The ESC Textbook of Heart Failure

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The ESC Textbook of

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Petar M Seferovic Andrew J 5 Coats Gerasimos Filippatos Stefan D Anker Johann Bauersachs Giuseppe Rosaro

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European Society

of Cardiology

The ESC Textbook of

Heart Failure

European Society of Cardiology publications portfolio The ESC Textbook of Cardiovascular Medicine (Third Edition) Edited by A. John Camm, Thomas F. Lüscher, Gerald Maurer, and Patrick W. Serruys The ESC Textbook of Preventive Cardiology Edited by Stephan Gielen, Guy De Backer, Massimo Piepoli, and David Wood The EHRA Book of Pacemaker, ICD, and CRT Troubleshooting: Case-​based learning with multiple choice questions Edited by Haran Burri, Carsten Israel, and Jean-​Claude Deharo The EACVI Echo Handbook Edited by Patrizio Lancellotti and Bernard Cosyns The ESC Handbook of Preventive Cardiology: Putting prevention into practice Edited by Catriona Jennings, Ian Graham, and Stephan Gielen The EACVI Textbook of Echocardiography (Second Edition) Edited by Patrizio Lancellotti, José Luis Zamorano, Gilbert Habib, and Luigi Badano The EHRA Book of Interventional Electrophysiology: Case-​based learning with multiple choice questions Edited by Hein Heidbuchel, Mattias Duytschaever, and Haran Burri The ESC Textbook of Vascular Biology Edited by Robert Krams and Magnus Bäck The ESC Textbook of Cardiovascular Development Edited by José Maria Pérez-​Pomares and Robert Kelly The EACVI Textbook of Cardiovascular Magnetic Resonance Edited by Massimo Lombardi, Sven Plein, Steffen Petersen, Chiara Bucciarelli-​Ducci, Emanuela Valsangiacomo Buechel, Cristina Basso, and Victor Ferrari The ESC Textbook of Sports Cardiology Edited by Antonio Pelliccia, Hein Heidbuchel, Domenico Corrado, Mats Borjesson, and Sanjay Sharma The ESC Handbook of Cardiac Rehabilitation: A practical clinical guide Edited by Ana Abreu, Jean-​Paul Schmid, and Massimo Piepoli The ESC Textbook of Intensive and Acute Cardiovascular Care (Third Edition) Edited by Marco Tubaro, Pascal Vranckx, Susanna Price, Christiaan Vrints, and Eric Bonnefoy The ESC Textbook of Cardiovascular Imaging (Third Edition) Edited by José Luis Zamorano, Jeroen J. Bax, Juhani Knuuti, Patrizio Lancellotti, Fausto J. Pinto, Bogdan A. Popescu, and Udo Sechtem The ESC Textbook of Cardiovascular Nursing Edited by Catriona Jennings, Felicity Astin, Donna Fitzsimons, Ekaterini Lambrinou, Lis Neubeck, and David R. Thompson The EHRA Book of Pacemaker, ICD, and CRT Troubleshooting Vol. 2: Case-​based learning with multiple choice questions Edited by Haran Burri, Jens Brock Johansen, Nicholas J. Linker, and Dominic Theuns The EACVI Handbook of Cardiovascular CT Edited by Oliver Gaemperli, Pál Maurovich-​Horvat, Koen Nieman, Gianluca Pontone, and Francesca Pugliese The ESC Textbook of Thrombosis Edited by Raffaele De Caterina, David J. Moliterno, and Steen Dalby Kristensen

The ESC Textbook of

Heart Failure Edited by

Petar M. Seferović

S​ erbian Academy of Sciences and Arts, University Medical Center Belgrade, Belgrade, Serbia

Andrew J.S. Coats

​Heart Research Institute, Sydney, Australia

Gerasimos Filippatos

​Attikon University Hospital, Athens, Greece

Stefan D. Anker

​Charité University Hospital, Berlin, Germany

Johann Bauersachs

​Hannover Medical School, Hannover, Germany

Giuseppe Rosano

​St Georges Medical School, London, UK

Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © European Society of Cardiology 2023 The moral rights of the authors have been asserted First Edition published in 2023 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2023937963 ISBN 978–​0–​19–​889162–​8 DOI: 10.1093/​med/​9780198891628.001.0001 Printed in the UK by Bell & Bain Ltd., Glasgow Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Contents

Contributors  ix Symbols and abbreviations  xix

SECTION 1 Universal definition of heart failure 1.1 Universal definition of heart failure  3 Andrew JS Coats, Biykem Bozkurt, and Petar M Seferović

SECTION 2 Epidemiology of heart failure 2.1 Epidemiology of heart failure  13 Amy Groenewegen, Ivan Milinković, Arno W Hoes, Arend Mosterd, and Frans H Rutten

SECTION 3 Aetiology of heart failure 3.1 The role of ischaemic heart disease in heart

failure  27

Rocco A Montone, Maurizio Volterrani, Jian Zhang, and Filippo Crea

3.4.3  Hypertrophic cardiomyopathy  70 Perry Elliott, Michel Noutsias, and Aris Anastasakis 3.4.4  Restrictive cardiomyopathy  83 Claudio Rapezzi†, Alberto Aimo, Ales Linhart, and Andre Keren 3.4.5  Arrhythmogenic right ventricular

cardiomyopathy  99

Cristina Basso, Hugh Calkins, and Domenico Corrado

3.4.6  Peripartum cardiomyopathy  109 Karen Sliwa and Johann Bauersachs 3.4.7  Takotsubo syndrome  116 Jelena Templin-​Ghadri, Michael Würdinger, Johann Bauersachs, and Christian Templin 3.5 Myocarditis and pericarditis  127 Stephane Heymans, Arsen D Ristić, Yehuda Adler, and Massimo Imazio 3.6 Congenital heart disease  137 Werner Budts and Jolien Roos-​Hesselink

3.2 From hypertension to heart failure  33 Athanasios J Manolis and Yuri Lopatin

3.7 Endocrine and metabolic abnormalities  147 Martin Huelsmann, Jelena P Seferović, and Francesco Cosentino

3.3 Heart failure in valvular heart disease  39 Ana Pardo Sanz, Ivan Milinković, and José Luis Zamorano

3.8 Obesity  155 Lina Badimon, Stefan D Anker, and Stephan von Haehling

3.4 Cardiomyopathies  51

3.9 Cancer and cancer therapy  163 Dimitrios Farmakis, Alexander Lyon, Teresa Lopez Fernandez, and Daniela Cardinale

3.4.1  Genetic basis of cardiomyopathies  51 Thomas Thum, Stephane Heymans, and Johannes Backs 3.4.2 Dilated and hypokinetic non-​dilated

cardiomyopathy  60

Petar M Seferović, Biykem Bozkurt, and Marija Polovina

3.10 Toxins and infections  173 Antonello Gavazzi, Maria Carmo Nunes, and Fausto Pinto † Author deceased.

vi

C onte n ts

SECTION 4 Prevention of heart failure 4.1 Prevention of heart failure  185 Massimo Francesco Piepoli, Maria Benedetta Matrone, Paul Dendale, and Shelley Zieroth

SECTION 5 Pathophysiology of heart failure 5.1 Molecular and cellular mechanisms  203 Junjie Xiao, Thomas Thum, Gianluigi Condorelli, and Johannes Backs 5.2 Alterations in myocardial metabolism  211 Edoardo Bertero and Christoph Maack 5.3 Ventricular remodelling  227 Javier Díez and Hans-​Peter Brunner-​La Rocca 5.4 Neurohormonal activation in heart failure  233 Antoni Bayes-​Genis and Faiez Zannad 5.5 Immune-​mediated mechanisms  243 Ulrich Hofmann, Stefan Frantz, and Nikolaos Frangogiannis 5.6 Inflammation, oxidative stress, and endothelial

dysfunction  249

Stephane Heymans 5.7 Alterations in renal haemodynamics and

function in heart failure  255

Patrick Rossignol and Kevin Damman 5.8 Systemic adaptations in metabolism and

nutritional status  261

Stephan von Haehling and Wolfram Doehner

SECTION 6 Clinical phenotypes of chronic heart failure 6.1 Clinical phenotypes of heart failure with

reduced ejection fraction  271

Brian P Halliday and Thomas F Lüscher 6.2 Heart failure with mildly reduced ejection

fraction  285

Adriaan A Voors, Benda Moura, Lars Lund, and Carolyn SP Lam 6.3 Heart failure with preserved ejection

fraction  299

Rudolf A de Boer, Burkert Pieske, and Barry A Borlaug

6.4. Right heart failure  311 Thomas F Lüscher, Thomas M Gorter, Susanna Price, Anneline Riele, and Michael A Gatzoulis

SECTION 7 Chronic heart failure: diagnostic and prognostic assessment 7.1 Heart failure clinical assessment  347 Michel Komajda, Piotr Ponikowski, and Evgeny Shlyakhtho 7.2 Biomarkers in diagnostic and prognostic

assessment  355

Rudolf A de Boer, Antoni Bayes-​Genis, and James L Januzzi 7.3 Imaging in heart failure  365 7.3.1  Echocardiography  365 Philippe Debonnaire, Victoria Delgado, Thor Edvardsen, Bogdan A Popescu, and Jeroen J Bax 7.3.2  Nuclear medicine  378 Danilo Neglia and Alessia Gimelli 7.3.3  Computed tomography in heart failure  387 Stephan Achenbach and Amina G Rakisheva 7.3.4  Cardiac magnetic resonance in heart

failure: diagnostic and prognostic assessment  396

Anna Baritussio, Noor Sharrack, Sven Plein, and Chiara Bucciarelli-​Ducci

7.3.5  Cardiopulmonary exercise testing  404 Luca Moderato, Davide Lazzeroni, Stamatis Adamopoulos, Alain Cohen-​Solal, and Massimo Piepoli 7.4 Cardiac catheterization, invasive imaging, and

haemodynamics  417

Christian W Hamm, Birgit Assmus, and Veselin Mitrovic

SECTION 8 Chronic heart failure: pharmacological management 8.1 Angiotensin-​converting enzyme inhibitors  437 Roberto Ferrari, Gabriele Guardigli, and Biykem Bozkurt 8.2 Angiotensin receptor blockers in heart

failure  447

Ileana L Piña and Magdy Abdelhamid

C on t e n ts 8.3 Angiotensin II receptor–​neprilysin inhibitor  459 Petar M Seferović, Michele Senni, Marija Polovina, and Andrew JS Coats

9.5 Ancillary procedures  621 Andrew JS Coats, Piotr P Ponikowski, Maria-​Rosa Costanzo, and William T Abraham

8.4 Beta-​blocker therapy  473 Daniela Tomasoni, Marianna Adamo, Hiroyuki Tsutsui, and Marco Metra

9.6 Cardiovascular rehabilitation and lifestyle

8.5 Mineralocorticoid receptor antagonists  481 Bertram Pitt, João Pedro Ferreira, and Faiez Zannad 8.6 Heart rate reduction with ivabradine in heart

failure  489

Michael Böhm and Michel Komajda 8.7 Vasodilators in heart failure  497 Eftihia Polyzogopoulou, Maria Nikolaou, John Parissis, and Alexandre Mebazaa 8.8 Digitalis glycosides  505 Udo Bavendiek and Johann Bauersachs 8.9 Diuretics  517 Jeroen Dauw, Stephen Gottlieb, and Wilfried Mullens 8.10 Inotropes and inodilators  531 Jan Biegus, Piotr Ponikowski, and Christoph Maack 8.11 Sodium–​glucose cotransporter 2 inhibitors  541 Petar M Seferović, Francesco Cosentino, Giuseppe Rosano, and James Januzzi 8.12 Ancillary pharmacological treatment

options  551

Stefan Agewall, Isabelle C van Gelder, and Irina Savelieva 8.13 New and emerging therapies in heart failure  565 Giuseppe Rosano, Gerasimos Filippatos, and Randall Starling

SECTION 9 Chronic heart failure: non-​pharmacological management 9.1 Implantable cardioverter–​defibrillators  573 Gianluigi Savarese, Cecilia Linde, and Kenneth Dickstein 9.2 Cardiac resynchronization therapy for

heart failure  583

Pieter Martens, Eva Goncalvesova, and Wilfried Mullens 9.3 Cardiac surgery (bypass surgery and

remodelling surgery)  597

Felix Schoenrath, Franz-​Josef Neumann, Miguel Sousa Uva, and Volkmar Falk 9.4 Valve interventions  607 Stefan Orwat, Stefan D Anker, and Helmut Baumgartner

modifications  629

Maurizio Volterrani, Alain Cohen-​Solal, Stamatis Adamopulos, Dimitris Miliopoulos, Ferdinando Iellamo, and Massimo Piepoli

SECTION 10 Acute heart failure 10.1 Acute heart failure: diagnostic and prognostic

assessment  645

Ovidiu Chioncel, Gerasimos Filippatos, Alexandre Mebazaa, Veli-​Pekka Harjola, and Josep Masip 10.2 Acute heart failure: pharmacological and

non-​pharmacological management 

657

Katerina Fountoulaki, John Parissis, Sean Collins, Mehmet Birhan Yilmaz, and Alexandre Mebazaa

SECTION 11 Advanced heart failure 11.1 Advanced heart failure: assessment  671 Tuvia Ben Gal, Mariell Jessup, and Maria-​Rosa Costanzo 11.2 Advanced heart failure: management  689 Daniela Tomasoni, Marianna Adamo, and Marco Metra 11.3 Mechanical circulatory support  701 Mandeep Mehra and Finn Gustafsson 11.4 Heart transplantation  715 Davor Miličić, Mandeep Mehra, and Randall C Starling 11.5 Palliative care in the heart failure trajectory  735 Tiny Jaarsma, Donna Fitzsimons, Lisa Hjelmfors, Loreena Hill, Ekaterini Lambrinou, and Anna Strömberg

SECTION 12 Comorbidities and clinical conditions 12.1 Clinical aspects of chronic kidney disease in

heart failure  747

Pieter Martens and Hans-​Peter Brunner-​La Rocca 12.2 Dyskalaemia in heart failure  759 João Pedro Ferreira, Kevin Damman, Wilfried Mullens, and Javed Butler 12.3 Chronic lung disease  773 Josep Masip, Karina Portillo, and Mattia Arrigo

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viii

C onte n ts 12.4 Ventilatory abnormalities and sleep

disordered breathing  785

Piergiuseppe Agostoni, Elisabetta Salvioni, Maria Rosa Costanzo, and Andrew JS Coats 12.5 Pulmonary hypertension associated with left

heart disease  795

Irene M Lang and Stephan Rosenkranz 12.6 Ventricular arrhythmias and sudden death in

heart failure  805

Alessandro Trancuccio, Alessia Chiara Latini, Carlo Arnò, Deni Kukavica, Andrea Mazzanti, and Silvia G Priori 12.7 Management of atrial fibrillation in heart

failure  821

Andreas Metzner, Laura Rottner, Ruben Schleberger, Fabian Moser, and Paulus Kirchhof 12.8 Diabetes, prediabetes, and heart

failure  831

Giuseppe Rosano, Javed Butler, Petar M Seferović, Jelena Seferović, and Francesco Cosentino 12.9 Heart failure in systemic immune-​mediated

diseases  843

Giacomo De Luca, Luca Moroni, Alessandro Tomelleri, Renzo Marcolongo, Lorenzo Dagna, Alida LP Caforio, and Marco Matucci-​Cerinic 12.10 Liver and gut dysfunction  851 Yuri Lopatin and Gianluigi Savarese 12.11 Iron deficiency in heart failure  857 Ewa A Jankowska, Stefan D Anker, and Piotr Ponikowski 12.12 Cognitive impairment and depression  865 Wolfram Doehner, Cristiana Vitale, and Mehmet Birhan Yilmaz 12.13 Cancer and heart failure  871 Dimitrios Farmakis, Alexander Lyon, Rudolf de Boer, and Yuri Belenkov 12.14 Pregnancy and heart failure  883 Johann Bauersachs, Denise Hilfiker-​Kleiner, and Karen Sliwa

12.15 Frailty in heart failure  899 Ewa A Jankowska, Cristiana Vitale, and Dong-​Ju Choi

SECTION 13 Self-​care and patient education 13.1 Self-​care and patient education  905 Tiny Jaarsma, Loreena Hill, Ekaterini Lambrinou, Anna Strömberg, and Tina Hansen

SECTION 14 Multidisciplinary approach to heart failure management 14.1 Multidisciplinary approach to heart failure

management  913

Loreena Hill, Friedrich Koehler, Tiny Jaarsma, Marija Polovina, Katherine McCreary, and Andrew JS Coats

SECTION 15 Clinical trial design and interpretation 15.1 Clinical trial design and interpretation  925 Gianluigi Savarese, Marija Polovina, and Gerasimos Filippatos

SECTION 16 Digital health in heart failure 16.1 Digital health in heart failure  937 Arvind Singhal and Martin R Cowie

SECTION 17 Big data in heart failure 17.1 Big data in heart failure  953 Mamas A Mamas and Dipak Kotecha

SECTION 18 Telemedicine and remote monitoring 18.1 Telemedicine and remote monitoring in

heart failure  965

Tarek Bekfani, Friedrich Koehler, and William T Abraham

Index  979

Contributors

Magdy Abdelhamid Department of Cardiology, Kasr Al Ainy, Faculty of Medicine, Cairo University, Egypt William T Abraham Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA Stephan Achenbach Department of Cardiology, Friedrich-​Alexander-​Universität Erlangen-​Nürnberg, Erlangen, Germany Marianna Adamo Institute of Cardiology, ASST Spedali Civili di Brescia and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy Stamatis Adamopoulos Heart Failure and Transplant Unit, Onassis Cardiac Surgery Centre, Athens, Greece Yehuda Adler Leviev Heart Centre, Chaim Sheba Medical Centre, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Stefan D Anker Department of Cardiology of German Heart Center Charité; Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany Carlo Arnò Insubria University, Italy Mattia Arrigo Department of Internal Medicine, Stadtspital Zurich, Zurich, Switzerland Birgit Assmus Department of Internal Medicine, Cardiology and Angiology, Cardio-​Pulmonary Institute (CPI), Justus-​Liebig University, Giessen, Germany Johannes Backs Institute of Experimental Cardiology, Heidelberg University, Heidelberg; and DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/​Mannheim, Heidelberg, Germany

Stefan Agewall Oslo University Hospital Institute of Clinical Medicine, University of Oslo, Norway; Karolinska Institute, Danderyd Hospital, Sweden

Lina Badimon Cardiovascular Program-​ICCC, IR-​Hospital de la Santa Creu i Sant Pau, IIBSantPau, CiberCV, National Scientific Research Council (CSIC), Autonomous University of Barcelona, Barcelona, Spain

Piergiuseppe Agostoni Centro Cardiologico Monzino, IRCCS, Milan; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Anna Baritussio Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padua University Hospital, Padua, Italy

Alberto Aimo Interdisciplinary Center for Health Sciences, Sant’Anna School of Advanced Studies, Pisa; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy Aris Anastasakis Onassis Cardiac Surgery Center, Athens, Greece

Cristina Basso Cardiovascular Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy Johann Bauersachs Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany

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C ontribu tors Helmut Baumgartner Department of Cardiology III: Adult Congenital and Valvular Heart Disease, University Hospital Münster, Münster, Germany

Hans-​Peter Brunner-​La-​Rocca Department of Cardiology, School for Cardiovascular Diseases CARIM, Maastricht University and Maastricht University Medical Centre, Maastricht, the Netherlands

Udo Bavendiek Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany

Chiara Bucciarelli-​Ducci Royal Brompton and Harefield Hospitals, Guys and St Thomas NHS Trust and School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK

Jeroen J Bax Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands Antoni Bayes-​Genis Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona; Universitat Autonoma de Barcelona, Barcelona, Spain Tarek Bekfani Department of Internal Medicine and Cardiology, University Hospital Magdeburg, Magdeburg, Germany Yuri Belenkov Department of Hospital Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation Tuvia Ben Gal Heart Failure Unit, Cardiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Edoardo Bertero Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany; Department of Internal Medicine and Specialties, University of Genova, Genova, Italy Jan Biegus Institute of Heart Diseases, Wroclaw Medical University, Poland Rudolf A de Boer Department of Cardiology, Erasmus MC, Rotterdam, the Netherlands Michael Böhm Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Saarland University, Homburg/​Saar, Germany Barry A Borlaug Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA Biykem Bozkurt Winters Center for Heart Failure, Cardiology, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas, USA

Werner Budts Congenital and Structural Cardiology, University Hospitals Leuven; Department of Cardiovascular Sciences, Catholic University of Leuven, Leuven, Belgium Javed Butler Baylor Scott and White Research Institute, Dallas, Texas and University of Mississippi Medical Center, Jackson, Mississippi, USA Alida LP Caforio Cardiology, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy Hugh Calkins Cardiology Division, Department of Medicine, Johns Hopkins Institutions, Baltimore, Maryland, USA Daniela Cardinale Cardioncology Unit, Division of Cardioncology and Second Opinion, European Institute of Oncology, IRCCS, Milan, Italy Ovidiu Chioncel Emergency Institute for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, Bucharest, Romania and University of Medicine Carol Davila, Bucharest, Romania Dong-​Ju Choi Department of Cardiology, Cardiovascular Center, Seoul National University Bundang Hospital and Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, South Korea Andrew JS Coats Heart Research Institute, Sydney, Australia Alain Cohen-​Solal Université Paris Cité, IMRS 942 MASCOT, Department of Cardiology, Hopital Lariboisiere, AP-​HP, Paris, France Sean Collins Department of Emergency Medicine, Vanderbilt University Medical Center, Veterans Affairs Tennessee Valley Healthcare System, Geriatric Research, Education and Clinical Center (GRECC), Nashville, Tennessee, USA

C ont ri bu tor s Gianluigi Condorelli Department of Cardiovascular Medicine, IRCCS-​Humanitas Research Hospital, Rozzano (MI) and Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy Domenico Corrado Department of Cardiac, Thoracic and Vascular Sciences, University of Padova Medical School, Padova, Italy Francesco Cosentino Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden Maria-​Rosa Costanzo Heart Failure Program, Midwest Cardiovascular Institute, Naperville, Illinois, USA Martin R Cowie Royal Brompton Hospital, London; School of Cardiovascular Medicine, Faculty of Medicine and Life Sciences, King’s College London, London, UK Filippo Crea Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome and Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy Lorenzo Dagna Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, and School of Medicine, Vita-​Salute San Raffaele University, Milan, Italy Kevin Damman Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Jeroen Dauw Department of Cardiology, AZ Sint-​Lucas, Ghent and Hasselt University, Diepenbeek, Belgium Philippe Debonnaire Department of Cardiology, Sint-​Jan Hospital Bruges, Bruges, Belgium

Kenneth Dickstein Stavanger University Hospital, University of Bergen, Stavanger, Norway Javier Díez Department of Cardiovascular Diseases, Center of Applied Medical Research and School of Medicine, University of Navarra, Pamplona, Spain Wolfram Doehner BIH Center for Regenerative Therapies, Charité-​ Universitätsmedizin Berlin, Berlin; Department of Cardiology, Virchow Campus; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin; and Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Germany Thor Edvardsen Department of Cardiology, Oslo University Hospital, Oslo and Institute for Clinical Medicine, University of Oslo, Oslo, Norway Perry Elliott Institute of Cardiovascular Science, University College London; Barts Heart Centre, Inherited Cardiovascular Disease, St Bartholomew’s Hospital, London, UK Volkmar Falk Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin; Charité –​Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-​ Universität zu Berlin, and Berlin Institute of Health; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany; Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland Dimitrios Farmakis Second Department of Cardiology, Athens University Hospital Attikon, National and Kapodistrian University of Athens Medical School, Athens, Greece Roberto Ferrari Centro Cardiologico Universitario di Ferrara, University of Ferrara, Ferrara, Italy

Victoria Delgado Department of Cardiology, Hospital University Germans Trias i Pujol, Badalona, Spain

João Pedro Ferreira Unidade de Investigaçao Cardiovascular-​UnIC, Faculdade de Medicina Universidade do Porto, Porto, Portugal and Centre d’Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU, FCRIN INI-​CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Nancy, France

Giacomo De Luca Vita-​Salute San Raffaele University, Milan; IRCCS San Raffaele Hospital -​Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, Italy

Gerasimos Filippatos Attikon University Hospital, Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

Paul Dendale Faculty of Medicine and Life Sciences, Hasselt University and Jessa Hospital, Hasselt, Belgium

Donna Fitzsimons School of Nursing and Midwifery, Queen’s University, Belfast, Northern Ireland, UK

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C ontribu tors Katerina Fountoulaki 2nd Department of Cardiology, National and Kapodistrian University of Athens Medical School, Athens, Greece Nikolaos G Frangogiannis Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Stefan Frantz University Hospital of Würzburg, Department of Internal Medicine I, Würzburg, Germany Michael A Gatzoulis Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton and Harefield Hospitals, Guys & St Thomas’s NHS Trust and Imperial College, London, UK Antonello Gavazzi FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy Isabelle C van Gelder University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Alessia Gimelli Fondazione Toscana Gabriele Monasterio, Imaging Department, Pisa, Italy Eva Goncalvesova National Cardiovascular Institute, Bratislava, Slovakia Thomas M Gorter Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands

Brian P Halliday Royal Brompton and Harefield Hospitals, Heart Division, Imperial College, National Heart and Lung Institute, King’s College, London, UK Christian W Hamm Department of Internal Medicine, Cardiology and Angiology, Cardio-​Pulmonary Institute (CPI), Justus-​Liebig University, Giessen; Department of Cardiology, Kerckhoff-​Klinik, Bad Nauheim, Germany Tina Hansen Department of Cardiology, Zealand University Hospital, Denmark Veli-​Pekka Harjola Emergency Medicine, University of Helsinki and Department of Emergency Medicine and Services, Helsinki University Hospital, Helsinki, Finland Stephane Heymans Department of Cardiovascular Sciences, Center for Vascular and Molecular Biology, KU Leuven, Leuven, Belgium and Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands Denise Hilfiker-​Kleiner Department of Cardiology and Angiology, Hannover Medical School, Hannover and Institute of Cardiovascular Complications in Pregnancy and in Oncologic Therapies, Comprehensive Cancer Centre, Philipps-​Universität Marburg, Germany Loreena Hill School of Nursing and Midwifery, Queen’s University, Belfast, Northern Ireland, UK

Stephen Gottlieb University of Maryland School of Medicine and Baltimore VAMC, Baltimore, Maryland, USA

Lisa Hjelmfors Department of Health, Medicine and Caring Sciences, Linkoping University, Linkoping, Sweden

Amy Groenewegen Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands

Arno W Hoes University Medical Center Utrecht, Utrecht, the Netherlands

Gabriele Guardigli Centro Cardiologico Universitario di Ferrara, University of Ferrara, Ferrara, Italy Finn Gustafsson Rigshospitalet –​Copenhagen University Hospital, Copenhagen, Denmark Stephan von Haehling Department of Cardiology and Pneumology, Heart Center, University of Göttingen Medical Center, Georg-​August-​University, Göttingen and German Center for Cardiovascular Research, Partner Site Göttingen, Göttingen, Germany

Ulrich Hofmann University Hospital of Würzburg, Department of Internal Medicine I, Würzburg, Germany Martin Huelsmann Department of Cardiology, University of Vienna, Vienna, Austria Ferdinando Iellamo Department of Clinical Science and Translational Medicine –​ University Tor Vergata, Rome, Italy Massimo Imazio Cardiology and Cardiothoracic Department, University Hospital ‘Santa Maria della Misericordia’, ASUFC, Udine; Department of Medicine, University of Udine, Udine, Italy

C ont ri bu tor s Tiny Jaarsma Department of Health, Medicine and Caring Sciences, Linkoping University, Sweden and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands Ewa A Jankowska Institute of Heart Diseases, Wroclaw Medical University and University Hospital in Wroclaw, Wroclaw, Poland James L Januzzi Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA Mariell Jessup University of Pennsylvania, Philadelphia; American Heart Association, Dallas, Texas, USA Andre Keren Cardiology Division, Hadassah Hebrew University Hospital, Jerusalem and Heart Failure Center, Clalit Health Services, Jerusalem, Israel Paulus Kirchhof Department of Cardiology, University Heart and Vascular Center Hamburg; German Center for Cardiovascular Research (DZHK), partner Site Hamburg/​Kiel/​Lübeck, Germany and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK Friedrich Köhler Centre for Cardiovascular Telemedicine, Deutsches Herzzentrum der Charité, Berlin, and Charité –​ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-​Universität zu Berlin, Berlin, Germany Michel Komajda Department of Cardiology, Groupe Hospitalier Paris Saint Joseph and Sorbonne University, Paris, France Dipak Kotecha Institute of Cardiovascular Sciences, University of Birmingham, Birmingham; UK Health Data Research UK Midlands, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Deni Kukavica University of Pavia, Pavia; Istituti Clinici Scientifici Maugeri, IRCCS, Maugeri, Italy; and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Carolyn SP Lam National Heart Centre Singapore; Duke-​National University of Singapore, Singapore Ekaterini Lambrinou Department of Nursing, School of Health Sciences, Cyprus University of Technology, Limassol, Cyprus

Irene Marthe Lang Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria Alessia Chiara Latini Humanitas University, Italy Davide Lazzeroni Prevention and Rehabilitation Unit, IRCCS Fondazione Don Carlo Gnocchi ONLUS, Florence, Italy Cecilia Linde Department of Medicine, Karolinska Institutet; Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden Ales Linhart General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic Yuri Lopatin Department of Cardiology, Volgograd State Medical University, Volgograd, Russian Federation Teresa López-​Fernández Cardio-​oncology Unit, Cardiology Department, La Paz University Hospital, IdiPAZ Research Institute, Spain Lars H Lund Department of Medicine, Karolinska Institutet and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden Thomas F Lüscher Royal Brompton and Harefield Hospitals, Heart Division, Imperial College, National Heart and Lung Institute, King’s College London, UK and Center for Molecular Cardiology, University of Zurich, Switzerland Alexander R Lyon Royal Brompton Hospital, London, UK Christoph Maack Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany Mamas A Mamas Keele Cardiovascular Research Group, Centre for Prognosis Research, Institute for Primary Care and Health Sciences, Keele University, UK Athanasios Manolis Cardiology Department, Metropolitan Hospital, Piraeus, Greece Renzo Marcolongo Cardiology, Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, Padova, Italy

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C ontribu tors Pieter Martens Ziekenhuis Oost Limburg, Genk, -​University Hasselt, Hasselt, Belgium and Kaufman Center for Heart Failure Treatment and Recovery, Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA Josep Masip Research Direction, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain Maria Benedetta Matrone Cardiac Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy Marco Matucci-​Cerinic Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan; Department of Experimental and Clinical Medicine, University of Florence; and Division of Rheumatology AOUC, Florence, Italy Andrea Mazzanti University of Pavia, Pavia; Istituti Clinici Scientifici Maugeri, IRCCS, Maugeri, Italy; and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Katherine McCreary Cardiovascular Department, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK Alexandre Mebazaa Department of Anaesthesiology and Intensive Care, Hôpitaux Universitaires Saint Louis –​Lariboisière, Paris, France Mandeep R Mehra Center for Advanced Heart Disease, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA Marco Metra Institute of Cardiology, ASST Spedali Civili di Brescia and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy Andreas Metzner Department of Cardiology, University Heart and Vascular Center Hamburg and German Center for Cardiovascular Research (DZHK), partner Site Hamburg/​Kiel/​Lübeck, Germany Davor Miličić University of Zagreb School of Medicine, Department of Cardiovascular Diseases, University Hospital Center Zagreb, Zagreb, Croatia Ivan Milinković Faculty of Medicine, Belgrade University, Belgrade and University Clinical Center of Serbia, Department of Cardiology, Belgrade, Serbia

Dimitris Miliopoulos Heart Failure and Transplant Units, Onassis Cardiac Surgery Centre, Kallithea, Greece Veselin Mitrović Department Administration Forschung und Lehre, Kerckhoff-​ Klinik, Bad Nauheim, Germany Luca Moderato Heart Failure Unit, Cardiology, Guglielmo da Saliceto Hospital, Piacenza, Italy Rocco A Montone Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Luca Moroni Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, Italy Fabian Moser Department of Cardiology, University Heart and Vascular Center Hamburg, Germany Arend Mosterd Meander Medical Center, Department of Cardiology, Amersfoort, the Netherlands Brenda Moura Cardiology Department, Porto Armed Forces Hospital and CINTESIS-​Center for Health Technology and Services Research, Porto, Portugal Wilfried Mullens Department of Cardiology, Ziekenhuis Oost Limburg Genk, and Faculty of Medicine and Life Sciences, University Hasselt, Belgium Danilo Neglia Department of Cardiology, Fondazione Toscana Gabriele Monasterio, Pisa, Italy Franz-​Josef Neumann Department of Cardiology and Angiology, University Heart Centre Freiburg-​Bad Krozingen, Bad Krozingen, Germany Maria Nikolaou Cardiology Department, Sismanoglio General Hospital, Athens, Greece Michael Noutsias Department of Cardiology, Hospital of Brilon, Brilon and Faculty of Medicine, Martin-​Luther-​University Halle-​ Wittenberg, Halle (Saale), Germany Maria Carmo Nunes Hospital das Clinicas, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

C ont ri bu tor s Stefan Orwat Department of Cardiology III: Adult Congenital and Valvular Heart Disease, University Hospital Münster, Münster, Germany

Bogdan A Popescu Department of Cardiology, University of Medicine and Pharmacy ‘Carol Davila’-​Euroecolab, Emergency Institute for Cardiovascular Diseases ‘Prof. Dr. C. C. Iliescu’, Bucharest, Romania

Ana Pardo Sanz Department of Cardiology, Ciber CV, University Hospital Ramón y Cajal, Madrid, Spain

Karina Portillo Pneumology Department, Hospital Universitari Germans Trias i Pujol, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Universitat Autònoma de Barcelona, Spain

John T Parissis University Clinic of Emergency Medicine, Attikon General Hospital, University of Athens, Athens, Greece Massimo Francesco Piepoli Clinical Cardiology, IRCCS Policlinico San Donato, Milan, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy and Department of Preventive Cardiology, Wroclaw Medical University, Wroclaw, Poland Burkert Pieske Department of Internal Medicine and Cardiology, Charité, Universitätsmedizin Berlin; Campus Virchow Klinikum; and German Center for Cardiovascular Research (DZHK), Berlin, Partner Site, Berlin, Germany Ileana L Piña Thomas Jefferson University, Philadelphia; Central Michigan University, Midlands, Michigan, USA Fausto Pinto Cardiology Department, Heart and Vascular Department, University Hospital, Lisbon, Portugal Bertram Pitt School of Medicine, University of Michigan, Ann Arbor, Michigan, USA Sven Plein Multidisciplinary Cardiovascular Research Centre and Biomedical Imaging Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds and School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King’s College London, UK Marija Polovina Faculty of Medicine, Belgrade University, Belgrade and Department of Cardiology, University Clinical Centre of Serbia, Belgrade, Serbia Eftihia Polyzogopoulou Emergency Medicine, Attikon General Hospital, University of Athens, Athens, Greece Piotr P Ponikowski Institute of Heart Diseases, Wroclaw Medical University, Poland

Susanna Price Royal Brompton and Harefield Hospitals, Heart Division, Imperial College, National Heart and Lung Institute, King’s College London, UK Silvia G Priori University of Pavia, Pavia; Istituti Clinici Scientifici Maugeri, IRCCS, Maugeri, Italy; and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Amina G Rakisheva Department of Cardiology, Scientific Institution of Cardiology and Internal Diseases, Almaty; Oonaev City Hospital, Almaty Region, Kazakhstan Claudio Rapezzi† Cardiologic Centre, University of Ferrara and Maria Cecilia Hospital, GVM Care and Research, Cotignola (Ravenna), Italy Anneline te Riele Division of Cardiology, Department of Heart and Lungs, University Medical Centre Utrecht, Utrecht; Netherlands Heart Institute, Utrecht, the Netherlands Arsen D Ristić Department of Cardiology, University Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Jolien W Roos-​Hesselink Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands Giuseppe Rosano IRCCS San Raffaele and San Raffaele University, Roma, Italy Stephan Rosenkranz Heart Center at the University of Cologne, Cologne, Germany Patrick Rossignol Université de Lorraine, INSERM, Centre d’Investigations Cliniques 1433, CHRU de Nancy, Inserm 1116 and INI-​ CRCT (Cardiovascular and Renal Clinical Trialists) F-​CRIN Network, Nancy, France; and Medical specialties –​Nephrology Hemodialysis Departments, Princess Grace Hospital Monaco, and Monaco Private Hemodialysis centre, Monaco, Monaco † Author deceased.

