyl-coenzyme A/

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Cardiac Resynchronisation Therapy and Cellular Bioenergetics coenzyme A and reduced nicotinamide adenine dinucleotide (NADH)/ oxidised nicotinamide adenine dinucleotide (NAD+), which both inhibit pyruvate dehydrogenase activity.22 Conversely, in the fed state, malonyl-coenzyme A, a by-product of glucose oxidation, inhibits fatty acid oxidation and promotes lipogenesis by inhibiting carnitine palmitoyltransferase.23 It appears that in heart failure, stressors – in the form of oxidative stress or adrenergic signalling – continuously promote glucose use as a substrate for energy production, because of its effects beyond ATP production.24 In the long term, changes in enzyme levels or activity are involved in regulating substrate use. Indeed, enzymes involved in fatty acid oxidation are downregulated in heart failure; a return to the foetal pattern.25,26 More specifically, entry of glucose catabolism products into the Krebs cycle is facilitated through a reduction of pyruvate dehydrogenase kinase – which phosphorylates and inhibits pyruvate dehydrogenase, necessary for the conversion of pyruvate to acetylcoenzyme A – while transcript levels of carnitine palmitoyltransferase – necessary for acylcarnitine reconversion into acyl-coenzyme A and carnitine after entry into mitochondria – are downregulated.25,27 Furthermore, beta-oxidation is itself inhibited by reduced levels of some acyl-coenzyme A dehydrogenases, both in foetal and failing hearts. Citrate synthase messenger RNA levels are also found to be reduced in the foetal gene-expression pattern, leading not merely to a metabolism based on glucose, but more specifically a glycolytic one. Increased glucose availability – at least prior to development of insulin resistance – may underlie the myosin isoform switch, through O-glycosylation of transcriptional factors.28 Furthermore, the foetal pattern promotes cell survival by means of innate antiapoptotic pathway activation, such as that mediated by the protein kinase B/mammalian target of rapamycin.29 The exact triggers for this switch are not well understood, but it is thought that exposure to a hypoxic milieu – caused, in heart failure, by vascular disease, fibrosis and increased workload – is reminiscent of the in utero environment and is the underlying cause of this change, leading to faster adaptation to changing stimuli mediated by a multitude of mechanisms acting on both the transcriptional and epigenetic level.28,30 The main activator of fatty acid oxidation is peroxisome proliferatoractivated receptor-alpha (PPAR-alpha), which increases expression of genes involved in the entry, transport to mitochondria and betaoxidation of fatty acids and downregulates expression of genes of proteins participating in glucose metabolism. Reduced PPAR-alpha expression has been described in heart failure and has been linked to fibrosis and mitochondrial fragmentation.31 This phenomenon may represent an adaptational attempt given that, stoichiometrically, the amount of oxygen consumed per ATP produced is higher for fatty acids than for glucose.32 Potential causes of lipotoxicity are detailed in Table 4. In fact, increased glycolytic capacity has been related to increased survival in heart failure.33 Furthermore, localisation of glycolytic enzymes in the sarcoplasm and a preferentially glycolytic metabolism allows for ATP use in housekeeping processes – such as sodium–potassium ATPases and SERCAs – and provides substrates for the pentose phosphate pathway. The pentose phosphate pathway is critical for synthesis of antioxidants such as NADPH, allowing cellular survival – maintaining proper ionic concentrations and membrane potential – albeit at the cost of functionality.24,34 This is advantageous in the short term but

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Table 3: Features Necessary for Normal Effectiveness and Efficiency of Cardiac Metabolism Features necessary for normal effectiveness and efficiency of cardiac metabolism include: • sufficient oxygen and metabolic substrate flow to the mitochondria; • normal mitochondrial oxidative capacity; • normal concentrations of high-energy pyrophosphate bonds and, more specifically, normal phosphocreatinine:ATP ratio; • efficient transport of these bonds from mitochondria to energy consuming complexes; • efficient regulation of ATP:ADP ratio; and • efficient feedback systems for rapid adjustment of energy production to consumption. ADP = adenosine diphosphate; ATP = adenosine triphosphate.

Table 4: Proposed Mechanisms of Lipotoxicity Proposed mechanisms of lipotoxicity include: • Fatty acid-caused activation of calcium channels at the sarcoplasmic membrane leading to increased energy expenditure to sequester calcium ions; • Escape of fatty acids from the mitochondrial matrix through uncoupling protein-3, leading to energy consumption for their recovery; • Protonation at the outer layer of the membrane, flipping to the inner one and (because of the alkaline environment) deprotonation, reducing the electrochemical gradient that ensures ATP synthase function (protonophorelike action); and • Lipotoxicity caused by high fatty acid concentrations that lead to cellular apoptosis and contractile dysfunction.205–207 ATP = adenosine triphosphate.

detrimental in chronic conditions. Given the much higher amount of ATP produced per fatty acid molecule, many glucose molecules must be oxidated to match this yield. However, in advanced heart failure a reduced glucose oxidation capacity is found, primarily attributed to the insulin resistance of the failing heart because of an increased concentration of non-metabolised fatty acids and sympathetic system and renin-angiotensin-aldosterone axis activation.25,35–37 Downregulation of sarcoplasmic membrane glucose transporters has also been noted.38 This is especially true for septal segments in dyssynchronous heart failure where decreased workload – contraction against relaxed lateral segments – allows for reduced glucose consumption.39,40 Moreover, beta-oxidation leads to the production of Krebs cycle intermediates (anaplerotic reactions).33 Obviously this deprives the heart of its fuel, leading to energy starvation.9 As such, myocardial substrate metabolism tuning crucially affects left ventricular energetics in vivo, to the extent that preservation of fatty acid metabolism preference has been found to be linked with lack of clinical response to CRT.41,42 A twofold explanation may be given; either the failing myocardium has not switched to glucose metabolism as a compensatory mechanism and so continues to use an ineffective fuel, or full metabolic compensation at the microscopic level has been achieved so normal preference to fatty acids is maintained and no potential for further improvement exists.43 The latter interpretation is more likely given that CRT has been found to increase fatty acid metabolism, in itself facilitating oxidative metabolism. PCr kinase levels are decreased in heart failure.44,45 This leads to a lower ATP/ADP ratio which – aside from the obvious negative effects discussed previously – may serve an unexpected adaptive purpose. That is, ensuring – by the opening of ATP-gated potassium channels of

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Heart Failure and Arrhythmias the mitochondrial membrane, which hyperpolarise the organelle – that cytochrome c will not be released and apoptotic processes will not be triggered.46 Furthermore, the mitochondrial isoform of PCr kinase partakes in a feedback mechanism ensuring that energy production is matched to consumption; ADP from the sarcoplasm is pumped into the mitochondria by the adenosine nucleotide transporter, converted to ATP by the mitochondrial PCr kinase and shuttled back through the same path. Loss of PCr means that the mitochondria can no longer respond accordingly to increased sarcoplasmic ADP.47 A complementary ATP-replenishing system involves adenylate kinase, which converts two ADP molecules into ATP and adenosine monophosphate (AMP). In addition, increased AMP levels lead to AMP-dependent protein kinase (AMPK) activation, which constitutes a central element of adaptational mechanisms in low-fuel conditions.48 Specifically, AMPK, when acutely activated, shuts down ATPconsuming processes such as fatty acid and glucose synthesis, activates ATP-producing pathways such as fatty acid oxidation and glucose intake through glucose transporter type 4, and increases insulin sensitivity, ensuring cellular survival.17,48–50 However, chronic activation is detrimental because fatty acid metabolism is reduced through mitochondrial transport inhibition and apoptosis is activated.51 Heart failure is a state of severe energy wasting, i.e. energy consumption not leading to useful work but lost as heat.52 Increased uncoupling protein concentration has been observed, leading to proton leak back into the matrix.9,33 Altered calcium homeostasis may lead to the myosin head performing the power stroke while unbound to actin (troponin C dysfunction), so not leading to sarcomere shortening.53,54 Finally, abnormalities in proteins connecting sarcomeres to the extracellular matrix lead to decoupling and prevent sarcomere shortening translating into cardiomyocyte contraction.55 Mitochondrial dysfunction in heart failure merits further consideration. Increased reactive oxygen species (ROS) concentrations in heart failure lead to electron transport chain dysfunction and damage mitochondrial proteins and genome.34,46 However, a burst of ROS may actually prove beneficial inasmuch as it triggers activation of the master regulator of mitochondrial biogenesis and oxidative capacity; peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1). This protein allows for increased expression of nucleus-encoded mitochondrial transcription factor 1, increasing mitochondrial biogenesis, oxidative capacity and fatty acid use.8,56 Furthermore, PGC-1 increases synthesis of antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) in response to redox signalling.57 Chronically elevated catecholamine and angiotensin levels and increased TNF-alpha and endothelin-1 lead to protein kinase B activation, which, in turn, downregulates PGC-1, causing mitochondrial fragmentation (inability to replicate) and decreased concentrations of electron transport chain complexes and ATP synthase.5,7,9,10,33 Although CRT does increase protein kinase B phosphorylation/activity, this should be viewed in light of global prosurvival effects of this kinase, rather than its adverse actions on cellular bioenergetics, which are mitigated through different pathways by resynchronisation.58,59 Finally, and especially pertaining to dyssynchronous heart failure, with abnormal stretching of non-activated cells, an intimate crosstalk exists between cardiomyocyte stretch and apoptosis. This appears to be mediated by mitochondria, as evidenced by proapoptotic

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molecule (p53 and Bax) increases, leading to mitochondrial membrane depolarisation and release of cytochrome c and other complexes triggering apoptosis upon cellular stretching.60 In short, teleologically, heart failure initially redirects cardiomyocyte metabolism towards glucose use, which ensures cellular survival at the cost of function. However, insulin resistance in advanced stages of heart failure prevents use of glucose as efficiently.61 Studies have suggested that the failing heart may attempt to switch to ketone bodies oxidation in an effort to sustain its metabolism and increase its efficiency (conversion into usable substrate not requiring much energy).27,62,63 Ketone bodies oxidation is a rapidly usable and relatively dense – requiring two steps to enter the Krebs cycle as acetylcoenzyme A and each yielding two acetyl-coenzyme A molecules – source of energy, supplemented by the liver. Branched chain amino acid catabolic pathways have been found to be downregulated in a murine heart failure model – with reduced expression of key enzymes such as the branched-chain alpha-keto acid dehydrogenase complex – presumably because of oversupply of ketone bodies by the liver (two out of three proteinogenic branched chain amino acids are ketogenic).64 However, this leads to an accumulation of branched-chain keto acids, which induces inhibition of mitochondrial respiration.65 Moreover, factors promoting fatty acid oxidation (PPAR-alpha and PGC-1) are also regulators of cellular oxidative capacity in general.34 As such, their downregulation leads not only to preferential glucose use but also to reduced oxidative potential of the cell. Several of the previously mentioned disturbances are (partially) reversed by effective resynchronisation, as discussed in the following sections.

Chamber Mechanics and Energy Consumption in Dyssynchronous Heart Failure It should be noted that most studies attempting to clarify effects of resynchronisation on chamber mechanics, substrate metabolism and energy efficiency have been conducted in dilated cardiomyopathy models with concomitant left bundle branch block because of the perceived homogeneous myocardial involvement that leads to more predictable behaviour, i.e. excitation sequence, after CRT initiation. Conversely, ischaemic cardiomyopathy of such severity (ejection fraction ≤35%) usually involves the presence of extensive dense scar regions, which critically modify electrophysiological properties (the stimulus may need to bypass a fixed line of block and, in the process, depolarise different myocardial segments). This is reflected by ischaemic aetiology being considered a negative prognosticator for response to CRT.66–74 The patients expected to gain the greatest benefits from chamber resynchronisation are those with the most pronounced basal dyssynchrony, exhibiting the widest QRS complexes.75–77 Modern views on dyssynchronous heart failure include the notion of adverse mechanoenergetics, leading to reduced energy efficiency, evidenced by a reduced ratio between energy consumed (in the form of oxygen) and external work performed (stroke work).78–80 Several explanations can be offered (Table 5). Compared with inotropes, CRT has been found to acutely improve dP systolic function (increased dt ) while reducing oxygen consumption max assessed by arterial/coronary sinus oxygen difference and minute oxygen consumption).81 Chamber segments resynchronisation offers a plausible interpretation – by negating increased interior work – for

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Cardiac Resynchronisation Therapy and Cellular Bioenergetics improved energetics upon CRT introduction. An additional beneficial effect of CRT could lie in the reversal of the shortening of diastolic period and diastolic dysfunction, both present in dyssynchronous heart failure in general and particularly so in the left bundle branch block variety.82–84 More specifically, divergence in the timing of systole between myocardial segments in left bundle branch block dilated cardiomyopathy has been shown to worsen microvascular function of the left anterior descending artery territory (perfusion occurring during diastole) and consequently flow reserve, raising the potential for therapeutic interventions.85 In the mechanoenergetics context, although not improving efficiency, CRT could improve overall available energy by increasing oxygen and substrate delivery to myocardium. The most robust method of assessing substrate metabolism relies on the use of glucose and fatty acid radioactive isotopes and their in vivo turnover rates.43,86–89 Substrate metabolism, but not perfusion, is also altered in dyssynchronous heart failure. The septal wall uses less glucose than lateral segments, potentially owing to the preferential conversion of mechanical work to stretching of inactive myocardium, as opposed to blood expulsion through the aortic valve, mediated molecularly by reduced glucose transporter expression.38,90,91 Conversely, upon contraction, the lateral wall consumes higher amounts of glucose-derived energy because of its pre-stretched condition (exceeding Frank-Starling law limits). Furthermore, this is in accordance with preferential glucose use in advanced heart failure, as the lateral wall could be considered to be at a more locally advanced heart failure stage. Consequently, glucose uptake by 13-fluorodeoxyglucose – measured by PET – may represent increases in glycolysis rather than oxidative phosphorylation and prioritisation of survival over function. As such, this pendulum-like internal energy transfer accounts for significant macroscopic causes of reduced mechanical efficiency. When oxidative metabolism is specifically assessed by means of acetate clearance – a precursor to acetyl-coenzyme A that enters the Krebs cycle – an increase in septal and a decrease in lateral oxidative metabolism upon CRT was noted, leading to global homogenisation without increases in metabolic demand, despite increases in mechanical work output.92 This appears to contradict previous interpretations of CRT effects on substrate metabolism, yet it can be hypothesised that the increased septal work reactivated oxidative phosphorylation to increase energy output, whereas the lateral wall operates at less-thanmaximal oxidative capacity and can reduce oxidative metabolism, also reducing ROS burden in the process. Predictably, CRT has been found to rectify and homogenise glucose use throughout the myocardium without affecting perfusion to the same degree; septal:lateral glucose use ratio increased from 0.62 to 0.91 after CRT, p<0.001.39,93,94 Regarding the septum in particular, a slower – anticipated by the fact the lateral segments are also simultaneously actively contracting – yet more effective contraction has been reported.95 The importance of myocyte length has been further demonstrated by the dependence of generated pressure and oxygen consumption (both increasing, the former more than the latter, leading to improved efficiency) on atrioventricular delay during CRT, with extremely short delays completely negating haemodynamic effects of resynchronisation.96 Moreover, CRT appeared to confer a benefit with regard to the metabolic reserve and mechanical efficiency (response to beta-stimulation) of the failing heart, even after long-term application.72 The same increases in output were noted

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Table 5: Possible Mechanisms Underlying Reduced Energy Efficiency in the Failing Cardiomyocyte • H igh-energy bonds procured from metabolism yield diminished energy upon hydrolysis (supported by the reduced ratio of PCr:ATP in dyssynchronous cardiomyocytes, as assessed by 31P magnetic resonance spectroscopy, leading to a reduction in free energy yield).208,209 • Energy is wasted or reallocated in the cardiomyocyte; consumed oxygen forms ROS instead of forming water, glycolysis increases and energy is redirected towards cellular survival. • Energy is increasingly allocated to internal work, that is, stretching of the initially relaxed late-activated segments of myocardium by the actively and timely contracting ones and vice versa. Furthermore, the latter begin contraction against higher wall stresses inasmuch as the early-activated myocardium is at peak systolic stiffening.40,210,211 Finally, mechanical dyssynchrony adversely affects flow energetics and leads to a decreased amount of blood inflow kinetic energy being directly converted to outflow energy (the shape of the chamber performing the role of merely redirecting flow).98 On the contrary, a turbulent pattern with work-consuming vortices formation emerges in dyssynchronous hearts, requiring energy expenditure to accelerate blood towards the aorta. ATP = adenosine triphosphate; ROS = reactive oxygen species; PCr = phosphocreatine.

upon dobutamine administration compared with dyssynchronous hearts, yet were accompanied by increased efficiency and acetate extraction (operation at less-than-maximal oxidative capacity at rest).93 This long-term trend – present even 13 months after CRT initiation – alludes to intrinsic metabolism alterations after prolonged CRT application, consistent with the notion of detrimental effects of dyssynchrony itself on energy efficiency.72,97 Additionally, a trend for beneficial effects of CRT on fluid dynamics, leading to increased direct conversion of inflow to outflow kinetic energy, has been reported. This complements previous reports on the effects of dyssynchrony on rheodynamics and potentially offers a novel marker for predicting response to CRT.98–101 Although similar metabolism alterations have been reported in ischaemic cardiomyopathy and analogous CRT effects are indeed observed in the majority of dyssynchronous cases, a sizeable minority (32%) do not exhibit septal reverse mismatch (lower glucose use relative to perfusion).102 This is attributable to perfusion deficits of the lateral wall – present in 91% of the subgroup discussed – precluding higher glucose use there and, in effect, leaving the septum responsible for cardiac output. An important inherent limitation of this approach for metabolism assessment lies in the assumption of intracellular homogeneity that ignores the high degree of compartmentalisation and sequestration in the sarcoplasm.9,103 That is, intracellular presence of a metabolite does not account for the site and mode of its breakdown, its vicinity to the energy-consuming areas of the cell and ultimately its energy yield, alterations of which may crucially affect efficiency. A novel pacing modality, multisite pacing – constituting an advanced form of CRT – has started to yield interesting results regarding the previously mentioned parameters. It entails administration of two, rather than one, left ventricular pacing pulses, followed by a stimulus to the right ventricle. As such, it allows for sculpting of the activation sequence of the myocardium, potentially bypassing limitations posed by dense scar presence and allowing for further optimisation.104 Interesting results have been obtained regarding haemodynamics and stroke work improvement, and clinical studies attempting to correlate

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Heart Failure and Arrhythmias multisite pacing optimisation with energy efficiency improvement at the cardiovascular system level, through use of ventriculoarterial coupling, are underway.105,106 Dyssynchronous heart failure, specifically in the form of left bundle branch block presence, leads to mechanical dispersion and altered stretching of the different myocardial segments, affecting calcium ion homeostasis – potentially via mechanosensitive ion channels – leading to proarrhythmia, theoretically reversible by CRT.107,108 However, CRT can, itself, under certain conditions, exhibit proarrhythmic effects as a result of:109 • increased transmural dispersion of repolarisation (pulse delivered at left ventricular epicardium); • wave break at the collision area of the two pulses (left and right ventricular) and potential re-entry; and • in-scar pacing, amenable to time-dependent alteration, potentially underlying electrical storm events.110,111 As as result of the first pulse being delivered with increased width, multisite pacing may not be involved in re-entry occurring because of localised in-scar pacing.104 This implies that CRT, besides its acute haemodynamic effects – stroke volume increases were noted in the previously mentioned studies – has profound effects on myocardial energy management.72,93 This raises the intriguing possibility that, depending on currently undetermined individual parameters, response to CRT may not manifest as an overt improvement in ejection fraction, chamber volumes and pressures, but in covert alterations in metabolism, increasing efficiency and reserve, rendering the heart more able to respond to abrupt increases in output demand.112 Such effects have been reported even when classical adverse prognosticators – QRS widening upon biventricular pacing – are observed, suggesting a degree of independence between effects on mechanics and bioenergetics, owing to differing underlying molecular pathways.113 The inhomogeneous myocardial involvement in ischaemic cardiomyopathy, leading to divergent and unpredictable effects of dyssynchrony on metabolism, may also affect these covert responders, at least at the macroscopic (chamber) level.102

CRT Effects on Bioenergetics at the Ultramicroscopic Level Mitochondria are one of the key sites of CRT effects at the ultramicroscopic level. Proteomic analysis in a canine model has revealed levels of 31 mitochondrial proteins to be altered after CRT application, with almost half constituting subunits of the respiratory chain.114 A concerted effect is observed whereby CRT increases activity of key enzymes in anaplerotic pathways, providing more intermediates of the Krebs cycle, which can otherwise be consumed to biosynthetic processes such as amino acid synthesis, increasing its activity, facilitating acetyl-coenzyme A entry into the cycle and consequently NADH/flavin adenine dinucleotide (FADH2) formation and funnelling of electrons into their transport chain to complete aerobic oxidation.115 Moreover, all complexes of the respiratory (electron transport) chain, with the exception of cytochrome c oxidase (complex IV), have critical subunits upregulated. This includes complex II (succinate dehydrogenase), which links the Krebs cycle with electron transport chain; it catalyses succinate to fumarate conversion along with FADH2 formation, immediately introduces FADH2-derived electrons into the