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C ontribu tors Laura Rottner Department of Cardiology, University Heart and Vascular Center Hamburg and German Center for Cardiovascular Research (DZHK), partner Site Hamburg/​Kiel/​Lübeck, Germany

Karen Sliwa Cape Heart Institute, Department of Medicine and Cardiology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

Frans H Rutten Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands

Randall C Starling Kaufman Center for Heart Failure Treatment and Recovery, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA

Elisabetta Salvioni Centro Cardiologico Monzino, IRCCS, Milan, Italy Gianluigi Savarese Division of Cardiology, Department of Medicine, Karolinska Institutet; Heart, Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden Irina Savelieva Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK Ruben Schleberger Department of Cardiology, Albertinen Heart and Vascular Center, Albertinen Hospital, Hamburg Felix Schoenrath Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin; Charité –​Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-​Universität zu Berlin, and Berlin Institute of Health; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany Jelena P Seferović Endocrinology, Diabetes and Metabolic Disorder Clinic, Clinical Center of Serbia, Belgrade, Serbia Petar M Seferović Faculty of Medicine, Belgrade University and Serbian Academy of Science and Arts, Belgrade, Serbia Michele Senni University of Milano-​Bicocca; Cardiovascular Department and Cardiology Unit, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy Noor Sharrack Multidisciplinary Cardiovascular Research Centre and Biomedical Imaging Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK Evgeny Shlyakhtho Almazov National Medical Research Centre, Saint-​Petersburg, Russian Federation Arvind Singhal Department of Cardiology, St Bartholomew’s Hospital, London, UK

Anna Strömberg Department of Health, Medicine and Caring Sciences and Department of Cardiology, Linkoping University, Sweden Christian Templin Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland Jelena-​Rima Templin-​Ghadri Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland Thomas Thum Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover; and REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany Daniela Tomasoni Institute of Cardiology, ASST Spedali Civili di Brescia and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy Alessandro Tomelleri Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan and School of Medicine, Vita-​Salute San Raffaele University, Milan, Italy Alessandro Trancuccio University of Pavia, Pavia; Istituti Clinici Scientifici Maugeri, IRCCS, Maugeri, Italy; and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Miguel Sousa Uva Cardiac Surgery Department, Hospital Santa Cruz, Carnaxide, and Avenue Prof Reynaldo dos Santos, 2790-​134 Carnaxide, Portugal.Cardiovascular Research Centre, Department of Surgery and Physiology, Faculty of Medicine-​University of Porto, Porto, Portugal Cristiana Vitale Department of Medical Sciences, St George’s Hospital Medical School, London, UK Maurizio Volterrani Cardiopulmonary Department, IRCCS San Raffaele, Rome; Exercise Science and Medicine, San Raffaele Open University, Rome, Italy

C ont ri bu tor s Adriaan Voors Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

José Luis Zamorano Cardiology Department, University Hospital Ramon y Cajal, Madrid, Spain

Michael Würdinger Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland

Faiez Zannad Université de Lorraine, Nancy, France

Junjie Xiao Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai, China Mehmet Birhan Yilmaz Faculty of Medicine, Department of Cardiology, Dokuz Eylul University, Izmir, Turkey

Jian Zhang Fuwai Hospital Chinese Academy of Medical Science, Beijing, China Shelley Zieroth University of Manitoba, Cardiac Sciences Program, St. Boniface Hospital, Winnipeg, Canada

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Symbols and abbreviations

% cross-​reference ~ approximately ≥ equal to or greater than ≤ equal to or less than > greater than < less than AAV antineutrophil cytoplasmic antibody-​ associated vasculitides AC adenylyl cyclase ACC American College of Cardiology ACCF American College of Cardiology Foundation ACCOMPLISH Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (trial) ACE angiotensin-​converting enzyme ACEI angiotensin-​converting enzyme inhibitor ACEP American College of Emergency Physicians ACHD adult congenital heart disease ACLI acute cardiogenic liver injury ACM alcoholic cardiomyopathy; arrhythmogenic cardiomyopathy ACPO acute cardiogenic pulmonary oedema ACS acute coronary syndrome ADHERE Acute Decompensated Heart Failure National Registry ADHF acute decompensated heart failure ADP adenosine diphosphate ADPR ADP-​ribose AF atrial fibrillation AF-​CHF Atrial Fibrillation in Congestive Heart Failure (trial) AHA American Heart Association A-​HeFT African-​American Heart Failure Trial AHF acute heart failure AHI apnoea–​hypopnoea index AI artificial intelligence; angiotensin I AICD automatic implantable cardioverter–​defibrillator AII angiotensin II

AIRE AIT AJR AKI AL ALDOB ALLHAT

Acute Infarction Ramipril Efficacy amiodarone-​induced thyrotoxicosis abdominal-​jugular reflux acute kidney injury amyloid light chain fructose-​bisphosphate aldolase B Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ALT alanine aminotransferase ALVC arrhythmogenic left ventricular cardiomyopathy AMI acute myocardial infarction AMP adenosine monophosphate AMPK adenosine monophosphate-​activated protein kinase AMR antibody-​mediated rejection ANCA antineutrophil cytoplasmic antibody ANDROMEDA Antiarrhythmic trial with DROnedarone in Moderate to severe congestive heart failure Evaluating morbidity DecreAse (study) ANP atrial natriuretic peptide APB atrial premature beat APD action potential duration APO acute pulmonary oedema APS antiphospholipid syndrome A1R adenosine A1 receptor AR adrenergic receptor; aortic regurgitation ARB angiotensin receptor blocker ARDS acute respiratory distress syndrome ARF acute rheumatic fever ARIC Atherosclerosis Risk in Communities ARNI angiotensin receptor–​neprilysin inhibitor ARVC arrhythmogenic right ventricular cardiomyopathy AS aortic stenosis; antisynthetase syndrome ASA acetylsalicylic acid ASCEND-​HF Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure

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Symb ols an d abbreviations ASD atrial septal defect AST aspartate aminotransferase ASV adaptive servo-​ventilation AT angiotensin AT1 angiotensin II type 1 (receptor) AT2 angiotensin II type 2 (receptor) ATHENA-​HF Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure ATP adenosine triphosphate; anti-​tachycardia pacing ATTR amyloid transthyretin ATTRv variant ATTR ATTRwt wild-​type ATTR AUC area under the curve AV atrioventricular AVA aortic valve area AVAi indexed aortic valve area AVC arrhythmogenic ventricular cardiomyopathy AVP arginine–​vasopressin β-​OHB β-​hydroxybutyrate BAT baroreflex activation therapy BB beta blocker BCAA branched-​chain amino acid BCATm branched-​chain amino-​transaminase BCKDH branched-​chain α-​keto acid dehydrogenase BCKDK branched-​chain ketoacid dehydrogenase kinase BDH1 β-​hydroxybutyrate dehydrogenase 1 BEST Beta-​Blocker Evaluation in Survival Trial beta3AR beta-​3 adrenergic receptor BIMA bilateral internal mammary artery BiPAP bilevel positive airway pressure B2M beta-​2-​microglobulin BMI body mass index BNP B-​type/​brain natriuretic peptide BP blood pressure BPG benzathine benzylpenicillin BR breathing reserve B19V parvovirus B19 Ca2+​ calcium [Ca2+​]I intracellular calcium concentration CA central apnoea; cardiac amyloidosis CABG coronary artery bypass graft CAD coronary artery disease CAMIAT Canadian Amiodarone Myocardial Infarction Trial CaMKII Ca2+​/​calmodulin-​dependent protein kinase II cAMP cyclic adenosine monophosphate CANVAS CANagliflozin ardiovascular Assessment Study CaO2 arterial oxygen content CAV cardiac allograft vasculopathy

CCB CCL CCM CCS CCT ccTGA

calcium channel blocker CC-​chemokine ligand cardiac contractility modulation Canadian Cardiovascular Society cardiac computed tomography congenitally corrected transposition of the great arteries CCU coronary care unit CD38 cyclic ADP ribose hydrolase CDS clinical decision supports CEC Clinical Events Committee CE-​CMR contrast-​enhanced cardiac magnetic resonance CFR coronary flow reserve CFVR coronary flow velocity reserve cGMP cyclic guanosine monophosphate CH congestive hepatopathy CHAMPION CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in Class III Heart Failure CHAMPIT acute Coronary syndrome, Hypertension emergency, Arrhythmia, acute Mechanical cause, Pulmonary embolism, Infections and Tamponade CHD congenital heart disease CHF congestive heart failure CHS Cardiovascular Health Study CI cardiac index; confidence interval CIBIS II Cardiac Insufficiency Bisoprolol Study II CIED cardiac implantable electronic device CK creatine kinase CKD chronic kidney disease CKD-​EPI Chronic Kidney Disease Epidemiology Collaboration Cl− chloride CLD chronic lung disease CMD coronary microvascular dysfunction CMR cardiac magnetic resonance CMR-​FT CMR feature tracking CMRI cardiac magnetic resonance imaging CMV cytomegalovirus CNOS constitutive nitric oxide synthase CNP C-​type natriuretic peptide CO cardiac output; carbon monoxide CO2 carbon dioxide CoA coenzyme A COAPT Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation COMET Carvedilol Or Metoprolol European Trial COMPASS Cardiovascular Outcomes for People Using Anticoagulation Strategies (trial)

Sym b ol s a n d a b b rev iat i on s CONSENSUS

Cooperative North Scandinavian Enalapril Survival COPD chronic obstructive pulmonary disease COPERNICUS Carvedilol Prospective Randomized Cumulative Survival (trial) CoQ10 coenzyme Q10 COVID-​19 coronavirus disease 2019 CP constrictive pericarditis CPAP continuous positive airway pressure CPB cardiopulmonary bypass CpC-​PH combined precapillary and post-​capillary pulmonary hypertension CPET cardiopulmonary exercise testing CPFE combined pulmonary fibrosis and emphysema CPT1 carnitine palmitoyltransferase 1 Cr creatine CR controlled release CrCl creatinine clearance CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (trial) CRF cardiorespiratory fitness CRISPR clustered regularly interspaced short palindromic repeats CRP C-​reactive protein CRT cardiac resynchronization therapy CRT-​D CRT-​defibrillator CRT-​P CRT-​pacemaker CS cardiogenic shock CSA central sleep apnoea CSR Cheyne–​Stokes respiration CT computed tomography CTA computed tomographic angiography CTCA CT coronary angiography CTEPH chronic thromboembolic pulmonary hypertension CTLA-​4 cytotoxic lymphocyte-​associated protein 4 cTn cardiac troponin CTPA computed tomography pulmonary angiography CV cardiovascular CVAE cardiovascular adverse event CVD cardiovascular disease CvO2 mixed venous oxygen content CVOT cardiovascular outcomes trial CVP central venous pressure CXCL12 CXC motif ligand-​12 2D two-​dimensional 3D three-​dimensional 4D four-​dimensional DAMP damage-​associated molecular pattern DAPT dual antiplatelet therapy DBP diastolic blood pressure DCA dichloroacetate

DCM DD DECISION

dilated cardiomyopathy diastolic dysfunction Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands DI dyssynchrony index DIAMOND Danish Investigations of Arrhythmia and Mortality on Dofetilide (trial) DIGIT-​HF DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure (trial) DNP D-​type natriuretic peptide DOAC direct-​acting oral anticoagulant DOSE Diuretic Strategies in Patients with Acute Decompensated Heart Failure (trial) DPD 3,3-​diphosphono-​1,2-​propanodicarboxylic acid DPI dual-​pathway inhibition DPP4 dipeptidyl peptidase 4 DSA donor-​specific antibodies d-​TGA dextro-​transposition of the great arteries Ea arterial elastance EACTS European Association for Cardio-​Thoracic Surgery EACVI European Association of Cardiovascular Imaging EAPC European Association of Preventive Cardiology EC excitation–​contraction ECG electrocardiography ECHO echocardiography ECMO extracorporeal membrane oxygenation ecNOS endothelial constitutive NO synthase ECV extracellular volume ED Emergency Department EDPVR end-​diastolic pressure–​volume relationship EDV end-​diastolic volume Ees end-​systolic elastance EF ejection fraction eGFR estimated glomerular filtration rate EGFR epidermal growth factor receptor EHRA European Heart Rhythm Association EI endotracheal intubation ELISA enzyme-​linked immunosorbent assay ELITE Evaluation of Losartan in the Elderly (trial) EMA European Medicines Agency Emax elastance EMB endomyocardial biopsy EMCDDA European Monitoring Centre for Drugs and Drug Addiction EMF endomyocardial fibrosis eNAC epithelial Na+​ channel eNOS endothelial nitric oxide synthase EORP EURObservational Research Programme EOV exertional oscillatory ventilation Epac exchange protein directly activated by cAMP EROA effective regurgitant orifice area

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Symb ols an d abbreviations ERS European Respiratory Society ESC European Society of Cardiology ESH European Society of Hypertension ESPVR end-​systolic pressure–​volume relationship ESV end-​systolic volume ET endothelin ETC electron transport chain EURIDIS EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maintenance of Sinus rhythm EUROPA EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease EuroSCORE II European System for Cardiac Operative Risk Evaluation II EVALUATE-​HF Effects of Sacubitril/​Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction EVEREST Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan EVM endocardial voltage mapping EWGSOP European Working Group on Sarcopenia in Older People FA fatty acid FAC fractional area change FDA Food and Drug Administration FDG fluorodeoxyglucose Fe2+​ ferrous ion FEV1 forced expiratory volume in 1 second FFA free fatty acid FFR fractional flow reserve FGE fast gradient echo FGF fibroblast growth factor FHS Framingham Heart Study FoCUS focused cardiac ultrasound FSV forward stroke volume FVC forced vital capacity GAG glycosaminoglycan Gb3 globotriaosylceramide GDMT guideline-​directed medical therapy GDT guideline-​directed therapies GESICA Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (trial) GFR glomerular filtration rate GH growth hormone GISSI-​3 3 Gruppo Italiano per lo Studio della Soprovvivenza nell’Infarto Miocardico GLP1 glucagon-​like peptide 1 GLS global longitudinal strain GLUT glucose transporter GPX glutathione peroxidase GRE gradient echo

Gs stimulatory G protein GSH glutathione GWAS genome-​wide association study GWTG-​HF Get With The Guidelines–​Heart Failure (registry) HAPE high-​altitude pulmonary oedema Hb haemoglobin HbA1c glycosylated haemoglobin HBP hexosamine biosynthetic pathway HCM hypertrophic cardiomyopathy HCN hyperpolarization-​activated cyclic nucleotide-​ gated (channel) HDAC histone deacetylase HDL-​C high-​density lipoprotein cholesterol HED hydroxyephedrine HER2 human epidermal growth factor receptor 2 HES hypereosinophilic syndrome HF heart failure HFA Heart Failure Association of European Society of Cardiology HfimpEF heart failure with improved ejection fraction HfmrEF heart failure with mildly reduced (mid-​range) ejection fraction HfpEF heart failure with preserved ejection fraction HfrecEF heart failure with recovered ejection fraction HfrEF heart failure with reduced ejection fraction HFSA Heart Failure Society of America HH hereditary haemochromatosis HHF hospitalization for heart failure HHV human herpesvirus HIF hypoxia inducible factor HIIT high-​intensity interval training HIV human immunodeficiency virus HMDP hydroxymethylene diphosphonate HMG-​CoA hydroxymethylglutaryl coenzyme A HMOD hypertension-​mediated organ damage HNDC hypokinetic non-​dilated cardiomyopathy HNO nitroxyl HNOCM hypertrophic non-​obstructive cardiomyopathy H2O water H2O2 hydrogen peroxide HOCM hypertrophic obstructive cardiomyopathy HOPE Heart Outcomes Prevention Evaluation (trial) HR heart rate; hazard ratio Hrmax maximal heart rate HRR heart rate recovery HRS Heart Rhythm Society HRV heart rate variability hs high-​sensitivity hsCRP high-​sensitivity C-​reactive protein hs-​cTn high-​sensitivity cardiac troponin

Sym b ol s a n d a b b rev iat i on s HT heart transplantation HTN hypertension IABP intra-​aortic balloon pump ICa influx of calcium ICA invasive coronary angiography ICD International Classification of Disease; implantable cardioverter–​defibrillator ICI immune checkpoint inhibitor ICM ischaemic cardiomyopathy ICU intensive care unit ID iron deficiency IDH2 isocitrate dehydrogenase type 2 iFR instantaneous wave-​free ratio IGF-​1 insulin-​like growth factor 1 IGFBP7 insulin-​like growth factor binding protein 7 IgG immunoglobulin G IHD ischaemic heart disease IL-​6 interleukin-​6 IL-​6R interleukin-​6 receptor ILD interstitial lung disease IMA internal mammary artery IMAC inner membrane anion channel IMM inner mitochondrial membrane IMR index of microvascular resistance iNO inhaled nitric oxide INR international normalized ratio IOC iron overload cardiomyopathy IPAC Investigations of Pregnancy-​Associated Cardiomyopathy (study) IpC-​PH isolated post-​capillary pulmonary hypertension IPD individual patient data IPF idiopathic pulmonary fibrosis IQR interquartile range IRD incidence rate difference IRR incidence rate ratio ISIS-​4 4th International Study of Infarct Survival ITF International Task Force ITT intention-​to-​treat IVIg intravenous immunoglobulin JHFS Japanese Heart Failure Society JVP jugular venous pressure K+​ potassium KorAHF Korean Acute Heart Failure LA left atrial/​atrium LAD left anterior descending artery LAP left atrial pressure LBBB left bundle branch block LDH lactate dehydrogenase LDL-​C low-​density lipoprotein cholesterol L-​FABP liver fatty acid-​binding protein LGE late gadolinium enhancement LIMA left internal mammary artery LMS left main stem LMWH low-​molecular weight heparin

LNA locked nucleic acid LPS lipopolysaccharide LTCC L-​type calcium channel LV left ventricular/​left ventricle LVAD left ventricular assist device LVD left ventricular dysfunction LVEDP left ventricular end-​diastolic pressure LVEDVI left ventricular end-​diastolic volume index LVEF left ventricular ejection fraction LVESD left ventricular end-​systolic diameter LVESV left ventricular end-​systolic volume LVESVI left ventricular end-​systolic volume index LVFP left ventricular diastolic filling pressure LVH left ventricular hypertrophy LVOT left ventricular outflow tract LVOTO left ventricular outflow tract obstruction LVP left ventricular pressure LVSD left ventricular systolic dysfunction LVSWI left ventricular stroke work index LVWT left ventricular wall thickness m6A N6-​methyladenosine MACE major adverse cardiovascular/​cardiac events MADIT-​CRT Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy MAP mitogen-​activated protein MAPK mitogen-​activated protein kinase MasR Mas receptor MBF myocardial blood flow MCD malonyl-​CoA decarboxylase MCE moderate continuous exercise MCP-​1 monocyte chemoattractant protein 1 MCS mechanical circulatory support MCU mitochondrial Ca2+​ uniporter MDCT multidetector computed tomography MDRD Modification of Diet in Renal Disease MECKI Metabolic Exercise test data combined with Cardiac and Kidney Indexes score MELD Model for End Stage Liver Disease MELD-​XI Model for End Stage Liver Disease excluding INR MEF 2 myocyte enhancer factor 2 MERIT-​HF Metoprolol CR/​XL Randomised Intervention Trial in Congestive Heart Failure MESA Multi-​Ethnic Study of Atherosclerosis MET metabolic equivalent 2+​ Mg magnesium MHD mean heart dose 6MHW 6-​minute hall walk MI myocardial infarction MIBG meta-​iodobenzylguanidine miRNA microRNA MLHFQ Minnesota Living with Heart Failure Questionnaire

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Symb ols an d abbreviations MMP MNA Mn-​SOD

matrix metalloproteinase Mini Nutritional Assessment manganese-​dependent superoxide dismutase MODS multiple organ dysfunction syndrome MOLLI modified look-​locker inversion recovery mPAP mean pulmonary artery pressure MPC mitochondrial pyruvate carrier mPCWP mean pulmonary capillary wedge pressure MPS myocardial perfusion scintigraphy mPTP mitochondrial permeability transition pore MR mitral regurgitation; mineralocorticoid hormone receptor MRA mineralocorticoid receptor antagonist mRAP mean right atrial pressure MRI magnetic resonance imaging mRNA messenger RNA Mrp4 multidrug resistance protein 4 MR-​proANP mid-​regional pro-​atrial natriuretic peptide MT metabolic threshold mTOR mechanistic/​mammalian target of rapamycin MVO microvascular obstruction MVO2 oxygen consumption MVR mitral valve repair MVV maximal voluntary ventilation 6MWT 6-​minute walking test Na+​ sodium NAD nicotinamide adenine dinucleotide NADPH nicotinamide adenine dinucleotide phosphate NAM nicotinamide NAMPT nicotinamide phosphoribosyl transferase nc non-​coding NCC Na+​/​Cl− cotransporter NCDR National Cardiovascular Data Registry NCLX Na+​/​Ca2+​ exchanger NCX sodium–​calcium exchanger NDCC non-​dihydropyridine calcium channel blocker NEPi neprilysin inhibitor NFAT nuclear factor of activated T cells NF-​κB nuclear factor kappa B NHANES National Health and Nutrition Examination Survey NHE Na+​/​H+​ exchanger NICE National Institute for Health and Care Excellence NIH National Institutes of Health NIPPV non-​invasive positive pressure ventilation NIV non-​invasive ventilation NKA Na+​/​K+​-​ATPase NKCC2 Na+​–​K+​–​2Cl− cotransporter 2 NMN nicotinamide mononucleotide NNT nicotinamide nucleotide transhydrogenase NO nitric oxide

NOAC non-​vitamin K oral anticoagulant NOS nitric oxide synthase NP natriuretic peptide N-​3-​PUFA N-​3 polyunsaturated fatty acids NPY neuropeptide Y NR nicotinamide riboside NSAID non-​steroidal anti-​inflammatory drug NSAT non-​sustained atrial tachycardia NSF nephrogenic systemic fibrosis NSVT non-​sustained ventricular tachycardia NT-​proBNP N-​terminal pro-​B-​type natriuretic peptide NYHA New York Heart Association O2 oxygen O2.− superoxide OAC oral anticoagulant OAT organic anion transporter OCTAVE Omapatrilat Cardiovascular Treatment Versus Enalapril (trial) O­GlcNAcylation O­linked glycosylation OM omecamtiv mecarbil OMT optimal medical therapy ONPHEC Ontario Population Health and Environment Cohort OPTIC Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (trial) OPTIMIZE-​HF Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure OR odds ratio OSA obstructive sleep apnoea OUES oxygen uptake efficiency slope OVERTURE Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing events PA pulmonary artery PAC pulmonary artery catheterization PAH pulmonary arterial hypertension PAI-​1 plasminogen activator inhibitor 1 PALLAS Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy PaO2 partial oxygen pressure PAP pulmonary artery pressure PAR population attributable risk PARADIGM-​HF Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (trial) PARAGON-​HF Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (trial) PARAMOUNT Prospective comparison of ARNI with ARB on the Management Of heart failUre with preserved ejection fraction (trial) PARP poly (ADP-​ribose) polymerase PASP pulmonary artery systolic pressure

Sym b ol s a n d a b b rev iat i on s PB periodic breathing PCI percutaneous coronary intervention PCr phosphocreatine PCWP pulmonary capillary wedge pressure PD-​1 programmed cell death protein 1 PDE3 phosphodiesterase 3 PDE4 phosphodiesterase 4 PDGFR platelet-​derived growth factor receptor PDH pyruvate dehydrogenase PD-​L1 programmed cell death ligand 1 PE pulmonary embolism PEA pulseless electrical activity PEEP positive end-​expiratory pressure PEF peak expiratory flow PESI Pulmonary Embolism Severity Index PET positron emission tomography PETCO2 end-​tidal partial pressure of carbon dioxide PFK-​1 phosphofructokinase 1 PGmean mean pressure gradient PH pulmonary hypertension PH-​LHD pulmonary hypertension with left heart disease PHM predicted heart mass PI proteasome inhibitor PICP procollagen type I carboxy-​terminal propeptide PI3K phosphoinositide 3-​kinase PISA proximal isovelocity surface area PKA protein kinase A PKG protein kinase G PLB phospholamban PLE protein-​losing enteropathy PLN phospholamban pMCS percutaneous mechanical circulatory support POCUS point-​of-​care ultrasound Pplat plateau pressure PPAR peroxisome proliferator-​activated receptor ppb part per billion pPCI primary percutaneous coronary intervention PPCM peripartum cardiomyopathy PPG photoplethysmography ppm part per million PQC protein quality control PRA panel reactive antibody PREVEND Prevention of Renal and Vascular End-​stage Disease (study) PRIME Pharmacological Reduction of Functional, Ischemic Mitral Regurgitation (study) PROVE-​HF Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/​Valsartan Therapy for HF PRX peroxiredoxin PSRF psychosocial risk factor pSS primary Sjogren syndrome PTP pretest probability PV pressure–​volume (loop)

PVC premature ventricular complex PVR pulmonary vascular resistance PVRi pulmonary vascular resistance index PYP pyrophosphate QoL quality of life Qp/​Qs pulmonary-​to-​systemic flow ratio QUIET Quinapril Ischemic Event Trial RA radial artery; right atrium RAID Ranolazine Implantable Cardioverter–​ Defibrillator (study) RAS renin–​angiotensin system RAAS renin–​angiotensin–​aldosterone system RAP right atrial pressure RATE-​AF Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (trial) RBBB right bundle branch block RBM20 RNA-​binding motif protein 20 RCM restrictive cardiomyopathy RCP respiratory compensation point RCT randomized controlled trial RDN renal denervation REALITY-​AHF Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure RER respiratory exchange ratio REVERSE REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (trial) RHC right heart catheterization RHD rheumatic heart disease RHR resting heart rate RIMP RV index of myocardial performance RNA ribonucleic acid ROS reactive oxygen species RPE Rating of Perceived Exertion RR respiratory rate RRT renal replacement therapy RV right ventricle/​right ventricular RVD right ventricular dysfunction RVEDP right ventricular end-​diastolic pressure RVEF right ventricular ejection fraction RVMI right ventricular myocardial infarction RVOT right ventricular outflow tract RVP right ventricular pressure RVSW right ventricular stroke work RVSWI right ventricular stroke work index RyR ryanodine receptor SAM systolic anterior motion SARF severe acute respiratory failure SARS-​CoV-​2 severe acute respiratory syndrome coronavirus 2 SAT subcutaneous adipose tissue SAVE Survival and Ventricular Enlargement (trial)

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Symb ols an d abbreviations SAVR SBP SCAI

surgical aortic valve replacement systolic blood pressure Society for Cardiovascular Angiography and Interventions SCD sudden cardiac death SCOT succinyl-​CoA:3 oxoacid-​CoA transferase SCS spinal cord stimulation SD systolic dysfunction; sudden death SDF stromal cell-​derived factor SEE-​HF Screening for Advanced Heart Failure Treatment SENIORS Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure SERCA sarcoplasmic reticulum calcium-​ATPase SET systolic ejection time sGC soluble guanylate cyclase SGLT sodium–​glucose cotransporter SGLT2i sodium–​glucose cotransporter 2 inhibitor SHFM Seattle Heart Failure Model SHIFT Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial S-​ICD subcutaneous implantable cardioverter–​defibrillator SIRT sirtuin SLE systemic lupus erythematosus sMDRD simplified Modification of Diet in Renal Disease SMR secondary mitral regurgitation SNS sympathetic nervous system SNV single-​nucleotide variant SOLVD Studies of Left Ventricular Dysfunction (trial) SPAP systolic pulmonary artery pressure SPECT single-​photon emission computed tomography SPRM Seattle Proportional Risk Model SR sarcoplasmic reticulum SRV systemic right ventricle SSc systemic sclerosis SS-​31 Szeto–​Schiller peptide 31 SSFP steady-​state free precession SSRI selective serotonin reuptake inhibitor sST2 soluble ST2 STAND-​UP AHF Study Assessing Nitroxyl Donor Upon Presentation with Acute Heart Failure STE speckle tracking echocardiography STEMI ST-​segment elevation myocardial infarction STICH Surgical Treatment for Ischaemic Heart Failure (trial) STICHES STICH Extension Study (trial) STS Society of Thoracic Surgeons

STS-​PROM

Society of Thoracic Surgeons Predicted Risk of Mortality SV stroke volume SVC superior vena cava SVR systemic vascular resistance; surgical ventricular reconstruction SVRi systemic vascular resistance index TAG triacylglycerol TAPSE tricuspid annular plane systolic excursion TAVI transcatheter aortic valve implantation TAVR transcatheter aortic valve replacement TCPC total cavo-​pulmonary connection TDI tissue Doppler imaging T2DM type 2 diabetes mellitus T-​DM1 trastuzumab-​DM1 TEER transcatheter edge-​to-​edge repair TGA transposition of the great arteries TGF-​β transforming growth factor beta Th1 T helper 1 TIMI Thrombolysis in Myocardial Infarction TIPS trans-​jugular intrahepatic portosystemic shunt TKI tyrosine kinase inhibitor TLR Toll-​like receptor TMAO trimethylamine N-​oxide TMZ trimetazidine TNF tumour necrosis factor TPG transpulmonary gradient TR tricuspid regurgitation TRACE Trandolapril Cardiac Evaluation (trial) TRANSFORM-​HF ToRsemide compArisoN With furoSemide FORManagement of Heart Failure (trial) Tregs T regulatory cells TRUE-​AHF Trial of Ularitide Efficacy and Safety in Acute Heart Failure TRX thioredoxin TSE turbo spin echo TSH thyroid-​stimulating hormone T2 STIR T2-​weighted short tau inversion recovery TTE transthoracic echocardiography TTNtv TTN-​truncating variants TTR transthyretin TTS Takotsubo syndrome UDHF universal definition of heart failure UDP-​GlcNAc uridine diphosphate­β­N­acetylglucosamine UFH unfractionated heparin VAC ventricular–​arterial coupling VAD ventricular assist device VA ECMO veno-​arterial ECMO Val-​HeFT Valsartan Heart Failure Trial VANISH Ventricular Tachycardia Ablation or Escalated aNtiarrhythmic Drugs in Ischemic Heart Disease (trial)

Sym b ol s a n d a b b rev iat i on s VAT VD VE VEGF VF VHD V-​HeFT VKA VMAC VO2 VPC VRA

visceral adipose tissue; ventilatory anaerobic threshold dead-​space ventilation minute ventilation vascular endothelial growth factor ventricular fibrillation valvular heart disease Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure vitamin K antagonist Vasodilatation in the Management of Acute Congestive Heart Failure oxygen uptake/​consumption ventricular premature complex vasopressin receptor antagonists

VSD VT VTE WARCEF WAT WES WGS WHO WR WRF WSPH XL XO

ventricular septal defect ventricular tachycardia; tidal volume venous thromboembolism Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (trial) white adipose tissue whole-​exome sequencing whole-​genome sequencing World Health Organization work rate worsening renal function World Symposium on Pulmonary Hypertension extended release xanthine oxidase

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Universal definition of heart failure 1.1 Universal definition of heart failure 

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Andrew JS Coats, Biykem Bozkurt, and Petar M Seferović

CHAPTER 1.1

Universal definition of heart failure Andrew JS Coats, Biykem Bozkurt, and Petar M Seferović

Contents Introduction  3 How to define a disease  3 Historical definitions  4 A universal definition of heart failure: the 2021 international consensus  5 Staging  5 Left ventricular ejection fraction  6 Heart failure disease trajectories  6 Other subtypes of heart failure  8 Disorders that can mimic heart failure  8 Disorders that can incorporate an element of heart failure  8 Use in practice  8 Use in research  8 Summary  9 References  9

Introduction Defining a disease is essential for standardization of the criteria of the disease, so that accurate comparisons can be made across geographies, health systems, and timelines. Reliable criteria will also aid in research and for reviews of clinical practice that are essential for quality and safety improvement activities. There have been many definitions of heart failure (HF) over the decades, with significant changes being made as we understand more of the pathophysiology of the condition. Some of the early definitions tried to take a pathophysiological approach and incorporated terms and concepts that were impossible to apply in clinical practice, such as ‘the inability of the heart to provide the circulatory needs of metabolizing tissues’. Alternative definitions were more pragmatic, as they were designed to be used in large-​scale surveys or registries, and therefore it was necessary that they were easily understood by the non-​expert and equally applicable, even when detailed clinical examination findings and investigations were not available. None of these previous definitions were necessarily incorrect, even when they took very different approaches to diagnosing HF, but rather they reflected the variety of needs that pertain to a diagnosis of heart failure. In 2020/​1, a group of international HF associations, societies, and working groups partnered to develop an internationally collaborative venture that would, for the first time, standardize a definition of HF that could be applied worldwide and that could be used in a number of different settings and for multiple purposes (% Figure 1.1.1). The reader is referred to the report of this meeting and the consensus paper that provided further information.1

How to define a disease One primary consideration that is often missed is that we need to define the purpose, or purposes, we want our definition of HF to satisfy. Some disorders have a single identifiable aetiology, and hence the definition can be based on a precise pathway that identifies the causative agent that leads to a change in either physiology or pathology and which results in the clinical consequences recognized as the disease state. These disorders can be considered ‘categorical’ disorders in that they are either present or absent, and are defined by the above-​mentioned sequence and diagnosed by the presence of the accepted aetiological agent. These include many infections and cancers. Other conditions may not have a single aetiology and are in reality disorders of physiological function, defined by a certain numerical abnormality in an aspect of bodily function. Many chronic disorders follow this pathway, particularly disorders of the ageing modern society, such as obesity, chronic kidney disease (CKD), and chronic lung disease, and disorders of physiological control such as blood sugar levels in type 2 diabetes, bone mineral density in osteoporosis, or skeletal muscle mass and function in sarcopenia. In this regard, HF has more in

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Un iv e rsal def init ion of h ea rt fa i lu re Symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality

• as determined by LVEF 15, or • moderate/severe valvular obstructive or regurgitant lesion

and corroborated by at least one of the following

Elevated natriuretic peptide levels

Objective evidence of cardiogenic pulmonary or systemic congestion

• BNP ≥35 pg/mL if normal sinus rhythm or ≥105 pg/mL if atrial fibrillation • NT-proBNP ≥125 pg/mL if normal sinus rhythm or ≥3655 pg/mL if atrial fibrillation • Some diseases other than HF can affect natriuretic peptide levels

• by imaging (e.g. elevated filling pressures by echocardiography) • or by haemodynamic measurement (e.g. right heart catheterization, PA catheter)

Figure 1.1.1  A simplified description of the universal definition of heart failure. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endkorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021 Mar;23(3):352–​380. doi: 10.1002/​ejhf.2115. Reprinted by permission of John Wiley and Sons on behalf of the European Society of Cardiology.

common with such a quantitative disorder, and less with categorical diseases, and the historical definitions of HF have tended to follow this path. There is, however, no single measure of organ function that can be used to define a ‘failing’ heart. Neither cardiac output or left ventricular ejection fraction (LVEF) can fulfil the role that the glomerular filtration rate (GFR) does for the diagnosis of CKD. For HF, we are left with using the third type of disease state—​that of a recognized clinical syndrome involving a commonly accepted composite of signs, symptoms, and investigative findings that are recognized as forming the disease entity of HF.

Historical definitions Early definitions of HF tended to focus on a physiological explanation for HF, such as a condition associated with a disorder of the circulation such that it cannot provide tissues with sufficient blood supply to satisfy their metabolic needs at rest or on exercise, which, although being conceptually attractive, had limitations in terms of its applicability in routine practice because of the difficulty of ascertaining the adequacy of the circulatory supply to exercising muscular tissue. More recent definitions of HF, such as those published by major international cardiology societies in their regular guidelines, have regarded HF as a complex clinical syndrome, encompassing multiple aspects and usually including the triad of: (1) some description of a structural and/​or functional abnormality of the heart; (2) some classical symptoms; and (3)

some investigative parameters. Most, at some point, have also included a description of the process of fluid congestion as being either an absolute increase in blood volume or a redistribution of fluid that causes particular pathophysiology and, in many cases, symptoms of shortness of breath due to lung congestion. One criticism of these definitions is the lack of standardization, combined with poor applicability in routine clinical practice. Many require a definition of a physiological state that can rarely be verified in clinical practice and may be restricted to certain specialist fields or certain specialist hospitals. Other definitions of HF have been used for the purposes of disease coding in hospital systems, registries, and interventional clinical trials. For example, the Framingham Heart Study, an early and very influential epidemiological survey, utilized major and minor clinical criteria largely representing simple symptoms or clinical signs to define failure, based on a score made up of several less or more sensitive or specific parameters.2 While this served the purposes of the epidemiological survey quite well, it was not considered accurate or reliable enough to be used either in routine clinical practice or for the purposes of recruiting patients to interventional trials. The emergence of randomized controlled trials to establish the efficacy of pharmacological and device-​based treatments for HF has led to some standardization of the criteria for recruiting patients into such trials. These criteria, however, have been largely used to recruit patients at high risk of the type of subsequent clinical events against which the treatment is tested such as death or

Chapter 1.1  

an unplanned HF-​related hospitalization event. Certain ‘enrichment’ criteria were largely introduced to increase the risk of a patient experiencing such an event, without the intent of improving the specificity of the diagnosis. These include recruiting patients during an acute admission for HF, with very low LVEF and very elevated levels of natriuretic peptides or other markers of severe disease. The proponents of these criteria never initially suggested they should be used to define the disease, but the fact that a treatment has proven itself to be successful based on recruiting patients against these criteria has led some to consider they should be used to define the patient population that will likely respond to the treatment. Thus, we have recommended several treatments for use in the management of HF with reduced ejection fraction (HFrEF), not because the scientific community considered this was a separate disorder, but instead largely because trial evidence was accumulated for patients selected against such criteria.

A universal definition of heart failure: the 2021 international consensus In early 2021, the Heart Failure Society of America (HFSA), the Heart Failure Association of European Society of Cardiology (HFA), and the Japanese Heart Failure Society (JHFS), as part of their ongoing trilateral agreement, agreed to review the proposed new universal definition of heart failure (UDHF) and decided to propose a consensus paper entitled ‘Universal definition and

U n i ver s a l defi n i ti on of hea rt fa i lure

classification of heart failure’.1 A working group was established that had representatives of these three associations/​societies, as well as some from other HF associations and working groups representing groups from around the world. Four other associations endorsed the output of the working group; these were the Canadian Heart Failure Society, the Cardiac Society of Australia and New Zealand (CSANZ), the Heart Failure Association of India (HFAI), and the Chinese Heart Failure Association.

Staging Any scheme for the diagnosis of HF can be improved by the ability to subdivide the diagnosis into other clinically meaningful subgroupings to aid in conversations among clinicians and also to assist in assessing clinical services or interventions. One such subgrouping is based on the severity of the disease, either cross-​ sectionally as how severely limited the patient is at a particular point in time, or longitudinally by defining the progression of the disorder, assuming that disease progression is, to some extent, predictable or in a certain direction. Many attempts have been made to stage HF, the two most common being the symptomatic stages of the New York Heart Association (NYHA) functional classes,3 that has been in widespread clinical use for many years, and the more recent clinical staging of the American College of Cardiology Foundation/​ American Heart Association (ACCF/​ AHA) (% Figure 1.1.2).4

AT RISK OF HEART FAILURE

PRE-HEART FAILURE

SYMPTOMATIC HEART FAILURE

ADVANCED HEART FAILURE

(STAGE A)

(STAGE B)

(STAGE C)

(STAGE D)

Patients at risk of HF but without current or prior symptoms or signs of HF and without structural, biomarker, or genetic markers of heart disease

Patients with no past or present HF symptoms or signs but with any of:

Patients with current or prior symptoms and/or sings of HF caused by

Structural heart disease: e.g. LVH, chamber enlargement, wall motion abnormality, myocardial tissue abnormality, valvular heart disease

Severe symptoms and/ or signs of HF at rest, recurrent hospitalizations despite GDMT, refractory to or intolerant of GDMT

Structural and/or functional cardiac abnormality

Requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care

Patients with HTN, CVD, DM, obesity, known exposure to cardiotoxins, family history of cardiomyopathy

Abnormal cardiac function: e.g. reduced LV or RV ventricular systolic function, evidence of increased filling pressures or abnormal diastolic dysfunction Elevated natriuretic peptide levels or elevated cardiac troponin levels in the setting of cardiotoxicity

Disease progression NYHA I

NYHA II

NYHA III

NYHA IV

with GDMT and risk factor modification Figure 1.1.2  A simplified description of the clinical stages of the progression from risk factors to heart failure. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021 Mar;23(3):352–​380. doi: 10.1002/​ejhf.2115. Reprinted by permission of John Wiley and Sons on behalf of the European Society of Cardiology.

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This four-​stage classification into stages A to D has some advantages in that it recognizes the progression from risk factors for HF through early asymptomatic disease through to mildly and severely symptomatic disease. The staging system, however, has not been taken up extensively in routine practice and some people have felt it is suggesting that HF is a disease that can occur before symptoms, and this may be argued against the concept of HF as a symptomatic clinical syndrome. The consensus universal definition of HF paper proposes that stages A to D be incorporated into the new universal definition as a way of recognizing stages of disease that precede HF, translating stage A into ‘at risk of HF’ indicating patients with risk factors for the future development of HF, and stage B being called ‘pre-​HF’ indicating established LV dysfunction that, in future, may lead to HF, but which is at the pre-​symptomatic stage of the disorder. Stages C and D indicate the symptomatic stages of HF, with a rough translation being that stage C is similar to NYHA classes I, II, and IIIA, whereas stage D is more aligned to NYHA classes IIIB and IV or what is commonly called ‘advanced HF’. Other staging systems that are popular include staging by degree of reduction in LVEF, which will be discussed in the next section, the MOGES system that defines HF further by its morpho-​functional phenotype (M), organ involvement (O), genetic inheritance pattern (G), aetiological annotation (E), and functional status (S).5 Another staging system in widespread use in the assessment of advanced HF, especially for patients being considered for transplantation or a mechanical circulatory support device, is the INTERMACS system, to which the reader is referred.6 This system is a finer-​grained subclassification of advanced HF that allows simplified descriptions of the clinical status of a patient, so that assessments can be made of the urgency of interventions and priority for limited advanced treatment options. None of the systems are perfect, but each has demonstrated value in aspects of clinical practice and research. The importance of the new proposed UDHF is that it could work in concert with these staging systems.

Left ventricular ejection fraction The fractional emptying of the left ventricle with forward projection of the stroke volume into the aorta with each systole has a long history as a measure of cardiac systolic function. Folse and Braunwald (in Circulation, 1962) stated: ‘The determination of the fraction of left ventricular end-​diastolic volume ejected per beat and of the ventricle’s end-​diastolic and residual systolic volumes has been of interest to investigators for many years’.7 It was calculated as forward stroke volume (FSV)/​end-​diastolic volume (EDV). They noted it was strongly inversely related to EDV. Bruce and Chapman8 noted values of this fraction of 76.5% in normal males studied in the sitting position, thus realizing there was a normal range, even though, to this date, no universally accepted range of normal ejection fraction (EF) exists for all routinely used clinical imaging modalities. It was obvious that myocardial infarction, one of the most common causes of HF, often causes an enlarged, dilated, and remodelled left ventricle, with resulting low LVEF. The feature of low LVEF being a strong independent

predictor of increased mortality risk was repeatedly identified and utilized in the design of clinical trials to recruit patients with a higher death rate. It was also recognized quite early on that the syndrome of HF could, in fact, present with low LVEF or could also present with higher, or even normal, LVEF. These latter patients were identified as having a different range of clinical characteristics, compared to the low LVEF HF patients. The higher LVEF HF patients tended to be older, more frequently female, and more likely to have an underlying aetiology of hypertensive heart disease than ischaemic heart disease, which was more common in the low LVEF type of HF patients. As stated earlier, very many of the intervention trials recruited HF patients preferentially with low LVEF, as this established a higher event rate population. Initially there was no consistency in the cut-​off thresholds used for LVEF in such trials. Low LVEF trials used EF cut-​offs of 25%, 35%, 40%, 45%, or occasionally 50%, and the much smaller number of trials that recruited HF patients with higher LVEF often used LVEF thresholds of above 40%, 45%, or 50%. Thus, although there was a spectrum of LVEF in patients diagnosed with HF, in common usage, two forms of HF were identified early on: one with reduced EF (HFrEF), and the other with preserved EF (HFpEF), although initially they were termed systolic and diastolic HF. More recently, the European HF guidelines initially recommended a third group called HF with mid-​range EF (HFmrEF),7,9 but which has now been revised to HF with mildly reduced EF (still termed HFmrEF),9,10 in recognition of the fact that these patients pathophysiologically, and by their clinical characteristics and response to therapy, are more like HFrEF than they are like HFpEF patients. The now more widely accepted LVEF cut-​offs are: HFrEF, EF ≤40%; HFmrEF, EF 41–​49%; and HFpEF, EF ≥50%. A fourth category was specified as HF with improved EF (HFimpEF): HF with a baseline LVEF ≤40%, a ≥10-​ point increase from baseline LVEF, and a second measurement of LVEF >40% to emphasize the necessity to continue guideline-​ directed medical therapy (GDMT) among these patients. LVEF has shown its usefulness in recruiting patients into clinical trials, and as a result, many treatments are indicated only for selected subsets of HF patients on the basis of their LVEF. % Table 1.1.1 demonstrates the prominent role LVEF has played in selecting patients for inclusion into clinical trials.

Heart failure disease trajectories An important addition to the recently published UDHF is the concept of disease trajectories of HF. It is recognized with the extensive list of medications and devices that can modify outcomes in patients with HF that HF is not static in its severity. What previous definitions have failed to capture adequately is that patients can improve from more severe HF through the use of GDMT but remain at increased risk, compared to patients who never had HFrEF in the first place. Stages A to D of HF, classification systems based on LVEF, and the NYHA functional class classification schemes all failed to identify patients with improved or improving HF as a separate group. The UDHF paper included the concept of HFimpEF as a group defined as patients with an initial diagnosis

Chapter 1.1  

U n i ver s a l defi n i ti on of hea rt fa i lure

Table 1.1.1  The prominent role played by using LVEF to define a subset of HF patients recruited into clinical trials which subsequently have proved the value of the intervention (note that many more trials have selected patients with low LVEF (or using LVEF-​like parameters), compared to trials that did not select on the basis of LVEF or which recruited only patients with higher LVEF) Studies using LVEF-​related measures to select

V-​HeFT I (enlarged heart), CONSENSUS (enlarged heart size)

Studies using low LVEF as inclusion criterion

V-​HeFT II (large heart or LVEF 40%), I-​PRESERVE (≥45%), PARAGON-​HF (≥45%), TOPCAT (≥45%), EMPEROR-​REDUCED (>40%)

Studies not restricted by LVEF as inclusion criterion

SENIORS, SOLOIST-​WHF

Black =​positive trials, orange =​neutral trials.

of HFrEF, but in response to GDMT for HF have had an improvement, such that LVEF is increased by at least 10 percentage points and may now be in the range that would normally indicate HFpEF. These patients should not appropriately be classified as HFpEF but need a separate identity, which is why HFimpEF was introduced. Other terms that are used to describe the trajectory status of HF include a classification and whether HF is a new diagnosis or the patient previously had an established HF diagnosis (% Figure 1.1.3). The first is considered ‘de novo’ HF (also known as new-​onset HF) and it carries a temporarily increased risk of adverse clinical outcomes, particularly as patients are unlikely to be treated with optimal GDMT at the beginning of the illness. When a patient has had a history of HF and is under treatment, this is commonly called ‘chronic’ HF and during this course of the disease, the patient has relatively minor symptoms and can be managed as an outpatient. Many people have called this ‘stable’ HF in the past, but the UDHF group felt this was a misleading term as it might be construed as indicating the patient no longer has significant disease or does not require optimization of GDMT or regular monitoring or observation. Therefore, instead of ‘stable’ HF, ‘persistent’ HF is recommended. Similarly, patients who have New-onset/de novo HF: • Newly diagnosed HF • No former history of HF

Worsening HF: • Worsening symptom/sings/ functional capacity, and/or requiring escalation of therapies such as IV or other advanced therapies • and/or hospitalization

had resolution of symptoms and signs and had normalization of LV function have been commonly called ‘recovered’ HF patients. The high risk of recurrence of symptoms and LV dysfunction upon withdrawal of pharmacological therapy10 indicates that such patients should be continued on GDMT and should remain under regular review, and hence the term recovered HF is discouraged, with a preference for terms such as ‘HF in remission’ to suggest that the patient is at risk of deterioration at any time. The terms ‘worsening HF’ or acute decompensated HF (ADHF) are used for patients who have chronic HF but who subsequently develop an episode of acute or subacute decompensation, such as due to fluid retention or fluid maldistribution, leading to acute or subacute symptoms which may or may not require urgent hospital admission for increased treatment, particularly with use of intravenous diuretics and, in some cases, intravenous vasodilator or inotropic support. Because each episode of urgent admission for HF carries with it both short-​and long-​term increased risk, and each hospital admission is expensive and carries the opportunity for revising HF management, this has been a popular subclassification scheme for HF. By contrast, other markers of increasing risk, such as increasing levels of natriuretic peptides, have not translated

Improving HF: • Improving symptoms/signs and/or functional capacity

Persistent HF: • Persistent HF with ongoing symptoms/signs and/or limited functional capacity

Use persistent HF in preference to ‘stable’ HF

HF in remission: • Resolution of symptoms and signs of HF, with resolution of previous structural/functional heart disease after disease after a phase of symptomatic HF Do not use ‘recovered HF’ instead, use ‘HF in remission’

Figure 1.1.3  A nomenclature and classification for heart failure disease trajectories. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021 Mar;23(3):352–​380. doi: 10.1002/​ejhf.2115. Reprinted by permission of John Wiley and Sons on behalf of the European Society of Cardiology.

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Un iv e rsal def init ion of h ea rt fa i lu re

into clinically useful subclassifications. Subclassification of HF severity by the degree of elevation of natriuretic peptide levels may be something that develops in the future, but it has not been accepted widely to date.

Other subtypes of heart failure There are other syndromes that fulfil the definition of HF but may require specific treatment and management strategies targeting the underlying or proximate cause, beyond treatment of HF itself. For example, right HF, acute myocardial infarction (AMI) or acute coronary syndrome, cardiogenic shock, hypertensive emergency, hypertensive heart disease, congenital heart disease, valvular heart disease, and high-​output failure may fulfil the diagnostic criteria of HF but require specific treatment strategies beyond standard therapies of HF. The presence of right HF in the setting of left HF can be categorized as HF and may require modified treatment approaches. On the other hand, isolated right HF due to primary pulmonary hypertension aetiologies, although it may have symptoms or signs that mimic HF and may have elevated natriuretic peptide levels, would not be categorized under HF as the symptoms are not caused primarily by a structural and/​or functional cardiac abnormality. On the other hand, right HF due to primary right ventricular conditions, such as arrhythmogenic right ventricular cardiomyopathy, would be categorized under HF. AMI would be the overarching definition of the clinical episode for any HF event in proximity to the infarction for those patients with HF during an AMI. It is also possible that these patients may progress to chronic HF. Though cardiogenic shock is an extreme form of HF, it requires urgent advanced therapies and needs to be specified. HF can be the preceding cause of shock in advanced HF patients, and identified as advanced HF complicated with cardiogenic shock. In hypertensive emergency and hypertensive heart disease complicated with HF, treatment of hypertension is critical. Similarly, valvular heart disease, congenital heart disease, and high-​output cardiac failure can result in HF and require specific treatment strategies targeting the underlying anomaly and specific haemodynamic conditions. Given the unique nature of these diagnoses, it is appropriate for these to have unique identifications.

Disorders that can mimic heart failure Symptoms and signs in non-​cardiovascular conditions such as renal failure, liver failure, morbid obesity with peripheral oedema, and chronic respiratory failure with hypoventilation syndrome may mimic HF. In most, symptoms and signs of HF may disappear once the underlying primary cause is treated (e.g. symptoms and signs that mimic HF may disappear with haemodialysis in a patient with end-​stage CKD). In some of these disease states, volume overload and compensatory mechanisms may result in haemodynamic characterization and biomarker profiles similar to HF, and in fact, some of these patients may have concomitant HF, since obesity, diabetes, and CKD are also risk factors for development of HF. In these conditions, objective markers such as natriuretic peptide levels and haemodynamic characterization of increased filling pressures can be helpful.

Disorders that can incorporate an element of heart failure Certain disorders can be complicated with HF. The primary disease may require specific treatment strategies, but the development of HF as a complication usually confers a higher risk and worse prognosis, thus requiring treatment to also address the HF element. These can include cardiovascular causes such as AMI or acute coronary syndrome, hypertensive emergency as mentioned above, and also other cardiovascular diagnoses such as atrial fibrillation with a rapid ventricular response, prolonged ventricular arrhythmias, pulmonary embolus, pericardial diseases, and acute valvular dysfunction.

Use in practice Despite guidelines and expansion of evidence for guideline-​ directed therapies, registries with real-​world patients over the last 20 years have shown disappointing trends with little, if any, improvement in the use of GDMT, suggesting a lack of ability to standardize care in practice. Standardization of the definition of the HF syndrome is an important first step to enhance appropriate diagnosis and optimization of GDMT and achieve uniformity of care for HF universally. New revised terminologies of classification of HF as at risk of HF, pre-​HF, HF, and advanced HF likely will be easier to understand for patients and clinicians alike, and will help clarify treatment indications for pre-​HF, as well as for HF, along with incorporating asymptomatic phases under the UDHF umbrella without characterizing them as ‘HF’. EF classifications provide clarity and standardization for targeting GDMT. Emphasis for trajectory terminologies for ‘persistent’ HF rather than ‘stable’ HF, and HF ‘in remission’ rather than ‘recovered’ HF, will prevent inertia and increase the likelihood of optimization and continuation of GDMT for indicated patients. At the first encounter with the patient, clinicians should use the UDHF to diagnose, confirm, and document HF. They should then classify it according to LVEF to initiate and optimize GDMT. They should specify the stages of HF to initiate appropriate GDMT for prevention and treatment, and also assess and communicate the prognosis with the patient and consider referral to specialists for advanced HF patients. In the subsequent encounter, clinicians should address the trajectory of HF, continue and optimize GDMT, reassess the prognosis, and consider referral if indicated.

Use in research Historically in the last 10 years, most clinical trials have already incorporated objective findings such as elevated natriuretic peptide levels to increase specificity and also to enrich patient populations for increased risk. The UDHF provides a simple, but conceptually comprehensive, definition with acceptable sensitivity and specificity. We believe the UDHF will help achieve uniformity for standard diagnostic criteria for research studies, as well as for registries and databases. The refined definitions of stages provide clarity for targeting treatment strategies for at-​risk and pre-​HF stages, which await development of new treatment strategies to

Chapter 1.1  

prevent HF. This is a rapidly evolving field with advances in precision medicine. Genetic causes and biomarker characterization will help identify risk and targeted prevention and treatment strategies. The UDHF also provides a practical framework for modernization and harmonization of administrative codes for HF diagnosis and stages, and EF classification, which can impact the ability to capture quality measures and performance indicators in a reliable manner. The UDHF is envisioned to be very useful not only for clinicians, but also for researchers, administrators, regulatory agencies, and developers of performance measures, guidelines, and registries.

Summary A UDHF is proposed that simplifies and democratizes the definition of HF, unifies different staging schemes, and forms a framework that can encompass disease staging and trajectories and aid clinical practice, research, and patient education.

Disclosures Professor Coats declares no conflicts related to this work. Outside of this work, in the last 3 years, Professor Coats declares having received honoraria and/​ or lecture fees from: Astra Zeneca, Boehringer Ingelheim, Menarini, Novartis, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, Respicardia, and Viatris. Professor Bozkurt declares no conflicts related to this work. Outside of this work, in the last 3 years, Professor Bozkurt declares having received consulting fees from Bristol Myers Squibb Pharmaceuticals, Baxter Healthcare Corporation, Sanofi-​Aventis, Relypsa, and Amgen. She currently serves on the Clinical Event Committee for the GUIDE HF Trial sponsored by Abbott Vascular, and on the Data Safety Monitoring Committee of the ANTHEM (Autonomic REGULATION Therapy to Enhance Myocardial Function and Reduce progression of Heart Failure with reduced ejection fraction) trial sponsored by Liva Nova.

U n i ver s a l defi n i ti on of hea rt fa i lure

References 1. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021;23:352–​80. 2. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441–​6. 3. White PD, Myers MM. The classification of cardiac diagnosis. JAMA. 1921;77:1414–​15. 4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/​AHA guideline for the management of heart failure. Circulation. 2013;128:e240–​327. 5. Arbustini E, Narula N, Tavazzi L, et al. The MOGE(S) classification of cardiomyopathy for clinicians. J Am Coll Cardiol. 2014;64:304–​18. 6. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant. 2009;28:535–​41. 7. Folse R, Braunwald E. Determination of fraction of left ventricular volume ejected per beat and of ventricular end-​diastolic and residual volumes. Experimental and clinical observations with a precordial dilution technic. Circulation. 1962;25:674–​85. 8. Bruce TA, Chapman CB. Left ventricular residual volume in the intact and denervated dog heart. Circulation Res. 1965;17:379–​85. 9. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–​200. 10. McDonagh TA, Metra M, Adamo M, et al.; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021;42:3599–​726.

9

SECTION 2

Epidemiology of heart failure

2.1 Epidemiology of heart failure 

13

Amy Groenewegen, Ivan Milinković, Arno W Hoes, Arend Mosterd, and Frans H Rutten

CHAPTER 2.1

Epidemiology of heart failure Amy Groenewegen, Ivan Milinković, Arno W Hoes, Arend Mosterd, and Frans H Rutten Contents Introduction  13 Heart failure definitions and case ascertainment  13 To measure an epidemic  14 Heart failure occurrence  14 Prevalence  14 Incidence  16 Heart failure in the young  16

Lifetime risk  18 The global burden of heart failure  18 Sex differences in heart failure epidemiology  18 Prognosis of heart failure  19

Mortality of heart failure  19 Hospitalizations  20 Determinants of prognosis and prognostic models  20

Prevention of heart failure  20 Conclusions and future directions  21 Key messages  21 References  22

Introduction Heart failure has been described as an epidemic. It currently affects an estimated 64 million people worldwide, and the number of patients living with heart failure continues to increase due to a growing and ageing population. To quantify the exact burden of heart failure is challenging because it is a complex syndrome, and heart failure definitions have changed over time. This chapter provides an overview of heart failure occurrence and prognosis, and is a guide to the interpretation of differences across epidemiological reports.

Heart failure definitions and case ascertainment Heart failure is not a single disease, but a heterogenous syndrome, and a generally accepted ‘gold standard’ for its diagnosis is lacking. Case ascertainment and categorization of patients, as well as comparison of epidemiological research studies in the literature, thus remain challenging. Echocardiography is the cornerstone of heart failure diagnosis, and left ventricular ejection fraction (LVEF) is generally viewed as a clinically useful phenotypic marker indicative of underlying pathophysiological mechanisms, prognosis, and sensitivity to therapy.1 Heart failure patients are therefore most often categorized according to LVEF: heart failure with reduced (HFrEF, LVEF 250,000 low–​middle-​class people and defining heart failure according to the Framingham criteria, showed that heart failure prevalence steadily increased from 9 to 21 cases per 10,000 population between 2000 and 2007. Rates were higher in men than in women. The prevalence of HFpEF was higher than that of HFrEF, with the rates of HFpEF higher in women and HFrEF higher in

men.28 In a Swedish registry of primary and secondary care records of over 2 million inhabitants, the age-​and sex-​adjusted prevalence of 2.2% remained stable between 2006 and 2010.21

Incidence The global incidence of heart failure ranges from 1 to 9 cases per 1000 person-​years and depends again on the population studied and the diagnostic criteria used (% Figure 2.1.1).11 According to the HFA’s Atlas Survey, the median incidence of heart failure in European countries was 3.20 (interquartile range (IQR) 2.66–​ 4.17) cases per 1000 person-​years, ranging from ≤2 in Italy and Denmark to >6 in Germany.19 Recently, data from four community-​based cohorts with prospective case validation and echocardiographic data (FHS, Cardiovascular Health Study (CHS), Multi-​ Ethnic Study of Atherosclerosis (MESA), PREVEND study) were pooled for evaluation of the respective contributions of HFpEF, HFmrEF, and HFrEF to the population burden of heart failure (% Table 2.1.2). Age-​and sex-​standardized incidence of HFmrEF was only 0.7 cases per 1000 person-​years, compared to an incidence of 2.7 and 3.5 cases per 1000 person-​years for HFpEF and HFrEF, respectively. Interestingly, predictors of incident heart failure did not differ across LVEF categories.29 Trends in heart failure incidence High-​income countries have seen a stabilization of incidence rates between 1970 and 1990, and some now even are experiencing a decrease.11 Between 2000 and 2010, there was a substantial decline in age-​ and sex-​adjusted incidence of all-​type heart failure in the Olmsted County Cohort study in the United States, from 3.2 to 2.2 cases per 1000 person-​years.6 Because diagnostic criteria, which include echocardiographic measures, have remained uniform over time in this cohort, its data can be used to reliably chart trends in incidence of heart failure stratified by LVEF. The decline was greater in HFrEF (45% decline) than in HFpEF (28% decline). The proportion of incident heart failure cases with HFpEF increased from 38% in 1986 to 52% in 2010, concurrently with an increase in heart failure patients with prevalent hypertension, atrial fibrillation, and diabetes. A decline of 7% of all-​type heart failure was seen between 2002 and 2014 in the United Kingdom, based on primary care data from 4 million individuals, from 3.6 to 3.3 per 1000 person-​years (adjusted incidence rate ratio (IRR) 0.93, 95% confidence interval (CI) 0.91–​0.94).22 The largest decline was observed in patients aged 60–​84 years, whereas a worrying increase in incidence rate was reported in younger patients (18 years, age-​and sex-​adjusted

First-​time in-​hospital diagnosis of heart failure

>74 years: 16.4/​1000 p*y 65–​74 years: 6.3/​1000 p*y 55–​64 years: 2.0/​1000 p*y 45–​54 years: 0.50/​1000 p*y 35–​44 years: 0.13/​1000 p*y 18–​34 years: 0.04/​1000 p*y

2012

Conrad22

2002 2014

>74 years: 11.5/​1000 p*y 65–​74 years: 3.5/​1000 p*y 55–​64 years: 1.7/​1000 p*y 45–​54 years: 0.64/​1000 p*y 35–​44 years: 0.20/​1000 p*y 18–​34 years: 0.07/​1000 p*y UK, all ages, age-​and sex-​standardized

Hospital and primary care health records

3.6/​1000 p*y 3.3/​1000 p*y

Störk23

2009–​2013

Germany, all ages, age-​and sex-​standardized

Health-​care claims data

6.6/​1000 persons

Smeets25

2000

Belgium, aged ≥45 years, age-​standardized

Primary care health registry

Men: 3.1/​1000 persons Women: 2.2/​1000 persons

2015

Men: 2.8/​1000 persons Women: 2.3/​1000 persons

Studies using rigorous echocardiographic case validation Bahrami34

Enrolled 2000–​2002, median follow-​up 4 years

USA, MESA cohort, not adjusted

MESA criteria

African-​American: 4.6/​ 1000 p*y Hispanic: 3.5/​1000 p*y White: 2.4/​1000 p*y Chinese-​American: 1.0/​1000 p*y

Ho35

1981–​2008

USA, FHS cohort

Framingham criteria

5/​1000 p*y

Meyer

1997–​2010

Netherlands, PREVEND cohort

ESC criteria

Men: 3.7/​1000 p*y Women: 2.4/​1000 p*y

Tsao37

1990–​1999

Combined FHS and CHS cohorts, age Framingham and CHS criteria ≥60 years, age-​standardized

19.7/​1000 persons

USA, Olmsted County Cohort

3.2/​1000 p*y

36

2000–​2009 Gerber

6

2000 2010

Framingham criteria

18.9/​1000 persons 2.2/​1000 p*y

ARIC, Atherosclerosis Risk in Communities; NHANES, National Health and Nutrition Examination Survey; MESA, Multi-​Ethnic Study of Atherosclerosis; FHS, Framingham Heart Study; PREVEND, Prevention of Renal and Vascular End-​stage Disease; CHS, Cardiovascular Health Study; p*y person-​years.