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chain and allows for the flow of NADH-derived electrons that enter the chain further upstream – complex I – as a result of higher energy levels towards complex III/cytochrome bc1 complex.116 Finally, ATP synthase (complex V) subunit degradation is inhibited and, following phosphorylation, complex formation and ATP yield per proton flowing is improved (2.5 ADP molecules phosphorylated per oxygen atom consumed with CRT versus 1.4 in dyssynchronous heart failure – due to electron entry now more often occurring at complex I). Complex V activity increases 20% during CRT compared with dyssynchronous heart failure. As such, ultimately, electrons exiting the chain and protons flowing down their electrochemical gradient through complex V are paired with molecular oxygen, forming water. Several complementary effects have been noted, such as upregulation of fatty acid binding protein that allows their entry into mitochondrial matrix and subsequent beta-oxidation and downregulation of uncoupling proteins.117 The latter may be a defence mechanism, reducing energy production and – through substrate alteration – reducing contraction of the myocyte to prevent the occurrence of extreme stretches, especially during contraction against already shortened segments (lateral wall). Cytochrome c has, unexpectedly, been reported to be downregulated following biventricular pacing, owing to either methodological issues (post-translational modifications that alter its pI and so its localisation following protein electrophoresis) or in the context of preventing apoptotic cell death, promoted by several pathways in dyssynchronous heart failure, as previously discussed.114 Although electron and proton coupling with molecular oxygen is tightly controlled by complex IV, there is always the possibility of ROS formation through release of intermediates from complex IV or electron interaction with molecules other than oxygen. These can induce post-translational modifications to a multitude of mitochondrial energy production-related proteins and membrane lipids, severely impairing their functionality and even leading to cell death.118–122 Most importantly, endothelial nitric oxide synthase, under oxidative stress, becomes uncoupled from tetrahydrobiopterin (itself oxidated) and yields significant amounts of ROS.121 To negate this potentially detrimental side-effect of increased function and efficiency of oxidative metabolism, an increase in ROS-scavenging protein levels is necessary and sufficient. Indeed, CRT has been found to be linked to a significant rise in thioredoxin-dependent peroxide reductase, critical for the formation of reduced disulphide bonds that either constitute the reversal of oxidative events or may be coupled – as in the case of glutathione – to the reduction of a variety of oxidised molecules.114,123 Interestingly, post-translational modification of regulatory ATP synthase subunits (alpha subunits) has been reported (S-glutathionylation and S-nitrosation), along with novel disulphide bond formation. S-glutathionylation reversal by CRT was linked to a twofold increase in enzyme activity, providing a further mechanism for its effects on complex V.124 Despite this, downregulation of ATP synthase activity may be part of a feedback loop, where increases in oxidative stress, such as those caused by heart failure, prevent aerobic oxidation and ultimately limit ROS production.125–130 The ensuing increase in oxidative stress is alleviated by the aforementioned increases in ROS-scavenging proteins. These changes in protein levels are coupled with increased expression of proteins that translocate into mitochondria – synthesis of most energy production-related proteins has been relinquished to the

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Cardiac Resynchronisation Therapy and Cellular Bioenergetics nucleus – chief among which is prohibitin 2. Prohibitins are assembled into a ring-like structure in the inner mitochondrial membrane and their presumed roles involve being chaperones for respiration chain proteins (ensuring proper protein folding) or acting as general structuring scaffolds required for optimal mitochondrial morphology and function.131,132 Mitochondrial protein proteases have conversely been found to be downregulated post-CRT.133 Of note, according to transcriptomic analyses, gene level-related effects of dyssynchrony were sixfold more pronounced at the anterior than the lateral wall.134 Appropriately, CRT leads to pronounced local but not global changes in gene expression.26 Chronically increased stresses such as those observed upon dyssynchrony lead to profound alterations in key elements of the contractile apparatus, namely the transverse tubules (T-tubules), causing their disruption. This is mediated by downregulation of structural proteins such as junctophilin, and consequently impairs calcium handling (T-tubules bring into proximity the sarcolemmal and SR membranes).135,136 This indirectly affects energy use as much larger (potentially proarrhythmic) calcium spikes are necessary to cause calcium release from the SR and accomplish the excitation-contraction coupling; a disturbance that CRT can rectify. A potential master regulator of protein activity affected by CRT has been recognised in the form of CK2 (formerly casein kinase II), a serine-threonine protein kinase, using both ATP and guanosine-5’triphosphate as substrates and indispensable to cell survival and growth by preventing caspase access to cleavage sites of proteins, promoting DNA repair and suppressing p53 activity.137–139 In a canine model of tachypacing- and left bundle branch-related dyssynchronous heart failure, phosphoproteomics analysis identified CK2 as the most likely kinase whose downregulation is involved in protein phosphorylation alterations observed in dyssynchronous heart failure, a pattern reversed by the introduction of CRT. Although an intriguing finding, it cannot be inferred whether CRT effects are mediated by upregulation of CK2 or whether improved energetics and triphosphate nucleotide availability (used by CK2 as a phosphate donor during phosphorylation) account for increased kinase activity, promoting cell survival and function in a virtuous cycle. Finally, similar effects leading to increases in oxidative potential have been noted in peripheral muscles as well, potentially resulting in further improvement of patients’ functional status and exercise tolerance.140 Increased adrenergic signalling is usually thought of as deleterious in heart failure; evidenced by the benefits of its blockade with betablockers. Accordingly, there is intrinsically reduced responsiveness of the myocardium to adrenergic stimuli as a defence mechanism involving increased activation of inhibitory G-alpha subunits (deactivating rather than activating protein kinase A; PKA) and internalisation/degradation of receptors through phosphorylation by G-protein receptor kinase 2.141–144 However, the response of the myocardium to a transient increase in adrenergic signalling may be crucial in maintaining exercise capacity. CRT has been found to restore this parameter by upregulating regulator proteins of G-protein signalling (RGS) that inhibit inhibitory alpha-subunits of G-proteins (Gais).145 As such, SR-bound PKA may activate calcium-handling proteins, increasing calcium ion transient flux during depolarisation and its subsequent sequestration, ultimately enhancing the associated myocyte shortening, reversing the severely blunted calcium spikes of dyssynchronous heart failure.146–148 This post-translational effect on calcium-handling proteins is supported by the observation that their

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Figure 1A: Depiction of Cardiomyocyte Metabolism Under Physiological Conditions

Glucose

Lipoprotien

Sarcolemma

GLUT Free fatty acids Glucose Glycolysis Free fatty acids

Acyl-CoA

Mitochondrial matrix

Pyruvate

Beta acidosis Acyl-CoA Acetyl-CoA Krebs cycle NADH FADH2 CO2 Respiratory chain ATP ADP

ADP = adenosine diphosphate; ATP = adenosine triphosphate; CO2 = carbon dioxide; FADH2 = flavin adenine dinucleotide; GLUT = glucose transporter proteins; NADH = nicotinamide adenine dinucleotide.

Figure 1B: Alterations Induced Under Cardiac Resynchronisation Therapy

It should be stressed that dyssynchronous heart failure induces the opposite changes and, consequently, CRT effects represent a return towards normality. The possibility of the feedback response actually overshooting the initial derangement underlies the notion of inducing dyssynchrony in heart failure patients without any evidence of exhibiting the phenomenon, e.g. through right ventricular pacing, priming cardiomyocytes’ sensitivity to its correction and then applying CRT to evoke these effects. ATP = adenosine triphosphate; CRT = cardiac resynchronisation therapy.

encoding genes are not upregulated by CRT.149 Consequently, exercise tolerance may be further improved.

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Heart Failure and Arrhythmias The most intriguing observation stemming from a canine model study by Chakir et al. lies in the triggering of increased response to beta-adrenergic signalling following dyssynchrony introduction into synchronous heart failure.145 This allowed for radical hypotheses claiming that a CRT holiday (analogous to diuretic holiday) may enhance CRT effects – particularly in non-responders – and that purposeful transient dyssynchrony introduction in heart failure patients without an indication for CRT or a pacemaker may trigger the same beneficial results. Animal studies in the tachypacing-induced cardiomyopathy setting have since confirmed this assumption, reporting improved cardiac response to beta-adrenergic stimuli and suppression of heart failure in terms of chamber dilatation and cellular dysfunction, even in the context of synchronous heart failure.150 An obvious noted issue stems from potential intersubject differences in the required holiday period. A further path linking substrate preference to contractile function has been reported to be affected by CRT, namely phosphorylation of Z-disk and M-band proteins by the upregulated glycogen synthase kinase.151 Activation of this kinase leads to inactivation of glycogen synthase, potentially in the context of restoring the omnivorous nature of the cardiomyocyte. Target sarcomeric proteins (troponins I and T, myosin-binding protein C and myosin light chain isoforms) are involved in calcium sensing and consequently their activation sensitises the contractile apparatus to calcium ions’ presence and facilitates contraction. Moreover, CRT has been shown to increase messenger RNA levels of the alpha-myosin isoform and its relative ratio to those of betamyosin in advanced dyssynchronous heart failure patients, possibly because of improvements in energy metabolism that allow for a more ATP-consuming yet more efficient isoform to be chosen, restoring functionality.152 Interestingly, another subset of glycogen synthase kinase target sarcomeric proteins are involved in mechanosensing and may actually partake in the core mechanisms through which CRT exerts its effects. Figure 1 summarises the most important effects of CRT application to metabolism in dyssynchronous heart failure at the ultramicroscopic level.

Linking Mechanics to Metabolomics A fundamental issue regarding all the described effects of CRT on cellular bioenergetics is raised concerning mechanisms and signal transduction pathways underlying the translation of mechanical alterations to metabolic effects. A strong candidate is the cytoskeleton, linking sarcomeres – the contractile units of cardiomyocytes – with the extracellular matrix and ensuring that cellular contraction causes tissue shortening. As a result of changes in myocardial lamellae orientation and chamber architecture, mechanical deformation of the failing heart is significantly altered.153,154 The aforementioned changes in calcium concentration, owing to alterations in proteins such as SERCA, decrease peak contractile force at the same time as modified extracellular matrix synthesis (different collagen isoforms) and sarcomere architecture (reduced levels of titin, a spring-like protein conferring elasticity) render myocardial tissue stiff.155,156 Concomitantly, changes in gap junction proteins – connexin-43 is redistributed laterally rather than longitudinally – reduce both conduction velocity and synchronisation between adjacent cardiomyocytes.157,158 Protein kinase B, which is upregulated by CRT, has been found to phosphorylate connexin-43 and facilitate incorporation into gap junctions, allowing for initiation and coordination of the

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ischaemic injury response.21,159 Consequently, mitogen-activated protein kinase further phosphorylates connexin-43 leading to gap junction closure and severing communication between adjacent cells’ sarcoplasms, potentially preventing apoptosis spreading.159 As such, stiff cardiomyocytes exhibiting reduced functionality attempt to contract over a stiffer matrix, not amenable to deformation, leading to abnormally high tension to the cytoskeletal structures connecting them (focal adhesions and integrins).160 This condition is further aggravated by local (between adjacent cells) and regional (in dyssynchronous heart failure) lack of coordination.156,161 Focal adhesions are so intricately linked with sarcomeres – to ensure anchoring to sarcolemma/extracellular matrix and bidirectional mechanotransduction – that a specialised structure emerges called a costamere.162–164 Costameres are sub-sarcolemmal multiprotein complexes initially found to localise over Z-disks, perpendicularly to the cardiomyocyte axis, but subsequently shown to extend over M-lines and along the myocyte length.163,165,166 They can be thought of as a specialised striated and cardiac muscle version of focal adhesions. Two main constituent protein complexes have been identified; the dystrophin/glycoprotein complex that provides a link between laminin – an extracellular matrix protein – and filamentous actin-based cytoskeleton, and the integrin/talin/vinculin complex, which is potentially more involved in signal transduction given its association with integrin-linked and focal adhesion kinases.167–170 The importance of these protein complexes in the biomechanical stability of the heart, especially under mechanical stress, can be inferred by the fact that mice with cardiac-specific vinculin deletion display a dilated cardiomyopathy phenotype.171 Moreover, another integrin-associated protein, melusin – a chaperone, assisting in proper protein folding and assembly – performs a highly specialised role in cardiomyocyte response to stress stimuli by promoting cellular survival and hypertrophy through both mitogen-activated protein kinase family pathways and protein kinase B (also affecting energy metabolism and, as mentioned previously, upregulated by CRT).58,59,172–174 Indeed, in aortic stenosis patients, melusin levels have been found to correlate with systolic function preservation.175 As such, it could be theorised that persistent supraphysiological stress (stretch) levels, such as those in dyssynchronous heart failure, render melusin levels insufficient to induce and maintain proper cellular responses, leading to apoptosis and myocardial wall thinning. Similar findings have been reported in the case of integrins.176 Changes in integrin isoform gene expression profile have been noted during reverse remodelling of chambers upon left ventricular assist device therapy.176 CRT has been shown to lead to alterations in levels or activity of several sarcomeric and focal adhesions-related proteins involved in mechanosensing, such as cap-Z (reduced expression), muscle LIM protein (acetylation-activation), tensin, desmin and filamin-C.151,177–180 Spatial distribution of alpha-actinin – a microfilament protein necessary for the attachment of actin filaments to the Z-lines in skeletal muscle cells, coordinating sarcomeric contraction and providing links to focal adhesions and stress actin fibres – has been found to be disrupted in dyssynchronous heart failure, losing its periodicity and forming depositions, with CRT partially rectifying its pattern.181–183 Mitochondria, being linked to the cytoskeleton – both actin and microtubules – for reasons of localisation and transport, also sense the increased tension of dyssynchronous heart failure.55,184,185 This leads to increased expression of proapoptotic Bcl-2 family proteins, including

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Cardiac Resynchronisation Therapy and Cellular Bioenergetics Bax and Bad, which mediate cytochrome c release and apoptosis triggering, and to reduced complex IV activity (reduced by 21%) leading to reduced ATP formation and ROS accumulation because electrons are unable to combine with molecular oxygen and protons.60,186,187 In fact, the type of stretch caused by dyssynchrony (monotonous stretch) further accentuates these changes and directly reduces ATP synthase activity and mitochondrial biogenesis by reducing PGC-1alpha.188 In this framework, shutting down oxidative metabolism – with all its detrimental consequences – may again constitute a defensive mechanism of the cell to prevent apoptosis, in part caused by increased mechanical stretch. As such, not only is metabolism affected by anomalous stretch, but also its ability to adapt in response to such stressors is impaired.189 As such, an overarching hypothesis could be that alleviation by resynchronisation of the increased strain imposed on cardiomyocytes by dyssynchrony, which led to compensatory alterations/remodelling of sarcomeres and triggered changes in bioenergetics, now leads to altered input from specialised mechanosensors that is transduced to the cell, triggering the beneficial effects.53,190 A depiction of our current partial understanding of this link is attempted in Figure 2.

Conclusion CRT can be thought of as constituting a metabolic therapy, acting on two levels. Firstly, at the chamber level, it rehomogenises substrate use and improving mechanical output and energy efficiency by reducing energy spent on internal work. Secondly, at the cellular level, it increases oxidative cell capacity by acting at virtually all stages of oxidative metabolism. The latter effect may not be inseparable from the former, creating the potential for the existence of covert responders. Whether this is true for cases that do not have an indication for CRT or can be achieved through more advanced resynchronisation modalities, such as multisite pacing, or even by allowing (in dyssynchronous heart failure) or introducing (in synchronous heart failure) intermittent

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Figure 2: Linking Mechanical Stretch/Stress and Cellular Metabolism

Sarcolemma Focal adhesions (alpha-actinin, vinculin) Microtubules (intracellular transport)

Costameres

Sarcomeres

Actin (stress sensing fibre)

Z-disk (capZ, alpha-actinin) Mitochondrion

Actin stress fibres (not to scale) transmit mechanical stimuli to mitochondria and lead, in cases of increased stretch, to PGC-1 decreases, reduced complex IV activity, increased ROSs production and increased release of proapoptotic molecules. Moreover, microtubules (not to scale) are also affected by increases stretch and this may interfere with mitochondrial biogenesis, if only in mechanical terms (separation of mitochondria).212 Crosstalk between focal adhesions and sarcomeres, through the protein mesh of costameres, leads to decreased efficacy of contraction, in part mediated by alpha-actinin, capZ and vinculin. PGC-1 = peroxisome proliferator-activated receptor-gamma coactivator-1; ROS = reactive oxygen species.

dyssynchrony, requires further study. It is possible that advanced computational models will be needed to determine the optimal site of leads and timing parameters to achieve conventional CRT/multisite pacing optimisation. Certain models can already integrate projected changes in bioenergetics, in the form of ATP use homogenisation assessed concomitantly with stroke work maximisation, to propose adequate lead implantation sites.156,191 Although challenging, especially to the clinician, comprehending these principles will probably prove necessary to promote our insight into the effects of resynchronisation beyond chamber mechanics, improving care for our patients.

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Cell Mol Physiol 2004;287:L486–96. https://doi.org/10.1152/ ajplung.00389.2003; PMID: 15090367. 188. Bartolák-Suki E, Imsirovic J, Parameswaran H, et al. Fluctuation-driven mechanotransduction regulates mitochondrial-network structure and function. Nat Mater 2015;14:1049–57. https://doi.org/10.1038/nmat4358; PMID: 26213900. 189. Lyra-Leite DM, Andres AM, Petersen AP, et al. Mitochondrial function in engineered cardiac tissues is regulated by extracellular matrix elasticity and tissue alignment. Am J Physiol Heart Circ Physiol 2017;313:H757–67. https://doi.org/10.1152/ ajpheart.00290.2017; PMID: 28733449. 190. Kirk JA, Kass DA. Cellular and molecular aspects of dyssynchrony and resynchronization. Card Electrophysiol Clin 2015;7:585–97. https://doi.org/10.1016/j.ccep.2015.08.011; PMID: 26596804. 191. Hu Y, Gurev V, Constantino J, et al. Optimizing cardiac resynchronization therapy to minimize ATP consumption heterogeneity throughout the left ventricle: a simulation analysis using a canine heart failure model. Heart Rhythm 2014;11:1063–9. https://doi.org/10.1016/j.hrthm.2014.03.021; PMID: 24657430. 192. Eichhorn EJ, Heesch CM, Barnett JH, et al. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, doubleblind, placebo-controlled study. J Am Coll Cardiol 1994;24:1310– 20. https://doi.org/10.1016/0735-1097(94)90114-7; PMID: 7930255. 193. Eichhorn EJ, Bedotto JB, Malloy CR, et al. Effect of betaadrenergic blockade on myocardial function and energetics in congestive heart failure. Improvements in hemodynamic, contractile, and diastolic performance with bucindolol. Circulation 1990;82:473–83. PMID: 1973638. 194. Saxon LA, Ellenbogen KA. Resynchronization therapy for the treatment of heart failure. Circulation 2003;108:1044–8. https:// doi.org/10.1161/01.cir.0000085656.57918.b1; PMID: 12952826. 195. Penicka M, Bartunek J, De Bruyne B, et al. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation 2004;109:978–83. https://doi.org/10.1161/01. cir.0000116765.43251.d7; PMID: 14769701. 196. Bax JJ, Bleeker GB, Marwick TH, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834–40. https://doi.org/10.1016/j.jacc.2004.08.016; PMID: 15519016. 197. Yu CM, Fung WH, Lin H, et al. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol 2003;91:684–8. https://doi. org/10.1016/S0002-9149(02)03404-5; PMID: 12633798. 198. Molhoek SG, van Erven L, Bootsma M, et al. QRS duration and shortening to predict clinical response to cardiac resynchronization therapy in patients with end-stage heart failure. Pacing Clin Electrophysiol 2004;27:308–13. https://doi. org/10.1111/j.1540-8159.2004.00433.x; PMID: 15009855. 199. Lecoq G, Leclercq C, Leray E, et al. Clinical and

electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure. Eur Heart J 2005;26:1094–100. https://doi.org/10.1093/ eurheartj/ehi146; PMID: 15728648. 200. Davis DR, Krahn AD, Tang AS, et al. Long-term outcome of cardiac resynchronization therapy in patients with severe congestive heart failure. Can J Cardiol 2005;21:413–7. PMID: 15861258. 201. Buck S, Maass AH, van Veldhuisen DJ, et al. Cardiac resynchronisation therapy and the role of optimal device utilisation. Neth Heart J 2009;17:354–7. PMID: 19949479. 202. van Hemel NM, Scheffer M. Cardiac resynchronisation therapy in daily practice and loss of confidence in predictive techniques to response. Neth Heart J 2009;17:4–5. PMID: 19148330. 203. Bleeker GB, Holman ER, Steendijk P, et al. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol 2006;48:2243–50. https://doi. org/10.1016/j.jacc.2006.07.067; PMID: 17161254. 204. Warnholtz A, Nickenig G, Schulz E, et al. Increased NADHoxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the reninangiotensin system. Circulation 1999;99:2027–33. https://doi. org/10.1161/01.CIR.99.15.2027; PMID: 26078378. 205. Paolisso G, Gambardella A, Galzerano D, et al. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 1994;43:174–9. https://doi.org/10.1016/00260495(94)90241-0; PMID: 8121298. 206. Lommi J, Kupari M, Yki-Järvinen H. Free fatty acid kinetics and oxidation in congestive heart failure. Am J Cardiol 1998;81:45– 50. https://doi.org/10.1016/S0002-9149(97)00804-7; PMID: 9462605. 207. Zhou YT, Grayburn P, Karim A, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 2000;97:1784–9. https://doi.org/10.1073/pnas.97.4.1784; PMID: 10677535. 208. Hudsmith LE, Neubauer S. Magnetic resonance spectroscopy in myocardial disease. JACC Cardiovasc Imaging 2009;2:87–96. https://doi.org/10.1016/j.jcmg.2008.08.005; PMID: 19356540. 209. Abdurrachim D, Prompers JJ. Evaluation of cardiac energetics by non-invasive 31P magnetic resonance spectroscopy. Biochim Biophys Acta Mol Basis Dis 2018;1864: 1939–48. https://doi.org/10.1016/j.bbadis.2017.11.013; PMID: 29175056. 210. Park RC, Little WC, O’Rourke RA. Effect of alteration of left ventricular activation sequence on the left ventricular endsystolic pressure-volume relation in closed-chest dogs. Circ Res 1985;57:706–17. PMID: 4053304. 211. Wyman BT, Hunter WC, Prinzen FW, et al. Mapping propagation of mechanical activation in the paced heart with MRI tagging. Am J Physiol 1999;276:H881–91. https://doi. org/10.1152/ajpheart.1999.276.3.H881; PMID: 10070071. 212. Karbowski M, Spodnik JH, Teranishi M, et al. Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. J Cell Sci 2001;114:281–91. PMID: 11148130.