17

18

SECTION 2  

E pide miol o gy of h eart failu re

However, recent studies suggest that the burden of heart failure in the younger population may be increasing. In a Danish nationwide cohort study of hospitalized patients, the incidence rate of heart failure decreased substantially between 1995 and 2021 (IRR 0.90, 95% CI 0.88–​0.93). The mean age simultaneously declined, however, and the proportion of patients with new-​onset heart failure aged 50 years or younger doubled over the same time span (from 3% to 6%).33 Similar trends were observed in Sweden—​by linking nationwide hospital discharge and death registries between 1987 and 2006, investigators found a worrisome increase in heart failure incidence of 43% among people aged 35–​44 years and even of 50% among people aged 18–​34 years.39 It remains unclear why heart failure incidence increases in the younger population, despite the overall observed decrease. The data may simply reflect better awareness and registration. Links have also been made with the higher prevalence of hypertension and obesity and obesity-​related diseases, such as type 2 diabetes, which occur increasingly frequently in younger patients.

Lifetime risk In the Cardiovascular Lifetime Risk Pooling project, using data from nearly 40,000 individuals included in American cohorts, the overall chance that a 45-​year old develops heart failure before the age of 95 was 30–​42% in white men, 20–​29% in black men, 32–​39% in white women, and 24–​46% in black women.40 The lower lifetime risk in black men, compared to white men, was attributed to competing risks, since black men have a higher risk of developing heart failure, according to community-​based cohorts.30 In contrast, from a British study of health records (from primary and hospital care and national registries) of 1.25 million inhabitants, the lifetime risk of developing heart failure at age 30 was only 5%. In hypertensive individuals (systolic blood pressure >140 mmHg), this risk increased to 7.8%.41 The risks differ between these reports partly because of differences in the population under study—​in the latter study, all individuals who had any type of pre-​existing cardiovascular disease were excluded. Because heart failure is strongly associated with age and prior cardiovascular disease, the lower lifetime risks found in this study are not surprising.

The global burden of heart failure Lower-​and middle-​income countries are estimated to carry over three-​quarters of the cardiovascular disease burden, but very few studies provide reliable data on heart failure occurrence and outcomes in these regions.11,42 Recently, a population-​based study using insurance information in China estimated the prevalence to be 1.1% for both men and women, accounting for a total of 12.1 million Chinese inhabitants currently living with heart failure.43 The incidence was 2 per 1000 person-​years. In another report from China, the age-​standardized rate increased by 5.4% between 2010 and 2015.44 Based on scarce epidemiological data from other Asian regions, the prevalence ranges between 1% and 1.3%, similar to China. The only South American population-​based study found a heart failure incidence of 2 per 1000 person-​years,

based on self-​reporting in Brazil. The prevalence was estimated to be 1% in Cuba. The prevalence in Australia is similar to that in Europe (1–​2%), although much higher rates are found in echocardiographic screening studies among Indigenous communities (5.3%) despite a lower mean age. There are no population-​based studies providing data on heart failure occurrence in African countries. Over the last 15 years, clinical trials have enrolled an increasing number of patients from regions other than Europe and Northern America, promoting our understanding of regional differences in heart failure phenotypes. Based on data from the PARADIGM-​ HF trial, HFrEF patients from Latin America and the Asia-​Pacific region are 10 years younger than their European and Northern American counterparts.45 In South East Asia, the prevalence of overweight is much lower than in the United States, but the prevalence of diabetes is remarkably high and gives rise to a unique ‘lean diabetic’ HFpEF phenotype. This HFpEF phenotype is responsible for an estimated 20% of all heart failure cases in South East Asia and has a relatively high rate of all-​cause mortality.46 According to the Global Burden of Disease study, four underlying causes (ischaemic heart disease, COPD, hypertensive heart disease, and rheumatic heart disease) are responsible for over two-​ thirds of heart failure cases worldwide.47 Undeveloped countries are disproportionally affected by rheumatic heart disease and hypertension. Infectious diseases, including human immunodeficiency virus (HIV), remain important causes of heart failure in lower-​income countries worldwide. In Latin America, approximately half of heart failure cases are caused by Chagas’ cardiomyopathy, a preventable parasitic disease.48,49 Because infections occur at all ages, heart failure populations in developing regions tend to be relatively young. In sub-​Saharan Africa, half of patients hospitalized for heart failure were aged 55 years or younger.50 Simultaneously, diseases typically associated with a more Western-​type lifestyle, such as diabetes and obesity, are increasingly common in low-​and middle-​income regions. This double disease burden is evidenced by data from the Global Burden of Disease Study that showed increased age-​standardized rates of ischaemic heart disease in lower-​income regions.47

Sex differences in heart failure epidemiology Even though the incidence of all-​type heart failure is fairly similar for men and women, the proportion of subtypes is decidedly different; notably HFpEF is more common in women.6,22 In the Swedish Heart Failure registry, women accounted for 55% of all HFpEF patients and only 29% of all HFrEF patients.51 In the Olmsted County Cohort study, women were over-​represented among individuals with incident HFpEF by 2:1. Between 2000 and 2010, the proportion of patients with incident heart failure who had HFpEF increased from 48% to 52%. The overall heart failure incidence decreased for both men and women, but women exhibited a markedly larger decline in the incidence of HFrEF than HFpEF (−61% vs −27%), compared with men (−29% vs −27%).6 The relationship between hypertension and the development of LV hypertrophy, diastolic dysfunction, and HFpEF seems to be

Chapter 2.1  

stronger in women than in men. Similarly, the excess risk associated with diabetes, which is a stronger risk factor for HFpEF than for HFrEF, is more pronounced in women,52 also independent of age.53 These findings led to the general idea that women are more susceptible to HFpEF than men. However, in pooled data from the CHS and MESA studies, female sex was not associated with a higher lifetime risk of HFpEF, but with a lower lifetime risk of HFrEF, compared to male sex (5.8% vs 10.6%).54

Prognosis of heart failure Mortality of heart failure Despite trials yielding effective treatments for HFrEF, and to a lesser extent HFmrEF, patients, heart failure prognosis remains poor. Estimates of the mortality associated with heart failure strongly depend on the baseline risk of the population under study, heart failure criteria and LVEF cut-​off values used, as well as the introduction of bias through exclusion of patients with missing LVEF values.11 Mortality rates are generally higher in observational studies than in clinical trial populations, which often include younger patients with fewer comorbidities.55 Prognosis of the ‘average’ heart failure patient is therefore best evaluated in community-​based cohorts, following up new cases of echocardiographically confirmed heart failure. Such studies include the Olmsted County Cohort, FHS, and CHS. Combined data from the FHS and CHS cohorts, both of which use expert panels to determine the presence or absence of heart failure (HFpEF defined as LVEF ≥50%, and HFrEF as LVEF 50%, borderline significance), an effect that disappeared in multivariate analysis.6 (See % Table 2.1.3.) Hospitalization is overall a strong prognostic predictor. In the Get With The Guidelines-​Heart Failure cohort including 40,000 patients hospitalized with heart failure, aged ≥65 years,

Epi dem i ol o g y of hea rt fa i lure

stratified into HFrEF (46%), HFmrEF (8%), and HFpEF (46%), an alarming 5-​year mortality rate of 75% was found, regardless of LVEF.58 In a study of 2.1 million individuals in the United Kingdom, patients with heart failure newly recorded in primary care, and who had no prior hospital admission, had a 5-​year mortality rate of 56%, compared to 78% in patients who were hospitalized for heart failure but did not have a primary care record.59 In general, the steepest drop in the survival curve is during the initial weeks after admission. The value of in-​hospital mortality estimates is dubious, as the length of hospital stay may, in part, depend on whether or not the patient is thought to have reached the palliative stage. Estimates of 30-​day mortality rate are less susceptible to bias and range from 5% to 20% (% Figure 2.1.1).11,30,31 How outcomes differ across the LVEF spectrum remains unclear. Some population-​based studies report the risk of death to be as high, or nearly as high, in patients with HFpEF and HFmrEF, compared to HFrEF.6,37 Randomized controlled trials, which tend to include only severe cases of heart failure as a strategy to increase cardiovascular outcomes, often find larger differences in survival between HFrEF patients and those with HFpEF and HFmrEF. In the CHARM trial, which included heart failure patients regardless of LVEF, the risk of all-​cause death over 3 years of follow-​up was 30.0%, 15.8%, and 16.6% in HFrEF, HFmrEF, and HFpEF patients, respectively. When LVEF was applied as a continuous variable, the risk decreased steeply with increasing ejection fraction until an ejection fraction of around 50%, and the risk was flat thereafter.8 Trends in mortality of heart failure A recent meta-​analysis pooling 60 observational studies, including 1.5 million ambulatory patients with chronic all-​type heart failure, showed that survival rates have improved by approximately 20% since 1970. However, the decline in mortality has been only modest in the last decades, and 1-​and 5-​year mortality rates in heart failure remain high at 10.7% and 40.3%, respectively.60 The reasons for this deflection remain uncertain, but it may include the shift from HFrEF to HFpEF (for which no evidence-​based treatment is available) and the increased burden of comorbidities. The studies included in this meta-​analysis were heterogeneous and often relied on primary care databases and health data registries. In lacking echocardiographic case validation, these

Table 2.1.3  Age-​adjusted mortality (%) after onset of heart failure in women and men in population-​based cohort studies during the period 1970–​2010 Period

Olmsted County Cohort6,56

Framingham Heart Study57

1-​year mortality

5-​year mortality

1-​year mortality

Women

Women

Women

Men

Women

Men

28

41

59

75

Men

Men

1970–​1979

5-​year mortality

1980–​1989

20

30

51

65

27

33

51

65

1990–​1999

17

21

46

50

24

28

45

59

2000–​2010

20*

53*

* No percentages were reported for men and women separately.

19

20

SECTION 2  

E pide miol o gy of h eart failu re

estimates are more susceptible to changes in coding practices and heart failure definitions over time. In an echocardiographic study using a subsample of the FHS cohort and looking back across three decades (1985–​2014), all-​ cause mortality did not change significantly over time or between the subgroups of HFrEF, HFmrEF, and HFpEF. However, cardiovascular mortality associated with HFrEF declined across the decades by 40% (hazard ratio 0.61, 95% CI 0.39–​0.97), remaining unchanged in patients with HFmrEF and HFpEF. The absolute mortality rate in individuals with HFrEF was higher than in the other two groups in the initial decade (1985–​1994) but converged thereafter, underscoring again the effectiveness of evidence-​based strategies for HFrEF and the want of those for HFpEF.61

Hospitalizations Heart failure hospitalizations represent 1–​2% of all hospital admissions (% Figure 2.1.1),62 making it the most common diagnosis in hospitalized patients aged 65 years and older.63 In the European Heart Failure Atlas Survey, the median number of heart failure discharges per million people was 2671 (IQR 1771–​4317), ranging from 6000 in Romania, Norway, and Germany. The length of hospital stay also varied across countries, ranging from ≤6 days to ≥11 days, with a median of 8.5 days. The authors hypothesized that the heterogeneity reflects differences in hospital admission policies and criteria, access to, and quality of, hospital care and dedicated centres, and adherence to therapy. In the community-​based Olmsted County Cohort study, heart failure patients were admitted approximately once a year, regardless of LVEF.6 By contrast, in the CHARM trial, the hospitalization rate declined with increasing LVEF until an LVEF of 40%, levelling off thereafter.8 About two-​thirds of heart failure hospitalization is for non-​cardiovascular causes;6 in some studies, this percentage is even higher in patients with HFpEF, reflecting older age and higher comorbidity burden.64 After a peak in the number of hospitalizations for heart failure during the 1990s in Europe and the United States, most community-​based studies now show a marked decline. In a nationwide sample in Denmark, hospitalization rates decreased by 25% for women (from 192 to 144 per 100,000 persons) and by 14% for men (from 217 to 186) between 1983 and 2012.33 Heart failure is associated with the highest 30-​day readmission rate of any diagnosis (approximately 20%, slightly higher in HFpEF compared to HFrEF).64 Over half of patients will be rehospitalized during the first year after discharge, and over 80% within 5 years.58,64 In the IMPACT-​HF study, over half of all patients were discharged with unresolved symptoms. After 2 months of follow-​up, half had worsening symptoms, a quarter were readmitted, and a little over 10% had died.65

Determinants of prognosis and prognostic models Many determinants of prognosis have been identified. Because prognostic determinants are not necessarily causally related to the prognosis, correction does not always improve outcome. Age, New York Heart Association (NYHA) or AHA classification,

and comorbidity burden are important indicators of severity and prognosis. The cause of heart failure also clearly relates to the prognosis—​heart failure resulting from viral myocarditis or Takotsubo cardiomyopathy may be completely reversible, whereas patients with heart failure after a first myocardial infarction face a 5-​year (age-​and sex-​adjusted) mortality rate of 39%.66 Comorbidity is strongly associated with increased mortality. In a Danish nationwide cohort study, using low comorbidity as a reference, the 5-​year mortality rate ratio was increased by 43% for moderate, 66% for severe, and 220% for very severe comorbidity.67 Several multivariable prognostic risk scores have been developed for different populations of heart failure patients. These may help predict mortality but are less useful for the prediction of hospitalization. The C-​statistic, a measure of how well a model discriminates that varies from 0.5 (not better than a coin flip) to 1.0 (perfect prediction), seldom reaches 0.8 or higher in heart failure models. In a meta-​analysis of 117 models (249 different variables), the prediction of death was only modestly accurate (average C-​statistic 0.71). Models predicting the combined end point of death and heart failure hospitalization were even less discriminative (average C-​statistic of 0.63).68 In another systematic review of 64 models, a few variables emerged as consistent predictors of mortality: age, renal function, blood pressure, sodium level, ejection fraction, male sex, natriuretic peptide levels, NYHA class, diabetes, body mass index, and exercise capacity. Interestingly, only two of the included studies had used repeated measurements.69 As pointed out previously, one of the reasons why it is more difficult to predict mortality in heart failure populations than it is in the general population is that age and sex have a much lower C-​ statistic in heart failure patients. For example, in the Framingham cohort, a very simple model for predicting all-​cause death in the general population containing only age and sex had a C-​statistic of 0.75, which is already better than the average risk model for mortality in heart failure patients (average C-​statistic of 0.71, often containing >10 factors).70 In other words, once a patient develops severe heart failure, the risk of death is high, irrespective of age and sex.

Prevention of heart failure The population attributable risk is the proportion of cases for an outcome that can be attributed to a certain risk factor among the entire population. Secular trends in population attributable risk are therefore particularly important from a prevention and public health point of view. In the Olmsted County Cohort study, patients with coronary heart disease and diabetes had the highest risk of developing (all-​ type) heart failure. However, due to their very high prevalence, hypertension and coronary heart disease have a much greater population attributable risk than diabetes, each accounting for 20% of cases (against 12% for diabetes).71 In the ARIC study, suboptimal control of five modifiable risk factors (smoking, diabetes, hypertension, hyperlipidaemia, and obesity) accounted for an estimated 88.8% of incident cases of heart failure.72 Because of

Chapter 2.1  

Epi dem i ol o g y of hea rt fa i lure

Table 2.1.4  Comparison of non-​standardized effects of reductions in systolic blood pressure on heart failure occurrence stratified by class of blood pressure-​lowering drug Intervention ACE inhibitor ARB Beta blocker CCB Diuretics

Control

Studies

Events

Participants

Events

Participants

RR (95% CI)

13

1494

32,304

2706

50,277

0.98 (0.96–​1.04)

8

1141

26,418

1187

26,311

0.81 (0.92–​1.05)

8

652

33,953

634

34,185

1.04 (0.93–​1.16)

22

2104

72,323

2955

90,403

1.17 (1.11–​1.24)

8

1108

32,580

1570

35,435

0.81 (0.75–​0.88)

ACE, angiotensin-​converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; RR, relative risk; CI, confidence interval. Reproduced from Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-​analysis. Lancet. 2016 Mar 5;387(10022):957–​967. doi: 10.1016/​S0140-​6736(15)01225-​8 with permission from Elsevier.

the high prevalence of these risk factors, even a modest reduction may translate into a large improvement at population level. For example, a hypothetical reduction of 5% in diabetes prevalence among citizens in the United States was estimated to prevent 30,000 incident cases of hospitalization for heart failure per year. A 30% reduction in obesity and overweight could prevent 8.5% of incident heart failure cases.73 Every 10-​ mmHg systolic blood pressure reduction significantly reduces the risk of heart failure (RR 0.72, 95% CI 0.67–​ 0.78).74 However, not all antihypertensive drugs are equal in their propensity to prevent heart failure; diuretics seem the best (% Table 2.1.4). Despite many strategies that might reduce the loss of disability-​ adjusted life-​years due to heart failure, age remains the most important risk factor and will eventually take its toll. Simulation studies showed that, in a population of individuals with ideal risk factor profiles, heart failure incidence will only be about 25% less than in the current population.75 Postponing heart failure, however, could still save hundreds of millions of years lived without disability and thereby reduce the burden of disease considerably.

Conclusions and future directions The heart failure epidemic is changing. Incidence rates seem to have stabilized, but the number of patients living with heart failure is still increasing. Over the last decades, much better information is gathered about the heart failure epidemic, notably by large longitudinal population-​based studies, although mainly in high-​income countries. Special attention should be paid to the epidemiology of heart failure in low-​and middle-​ income countries, which are disproportionally affected by preventable causes of heart failure. The case mix of heart failure is changing, with a larger proportion of patients with HFpEF. There is still much to learn in phenotyping beyond LVEF, and more information is needed on heart failure occurrence in specific populations, including women and the young. Before we can apply precision medicine, drug trials are needed to evaluate dosage of drugs in females and a more personalized treatment effect of a drug or a combination of drugs using individual patient data.

Key messages ◆ Heart failure affects an estimated 64 million people worldwide. ◆ Four underlying causes (ischaemic heart disease, COPD, hypertensive heart disease, and rheumatic heart disease) are responsible for over two-​thirds of heart failure cases worldwide. ◆ Suboptimal control of five modifiable risk factors (smoking, diabetes, hypertension, hyperlipidaemia, and obesity) account for an estimated 88.8% of incident cases of heart failure. ◆ Estimations of prevalence and incidence vary widely due to a lack of uniformity in the definition and diagnostic criteria of heart failure. ◆ Global heart failure incidence ranges from 1 to 9 cases per 1000 person-​ years, depending on the population studied and the diagnostic criteria used. Age-​and sex-​standardized incidence of HFmrEF is only 0.7 cases per 1000 person-​years, compared to an incidence of 2.7 and 3.5 cases per 1000 person-​years for HFpEF and HFrEF, respectively. However, recent studies suggest that the heart failure burden in the younger population may be increasing. ◆ Heart failure prevalence is estimated at 1–​2% of the general adult population, with an age-​and sex-​adjusted prevalence of 2.2%. All-​type heart failure prevalence estimates range from 0.7% to 1.3% for those aged 75 years old. The median length of hospital stay is around 8.5 days. About two-​ thirds of heart failure hospitalizations is for non-​cardiovascular causes, and in some studies higher in patients with HFpEF, reflecting older age and a higher comorbidity burden. Heart failure is associated with 30-​day readmission rates of around 20%, with over half of patients rehospitalized during the first year, and over 80% within 5 years after discharge. ◆ One-​and 5-​year mortality rates are 10.7% and 40.3%, respectively.

21

22

SECTION 2  

E pide miol o gy of h eart failu re

◆ Determinants of prognosis: age, renal function, blood pressure, sodium level, ejection fraction, male sex, natriuretic peptide levels, NYHA class, diabetes, body mass index, and exercise capacity.

References 1. Borlaug BA, Redfield MM. Diastolic and Systolic Heart Failure Are Distinct Phenotypes Within the Heart Failure Spectrum. Circulation 2011;123:2006–​14. 2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–​726. 3. Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-​range or mildly reduced ejection fraction. Nat Rev Cardiol 2022;19(2):100–​16. 4. Selmeryd J, Henriksen E, Leppert J, Hedberg P. Interstudy heterogeneity of definitions of diastolic dysfunction severely affects reported prevalence. Eur Heart J 2016;17:892–​9. 5. Petrie MC, Hogg K, Caruana L, McMurray JJ V. Poor concordance of commonly used echocardiographic measures of left ventricular diastolic function in patients with suspected heart failure but preserved systolic function: is there a reliable echocardiographic measure of diastolic dysfunction? Heart 2004;90:511–​17. 6. Gerber Y, Weston SA, Redfield MM, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA 2015;175:996–​1004. 7. Lauritsen J, Gustafsson F, Abdulla J. Characteristics and long-​term prognosis of patients with heart failure and mid-​range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-​analysis. ESC Heart Fail 2018;5:685–​94. 8. Lund LH, Claggett B, Liu J, et al. Heart failure with mid-​range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail 2018;20:1230–​9. 9. Lam CSP, Solomon SD. Fussing Over the Middle Child: Heart Failure With Mid-​Range Ejection Fraction. Circulation 2017;135:1279–​80. 10. Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM. Longitudinal Changes in Ejection Fraction in Heart Failure Patients With Preserved and Reduced Ejection Fraction. Circ Heart Fail 2012;5:720–​6. 11. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail 2020;22:1342–​56. 12. Quach S, Blais C, Quan H. Administrative data have high variation in validity for recording heart failure. Can J Cardiol 2010;26:306–​12. 13. Quan H, Li B, Saunders LD, et al.; IMECCHI Investigators. Assessing validity of ICD-​9-​CM and ICD-​10 administrative data in recording clinical conditions in a unique dually coded database. Health Serv Res 2008;43:1424–​41. 14. Goff DC, Pandey DK, Chan FA, Ortiz C, Nichaman MZ. Congestive Heart Failure in the United States. Arch Intern Med 2000;160:197. 15. Rosamond WD, Chang PP, Baggett C, et al. Classification of heart failure in the atherosclerosis risk in communities (ARIC) study a comparison of diagnostic criteria. Circ Heart Fail 2012;5:152–​9. 16. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 Diseases and Injuries for 195 countries and territories, 1990-​2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1789–​858. 17. Riet EES Van, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: The prevalence of heart failure and ventricular dysfunction

in older adults over time. A systematic review. Eur J Heart Fail 2016;18:242–​52. 18. Banerjee A, Mendis S. Heart failure: the need for global health perspective. Curr Cardiol Rev 2013;9:97–​8. 19. Seferović PM, Vardas P, Jankowska EA, et al. The Heart Failure Association Atlas: Heart Failure Epidemiology and Management Statistics 2019. Eur J Heart Fail 2021;23:906–​14. 20. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and Prevalence of Heart Failure in Elderly Persons, 1994–​2003. Arch Intern Med 2008;168:418. 21. Zarrinkoub R, Wettermark B, Wändell P, et al. The epidemiology of heart failure, based on data for 2.1 million inhabitants in Sweden. Eur J Heart Fail 2013;15:995–​1002. 22. Conrad N, Judge A, Tran J, et al. Temporal trends and patterns in heart failure incidence: a population-​based study of 4 million individuals. Lancet 2018;391:572–​80. 23. Störk S, Handrock R, Jacob J, et al. Epidemiology of heart failure in Germany: a retrospective database study. Clin Res Cardiol 2017;106:913–​22. 24. Benjamin EJ, Salim Virani CS, et al. Heart Disease and Stroke Statistics: 2018 Update A Report From the American Heart Association. Circulation 2018;137:67–​492. 25. Smeets M, Vaes B, Mamouris P, et al. Burden of heart failure in Flemish general practices: a registry-​based study in the Intego database. BMJ Open 2019;9:e022972. 26. Caruana L, Petrie MC, Davie AP, McMurray JJ. Do patients with suspected heart failure and preserved left ventricular systolic function suffer from ‘diastolic heart failure’; or from misdiagnosis? A prospective descriptive study. BMJ 2000;321:215–​18. 27. Dunlay SM, Roger VL. Understanding the Epidemic of Heart Failure: Past, Present, and Future. Curr Heart Fail Rep 2014;11:404–​15. 28. Gomez-​Soto FM, Andrey JL, Garcia-​Egido AA, et al. Incidence and mortality of heart failure: A community-​based study. Int J Cardiol 2011;151:40–​5. 29. Bhambhani V, Kizer JR, Lima JAC, et al. Predictors and outcomes of heart failure with mid-​range ejection fraction. Eur J Heart Fail 2018;20:651–​9. 30. Loehr LR, Rosamond WD, Chang PP, Folsom AR, Chambless LE. Heart Failure Incidence and Survival (from the Atherosclerosis Risk in Communities Study). Am J Cardiol 2008;101:1016–​22. 31. Jhund PS, Macintyre K, Simpson CR, et al. Long-​Term Trends in First Hospitalization for Heart Failure and Subsequent Survival Between 1986 and 2003. Circulation 2009;119:515–​23. 32. Yeung DF, Boom NK, Guo H, Lee DS, Schultz SE, Tu JV. Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007. CMAJ 2012;184:E765–​73. 33. Christiansen MN, Køber L, Weeke P, et al. Age-​Specific Trends in Incidence, Mortality, and Comorbidities of Heart Failure in Denmark, 1995 to 2012. Circulation 2017;135:1214–​23. 34. Bahrami H, Kronmal R, Bluemke DA, et al. Differences in the Incidence of Congestive Heart Failure by Ethnicity. Arch Intern Med 2008;168:2138. 35. Ho JE, Lyass A, Lee DS, et al. Predictors of new-​onset heart failure: differences in preserved versus reduced ejection fraction. Circ Heart Fail 2013;6:279–​86. 36. Meyer S, Brouwers FP, Voors AA, et al. Sex differences in new-​onset heart failure. Clin Res Cardiol 2015;104:342–​50. 37. Tsao CW, Lyass A, Enserro D, et al. Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. JACC Heart Fail 2018;6:678–​85.

Chapter 2.1  

38. Chen J, Normand S-​LT, Wang Y, Krumholz HM. National and Regional Trends in Heart Failure Hospitalization and Mortality Rates for Medicare Beneficiaries, 1998–​2008. JAMA 2011;306:1669. 39. Barasa A, Schaufelberger M, Lappas G, Swedberg K, Dellborg M, Rosengren A. Heart failure in young adults: 20-​year trends in hospitalization, aetiology, and case fatality in Sweden. Eur Heart J 2014;35:25–​32. 40. Huffman MD, Berry JD, Ning H, et al. Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project. J Am Coll Cardiol 2013;61:1510–​17. 41. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-​years lost, and age-​specific associations in 1.25 million people. Lancet 2014;383:1899–​911. 42. Yusuf S, Rangarajan S, Teo K, et al. Cardiovascular risk and events in 17 low-​, middle-​, and high-​income countries. N Engl J Med 2014;371:818–​27. 43. Wang H, Chai K, Du M, et al. Prevalence and Incidence of Heart Failure Among Urban Patients in China: A National Population-​ Based Analysis. Circ Heart Fail 2021;14:e008406. 44. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 Diseases and Injuries for 195 countries and territories, 1990–​2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;1789–​858. 45. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–​Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014;371:993–​1004. 46. Tromp J, Tay WT, Ouwerkerk W, et al. Multimorbidity in patients with heart failure from 11 Asian regions: A prospective cohort study using the ASIAN-​HF registry. PLoS Med 2018;15:1–​22. 47. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–​2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163–​96. 48. Bocchi EA, Marcondes-​Braga FG, Bacal F, et al. [Updating of the Brazilian guideline for chronic heart failure –​2012]. Arq Bras Cardiol 2012;98:1–​33. 49. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Hear Fail 2014;1:4–​25. 50. Damasceno A, Mayosi BM, Sani M, et al. The Causes, Treatment, and Outcome of Acute Heart Failure in 1006 Africans From 9 Countries. Arch Intern Med 2012;172:1386. 51. Stolfo D, Uijl A, Vedin O, et al. Sex-​Based Differences in Heart Failure Across the Ejection Fraction Spectrum: Phenotyping, and Prognostic and Therapeutic Implications. JACC Heart Fail 2019;7:505–​15. 52. Vogel B, Acevedo M, Appelman Y, et al. The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030. Lancet 2021;397:2385–​438. 53. Boonman-​De Winter LJM, Rutten FH, Cramer MJM, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia 2012;55:2154–​62. 54. Pandey A, Omar W, Ayers C, et al. Sex and race differences in lifetime risk of heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Circulation 2018;137:1814–​23. 55. Heiat A, Gross CP, Krumholz HM. Representation of the Elderly, Women, and Minorities in Heart Failure Clinical Trials. Arch Intern Med 2002;162:1682–​8. 56. Roger VL, Weston SA, Redfield MM, et al. Trends in Heart Failure Incidence and Survival in a Community-​Based Population. JAMA 2004;292:344.

Epi dem i ol o g y of hea rt fa i lure

57. Levy D, Kenchaiah S, Larson MG, et al. Long-​Term Trends in the Incidence of and Survival with Heart Failure. N Engl J Med 2002;347:1397–​402. 58. Shah KS, Xu H, Matsouaka RA, et al. Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-​Year Outcomes. J Am Coll Cardiol 2017;70:2476–​86. 59. Koudstaal S, Pujades-​Rodriguez M, Denaxas S, et al. Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population-​based linked electronic health record cohort study in 2.1 million people. Eur J Heart Fail 2017;19:1119–​27. 60. Jones NRN, Roalfe AK, Adoki I, Hobbs FDR, Taylor CCJ. Survival of patients with chronic heart failure in the community: a systematic review and meta-​analysis. Eur J Heart Fail 2019;21:1306–​25. 61. Vasan RS, Xanthakis V, Lyass A, et al. Epidemiology of Left Ventricular Systolic Dysfunction and Heart Failure in the Framingham Study: An Echocardiographic Study Over 3 Decades. JACC Cardiovasc Imaging 2018;11:1–​11. 62. Alla F, Zannad F, Filippatos G. Epidemiology of acute heart failure syndromes. Heart Fail Rev 2007;12:91–​5. 63. Braunwald E. The war against heart failure: the Lancet lecture. Lancet 2015;385:812–​24. 64. Cheng RK, Cox M, Neely ML, et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J 2014;168:721–​30.e3. 65. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in Acute Heart Failure Syndromes: An Essential Target of Evaluation and Treatment. Am J Med 2006;119:S3–​10. 66. Gerber Y, Weston SA, Enriquez-​Sarano M, et al. Mortality Associated With Heart Failure After Myocardial Infarction. Circ Heart Fail 2016;9:e002460. 67. Schmidt M, Ulrichsen SP, Pedersen L, Bøtker HE, Sørensen HT. Thirty-​year trends in heart failure hospitalization and mortality rates and the prognostic impact of co-​morbidity: a Danish nationwide cohort study. Eur J Heart Fail 2016;18:490–​9. 68. Ouwerkerk W, Voors AA, Zwinderman AH. Factors Influencing the Predictive Power of Models for Predicting Mortality and/​or Heart Failure Hospitalization in Patients With Heart Failure. JACC Heart Fail 2014;2:429–​36. 69. Rahimi K, Bennett D, Conrad N, et al. Risk Prediction in Patients With Heart Failure: A Systematic Review and Analysis. JACC Heart Fail 2014;2:440–​6. 70. Levy WC, Anand IS. Heart Failure Risk Prediction Models. JACC Heart Fail 2017;2:437–​9. 71. Dunlay SM, Weston SA, Jacobsen SJ, Roger VL. Risk factors for heart failure: a population-​ based case-​ control study. Am J Med 2009;122:1023–​8. 72. Folsom AR, Yamagishi K, Hozawa A, Chambless LE. Atherosclerosis Risk in Communities Study Investigators. Absolute and Attributable Risks of Heart Failure Incidence in Relation to Optimal Risk Factors. Circ Heart Fail 2009;2:11–​17. 73. Avery CL, Loehr LR, Baggett C, et al. The Population Burden of Heart Failure Attributable to Modifiable Risk Factors. J Am Coll Cardiol 2012;60:1640–​6. 74. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: A systematic review and meta-​analysis. Lancet 2016;387:957–​67. 75. Engelfriet PM, Hoogenveen RT, Poos MJJC, Blokstra A, van Baal PHM, Verschuren WMM. Heart failure: epidemiology, risk factors and future. [In Dutch]. Report by the Dutch National Institute for Public Health and the Environment (RIVM). 2012. Available from: https://​w ww.rivm.nl/​bibl​ioth​eek/​rappor​ten/​ 260401​006.html.

23

SECTION 3

Aetiology of heart failure 3.1 The role of ischaemic heart disease in heart failure 

27

Rocco A Montone, Maurizio Volterrani, Jian Zhang, and Filippo Crea

3.2 From hypertension to heart failure  Athanasios J Manolis and Yuri Lopatin

33

3.3 Heart failure in valvular heart disease 

39

Ana Pardo Sanz, Ivan Milinković, and José Luis Zamorano

3.4 Cardiomyopathies 

51

3.4.1 Genetic basis of cardiomyopathies  51 Thomas Thum, Stephane Heymans, and Johannes Backs 3.4.2 Dilated and hypokinetic non-​dilated cardiomyopathy  60 Petar M Seferović, Biykem Bozkurt, and Marija Polovina 3.4.3 Hypertrophic cardiomyopathy  70 Perry Elliott, Michel Noutsias, and Aris Anastasakis 3.4.4 Restrictive cardiomyopathy  83 Claudio Rapezzi †, Alberto Aimo, Ales Linhart, and Andre Keren 3.4.5 Arrhythmogenic right ventricular cardiomyopathy  99 Cristina Basso, Hugh Calkins, and Domenico Corrado 3.4.6 Peripartum cardiomyopathy  109 Karen Sliwa and Johann Bauersachs 3.4.7 Takotsubo syndrome  116 Jelena Templin-​Ghadri, Michael Würdinger, Johann Bauersachs, and Christian Templin

3.5 Myocarditis and pericarditis 

127

Stephane Heymans, Arsen D Ristić, Yehuda Adler, and Massimo Imazio

3.6 Congenital heart disease 

137

Werner Budts and Jolien Roos-​Hesselink

3.7 Endocrine and metabolic abnormalities 

147

Martin Huelsmann, Jelena P Seferović, and Francesco Cosentino

3.8 Obesity 

155

Lina Badimon, Stefan D Anker, and Stephan von Haehling

3.9 Cancer and cancer therapy  

163

Dimitrios Farmakis, Alexander Lyon, Teresa Lopez Fernandez, and Daniela Cardinale

3.10 Toxins and infections  

173

Antonello Gavazzi, Maria Carmo Nunes, and Fausto Pinto

CHAPTER 3.1

The role of ischaemic heart disease in heart failure Rocco A Montone, Maurizio Volterrani, Jian Zhang, and Filippo Crea

Contents Introduction  27 Pathophysiological role of coronary artery disease in heart failure  27 Diagnostic approach in patients with coronary artery disease and heart failure  29 Management of patients with coronary artery disease and heart failure  29 Future directions  30 Summary  31 References  31

Introduction In last decades, ischaemic heart disease (IHD) emerged as the most important risk factor for the occurrence of heart failure (HF) because of improved survival following acute myocardial infarction (MI) and the declining prevalence of valvular heart disease.1,2 According to contemporary reports, nearly two-​thirds of HF cases are caused by IHD due to obstructive coronary artery disease (CAD). 1,2 However, these data may underestimate the prevalence of ischaemic mechanisms underlying HF. Indeed, it is worth noting that the presence of non-​obstructive CAD at coronary angiography does not exclude the existence of alternative ischaemic mechanisms that may explain HF, in particular the presence of coronary microvascular dysfunction (CMD).3 Thus, myocardial ischaemia may represent an important pathophysiological substrate along the entire spectrum of HF presentation, including both HF with reduced ejection fraction (EF) (HFrEF) and HF with preserved EF (HFpEF). Moreover, the presence of IHD has important prognostic implications, as it has been shown to be independently associated with a worsened long-​term outcome both in HFpEF and HFrEF patients.1,4 In this chapter, we review the pathophysiological mechanisms underlying ischaemic HF, along with the diagnostic and therapeutic approaches.

Pathophysiological role of coronary artery disease in heart failure Myocardial ischaemia is involved in the pathogenesis of HF across the entire spectrum of left ventricular (LV) function, including both HFrEF and HFpEF (% Figure 3.1.1). Ischaemic mechanisms underlying HFrEF are mainly related to the consequences of acute MI, with LV remodelling occurring in the chronic phase after MI due to extensive scar formation. In particular, in patients with acute MI, prolonged ischaemia induces necrosis of different cellular lineages, including cardiomyocytes and endothelial cells.5,6 This process triggers a pro-​inflammatory response with recruitment of inflammatory cells not only into the infarcted zone, but also into the border zone, thereby extending the ischaemic area and promoting adverse myocardial remodelling.2,6 Moreover, in the acute phase of MI, there is sudden modification in loading conditions of the left ventricle (LV) that triggers a cascade of neurohormonal activation that may contribute to the acute and chronic pathological changes underlying the occurrence of HF.2 Primary percutaneous coronary intervention (PCI) emerged in

28

SECTION 3  

Aetiol o gy of h eart failu re

Figure 3.1.1  Pathophysiology, diagnosis, and management of coronary artery disease in patients with heart failure. CAD, coronary artery disease; MI,

myocardial infarction; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; LV, left ventricle; TT-​Echo, transthoracic echocardiography; ECG, electrocardiogram; LGE-​CMR, late gadolinium enhancement cardiac magnetic resonance; stress Echo, stress echocardiography; SPECT, single-​photon emission computed tomography; PET, position emission tomography; MPI, myocardial perfusion imaging; CV, cardiovascular; ARNI, angiotensin receptor–​neprilysin inhibitor; MRA, mineralocorticoid receptor; SGLT2I, sodium–​glucose cotransporter 2 inhibitor; BB, beta-​blocker; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; ICD, implantable cardioverter–​defibrillator; CTA, computed coronary angiography; NOCAD, non-​obstructive coronary artery disease; ACEi, angiotensin-​converting enzyme inhibitor; FFR, fractional flow reserve; IFR, instantaneous wave-​free ratio; IMR, index of microvascular resistance; CFR, coronary flow reserve.

the last decades as the preferred strategy for revascularization in ST-​segment elevation MI. However, even in the context of successful restoration of epicardial blood flow by primary PCI, a considerable proportion of patients, nearly 50%, still do not achieve optimal myocardial reperfusion,5,6 due to the occurrence of coronary microvascular obstruction (MVO). Several interacting mechanisms have been suggested to be involved in the pathogenesis of MVO such as distal atherothrombotic embolization, ischaemia–​reperfusion injury, and individual susceptibility to microvascular dysfunction.6 If prolonged ischaemia induces ‘irreversible’ damage resulting in cellular necrosis, brief episodes of acute myocardial ischaemia may cause a ‘reversible’ injury, the so-​called myocardial stunning.7 This is a condition characterized by prolonged and reversible contractile dysfunction in the presence of near-​normal resting blood flow, but with a reduced coronary flow reserve (CFR), and usually results from transient severe ischaemia that persists after normal epicardial blood flow is restored. Stunned myocardium is mainly characterized by transient metabolic derangement at the cellular level.8 Hibernating myocardium is another important phenomenon involving myocardial injury and dysfunction. Hibernating myocardium refers to a chronic condition characterized by a dysfunctional, but viable, myocardium with reduced coronary blood flow at rest.7 Compared with myocardial stunning, in the

hibernating myocardium, there is extensive myocyte damage secondary to a longer duration of myocardial ischaemia and more severe reduction in myocardial perfusion. It is conceivable that stunning and hibernation represent a continuum of the same process, with repetitive episodes of stunning resulting in a progressive reduction in resting CFR and increased level of ultrastructural damage of cardiomyocytes.7 The final common pathway of these ischaemic injuries at the myocardial level is the occurrence of LV adverse remodelling,2,9 often associated with valvular abnormalities, such as functional mitral regurgitation (MR), that can further accelerate the deleterious structural changes in the LV through volume overload.2 The absence of obstructive coronary arteries does not rule out an ischaemic substrate underlying HF. Indeed, several studies suggest that CMD may play a key role in HFpEF and it should be considered as a possible contributor to myocardial dysfunction also in HFrEF.3,10 Indeed, endothelial dysfunction reduces nitric oxide (NO) bioavailability, cyclic guanosine monophosphate content, and protein kinase G in adjacent cardiomyocytes. These changes are known to favour hypertrophy and fibrosis contributing to diastolic dysfunction.10 In addition, microvascular inflammation contributes to the induction of cardiac fibrosis and vascular rarefaction. Transforming growth factor beta (TGF-​β) is likely to play a major role in this setting, as suggested by the

Chapter 3.1  

The rol e of i s cha em i c hea rt di sease i n hea rt fa i lure

observation that disruption in TGF signalling attenuates cardiac pressure overload-​ induced interstitial fibrosis.11 Accordingly, functional studies performed with use of pressure wires demonstrated a linear correlation between the index of microvascular resistance (IMR) and LV end-​diastolic pressure (LVEDP) and a reduced endothelium-​dependent vasodilator response to acetylcholine in HFpEF patients.12 Moreover, Taqueti et al. documented that in patients with suspected angina, reduction in the CFR, together with diastolic dysfunction, predicted the risk of major adverse cardiovascular events (MACE) and hospitalizations due to HF during follow-​up.13

Diagnostic approach in patients with coronary artery disease and heart failure A detailed medical history and an accurate physical examination should always be carried out in all patients presenting with HF (% Figure 3.1.1). In particular, signs and symptoms of ischaemia should be carefully evaluated, along with assessment of a baseline ECG, a chest X-​ray, and plasma biomarker levels (including high-​ sensitivity troponins and natriuretic peptides). Moreover, the use of non-​invasive electrocardiography (ECG) or imaging stress tests, such as cardiac magnetic resonance (CMR), stress echocardiography, single-​ photon emission computed tomography (SPECT), or positron emission tomography, is recommended for the assessment of myocardial ischaemia and viability in patients with HF.14 Echocardiography represents a first-​ line investigation allowing quantification of LV systolic and diastolic function, along with segmental kinetic alterations, as well as assessing for the presence of concomitant valvular diseases. In HFrEF patients, severe LV dilatation is a marker of non-​viable myocardium and LV wall thickness has been shown to be an important predictor of viability.15 Stress echocardiography is important to evaluate the presence of ischaemic myocardium, by assessing the pathological response during exercise or during intravenous administration of dobutamine or dipyridamole. Moreover, dobutamine stress echocardiography is particularly indicated to assess for the presence of viable myocardium in patients with HFrEF, and is performed as a two-​step assessment, first with low-​dose (5–​10 μg/​kg/​min) and then with high-​dose (10–​ 40 μg/​kg/​min) dobutamine. Biphasic response with increased myocardial contractility at low doses, and paradoxical deterioration of myocardial contractility at higher doses, is considered highly suggestive of viable myocardium.16 Dipyridamole stress echocardiography allows also evaluating the coronary flow velocity reserve (CFVR) in the left anterior descending coronary artery and may be particularly useful in assessing for the presence of CMD. SPECT is an imaging technique based on the assessment of myocardial uptake of radiotracer compounds (i.e. thallium-​201 and technetium-​99m). It is a widely available technique and provides an estimation of resting perfusion, stress-​induced ischaemia, scar tissue, and cardiac systolic function. SPECT demonstrated high sensitivity (83–​87%) and low specificity (53–​68%)

for the prediction of recovery of contractile function following successful revascularization.2,17 However, SPECT may underestimate tissue viability and its diagnostic accuracy is limited by lower-​energy tracers, lower spatial resolution, and increased frequency of attenuation artefacts.17 CMR imaging is currently emerging as the most important examination in the assessment of myocardial ischaemia and viability. Indeed, along with information regarding cardiac structure and function, including shape, size, and wall thickness, CMR with gadolinium-​chelated contrast enhancement (late gadolinium enhancement (LGE)) is important to evaluate the extent of non-​viable myocardial scar tissue in HFrEF. In general, the absence of scar tissue is associated with a likelihood of myocardial contractile recovery of approximately 78%; however, when scar transmurality is >50%, the likelihood of functional recovery drops to approximately 8%.18,19 In patients with scar transmurality of 1–​50%, LGE CMR has a lower accuracy for predicting contractile recovery and additional evaluation with low-​dose dobutamine stress CMR may be able to assess for the presence of contractile reserve and should be considered in order to improve the diagnostic accuracy of detecting myocardial viability.20 Finally, stress CMR with adenosine administration may be useful in assessing for the presence of ischaemia due to CMD. Coronary angiography is recommended in patients with HF who suffer from angina pectoris despite optimal medical therapy, provided the patient is otherwise suitable for coronary revascularization.14 Coronary angiography should be considered in patients with HFrEF or HFpEF and those with intermediate-​ to-​high pretest probability of CAD and the presence of ischaemia from non-​invasive stress tests in order to establish the ischaemic aetiology and CAD severity.14 In patients with angiographically non-​obstructive CAD, functional assessment with pressure wire (i.e. fractional flow reserve (FFR) or instantaneous wave-​free ratio (iFR)) should be considered to exclude significant stenosis or to diagnose the presence of CMD by evaluating the IMR and CFR, especially in patients with HFpEF. Coronary computed tomographic angiography (CTA) has been shown to have a very high negative predictive value and high sensitivity in evaluating severe stenosis. Thus, CTA may be considered in patients with a low-​to-​ intermediate pretest probability of CAD or those with equivocal non-​invasive stress tests.14 CTA is not recommended in cases of extended coronary calcifications, irregular heart rate, significant obesity, or other conditions that prevent the acquisition of good-​ quality images.14

Management of patients with coronary artery disease and heart failure Medical management remains the cornerstone for treatment of patients with HF across the wide spectrum of EF, and both in patients with HFrEF and in those with HFpEF, lifestyle intervention and drug therapy are of utmost importance to control existing cardiovascular risk factors. However, available therapeutic strategies are quite different for HFrEF compared with HFpEF.

29

30

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In HFrEF patients, data from randomized trials have shown that three drug classes (mineralocorticoid receptor antagonists (MRAs), angiotensin receptor–​ neprilysin inhibitors (ARNIs), and sodium–​glucose cotransporter 2 (SGLT2) inhibitors) reduce mortality beyond conventional therapy with either an angiotensin-​ converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) plus a beta blocker (BB).14,21,22,23 Of interest, the selective cardiac myosin activator omecamtiv mecarbil has also been shown to be effective in the recent GALACTIC-​HF trial by stimulating the cardiac sarcomere, reducing the risk of HF events or cardiovascular death by 8% at 21.8 months.24 However, in patients with HFrEF due to ischaemic heart disease, therapy requires a comprehensive approach that also includes secondary prevention measures (including lipid and antiplatelet therapy) and, if indicated, device therapies and coronary revascularization.14 In particular, there is still ongoing debate regarding the prognostic benefit of revascularization therapy. Surgical revascularization (in addition to optimal medical therapy) has a class I, level of evidence A indication, according to the 2018 European Society of Cardiology (ESC) revascularization guidelines for patients with ischaemic cardiomyopathy with LVEF ≤35% and CAD (in particular those with two-​or three-​vessel CAD) amenable to surgical revascularization to improve prognosis.25 The Surgical Treatment for Ischemic Heart Failure (STICH) trial, to date, is the largest randomized trial specifically addressing the role of revascularization in patients with LVEF ≤35% and CAD. The STICH trial randomly assigned 1212 patients to medical therapy plus coronary artery bypass graft (CABG) surgery or medical therapy alone. At a median follow-​up of 56 months, all-​cause mortality was not significantly different between the two arms (41% optimal medical therapy vs 36% CABG).26 Regarding secondary outcomes, there was a trend towards reduced cardiovascular mortality in the CABG group that did not meet statistical significance. However, the STICH Extension Study (STICHES), which extended the follow-​up to a median of 9.8 years in the same population, showed that the primary outcome of all-​cause mortality was significantly lower in the CABG group, compared to the optimal medical therapy group, as well as the prespecified secondary outcomes of cardiovascular mortality and the combination of all-​cause mortality with cardiovascular hospitalization.27 Of note, in a viability substudy of the STICH trial, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone. An increase in LVEF was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in LVEF and subsequent death.28 Of note, to date, there are no randomized controlled trials (RCTs) exploring the efficacy of PCI, compared to that of CABG, and the relative efficacy of PCI versus CABG for revascularization is unknown, although data from non-​randomized registry suggest no difference in mortality between CABG and PCI.29 Device therapy, such as implantable cardioverter–​defibrillators (ICDs),

cardiac resynchronization therapy (CRT), and edge-​to-​edge repair of severe functional MR have also been shown to improve prognosis in patients with HFrEF and may be considered, if indicated, also in patients with HFrEF of ischaemic origin.14 Cardiogenic shock occurs in 7–​10% of patients with acute MI and is associated with 40% mortality at 30 days.30 In these patients, immediate coronary angiography is recommended (within 2 hours of hospital admission), with an intent to perform coronary revascularization, as early revascularization has been shown to reduce mortality.14 Most patients with cardiogenic shock present with multivessel CAD, which is associated with higher mortality than single-​vessel disease. The benefit of multivessel PCI in these patients has been a matter of debate for a long time. However, the recent CULPRIT-​SHOCK trial demonstrated that the risk of death or renal replacement therapy at 30 days was lower with culprit lesion-​only PCI than with immediate multivessel PCI, and mortality did not differ significantly between the two groups at 1-​year follow-​up.31 In selected patients with acute MI and cardiogenic shock, short-​ term mechanical circulatory support may be considered. However, recently, the IABP-​SHOCK II trial showed that use of an intra-​aortic balloon pump (IABP) did not improve outcomes in this subset of patients,30 and evidence for a clinical benefit of other devices (i.e. Impella® or extracorporeal membrane oxygenation (ECMO)) is still lacking.32,33 If several therapeutic strategies have been developed in the last decades for HFrEF, this has not been the case for HFpEF. Indeed, no medical treatment has been shown to improve all-​ cause mortality in the HFpEF population, as all failed to reduce their prespecified primary end points in their respective cardiovascular outcomes trials, although some have shown potential improvements in their secondary outcomes.34 The presence of obstructive CAD is associated with increased mortality and greater deterioration in ventricular function, and complete revascularization may be associated with improved survival and less deterioration in LV function over time, even if these data need be confirmed in dedicated prospective trials.35 CMD emerged in recent years as an important therapeutic target in HFpEF, and drugs that demonstrated a clinical benefit in patients with microvascular angina (i.e. BBs, ACE inhibitors, ranolazine, and statins) may be also considered for HFpEF patients. However, currently, there are no trials specifically evaluating the role of therapeutic strategies addressing CMD in this subset of patients.

Future directions In last decades, much progress in the management of patients with ischaemic HF has been made. However, there are still many knowledge gaps that need to be addressed in future studies. Indeed, in HFrEF, the importance of myocardial viability as a guide for coronary revascularization needs to be clarified. Moreover, the benefit of PCI versus CABG in patients with multivessel disease and HFrEF should be evaluated in dedicated clinical trials.

Chapter 3.1  

The rol e of i s cha em i c hea rt di sease i n hea rt fa i lure

Finally, further studies aiming at assessing the pathogenic role of CMD in the occurrence of HF are needed, as well as studies evaluating therapies targeting CMD. This latter point represents an important clinical need, especially in patients with HFpEF.

Summary IHD represents the most important cause underlying the occurrence of HF. Multiple pathophysiological mechanisms may explain the association between myocardial ischaemia and HF, and understanding the exact mechanism of disease is crucial to obtaining a proper diagnosis and starting appropriate therapy. Medical management remains the cornerstone for treatment of patients with HF. Revascularization of obstructive CAD represents a possible solution when indicated. However, in HFrEF, the importance of myocardial viability as a guide for coronary revascularization needs to be clarified. Moreover, the benefit of PCI versus CABG in patients with multivessel disease and HFrEF is still a matter of debate. Finally, further studies aiming at assessing the pathogenic role of CMD in the occurrence of HF are needed, as well as studies evaluating therapies targeting CMD, especially in patients with HFpEF.

References 1. Gheorghiade M, Sopko G, De Luca L, et al. Navigating the crossroads of coronary artery disease and heart failure. Circulation. 2006;114:1202–​13. 2. Cabac-​Pogorevici I, Muk B, Rustamova Y, Kalogeropoulos A, Tzeis S, Vardas P. Ischaemic cardiomyopathy. Pathophysiological insights, diagnostic management and the roles of revascularisation and device treatment. Gaps and dilemmas in the era of advanced technology. Eur J Heart Fail. 2020;22:789–​99. 3. Crea F, Bairey Merz CN, et al.; Coronary Vasomotion Disorders International Study Group (COVADIS). The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift. Eur Heart J. 2017;38:473–​7. 4. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63:2817–​27. 5. Niccoli G, Montone RA, Ibanez B, et al. Optimized treatment of ST-​ elevation myocardial infarction. Circ Res. 2019;125:245–​58. 6. Niccoli G, Scalone G, Lerman A, Crea F. Coronary microvascular obstruction in acute myocardial infarction. Eur Heart J. 2016;37:1024–​33. 7. Kloner RA. Stunned and hibernating myocardium: where are we nearly 4 decades later? J Am Heart Assoc. 2020;9:e015502. 8. Poole-​ Wilson PA, Holmberg SR, Williams AJ. A possible molecular mechanism for ‘stunning’ of the myocardium. Eur Heart J. 1991;12:25–​9. 9. Briceno N, Schuster A, Lumley M, Perera D. Ischaemic cardiomyopathy: pathophysiology, assessment and the role of revascularisation. Heart. 2016;102:397–​406. 10. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131:550–​9. 11. Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-​beta function blocking prevents myocardial fibrosis and

diastolic dysfunction in pressure-​ overloaded rats. Circulation. 2002;106:130–​5. 12. D’Amario D, Migliaro S, Borovac JA, et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2019;10:1347. 13. Taqueti VR, Solomon SD, Shah AM, et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur Heart J. 2018;39:840–​9. 14. Ponikowski P, Voors AA, Anker SD, et al.; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–​200. 15. Cwajg JM, Cwajg E, Nagueh SF, et al. End-​diastolic wall thickness as a predictor of recovery of function in myocardial hibernation: relation to rest-​redistribution T1-​201 tomography and dobutamine stress echocardiography. J Am Coll Cardiol. 2000;35:1152–​61. 16. Cornel JH, Bax JJ, Elhendy A, et al. Biphasic response to dobutamine predicts improvement of global left ventricular function after surgical revascularization in patients with stable coronary artery disease: implications of time course of recovery on diagnostic accuracy. J Am Coll Cardiol. 1998;31:1002–​10. 17. Schinkel AF, Bax JJ, Poldermans D, Elhendy A, Ferrari R, Rahimtoola SH. Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol. 2007;32:375–​410. 18. Romero J, Xue X, Gonzalez W, Garcia MJ. CMR imaging assessing viability in patients with chronic ventricular dysfunction due to coronary artery disease: a meta-​analysis of prospective trials. JACC Cardiovasc Imaging. 2012;5:494–​508. 19. Kim RJ, Wu E, Rafael A, et al. The use of contrast-​enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med. 2000;343:1445–​53. 20. Wellnhofer E, Olariu A, Klein C, et al. Magnetic resonance low-​dose dobutamine test is superior to SCAR quantification for the prediction of functional recovery. Circulation. 2004;109:2172–​4. 21. Packer M, Anker SD, Butler J, et al.; EMPEROR-​Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–​24. 22. McMurray JJ, Packer M, Desai AS, et al.; PARADIGM-​HF Investigators and Committees. Angiotensin–​neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–​1004. 23. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-​modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396:121–​8. 24. Teerlink JR, Diaz R, Felker GM, et al.; GALACTIC-​HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2022;384:105–​16. 25. Neumann FJ, Sousa-​ Uva M, Ahlsson A, et al.; ESC Scientific Document Group. 2018 ESC/​ EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87–​165. 26. Velazquez EJ, Lee KL, Deja MA, et al.; STICH Investigators. Coronary-​artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med. 2011;364:1607–​16. 27. Petrie MC, Jhund PS, She L, et al.; STICH Trial Investigators. Ten-​ year outcomes after coronary artery bypass grafting according to age in patients with heart failure and left ventricular systolic dysfunction: an analysis of the extended follow-​ up of the STICH

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Trial (Surgical Treatment for Ischemic Heart Failure). Circulation. 2016;134:1314–​24. 28. Panza JA, Ellis AM, Al-​Khalidi HR, et al. Myocardial viability and long-​term outcomes in ischemic cardiomyopathy. N Engl J Med. 2019;381:739–​48. 29. Bangalore S, Guo Y, Samadashvili Z, Blecker S, Hannan EL. Revascularization in patients with multivessel coronary artery disease and severe left ventricular systolic dysfunction: everolimus-​eluting stents versus coronary artery bypass graft surgery. Circulation. 2016;133:2132–​40. 30. Thiele H, Zeymer U, Neumann FJ, et al.; IABP-​SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367:1287–​96. 31. Thiele H, Akin I, Sandri M, et al.; CULPRIT-​SHOCK Investigators. One-​year outcomes after PCI strategies in cardiogenic shock. N Engl J Med. 2018;379:1699–​710.

32. Schrage B, Ibrahim K, Loehn T, et al. Impella support for acute myocardial infarction complicated by cardiogenic shock. Circulation. 2019;139:1249–​58. 33. Dhruva SS, Ross JS, Mortazavi BJ, et al. Association of use of an intravascular microaxial left ventricular assist device vs intra-​aortic balloon pump with in-​hospital mortality and major bleeding among patients with acute myocardial infarction complicated by cardiogenic shock. JAMA. 2020;323:734–​45. 34. Del Buono MG, Iannaccone G, Scacciavillani R, et al. Heart failure with preserved ejection fraction diagnosis and treatment: an updated review of the evidence. Prog Cardiovasc Dis. 2020;63:570–​84. 35. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63(25 Pt A):2817–​27.

CHAPTER 3.2

From hypertension to heart failure Athanasios J Manolis and Yuri Lopatin

Contents Introduction  33 Pathophysiology  35 Prevention  35 Blood pressure targets in heart failure patients  36 Treatment of arterial hypertension in patients with heart failure  36 ACEIs and ARBs  36 Beta- blockers  36 ARNIs  37 MRAs  37 Diuretics  37 SGLT2 inhibitors  37

Summary  37 References  37

Introduction According to recently published European Society of Cardiology (ESC)/​European Society of Hypertension (ESH) hypertension (HTN) guidelines, HTN is defined as a systolic blood pressure (SBP) of 140 mmHg or more, or a diastolic blood pressure (DBP) of 90 mmHg or more, or where there is a requirement for antihypertensive medication.1 In some cases, such as in the elderly or frail patients, these cut-​offs are more flexible. According to ESC heart failure (HF) guidelines, HF is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling, fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, peripheral oedema) caused by a structural and/​or functional cardiac abnormality, resulting in a reduced cardiac output and/​or elevated intracardiac pressures at rest or during stress.2 HTN affects close to 1 billion adults worldwide, and this number is forecast to increase to over 1.5 billion by 2025.3 More than 7.5 million deaths per year are attributable to HTN. HTN is the most important risk factor for cardiovascular (CV) morbidity and mortality. Untreated high blood pressure (BP) may progress, leading to many organ-​specific changes, which are referred to in the new ESC/​ESH hypertension guidelines as ‘hypertension-​mediated organ damage (HMOD)’ (% Figure 3.2.1). HTN leads to endothelial dysfunction, subclinical or clinical organ damage such as left ventricular hypertrophy (LVH), microalbuminuria, increased intimal medial thickness, hypertensive retinopathy, coronary heart disease, chronic kidney disease, arrhythmias, stroke, HF with preserved (HFpEF) or reduced (HFrEF) ejection fraction, and neurovascular changes including stroke and dementia (% Figure 3.2.2). Individuals with high BP are more susceptible to ischaemic heart disease, and may have a 6-​fold greater risk of myocardial infarction.4 Due to its high prevalence, HTN carries the greatest risk of developing HF. HTN is also associated with the prevalence of atrial fibrillation and ventricular arrhythmias.5 Increased left atrial pressure and left atrial enlargement are the most important risk factors for atrial fibrillation. Various trials have shown an association between long-​standing HTN and HF. There is a continuous relationship between BP and CV and renal events. Epidemiological data have shown a linear correlation between BP and CV risk from very low levels of BP (i.e. SBP >115 mmHg).6 A meta-​analysis of 23 trials including 193,424 patients with HTN or at ‘high’ CV risk, of whom the majority were hypertensive patients, showed that 28.9% developed HF, accounting for 9.1 events per 1000 patients. HF development was more prevalent among older subjects aged >65 years (P  1.05 and reaching anaerobic treshold on optimal medical therapy. In a patient receiving a beta-​blocker peak oxygen comsumption cut-​ off is defined as ≤ 12 ml/​ kg/​ min, and in a patient intolerant of a beta-​blocker, a cut-​off peak oxygen

chapter 11.4  

Slovenia

10.5 6.7 7 6.6

Czechia Austria

5.9

Spain

5.8

France Denmark

9.3 6.5 6.6

5.7

5.2

5.6

Norway Switzerland

4.5

5.2 3.8

8

5.3

Sweden Slovekia

6

4.9 4.7

Belgium

7.2

4.6

Hungary 4

Finland

11.4

7.6

6.1

Croatia

7.4 5.4

4

Germany

4.2 3.9 4.1 3.8 3.8 3.7

Italy Poland Lithuania

2.8

Portugal

2.8 2.6 2.8 2.4 2.2

United Kingdom Netherlands 1.8

Ireland

0.9

Greece

3.2

3.1

1.1

Latvia 0

1.4

0.1 0.3

Bulgaria 0

1

2

3

4

5 6 7 8 Rate per million population 2019

Sources EDQM; ONT © Statista 2021

Hea rt tr a n spl a n tat i on

9

10

11

12

13

2020

Additional Information Europe; EDQM; ONT; 2019 to 2020

Figure 11.4.2  Rate of heart transplants per million population in Europe, 2019–​2020.

consumption as a criterion for listing should be ml/​kg/​min.3 In women and generally in patients < 50 years, ≤ 50% of predicted VO2 can be considered as additional criterion.3

context of cardiopulmonary stress testing and right-​heart catheterization parameters.3

2. Heart failure prognostic survival scores should be used in addition to cardiopulmonary stress testing in ambulatory patients.