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Heart Failure and Arrhythmias

Insights for Stratification of Risk in Brugada Syndrome Daniel García Iglesias, 1,2 José Rubín, 1,2 Diego Pérez, 1,2 César Morís 1,2 and David Calvo 1,2 1. Arrhythmia Unit, Cardiology Department, Hospital Universitario Central de Asturias, Oviedo, Spain; 2. Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain

Abstract Brugada syndrome (BrS) is an inherited disease with an increased risk of sudden cardiac death (SCD). However, testing identifies genetic disorders in only 20–30% of patients analysed, indicating a gap in knowledge of its genetic aetiology. Diagnosis relies on ECG, and risk stratification in BrS patients is challenging, primarily because of the complexity of the issue. As a result, clinicians fail to provide the appropriate strategy for SCD prevention for many patients. Several variables and interventions are being studied to improve diagnostics and maximise patient protection. In addition, the scientific community must increase efforts to provide patient care according to knowledge and research for improving stratification of risk. In this article, the authors summarise contemporary evidence on clinical variables and provide an overview of future directions in risk stratification and SCD prevention.

Keywords Brugada syndrome, sudden cardiac death, ECG, risk stratification, patient management Disclosure: The authors have no conflicts of interest to declare. Received: 16 December 2018 Accepted: 11 February 2019 Citation: European Cardiology Review 2019;14(1):45–9. DOI: https://doi.org/10.15420/ecr.2018.31.2 Correspondence: David Calvo Cuervo, Hospital Universitario Central de Asturias, C/Avd de Roma, s/n 33006, Oviedo, Spain. E: dcalvo307@secardiologia.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Brugada syndrome (BrS) is an inherited disease with an increased risk of sudden cardiac death (SCD). Despite the wide spectrum of clinical manifestations, young and apparently healthy individuals are the most frequently affected by this devastating event.1,2 During the last 20 years, the genetic basis of Brugada syndrome has been extensively investigated, leading to major changes in gene encoding of the alpha-subunit of the Nav1.5 (SCN5A, driving the fast depolarising sodium current), the gene most frequently associated with functional abnormalities underlying arrhythmogenicity. However, testing identifies genetic disorders in only 20–30% of the patients analysed, indicating a big gap in knowledge and understanding of the genetic aetiology of the syndrome.3,4 Indeed, diagnosis relies on conventional ECG, with a record of the type 1 BrS pattern – occurring either spontaneously or provoked with a sodium channel blocker – being the necessary condition for diagnosis (Figure 1).5,6 The first investigation into a plausible relationship between the characteristic ECG tracing and the risk of SCD was performed in the late 1980s.7 However, it was not until 1992 that the Brugada brothers popularised the syndrome and provided strong evidence for a distinct clinical entity causing SCD in patients with apparently normal heart structure.8 Since the first descriptions reporting high mortality, the incidence of SCD has been declining and remains a source of debate. It is now clear that the population of patients with BrS is heterogeneous. Some patients accumulate the highest risk for developing malignant ventricular arrhythmias, while others follow a benign course with a long life expectancy. This may be because BrS is a dynamic entity, with ECG patterns alternating between the different types and normal records in the same patient. This situation creates

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uncertainty because, if conditions are changing, our risk stratification may need to be recalculated with time. What makes the heart of a patient with BrS change from periodic rhythmicity to the sudden turbulence of fibrillation that renders the heart unable to pump blood? Can we predict that transition and take preventative measures? In such a complex scenario, risk stratification emerges as the key issue in clinical practice. In this article, we summarise contemporary evidence on clinical variables and provide an overview of future directions in risk stratification and SCD prevention.

Syncope and Sudden Cardiac Arrest Prior cardiac arrest is the strongest factor predicting recurrence of ventricular arrhythmias and SCD. There is no doubt about the convenience of an ICD in this clinical scenario. However, conclusions about the link with syncope – believed to be the consequence of self-limited ventricular arrhythmias in a significant proportion of patients – are less certain. In some studies, history of syncope was strongly associated with an increased risk of SCD, with about four-times greater risk compared with asymptomatic patients.3,9 The clinical presentation of the syncope may help to distinguish between malignant syncope as a result of polymorphic ventricular tachycardia or fibrillation, and neuromediated syncope, which is the most frequent cause of syncope in BrS and confers a benign prognosis.1 Evaluation of symptoms associated with the syncope event, prodromals, situational circumstances and witness description, is fundamental in the clinical management of syncope in BrS patients.10 For those patients with malignant syncope, the ICD is a well-established recommendation, whereas patients with neuromediated syncope require general recommendations, similar to those provided for the

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Heart Failure and Arrhythmias Figure 1: Example of Different Types of Brugada Pattern A

Another strategy is the employment of multi-parameter scores in an attempt to improve stratification of risk and detect special cohorts of asymptomatic patients with increased risk. Based on some risk variables – aborted SCD, syncope, male gender, spontaneous type 1 pattern, family history of SCD, sinus node dysfunction or VF induction – the incidence of SCD in these patients can be reasonably well predicted. Although these scores may have future importance, they are not yet validated in an external sample, so their usefulness in clinical practice is still unknown. Another criticism is that none of the models were specifically constructed from cohorts of asymptomatic patients, so validation will require additional efforts.14

This article will now provide evidence regarding individual variables in the risk stratification of BrS patients.

Spontaneous Versus Induced Type 1 Brugada ECG Pattern

A: Normal ECG; B: Type 3 Brugada pattern; C: Type 2 Brugada pattern; D: Type 1 Brugada pattern. Adapted from: García Iglesias et al. 2018.36 Used with permission from MDPI.

general population. However, a gray zone exists, consisting of those patients in who clinicians cannot distinguish between a benign and a malignant pattern. General recommendations are not conclusive, but intense monitoring, i.e. implantable loop recorders and close followup, is usually indicated. This should include alerting the patient to the relevance of syncope as an alarm symptom that must be followed by immediate admission to an accident and emergency department for acute evaluation.2

Asymptomatic Brugada Syndrome Patients Asymptomatic patients with BrS tend to display a more benign disease course than those with symptoms. In several studies and registries the incidence of arrhythmic events or sudden cardiac arrest (SCA) in asymptomatic patients was between 0.8% and 1.0% per year.3,11 However, some studies demonstrate that most of the BrS patients experiencing a SCA were previously asymptomatic and were classified as at low-risk of arrhythmic events.12 In addition, the risk seems to be cumulative with time. Some clinical series demonstrated that the cumulative risk at 10 years of follow-up progressed linearly up to 10%.13 Such a situation remains unacceptable from a clinical point of view and suggests a need for better methods of risk stratification to predict low-risk arrhythmic events, which have tremendous clinical relevance. Thus, the more up to date the risk stratification of asymptomatic BrS patients is, the more relevant it is for decision making in clinical practice. Two combined strategies might provide efficient clinical management. One strategy is effective lifestyle measures, including advising patients to avoid situations with increased risk for arrhythmic events – for example, avoid drugs with potential adverse effects and promptly seek treatment for any episodes of fever – and reminding them of the role of syncope as an alarm symptom to which they should pay special attention. We have previously suggested that patients without an ICD experiencing a SCA have better surveillance if they previously had a premonitory syncope.2 Time-to-contact with medical services should not be delayed in cases of newly detected syncope because these patients would benefit from urgent evaluation.

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The presence of spontaneous type 1 BrS pattern is a cornerstone in the process of risk stratification. It confers a 2.98- to 4.20-fold increase in the risk of SCD, compared with patients with the drug-induced pattern.3,9 However, it must be considered that the relevance of this variable in predicting SCD is strongly modulated by additional factors. First, in patients with prior cardiac arrest, it has not been demonstrated that the spontaneous versus induced type 1 pattern influences prognosis. As such, clinical decision making regarding ICD implantation is not affected. Second, the presence of malignant syncope in a patient with spontaneous type 1 ECG seems to confer a high risk of SCD. On the contrary, asymptomatic patients with spontaneous type 1 ECG seem to follow a benign clinical course unless their clinical status changes because of the occurrence of new episodes of syncope. Third, we must consider the dynamic nature of the ECG patterns. As the type 1 pattern may be intermittent, it is not known if patients who continuously express the type 1 pattern are at higher risk of SCD compared with those with an intermittent manifestation. This point introduces some uncertainty in how often the ECG screening must be done in patients with drug-induced type 1 pattern. We have previously demonstrated that clinical follow-up in the absence of intensive screening, i.e. intense Holter monitoring, may render an 8% reclassification of patients.5 In the absence of standardised recommendations, we believe that BrS patients with drug-induced type 1 ECG must be followed up at least annually for reclassification of risk and reminders of general measures to control their risk of SCD – that is, lifestyle measures, avoidance of drugs with potential adverse effects, prompt treatment of fever episodes and considering new episodes of syncope to be an alarm symptom. The relationship between the type 1 BrS pattern and fever, or some drugs, is clear, highlighting the importance of patient education on preventative measures.

Gender, Family History and Genetic Testing The incidence of SCD peaks in young men, with the highest risk in those under 40 years old. Women and elderly patients are usually considered to be at lower risk. Overall, women have a lower incidence of BrS and lower risk of SCD than men.15–17 Despite this, the influence of gender and age as variables for risk stratification continues to be a matter of discussion, probably because of the wide variety of precipitating factors and circumstances that surround episodes of SCD in patients with BrS.2 In fact, age and gender have never been proven as an indication for ICD implantation.1

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Risk Stratification in Brugada Syndrome

The role of PVS for risk stratification has been debated since its first description in the late 1990s. The potential benefits of the technique are not agreed upon, with some authors describing VF induction as a strong predictor of SCD,21 while others failed to confirm any significant association.3 Sustained VF can be induced in up to 40% of BrS patients (Figure 2A), which is significantly higher than the induction rate found in the general population.1,22,23 However, many factors seem to influence inducibility, from the number of induction attempts and the aggressiveness of the pacing protocol to particular conditions of the patient that would make VF inducibility more or less easy at different times. This is reflected by the fact that the same patient may change from inducible to non-inducible during sequential PVS procedures, which may be particularly important in interpreting results. Some questions arise in light of these results, for example, even if noninducibility is a protective state for a particular patient, how long can that condition apply during follow-up? Should we periodically reassess the risk by repeated PVS procedures? If yes, how often should risk be reassessed? Also, there is no consensus about how the PVS should be done (number of pacing sites, number of extra stimuli, and so on), as the more aggressive the protocol is the higher the rate of false positive results and the lower the specificity we achieve.24 A twoextra-stimuli PVS protocol would probably be the most accurate for risk stratification.1 Moreover, VF induction may be dependent on the basal risk profile of the patient. In symptomatic patients with malignant syncope, VF induction does not seem to add additional value for stratification of risk. For asymptomatic BrS patients, the interpretation is contradictory, with some groups suggesting a relevant role in deciding on ICD implantation in primary prevention,25 while others do not support that conclusion.3 In a meta-analysis, VF inducibility correlated with SCD, with an inverse relationship between the number of extra stimuli needed to induce VF and the risk of SCD.21 However, it was also found that non-inducibility does not protect enough patients against SCD, which highlights the role of other clinical variables – such as syncope and spontaneous type 1 BrS pattern – for risk stratification. In addition, an expert consensus document stated that the association between VF inducibility and SCD/ ventricular arrhythmias is not statistically significant in asymptomatic BrS patients.26 While testing VF induction has been the main goal during PVS, the clinical significance of other findings during the electrophysiological

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V1 V2

Hilbert phase (all frequencies) 3 V1 V2 V3 V4 V5 V6

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Figure 2: Example of VF Induction

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The role of information provided by relatives and genetic testing in risk stratification is also not clear. To date, a positive family history of BrS or SCD is not consistently associated with an increased risk of SCD in BrS patients. However, some authors propose that those variables should be considered for clinical decision making as they might modulate the risk in combination with other variables. That is the case for programmed ventricular stimulation (PVS) attempting VF induction, which seems to increase predictability in BrS patients with a positive family history of SCD.18 In the same way, the effect of mutations in different genes that have causative relationships with BrS – including SC5NA mutations – display contradictory results in the literature.11,19,20 Overall, this has been an extensive area of research with disappointing results; first, because of the low incidence of causative mutations – not exceeding 30% of patients – and second, because of the high heterogeneity in the mutations found and in the patients’ profiles, which makes it difficult to draw general conclusions.

120

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A: Example of VF induction during a programmed ventricular stimulation with three coupled extra-stimuli (arrows). It lasts 17 seconds and needs an external cardiac defibrillator shock to finish. B: Example of Hilbert transform of VF signal in a patient with Brugada syndrome. It provides the time course of the phases along the precordial locations. C: Cumulative data of phases in a subset of patients with Brugada syndrome. B and C show that the phase distribution of the signals denotes a sequence from early in V1 to late in V6 (black arrow, 95% CI). Overall, organisation of the phase-frequency content during VF points to the outflow tracts as the source of high-frequency inputs maintaining VF. Source: Calvo et al. 2015.43 Adapted with permission from Wolters Kluwer Health.

study may be of interest. The PRogrammed ELectrical stimUlation preDictive valuE (PRELUDE) study evaluated the role of refractory periods of the ventricle in predicting SCD/ventricular arrhythmias during follow-up.3 The authors found that a refractory period of less than 200 ms effectively predicted events. Other authors reported the role of sinus node dysfunction or the length of the HV interval with similar results. However, confirmation of the role of these variables in systematic stratification of BrS patients requires additional studies.

Future Directions in Risk Stratification and Prevention of Sudden Cardiac Death There is a need for improved sensitivity and specificity in the diagnosis of BrS. Provocative testing with drugs blocking the sodium channel provides a sensitivity of around 80%. Ajmaline looks superior to flecainide and may help to clarify diagnosis in patients with suspected false negative responses to flecainide.5 The time for monitoring seems to influence the result of provocative testing with flecainide, with extended monitoring time allowing detection of late positive responses.6 In addition, routine performance of ECG recording, ECG recording during fever episodes and alternative provocative testing, such as the full stomach test and exercise testing, may also be recommended for borderline cases in which a false negative response is suspected and cardiac syncope alerts to a risky clinical situation.27–30 This displays a complex scenario that calls for urgent definition of the appropriate standards in the diagnostic work flow to avoid false negative responses. A variety of ECG findings might also help in discerning diagnosis and at-risk patients. For the last 10 years, several authors have focused on fragmentation of the QRS, association with early repolarisation syndrome, increased Tpeak–Tend intervals, quantitative measurements on

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Heart Failure and Arrhythmias Figure 3: High-frequency Content Analysis Along the QRS A

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Time (ms) High-frequency content analysis along the QRS with the wavelet analysis for comparison between patients with and without prior history of arrhythmic events. A: Power spectrum of the QRS; B: Cumulative power of the content at each each epoch (the red dotted line marks the peak power and the green dotted line marks time time to peak power); C: Time distribution of the highfrequency content for each group at each time epoch; D: Boxplot comparing the peak power. Source: García Iglesias et al. 2018.36 Adapted with permission from MDPI.

Figure 4: Suggested Risk Stratification for Primary Prevention in Brugada Syndrome Patients • Sick sinus syndrome

Cardiac syncope

Yes

Spontaneous type 1 pattern

Consider other risk markers

Not spontaneous type 1 pattern

Consider PVS

or AV conduction abnormalities

• Other ECG

abnormalities (i.e. QRS fragmentation, malignant early repolarisation, extension to other leads than right precordial)

• SC5Na phenotype • Family history

Class IIa Close follow-up (look for symptoms) General recommendations Negative ICD implantation for primary prevention of SCD

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AV = atrioventricular; PVS = programmed ventricular stimulation; SCD = sudden cardiac death.

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the terminal R wave in lead V1 and the extension of the PR interval as ECG markers denoting either increased clinical suspicion or increased risk profile.31–35 However, for most of these features there were a limited number of patients considered, which precludes extensive and conclusive implementation in the clinic. While promising, more studies are needed for characterisation. We have demonstrated that the frequency domain analysis of the surface ECG may provide additional insights.36 In a wide population of patients at risk of ventricular arrhythmias, including BrS patients, the spectral properties of the highfrequency content behave distinctly compared with controls at low risk (Figure 3). Those frequency components might reflect a substrate for conduction delay or even voltage gradients promoting phase-two re-entry, which leads some investigators to associate their presence with an increased risk of SCD. Usually demonstrated with a signalaveraged ECG, other novel techniques are now under investigation.36–38 However, validity in the BrS population still requires confirmation. The role of drugs in preventing arrhythmic events in BrS patients is an area of interest. In particular, those drugs with a blockade effect in transient outward potassium current may have a special role

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Risk Stratification in Brugada Syndrome because its differential expression explains action potential dispersion leading to endo-epicardial voltage gradients.39 Notably, quinidine has demonstrated a reduction in VF inducibility during a PVS protocol and significantly ameliorates VF recurrence during follow-up.40 However, studies report the main limitation with the use of quinidine is the gastrointestinal intolerance, which leads to therapy discontinuation in an important number of patients. Another promising therapy seems to be ablation of the arrhythmogenic substrate at the epicardium of the ventricular outflow tracts, where areas of abnormal potentials during sinus rhythm have been related to VF inducibility.41,42 Also VF in BrS patients seems to organise in well-demarcated sequences, pointing to the outflow tract as the preferential location of VF sources (Figures 2B and 2C).43 The ablation of abnormal potentials at the outflow tract is able to revert the expression of the type 1 BrS pattern and normalise the ECG, which paves the way for interventional procedures aimed at substrate modification to

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14.

15.

ntzelevitch C, Yan G-X, Ackerman MJ, et al. J-Wave A syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Europace 2017;19:665–94. https://doi.org/10.1093/europace/euw235; PMID: 28431071. Calvo D, Flórez JP, Valverde I, et al. Surveillance after cardiac arrest in patients with Brugada syndrome without an implantable defibrillator: An alarm effect of the previous syncope. Int J Cardiol 2016;218:69–74. https://doi.org/10.1016/ j.ijcard.2016.05.018; PMID: 27232914. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37–45. https://doi.org/10.1016/j.jacc.2011.08.064; PMID: 22192666. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7:33–46. https://doi. org/10.1016/j.hrthm.2009.09.069; PMID: 20129283. Pablo Flórez J, García D, Valverde I, et al. Role of syncope in predicting adverse outcomes in patients with suspected Brugada syndrome undergoing standardized flecainide testing. Europace 2018;20:f64–71. https://doi.org/10.1093/ europace/eux315; PMID: 29309564. Calvo D, Rubín JM, Pérez D, et al. Time-dependent responses to provocative testing with flecainide in the diagnosis of Brugada syndrome. Heart Rhythm 2015;12:350–7. https://doi. org/10.1016/j.hrthm.2014.10.036; PMID: 25460174. Martini B, Nava A, Thiene G, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J 1989;118:1203–9. PMID: 2589161. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome: A multicenter report. J Am Coll Cardiol 1992;20:1391–6. PMID: 1309182. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome. Circulation 2016;133:622–30. https://doi.org/10.1161/ CIRCULATIONAHA.115.017885; PMID: 26797467. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:1883–948. https://doi.org/10.1093/eurheartj/ ehy037; PMID: 29562304. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation 2010;121: 635–43. https://doi.org/10.1161/CIRCULATIONAHA.109. 887026; PMID: 20100972. Raju H, Papadakis M, Govindan M, et al. Low prevalence of risk markers in cases of sudden death due to Brugada syndrome. J Am Coll Cardiol 2011;57:2340. https://doi. org/10.1016/j.jacc.2010.11.067; PMID: 21636035. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome. Circulation 2013;128:1739–47. https://doi. org/10.1161/CIRCULATIONAHA.113.001941; PMID: 23995538. Letsas KP, Asvestas D, Baranchuk A, et al. Prognosis, risk stratification, and management of asymptomatic individuals with Brugada syndrome: A systematic review. Pacing Clin Electrophysiol 2017;40:1332–45. https://doi.org/10.1111/ pace.13214; PMID: 28994463. Milman A, Gourraud J-B, Andorin A, et al. Gender differences in patients with Brugada syndrome and arrhythmic events: data from a survey on arrhythmic events in 678 patients. Heart Rhythm 2018;15:1457–65. https://doi.org/10.1016/ j.hrthm.2018.06.019; PMID: 29908370.

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improve patient prognosis.41 Despite this approach providing exciting perspectives, no work has yet demonstrated benefits in the long term. In the coming years prospective studies will clarify any potential role.

Conclusion Risk stratification in BrS patients is challenging. Implantation of an ICD is generally accepted if the estimated 5-year risk is higher than about 6.0% or the annual risk is higher than about 1.2%.9,27,28 Stratification of risk currently relies on a set of limited clinical variables that provide the best results according to evidence-based medicine (Figure 4). However, the predictive values of stratification procedures are far from perfect and for many patients we fail to provide the appropriate strategy for SCD prevention. Many different variables and interventions are being studied to increase the diagnostic yield and to maximise patient protection. Meanwhile, the scientific community has to increase efforts in providing patient care according to knowledge and research for improving stratification of risk.

16. Y uan M, Tian C, Li X, et al. Gender differences in prognosis and risk stratification of Brugada syndrome: a pooled analysis of 4,140 patients from 24 clinical trials. Front Physiol 2018;9:1127. https://doi.org/10.3389/fphys.2018.01127; PMID: 30246798. 17. Berthome P, Tixier R, Briand J, et al. Clinical presentation and follow-up of women affected by Brugada syndrome. Heart Rhythm 2019;16:260–7. https://doi.org/10.1016/ j.hrthm.2018.08.032; PMID: 30193851. 18. Delise P, Allocca G, Marras E, et al. Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach. Eur Heart J 2011;32:169–76. https://doi.org/10.1093/eurheartj/ehq381; PMID: 20978016. 19. Yamagata K, Horie M, Aiba T, et al. Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry. Circulation 2017;135:2255–70. https://doi.org/10.1161/ CIRCULATIONAHA.117.027983; PMID: 28341781. 20. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105:1342–7. PMID: 11901046. 21. Brugada P, Brugada R, Mont L, et al. Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart. J Cardiovasc Electrophysiol 2003;14:455–7. PMID: 12776858. 22. Triedman JK. Brugada and short QT syndromes. Pacing Clin Electrophysiol 2009;32:S58–62. https://doi.org/10.1111/j.15408159.2009.02386.x; PMID: 19602164. 23. Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada electrocardiogram: a metaanalysis. J Cardiovasc Electrophysiol 2006;17:577–83. https://doi. org/10.1111/j.1540-8167.2006.00455.x; PMID: 16836701. 24. Fauchier L, Isorni MA, Clementy N, et al. Prognostic value of programmed ventricular stimulation in Brugada syndrome according to clinical presentation: an updated meta-analysis of worldwide published data. Int J Cardiol 2013;168:3027–9. https://doi.org/10.1016/j.ijcard.2013.04.146; PMID: 23642819. 25. Sieira J, Conte G, Ciconte G, et al. Prognostic value of programmed electrical stimulation in Brugada syndrome: 20 years experience. Circ Arrhythm Electrophysiol 2015;8:777–84. https://doi.org/10.1161/CIRCEP.114.002647; PMID: 25904495. 26. Kusumoto FM, Bailey KR, Chaouki AS, et al. Systematic review for the 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018;15:e253–74. https://doi.org/10.1016/j. hrthm.2017.10.037; PMID: 29097318. 27. Shimeno K, Takagi M, Maeda K, et al. Usefulness of multichannel Holter ECG recording in the third intercostal space for detecting type 1 Brugada ECG: comparison with repeated 12-lead ECGs. J Cardiovasc Electrophysiol 2009;20:1026– 31. https://doi.org/10.1111/j.1540-8167.2009.01490.x; PMID: 19470036. 28. Adler A, Topaz G, Heller K, et al. Fever-induced Brugada pattern: how common is it and what does it mean? Heart Rhythm 2013;10:1375–82. https://doi.org/10.1016/ j.hrthm.2013.07.030; PMID: 23872691. 29. Ikeda T, Abe A, Yusu S, et al. The full stomach test as a novel diagnostic technique for identifying patients at risk of Brugada syndrome. J Cardiovasc Electrophysiol 2006;17:602–7. https://doi.org/10.1111/j.1540-8167.2006.00424.x; PMID: 16836706.

30. M akimoto H, Nakagawa E, Takaki H, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome. J Am Coll Cardiol 2010;56:1576–84. https://doi.org/10.1016/ j.jacc.2010.06.033; PMID: 21029874. 31. Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118:1697– 704. https://doi.org/10.1161/CIRCULATIONAHA.108.770917; PMID: 18838563. 32. Takagi M, Aonuma K, Sekiguchi Y, et al. The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome: multicenter study in Japan. Heart Rhythm 2013;10:533–9. https://doi.org/10.1016/ j.hrthm.2012.12.023; PMID: 23274366. 33. Maury P, Sacher F, Gourraud J-B, et al. Increased Tpeak-Tend interval is highly and independently related to arrhythmic events in Brugada syndrome. Heart Rhythm 2015;12:2469–76. https://doi.org/10.1016/j.hrthm.2015.07.029; PMID: 26209263. 34. Sugrue A. New electrocardiographic criteria to differentiate the type-2 Brugada pattern from electrocardiogram of healthy athletes with r’-wave in leads V1/V2. Europace 2015;17:504–5. https://doi.org/10.1093/europace/euu348; PMID: 25722479. 35. Migliore F, Testolina M, Zorzi A, et al. First-degree atrioventricular block on basal electrocardiogram predicts future arrhythmic events in patients with Brugada syndrome: a long-term follow-up study from the Veneto region of Northeastern Italy. Europace 2019;21:322–31. https://doi. org/10.1093/europace/euy144; PMID: 29986018. 36. García Iglesias D, Roqueñi Gutiérrez N, De Cos JF, Calvo D. Analysis of the high-frequency content in human QRS complexes by the continuous wavelet transform: an automatized analysis for the prediction of sudden cardiac death. Sensors 2018;18:E560. https://doi.org/10.3390/ s18020560; PMID: 29439530. 37. Gramatikov B, Iyer V. Intra-QRS spectral changes accompany ST segment changes during episodes of myocardial ischemia. J Electrocardiol 2015;48:115–22. https://doi.org/10.1016/ j.jelectrocard.2014.09.005; PMID: 25266140. 38. Gramatikov B, Brinker J, Yi-Chun S, Thakor NV. Wavelet analysis and time-frequency distributions of the body surface ECG before and after angioplasty. Comput Methods Programs Biomed 2000;62:87–98. PMID: 10764935. 39. Brodie OT, Michowitz Y, Belhassen B. Pharmacological Therapy in Brugada Syndrome. Arrhythmia Electrophysiol Rev 2018;7:135– 42. https://doi.org/10.15420/aer.2018.21.2; PMID: 29967687. 40. Andorin A, Gourraud J-B, Mansourati J, et al. The QUIDAM study: hydroquinidine therapy for the management of Brugada syndrome patients at high arrhythmic risk. Heart Rhythm 2017;14:1147–54. https://doi.org/10.1016/ j.hrthm.2017.04.019; PMID: 28411139. 41. Brugada J, Pappone C, Berruezo A, et al. Brugada syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol 2015;8:1373–81. https://doi.org/10.1161/ CIRCEP.115.003220; PMID: 26291334. 42. Pappone C, Ciconte G, Manguso F, et al. Assessing the malignant ventricular arrhythmic substrate in patients with Brugada syndrome. J Am Coll Cardiol 2018;71:1631–46. https:// doi.org/10.1016/j.jacc.2018.02.022; PMID: 29650119. 43. Calvo D, Atienza F, Saiz J, et al. Ventricular tachycardia and early fibrillation in patients with Brugada syndrome and ischemic cardiomyopathy show predictable frequencyphase properties on the precordial ECG consistent with the respective arrhythmogenic substrate. Circ Arrhythm Electrophysiol 2015;8:1133–43. https://doi.org/10.1161/CIRCEP.114.002717; PMID: 26253505.

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Risk Factors and Cardiovascular Disease Prevention

The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives Sotirios Tsalamandris, Alexios S. Antonopoulos, Evangelos Oikonomou, George-Aggelos Papamikroulis, Georgia Vogiatzi, Spyridon Papaioannou, Spyros Deftereos and Dimitris Tousoulis First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

Abstract Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.

Keywords Inflammation, diabetes, obesity, metabolic disorders, adipose tissue, anti-inflammatory treatment Disclosure: The authors have no conflicts of interest to declare. Received: 21 December 2018 Accepted: 18 February 2019 Citation: European Cardiology Review 2019;14(1):50â&#x20AC;&#x201C;9. DOI: https://doi.org/10.15420/ecr.2018.33.1 Correspondence: Sotirios Tsalamandris, Vasilissis Sofias 114, PO 11528, Hippokration Hospital, Athens, Greece. E: stsalamandris@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Diabetes is a multifaceted metabolic disorder affecting the glucose status of the human body. Impaired glucose tolerance and hyperglycaemia are the main clinical and diagnostic features and the result of an absolute or relative insulin deficiency or resistance to its action. Chronic hyperglycaemia associated with diabetes can result in end organ dysfunction and failure which can involve the retina, kidneys, nerves, heart and blood vessels.1 The clinical relationship between diabetes and atherosclerotic cardiovascular disease are well established, with the risk for cardiovascular disease (CVD) being significantly elevated in patients with diabetes.2,3 Moreover, CVD typically occurs one to two decades earlier in people with diabetes, with more aggressive, severe and diffuse distribution.4,5 The first WHO global report on diabetes published in 2016 demonstrates that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults and this is expected to rise to 552 million by 2030.6,7 Thus, the need for effective novel therapeutic approaches for the treatment and/or prevention of diabetes and atherosclerotic disease is crucial. Traditionally, the majority of cases of diabetes fall into two broad pathogenetic categories, type 1 (T1D) and type 2 (T2D). However, in some people this rigid classification is not applicable because other genetic, immunological or neuroendocrinological pathways are involved in its pathogenesis. T1D is related to an absolute lack of insulin

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due to a vaguely understood mechanism, where an immune-mediated destruction of pancreatic beta cells is the hallmark of the disorder, with hyperglycaemia only emerging when more than 90% of the beta cells are lost.8 T2D is the most common form of diabetes, accounting for 90â&#x20AC;&#x201C;95% of cases. Its development is secondary to a relative insulin deficiency but the primary defect is insulin resistance.9 Various proposals and hypotheses have been developed to describe the mechanisms which are usually involved in the propagation of diabetes, mainly focusing on T2D. The increase in prevalence of the condition has been related to well-recognised risk factors, such as the adoption of a western lifestyle, sedentary lives, lack of physical activity and an energy-dense diet.10,11 Genetic predisposition, ethnicity and ageing are not modifiable risk factors for T2D, while others, such as being overweight or obese, an unhealthy diet, insufficient physical activity and smoking are modifiable through behavioural and environmental changes. However, increasing evidence has shown that inflammatory pathways are the principal, common pathogenetic mediators in the natural course of diabetes under the stimulus of the risk factors described above.12 In this article, we will highlight the emerging role of inflammation in the pathophysiology of diabetes and we will analyse the implicated inflammatory pathways and biomarkers of inflammation in diabetes and metabolic diseases. The focus of this article is to provide an

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Inflammation in Diabetes overview of the current state of knowledge on anti-inflammatory therapies for diabetes, along with perspectives on future therapies for the disease.

Historical Perspectives Observational studies provided the first evidence for the possible association between inflammation and diabetes. Over a century ago, the administration of high doses of sodium salicylate led to decreased glycosuria in people with a suspected or definite diagnosis of diabetes.13,14 Later studies on the role of inflammation in diabetes, revealed that this hypoglycaemic action was related to the inhibition of the serine kinase IkappaB kinase-beta (IKKbeta), which correlates with the post-receptor action of insulin.15 A landmark study to correlate inflammation with diabetes was conducted in animal models by Hotamisiligil et al., in 1993 and it revealed that the role of tumour necrosis factor-alpha (TNFalpha) in obesity and particularly in insulin resistance and diabetes.16 Epidemiologic associations of inflammation with obesity and T2D were made when circulating concentrations of markers and mediators of inflammation and acute-phase reactants including fibrinogen, C-reactive protein, interleukin (IL)-6, plasminogen activator inhibitor-1, sialic acid and white cells, have been shown to be elevated in these conditions.17–21 Over the next decades, numerous studies on human and animal models provided further supporting evidence for the role of inflammation in the initiation and progression of diabetes.12,22 Accumulative evidence suggests that chronic activation of proinflammatory pathways in target cells of insulin action may contribute to obesity, insulin resistance and related metabolic disorders including T2D.22 The identification of potential pathways connecting inflammation to diabetes has produced growing interest in targeting inflammation to help prevent and control diabetes and related conditions, as well as improving risk stratification for diabetes by using inflammatory biomarkers as potential indexes.23,24

Inflammation in Type 1 Diabetes T1D is an autoimmune disorder characterised by a selective, specific destruction of insulin-producing pancreatic beta cells, without apparent pathological alterations of other Langerhans cells.25 However, T1D shows significant heterogeneity in regard to the age of onset, severity of autoimmune response and efficacy of therapy, while it has also been demonstrated that both humoral and cellular immunity is involved in the pathogenesis of T1D.26–28 The first theories about predisposition support that environmental trigger factors in early life, such as infections, nutrition and chemicals that are able to activate self-targeting immune cascades, remain applicable even though the initial event is still unclear.29,30

Inflammatory Infiltrates in Type 1 Diabetes Progress in understanding the pathophysiology of T1D has been made in parallel with the advances in the field of immunology. The predominant theory is that the beta cell pancreatic islets in patients with T1D are inflamed, called insulitis, through the course of T1D. Anderson et al., demonstrated that failure in both central and peripheral immune tolerance mechanisms contribute to the emergence of autoreactive T cells in the periphery of non-obese mice with diabetes.31 Regulatory T cells (Tregs) have been shown to also be defective in this autoimmune disease setting, along with evidence from animal models demonstrating the participation of both CD4+ and CD8+ T cells (effector T-cells/Teff) in the development of T1D as they

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Figure 1: Inflammatory Mediators in Type 1 Diabetes Type 2 diabetes

Pancreas (islet inflammation)

• Impaired insulin secretion • β-cell failure

Liver dysfunction

• Hyperglycaemia • Dyslipidaemia • Metabolic syndrome

Inflammation

• Tissue inflammation

Adipose tissue

Gut microbiome -> immune system interaction

Muscle

Activation of several immune cells are involved in pancreatic beta-cell death through a variety of inflammatory cytokines. Regulatory T cells are defective in this autoimmune disease, while effector T-cells (Teff) participate in the development of type 1 diabetes targeting several beta-cell autoantigens and related peptide epitopes. The profile of immune B cells also changes during disease progression and macrophages are also critical mediators of islet inflammation due to their direct toxicity on beta-cells by reactive oxygen species. Dendritic cells, natural killer cells and natural killer T cells may have a partial role in the process.

target several beta cell autoantigens and related peptide epitopes.32–35 Moreover, by using adoptive T-cell transfer models of T1D, it has been demonstrated that T-cell subtypes are capable of inducing destructive peri-islet inflammatory infiltrate and overt diabetes.36,37 This was further depicted in human studies using pancreas samples obtained post mortem from subjects diagnosed with recent-onset T1D.27,38 Interestingly, the immune B cell (CD20+) profile also changes during disease progression, as initial studies found they align closely with the migration of CD8+ T cells, following two different patterns, either that of high or low infiltration in islets as reported by Wilcox et al.27,38 Macrophages are also critical mediators of islet inflammation due to their ability to secrete cytokines, such as Interleukin 1 beta (IL-1beta) and tumour necrosis factor alpha (TNF-alpha) and produce reactive oxygen species (ROS).27,39 Additional studies have shown that the surrounding pancreatic exocrine tissue is abundant in both lymphocytes and neutrophils in T1D and it is suspected that these cells might also contribute to the evolution of disease.40,41 In some studies, dendritic cells, natural killer (NK) cells and NKT cells have also been found in the islet infiltrate and may have a partial role in the whole process, however, it seems that overall the interaction among different cell types regulates diabetes progression.42,43

Mediators of Inflammation in Type 1 Diabetes The three cytokines that seem to be implicated in the inflammation of pancreatic beta cells in T1D, are the synergic action of interferon gamma (IFN-gamma) and the innate inflammatory cytokines TNFalpha and IL-1beta.44 The combined action of these inflammatory molecules results in the upregulation of inducible nitric oxide synthase (iNOS), with subsequent production of nitric oxide (NO).45 However,

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Risk Factors and Cardiovascular Disease Prevention Table 1: Representative Clinical Trials of Anti-inflammatory Treatments on Type 1 Diabetes Mechanism of action

Drug

Main findings

Monoclonal anti-CD20 antibody

Rituximab

References

Rate of C peptide decline ↓, lower insulin requirements, HbA1c ↓

49,50

Engineered DNA plasmid encoding proinsulin BHT-3021

↓ CD8+ T cells frequency reactive to proinsulin, C peptide preservation, no change to Interferon-gamma, IL-4, IL-10

Proinsulin peptide

Human leukocyte antigen-DR4 (DRB1*0401)

↑ C-peptide, ↑ proinsulin-stimulated IL-10 production, favourable beta-cell stress markers (proinsulin/C-peptide ratio)

189

TNF antagonism

Etarnecept

HbA1c ↓, endogenous insulin production ↑

Anti-inflammatory serum protein

Alpha 1 antitrypsin (AAT)

IL-1beta response to monocytes and dendritic monocytes ↓, beta-cell function improvement

Vitamin D analogue

Alfacalcidol

Beta-cell preservation especially in male subjects

Vitamin D analogue

Calcitriol

↑ in fasting C peptide from diagnosis to 1 year, daily insulin dose ↓ in the treatment group

190

IL-1 receptor blockade

Anakinra

No C peptide response

IL-1 receptor blockade

Anakinra

↓ insulin requirements compared with controls, ↓ insulin dose adjusted

191

IL-1beta antagonism

Canakinumab

No C peptide response

IL-1 receptor blockade IL-1beta antagonism (plasma-induced transcriptional meta-analysis)

Anakinra/canakinumab

Immunomodulation/reverse relationship between inflammation and C peptide stimulation

192

ALPHAti-CD3 mAbs

Teplizumab/otelixizumab

CD20 = cluster of differentiation 20, IL = interleukin, mAbs = monoclonal antibodies, TNF = tumour necrosis factor.

even though ROS plays a role in beta cell destruction, more recent studies have demonstrated that NO is not implicated in the damage of pancreatic beta cell.46 Furthermore, studies demonstrating that the biology of the beta cell could directly influence the response to an inflammatory environment, through specific gene-guided modulation of beta cell apoptosis induced by IFN-gamma modulated by the PTPN2 gene (Figure 1).47 The mechanisms mentioned above strongly suggest that multiple pathways may exist which can contribute to pancreatic beta cell death. During this process, the control and regulation of local inflammatory cytokines production are likely to be critical factors in determining the outcome of the autoimmune progression. The disruptive effects of inflammatory and autoimmune-mediated pancreatic islet attack may lead to a vicious cycle where initial cytokine stress may urge the metabolic stress and an additional loss in beta cell function.48

Anti-Inflammatory Trials on Type 1 Diabetes Given the obvious genetic influences in the initiation and progression of T1D, the immune cell type and the pattern that occurs in any given patient offers an important perspective on the design of clinical trials intended to slow or terminate the progression of the disease. Two initial clinical trials with rituximab, a monoclonal anti-CD20 antibody, were only partially successful.49,50 Furthermore, strategies are being developed targeting the antigen-specific T-cell response, such as the application of plasmid DNA (pDNA) vaccination with promising results.51 Moreover, two humanised anti-CD3 monoclonal antibody (mAbs), teplizumab and otelixizumab, have been evaluated in people with new and recently diagnosed T1D and showed a reduced rate of loss of beta cell function in the majority of participants.52

an anti-TNF-alpha therapy, etanercept, on paediatric patients newly diagnosed with T1D and demonstrated an increased endogenous insulin production and better metabolic control.53 Administration of alpha-1 antitrypsin (AAT), an anti-inflammatory serum protein, to a small group of people with T1D resulted in a reduced IL-1beta response in monocytes and dendritic cells and improved beta cell function.54 Furthermore, given the broad anti-inflammatory properties of vitamin D, it has also been identified as a potential therapeutic target.55 However, small studies of vitamin D supplementation in recent onset T1D have only resulted in modest beta cell protection.56,57 On a larger scale, interleukin-1 receptor antagonist (IL-1RN) and human monoclonal IL-1beta antibody were employed in two randomised, placebo-controlled trials in people with recent onset T1D.58 Canakinumab and anakinra were found to be safe but they were not effective as single immunomodulatory drugs in recent-onset T1D and they did not result in preserved beta cell function, as measured by stimulated C-peptide area under the curve (Table 1). In conclusion, the immunotherapeutic trials that have been completed in human T1D have always focused on patients after clinical onset of diabetes, well after the establishment of targeted adaptive immune responses towards beta cell islets. Targeting these factors is likely to preserve remaining beta cell function, but curative treatments can only be realistically achieved by attempting at the same time to replace part of the beta cell mass that has been lost during the autoimmune process.