Right heart catheterization (RHC) should be considered as mandatory for all adult candidates for heart transplantation, and should be repeated at least annually. The need for more frequent RHC should be individualized according to the severity of pulmonary hypertension, clinical stability of heart

An estimated 1-​ year survival calculated by the Seattle heart Failure Model of < 80% or the Heart Failure Survival Score in the medium-​to high-​risk range should be considered for listing in a

3. Diagnostic right-​heart catheterization

717

718

SECTION 11  

Advanced h eart failu re

Box 11.4.1  Indications and contraindications for heart transplantation

Indications

Advanced heart failure No other therapeutivc option except for LVAD as BTT

Contraindications Active infection except LVAD/​driveline infection Severe peripheral or cerebrovascular disease Irreversible pulmonary hypertension despite pharmacological challenge Malignancy (to be decided in collaboration with oncologist) Irreversible liver dysfunction and/​or cirrhosis Irreversible renal dysfunction (e.g. creatinine clearence < 30 mL/​min/​1.73 m2) Systemic disease with multi-​organ involvement Any other serious comorbidity with poor prognosis BMI > 35 kg/​m2 Current alcochol or drug abuse Psychological instability incompatible with appropriate post-​ transplant magamement Social conditions or insufficient social support incompatible with compliant outpatient care Source data from McDonagh TA, Metra M, Adamo M, et al; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-​3726. doi: 10.1093/​ eurheartj/​ ehab368; and Crespo-​ Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018 Nov;20(11):1505-​1535. doi: 10.1002/​ejhf.1236.

failure, and presence of MCS.3 Frequency of RHC if more than once a year also depends on individual centre preferences/​capabilities. Periodic RHC should in general not be performed in children.3 Irreversible pulmonary hypertension, transpulmonary gradient above the defined limit and/​or elevated pulmonary vascular resistance (PVR) significantly increase risk of post transplantation right heart failure and mortality.3 Cut-​off limits of haemodynamic parameters are as follows3: ◆ PVR > 5 Wood Units or in children PVRI >6 Wood Units ◆ Transpulmonary pressure gradient > 16-​20 mmHg ◆ Systolic pulmonary artery pressure > 60 mmHg in conjunction

with any of the forementioned parameters ◆ PVR not reducible to < 2.5 Wood Units with a vasodilator, without a consequent fall of systolic blood pressure 35 kg/​m2 is associated with higher post transplant morbitiy and mortality, and patients should be recommended to achieve their BMI < 35 kg/​m2 before being listed for heart transplantation.9,10 Diabetes with HbA1c > 7.5% or 58 mmol/​l or end-​organ damage, with an exception of non-​proliferative retinopathy, is considered as a relative contraindication for heart transplantation.3 Renal dysfunction as a relative contraindication for heart transplantation should be defined as eGFR < 30 ml/​min/​1.73 m.2,3 Renal diagnostic work up is mandatory to prove or exclude irreversibility of renal failure, which includes renal imaging by use of sonography and/​or CT or MRI, estimation of proteinuria and renal arterial flow. Post-​renal dysfunction should be evaluated and treated, if possible. Peripheral and cerebrovascular disease not amenable to revascularization should be considered as major comorbidities with a significant negative impact on post-​transplant survival and quality of life.3 Serious peripheral arterial disease should limit eligibility for transplantation, as it substantially limits rehabilitation. Symptomatic cerebrovascular disease should be considered as a contraindication for heart transplantation, as it could be related to increased risk of post-​transplant stroke and functional decline.11 Active systemic infection means a serious contraindication for transplantation, as it could seriously interfere with the clinical course in patients receiving high doses of immunosuppressive medications in the early post-​transplant period. Chronic persistent infections, such as HIV and hepatitis B and C, should be carefully evaluated and elaborated together with experienced HIV or hepatology specialists. Exceptionally, stable HIV patients compliant with antiretroviral therapies and with no detectable HIV-​RNA and CD4 counts > 200 cells/μl, and with no opportunistic infections could be considered for listing.3 Data on carefully selected HIV patients receiving heart transpants showed similar short-​term survival rates as in general post transplant population, but there is no data on their long-​term survival.13,14,15,16,17 As well as donor organ shortage, another serious limitation for listing patients with HIV are numerous interactions between immunusupressive medications and antiretroviral drugs.15,18 Acute hepatitis B and C represent contraindications for heart transplantation.3 Resolved hepatitis B or C infection in potential candidates for heart transplantation should receive hepatobiliar system imaging and liver biopsy, as cirrhosis and hepatocellular carcinoma represent absolute contraindications for transplantation. Serological and viral load testing and checking every 3 months and at the time of transplantation is mandatory. In chronic hepatitis C infection, HCV genotype should be determined.3 In the light of new antiviral therapies the issue of heart transplantation in patients with controlled hepatitis B or C

chapter 11.4  

becomes a challenge, and long-​term outcomes for those potential recipents are unknown.12 Malignancies: Active malignancy is an absolute contraindication for heart transplantation, with the exception of superficial skin basal or squamous cell carcinoma.3 Patients in a complete remission for at least 5 years could be considered for transplantation in agreement with consultant oncologist. In the meantime, oncology patients with the advanced heart failure with a favourable prognosis regarding their malignant disease, could be supported with LVAD as a bridge to candidacy (BTC) or, if transplantation is contraindicated, to maintain with LVAD-​ support as a DT.3 Frailty is an evolving issue, particularly while assessing older potential heart recipients. There are several proposed modalities to assess frailty, from grip strength or gait speed to established questionnaires.19,20,21 Frailty should become a matter of concern if three of the following symptoms are present: unintentional weight loss ≥ 10 pounds/​≥ 5 kg within the past year, muscle loss, fatigue, slow walking speed, and low degree of physical activity.3 Psychosocial inadequacy could represent a temporary or definite contraindication for heart transplantation. Thus, a comprehensive psychosocial work-​ up is an essential part of the evaluation of potential transplant candidates. Compliance with recommended pharmacological therapies, regular follow-​ up, and lifestyle changes are essential for post transplant short-​and long-​term outcomes.3 Active psychosis, intellectual disability, dementia, and/​or inability to comply with instructions represent prohibiting elements for listing a patient for a heart transplant. Inadequate social conditions could also seriously limit candidacy for listing, if the heart team presumes serious difficulties in complying with a complex post transplant regimen.3 Tobacco, alcohol and other substance abuse: Active tobacco smoking and smoking during the 6 months prior to transplantation are associated with poorer outcomes, and therefore considered as a relative contraindication for listing.3 In general, there is an evidence-​based consensus of a deleterious effect of smoking history for post transplant outcomes. The largest, recent multicentre analysis on more than 32,000 patients revealed that cigarette smoking history in heart transplant recipients represents an independent risk for 1, 2, and 10-​year mortality, and morbidity including higher risk of hospitalization for acute rejection and infection, increased risk of graft failure, and higher incidence of malignancies.22 It has been also documented that cigarette smoking in a donor was associated with increased post transplant mortality.22 Active alcochol and drugs abusers should also not be considered as heart transplant candidates.3

Special considerations End-​stage heart disease without inherent left ventricular dilatation and severely reduced systolic function: Among all myocardial phenotypes in patients under consideration for heart transplantation, there is proportionally small but important group of patients with the end-​stage heart failure due to non-​dilated and non-​ ischaemic cardiomyopathies, that is, hypertrophic, restrictive, infiltrative, and arrhythmogenic right ventricular

Hea rt tr a n spl a n tat i on

cardiomyopathy/​dysplasia (ARVC/​D). These patients, if refractory to conventional medical and device therapies, would generally not be candidates for an LVAD, neither as a BTT, nor as a DT. Thus transplantion represents the only active treatment option in appropriately selected patients.3 Non-​obstructive hypertrophic cardiomyopathy is a rare but serious disease, as time from diagnosis to the terminal heart failure has been reported as from 4 to 10 years, with worse predictable outcomes in younger patients and if already family members affected.3,23,24 Severe heart failure refractory to conventional treatment can occur in patients with severe diastolic dysfunction and preserved systolic function, and these patients could substantially benefit from heart transplantation, as much as patients with more common indications for transplantation.23,24 The other, more frequent scenario of advanced heart failure in hypertrophic cardiomyopathy is due to severe myocardial remodelling leading in the terminal phase to a phenotype resembling dilated cardiomyopathy: dilated and thinned, fibrotic and hypocontractile left ventricle with a combined systolic and diastolic dysfunction and symptoms and signs of severe heart failure. ARVC/​D is a genetically determined, rare disease, which could, as well as the right ventricle, affect the other myocardial territories.25 It is usually complicated by serious and/​or fatal ventricular arrhythmias, and rarely with the advanced heart failure.26 Left-​ventricular non-​compaction also represents a rare, genetically determined disease which could lead to the advanced heart failure and thus could be evaluated for heart transplantation.27 Restrictive and infiltrative cardiomyopathies are of a heterogeneous origin, but phenotypically characterized by stiff and thickened, not-​dilated ventricles with preserved or mildly reduced ventricular contractility and dilated atria.28 Defining aetiology is mandatory in the diagnostic work-​up as, with the exception of idiopathic restrictive cardiomyopathy, some patients suffer from systemic disorders with predominant myocardial involovement, and usually need cause-​targeted therapies, such as enzyme replacement in Anderson–​Fabry disease,29 immunosuppression in sarcoidosis and endomyocardial fibrosis, or disease-​specific therapies in amyloid light-​chain (AL) or transthyretin related (TTR) amyloidosis. AL-​amyloidosis in which amyloid derives from and indolent clone of plasma cells, can represent an indication for heart transplantation in a patient with seriously affected myocardium, and consecutive severe heart failure, which does not allow implementation disease-​specific therapy.30 Transplantation should be realized in experienced multidisciplinary centres, and autologous stemm cell transplantation performed as soon as possible after post heart transplantation recovery. Collaboration with haematologists is essential.3,30 TTR amyloidosis (ATTR) is a multi-​organ infiltrative disease caused by depositions of TTR amyloid, which is produced predominantly in the liver. Thus liver transplantation can stop disease progression, and bring favourable outcomes in appropriately selected patients.3,31 Cardiomyopathy caused by TTR amyloidosis is frequently misdiagnosed and underdiagnosed.31 There are two

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types of TTR amyloidosis: hereditary (hATTR) and wild type (ATTRwt). hATTR is an autosomal dominant inherited disorder, with variable penetration. Range of potential phenotypes coresponds with various genotypes, from polineuropathy to cardiomyopathy and mixed phenotype. Age at diagnosis varies according to certain genotype, and median life expectancy at time of diagnosis is 2–​5 years.31 ATTRwt is the most common cause of amyloidosis-​related cardiomyopathy, and causes 13–​37% cases of heart failure with preserved ejection fraction (HFpEF).3,31 Clinical presentiation occurs more in older men, with a median survival at time of diagnosis 3–​5 years.31 Heart transplantation with or without combined liver transplantation is a viable treatment option with favourable outcomes in appropriately selected patients with TTR amyloid cardiomyopathy.32,33

Allocation of donor hearts Organs are allocated according to legal regulations of each country, either per country or within countries associations, for example, EUROTRANSPLANT or Scandinavia Transplant. Principles of organs allocation are organ recipient-​oriented and include blood group, body size, emergency status, and waiting time on a transplant list. Arbitary upper age limit for heart donation is 65 years. Absolute contraindications for heart donation are cardiac and non-​cardiac disorders. Cardiac contraindication is a significant structural and/​ or functional myocardial, valvular, pericardial, or congential heart disease, clinically relevant arrhythmogenic substrate, complex coronary artery disease, or prior coronary artery by pass surgery. Non-​cardiac absolute contraindications are sepsis or uncontrolled infections, and active malignant diseases.3

Donor evaluation Every brain-dead patient should be considered as a potential multi-​organ donor. Basic work-​up of a potential heart donor consists of medical history and clinical examination, ECG, transthoracic echocardiography (TTE), bedside haemodynamics, and, in haemodynamically unstable patients Swan–​Ganz catheterization, in order to optimize haemodynamic management of a potential donor. If TTE insite is insufficient due to a poor acoustic window, transoesophageal echocardiography (TEE) should be performed to acquire adequate information about donor heart structure and function. Coronary angiography is a part of a standard work-​up in all potential donors from the age from 50 years upwards, but also in younger patients with cardiovascular risk factor(s). The rest of a work-​up is standardized as for other organ donor evaluation, including virology/​serology tests.3

Donor–​recipient matching Decision making about realization of heart transplantation should be done by experienced advanced heart failure cardiologist(s) and heart transplant surgeon(s), with the possibility of consulting other experts, for example, immunologists, anaesthesiologists. Independent transplant coordinators from

national or transnational transplant organizations conduct initial matching and propose potential transplant candidate(s) to transplant centres chosen by predefined criteria. In the chosen centre, a heart transplant cardiologist in collaboration with a transplant surgeon designates the transplant recepient according to urgency status, waiting time, recipient’s availability, and immunological and anthropometric compatibility with a donor. ABO-​incompatibility is an absolute contraindication for heart transplantation. Exceptionally, it can be considered in infants with immature immunological system, and only in experienced paediatric heart transplantation centres.3,34 Immunoincompatibility, that is high panel reactive antibody (PRA) is associated with a significantly reduced number of potential donors. It can be seen more often in multiparous women, patients supported by mechanical assist devices, patients who have received multiple blood transfusions, congenital heart disease patients surgically implanted with autologous homografts, and others. Patients waiting on transplant lists should be periodically checked for PRA in order to confirm their reactivity is below 20%.35 Human leucocyte antigen (HLA) matching for heart transplantation is in general not mandatory for approving heart transplantation. Despite some controversies about HLA-​missmatch and its influence on post transplant complications, there is a general agreement that HLA-​DR missmatch is associated with worse prognosis in transplant recipents.36 A modern approach might move us forward towards precision medicine, and may include typing at serological split antigen levels by use of the Epitope Mismatch Algorithm to calculate the number of amino acid differences in antibody-​verified HLA eplets, that is amino acid mismatch load (AAMM) with regard to HLA-​DR and HLA-​AB between donor and recipient.37 Currently, HLA and in particular HLA-​DSA (donor-​specific antibodies) can be used as parameters for prediction of possible graft outcomes, rather than for recipient–​donor matching. Donor–​ recipient size matching is usually based on body weight and BMI. Traditionally it has been considered that > 20% discrepancy in body weight should be regarded as significant for heart transplantation. However, there are no clear data about significant correlations of body weight and size of the heart, except for extreme diferencies in body weight, as in body height and body surface area.38 According to the ISHLT guidelines, the difference in BMI between donor and recipient should not be > 20%, and also that no transplantation should be done from a donor with body weight < 70% of the recipient.38 However, it seems that the graft size and function is more important than the body weight, and that undersizing should not be a matter of serious concern in male-​to-​male, male-​to-​female, or female-​to-female heart transplantation.39 One of the novel paremeters for donor–​ recipient matching, still not in a ruotine use, is predicted heart mass (PHM), which can be calculated including weight, height, sex, and age.39,40 In a case of the same height and weight of the donor and recipient, for opposite sexes the difference in PHM for male vs female is 19%.40,41

chapter 11.4  

Sex donor–​recipient difference could be associated with worse outcomes if the donor is a female, and the recipient is a male, but not vice versa. In practice, additional attention should be focused on male recipients receiving a heart from female donors, in particular regarding the graft quality.3,39,40,41

Mechanical circulatory support as a bridge to transplant MCS is a very useful and often unavoidable treatment modality for a substantial proportion of patients on transplant lists, as the world is faced with increasing numbers of heart transplant candidates, and not enough donor hearts by far. Currently at least of 50% of patients listed for heaart transplantation are bridged with MCS.4 Patients with cardiogenic shock (INTERMACS 1 and 2) could be bridged by use of paracorporeal circulatory support as a BTT or bridge to bridge. Despite some centres still using the intra-​ aortic balloon pump (IABP), state of the art temporary support is either extracorporeal membrane oxygenation (ECMO), which ensures both circulatory and respiratory support, or temporary continuous flow assist devices for supporting the left ventricle, or exceptionally the right ventricle or both ventricles (see % Chapter 11.3). Durable LVAD is an option for patients with indicators of predictable deterioration while waiting for a donor heart, such as repeated heart failure hospitalizations, a need for escalating dose of diuretics, inotrope dependence, intolerance of conventional medical therapy for heart failure, progression of functional incapability, or secondary deterioration of other organs function, particularly liver and kidney. Post transplant survival in patients previously implanted with continuous flow LVAD seems not to be significantly adversly affected in comparison with those only transplanted and previously not bridged with LVAD.4 Patients with a potential temporary contraindication for transplantation, such as high PVR or unresolved outcome of a malignant disease, should be also considered for implantable continuous flow LVAD.1,2,3,4 Obesity, uncontrolled diabetes mellitus, potentially reversible renal dysfunction, and alcohol, tobacco, and drug abuse could be indications for BTC with LVAD.3 If the aforementioned unfavourable haemodynamics and risk factors ameliorate during VAD support, then the patient can be considered for heart transplantation, otherwise VAD support should remain as the DT. MCS may raise some unfavourable issues for transplantation, such as allosensitization. It is recommended to screen VAD patients for sensitization at various intervals and reconsider transplantation in patients with high PRAs. However, it has been stated recently that sensitization in the LVAD population may not be related to higher rejection rates or worse survival after transplantation, and thus the value of desensitization therapy remains questionable.4 Dynamic listing should be a part of listing strategies in ambulatory, non-​ inotrope-​ dependent patients. Those patients

Hea rt tr a n spl a n tat i on

should be re-​evaluated every 3–​6 months after listing, including cardiopulmonary stress testing and heart failure survival prognostic scores, as well as their tolerance and responsiveness to the guideline-​approved conventional medical and device therapies.3. That might imply de-​listing a patient due to clinical and functional improvement, or re-​listing of a previously de-​listed patient due to deterioration.

Recipient work-​up at the time of transplantation Patients listed for heart transplantation should be regularly checked at 3–​6 month intervals,3, and contact maintained with the heart transplant centre in case of any relevant clinical or laboratory change. However, a careful but breif update at transplant admission time is mandatory to rule out potential new, clinically relevant problems. Routine haematology and biochemistry tests, and chest X-​ray should be performed, and, if neccessary, any kind of additional diagnostics, for example, right heart catheterization. Heart transplant centres should be established within comprehensive, tertiary hospitals, enabling permanent provision of any necessary medical/​surgical consultancy, diagnostics or therapy.

Donor heart explanation and preservation The most used method of donor heart preservation is heart preservation in cardiac arrest followed by static cold storage in a crystalloid heart preservation solution. Acceptable level of such heart protection is < 6 hours.42 To minimize graft dysfunction caused by ischaemia-​ reperfusion graft injury, preservation solutions have been developed to ameliorate ischaemia tolerance and reduce harm from graft ischwemia.43 Recently various methods for beating heart warm preservation have been developed.43 Apart from the ability to prolong out-​of-​body time between donor heart explantation and opening of the aortic clamp in the recipient patient, these systems offer more options for better donor organ diagnosis and management, including coronary angiography.43

Surgical aspects of heart transplantation For years the prevailing surgical approach was the Shumway and Lower biatrial technique, whereby the recipient right atrium is anastomosed to the donor right atrium, the recipient left atrium to the donor left atrium, and the pulmonary artery and the aorta to the respective anatomic structures of the donor heart.45 Biatrial technique results in abnormally enlarged atria and distorted atrial geometry, with a potential consequence of atrivetricular valves regurgitation, particulary tricuspid insufficiency. In addition, because of the proximity of the right atrial suture line to the sinus node, sinus node dysfunction can occur as a consequence of the sinus node injury.46 This method has been largely replaced by the bicaval technique, thereby avoiding annular distorsion of the donor tricuspid valve, and with less need for permanent pacemaker implantation, also with better haemodynamic results, and improved long-​ term post transplant survival.44 The bicaval technique is therefore recommended as the method of choice as long as there is no

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caval vein anomaly. The bicaval approach preserves donor atria, combining the standard left atrial anastomosis with the bicaval anastomosis.46,47

Immediate post transplant management After the surgical procedure, the newly transplanted patient is transferred from the operating room to the dedicated intensive care unit. Intensive postoperative management should be conducted by an experienced team, in order to prevent and treat postoperative complications, ensure appropriate haemodynamic status, and normal allograft function. Immediate care should be focused on both recovery from the surgical procedure and innitial immunosuppressive strategies.48 Invasive haemodynamic monitoring and support is challenged by a threat of vasodilatory hypotension, right heart failure, and acute allograft dysfunction. It is critical to allow the ventricles and the sinus node to recover from ischaemic injury.48 Vasopressor and inotropic support should be carefully guided by assessing cardiac performance. The first step would be a gradient vasoconstrictor removal, and usually continuation with dobutamin and/​or milrinone for at least 48 hours to allow the transplanted myoardium to recover from ischaemic injury.49,50 Most patients can be extubated and weaned from ventilator within the first 24 hours, and others should be extubated as soon as possible, to avoid the risk of ventilator-​associated pneumonia. Antibiotics are given routinely, primarily to prevent operative site infection, for 24 hours or more. However, it seems that a preventative antibiotic regimen did not show clear evidencebased benefits in solid organs in the immediate post transplant period.48 For discussion of immunosuppressant induction, % Immuno­ suppression, p. 724.’

Postoperative complications Most relevant postoperative complications include vasodilatory hypotension, acute allograft dysfunction, renal failure, and post transplant arrhythmias.

Vasodilatory hypotension Vasodilatory hypotension is a frequent complication after heart transplantation or any open heart surgery using cardiopulmonary bypass with membrane oxygenation. It can be, at least partially, explained by a systemic inflammatory response with consecutive vasodilatory cytokines release.52 Alternatively vasodilatory hypotension could be baroreflex-​mediated endogenous arginine vasopressin depletion.53 It has been hypothesized that preoperative excessive vasopressin release in patients with severely decompensated heart failure could induce endogenous arginine vasopressin depletion, potentiated by an acute stress such as cardiopulmonary bypass.54 Postoperative vasoplegia can be also mediated by preoperative use of vasodilatory drugs, either neurohormonal inhibitors for chronic heart failure treatment, or inodilators such as milrinone.1 The mainstay treatment of postoperative vasodilation is norepinephrine, although there is a potential problem of catecholamine resistance as well as toxicity, if administered in higher

dosages. According to several underpowered trials testing vasopressin compared to norepinephrine in postcardiotomy surgery, and the most relevant, the VANCS trial, 50, administration of vasopressin could be superior, particularly in regard to less serious complications, rather than mortality alone. However, it seems not be applicable for vasoplegia in septic shock.51

Acute graft dysfunction Acute graft dysfunciton could be a very serious and fatal perioperative complication in heart transplant recipients, accounting for 30% of early post transplant deaths.55 Among other reasons, it can be caused by unrecognized or neglected donor organ dysfunction, having in mind that myocardial inury to some extent occurs in all brain death organ donors, and in some cases could be prohibitive for organ harvesting.56 Furthermore, acute graft dysfunction can be caused by prolonged ischaemic time, inappropriate organ preservation, and ischaemia–​reperfusion injury.57 Hyperacute graft rejection can occur as the most dramatic cause of graft dysfunction and death, in patients with pretransplant elevated PRA, that is previously formed antibodies to HLAs. Prospective HLA cross matching in those patients can be useful to prevent that complication.3 In order to start on-​time treatment and stop progression of the acute graft failure, transplanted patients should be carefully monitored perioperatively, from intraoperative transesophageal monitoring of the heart function, to measuring pulmonary artery saturation and cardiac output in intensive care setting. ECG dynamics, such as ST-​segment changes, QRS microvoltage, and arrhythmias, although non-specific for acute rejection, should raise awareness of its possiblility and initiate work up to define other potential causes, such as pericarditis/​pericardial effusion or acute myocardial infarction. Treatment of graft dysfunction begins with inodilators, such as dobutamine or milrinone, and more severe cases usually require various modalities of NCS, from ECMO and/​or temporary VAD to durable VAD support. In patients without irreversible other organ damage, high-​risk retransplantation may be considered as well.57

Right heart failure Right heart failure is one of the most frequent post transplant complications, and could be caused be innapropriate graft preservation or reperfusion, ischaemic injury, and also by the allograft right ventricle afterload missmatch, as many heart transplant patients suffer from a certain grade of pretransplant pulmonary hypertension. Last but not least, donor–​ recipient missmatch, such as a smaller donor heart transplanted to a larger recipient can also result in right heart frailure.57 Elevated central venous pressure combined with a low cardiac output can be indicative of right heart failure, and thus a Swan–​ Ganz catheter might be used to continuously evaluate haemodynamics and tailor precise fluid management. Echo-​guided right ventricular shape and function follow-​up is also mandatory, often by use of the transoesophageal approach for an adequate right ventricle visualization.

chapter 11.4  

Inotropes may be given sometimes for several weeks, and milrinone should be usually prefered over dobutamine, due to its vasodilatory effect within the pulmonary vascular bed.57 Inhaled nitric oxide could be beneficial in patients with pulmonary hypertension and low cardiac output.58

Post transplant renal failure Post transplant renal failure is a frequent complication occuring in up to 50% transplanted patients.57 Preoperatively, many transplant candidates suffer from some either reversible or ireversible renal dysfunction. Perioperatively they often experience ischaemic kidney injury due to aortic crosss clamping or post operative hypotension, and also from nephrotoxic medications, for example, calcineurin inhibitors, antibiotics, etc. Although there are controversies regarding cut-​off glomerulal filtration for listing a patient on a transplant list,59 a need for haemodialysis in the immediate post transplant period, as well as a decrease in glomerulal filtration of more than 25% during the first post transplant year, have been found to be substantially associated with a worse survival in heart transplant recipients.59 A significant preoperative congestion, followed by perioperative need for blood transfusions, increases the fluid overload, and could be a trigger for renal failure, and therefore has to be managed by loop diuretics or, if neccessary, temporary mechanical renal replacement.57

Post transplant rhythm disturbancies Post transplant rhythm disturbances include bradycardia and taachyarrhythmias. As a transplanted heart is denervated, the usual postoperative sinus node frequency at rest is 90 or more per minute. The bicaval technique reduces the probability of sinus node dysfunction compared to the biatrial approach. However, epicardial pacing wires should remain until sinus node dysfunction is ruled out or recovered.57 Among supraventricular arrhythmias, atrial fibrillation or flutter are the most common, and can be indicative of immune rejection, prior to other symptoms, or signs of myocardial dysfunction on echocardiography. Ventricular arhythmias occur less often, and can be rather associated with myocardial ischaemia or perioperative myocardial infarction, than with the graft rejection.57

Extended post transplantation management and follow-​up Surveillance, diagnosis, and classification of heart allograft rejection Cardiac allograft rejection remains one of the major post transplant complications, despite advances in immunosuppressive medications resulting in gradually reduced rejection rates. It is also well known that over the course of the post transplant period, the risk of rejection decreases, in parallel with decreased intensity of immunosuppressive treatment. Clinical presentation of the rejection may be acute or chronic, and immune rejection mechanisms cellular, humoral, or mixed.

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Endomyocardial biopsy (EMB) is still considered the gold standard for diagnosing and grading potential allograft rejection, enabling histopatological evaluation of the allograft tissue. It is performed either via the right jugular vein or femoral vein, using a percutaneous approach.60 There is no consensus regarding post transplantation EMB biopsy regimen and EMB scheduling protocols vary widely among transplant centres. A conservative aproach includes weekly EMB at the first month post transplantation, biweekly at the second month, monthly between the third and the sixth month, then every 3 months between month 7 and 12, every 3 months, between months 12 and 18, and every 6–​12 months after the nineteenth month post transplantation.57 In the era of efficient immunosuppressive protocols, non-​invasive surveillance methods, including gene profiling, can help reduce significantly EMB frequency, especially after the first post transplant year. Thus routine surveillance EMB is tending to be replaced by symptom-​triggered EMB.62,63 There was a diversity of rejection grading systems up to the 1980s, then in 1990, the ISHLT published a simple, universal rejection grading system, which was widely adopted, and enabled uniformity in rejection evaluation, easier communication among transplant centres, multicentre evaluation of transplant outcomes, and multicentre trials in the field. That classification served successfully over a decade, until in 2005, ISHLT published a revised Position Statement on this issue, to address new challenges and inconsistencies, and incorporate recent knowledge on antibody-​mediated rejection (AMR) (% Table 11.4.1). % Table 11.4.2 is taken from the 2005 ISHLT Position Statement and compares ISHLT rejection grading schemes 2005 vs 1990.64 Table 11.4.1  ISHLT AMR grading Grade

Description

pAMR 0: Negative for pathologic AMR

Both histologic and immunopathologic studies are negative

pAMR 1 (H+​): Histopathologic AMR alone

Histologic findings are present while immunopathologic findings are negative

pAMR 1 (I+​): Immunopathologic AMR alone

Histologic findings are negative while immunopathologic findings are positive (CD68+​and/​or C4d+​)

pAMR 2: Pathologic AMR

Both histologic and immunopathologic findings are present

pAMR 3: Severe pathologic AMR

Interstitial haemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis, and/​or karyorrhexis, and marked oedema and immunopathologic findings are present

AMR, antibody mediated rejection. Reproduced from Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005 Nov;24(11):1710-​20. doi: 10.1016/​ j.healun.2005.03.019 with permission from Elsevier.

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Table 11.4.2  ISHLT standardized cardiac biopsy grading acute cellular rejection 2004

1990

Grade 0 R*

No rejection

Grade 0

No rejection

Grade 1 R, mild

Interstitial and/​or perivascular infiltrate With up to 1 focus of myocyte damage

Grade 1, mild A-​Focal

Focal perivascualar and/​or interstitial infiltrate without myocyte damge

D–​Diffuse

Diffiuse infiltrate without myocyte damage

Grade 2 moderate (focal)

Once focus of infiltrate with associated myocyte damge

Grade 2 R, moderate

Two or more foci of inflitrate with associated myocyte damage

Grade, moderate A–​Focal

Multifocal infiltrate with myocyte damage Diffuse inlitrate with myocyte damage Diffiuse, polymorphous infiltrate with extensive myocyte damage ± oedema, ± haemorrhage +​ vasculitis

Grade 3 R, sever

Diffuse infiltrate with multifocal myocyte damage ± oedema, ± haemorrhage ± vasculitis

B–​Diffuse

Diffuse, polymorphous infiltrate with extensive myocyte damage ± oedmea, ± haemorrhage +​ vasculitis

*R denotes revised grade to avoid confusion with 1990 scheme. Reproduced from Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005 Nov;24(11):1710-​20. doi: 10.1016/​j.healun.2005.03.019 with permission from Elsevier.

Immunosuppression Introduction of cyclosporine into clinical practice in the 1980s allowed solid organ transplantation to progress from anecdotal attempts to routine method for treating end-​stage organ failure. In the meantime, development of potent immunosuppressive medications and combined immunosuppression protocols did not eliminate the threat of acute or chronic organ rejection as one of the major potential complications in patients with transplanted organs. Immune rejection can be T-​cell mediated, that is cellular, and/​or antibody mediated, that is humoral. Therapeutic modulation of the immune response in transplant recipients consists of three main strategies: (1) induction, (2) maintenance, and (3) rejection therapy. Glucocorticoids play an important role in induction therapy, in treating rejection episodes, and also are still used as part of maintanance immunosuppression in a certain proportion of transplanted patients. They inhibit the transcription factors activator protein-​1 and nuclear factor kappa-​B, which play important role in production of plethora of cytokines.65 Glucocorticoids provide a general, non-​specific immune supression, by limiting function and number of white blood cells, primarily depleting lymphocytes.66 Perioperatively, high-​dose steroids are used parenterally, with a quick transition to an oral regimen, Due to numerous side-​ effects, the goal is to gradually de-​escalate steroids over the first 6 months, and finally to withdraw them. However, for treating acute rejection, high-​dose parenteral steroids remain the first therapeutic option.66 Most centres prescribe oral steroids after transplantation with biopsy guided tapering. By introduction of novel immunusuppressants, early steroid weaning, or even steroid avoidance remain sustainable options for a substantial proportion of transplanted patients, particularly in those who develop significant

steroid-​associated side-​effects. However, although many patients may be completely weaned off steroids, it has been reported that about 60% of pateints take glucocorticoids permanently.66 Commonly used immunosuppressive agents in heart transplantation, and their most common side-​effects are summarized in % Table 11.4.3.

Induction therapy Induction therapy includes a combination of polyclonal or monoclonal antibody medications together with a foundational immunosuppressive drugs. Current practice reflects heterogenous use of induction immunosuppressant protocols in various centres. Approximately 50% of patients undergoing heart transplantation receive immunnsuppressant induction with either polycloncal anti-​thymocyte globulin (ATG) or a monoclonal, interleukin-​2 receptor antibody –​basiliximab or dacilizumab.66 Polyclonal ATG is available from two species: rabbit, following immunization with human thymocytes, and horse, following immunization with human T-​cells. Application of ATG results in rapid depletion of recipient T-​lymphocytes. It seems that rabbit ATG is more potent in decreasing circulating T-​ lymphocyte counts, with no difference in safety compared to horse-​derived ATG, including risk of the posttransplant lymphoprolipherative disorder (PTLD) or infections.67 Interleukin-​2 receptor antagonists are directed to the apha-​ subunit of IL-​2 receptor on activated T-​cells, thus attenuating T-​ cell proliferation and allograft directed immune reaction.68 Potential advantages of IL-​2 receptor antagonists –​basiliximab, and dacilizumab –​are fewer PTLDs and infections, with continued effectiveness in reducing acute rejection.68 Monoclonal antithymocyte antibody –​muromonab (OKT3) –​is a murine antibody targeted towards T-​cell CD-​3+​receptor, which results in opsonization of T-​cells and their removal by

chapter 11.4  

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Table 11.4.3  Commonly used immunosuppressive agents in heart transplantation. Quoted doses and levels vary between centers and individual patients according to required efficacy and adverse events Agent

Doses/​target levels

Common side effects**

Anti-​thymocyte globulin

0.75 mg–​1.5 mg/​kg (3 days)

Thrombocytopenia, allergic reaction

Basiliximab

20 mg day 1 and 4

Allergic reaction

Cyclosporine

Month 0–​3: 200–​300 µg/​L* Month 3–​12: 100–​200 µg/​L* >12 months: 80–​120 µg/​L*

Renal failure, tremor, hypertension, hyperlipidemia, diabetes, hirsutism, gingival hyperplasia

Tacrolimus

Month 0–​3: 12–​15 µg/​L* Month 3–​12: 10–​12 µg/​L* >12 months: 5–​8 µg/​L*

Renal failure, tremor, hypertension, hyperlipidemia, diabetes

Mycophenolate mofetil (MMF)

1.0–​1.5 g bid

Leucopenia, diarrhoea

Azathioprine

50–​150 mg od

Bone marrow suppression

Methylprednisolone

At transplant: 1–​2 g iv

Diabetes, osteoporosis, hyperlipidemia, hypertension, cushingoid appearance, acne

Prednisolone

0.2 mg/​kg tapering to 0.1 mg/​kg or taper to 0

Diabetes, osteoporosis, hyperlipidemia, hypertension, cushingoid appearance, acne

Everolimus

3–​8 µg/​L

Diarrhea, bone marrow suppression, oedema, stomatitis, pneumonitis

Sirolimus

4–​8 µg/​L

Diarrhea, bone marrow suppression, oedema, stomatitis, pneumonitis

Induction therapy

Maintenance therapy Calcineurin inhibitors

Antiproliferative drugs

Glucocorticoids

Proliferation signal inhibitors

*When combined with MMF or azathioprine, ** All agents: infection, increased cancer risk; od: once daily; bid: twice daily. Courtesy of F. Gustafsson.

circulating macrophages.66 Because of potential side-​effects, particularly ‘cytokine release syndrome’, such as headache, nausea, vomiting, fever, chest pain, or pulmonary oedema, as well as increased risk for PTLD, cytomegalovirus (CMV), or fungal infections, the use of muronomab has been practically abandoned.69 A meta-​analysis of the available randomized trials in heart transplantation indicate that ATG is probably associated with a lower risk of biopsy-​proven rejection compared with basiliximab, but no difference in mortality has been demonstrated.68 Risks with both drugs include higher rates of infection.68 Induction therapy allows for delayed introduction of calcineurin inhibitors, which is an advantage in recipients with renal impairment. However, there is no clear evidence for use of induction therapy, but it remains in many centres either as a universal strategy, or implemented in high-​risk patients, e.g. with preformed antibodies, positive retrospective crossmatch or renal dysfunction).70

Maintenance immunosuppressive therapy Maintenance immunosuppressive therapy includes combination of foundational immunosuppressive medications. Beside

glucocorticoids , discussed previously in this text, maintenance treatment includes combination of two of three classes of medications: Calcineurin inhibitors plus anti-​metabilites, or proliferation signal inhibitors. Calcineurin inhibitors include cyclosporine A or tacrolimus. Anti-​metabolites include mycophenalate mofetil, enteric coated mycophenolate sodium, and azathioprine. Proliferation signal inhibitors include sirolumus and everloimus.66 For glucocorticoids, a preferable strategy should aim to deescalate dosages of steroid oral formulation over the first six months, and then to withdraw steroid from the maintenance therapy.70 Some of the possible maintenance strategies are schematically presented in % Figure 11.4.3.

Calcineurin inhibitors Calcineurin inhibitors (CNIs) inhibit the phosphatase action of calcineurin, wihch is a crucial enzyme for the production of inflammatory cytokynes, including IL-​2, thus inhibiting the expansion of CD4+​and CD8+​cells, and differentiation of CD4+​ T cells.71 For many years, cyclosporine was the mainstay of maintanance immunosuppression, but today it has been replaced by tacrolimus

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Advanced h eart failu re TAC MMF PRED

TAC MMF

CyA MMF PRED

CyA MMF

TAC MMF

CYA EVE MMF PRED

EVE MMF +/–PRED

TAC

TAC PRED

3 months

12 months

Figure 11.4.3  Immunosuppressive maintenance strategies. Courtesy of F. Gustafsson.

(TAC) in most centres. Studies, including meta-​analysis, have suggested that tacrolimus might slightly be more effective in preventing acute cellular rejection than cyclosporine.72 The adverse event profiles for the two CNIs are quite similar, with renal dysfunction being of major clinical importance. Recent data from ISHLT show that at 1 year after heart transplant more than 90% of patients are treated with TAC. Studies have shown that patients may even be managed with TAC as monotherapy. Recently a once-​daily formulation of TAC has been introduced, and while its use may be associated with higher adherence rates, no effect on outcome in allograft recipients has been demonstrated.72

Antiproliferative agents/​cell cycle inhibitors Azathioprine (AZA) was a part of original transplant protocols, but now has been almost completely replaced by mycophenolate mofetil (MMF), as MMF has demonstrated superior outcomes to AZA, especially with respect to development of allograft vasculopathy.73 However, MMF is relatively often associated with gastrointestinal side-​effects and leucopenia. AZA is mainly used in patients with intolerable gastrointestinal adverse reactions to MMF, particulary if enteric-​coated formulation of MMF is not sufficient in reducing side–​effects.66 AZA becomes an active metabolite which is converted into a purine analogue. When incorporated into nuclear DNA, that metabolite inhibits DNA synthesis and consequential T-​and B-​ cells proliferation.66 MMF is a non-​competitive inhibitor of of inosine monophhosphate dehydrogenase, which is a key enzyme in guanine nucleotide production. MMF selectively blocks de novo guanine nucleotide production in proliferating lymphocytes,

where the only pathway for purine synthesis is de novo.66 MMF is a pro-​drug which is being metabolized to mycophenolic acid.

Proliferation signal inhibitors/​ mTOR inhibitors Sirolimus (rapamycin) and everolimus are proliferation signal inhibitors (PSIs) that inhibit the enzyme kinase mammalian target of rapamycin (mTOR), which phosphorylates cell-​cycle regulatory proteins involved in T-​cell proliferation, and thus disrupts growth and differentiation of T-​and B-​lymphocytes and inhibits vascular smooth muscle cells proliferation.66 Everolimus is the most commonly used PSI in adult heart transplant recipients, as a substitute for either antiproliferative drugs or for CNIs. PSIs are associated with lower rates of allograft vasculopathy than AZA and MMF,74 and if used, either with low doses of CNI, or, even more so, with MMF in the absence of CNIs (CNI-​free regimen), improvement in renal function is obtained. Early introduction of a PSI-​based CNI-​free regimen is associated with the greatest improvement in renal function, but carries an increased risk of acute rejection.75 Furthermore, PSIs are not tolerated by approximately 30% of patients, and for these reasons PSIs are rarely used as a primary strategy but often in patients who develop renal dysfunction with CNIs. Candidates for being converted from MMF to PSI are patients with rejection from de novo donor-​specific antibodies (DSA), as well as patients with CMV mismatch, or acquired CMV infection, or cardac allograft vasculopathy. In some malignancies, especially PSI or CNI-​free regimen with PSI and MMF might be used, with low mainanance immunosuppresants doses.76

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Rejection surveillance and treatment There should be comprehensive rejection surveillance and treatment performed by assessing symptoms and clinical status, ECG, biomarkers, echocardiogram, and periodical endomyocardial biopsies, as the gold standard for diagnosing and grading allograft rejection. Signs and symptoms or heart failure can signal rejection, as well as arrhythmias, among which atrial fibrillation or flutter appear most frequently. Microvoltage in ECG can be associated with oedema of myocardium allograft walls and/​or presence of pericardial effusion. Elevation of natriuretic peptides and/​or cardiac troponin can also be a consequence of rejection.57 Echocardiography can show reduced contractility, thickened myocardium due to oedematous walls, pericardial effusion, and/​ or dilation of myocardial chambers with atrioventricular valves relative insufficiency. Endomyocardial biopsies (EMB) should be performed periodically according to defined schedules, especially immediately after heart transplantation and later on, usually up to 5 years or more if clinically relevant rejection was diagnosed in the previous post transplant follow-​up.57 The EMB should assess both cellular and humoral (AMR) according to the ISHLT criteria (% Box 11.4.1 and % Table 11.4.4).64 Occasionaly, rejection diagnosis can be supported by use of cardiac CT, positron emmsion tomography or MRI, where late gadolinium enhancement could be associated with rejection, but in general those methods should not be used as a replacement for EMB. Mild, asymptomatic cellular rejection (ISHLT-​1R) does not require treatment, but closer clinical surveillance. Asymptomatic moderate cellular rejection (ISHLT-​2R) especially if later than 12 months after transplantation, may also not require specific treatment, but in most cases just a modification of a mantainance therapy, and closer surveillance, including clinical assessment, echocardiography evaluation, and follow up EMB.77 Severe cellular rejection (ISHLT-​3R) should be treated, regardless of symptoms.77 Usual management of rejection should include a high dose of glucocrticoid, i.e. methylprednisolone 500 mg intravenously over 3 days, then in parallel with reduction of the high dosage, rabbit ATG could be added for its cytolytic T-​and B-​lymphocites activity.57,77 Control EMB should be done usually from day 7 after starting rejection treatment. In a case of suspected rejection, HLA antibodies should be checked, and if there are no HLA antibodies, non-​HLA antibodies should be assessed in addition. AMR can occur immediately after heart transplantation in a hyperacute form, or later, as acute or chronic. If AMR is suspected, EMB analysis should be expanded to include immunocytochemistry stains for complement split products, IgM, IgG, and IgA, and possibly antibody.70,77 The goals of AMR treatment should be: (i) to disrupt injury of the allograft mediated by the humoral immune reaction, by use of intravenous corticosteroid and cytolytic medications (e.g. ATG); (ii) to remove circulating anti-​ HLA antibodies by use of (a) plasmapheresis, (b) intravenous immunoglobulin (IVIG can be applied 1 g/​kg daily for 2 days up to the maximal total dosage of 140 g) and /​or (c) immune apheresis

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(immunoadsorption).57,70,77 In a hyperacute AMR, besides intravenous corticosteroid and cytolytic medications, intravenous calcineurin inhibitor (cyclosporine A or TAC), and metabolic cycle inhibitor (MMF) may be considered.77 In a rejection presenting with cardiogenic shock, inotropes and vasopressors along with Swan–​ Ganz catheter haemodynamic monitoring should be titrated to achieve cardiac index > 2.0 L/​min/​m2. As a bridge to recovery, acute MCS may be indicated.57,76,77 In some cases retransplantation may also be considered, having in mind that in a case of a hyperacute AMR, survival after retransplantation is rather poor.77

Special considerations Sensitization and desensitization The exposure of the immune system to foreign HLA molecules results in anti-​HLA antibody production and therefore sensitized patients. Most relevant risk factors for allosensitization are: blood product transfusions, multiparity, black ethnicity, viral infections, homograft or VAD implantation and retransplantation. 79,80 Sensitization is traditionally measured with the panel-​reactive antibody (PRA) testing, which is calculated by the percentage of positive reactions in the PRA assay, and is defined by a result ranging from 10 to 25%.80 Currently, calculated PRA (cPRA) may be preferred. cPRA is derived from HLA frequencies among approximately 12,000 donors in the United States and it represents the percentage of actual organ donors who express one or more of the unacceptable HLAs as defined by the recipient anti-​HLA antibodies.81 Desensitization is usually reserved for highly sensitized patients defined by a cPRA value ≥ 50–​80% or by multiple positive crossmatches.80 Desensitization treatments are aimed to counteract immune mechanisms responsible for sensitization. That includes removal of antibodies via plasmapheresis, immunoadsorption or total plasma exchange, inhibition of antibodies with use of intravenous immunoglobulin (IVIG), B cell depletion with rituximab, plasma cell depletion with bortezomib, or complement inhibition by use eculizumab and/​or IVIG. Contemporary strategies usually include a combination of treatments targeting different of mechanisms, for example, plasmapheresis and/​or IVIG and/​or rituximab.82–​84 In the case of recurrent rejections, photopheresis could be considered as an add-​on treatment.78 Donor specific anti-​HLA antibodies (DSA) remain an issue in the early and late post-​transplant period. Specifically de novo DSA development has an increased chance to occur over time, and DSA presence has been associated with worse prognosis.85 It is also important to note that DSA developing de novo after the first post-​transplant year has a worse prognosis.86

Cardiac allograft vasculopathy Cardiac allograft vasculopathy (CAV) with a prevalence of 30% at 5 years and 50% at 10 years after heart transplantation has been identified as the main cause of mortality 3–​10 years after transplantation.87 Pathogenesis of CAV is related to repetitive endothelial damage caused by a combination of immunologic and

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non-immunologic mechanisms. Alloimunity in CAV includes HLA mismatch, DSA and/​or episodes of acute cellular rejection and AMR.88 Direct endothelial damage and inflammation stimulate proliferation of smooth muscle cells and deposition of the extracellular matrix, which leads to progressive vessel lumen narrowing. Cytomegalovirus, hepatitis C, and hepatitis B virus may increase the risk of CAV by both direct and immune-​mediated injury.88 Some non-​immunological factors, such as dyslipidaemia, diabetes, hypertension, and smoking, enhance donor-​transferred coronary atherosclerosis, and therefore should be appropriately modified and treated.89 While obliterative intimal proliferation with diffuse distal vessel pruning reflects the CAV caused by immune-​mediated mechanisms, focal and eccentric lesions in proximal segments of coronary arteries reflect predominant atherosclerotic aetiology.88,89 Serial screening for CAV is recommended since graft denervation masks angina symptoms, and allows silent progression of ischaemia until it causes complications with graft failure, myocardial dysfunction, arrhythmias, infarction, or sudden cardiac death. The gold standard for diagnosing CAV is coronary angiography. An increase in maximal intimal thickness of ≥ 0.5 mm during the first post transplant year on intravascular ultrasound is often used as a surrogate marker of rapidly progressive CAV.90 When vascular changes are concentric and longitudinal, angiography may underestimate the severity of vascular changes, and only intravascular ultrasound or optical coherence tomography can diagnose graft vasculopathy in a patient with unexplained graft failure and no evidence of rejection. Dobutamine stress echocardiography is the best-​validated non-invasive method, and may be used instead of angiography in heart recipients with significantly reduced renal function, or free of angiographically proven disease five years after transplantation.91 In patients with poor acoustic window, stress myocardial perfusion scintigraphy is an alternative. In general, patients diagnosed with CAV should be regularly checked by echocardiography, and annually by coronary angiography.90 Despite evolving treatment approaches for CAV, focus should be on prevention and early detection, as already haemodynamically significant CAV can be treated only palliatively. Besides better survival, the use of MMF, as opposed to AZA for immunosuppression, was associated with a trend toward a lower maximal intimal thickness.92 mTOR inhibitors inhibit the proliferation of vascular fibroblast and smooth muscle cells, with a beneficial effect on graft vessels.93 However, the use of everolimus and sirolimus is limited by side-​effects, including increased risk of early post transplant infection and enhanced nephrotoxicity of CNIs, which may be alleviated by use of CNI-​minimization immunosuppressive protocols. Besides CAV prevention, early introduction of everolimus in CNI-​free protocols was shown to improve renal function, although at the expense of more frequent graft rejection.94 Statins are routinely prescribed for the majority of heart transplant recipients, aimed primarily to prevent CAV and atherosclerosis. Once CAV is established, CNI replacement with sirolimus and continuation of MMF and steroid, or replacement of MMF with

sirolimus and continuation of CNI and steroid may be useful.93 Unlike in conventional coronary atherosclerosis, PCI in CAV has unsatisfactory long-​term results. Due to high restenosis rates, control angiography is recommended 6 months after PCI. In selected patients, retransplantation remains as the curative option. There is no consensus on the role of prophylactic implantable cardioverter–​defibrillators in patients with severe CAV.

Infections Infections in heart recipients represent an important cause of morbidity and mortality. The risk of infections in allograft recipients depends on the intensity of immunosuppression, and on epidemiologic exposure of both donor and patient. Donor selection process should include infection screening with respect to the risk of microbial transmission, such as hepatitis B and C, or HIV, and a stratification of future infection risk in order to tailor anitmicrobial prophylaxis in recipients (e.g. CMV serology).70 Considering the COVID-​19 pandemic, all donors and recipients should be screened for the presence of SARS-​Cov-​ 2, and if positive, not accepted for heart transplantation. On top of the standard vaccination protocol (see ISHLT Listing Critera for Heart Transplantation),3 vaccination against COVID-​19 should be performed in both transplant candidates and transplant recipients, as it has been shown as safe and effective.95 Many heart transplant centres give prophylactic peri-​operative antibiotic therapy according to the specific hospital microbial flora to reduce early infection risk. An obligatory part of pre-​transplant patient work-​up is a thorough evaluation of microbial exposure to prevent opportunistic infections in the post transplant period. In heart allograft recipients, as in other solid organ recipients, post transplant infections are defined as early (within 1 month), intermediate (1–​12 months), and late (> 12 months). Infections occurring within 1 month following heart transplantation are most commonly hospital-​related and dependent on donor/​recipient factors. Intermediate infections are mostly opportunistic, with decreasing risk by the end of the first post transplant year that correlates with routine reduction in immunosuppressive therapy, especially steroids. Antimicrobial prophylaxis is given for opportunistic infections, and usually prescribed during the first 3–​12 post-​transplantation months. Although the majority of late infections are by their nature community-​ acquired, it is important to be vigilant for late reactivation of opportunistic agents such as Mycobacterium tuberculosis, Aspergillus family fungi, or CMV, that may mimic non-​infectious diseases.70 Different centres suggest and use diverse post transplant follow-​up protocols, that include particular antimicrobial drugs regimens. A significant number of infections can be prevented by patient education, patient exposure reduction, reduction in immunosuppressive drug levels (e.g. steroid-​free protocols), and vaccination. COVID-​19 outbreak brought COVID-​19 infection as an important issue in allgoraft recipients. Recently a flow diagram of managament COVID-​19 infection in heart transplant patients has been proposed (% Figure 11.4.4).96

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OHT patient with confirmed COVID19

Endomyocardial biopsy to differentiate between rejection versus viral myocarditis and treat accordingly

Yes

• Inform heart transplant team • Obtain vitals and O2 sat • Labs: CBC with diff, CMP, immunosuppressive medication levels, d-dimer, fibrinogen, ferritin, CRP, LDH, cardiac biomarkers • Imaging: CXR; Chest CT if moderate to severe disease*

Elevated cardiac biomarkers

No

COVID directed therapy

Immunosuppression management

Mycophenolate mofetil

mTOR/Calcineurin inhibitors

Prednisone

Supportive care

No

ModerateSevere infection* Yes

Leukopenia/ lymphopenia/ moderate-severe infection*

No

Continue mycophenolate at lower dose

Elevated serum level

Yes

Yes

Hold mycophenolate

Hold and resume once level is in therapeutic range

No

Continue home dose

Continue home dose unless treating with dexamethasone

Dexamethasone + Remdesivir + Supportive care

Figure 11.4.4  Flow diagram with suggested management in heart transplant patients affected with COVID-​19.

Reproduced from Ballout JA, Ahmed T, Kolodziej AR. COVID-​19 and Heart Transplant: A Case Series and Review of the Literature. Transplant Proc. 2021 May;53(4):1219-​1223. doi: 10.1016/​j.transproceed.2021.02.015 with permission from Elsevier.

Arterial hypertension

Dyslipidaemia

Arterial hypertension is a common comorbidity in heart transplant recipients and associated with worse outcome.97 Denervation status of transplanted heart, water, and salt retention as a side-​effect of glucocorticoid therapy, and vasoconstriction mediated by CNI, make heart transplant recipients prone to hypertension development. Everolimus-​based regimens have shown a more favourable blood pressure profile over the first 1 to 3 years after heart transplantation.98 Despite obligatory diet and lifestyle modification, majority of patients need antihypertensive medications for the appropriate blood pressure regulation. No class of antihypertensive drugs has been proven to be superior in heart transplant recipients, and usually patients need a combination of antihypertensives for hypertension management.99 However, medications should be prescribed with caution, as dydiropropyridine calcium channel antagonists may be associated with increased circulating levels of cyclosporine, and renin-​ angiotensin-​ aldosterone antagonists may interfere with renal function.

The use of glucocorticoids, CNIs, and PSIs, such as everolimus or sirolimus, as well as other transplant-​related medications, such as triazole angifungals, are associated with an elevated prevalence of dyslipidemia in heart transplant recipients. Statins are usually effective in reducing total cholesterol and low-​density lipoprotein cholesterol. However, it seems that the role of statins in management of heart transplant patients are far greater than lipid lowering, and therefore statins should be initiated very early after heart transplantation, irrespective of the lipid profile. According to the evidence from the pooled analysis, it has been suggested that statins improve survival, may prevent fatal rejection episodes, decrease the incidence of coronary vasculopathy, and even may decrease terminal cancer risk.100 Diabetes mellitus Diabetes mellitus can adversely affect both graft and patient survival,77 and is frequent in patients after heart transplantation, with a greater than 30% incidence of post transplant diabetes

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mellitus%.101 High doses of glucocorticoids in the early postoperative phase and glucocorticoids in maintenance therapy, as well as calcineurin inhibitors, may predispone heart transplant recipients to new onset diabetes mellitus.70 Therefore the use of diabetogenic immunosuppressive medications should be minimized in patients with either pre-​existing or newly developed diabetes mellitus. Diabetes in post transplant patients should be controlled according to current diabetes management guidelines, although a less restrictive approach of HbA1c goal in the range 7.5–​8.0% range has been proposed.102

Osteoporosis Osteoporosis is a common side-​ effect of immunosuppressive therapies, in particular glucocorticoids. Bone mineral density loss occurs already early post transplant, and bone fractures peak during the first 2 years after heart transplantation.102 As osteoporosis leads in general to an increased morbidity and mortality, prevention of osteoporosis with vitamin D and bisphosphonates should be considered and has proven to be useful in heart transplant recipients.103

Malignancies According to the ISHLT Register, malignancies are the second most common cause of death in heart transplant recipients, and the most common cause of death in the first 5 years after heart transplantation.6 The most frequent post transplant cancer risk factors are higher recipient age, male sex, smoking, pre-​ transplant malignancy, diabetes mellitus, more than one hospitalization for rejection during the first year after transplantation.6,104 The Registry data from 2006-​2011 show that within the first five post transplant years 12.4% of patients developed malignancy: 8.4% had a skin malignancy; 4.5% non-​skin solid cancer; and 0.9% post transplant lymphoproliferative disorder (PTLD).2 The most common post-​transplant malignancy is non-​ melanoma skin cancer. Cumulative skin cancer incidence varies from 14.9% to 42%, being up to eight times higher than in general population. Any kind of solid organ cancer appeared in 2.9% in 1-​year, 6.2% in 5-​year, and 10.1% in 10 year survivors.104 Lung cancer is the most frequent post-​transplant solid organ cancer followed by prostate, colorectal, and breast cancers.105 PTLD is a unique type of malignancy after organ transplantation. Risk of lymphomas is 20–​30 times higher in children and young adults after heart transplant than in the non-​transplant population. Most PTLD results from Epstein-​Barr virus infection. Induction therapy with ATG is considered as a risk factor for PTLD. More recent studies demonstrate a lower risk of PTLD in using a cumulative reduced doses of ATG.106 There is existing evidence that swithching from CNI to mTOR inhibitor might help reducing de novo malignancies. A single-​centre cohort analysis with a mean follow-​up of 10 years has shown a reduced incidence of de novo malignancies and PTLD in heart transplant patients who were converted to sirolimus with complete CNI withdrawal.107 Furthermore, switching to mTOR containing immunosuppression after the initial diagnosis of malignancy has been shown to decrease mortality.108

Retransplantation This should be reserved for highly selected patients with severe graft dysfunction and failure. As we are facing a far lower supply of donor hearts than is needed to meet demand, a rational approach in listing patients for retransplantation should be mandatory, to prevent futile attempts to save pateints with predictable poor outcomes. According to the ISHLT data, cardiac retransplantation represents about 3% of the total number of transplants.6 It is very important to know that potential retransplant candidates carry very different post retransplantation mortality risk, and therefore each decision should be made by an experienced team, taking into account the individual risk profile for each potential retransplant candidate. In general, patients with chronic rejection and/​or CAV have an acceptable survival prognosis after the retransplantation, compared with patients with primary graft dysfunction, and especially with patients with acute rejection or early graft failure, that is within the first year post original transplantation.109-​111

Future directions As the number of donors is far too small compared to the numbers of potential recipients, further development in MCS, especially implanted ventricular assist devices and/​or total artificial heart is aimed to compensate a huge gap between allograft availability and patients in a need for a transplant. To expand the donor pool, use of extended criteria donor hearts has been implemented in some transplantation centres for high-​ risk recipients. Extended criteria hearts include donor hearts with impared global systolic function and/​or regional wall-​motion abnormalities, coronary artery diseases, as well as hypertensive hearts, and those from donors with cardiovascular death (DCD). To minimize ischaemia-​induced damage in DCD hearts, a methodology of ex vivo perfusion systems have been developed, with favourable short-​term clinical outcomes.112,113

Conclusion Despite all advances in drug and device therapies for heart failure, it is a progressive entity that may develop in to the advanced form, which is by definition refractory to conventional treatments. After the introduction of cyclosporine in the 1980s, heart transplantation, as for other solid organ allotransplantations, became a state-​of-​the-​art therapy for the end-​organ failure in appropriately selected patients. In the meantime, development of surveillance tools as well as advances in immunosuppressive regimens, and other evidence-​based therapeutic procedures, established heart transplantation as the best treatment option for terminal myocardial disease, with a median survival of about 13.5 years and a very good quality of life for the majority of recipients, selected according to the current guidelines. However, the world is faced with a growing population affected by advanced heart failure, and, at the same time, far too few donor organs are available. Therefore, durable continuous flow (left) ventricular assist devices should be widely but carefully used, to safely bridge potential transplant recipients to the transplantation. For now, it seems unlikely that sophisticated implantable heart pumps, total

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artificial hearts, regenerative therapies, or genetically engineered xenotransplants will be able in the near future to replace cardiac allograft transplantation as the only real currative method for treating patients with terminal heart disease. In conclusion, heart transplantation, despite the threat of the graft rejection and numorous potential non-​ immunologically driven complications, remains the golden therapeutic standard for all patients with advanced heart failure suitable for transplantation.

References 1. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, European Heart Journal 2021;42(36):3638–​44. 2. Crespo-​Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:1505–​35. 3. Mehra MR, Canter CE, Hannan MM, et al. International Society for Heart Lung Transplantation (ISHLT), Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-​year update. J Heart Lung Transplant 2016; 35:1–​23. 4. Khush KK, Cherikh WS, Chambers DC, et al. International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation; Thirty-​sixth adult heart transplantation report –​2019; focus theme: donor and recipient size match. J Heart Lung Transplant 2019;38(10):1056–​66. 5. Lund LH, Edwards LN, Kucheryaya AY, et al. International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation. Thirtieth official adult heart transplant report –​2013; focus theme: age. J Heart Lung Transplant 2013;32:951–​64. 6. Klush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation Report –​2018; focus theme: multiorgan transplantation. J Heart Lung Transplant 2018;37:1155–​68. 7. Stuart C. Newsletter Transplant: International Figures on Donation and Transplantation 2020, pp 54–​59. European Directorate for the Quality of Medicines & HealthCare Strasbourg. 8. Goldstein DJ, Bello R, Shin JJ, et al. Outcomes of cardiac transplantation in septuagenarians. J Heart Lung Transplant 2012; 31:679–​85. 9. Weiss ES, Allen JG, Russel SDl Shah AS, Conte JV. Impact of recipient body mass index on organ allocation and mortality in orthotopic heart transplantation. J Heart Lung Transplant 2009;28:1150–​7. 10. Russo MJ, Hong KN, Davies RR, et al. The effect of body mass index on survival following heart transplantation: do outcomes support consensus guidelines? Ann Surg 2010; 251:144–​52. 11. Patlolla V, Mogulla V, DeNofrio D, Konstam MA, Krishnamani R. Outcomes in patients with symptomatic cerebrovascular disease undergoing heart transplantation. J Am Coll Cardiol 2011; 58:1036–​41. 12. Sekar B, Newton PJ, Williams SG, Shaw SM. Should we consider patients with coexistent hepatitis B or C infection for orthotopic heart transplantation? J Transplant 2013;2013:748578. 13. Blumberg EA, Rogers CC, and the AST Infectious Diseases Community of Practice. Human immunodeficiency virus in solid organ transplantation. Am J Transplant. 2013;13:169–​78.

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14. Uriel, N, Nahumi N,Colombo PC, et al. Advanced heart failure in patients infected with human immunodeficiency virus: is there equal access to care? J Heart Lung Transplant 2014; 33:924–​30. 15. Aguero F, Castel MA, Cocchi S, et al. An update on heart transplantation in human immunodeficiendy virus-​infected patients. Am J Transplantation 2016;16:21–​8. 16. Simps DB, Uriel N, Gonzales-​Costello J, et al. Human immunodeficiency virus infection and left ventricular assist devices: a case series. J Heart Lung Transplant 2011;30:1060–​4. 17. Castel MA, Perez-​Villa F, Miro JM. Heart transplantation in HIV infected patients: more cases in Europe. J Heart. Lung Transplant 2011;30:1418. 18. Van Maarseveen EM, Rogers CC, Trofe-​Clark J, van Zuilen AD, Mudrikovas T. Drug-​naive interactions between antiretroviral and immunosuppressive agent sin HIV-​ infected patients after solid organ transplantation: a review. AIDS Patient Care STDS 2012; 26: 568–​81. 19. Afilalo J, Mottillo S, Eisenberg MJ, et al. Addition of frailty and disability to cardiac surgery risk scores identifies elderly patients at high risk of mortality or major morbidity. Circ Cardiovasc Qual Outcomes 2012;5:222–​8. 20. Khan H. Kalogeropoulos AP, Georgiopoulou VV, et al. Frailty and risk for heart failure in older adults; the health, aging and body somposition study. Am Heart J 2013; 166:887–​94. 21. Afilalo. J, Eisenberg MJ, Morin JF, et al. Gait speed as incremental predictor of mortality and major morbidity in elderly patients undergoing cardiac surgery. J Am Coll Cardiol 2010; 56:1668–​76. 22. Ohiomoba RO, Youmans QR, Akanyirige PW, et al. History of cigarette smoking and heart transplant outcomes. Int J Cardiol Heart Vasc. 2020;30:100599, 23. Biagini E, Spirito P, Leone O, et al. Heart transplantation in hypertrophic cardiomyopathy. Am J Cardiol 2008; 101:387–​92, 24. Maron MS, Kalsmith. BM, Udelson JE, et al. Survival after cardiac transplantation in patients with hypertrophic cardiomyopathy. Circ Heart Fail 2010; 3:574–​9, 25. Marcus FI, McKenna WJ, Sherill. D, et al. Diagnosisof arrhythmogenic right ventricular cardiomyopathy/​dysplasia: proposed modification of the task force criteria. Circulation 2010; 121:1533–​41, 26. Pinamonti B, Dragos AM, Pyxaras SA et al. Prognostic predictors in arrhythmogenic right ventricular cardiomyopathy: results from a 10-​year registry. Eur Hear J 2011; 32:1105–​13. 27. Ottaviani G, Segura AM, Rajapreyar IN, et al. Left ventricular nonconpaction cardiomyopathy in end-​stage heart failure patients undergoing orthotopic heart transplantation. Cardiovasc Pathol 2016; 25(4):293–​9. 28. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the Council on Clinical Cardiology. Heart Failure and Transplantation Committee: Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups: and Council on Epidemiology and Prevention. Circulation 2006; 113:1807–​16. 29. Scaefer RM, Tylki-​Szumanska A, Hilz MJ. Enzyme replacement therapy for Fabry disease: a systemic review of available evidence. Drugs 2009;69:2179–​205. 30. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-​Chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol 2016; 68:1323–​41. 31. Rugberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC State-​ of-​ the-​ Art Review. J Am Coll Cardiol 2019; 11:73:2872–​91.

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32. Chen Q, Moriguchi J, Levine R, et al. Outcomes of heart transplantation in cardiac amyloidosis patients: a single center experience. Transplant Proc 2021; 53:329–​334 33. Kirsten AV, Kreusser MM, Blum P, et al. Improved outcomes after heart transplantation for cardiac amyloidosis in the modern era. J Heart Lung Transplant 2018; 7:611–​18. 34. West J, Pollock-​Barziv SM, Diopchaud AI, et al. ABO-​incompatible heart. Transplantation in infants. N Eng J Med 2021;344:793–​800. 35. Chen JM, Edwards NM. Donor selection and management of the high-​ risk donor. In: Cardiac Transplantation, NM Edwards, JM Chen and Mazzeo PA, editors, Humana Press Inc. 2004, pp 19–​36 36. Cacciatore F, Palmieri V, Amerelli C, Malello C, Napoli C. Further evidence of HLA DR matching in determining heart transplantation outcome. Transpl Int 2020; 33:1551–​2. 37. Osoria Jaramillo E, Hasnoot GW, Kaider A, et al. Molecular level HLA mismatch is associated with rejection and worsened graft survival in heart transplant recipients –​a retrospective study. Transpl Int 2020; 202;9:1078–​88. 38. Chan BBK, Fleischer KJ, Bergin JD, et al. Weight is not an accurate criterion for adult cardiac transplant size matching. Ann Thorac Surg 1991;52:1230–​6. 39. Oprzedkiewicz, A, Mado H, Szezurek W, et al. Donor-​recipient matching in heart transplantation. The Open Cardiovascular Medicine Journal 2020;14:42–​7. 40. Kransdorf EP, Kittleson MM, Bench LR, et al. Predicted heart mass is the optimal metric size for match in heart transplantation. J Heart Lung Transplant 2019;38:156–​65. 41. Reed RM, Netzer G, Hunsicker L. et al. Cardiac size and sex-​ matching in heart transplantation: size matters in matters of seks and the heart. JACC Heart Fail 2014;2:73–​83. 42. Ghodsizad A, Bordel V, Ungerer M, Karck M, Bekeredjian R, Ruhparwar A. Ex-​vivo coronary angiography of a donor heart in the organ care system. Heart Surg Forum 2012; 15:161–​3. 43. Li, Y, Guo S, Liu G, et al. Three preservation solutions for cold storage of cardiac allografts: A systematic review and meta-​analysis. Artif Organs 2016; 40:489–​96 44. Monteguado Vela M, Garcia Saez D, Simon AR. Current approaches in retrieval and heart preservation. Ann Cardiothor Surg 2018; 7:67–​74. 45. Shumway NE, Lower R, Stofer RC. Transplantation of the heart. Adv Surg 1966;2:265–​84. 46. Forni A, Faggian G, Luciani GB, et al. Reduced incidence of cardiac arrhythmias after orthotopic heart transplantation with direct bicaval anastomosis. Transplant Proc 1996;28:289–​92. 47. Aziz TM, Burgess MI, El-​Gamel A, et al. Orthotopic cardiac transplantation technique: survey of current practice. Ann Thorac Surg, 1999: 68; 1242–​6 and Davies RR et al. Standard vs. bicaval techniques for orthotopic heart transplantation: An analysis from the United Network of Organ Sharing database. J Thorac Cardiovasc Surg 2010; 140: 700–​8. 48. Siney PP. Posttransplant management. In Cardiac Transplantation: The Columbia University Medical Center/​New York-​Presbyterian Hospital Manual, Edwards NM, Chen JM, Mazzeo PA, editors; Humana Press, Totowa, New Jersey, 2004, pp 123–​55. 49. Lisboa LA, de Amelda JP, Gerent AM, et al. Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery. The VANCS randomized controlled trial. Anesthaesiology 2017; 126:85–​93. 50. Hajjar LA, Vincent JL, Galas, FRBG, et al. Vasopressin versus norepinephrine in patients with vasoplegic shockafter cardiac surgery. The VANCS randomized controlled trial. Anesthesiology 2017;126:85–​93. 51. Russel JA. Vassopressin, norepinephrine and vasodilatory shock after cardiac surgery: another VASST difference? Anesthesiology 2017;126:9–​11.