Metabolic Disorders and Inflammation in Type 2 Diabetes Inflammation in Type 2 Diabetes

Cytokines are another promising target for therapy for T1D, given their involvement in the process of beta cell pathology. IL-1beta and TNF-alpha appear to be attractive initial targets for designing clinical trials based on this concept. A pilot study examined the effects of

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Several pathophysiological studies have strengthened our understanding of insulin resistance and secretion in the course of disease onset and progression.59,60 Subjects at risk of T2D display an initial state of insulin resistance compensated by hypersecretion of

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Inflammation in Diabetes insulin in the beta cells. However, in the clinical course of the disease this pancreatic functional reserve is eventually unable to cope with the required insulin secretion and by the time diabetes is diagnosed, beta cells are no longer able to secrete enough insulin.61 Although the relative contribution of beta cell dysfunction and insulin resistance can vary in people with T2D, it is generally accepted that abnormal insulin sensitivity precedes the clinical diagnosis of diabetes by up to 15 years.62 Therefore, along with mechanistic studies investigating mechanisms forming the basis of insulin resistance, more recent research has also focused on the pathways leading to beta cell failure.63

The Role of Adipose Tissue and Obesity There has been intensive research conducted into the pathophysiology of diabetes and its association with obesity and the biological role of adipose tissue. As addressed before, insulin resistance is a key component in the course of T2D. Liver and muscles have long been recognised as major contributors of systemic insulin resistance.64 Fat accumulation in the liver (steatosis) precedes overt T2D, is commonly associated with obesity and is considered a major determinant of the reduced hepatic insulin sensitivity resulting in fasting hyperglycaemia.65–67 Furthermore, it is now well accepted that the accumulation of energy due to excessive calorie intake and the lack of physical activity leads initially to fat accumulation in the subcutaneous tissue and later to other tissue compartments such as the liver, pancreas, muscles, perivascular and pericardium.67 This fat accumulation increases tissues’ insulin resistance, while pancreatic fat accumulation further determines beta cell dysfunction.64,68 Obesity and its associated conditions including metabolic syndrome, hypertension and dyslipidaemia, is positively associated with concentrations of inflammatory biomarkers, which are predictive of insulin resistance and the incidence of T2D and CVD.69–71 Obesity and metabolic syndrome specifically comprise a cluster of diseases associated with too much food and insufficient physical activity, conditions where sub-acute chronic inflammation is a common and potentially unifying mechanistic cause, accompanied by activation of at least two major inflammatory pathways, stress-activated Jun N-terminal kinases (JNK) and the transcription factor NF-kappaB.12,16,72–77 This inflammatory state via production of pro-inflammatory cytokines, is further amplified by adipokines, though a number of studies have demonstrated that adipokines stimulate additional inflammatory responses in obesity and promote obesity-induced metabolic and cardiovascular diseases.78 Animal studies have demonstrated that brown adipose tissue (BAT) has an important role in regulating energy and glucose homeostasis and is associated with peripheral insulin resistance and glucose levels.79–81 However, white adipose tissue (WAT) and mainly visceral WAT (around the trunk, upper body or abdomen) appears to be the major source of inflammatory markers in T2D, but also a target of the inflammatory process in people with diabetes. It produces cytokines and several other bioactive substances involved in the inflammatory pathways, such as TNF-alpha, IL-1, IL-6, IL-10, leptin, adiponectin, monocyte chemoattractant protein, angiotensinogen, resistin, chemokines, serum amyloid protein, and many others collectively referred to as adipokines.82–85 Further infiltration of adipose tissue by macrophages and immune cells (B cells and T cells) trigger local and systemic chronic low-grade inflammation, by producing more cytokines and chemokines that serve as a pathologic link between obesity, insulin resistance and diabetes.86

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The Role of Gut Microbiota in Type 2 Diabetes The role of the gut in the pathophysiology of diabetes can be approached from two different viewpoints. Studies have suggested that several mechanisms may be involved in weight loss and diabetes control after bariatric surgery, beyond malabsorption or anatomical restriction.87 Indeed, complex changes in multiple gut hormones have been shown after bariatric procedures and have been proposed as adjunctive mechanisms for short- and long-term positive metabolic effects, serving as possible novel therapeutic approaches to obesity and insulin resistance.88,89 In the past few years, a two-way relationship between the gut microbiome in the host’s energy balance and immune function has been demonstrated.90 The gut microbiome seems to differ between obese and lean subjects, flora composition influences metabolism and inversely, diet and metabolic status influence the composition of the gut flora, while a faecal microbiome transplantation from lean donors to insulin-resistant subjects results in beneficial metabolic effects.91–94 It has been postulated that products from the gut microbiome may interact with the immune system inducing a tissue metabolic modification, which feeds the molecular origin of the low-grade inflammation that characterises the onset of obesity and diabetes.95 An altered gut microbiota can directly affect immune cells in the gut and indirectly affect immune cells via microbial products including LPS, metabolites and short chain fatty acid (SCFAs), all of which can affect adipogenesis and/or insulin resistance.96–101 Lipopolysaccharide (LPS) is believed to cause low-grade inflammation mediated by the induction of inflammatory cytokines by immune cells and adipocytes, while SCFAs can modulate gene expression of human monocytes and reduce pro-inflammatory cytokine and chemokine production.102 SCFAs can also promote regulatory T-cell generation through several pathways, thereby suppressing the function of inflammatory T cells. These are able to block IFN-gamma inducible protein 10 (IP-10) release in human colonic sub-epithelial myofibroblasts, acting not only on immune cells systemically but also on intestinal tissue cells locally.103,104

The Role of Pancreatic Beta Cell Failure in Type 2 Diabetes Independent of the aetiopathogenetic mechanism among the different types of diabetes, the common pathway seems to be the inflammation in the pancreatic Langerhans beta cell islets (insulitis), in the concept of an auto-inflammatory process, which results in reduction in both beta cell number and function.105 It has been suggested that in people with a genetic predisposition, the ‘stressed’ beta cell may stimulate local inflammation and modify the balance between beta cell mass and function in the islets of Langerhans.106,107 Several experimental models as well as observational studies in humans have demonstrated that macrophages play a key role in the islet inflammation seen in T2D.108–111 Inflammasome/IL-1beta signalling is the most common, well-studied and high-impact pathway activated in islets of multiple T2D models that cause beta cell dysfunction.112,113 It is likely that other immune cell types are involved in islet inflammation in T2D, while islet autoimmunity has also been suggested to contributes to beta cell functional decline during the course of T2D.114,115 Among factors that stimulate islet macrophages to secrete IL-1beta in vivo in human islets are amyloid polypeptide, free fatty acids (FFAs) and endocannabinoids.110,111,116 However, it has been assumed

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Risk Factors and Cardiovascular Disease Prevention Figure 2: The Vicious Cycle of Inflammation in Various Target Organs in Type 2 Diabetes

Macrophage IL-1β

Pancreas in T1DM

NK cell TNF-α

Pancreatic β-Cells

IL-1β

Inflammatory cytokines Pancreatic islets lls

ROS IL-1β

TNF-α IFN-γ

B-cell

Current Knowledge on Diabetes Treatments Drugs with Pleiotropic Effects The current therapeutic approaches to T2D have anti-inflammatory properties in addition to their major modes of action. Non-pharmacological therapies, such as lifestyle interventions, but also pharmacological and bariatric surgical approaches for weight loss, appears to reduce inflammation assessed as circulating CRP and IL-6 concentrations, and improves cardiovascular and all-cause mortality.134–138

T-cell

IFN-γ Ab

IFN-γ

liver, the neural system and possibly skeletal muscle.129–133 However, more research is needed to support this evidence (Figure 2).

IL-1β

Inflammation has a key role in the pathophysiology of type 2 diabetes and its associated metabolic abnormalities.

that hyperglycaemia is produced initially in the inflammation in pancreatic beta cells by inducing apoptotic mechanisms.117 ALPHA particular pathway was proposed by Maedler et al. who showed that hyperglycaemia may induce the production of IL-1beta by stimulating pro-apoptotic receptor FFAs on beta cells.118 FFAs can also produce and secrete IL-1beta and IL-1-dependent proinflammatory cytokines in pancreatic islets and thus to reduce the inflammation. In addition, after its initial secretion, IL-1beta regulates its production in pancreatic beta cells by auto stimulation, while this process also increases nitric oxide production leading to reduction in ATP concentration in the mitochondria, which can cause further beta cell dysfunction and reduced insulin secretion.119–122 Oxidative stress may also potentiate the generation of ROS along with other proinflammatory cytokines and chemokines in the beta cells that disrupts the blood flow into them and destroys their function.108,123,124 Experimental studies have confirmed that IL-6 induces apoptosis in pancreatic islets together with other inflammatory cytokines and acts as a predictor and pathogenic marker for the progression of T2D.69,124,125 TNF-alpha is also considered to play an essential role, by creating a linkage among insulin resistance, obesity and islet inflammation.125 Its overproduction in adipose tissue seems to feed the inflammation and beta cell death in pancreatic islets and produces additional insulin resistance in peripheral tissues.126,127

Statins also have anti-inflammatory properties beyond their ability to lower levels of low-density lipoproteins (LDL) cholesterol. The Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) demonstrated that rosuvastatin reduced high-sensitivity CRP along with LDL cholesterol, however the effects of statins on glycaemic control are conflicting, implying that targeting inflammation with statins does not improve glycaemia and therefore does not provide an integrated anti-inflammatory approach for diabetes and CVD.139–141 Anti-diabetic agents, including insulin, have intrinsic anti-inflammatory effects associated with their primary mechanisms of action and are also associated with reductions in inflammatory markers. Insulin itself decreases NF-kappaB activity in peripheral blood mononuclear cells which reduces inflammation.142 The anti-inflammatory actions of thiazolidinediones through binding and activation to the peroxisome proliferator-activated receptor gamma (PPARgamma), seems to be related to trans-repression of NF-kappaB and reduced expression of NF-kappaB targets.143 In addition to its metabolic effects, metformin has anti-inflammatory actions that appear to be independent of glycaemia and are most prominent in immune cells and vascular tissues. 144–150 Dipeptidyl peptidase-4 inhibitors (DPP-4) and GLP-1 receptor agonists also have intrinsic anti-inflammatory properties, however, beyond their antidiabetic effects, the contribution of inflammation reduction to diabetes and cardiovascular improvements remains unknown.151–153 Finally, a new class of anti-diabetic drugs, sodium–glucose cotransporter-2 inhibitors (SGLT2 inhibitors) acts by increasing renal excretion of glucose. Preliminary data in humans demonstrate a possible improvement on the circulating biomarkers of inflammation by SGLT2-inhibitors; however, more studies are needed.152

Anti-Inflammatory Drugs in Type 2 Diabetes

Immune system activation is highly related to T2D incidence and progression and adaptive and innate immunity are involved in adipose tissue inflammation. The phenotype switching of macrophages from predominantly anti-inflammatory M2-type to increased proportions of pro-inflammatory M1-type macrophages plays a crucial role in the initiation and amplification of islet inflammation.128 However, the evidence shows that the recruitment of B cells and T cells precedes adipose tissue infiltration by macrophages.86

Multiple medical approaches that directly target inflammatory pathways have been studied in the past few years supporting the concept of antiinflammatory treatment for cardiometabolic diseases, such as diabetes and atherosclerotic CVD.154–156 For a long time, salicylates, especially aspirin, have been used to treat thrombosis in primary and secondary CVD prevention, as well as to treat rheumatoid diseases.157,158 They were the first class of drugs reported to lower glucose in diabetes more than a century ago, however, several studies with salicylate products have demonstrated an improved metabolic profile in patients with obesity and diabetes, suggesting a potential efficacy for diabetes prevention and control.159–166

Moreover, several other organs have been reported to participate in the metabolic homeostasis and inflammatory state in T2D, such as the

Methotrexate is a disease-modifying drug broadly used to treat rheumatic diseases among other conditions, while its efficacy on

Evidence of Inflammation in Other Organs in People with Type 2 Diabetes

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Inflammation in Diabetes Table 2: Representative Clinical Trials of Anti-Inflammatory Treatments on Type 2 Diabetes – Metabolic Profile Mechanism of Action

Drug

Main Findings

Reference

IL-1 receptor blockade

Anakinra

HbA1c, leukocyte ↓, CRP↓ insulin secretion↑

182

IL-1 receptor blockade

Anakinra

Sustained CRP ↓, insulin secretion ↑, insulin requirement ↓

181

IL-1 receptor blockade

Anakinra

Insulin sensitivity ↑

193

IL-1 receptor blockade

Anakinra

Insulin secretion ↑ (first-phase insulin secretion improved)

194

IL-1 receptor blockade

Anakinra

Insulin secretion↑

183

IL-1beta antagonism

Gevokizumab

HbA1c ↓, CRP ↓, insulin secretion ↑

112

IL-1beta antagonism

Canakinumab

Insulin secretion ↑, CRP ↓

185

IL-1beta antagonism

Canakinumab

CRP ↓, HbA1c ↓, insulin secretion ↑ (not statistically significant)

184

IL-1beta antagonism

Canakinumab

Significant CRP and IL-6 ↓, 6 month HbA1c ↓, but not consistent Hba1c ↓ long-term

188

IL-1beta antagonism

Canakinumab

CRP ↓, fibrinogen ↓, IL-6 ↓, no effect on HbA1c, glucose and insulin levels

187

IL-1beta antagonism

LY2189102

HbA1c ↓, CRP ↓, insulin secretion ↑

186

IKKbeta–NF-kappaB inhibition

Salsalate

FBG ↓, CRP ↓, insulin sensitivity ↑, adiponectin ↑

160

IKKbeta–NF-kappaB inhibition

Salsalate

FBG ↓, CRP ↓, adiponectin ↑

159

IKKbeta–NF-kappaB inhibition

Salsalate

FBG ↓, insulin ↑, CRP ↓

195

IKKbeta–NF-kappaB inhibition

Salsalate

HbA1c ↓, FBG ↓, triglyceride ↓, adiponectin ↑

165

IKKbeta–NF-kappaB inhibition

Salsalate

HbA1c ↓, FBG ↓, insulin secretion ↑, triglyceride ↓

162

IKKbeta–NF-kappaB inhibition

Salsalate

FBG ↓, adiponectin ↑

163

IKKbeta–NF-kappaB inhibition

Salsalate

HbA1c ↓, FBG ↓, triglyceride ↓, leukocyte ↓, uric acid ↓, adiponectin ↑

164

TNF antagonism

CDP571

No effect on insulin sensitivity

176

TNF antagonism

Single dose of soluble TNF receptor–Fc fusion protein (Ro 45–2081)

No effect on insulin sensitivity

177

TNF antagonism

Soluble TNF receptor–Fc fusion protein etanercept

CRP ↓, insulin secretion ↑, no effect on insulin sensitivity

178

TNF antagonism

Soluble TNF receptor–Fc fusion protein etanercept

CRP ↓, adiponectin ↑, LDL ↓, no effect on insulin sensitivity

179

TNF antagonism

Soluble TNF receptor–Fc fusion protein etanercept

FBG ↓

180

TNF antagonism

Infliximab

Fasting glucose improvement, ratio of high molecular weight to total adiponectin ↑, sICAM-1 ↑, no effect on CRP

170

Decrease in TNF and IL-1beta levels by an unknown mechanism of action

Diacerein

HbA1c ↓, FBG ↓, insulin secretion ↑

196

DHFR inhibitor – antimetabolite

Low-dose methotrexate

No effects on CRP, IL-1beta or IL-6

168

DHFR inhibitor (DMARD) – combination with sulphasalazine glycocorticosteroids/hydroxychloroquine

Methotrexate

HbA1c ↓

167

CRP: C-reactive protein; DHFR = dihydrofolate reductase inhibitor; FBG = fasting blood glucose; IKKbeta = IkappaB kinase-beta; IL = Interleukin; mAbs = monoclonal antibodies; NF-kappaB = nuclear factor-kappaB; sICAM-1 = soluble intercellular adhesion molecule-1; TNF = tumour necrosis factor.

glycaemic control was demonstrated in a small cohort study.167 The preliminary data drove the design and conduction of a large clinical trial with methotrexate among patients with previous MI and either T2D or metabolic syndrome, however, methotrexate had neutral findings on IL-1b, IL-6 and CRP levels, while more data are anticipated for the effects on T2D.168

stopping the initiation and progression of T2D. TNF-alpha antagonists have been used to treat inflammatory conditions and have been associated with improved glycaemic control and decreased incident of diabetes, while more studies on patients with unfavourable cardiometabolic profile did not demonstrate adequate results, with the exception of a randomised 6-month trial.169–180

Biological Agents as Anti-Inflammatory Therapy in Type 2 Diabetes

The mechanism of action of IL-1beta pathogenesis and progression of T2D secretory function and glycaemia, as well biomarkers in people with diabetes

Targeting cytokine production and secretion to prevent further activation of inflammation have been proposed with the intention of

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is consistent with the is. Improved beta cell as reduced inflammatory and pre-diabetes have

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Risk Factors and Cardiovascular Disease Prevention been demonstrated by IL-1beta antagonists, such as anakinra and gevokizumab. 112,120,181–6 Studies on CVD and atherosclerosis prevention with IL-1beta antagonists have also been conducted. One study showed that canakinumab reduced the inflammatory proteins CRP, IL-6, and fibrinogen in persons with T2D and high cardiovascular risk with no effect on HbA1C, glucose, and insulin at 4 months, while the large randomised trial with canakinumab – Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) – over a median period of 3.7 years did not reduce the incidence of diabetes in patients with prior MI and high-sensitivity CRP (hsCRP) ≥2 mg/l (Table 2).187,188

have not yet been reported. The potential for targeting cholinergic pathways, immune modulation or other mediators of inflammation such as JNK and toll-like receptors (TLRs) are also being researched.

Future Perspectives for the Treatment of Diabetes

T1D is considered to be more of an immunological response rather than a metabolic disorder and the preliminary results of trials using anti-inflammatory and immunomodulatory medication are promising. These treatments in combination with possible use of stem cells to regenerate pancreatic beta cells could potentially be the key to permanent treatment of T1D. Therefore, after a holistic review of the possible mechanisms that lead to T1D and T2D and the numerous already described inflammation pathways that are involved, it becomes more and more clear that future research should focus on simultaneous suppression of various inflammatory response pathways rather than focusing on one pathway at a time.

Novel approaches on T2D to evaluate anti-inflammatory diets and modulate an individual’s microbiome are under study. Clinical trials investigating the effects of vitamin D supplementation on serum levels of inflammatory markers have provided inconsistent results, with no evidence of effects in most trials, or effects on selected markers in others. There are also studies investigating whether antagonists of leukotriene production enzymes – 5-lipoxygenase (5-LO), 5-LO-activating protein and LTA4 hydrolase – or receptor binding BLT1 have cardiometabolic outcome benefits, however these results

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Conclusion The increasing prevalence of diabetes makes it imperative that research should focus on its prevention as well as its treatment. An improved understanding of the mechanisms linking inflammation to diabetes and related complications has stimulated interest in targeting inflammatory pathways as part of the strategy to prevent or control diabetes and its complications.

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Ann Intern Med 2016;164:804–13. https://doi.org/10.7326/M152113; PMID: 27064410. 158. Frantz B, O’Neill EA. The effect of sodium salicylate and aspirin on NF-kappa B. Science 1995;270:2017–9. https://doi. org/10.1126/science.270.5244.2017; PMID: 8533099. 159. Goldfine AB, Silver R, Aldhahi W, et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci 2008;1:36–43. https://doi. org/10.1111/j.1752-8062.2008.00026.x; PMID: 19337387. 160. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate

improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 2008;31:289–94. https://doi. org/10.2337/dc07-1338; PMID: 17959861. 161. Faghihimani E, Aminorroaya A, Rezvanian H, et al. Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes. Endocr Pract 2012;18:826-33. https://doi.org/10.4158/EP12064.OR; PMID: 22784842. 162. Faghihimani E, Aminorroaya A, Rezvanian H, et al. Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes. Acta Diabetol 2013;50:537–43. https://doi. org/10.1007/s00592-011-0329-2; PMID: 21938543. 163. Goldfine AB, Conlin PR, Halperin F, et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 2013;56:714–23. https://doi.org/10.1007/s00125-012-2819-3; PMID: 23370525. 164. Goldfine AB, Fonseca V, Jablonski KA, et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2013;159:1–12. https://doi.org/10.7326/00034819-159-1-201307020-00003; PMID: 23817699. 165. Goldfine AB, Fonseca V, Jablonski KA, et al. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2010;152:346–57. https:// doi.org/10.7326/0003-4819-152-6-201003160-00004; PMID: 20231565. 166. Rumore MM, Kim KS. Potential role of salicylates in type 2 diabetes. Ann Pharmacother 2010;44:1207–21. https://doi. org/10.1345/aph.1M483; PMID: 20516365. 167. de Rotte MC, de Jong PH, den Boer E, et al. Effect of methotrexate use and erythrocyte methotrexate polyglutamate on glycosylated hemoglobin in rheumatoid arthritis. Arthritis Rheumatol 2014;66:2026–36. https://doi. org/10.1002/art.38652; PMID: 24692301. 168. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752–62. https://doi.org/10.1056/ NEJMoa1809798; PMID: 30415610. 169. Yazdani-Biuki B, Stelzl H, Brezinschek HP, et al. Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur J Clin Invest 2004;34:641–2. https://doi. org/10.1111/j.1365-2362.2004.01390.x; PMID: 15379764. 170. Kiortsis DN, Mavridis AK, Vasakos S, et al. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005;64:765–6. https://doi.org/10.1136/ard.2004.026534; PMID: 15458960. 171. Yazdani-Biuki B, Mueller T, Brezinschek HP, et al. Relapse of diabetes after interruption of chronic administration of anti-tumor necrosis factor-alpha antibody infliximab: a case observation. Diabetes Care 2006;29:1712–3. https://doi. org/10.2337/dc06-0636; PMID: 16801612. 172. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006;24:83–6. PMID: 16539824. 173. Huvers FC, Popa C, Netea MG, et al. Improved insulin sensitivity by anti-TNFalpha antibody treatment in patients with rheumatic diseases. Ann Rheum Dis 2007;66: 558–9. https://doi.org/10.1136/ard.2006.062323; PMID: 17360784. 174. Marra M, Campanati A, Testa R, et al. Effect of etanercept on insulin sensitivity in nine patients with psoriasis. Int J Immunopathol Pharmacol 2007;20:731–6. https://doi. org/10.1177/039463200702000408; PMID: 18179745. 175. Timper K, Hruz P, Beglinger C, Donath MY. Infliximab in the treatment of Crohn disease and type 1 diabetes. Diabetes Care 2013;36:e90–1. https://doi.org/10.2337/dc13-0199; PMID: 23801815. 176. Ofei F, Hurel S, Newkirk J et al. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996;45:881–5. https://doi.org/10.2337/diab.45.7.881; PMID: 8666137. 177. Paquot N, Castillo MJ, Lefèbvre PJ, Scheen AJ. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab 200;85:1316–9.; PMID: 10720082. 178. Dominguez H, Storgaard H, Rask-Madsen C, et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res 2005;42:517–25. https://doi.org/10.1159/000088261; PMID: 16155368. 179. Bernstein LE, Berry J, Kim S, et al. Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med 2006;166:902–8. https://doi.org/10.1001/archinte.166.8.902; PMID: 16636217. 180. Stanley TL, Zanni MV, Johnsen S, et al. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 2011;96:E146–50. https://doi.org/10.1210/ jc.2010-1170; PMID: 21047923. 181. Larsen CM, Faulenbach M, Vaag A, et al. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 2009;32:1663–8. https://doi. org/10.2337/dc09-0533; PMID: 19542207. 182. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-

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Inflammation in Diabetes receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007;356:1517–26. https://doi.org/10.1056/NEJMoa065213; PMID: 17429083. 183. van Asseldonk EJ, Stienstra R, Koenen TB, et al. Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2011;96:2119–26. https://doi. org/10.1210/jc.2010-2992; PMID: 21508140. 184. Hensen J, Howard CP, Walter V, Thuren T. Impact of interleukin1beta antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab 2013;39:524–31. https://doi.org/10.1016/ j.diabet.2013.07.003; PMID: 24075453. 185. Rissanen A, Howard CP, Botha J, et al. Effect of anti-IL-1beta antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes Metab 2012;14:1088–96. https://doi.org/10.1111/j.1463-1326.2012.01637.x; PMID: 22726220. 186. Sloan-Lancaster J, Abu-Raddad E, Polzer Jet al. Doubleblind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1beta antibody, in patients with type 2 diabetes. Diabetes Care 2013;36:2239–46. https://doi. org/10.2337/dc12-1835; PMID: 23514733. 187. Ridker PM, Howard CP, Walter V, et al. Effects of interleukin-

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1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012;126:2739–48. https://doi.org/10.1161/ CIRCULATIONAHA.112.122556; PMID: 23129601. 188. Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol 2018;71:2392–401. https://doi.org/10.1016/j.jacc.2018.03.002; PMID: 29544870. 189. Alhadj Ali M, Liu YF, Arif S, et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci Transl Med 2017;9:eaaf7779. https://doi.org/10.1126/scitranslmed.aaf7779; PMID: 28794283. 190. Pitocco D, Crinò A, Di Stasio E, et al. The effects of calcitriol and nicotinamide on residual pancreatic beta-cell function in patients with recent-onset type 1 diabetes (IMDIAB XI). Diabet Med 2006;23:920–3. https://doi.org/10.1111/j.1464-5491.2006.01921.x; PMID: 16911633. 191. Sumpter KM, Adhikari S, Grishman EK, White PC. Preliminary studies related to anti-interleukin-1beta therapy in children with newly diagnosed type 1 diabetes. Pediatr Diabetes 2011;12:656–67. https://doi. org/10.1111/j.1399-5448.2011.00761.x; PMID: 21518168. 192. Cabrera SM, Wang X, Chen YG, et al. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1

diabetes during clinical trials conducted at disease onset. Eur J Immunol 2016;46:1030–46. https://doi.org/10.1002/ eji.201546005; PMID: 26692253. 193. van Asseldonk EJ, van Poppel PC, Ballak DB, et al. One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus. Clin Immunol 2015;160:155–62. https://doi.org/10.1016/j.clim.2015.06.003; PMID: 26073226. 194. van Poppel PC, van Asseldonk EJ, Holst JJ, et al. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes Obes Metab 2014;16:1269–73. https://doi.org/10.1111/dom.12357; PMID: 25039318. 195. Koska J, Ortega E, Bunt JC, et al. The effect of salsalate on insulin action and glucose tolerance in obese nondiabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 2009;52:385–93. https://doi.org/10.1007/s00125-008-1239-x; PMID: 19104769. 196. Ramos-Zavala MG, González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, González-López R, Santiago-Hernández NJ. Effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes: a randomized clinical trial. Diabetes Care 2011;34:1591–4. https://doi.org/10.2337/dc11-0357. PMID: 21610123.

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Risk Factors and Cardiovascular Disease Prevention

Obesity and Cardiovascular Risk After Quitting Smoking: The Latest Evidence Koji Hasegawa, Maki Komiyama and Yuko Takahashi National Hospital Organization Kyoto Medical Center, Japan

Abstract Smoking cessation is one of the most effective ways to reduce cardiovascular risk. However, weight gain and abdominal obesity generally occur after quitting smoking, as a result of nicotine withdrawal. Obesity increases various inflammatory markers, and weight gain after smoking cessation temporarily increases the risk of diabetes and reduces the benefit gained by smoking abstinence. The benefits of smoking cessation may be minimised by obesity in those who have stopped smoking. Pharmacological treatment with medications such as nicotine patches and varenicline is useful to suppress weight gain during smoking cessation. Supporting patients to continue smoking cessation and to gradually decrease their weight will be crucial.

Keywords Cardiovascular risk, diabetes, obesity, smoking cessation Disclosure: The authors have no conflict of interests to declare. Received: 8 January 2019 Accepted: 4 February 2019 Citation: European Cardiology Review 2019;14(1):60–1. DOI: https://doi.org/10.15420/ecr.2019.4.2 Correspondence: Koji Hasegawa, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan. E: koj@kuhp.kyoto-u.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Smoking is a strong risk factor for the development of arteriosclerotic cardiovascular disease (CVD). Quitting smoking is a cornerstone of improved cardiovascular health, reducing the risk of developing CVD and the risk of overall mortality.1 It is astonishing that 7–28% of patients with coronary heart disease still smoke, but around half of smokers are planning to quit.2,3 Because the habit is addictive, it is crucial for cardiologists to repeatedly encourage patients to quit smoking. In addition, evidence shows that passive smoking increases the risk of CVD and that a significant number of people with CVD are exposed to environmental tobacco smoke.4 Such exposure should be avoided in CVD patients. Smoking cessation is associated with weight gain.5 Individuals generally gain approximately 4–5 kg in the year after quitting smoking,and glucose and lipid metabolism also worsen.6 Weight gain often causes people to resume smoking. A study examined the factors associated with weight gain after quitting smoking based on data from the first visit to a smoking cessation clinic.8 Individuals with a higher score on the Fagerstrom Test for Nicotine Dependence displayed a greater change in percentage BMI after quitting smoking (Figure 1). These findings indicate that nicotine dependence and weight gain after quitting smoking are statistically related and strongly support the hypothesis that weight gain after stopping smoking is a symptom of nicotine withdrawal. If weight gain after quitting smoking can be predicted prior to smoking cessation interventions, then that weight gain might be prevented. It is not known whether weight gain after quitting smoking exacerbates CVD. The alpha1-antitrypsin LDL (AT-LDL) complex, a complex of

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alpha1-antitrypsin (AT)-oxidised LDL, is an important cardiovascular biomarker. Smokers have considerably increased serum AT-LDL levels, compared with non-smokers, and AT-LDL levels have been shown to significantly decrease 3 months after quitting smoking (Figure 2).9 A study that examined the effects of weight gain after quitting smoking on AT-LDL levels found that AT-LDL levels decrease as a result of quitting smoking, but this improvement was not reported in obese individuals after quitting smoking.10 Essentially, weight gain 3 months after quitting smoking may hamper improvements in AT-LDL levels. However, 1 year after quitting smoking the serum AT-LDL levels decreased to a greater extent than the levels 3 months after quitting smoking, regardless of whether obesity increased.11 In other words, the benefits of quitting smoking outweigh the disadvantages of weight gain over time, and quitting smoking reduces the risk of developing CVD. A large-scale 14-year cohort study examined the relationship between smoking cessation and stroke events among postmenopausal women.11 A significant reduction in stroke risk by smoking cessation was not attenuated by concurrent weight gain. Another large-scale follow-up study, conducted over 30 years, examined weight gain after quitting smoking and the subsequent risk of illness or death.12 According to this study, weight gain peaked 6 years after quitting smoking and 35% of the subjects gained 5 kg or more. If an individual gains 5 kg or more after quitting smoking, their risk of developing diabetes increases by 40–60% compared with individuals who continue to smoke. However, the increased risk peaks approximately 6 years after quitting smoking; 30 years after the individual quits smoking, they have the same risk of diabetes as that of a non-smoker.

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Obesity and Cardiovascular Risk

(n=13)

0.3 ± 3.2

(n=26)

0.8 ± 3.0

(n=32

1.5 ± 4.9

(n=32)

1.1 ± 4.0

(n=27)

2.0 ± 3.2

(n=35)

2.4 ± 3.6

(n=18)

3.4 ± 4.0

Changes in BMI after smoking cessation and nicotine dependency (FTND scores). The larger the FTND score, the larger the percentage change in BMI. FTND = Fagerstrom Test for Nicotine Dependence.

If an individual quits smoking, their risk of death as a result of CVD and any other cause significantly decreases, regardless of weight gain (even if they gain ≥10 kg). Nonetheless, individuals who do not gain weight display greater reduction in the risk of developing CVD than those who do gain weight. Clearly, weight management is crucial after quitting smoking. If an individual gains 20 kg 6 years after quitting smoking and does not lose that weight, their risk of cardiovascular death increases each year. Furthermore, individuals who have not lost that weight even 30 years after quitting smoking have the same risk of cardiovascular death as that of individuals who continue to smoke; hence, caution is required. A large-scale cohort study analysed patients with diabetes and those without who quit or continued to smoke.3 Compared with current smokers, patients without diabetes were reported to have a considerably reduced risk of developing CVD over 4 years after quitting smoking. This finding held true even if the people without diabetes gained a substantial amount of weight. In addition, the risk of developing CVD decreased the longer the people without diabetes abstained from smoking. People with diabetes displayed a reduced risk of developing CVD if they abstained from smoking for at least 4 years and if they gained less than 5 kg. However, gaining an excessive amount of weight (>5 kg) annulled the reduction in risk of

The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J 2012;33:1635–701. https://doi.org/10.1093/ eurheartj/ehs092; PMID: 22555213. Reiner Z. The importance of smoking cessation in patients with coronary heart disease. Int J Cardiol 2018;258:26–7. https://doi.org/10.1016/j.ijcard.2018.02.009; PMID: 29544941. Prugger C, Wellmann J, Heidrich J, et al. Readiness for smoking cessation in coronary heart disease patients across Europe: Results from the EUROASPIRE III survey. Europ J Prev Cardiol 2015;22:1212–9. https://doi. org/10.1177/2047487314564728; PMID: 25516535. Prugger C, Wellmann J, Heidrich J, et al. Passive smoking and smoking cessation among patients with coronary heart disease across Europe: results from the EUROASPIRE III survey. Eur Heart J 2014;35:590–8. https://doi.org/10.1093/ eurheartj/eht538; PMID: 24334711. Flegal KM, Troiano RP, Pamuk ER, et al. The influence of

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Serum AT-LDL levels and smoking status

Change in BMI (%), mean ± SD

Change in AT-LDL levels after smoking cessation

p<0.0001 p=0.01

p<0.0001 AT-LDL, μg/ml

FTND score

Figure 2: Serum Alpha1-antitrypsin LDL Levels and Smoking

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

AT-LDL, μg/ml

Figure 1: Changes in BMI and Nicotine Dependency After Smoking Cessation

Never

Former

Current

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

Baseline

After cessation

The AT-LDL level significantly increased in current smokers compared to never or former smokers. AT-LDL = Alpha1-antitrypsin LDL.

cardiovascular events caused by quitting smoking. Thus, people with diabetes should carefully monitor weight gain after quitting smoking. A randomised controlled trial examined the timing of instruction in weight management when implementing a smoking cessation intervention.14 According to this trial, the rate of successfully quitting smoking decreased when instructions regarding quitting smoking and managing weight were simultaneously provided from the beginning of the intervention. Individuals must be informed of the advantages of quitting smoking and they need to abstain from smoking. Once the individual has consistently abstained from smoking, they must be provided with support to gradually decrease their weight. Exercise therapy and psychological support help limit weight gain after quitting smoking. In conclusion, weight gain generally occurs after smoking cessation and this temporarily increases the risk of diabetes and reduces the benefits of smoking abstinence. The benefits of smoking cessation may be minimised by obesity in those who have stopped smoking. However, continued abstinence from smoking will, over time, outweigh this. CVD risks never increase by stopping smoking, even if excessive weight gain occurs. Based on these results, it is crucial that physicians and other medical professionals support patients to continue smoking cessation and to gradually decrease their weight.

smoking cessation on the prevalence of overweight in the United States. N Engl J Med 1995;333:1165–70. https://doi. org/10.1056/NEJM199511023331801; PMID: 7565970. 6. Aubin HJ, Farley A, Lycett D, et al. Weight gain in smokers after quitting cigarettes: meta-analysis. BMJ 2012;345:e4439. https://doi.org/10.1136/bmj.e4439; PMID: 22782848. 7. Komiyama M, Wada H, Ura S, et al. Analysis of factors that determine weight gain during smoking cessation therapy. PLoS One 2013;8:e72010. https://doi.org/10.1371/journal. pone.0072010; PMID: 23991026. 8. Wada H, Ura S, Satoh-Asahara N, et al. α1-antitrypsin lowdensity-lipoprotein serves as a marker of smoking-specific oxidative stress. J Atheroscler Thromb 2012;19:47–58. https://doi. org/10.5551/jat.9035; PMID: 22027559. 9. Komiyama M, Wada H, Ura S, et al. The effects of weight gain after smoking cessation on atherogenic α1-antitrypsin–lowdensity lipoprotein. Heart Vessels 2015;30:734–9.https://doi. org/10.1007/s00380-014-0549-9; PMID: 25086816. 10. 10. Komiyama M, Shimada S, Wada H, et al. Time-dependent Changes of Atherosclerotic LDL Complexes after Smoking

11.

12.

13.

14.

Cessation. J Atheroscler Thromb 2016;23:1270–5. https://doi. org/10.5551/jat.34280; PMID: 27298048. Dinh PC, Schrader LA, Svensson CJ, et al. Smoking cessation, weight gain, and risk of stroke among postmenopausal women. Prev Med 2019;118:184–90. https://doi.org/10.1016/j. ypmed.2018.10.018; PMID: 30359645. u Y, Zong G, Liu G, et al. Smoking cessation, weight change, type 2 diabetes, and mortality. N Engl J Med 2018;379:623–32. https://doi.org/10.1056/NEJMoa1803626; PMID: 30110591. Clair C, Rigotti NA, Pormeala B, et al. Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes. JAMA 2013;309:1014–21. https://doi.org/10.1001/jama.2013.1644; PMID: 23483176. Bush T, Lovejoy J, Javitz H, et al. Simultaneous vs. sequential treatment for smoking and weight management in tobacco quitlines: 6 and 12 month outcomes from a randomized trial. BMC Public Health 2018;18:678–90. https://doi.org/10.1186/ s12889-018-5574-7; PMID: 29855294.

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Pharmacotherapy

Cardiovascular Imaging and Theranostics in Cardiovascular Pharmacotherapy Mattia Cattaneo, 1,2 Alberto Froio 3 and Augusto Gallino 1,4 1. Cardiovascular Research Unit, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; 2. Department of Cardiovascular Intensive Care, Cardiocentro Ticino, Lugano, Switzerland; 3. Department of Surgery and Interdisciplinary Medicine, University of Milano-Bicocca, Milan, Italy; 4. University of Zurich, Zurich, Switzerland

Abstract Imaging plays a pivotal role in the diagnostic and prognostic assessment of cardiovascular diseases. During the past two decades, there has been an expansion of the available imaging techniques, some of which are now part of routine clinical practice. Cardiovascular imaging of atherosclerosis is a useful instrument, and it can corroborate and expand pathophysiological evidence on cardiovascular disease, providing proof of concept for medical therapy and can predict its responsiveness, and it may be able to be used as surrogate endpoints for clinical trials. Theranostics is an emerging therapy that combines imaging and therapeutic functions, using imaging-based therapeutic delivery systems. Theranostics could partially overcome current imaging limitations and translate experimental evidence and large-scale trials assessing clinical endpoints, rationalising cardiovascular drug development and paving the way to personalised medicine. The medical community cannot overlook the use of cardiovascular imaging as a complementary and supportive adjunct to trials investigating clinical endpoints, which remain the mainstay for investigating the efficacy and safety of cardiovascular pharmacotherapy.

Keywords Atherosclerosis, imaging, theranostic, cardiovascular pharmacotherapy Disclosure: MC has received research grants from the Swiss Heart Foundation unrelated to this topic. AG has received research grants from the Swiss Heart Foundation related to this topic. AF has no conflicts of interest to declare. Received: 20 January 2019 Accepted: 28 January 2019 Citation: European Cardiology Review 2019;14(1):62–4. DOI: https://doi.org/10.15420/ecr.2019.6.1 Correspondence: Mattia Cattaneo, Cardiovascular Research Unit, Ospedale Regionale di Bellinzona e Valli, 6500 Bellinzona, Switzerland. E: mm.cattaneo2@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Imaging has played an instrumental role in the diagnostic and prognostic assessment of cardiovascular diseases. Arterial Doppler ultrasound, echocardiography, myocardial perfusion imaging tests and angiography are now part of everyday clinical practice and represent a cornerstone of atherosclerosis management.1 During the past two decades, there has been an expansion of the available imaging techniques, some of which give us greater understanding of atherosclerosis in both coronary and peripheral arteries. This article summarises the current and potential role and limitations of emerging imaging techniques in demonstrating mechanisms of atherosclerosis, focusing on the potential translational role of theranostics in cardiovascular drug design and personalised cardiovascular medicine.

Cardiovascular Imaging: A Growing Field Acute cardiovascular events result from the multifaceted relationship between a patient’s atherosclerotic risk factors and local factors, such as the location, burden, metabolic and functional characteristics of atherosclerotic disease that go beyond simple lumen stenosis.2–4 Consequently, scientific interest has moved from the degree of the lumen stenosis to investigating vessel wall structure, haemodynamic features, and the molecular and cellular mechanisms underlying atherogenesis, progression and thrombosis. Optical coherence tomography (OCT); coronary intravascular ultrasound (IVUS); coronary CT angiography; high-resolution MRI; nuclear imaging such as PET and spectroscopy; molecular imaging by contrast media for OCT,

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ultrasound and MRI; and fusion imaging have the potential to broaden our structural, functional and biological understanding of plaque.5–9 Likewise, computational flow dynamics allows the appraisal of the biomechanical factors of atherosclerosis.10 These invasive and non-invasive techniques are shedding light on the identification of vulnerable plaque, which is one of the greatest challenges in cardiovascular medicine. Cardiovascular imaging has provided the proof of concept for medical therapy such as the stabilisation and regression of atherosclerosis with statins and, more recently, by the use of the PKSK9 inhibitors.11,12 Notably, cardiovascular imaging may be able to anticipate the beneficial effect of pharmacological agents on clinical endpoints and patients’ potential responsiveness to these agents.13 However, this may not provide sufficient evidence to change clinical practice, since it should be supported by large-scale trials possibly assessing both imaging and clinical endpoints. This would allow a rationalisation of cardiovascular drug development.

Limitations and Perspectives Currently, there is no consensus on the specific roles of different imaging modalities or the best targets for imaging in the clinical setting. Despite the expectations for being able to phenotype atherosclerosis by distinct features, imaging cannot predict clinical outcome with sufficient accuracy as a standalone technique. This is exemplified by

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Imaging and Theranostics in Cardiovascular Pharmacotherapy a randomised clinical trial of dalcetrapid, which failed to demonstrate a reduction in major cardiovascular events, despite initial encouraging results in MRI and PET/CT primary endpoints.14,15 An explanation may reside in the inability of the imaging’s surrogate endpoints to detect either the ancillary and/or systemic mechanisms of action of the drug being investigated or any genetic differences among patients that may affect the clinical outcome. The concept of the risk continuum in atherosclerosis is progressively taking over from the categorical classification of vulnerable plaque, and the vulnerable plaque (rupture- and erosion-prone) concept is being integrated with the vulnerable patient concept.16–19 Naghavi et al. have suggested a cumulative vulnerability index to assess total vulnerability burden and strengthening traditional risk assessment strategies with imaging and biological findings. This should include the consideration of local, systemic and haematic features and myocardial vulnerability.16 The scientific community must also consider the setbacks that hinder the translatability of the existing imaging techniques, particularly for radiation, contrast media exposure and high costs.20

Theranostics Considering the complexity, rationalising cardiovascular drug development and moving towards personalised, preventive and therapeutic medicine should be a mainstay of future research. Theranostics could be used to help bridge the gap between experimental evidence and large-scale trials. Theranostics combines imaging and therapeutic functions by using imaging-based therapeutic delivery systems. Studies have employed nanoparticles for contrast agent-assisted diagnostic imaging, therapeutic delivery and subsequent evaluation of therapeutic efficacy. Theranostics is a result of advances in multiple natural and material sciences, particularly nanotechnology. Primarily used in oncology, it has been gradually applied to early and late atherosclerotic lesions with encouraging results.21 In theranostics, drug delivery and subsequent action in a region of interest is controlled by an external energy field – mostly ultrasound, light, or a magnetic field – in an attempt to minimise systemic and local effects.22 Ultrasound’s intrinsic technical characteristics, including real-time imaging to avoid radiation, allowed its early implementation in theranostic. The Combined Lysis of Thrombus in Brain Ischemia using

Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. https://doi. org/10.1056/NEJMoa0807611; PMID: 19144937. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:2045–51. https://doi.org/10.1161/ ATVBAHA.108.179705; PMID: 22895665. Arbab-Zadeh A, Fuster V. The myth of the “vulnerable plaque”: transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J Am Coll Cardiol 2015;65:846–55. https://doi. org/10.1016/j.jacc.2014.11.041; PMID: 25601032. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226–35. https://doi.org/10.1056/NEJMoa1002358; PMID: 21247313. Ali ZA, Karimi Galougahi K, Maehara A, et al. Intracoronary optical coherence tomography 2018: current status and future directions. JACC Cardiovasc Interv 2017;10:2473–87. https://doi.org/10.1016/j.jcin.2017.09.042; PMID: 29268880. Matthews SD, Frishman WH. A review of the clinical utility of intravascular ultrasound and optical coherence tomography in the assessment and treatment of coronary artery disease. Cardiol Rev 2017;25:68–76. https://doi.org/10.1097/ CRD.0000000000000128; PMID: 28099219. Foy AJ, Dhruva SS, Peterson B, et al. Coronary computed tomography angiography vs functional stress testing for

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10.

11.

12.

13.

Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial and a later meta-analysis demonstrated the efficacy of ultrasound-enhanced fibrinolysis.23,24 However, this was not supported by a recent multicentre randomised controlled trial, showing no benefit in sonothrombolysis delivered within 3 hours of symptom onset over classical thrombolysis by alteplase.25 Contrast-enhanced ultrasound-targeted microbubbles have been used to promote angiogenesis in a model of critical limb ischaemia, to attenuated arterial neointimal formation and reduce microvascular dysfunction after acute MI in a large animal model.26–29 Based on a similar principle, MRI has been used for site-specific vascular intervention. A magnetic field attracts and activates metallic nanoparticles with a protective coating to detect and inhibit inflammatory processes in atherosclerosis.30,31 In another study, gold nanorods were synthesised to diagnose and attenuate macrophage activity and release by delivering photodynamic therapy.32,33 Similarly, paramagnetic nanoparticles have delivered anti-proliferative drugs and micro-RNA to inhibit either proliferation of smooth muscle cells or angiogenesis.34,35 In the past 5 years, a variety of new nanoparticles targeting lipids, inflammation signalling, vascular growth factors, endothelial function, oxidative stress, platelets function and apoptosis signalling have been delivered in pre-clinical studies using MRI, nuclear imaging and novel technical advances such as photoacoustic imaging.36,37 The development of imaging systems specifically designed for theranostic use will improve its potential. However, unsolved issues related to potential harmful exposures and costs need to be addressed before application of theranostics in extended human research and clinical practice could be feasible.

Conclusion Cardiovascular imaging of atherosclerosis is a useful instrument, which corroborates and expands pathophysiological evidence on cardiovascular disease, and provides proof of concepts for medical therapy. It might also be used to anticipate the beneficial effect on clinical endpoints and the responsiveness to medical therapy and can represent surrogate endpoints in clinical trials. Theranostics could further translate experimental evidence and large-scale trials assessing clinical endpoints, rationalising cardiovascular drug development and paving the way to more personalised medicine.

patients with suspected coronary artery disease: a systematic review and meta-analysis. JAMA Intern Med 2017;177:1623–31. https://doi.org/10.1001/jamainternmed.2017.4772; PMID: 28973101. den Hartog AG, Bovens SM, Koning W, et al. Current status of clinical magnetic resonance imaging for plaque characterisation in patients with carotid artery stenosis. Eur J Vasc Endovasc Surg 2013;45:7–21. https://doi.org/10.1016/j. ejvs.2012.10.022; PMID: 23200607. Osborn EA, Jaffer FA. The advancing clinical impact of molecular imaging in CVD. JACC Cardiovasc Imaging 2013;6:1327– 41. https://doi.org/10.1016/j.jcmg.2013.09.014; PMID: 24332285. Kwak BR, Back M, Bochaton-Piallat ML, et al. Biomechanical factors in atherosclerosis: mechanisms and clinical implicationsdagger. Eur Heart J 2014;35:3013–20. https://doi. org/10.1093/eurheartj/ehu353; PMID: 25230814. Girotra S, Murarka S, Migrino RQ. Plaque regression and improved clinical outcomes following statin treatment in atherosclerosis. Panminerva Med 2012;54:71–81. PMID: 22525562. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 2016;316:2373–84. https://doi.org/10.1001/jama.2016.16951; PMID: 27846344. van Thienen JV, Fledderus JO, Dekker RJ, et al. Shear stress sustains atheroprotective endothelial KLF2 expression

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more potently than statins through mRNA stabilization. Cardiovasc Res 2006;72:231–40. https://doi.org/10.1016/j. cardiores.2006.07.008; PMID: 16945356. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–99. https://doi.org/10.1056/NEJMoa1206797; PMID: 23126252. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;378:1547–59. https://doi. org/10.1056/10.1016/S0140-6736(11)61383-4; PMID: 21908036. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 2003;108:1772–8. https://doi.org/10.1161/01.CIR.0000087481.55887.C9; PMID: 14557340. Baber U, Mehran R, Sartori S, et al. Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study. J Am Coll Cardiol 2015;65:1065–74. https://doi.org/10.1016/j. jacc.2015.01.017; PMID: 25790876. Libby P, Pasterkamp G. Requiem for the ‘vulnerable plaque’. Eur Heart J 2015;36:2984–7. https://doi.org/10.1093/eurheartj/ ehv349; PMID: 26206212. Arbab-Zadeh A, Fuster V. The risk continuum of atherosclerosis and its implications for defining CHD by

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coronary angiography. J Am Coll Cardiol 2016;68:2467–78. https://doi.org/10.1016/j.jacc.2016.08.069; PMID: 27908353. Gallino A, Stuber M, Crea F, et al. “In vivo” imaging of atherosclerosis. Atherosclerosis 2012;224:25–36. https://doi. org/10.1016/j.atherosclerosis.2012.04.007; PMID: 22682779. Schinkel AF, Kaspar M, Staub D. Contrast-enhanced ultrasound: clinical applications in patients with atherosclerosis. Int J Cardiovasc Imaging 2016;32:35–48. https:// doi.org/10.1007/s10554-015-0713-z; PMID: 26206524. Eraso LH, Reilly MP, Sehgal C, et al. Emerging diagnostic and therapeutic molecular imaging applications in vascular disease. Vasc Med 2011;16:145–56. https://doi. org/10.1177/1358863X10392474; PMID: 21310769. Tsivgoulis G, Eggers J, Ribo M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke 2010;41:280–7. https://doi.org/10.1161/ STROKEAHA.109.563304; PMID: 20044531. Barreto AD, Alexandrov AV, Shen L, et al. CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke. Stroke 2013;44:3376–81. https://doi.org/10.1161/ STROKEAHA.113.002713; PMID: 24159060. Alexandrov AV, Köhrmann M, Soinne L, et al. Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial. CLOTBUST-ER Trial. Lancet Neurol 2019;18:338–47. https://doi.org/10.1016/S1474-4422(19)30026-2; PMID: 30878103. Leong-Poi H, Kuliszewski MA, Lekas M, et al. Therapeutic

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arteriogenesis by ultrasound-mediated VEGF165 plasmid gene delivery to chronically ischemic skeletal muscle. Circ Res 2007;101:295–303. https://doi.org/10.1161/ CIRCRESAHA.107.148676; PMID: 17585071. Kobulnik J, Kuliszewski MA, Stewart DJ, et al. Comparison of gene delivery techniques for therapeutic angiogenesis ultrasound-mediated destruction of carrier microbubbles versus direct intramuscular injection. J Am Coll Cardiol 2009;54:1735–42. https://doi.org/10.1016/j.jacc.2009.07.023; PMID: 19850216. Suzuki J, Ogawa M, Takayama K, et al. Ultrasoundmicrobubble-mediated intercellular adhesion molecule-1 small interfering ribonucleic acid transfection attenuates neointimal formation after arterial injury in mice. J Am Coll Cardiol 2010;55:904–13. https://doi.org/10.1016/j. jacc.2009.09.054; PMID: 20185042. Xie F, Lof J, Matsunaga T, et al. Diagnostic ultrasound combined with glycoprotein IIb/IIIa-targeted microbubbles improves microvascular recovery after acute coronary thrombotic occlusions. Circulation 2009;119:1378–85. https://doi.org/10.1161/CIRCULATIONAHA.108.825067; PMID: 19255341. Sun C, Lee JS, Zhang M. Magnetic nanoparticles in MR imaging and drug delivery. Adv Drug Deliv Rev 2008;60:1252–65. https://doi.org/10.1016/j.addr.2008.03.018; PMID: 18558452. Palekar RU, Jallouk AP, Lanza GM, et al. Molecular imaging of atherosclerosis with nanoparticle-based fluorinated MRI contrast agents. Nanomedicine (Lond) 2015;10:1817–32. https:// doi.org/10.2217/nnm.15.26; PMID: 26080701. Shon SM, Choi Y, Kim JY, et al. Photodynamic therapy

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using a protease-mediated theranostic agent reduces cathepsin-B activity in mouse atheromata in vivo. Arterioscler Thromb Vasc Biol 2013;33:1360–5. https://doi.org/10.1161/ ATVBAHA.113.301290; PMID: 23539220. Qin J, Peng Z, Li B, et al. Gold nanorods as a theranostic platform for in vitro and in vivo imaging and photothermal therapy of inflammatory macrophages. Nanoscale 2015;7:13991–4001. https://doi.org/10.1039/C5NR02521D; PMID: 26228112. Lanza GM, Yu X, Winter PM, et al. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation 2002;106:2842–7. https://doi.org/10.1161/01. CIR.0000044020.27990.32; PMID: 12451012. Winter PM, Neubauer AM, Caruthers SD, et al. Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol 2006;26:2103–9. https://doi.org/10.1161/01. ATV.0000235724.11299.76; PMID: 16825592. Bejarano J, Navarro-Marquez M, Morales-Zavala F, et al. Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: evolution toward prospective theranostic approaches. Theranostics 2018;8:4710–32. https://doi.org/10.7150/thno.26284; PMID: 30279733. Jung E, Kang C, Lee J, et al. Molecularly engineered theranostic nanoparticles for thrombosed vessels: h2o2activatable contrast-enhanced photoacoustic imaging and antithrombotic therapy. ACS Nano 2018;12:392–401. https:// doi.org/10.1021/acsnano.7b06560; PMID: 29257881.

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AF in Cancer Patients: A Different Need for Anticoagulation? Ana Pardo Sanz 1 and José Luis Zamorano Gómez 1,2 1. Cardiology Department, Ramón y Cajal Hospital, Madrid, Spain; 2. Cardiology Department, University of Alcalá, University Hospital La Zarzuela, Spain

Abstract Cancer and cancer therapies might be a risk factor for developing Atrial Fibrillation (AF). It remains unclear if one is the cause or consequence of the other, or if they simply coexist. An unpredictable response to anticoagulation can be expected, as a result of the lack of information in oncology patients. The balance between thromboembolic and bleeding risks of AF in these patients is particularly challenging. Little is known about whether embolic and bleeding risk scores used for the general population can be applied in oncologic patients. Cardiology involvement in the management of these patients seems to be associated with favourable AF-related outcomes.

Keywords Anticoagulation, cancer, cardio-oncology, vitamin K antagonist, direct oral anticoagulants, bleeding risk, embolic risk Disclosure: The authors have no conflicts of interest to declare. Received: 19 December 2018 Accepted: 10 February 2019 Citation: European Cardiology Review 2019;14(1):65–7. DOI: https://doi.org/10.15420/ecr.2018.32.2 Correspondence: Ana Pardo Sanz, Carretera de Colmenar Km 9,100 28034 Madrid, Spain. Email: anapardosanz0@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Search Strategy An independent literature search was performed on the topic ‘AF in cancer patients’ with the assistance of professional librarians. The search terms included anticoagulation, cancer, cardioncology, vitamin K antagonist, direct oral anticoagulants, bleeding risk and embolic risk. An electronic search was conducted using a minimum of two major databases (Cochrane Registry, MEDLINE) to identify relevant systematic reviews, randomised clinical trials and high-quality observational studies about the topic.

risk of cancer was threefold greater within 3 months of AF diagnosis and still elevated beyond 1 year. On the other hand, the risk of incident AF after diagnosis of cancer was 20% higher in the first 3 months after diagnosis of cancer, but not beyond.6 In the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), it was found that approximately one in four AF patients had a history of cancer.7 Patients with both diagnoses had a higher burden of cardiovascular risk factors and concomitant cardiovascular disease.

AF and Cancer AF is the most common sustained cardiac arrhythmia, with an estimated prevalence of 3% in adults aged 20 years, and higher in older people.1 An association between AF and malignant cancer has been reported, but is incompletely defined.2 Cancer is one of the chronic pathologies whose survival has increased in past decades. The onset of AF may be related to comorbidities, direct tumour effects, or it can be triggered by paraneoplastic conditions, left ventricular dysfunction or toxic effects of cancer treatment. It remains unclear if cancer acts as a risk factor or a marker of the arrhythmia, and the relationship between AF and cancer seems to be bidirectional. It has even been suggested that AF may act as a marker for occult cancer.3 In surgical patients admitted with a new diagnosis of colorectal or breast cancer, AF was twice as common (3.6% versus 1.6%) compared with patients admitted for non-neoplastic surgery.4 The highest incidence of cancer-related AF has been described in postoperative in patients undergoing lung resection.5 In the large Women’s Health Study cohort, the authors reported that the incidence of cancer was significantly higher in women with AF than in women without AF. The

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Specific Risks of AF in Cancer Patients Cancer is a prothrombotic state leading to increased risk of stroke.8 Moreover, stroke in patients with cancer has been associated with worse outcomes, including prolonged hospitalisation and disability, when compared with cerebrovascular events in patients without cancer.9 Some anticancer therapies have been associated with both thromboembolic complications and increased risk of bleeding events.10 Traditionally, anticoagulant therapy with warfarin has been the mainstay of treatment for stroke and systemic thromboembolism prevention in patients with AF. Its dose is adjusted by monitoring the international normalised ratio (INR). Maintaining INR at target is generally more difficult in cancer patients as a result of drug–drug interactions between warfarin and cancer treatment, changes in renal and hepatic function, dietary/nutritional status, chemotherapeutic toxicity and disease state. There are no current INR monitoring guidelines for patients with AF and concurrent malignancy.11 In the ORBIT-AF trial, AF patients with history of cancer treated with warfarin required more INR checks to obtain the target INR, compared with patients who did not have a history of cancer, but overall time in

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Pharmacotherapy therapeutic range was similar.7 In this study, the risk of stroke, systemic embolism, heart failure and cardiovascular death was similar between those with and without a history of cancer, but patients with a history of cancer were at higher risk of major bleeding.

factors and concomitant medications can influence VKA activity in patients with cancer and maintaining INR at target is challenging.18 A higher rate of thrombotic events has been described, regardless of the indication for anticoagulation.19

Risk Scores in Cancer Patients

Low-molecular-weight heparins seem to have a more favourable profile in this group of patients, and potential antitumour and antimetastatic effects have been suggested in some studies, although these effects have not been confirmed.20 There is a clear reduction in quality of life associated with long-term administration of subcutaneous drugs.

A European Society of Cardiology position paper admits that the embolic-haemorrhagic risk balance can be modified in AF and cancer, and points out the lack of validation of the main risk prediction scales CHA2DS2-VASc and HAS-BLED. When proposing anticoagulant treatment for cancer patients with AF, the same recommendations are followed as in non-oncological patients, despite the lack of specific evidence.12 Patell et al. found CHADS 2 and CHA 2DS2-VASc predicted risk of ischaemic stroke in cancer patients with baseline AF.13 CHADS2 score was more predictive of increased risk of stroke in patients with cancer and AF than CHA 2DS 2-VASc. Similarly, Hu et al. showed that in patients with cancer and pre-existing AF, increasing CHADS2 was predictive of new thromboembolism (CHADS 2 0–1: 6.7%, CHADS2 2–3: 15.8%, CHADS2 4–6: 27.0%; p=0.004).14 Patell et al. also found that a higher CHADS2 score was associated with increased mortality (HR 1.24; 95% CI [1.17–1.32]; p<0.001).13 However, Hu et al. found that CHADS2 was not associated with mortality (CHADS2 0–1: 32.0%, CHADS2 2–3: 34.2% and CHADS2 4–6: 35.6%; p=0.560).14

The advent of direct-acting oral anticoagulants (DOACs) – dabigatran, apixaban, rivaroxaban and edoxaban – has led to a revolution in the antithrombotic treatment of AF. In pivotal studies, a dosage of 150 mg twice daily of dabigatran reduced stroke and systemic embolism compared with warfarin, without significant differences in bleeding events, while dabigatran at a dosage of 110 mg twice daily was non-inferior to warfarin for prevention of stroke and embolism, with less bleeding. In this study, patients with a diagnosis of cancer were excluded.21 A dosage of 5 mg twice daily of apixaban also decreased the rate of bleeding and mortality – with greater protection against strokes and embolisms – than warfarin. Patients with a life expectancy of less than a year were excluded.22

A Different Treatment for Cancer Patients? The selection of antithrombotic therapy in patients with AF and cancer is challenging. European clinical practice guidelines for the management of AF make no distinctions in patients with concomitant oncological pathology, applying the same criteria for the use of antithrombotic treatment as in the general population.15 Little is known about how patients with AF and cancer are routinely treated in clinical practice and whether their risk for embolic or bleeding events is higher than patients without cancer. A study by O’Neal et al. aimed to examine the relationship between early cardiology involvement after AF diagnosis in patients with cancer.16 They found that cardiology involvement was less likely to occur among patients with a history of cancer than those without. Patients with a history of cancer were less likely to fill prescriptions for anticoagulants than those without cancer. Cardiology involvement was associated with increased anticoagulant prescription fills and favourable AF-related outcomes in AF patients with cancer (reduced risk of stroke without increased risk of bleeding).16 Patients with AF and a history of cancer carry a high burden of cardiovascular risk factors and frequently have cardiovascular disease. They appear to be similarly treated with antithrombotic and anticoagulant therapy, but in some studies they experience a higher risk of major bleeding than AF patients without cancer.7 Ning et al. followed 1,807 cancer patients for 7 years, noting that the cause of death in 51% was cancer, but in up to 33% it was cardiovascular disease that was the first cause of death not related to cancer.17 This shows the importance of cardiovascular disease in cancer patients. It is essential to try to optimally manage both pathologies, especially embolic and bleeding risk in AF. Patients with cancer may experience erratic control of INR. Therefore, vitamin K antagonists (VKAs) may not be the optimal anticoagulants for cancer patients, especially during chemotherapy. Both nutritional

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Rivaroxaban once daily proved non-inferior to warfarin for the prevention of strokes and embolisms, with a lower incidence of intracranial bleeding. Patients with a life expectancy of less than 2 years were excluded, so it is hard to obtain conclusions valid for cancer patients.23 In the Global Study to Assess the Safety and Effectiveness of Edoxaban versus Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGE-AF-TIMI 48), more than 21,000 patients with nonvalvular AF were randomised to warfarin or edoxaban. Edoxaban 60 mg once daily was non-inferior to warfarin, but it significantly reduced bleeding events and cardiovascular death.24 While all of these drugs have been tested in the general population, available information in patients with cancer and AF is scarce. Although cancer did not constitute an absolute contraindication for participation in the clinical trials, patients with a short life expectancy were excluded. As such, we do not have specific data on the safety and efficacy of DOACs in patients with AF and cancer. In the pivotal clinical trials of DOACs for patients with deep vein thrombosis, the number of patients with cancer was also small, between 2.6% and 6.0%. In addition, information on the type of cancer, the stage and the concomitant use of chemotherapy were not collected. These are retrospective analyses of the original trails, and the number of patients with cancer was too low to obtain solid conclusions.21–24 The relationship between stroke and cancer is complex. Stroke is common in cancer patients, and cancer patients with ischaemic stroke often show different risk factors, stroke biomarkers and stroke aetiology compared with non-cancer patients with ischaemic stroke.25 There has been controversy in regard to the risk factors in the pathogenesis of stroke in cancer patients. The presence of a hypercoagulable state and increased D-dimer levels are common.26,27 In a subanalysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in

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AF in Cancer Patients Atrial Fibrillation (ROCKET-AF), after adjusting for competing risks, the estimated 1-year cumulative incidence of ischaemic stroke in patients with cancer and AF was 1.4% (95% CI [0.0–3.4]).28

to bleeding, such as colorectal cancer. Also, the study by Zhang et al. showed a trend towards greater intracranial bleeding in patients with cancer and AF.31

In a subanalysis of the Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial, the subgroup of patients with cancer showed no significant associations between history of cancer and stroke/systemic embolism, major bleeding or death.29 The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, MI and death in active cancer (HR 0.30; 95% CI [0.11–0.83]) versus without cancer (HR 0.86; 95% CI [0.78-0.95]).

No specific clinical trials have been conducted comparing the use of DOAC versus VKA in cancer patients; all we have are observational studies. In the study by Shah et al., which included 16,000 patients with AF and cancer, the risk of major bleeding was significantly lower in patients taking apixaban than in patients taking VKA, rivaroxaban or dabigatran.10

In contrast, there is another analysis in regard to the behaviour of patients with cancer from ENGAGE-AF-TIMI 48.30 In the original trial there were 21,105 patients with AF randomised to edoxaban or warfarin.24 Patients with active malignancy – defined as a postrandomisation new diagnosis or recurrence of remote cancer – were followed for clinical events over a median 2.8 years. Patients with active malignancy, compared with those without, had increased death (12.0% per year versus 3.6% per year; univariate HR 3.3; 95% CI [3.0–3.7]) and major bleeding (7.4% per year versus 2.5% per year; HR 2.9; 95% CI [2.4–3.4]), but not stroke or systemic embolism (HR 0.8; 95% CI [0.6–1.2]). In the analysis by subgroup of ROCKET-AF and the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, the risk of bleeding in cancer patients was two- to six-times higher than in patients without cancer.21,23 This is probably because the pathology of our patients (breast cancer) does not confer a special tendency to bleeding, and in these studies the few patients with cancer who were analysed included other types of cancer with greater predisposition

Z oni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. https://doi.org/10.2147/CLEP.S47385; PMID: 24966695. 2. Farmakis D, Parissis J, Filippatos G. Insights into oncocardiology: atrial fibrillation in cancer. J Am Coll Cardiol 2014;63:945–53. https://doi.org/10.1016/j.jacc.2013.11.026; PMID: 24361314. 3. Ostenfeld EB, Erichsen R, Pedersen L, et al. Atrial fibrillation as a marker of occult cancer. PLoS One 2014;9:1–6. https://doi. org/10.1371/journal.pone.0102861; PMID: 25119880. 4. Guzzetti S, Costantino G, Vernocchi A, et al. First diagnosis of colorectal or breast cancer and prevalence of atrial fibrillation. Intern Emerg Med 2008;3:227–31. https://doi. org/10.1007/s11739-008-0124-4; PMID: 18320149. 5. Onaitis M, D’Amico T, Zhao Y, et al. Risk factors for atrial fibrillation after lung cancer surgery:. Ann Thorac Surg 2010;90:368–74. https://doi.org/10.1016/j. athoracsur.2010.03.100; PMID: 20667313. 6. Conen D, Wong JA, Sandhu RK, et al. Risk of malignant cancer among women with new-onset atrial fibrillation. JAMA Cardiol 2016;1:389–96. https://doi.org/10.1001/jamacardio.2016.0280; PMID: 27438314. 7. Melloni C, Shrader P, Carver J, et al. Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry. Eur Heart J Qual Care Clin Outcomes 2017;3:192–7. https://doi.org/10.1093/ehjqcco/qcx004; PMID: 28838088. 8. Rogers LR. Cerebrovascular complications in patients with cancer. Semin Neurol 2010;3:311–9. https://doi. org/10.1055/s-0030-1255224; PMID: 20577937. 9. Grisold W, Oberdonfer S, Struhal W. Stroke and cancer: a review. Acta Neurol Scand 2009;119:1–16. https://doi. org/10.1111/j.1600-0404.2008.01059.x; PMID: 18616624. 10. Shah S, Norby FL, Datta YH, et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv 2018;2:200–9. https://doi.org/10.1182/bloodadvances.2017010694. PMID: 29378726. 11. Pangilinan JM, Pangilinan PH Jr, Worden FP. Use of warfarin in the patient with cancer. J Support Oncol 2007;5:131–6. PMID: 17410812.

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With the available data, the lack of evidence for the use of DOACs in cancer patients means that their use must be discussed in each patient. Fluctuations in renal and hepatic function may affect the levels of these drugs and dose adjustments may be required. The pharmacokinetic properties of cancer therapies should be taken into account when considering the use of DOAC in patients having active chemotherapeutic treatment, although data on the clinical relevance of the interactions are scarce. Until clinical trials are conducted to verify the efficacy and usefulness of DOAC specifically in oncological patients, the clinician should rely on observational studies, as more robust evidence is not available.

Conclusion The management of antithrombotic therapy for stroke prevention in oncologic patients with AF is challenging and it can determine their outcomes in terms of bleeding and embolic events. It requires involvement of cardiologists and oncologists to individualise the treatment for each case and offer the best therapy. Specific clinical trials are needed to assess the best treatment for these patients. Given the available data from observational studies, DOACs seem to be a safe choice for this group of patients.

12. Z amorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J 2016;37:2768–801. https:// doi.org/10.1093/eurheartj/ehw211; PMID: 27567406. 13. Patell R, Gutierrez A, Rybicki L, Khorana AA. Usefulness of CHADS2 and CHA2DS2-VASc scores for stroke prediction in patients with cancer and atrial fibrillation. Am J Cardiol 2017;120:2182–6. https://doi.org/10.1016/j. amjcard.2017.08.038; PMID: 29033049. 14. Hu YF, Liu CJ, Chang PM, et al. Incident thromboembolism and heart failure associated with new-onset atrial fibrillation in cancer patients. Int J Cardiol 2013;165:355–7. https://doi. org/10.1016/j.ijcard.2012.08.036; PMID: 22989607. 15. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi.org/10.1093/eurheartj/ehw210; PMID: 27663299. 16. O’Neal WT, Claxton JS, Sandesara PB, et al. Provider specialty, anticoagulation, and stroke risk in patients with atrial fibrillation and cancer. J Am Coll Cardiol 2018;72:1913–22. https://doi.org/10.1016/j.jacc.2018.07.077; PMID: 30309468. 17. Ning Y, Shen Q, Herrick K, et al. Cause of death in cancer survivors. Cancer Res 2012;72:339. https://doi. org/10.1158/1538-7445.AM2012-LB-339. 18. Rose AJ, Sharman JP, Ozonoff A, et al. Effectiveness of warfarin among patients with cancer. J Gen Intern Med 2007;22:997–1002. https://doi.org/10.1007/s11606-0070228-y; PMID: 17476542. 19. Palareti G, Legnani C, Lee A, et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000;84:805–10. PMID: 11127860. 20. Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecularweight heparin. J Thromb Haemost 2003;1:1972–6. https://doi. org/10.1046/j.1538-7836.2003.00341.x; PMID: 12941039. 21. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. https://doi.org/10.1056/NEJMoa0905561;

PMID: 19717844. 22. G ranger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. https://doi.org/10.1056/NEJMoa1107039; PMID: 21870978. 23. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. https://doi.org/10.1056/NEJMoa1009638; PMID: 21830957. 24. Giugliano RP, Ruff CT, Braunwald E, et al. A-T 48. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. https://doi.org/10.1056/NEJMoa1310907; PMID: 24251359. 25. Kim K, Lee J-H. Risk factors and biomarkers of ischemic stroke in cancer patients. J Stroke 2014;16:91. https://doi. org/10.5853/jos.2014.16.2.91; PMID: 24949315. 26. Kim SG, Hong JM, Kim HY, et al. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke 2010;41:798–801. https:// doi.org/10.1161/STROKEAHA.109.571356; PMID: 20150545. 27. Seok JM, Kim SG, Kim JW, et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010;68:213–9. https://doi.org/10.1002/ana.22050; PMID: 20695014. 28. Laube ES, Yu A, Gupta D, et al. Rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation and active cancer. Am J Cardiol 2017;4:213–7. https://doi. org/10.1016/j.amjcard.2017.04.009; PMID: 28549819. 29. Melloni C, Dunning A, Granger CB, et al. Efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation and a history of cancer: insights from the ARISTOTLE trial. Am J Med 2017;130:1440–8. https://doi.org/10.1016/j. amjmed.2017.06.026; PMID: 28739198. 30. Fanola C, Ruff C, Murphy S, et al. Efficacy and safety of edoxaban in patients with atrial fibrillation and active malignancy: an analysis of ENGAGE AF-TIMI 48 randomized clinical trial. J Am Coll Cardiol 2017;69:325. https://doi. org/10.1016/S0735-1097(17)33714-2. 31. Zhang YY, Chan DK, Cordato D, et al. Stroke risk factor, pattern and outcome in patients with cancer. Acta Neurol Scand 2006;114:378–83. https://doi.org/10.1111/j.16000404.2006.00709.x; PMID: 17083337.

17/04/2019 15:30

Cardiology Masters

Featuring: Antonio Bayés de Luna

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 issue, we feature Professor Antonio Bayés de Luna, Senior Researcher at the Cardiovascular Research Foundation, Cardiovascular ICCC-Program, Research Institute, Hospital de Sant Pau, IIB Sant Pau, Barcelona, Spain. DOI: https://doi.org/10.154210/ecr.2019.14.1.CM1

Antonio Bayés de Luna is professor of cardiology at the University of Barcelona and a cardiologist at Hospital de Sant Pau in Barcelona, Spain. He studied cardiology at the University of Barcelona and the Institute of Cardiology at Hammersmith Hospital in London. Professor Bayés de Luna has served as Director of the Catalan Institute of Cardiology and the Hospital de la Santa Creu and Sant Pau in Barcelona. He has held senior positions in leading cardiovascular societies including president of the World Heart Federation, founder and first president of the Catalan Society of Cardiology, president of the Spanish Society of Cardiology, and president of the International Society of Cardiovascular Pharmacotherapy. He is an honorary doctor at the University of Lisbon and the Hungarian Academy of Sciences in Budapest. In 2003, he received the Creu de Sant Jordi award for his services to cardiology. This is the second-highest civil distinction awarded in Catalonia. Professor Bayés has authored or co-authored hundreds of articles in leading journals and has spoken at many international conferences and meetings around the world.

rt and medicine have been the two great recurring themes in my family. One of my great-grandfathers was Joaquim Vayreda, a famous 19th century landscape painter, whose works hang in the National Art Museum of Catalonia. My sister, who is known simply as Pilarin, is also a nationally known and much-loved artist. She has illustrated hundreds of children’s books and has won many awards. While the art gene appears to run deep in my family, the gene for medicine appears to run even deeper. It was first on display with another of my great-grandfathers, Antoni Bayés i Fuster, a skilled physician remembered primarily for his groundbreaking studies of medicinal waters. He was the first of a line of physicians that has spanned six generations including my grandfather, my father, myself, three of my children and my grandson. Maybe art and medicine are more closely related than some believe. Medicine is a science, but it is also an art, or at least should be approached as such. I have always felt that it is incumbent upon physicians to not only perform accurate diagnoses, but also to embrace the art of providing emotional support to our patients and their families.

Access at: www.ECRjournal.com

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Trying Years The emotional support I enjoyed during the very trying years of my early childhood undoubtedly played a key role in shaping the person I would become. I was born in Catalonia in 1936, just 4 months before the Spanish Civil War broke out. The years that followed were excruciatingly difficult for Spain and Catalonia. My father was largely absent during the war years, because he did not want to participate in a civil war. My determined mother fought to take care of our family, helped by my father’s parents with whom we lived. Although the war ended in 1939, the harsh years continued through the 1940s. I was fortunate as I had wonderful friends and the school I attended, San Miguel de Vic, was unusually liberal for the time. School became an oasis; a paradise where I could play sports and study maths and science under the tutelage of some very knowledgeable professors.

Predestined As I grew, the decision to pursue a career in medicine became easy. You might say that I was predestined – the only boy in town who

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Cardiology Masters: Antonio Bayés de Luna lived with a father and a grandfather who were both physicians. I had always been motivated by the desire to help people, and I saw that my father and grandfather were happy, despite their heavy workloads.

Antonio Bayés de Luna with his wife, Maria Clara

At the University of Barcelona, I threw myself fully into my studies, and finished at the top of my class, but I was unsure where I would go from there. At the time, the possibilities for young physicians in Spain were limited. My father had trained in Switzerland and specialised in pulmonology, but he recommended that I pursue cardiology. It turned out to be great advice. Thanks to recent advances in cardiac surgery, catheterisation and electrophysiology, cardiology was a speciality with a future – my future. This was the late 1950s and I spent the next 2 years studying at the School of Cardiology and working as an intern at the Clinical University Hospital of Barcelona. The school had recently been founded by four young cardiologists. At the time, the physicians who knew how to auscultate patients and read an ECG were cardiologists. It was there that I met two of my most important mentors, Miguel Torner Soler and Ignacio Balaguer. Prof Torner Soler was a remarkable, mostly self-taught, expert in congenital heart diseases with an exceptional gift for clinical observation and keen semiotic skills. He later became the president of the Spanish Society of Cardiology. Prof Balaguer, who also later served as the president of the Spanish Society of Cardiology, would become a pioneer in epidemiology. He sensed that ischaemic heart disease would be a future plague and in order to treat and prevent coronary atherosclerosis, its risk factors would need to be identified. This was at a time when most people assumed that heart disease was practically untreatable and unpreventable, and non-smokers were considered old-fashioned reactionaries. Essentially, the only drugs available to treat heart diseases were digitalis, nitroglycerin and mercurial diuretics. Along with its magnificent professors, this humble school had been making significant contributions to cardiology research both nationally and internationally. Between 1955 and 1958, researchers at the school published four original articles in the American Heart Journal, then the most prestigious cardiology journal in the world.

Wanderlust This was the exciting and nurturing atmosphere I found myself in after embarking on my new career in cardiology. But in my early 20s, I had an urge to see the world. That was not easy to do in Franco’s Spain and very few had the opportunity to leave. Of the 100 students in my class at medical school, only three of us had this privilege. Fortunately, I had relatives who lived in Gerrards Cross, Buckinghamshire, near London, and for the first time in my life, I ventured far from home. In London, I studied at the Royal Postgraduate Medical School at the Hammersmith Hospital and attended clinical demonstrations at the National Heart Hospital. The demonstrations were given by Paul Wood, widely considered the greatest British cardiologist of his time. Postgraduate physicians from all over the world were travelling to London to learn from him. I was very impressed by what I saw and heard in London, but I was also pleasantly surprised to discover that the remarkable School of Cardiology in Barcelona was not far behind.

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New Responsibilities My time in London was short but memorable. After only 8 months, I was offered a position in Barcelona I felt I could not turn down. I returned to take on a cardiology fellowship at the University Hospital and, shortly thereafter, a consultancy at the Hospital for Cardiac Diseases. My life had changed in another important way, too. It was in England that I met the love of my life, Maria Clara. She and I were from the same town and she was also studying abroad. We met only once in England, but we decided we would see each other again when we came back to Spain. When I returned, I knew it was time to take on adult responsibilities. Maria Clara and I were married when I was 25 and she was 20. We have been married for 56 years and she has been a great and constant source of strength and stability for me. In the years that followed, I became intrigued by the potential of Holter monitoring, a technology that had been developed in the US. I was fascinated by the prospect of being able to record many hours of heart activity and being able to interpret the results in just a few minutes. Having been attracted to non-invasive cardiology in general, I loved the technology and I could sense that it was a great step forward. I became one of the first cardiologists in Europe to use it.

Another Turning Point By this time, the School of Cardiology had moved to a larger space in the port of Barcelona, which provided improved technological resources. But the new location did not meet our growing needs and we were unable to treat the rapidly growing incidence of ischaemic heart disease. In 1970, we moved to the fantastic Hospital de Sant Pau. Along with its beautiful architecture, the Hospital de Sant Pau has a rich history steeped in the finest medical tradition, and it brings out the best in those who are fortunate enough to practise there. I have been blessed to spend more than half of my life at Sant Pau, where I became Chief of Cardiology. It has afforded me great freedom of movement as I have pursued my research – especially in electrophysiology,

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Cardiology Masters Hospital de Sant Pau, Barcelona, where Antonio Bayés de Luna has worked since the 1970s

My interest helped lead to a breakthrough study that was published in the American Heart Journal in 1989. Philippe Coumel, Jean François Leclercq and I studied tapes of patients who had died while wearing Holter devices. We found that the most frequent causes of sudden death were ventricular tachyarrhythmias (84% of cases) and bradyarrhythmias (16%). Only a small percentage of patients presented ischaemic ST changes. And among the patients who died due to bradyarrhythmias, the cause was more likely to be sinus depression than atrioventricular block.

Bayés Syndrome My interest in surface electrocardiography led to another study in the 1980s, published in the European Heart Journal, and for which I am probably best known. We demonstrated that patients with advanced interatrial block (AIB) were more likely to develop AF, and that the longer the P wave duration, the stronger the association. Adrian Baranchuk, who is from Buenos Aires, but practises and teaches in Canada, coined the name Bayés syndrome to describe this association. The syndrome is now well-known, and AIBs are recognised not only as risk markers of AF and stroke in patients with heart disease and we are trying to demonstrate its association with cognitive impairment and dementia. I have continued to devote most of my research to AIBs and their clinical implications, especially if it is necessary to provide anticoagulation for these patients to prevent stroke and cognitive impairment.

Championing ECG One of the paradoxical effects of the enormous expansion of medical knowledge over the years has been a decrease in training and research in the field of surface ECG and ECG interpretation. During specialty training, medical students are now expected to learn at least the basics of many other diagnostic techniques, including cardiac interventions and imaging modalities, and they may get the impression that those are more current and important than a diagnostic technique that is more than a century old.

electrocardiology, sudden death, Holter technology, ischaemic heart disease, silent ischaemia, and diseases of the pericardium. Among other things, I have had the time and resources to write the textbook Clinical Electrocardiography, which was published in Spanish in the 1970s and in English in 1993, and has now been translated into nine languages. It is widely regarded as one of the definitive books on the subject. When I was training and learning about electrocardiography, I found the subject so challenging that I decided to write a book for myself as I wanted to be sure that I understood the subject. Electrocardiography has been a passion of mine. In 1973, I became the chief of the Electrocardiography Laboratory at St Pau Hospital. A few years later, I organised the First International Symposium on Diagnosis and Treatment of Cardiac Arrhythmias and the first symposium on Holter monitoring, both held in Barcelona.

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As time goes on, there are fewer mentors who can provide basic electrophysiological instruction. Most ECG concepts were developed more than 50 years ago and now there is a lack of knowledge, even among cardiologists, about newer aspects of ECG diagnostics and how they correlate with invasive and non-invasive imaging. A few years ago, Miguel Fiol-Sala and I founded what we call the “passionate ECG club” with the support of the International Society for Holter and Noninvasive Electrocardiology. Our aim has been to convey its importance and foster the same passion and enthusiasm in young cardiologists. Prof Fiol-Sala and I also co-authored the book Electrocardiography in Ischemic Heart Disease: Clinical and Imaging Correlations and Prognostic Implications. Recently, several colleagues and I helped demonstrate the current relevance of ECG when correlated with contrast-enhanced cardiac MRI. We discovered what we referred to as the end of an electrocardiographic dogma: for decades, a prominent R wave in V1 had been considered the sign of a posterior MI. But in fact, the appearance of a prominent R wave in V1 reflects a lateral MI in most cases.

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Cardiology Masters: Antonio Bayés de Luna I am also proud to have been part of a study that showed colchicine is the most effective drug to prevent recurrences in patients with pericarditis.

the past. I can leave the administrative duties to the younger folks. Although Maria Clara and I might otherwise be inclined to rest a bit more, our grandchildren have an energising effect.

Hearts and Minds I have been fortunate to lead a rich and rewarding life. In one hand, I’ve had a happy family life with my first passion – my beloved wife and 5 sons (1 boy and 4 girls), who are already in their 50s and have given to us 13 maravelous grandchildren. We are fortunate to live all in Catalonia between Vic and Barcelona, and are able to meet frequently in our family house in Vic. Furthermore, my second passion is my professional activity as a cardiologist. I had the opportunity to be the founder and first president of the Catalan Society of Cardiology in the 1970s, and I was president of the Spanish Society of Cardiology in the 1980s. As president of the World Heart Federation in the 1990s, I had the idea for the first World Heart Day and published the first White Book of World Cardiology. I fervently believe that the developed world has a duty to spread its knowledge to developing countries. Finally, I have been president of the International Society of Cardiovascular Pharmacotherapy, a society that exclusively focuses on all aspects of treatment of heart disease with drugs. These days, I am slowing down a little. I still go to the hospital every day with the same joy, but I do not take on the worries I had in

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For our 50th anniversary, we went to the Olympic Games in London. I have always loved sports, especially the Olympics, and have always been fascinated by those who figure out new and better ways to do things. At the 1968 Olympics, a gangly civil engineering major named Dick Fosbury came out of nowhere to win the gold medal in the high jump by using a technique no one had ever thought of before. He threw himself over the bar backwards and head first. Now, the Fosbury Flop is the standard for all top high jumpers. I am also a fan of the great Spanish tennis player Rafael Nadal because I so admire the intense effort he puts forth on the court. Roger Federer may be a better player technically, but Nadal’s great heart pushes him to perform at the same level, which is a wonderful example for young people. Our minds and our hearts are what set us apart as a species. For me, the greatest joys have come from using my mind to better understand how all of our hearts function, along with the opportunity to share the knowledge I have gained not only with my colleagues in Catalonia and Spain, but also through my books and articles, to many other countries.

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13/04/2019 15:12 12/02/2019 09:10

NASSIR MARROUCHE, MD, FHRS CHAIR, DIGITAL HEALTH SUMMIT

Digital Health Summit Wednesday, May 8, 2019 | San Francisco, CA In partnership with the European Heart Rhythm Association

â&#x20AC;&#x153;HRS aims to take a leadership role in convening the right stakeholders and offering guidance in how to leverage digital health for the benefit of our patients.â&#x20AC;?

The EP community applies more biosensors in and on the human body than any other clinical specialty. Partnerships between digital health technology companies and healthcare providers are essential to ensure the earlier diagnosis and treatment of patients with chronic arrhythmias. We have assembled a diverse group of change agents and thought leaders for the Digital Health Summit with representatives from all stakeholder groups. Moderators and panelists include patients, academic and private practice clinicians, HRS and EHRA leadership, industry pioneers, FDA, CEOs, CMOs, and other key opinion leaders that are currently shaping the dialogue on digital health and bringing digital tech to medicine.

L E A R N M O R E A N D R E G I S T E R T O D AY H R S S E S S I O N S . O R G / D I G I TA L #HRS2019

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ECR 14.1

Articles inside

Foreword - Juan Carlos Kaski