52. Morales DLS, Gregg D, Helman DN, et al. Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac Surg 2000;69:102–​6. 53. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001;345:588–​95. 54. Robertson GL. The regulation of vasopressin function in health and disease. Rec Prog Horm Res 1997;33:333–​86. 55. Hosenpund JD, Bennet LE, Berkeley MK et al. The Registry of the International Society for Heart and Lung Transplantation: fifteenth official report –​1998. J Heart Lung Transplant 1998;17:656–​8. 56. Hosenpund JD, Novick RJ, Breen TJ, at al. The Registry of the International Society for Heart and Lung Transplantation: twelfth official report –​1995. J Heart Lung Transplant 1995;14:805–​15. 57. Pinney SP. Posttransplant management. In: Cardiac Transplantation, Edwards NM, Chen JM, Mazzeo PA, editors. Humanna Press Inc 2004, pp 123–​155 58. Ardehali A, Hughes K, Sadeghi A, et al. Inhaled nitric oxide for pulmonary hypertension after heart transplantation. Transplantation 2001; 72:638–​41. 59. Kolsrund O, Karason K, Holmberg E et al. Renal function and outcome after heart transplantation. J Thorac Cardiovasc Surg 2018; 155:1593–​604. 60. Murphy JM, Frantz R, Cooper L. Endomyocardial biopsy. In: Murphy J, Lloyd M, editors. Mayo Clinic Cardiology Concise Textbook. Minnesota: Rochester; 2007. p 1481 61. Stuart S, Winters GL, Fishbein C, et al. Revision of the 1990 working formulation of nomenclature in the diagnosis of heart rejection. ISHLT Consensus Report. J Heart Lung Transplant 2015; 24:1710–​20. 62. Oh KT, Mustehsan MH, Goldstein DJ, Saeed O, Jorde UP. Patel SR. Protocol endomyocardial biopsy beyond 6 months –​it is time to move on. Am J Transplant 2021;21:825–​9. 63. Wu YL, Ye Q, Ho C. Cellular and functional imaging of cardiac transplant rejection, Curr Cardiovasc Imaging Rep 2011;4:50–​62. 64. Stuart S, Winters GL, Fishbein C, et al. Revision of the 1990 working formulation of nomenclature in the diagnosis of heart rejection. ISHLT Consensus Report. J Heart Lung Transplant 2005; 24:1710–​20. 65. Stehlik J, Edward LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation twenty-​ seventh official adult heart transplant report –​2010 J Heart Lung Transp 2010; 29:1089–​103. 66. Lindenfeld J, Miller GG, Shakar SF, et al. Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. Circulation 2004;110:3858–​65. 67. Beiras-​Fernandez A, Thein A, Hammer C. Induction of immunosuppression with polyclonal antithymocyte globulins: an overview. Exp Clin Transplant 2003;1:79–​84. 68. Møller CH, Gustafsson F, Gluud C, Steinbrüchel DA. Interleukin-​2 receptor antagonists as induction therapy after heart transplantation: systematic review with meta-​analysis of randomized trials. J Heart Lung Transplant 2008;27:835–​42. 69. Opelz G, Henderson R. Incidence of non Hodkin lymphoma in kidney and heart transplant recipients. Lancet 1993;342:1514–​16. 70. Jessup M, Acker M. Cardiac transplantation. In: Heart Failure, Mann DL editor, Elsevier, Saunders 2011; pp 787–​801. 71. Urschel S, Altamirano-​Diaz LA, West LJ. Immunosupression armamentarium in 2010: mechanistic and clinical considerations. Pediatr Clin North Am 2010;57:433–​57. 72. Penninga L, Møller CH, Gustafsson F, Steinbrüchel DA, Gluud C. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-​analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol 2010;66:1177–​87. 73. Eisen HJ, Kobashigawa J, Keogh A, et al. Three-​year results of a randomized, double-​blind, controlled trial of mycophenolate mofetil

chapter 11.4  

versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant 2005;24:517–​25. 74. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant 2013;13:1203–​16. 75. Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant 2014;14:1828–​38. 76. Chang DH, Young JC, Dilibero D, Patel JK, Kobashigawa JA. Heart transplant immunusupression strategies at Cedars-​ Sinai Medical Center. Int J Heart Fail 2021; 3:15–​30. 77. Constanzo MR, Dipchand A, Starling R. et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29:914–​56. 78. Kirklin JK, Brown RN, Huang ST et al. Rejection with hemodynamic compromise: objective evidence for eficacy photopheresis. J Heart Lung Transplant 2006; 25:283–​8. 79. Al-​Mohaissen MA, Virani SA. Allosensitization in heart transplantation: an overview. Can J Cardiol 2014;30(2):161–​72. 80. Colvin MM, Cook JL, Chang PP, et al. Sensitization in heart transplantation: emerging knowledge: a scientific statement from the American Heart Association. Circulation 2019;139(12):e553–​78. 81. Cecka JM. Calculated PRA (CPRA) –​the new measure of sensitization for transplant candidates. Am J Transplant 2010;10:26–​9. 82. Leech SH, Lopez-​Cepero M, LeFor WM, et al. Management of the sensitized cardiac recipient: the use of plasmapheresis and intravenous immunoglobulin. Clin Transplant 2006;20(4):476–​84. 83. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med 2008;359(3):242–​51. 84. Kobashigawa JA, Patel JK, Kittleson MM, et al. The long-​term outcome of treated sensitized patients who undergo heart transplantation. Clin Transplant 2011;25(1):E61–​7. 85. Smith JD, Banner NR, Hamour IM, et al. De novo donor HLA-​specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am J Transplant 2011;11(2):312–​19. 86. Ho EK, Vlad G, Vasilescu ER, et al. Pre-​and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival. Hum Immunol 2011;72(1):5–​10. 87. Lund LH, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-​ third adult heart transplant report –​2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant 2016;35:1158–​69. 88. Patel CB, Holley CL. Cardiac allograft vasculopathy: a formidable foe. J Am Coll Cardiol 2019;74:52–​53. 89. Nikolova AP, Kobashigawa JA. Cardiac allograft vasculopathy: the enduring enemy of cardiac transplantation. Transplantation 2019;103:1338–​48. 90. Payne GA, Hage FG, Acharya D. Transplant allograft vasculopathy: role of multimodality imaging in surveillance and diagnosis. J Nucl Cardiol. 2016; 23:713–​27. 91. Elkaryoni A, Abu-​Sheasha G, Altibi AM, Hassan A, Ellakany K, Nanda NC. Diagnostic accuracy of dobutamine stress echocardiography in the detection of cardiac allograft vasculopathy in heart transplant recipients: A systematic review and meta-​analysis study. Echocardiography 2019;36(3):528–​36. 92. Kaczmarek I, Ertl B, Schmauss D, et al. Preventing cardiac allograft vasculopathy: long-​term beneficial effects of mycophenolate mofetil. J Heart Lung Transplant. 2006;25(5):550–​6. 93. Bellumkonda L, Patel J. Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy. Clin Transplant. 2020;34(1):e13769.

Hea rt tr a n spl a n tat i on

94. Schaffer SA, Ross HJ. Everolimus: efficacy and safety in cardiac transplantation. Expert Opin Drug Saf. 2010;9(5):843–​54. 95. Aslam S, Goldstein DR, Vos R, et al. COVID-​19 vaccination in our transplant recipients: The time is now. J Heart Lung Transplant. 2021;40(3):169–​71. 96. Ballout JA, Ahmed T, Kolodziej AR. COVID-​ 19 and Heart Transplant: A Case Series and Review of the Literature. Transplant Proc. 2021;53(4):1219–​23. 97. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-​ first official adult heart transplant report –​2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:996–​1008. 98. Andreassen AK, Broch K, Eiskjær H, et al. Blood pressure in de novo heart transplant recipients treated with everolimus compared with a cyclosporine-​based regimen: results from the randomized SCHEDULE trial. Transplantation 2019;103:781–​8. 99. Brozena SC, Johnson MR, Ventura H, et al. Effectiveness and safety of diltiazem or lisinopril in treatment of hypertension after heart transplantation: results of a prospective, randomized multicenter trail. J Am Coll Cardiol 1996;27:1707–​12. 100. Vallakati A, Reddy S, Dunlap ME, Taylor DO. Impact of statin use after heart transplantation. A meta analysis. Circ Heart Fail 2016;9:e003265. 101. Zielińska K, Kukulski L, Wróbel M, Przybyłowski P, Zakliczyński M, Strojek K. Prevalence and risk factors of new-​ onset diabetes after transplantation (NODAT). Ann Transplant. 2020 Aug 25;25:e926556. 102. Wallia A, Illuri V, Molitch ME. Diabetes care after transplant: definitions, risk factors, and clinical management. Med Clin North Am 2016;100:535–​50. 103. Leidig-​Bruckner G, Hosch S, Dodidou P, Ritschel D, Conradt C, Klose C, et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-​up study. Lancet 2001;357:342–​7. 104. Youn JC, Stehlik J, Wilk AR, , et al. Temporal trends of de novo malignancy development after heart transplantation. J Am Coll Cardiol. 2018;71(1):40–​9. 105. Crespo-​Leiro MG, Villa-​Arranz A, Manito-​Lorite N, et al. Lung cancer after heart transplantation: results from a large multicenter registry. Am J Transplant. 2011;11(5):1035–​40. 106. Hertig A, Zuckermann A. Rabbit antithymocyte globulin induction and risk of post-​transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: an update. Transpl Immunol 2015;32(3):179–​87. 107. Asleh R, Clavell AL, Pereira NL, et al. Incidence of malignancies in patients treated with sirolimus following heart transplantation. J Am Coll Cardiol. 201;73(21):2676–​88. 108. Rivinius R, Helmschrott M, Ruhparwar A, et al. Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy. Drug Des Devel Ther. 2014;9:93–​102. 109. Miller RJH, Clarke BA, Howlett JG, et al. Outcomes in patients undergoing heart transplantation: a propensity matched cohort analysis of the UNOS Registry. J Heart Lung Transpl 2019;38:1067–​74. 110. Radovancevic B, McGiffin DC, Kobashigawa JA, et al. Retransplantation in 7,290 primary transplant patients: a 10-​year multi-​institutional study. J Heart Lung Transplant 2003;22:862–​8. 111. Tjang YS, Tenderich G, Hornik L, Körfer R. Cardiac retransplantation in adults: an evidence-​based systematic review. Thorac Cardiovasc Surg. 2008;56(6):323–​7. 112. Kim IC. Youn JC, Komashigawa JA. The past, present and future of heart transplantation. Korean Circ J 2018; 48:565–​90. 113. Ardehalli A, Esmaillan F, Deng M, et al. Ex-​vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective open-​label, multicentre randomised non-​inferiority trial. Lancet 2015; 385:2577–​84.

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Palliative care in the heart failure trajectory Tiny Jaarsma, Donna Fitzsimons, Lisa Hjelmfors, Loreena Hill, Ekaterini Lambrinou, and Anna Strömberg Contents Introduction  735 Considering palliative care in the HF trajectory  735 Organization of palliative care provision to HF patients  736 Primary palliative care  737 Specialist palliative care  737 Interdisciplinary approach  737

Symptom management  738 Ethical issues  739

Challenging conversations with difficult decisions  739 Ethical issues related to implantation of devices: ICD/ CRT/ LVAD  739 Deprescribing of evidence-based medications  740

Communication with the patient and family during the HF trajectory  740

Timing of discussing the HF trajectory  740 Communication tools  741

Future directions  741 Summary and key messages  741 References  742

Introduction Palliation is an essential but often overlooked aspect of heart failure (HF) care that urgently requires implementation. As a result of advanced pharmaceutical, device, and surgical interventions, patients with HF have an improved longevity; however, this may come at a cost of greater symptom burden.1 HF can have a major influence on the patient’s emotional, physical, spiritual, and social well-​being and patients with HF often have typical palliative care needs.2 The World Health Organization (WHO) defines palliative care as ‘an approach that improves the quality of life of patients (adults and children) and their families who are facing problems associated with life-​threatening illness. It prevents and relieves suffering through the early identification, correct assessment and treatment of pain and other problems, whether physical, psychosocial or spiritual.’3 Palliative care aims to prevent and alleviate suffering through early detection, careful analysis, and treatment of physical, mental, social, and existential problems through collaboration across multi-​professional specialties. Palliative care should be offered/​available early in the disease trajectory along with life-​prolonging treatment. In this chapter, the relevance of palliative care in HF management is described. Furthermore, the importance of control and management of the most common HF symptoms are discussed. The chapter presents different organizational models of palliative care and argues for coordinated, interdisciplinary care, and it addresses ethical issues such as challenging conversations with difficult decisions, ethical issues related to implantation and deactivation of devices, and deprescribing medication. Finally, practical recommendations regarding how to communicate with the patient and family during the HF trajectory are provided.

Considering palliative care in the HF trajectory The trajectory of HF is often unpredictable, which is why it is has been difficult to pinpoint a specific time when palliative care should be considered. However, palliative care (according to the WHO definition) is relevant and important to all patients with HF regardless of stage of their illness. Optimal symptom control and a systematical addressing of patients’ and families’ needs and preferences for treatment should be the focus of care.4 In this way, palliative care can be offered in parallel with usual HF care throughout the whole illness trajectory.4 In the past two decades, there has been widespread discussion in the literature regarding the integration of palliative care within HF management and there is broad consensus that we should consider a palliative approach early within the patient journey.6,7 In addition, we must abandon outdated notions that we either offer disease-​modifying

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Advanced h eart failu re

Chronic care

Crisis care

Terminal care

Supporting patients, families/informal caregivers. Information, communication, shared decision making. Diagnosis

Death

Assess and optimize:

Assess and optimize:

Assess and optimize:

Discuss:

Discuss:

Discuss:

• Preferences & possibility for treatment & care • Role of patient, family, and informal caregivers

• Preferences for treatment, care, & place of care • Discuss and decide regarding device deactivation (taking laws & culture into consideration) • Deprescribing & anticipatory prescribing

Planning near future:

Planning near future:

• • • •

Evidence-based treatment Sign & symptoms Spiritual, psychosocial, & physical needs Comorbidities

• HF & self-care • Role of patient, family, & informal caregivers

Planning near future: • Explore preferences & expectations • Discuss trajectory & challenges to individualize prognosis

Advanced care planning: • Prepare management during crisis

• • • • •

Possible reason deterioration/reversible precipitants Evidence-based treatment Signs & symptoms Spiritual, psychosocial, & physical needs Coordination of intensified care

• Consider deprescribing and anticipatory prescribing • Palliative needs assessment • Consider referral to specialist palliative care team

Advanced care planning:

• Re-discuss HF trajectory • Revisit advanced care plan • Initiate end-of-life discussion

• Signs & symptoms • Spiritual, psychosocial, and physical needs

• Prepare & explain the dying process • Increase practical & emotional support for patient, family, and caregivers

Advanced care planning:

• Resuscitation status clarified • Focus to ensure a good death • Bereavement support

Figure 11.5.1  Integrating palliative care throughout the heart failure trajectory. Reproduced from Hill L, Prager Geller T, Baruah R, et al. Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper. Eur J Heart Fail. 2020 Dec;22(12):2327-​2339. doi: 10.1002/​ejhf.1994 with permission from John Wiley and Sons.

interventions, or palliative care –​because evidence confirms that it is the combination of the two that have the potential to offer greatest benefit to patients and their families.4,8 Indeed, it could be argued that all aspects of HF management are, in fact, palliative in nature, because the focus is on treating symptoms, rather than curing the disease. Thus, integrating palliative approaches into conventional HF management aimed at disease modification is a necessary and logical step (% Figure 11.5.1). For patients with HF, it is assumed that basic palliative care needs can be managed by the patient’s cardiologist, HF nurse, or general practitioner, while more complex palliative care needs should be managed by multidisciplinary specialist teams with specialist training in palliative care.5,9 Palliative care interventions that are combined with HF management can improve patient outcomes and decrease costs and utilization.10 The addition of palliative care to evidence-​based HF care can improve quality of life, psychosocial (anxiety/​depression), physical and spiritual well-​being.11

The implementation of palliative care in HF care is conventionally based on prognostication or risk of death, whereas it should be initiated on recognition of the palliative care needs of the patient and family.

Organization of palliative care provision to HF patients A variety of different models that integrate the provision of palliative care within a specialist HF services are available. An integrated approach is not widespread within clinical practice, and it is estimated that less than a quarter of European countries have designated palliative care units for people with advanced HF.12 It is important to recognize the heterogeneity of HF service provision between different countries, and to appreciate the impact of different healthcare infrastructures on the continuity of patient care. Thus a worldwide ‘one size fits all’ approach is unlikely to be feasible and we need to consider the wider contextual issues

chapter 11.5  

Pa l l iati ve ca re i n the hea rt fa i lu re t r aje c tory

• Hopp et al 2016

• Wong et al 2016

• Sidebottom et al 2015

Hospital

Transitional period

• Rogers et al 2017 • O’Donnell et al 2018 • Brannstrom et al 20

Community

Outpatient

Bekelman 2015 Evangelista 2014

• Johnson et al 2018 • Bakitas et al 2017

Figure 11.5.2  Studies illustrating setting of multidisciplinary care provision.

to determine the most appropriate model and affect meaningful change (% Figure 11.5.2).

Primary palliative care Perhaps the most common model of integrated palliative care in the HF field is the concept of primary palliative care that emphasizes the role of the generalist HF team members, such as a HF nurse of doctor. This approach assumes that all clinicians are competent in providing basic palliative care interventions and is consistent with the belief that palliative care should be available for all patients and begin from the point of diagnosis in HF.13 The core components of primary palliative care include symptom management, communication regarding the goals of care, advance care planning, and psychosocial care and care co-​ ordination.14 The unpredictable disease trajectory in HF means that it is vitally important not to delay the initiation of supportive and palliative care discussions, and in that context a primary approach is advantageous, because it does not require specialist referral. Given the rising incidence of HF associated with the aging demographic, it has been asserted that primary palliative care is the most sustainable model to effectively and efficiently address the patients’ needs.15 Many of the core components of palliative care such as symptom assessment and management, psychosocial support, and advance care planning are central to the provision of high-​quality HF care, and so the integrated approach has the potential to produce a more feasible and cost effective management plan.

Specialist palliative care A registry study that evaluated 31,060 deaths from heart disease concluded that only 10.6% of the patients with heart diseases died in a palliative care setting.16 Furthermore, few patients and their families were aware of the possible symptoms that could occur during the illness trajectory and the imminence of death.16 In a study from the United Kingdom, the worlds’ largest primary care database was explored to find how many patients with HF were recognized as needing a palliative care approach. Of the patients

with HF that were in the database, 7% (234/​3122) were in a palliative care register compared to 48% (3669/​7608) of cancer patients. Twenty-​nine patients with HF were entered into the register just within a week of their death.17 Most of the studies that have evaluated models of integration focus on adding a specialist palliative care referral into an existing heart failure service. Several large-​scale studies such as ENABLE CHF-​PC,18 PAL-​HF,11 and PREFER,19 have tested innovative models of integrated care. A recent systematic review of the available evidence considered data from 23 different studies and found an improvement in patient reported outcomes (symptom burden, depression, functional status, quality of life), as well as resource use and costs of care.20 However, it is also clear that where referral to specialist palliative care occurs, it is often late in the disease trajectory and patients’ symptoms may be advanced. It would seem that in terms of referral to Specialist Palliative Care, timing is everything for patients with advanced heart failure and their families, since many studies confirm that often we offer too little, too late.21 The HFA guidance document sets out important triggers that may precipitate involvement of a specialist palliative care team.15 It is very useful to reflect upon these critical opportunities, as key points when more specific expertise is valuable and if not already done, the concept of palliative care can be introduced to patients and their families (% Table 11.5.1).

Interdisciplinary approach The concept of palliative care takes a holistic view of the patient and their family, therefore palliative care provision is not the sole terrain of one profession, rather it requires effective interdisciplinary working, communication and collaboration.15,20 Within the literature, there is a strong evidence base for nurse-​ led HF care, and specialist HF nurses play an important role in the delivery of effective HF care at the end of life. However, given the complexity of the biopsychosocial issues affecting people with advanced HF, the contribution of pharmacists, social workers, psychologists etc. is also vital. Data from qualitative studies suggest that dealing with such complexity is challenging for patients

737

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SECTION 11  

Advanced h eart failu re

Table 11.5.1  Possible triggers for the involvement of specialist palliative care for those with HF Refractory or complex symptoms When there is spiritual or existential distress Recurrent HF admissions Increasingly frequent appropriate ICD shocks When considering ICD deactivation or non-​replacement Before LVAD implantation or transplant referral When initiating palliative inotropic therapy Declining functional status due to progressive HF or a comorbidity If patients and/​or informal carers/​surrogates disagree on goals of care If there is a request for assisted suicide

and caregivers in particular, with high levels of anxiety and uncertainty contributing to poor quality of life, widespread uncertainty, and inability to plan ahead.22 Thus co-​ordination across the care pathway is necessary because although these patients have high rates of repeat hospitalization, they will spend the majority of their time at home. In that context, the family doctor and community nursing team also play a significant role in helping to manage the complexity of symptoms and the unpredictable disease trajectory that typifies heart failure, even in the early stages.

Symptom management Successful symptom management is one of the cornerstones of palliative care in patients with HF and it can improve the quality of life for both patients and their families during the HF trajectory.15 A holistic palliative symptom management approach to patients with HF does not only address the physical aspect of

symptoms, but also the psychological, social, and spiritual dimensions of suffering to achieve total symptom relief. In order to manage symptoms, successfully clinicians need to systematically assess symptoms using clinical skills and tools for patient reported symptoms, for example, the Edmonton Symptom Assessment Scale, Kansas City Cardiomyopathy Questionnaire, the Memorial Symptom Assessment Scale-​Heart Failure.23–​26 Symptom-​monitoring is also an important component of self-​ care performed by the patients themselves or supported by their family caregivers.27–​29 To increase knowledge and skills related to symptom monitoring, patients with HF and their caregivers should be educated and supported to manage symptoms from diagnosis and throughout the HF trajectory, including information on frequency, how to assess intensity, rate, and duration of a symptoms. Telemonitoring may be a useful and effective tool to support both symptom monitoring and management in selected patients.30 The most common symptoms in HF are shortness of breath (breathlessness) and fatigue. Almost all patients in the more advanced stages of the condition have these symptoms. Breathlessness and fatigue can be unspecific and difficult to assess objectively but a visual analogue scale or numeric rating scale can be used, and patients can learn to monitor the different levels of breathlessness and fatigue and the impact it has on their daily life activities and exercise intolerance. Successful symptom management mainly relies on patients’ (and/​or their caregivers’) ability to monitor and interpret symptoms and take appropriate actions to manage the symptoms.28,29 Symptom management can include both self-​care and medical treatment as shown in % Table 11.5.2.31 Symptom management in HF is complex and there are several challenges related to symptoms in patients with HF. Since most

Table 11.5.2  Overview of the clinical and self-​care management of the most common heart failure symptoms Symptoms

Medical treatment

Self-​care

Breathlessness

Optimal medical therapy. Consider benzodiazepines for anxiety and opiates in end of life care Assess co-​morbidities

Non-​pharmacology: Sitting upright, hand-​held fans, relaxation techniques, breathing exercises Pharmacology: Optimal HF medical therapy. Consider benzodiazepines for anxiety and opiates (morphine) Little benefit of supplementary oxygen in advanced HF alone

Oedema

Flexible diuretic intake Optimal medical heart failure therapy

Support stockings

Fatigue

Optimal medical heart failure therapy Assess co-​morbidities

Exercise, physical activity, adequate nutrition

Thirst and xerostomia

Artificial saliva as gel or tablets

Intensified oral hygiene, rinse mouth frequently, free fluid intake, candies, chewing gum, suck ice cubes, or frozen fruit pieces

Pain

Assess cause of pain, e.g. cardiac, musculoskeletal, existential Use appropriate pain medication but avoid NSAIDs

Exercise, physical activity, relaxation techniques, breathing exercises

Nausea and/​or poor appetite

Assess cause of nausea. Prescribe antiemetic drugs Replace medications that may cause nausea or other gastrointestinal problems

Dietary changes, avoid triggering smells, alternative or complementary medicine, e.g. acupressure, acupuncture

Anxiety/​depression

SSRIs can be used safely and relatively well tolerated in HF but have limited evidence of efficacy

Psychoeducational support, exercise and psychological therapies, e.g. cognitive behavioral therapy

NSAIDs, non-​steroidal anti-​inflammatory drug; SSRIs, Selective serotonin reuptake inhibitors.

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patients with HF have both cardiac and non-​cardiac comorbidities causing end-​organ damage, this may lead to a range of persistent, distressing and debilitating symptoms. Furthermore, several of the co-​morbid conditions, that often occur simultaneously with HF, share a similar symptomatology, such as fatigue, shortness of breath and exercise intolerance. A deterioration of any of these symptoms in a person in addition suffering from more conditions, such as HF, chronic obstructive pulmonary disease (COPD), and renal failure can make it complicated to trace the cause of the deterioration. Additionally a high prevalence of cognitive impairment often occurs in combination with limited social support further complicating HF symptom monitoring and management.32 Recently frailty has been highlighted as an important clinical issue to assess in patients with HF. The Heart Failure Association has proposed a HF-​specific definition of frailty including four domains: clinical (co-​ morbidities, weight loss, falls), psycho-​ cognitive (cognitive impairment, dementia, depression), functional (activities of daily living, Instrumental activities of daily living), low/​non mobility, balance), and social (living alone, poor/​ no social support, institutionalization). Frailty is more common in persons with HF, compared to the general population within the same age span. There is much overlap between HF symptoms and components of frailty since the two syndromes mimic each other. Frail patients with HF are often more symptomatic, but frailty is not per se correlated linearly with HF disease severity.33 Due to the complexities already outlined, symptoms as experienced by patients may not always reflect an objective change in the HF condition.28 However, in more advanced stages symptoms are more obvious and easier to detect and interpret for patients. Patients with the greatest needs of symptom management are those with characteristics of advanced HF as described in % Table 11.5.3. Table 11.5.3  ‘Need Help’—​Characteristics of patients of advanced heart failure in great need of help with regard to symptom management N

NYHA /​Natriuretic peptides

Persisting NYHA class III or IV and/​or high NT-​proBNP

E

End-​organ dysfunction

Worsening renal or liver dysfunction

E

Ejection fraction

Very low ejection fraction < 20%

D

Defibrillator shocks

Recurrent appropriate defibrillator shocks

H

Hospitalizations

> One hospitalization with heart failure in the last 12 months

E

Oedema

Persisting fluid overload and/​or increasing diuretic requirement

L

Low blood pressure

Consistently low BP with systolic < 90 to 100 mmHg

P

Poor medication tolerance

Inability to up-​titrate (or need to decrease/​terminate) ACEI, beta-​ blockers, ARNIs, or MRAs

Source data from Crespo-​Leiro, M.G., et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail, 2018. 20(11): p. 1505–​1535.

Ethical issues Challenging conversations with difficult decisions Contrary to belief, communication to inform advanced planning and future decision-​making should ideally be undertaken when the patient’s HF symptoms are stable and he/​she has the ability to contribute to the conversation, rather than when death is imminent.34 A patient’s preference towards quality over quantity of life can change in accordance with symptoms and their treatment status. For example, hypothetically, members of the general public believed that if they had HF, 83% would prefer care focused on quality of life rather than on survival.35 In reality, however evidence confirms that despite multiple symptoms, patients with HF remain reluctant to trade quality of life for increased length of life.36,37 Professionals have a responsibility to respect patients’ autonomy and encourage informed shared decision-​making through-​out the HF trajectory. Choices are complex, rather than black and white, for example option of either curative treatment or palliative care, but a balanced arrangement aligned to both patients’ and healthcare professionals’ expectations. Unrealistic treatment expectations can have detrimental consequences, leading to unnecessary anxiety, distress, and lack of much needed specialist support.38 The communication and supportive relationship between the professional, patient, and informal caregiver may be thrown into disarray causing mistrust and confusion at a time when clarity and empathy are paramount. The Integrated Palliative Care Outcome Scale is a patient-​ reported outcome measure that has been found to empower patients to become more engaged in the clinical consultation and to highlight their unmet needs.39 Furthermore, a number of ‘checklists’ have been developed to encourage both patients and healthcare professionals to initiate difficult conversations, for example a ‘question prompt list’.40 Nevertheless, it is important to achieve this intricate balance between offering patients open, frank yet compassionate, personally connected conversations that acknowledge end-​of-​life, but yet do not remove hope for life before death.41

Ethical issues related to implantation of devices: ICD/​CRT/​LVAD The implantation of implantable cardioverter defibrillator (ICD) or cardiac resynchronization device +​/​-​ICD are perceived by many patients as life-​saving.42 Over the years the device may have discharged a successful shock, reinforcing this misconception. However, as HF progresses, the patient becomes more at risk of an arrhythmia and subsequent shock. As our society has a growing elderly population, with many experiencing at least one co-​morbidity (e.g. renal disease or cancer), there is an increased likelihood of inappropriate or futile shock being delivered when death is imminent. This was most vividly portrayed in the study that interrogated 125 ICDs post death and concluded more than one third of patients had experienced a ventricular tachyarrhythmia within the last hour of life.43

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Advanced h eart failu re

International guidelines recommend that professionals discuss the option of ICD deactivation with the patient and family.44,45 Deactivation is a simple non-​invasive procedure whereby the shock function of the ICD is ‘switched off ’. At end of life there is an increased risk of the patient experiencing painful and futile shocks. Nevertheless, all too often the discussion and decision is left until death is imminent, placing additional anxiety on family members. A number of studies have investigated the experience of a shock from the ICD and the subsequent cause of psychological distress with a negative impact on quality of life.46,47 This may be acceptable while there is equipoise between acceptable quality of life and longevity; however, when the patient transitions into the last phase of life,15 this argument may no longer be sustainable. There is increasing awareness of the importance of informed choice concerning advanced HF therapies, such as ventricular assist devices (VAD) and the importance of inclusion of a palliative approach is recommended.48 Patients in the advanced stages of HF, particularly those referred to or awaiting VAD or transplantation should receive a palliative care consultation before their intervention, to enable realistic treatment expectations and encourage family-​centred discussions about provisions following their demise.

Deprescribing of evidence-​based medications The deprescribing of medications is not giving up hope, rather it is a proactive, individualized approach that requires a continuous revision of good prescribing principles and takes into consideration the context of goals of care, life expectancy, values, and preferences.49 There are several reasons to de-​prescribe, which may include risk of adverse drug event (increased with polypharmacy), limited benefit of evidence-​based medications, and poor adherence to recommended treatment regimen. Professionals may encounter difficulties in discontinuing therapy due to robust prescribing guidelines, the dearth of deprescribing advice, adverse events recurrence after discontinuation, and patient’s medication attachment (https://​depres​crib​ing.org). Many patients will have become familiar with their medication regimen and will have been informed at the time of initiation of the purposes of the medications. Any changes to this regimen will lead to unease and an awareness of declining health. Deprescribing requires professionals to be sensitive to potential issues and adopt an approach of good communication and information to ensure the patient and family members are committed and agree with changes made to medications. A step-​wise approach to deprescribing includes49: 1. A polypharmacy recognizing phase (appropriate indication, drug interaction) 2. Identifying futile treatment and adverse drug effects, and prioritizing the worse drug withdrawal 3. Withdrawal planning, communication to patient and caregiver, and process coordination 4. Monitoring withdrawal adverse drug events after gradual discontinuation

Communication with the patient and family during the HF trajectory Patients with HF might not always be aware that their illness is life-​limiting and often health-​care professionals lack insight into their patients’ future treatment preferences.34 Explanations such as ‘reluctance to dispel hope’, ‘uncertainty how and when to initiate conversations’, and ‘inadequate training’ have been documented as reasons why this stalemate situation may occur.50–​52 Recent position papers from both Palliative and HF Associations outlined a number of key recommendations that include the systematic review and addressing of patients’ and family members’ supportive needs and their preferences for care, as well as highlighting advance care planning and appropriate communication.15,53 Patients with HF prefer clear and honest and repeated opportunities to discuss these matters at a time when they are in a stable physical and/​or cognitive state; they also prefer being able to process and respond to the information they receive.52,54 Trust, empathy and hope are the core of patient centered communication.3,46 Both health professionals and patients enter an emotionally laden condition where they must confront and manage with issues about treatment, care, self-​care, and the process of dying and at the same time issues beyond their health condition concerning patients’ personal life. There can be uncertainties about life expectancy as well as treatment outcomes, and high-​level communication skills are critical to each end-​of-​life decision-​ making discussion.15,55 Bad news can be defined as any information viewed by a patient as negative to his/​her current and future situation, which results in a cognitive or emotional deficit for a period of time after it is received.56 Effective communication goes beyond what is said and what is done during an encounter with a patient. Moreover, what palliative care communication offers is the further ability to respond to rhetorical questions about life and death; the ability to know when to speak and when to say nothing; to provide the hand of comfort to the patient. It is much more than the giving of and asking for information. Decision-​making considers a constellation of physiological, psychosocial, and spiritual concerns, and their combined effect on the patient’s medical treatment and quality of life at the end of life. This process includes the conversation in which health-​ care professional gives the patient or their family bad news, and subsequent conversations related to treatment and care. Cultural and religious beliefs should also be considered to better ensure responsive healthcare practice.57

Timing of discussing the HF trajectory Since HF is a condition with a fluctuating and unpredictable disease trajectory associated with a severe symptom burden and poor quality of life, it is important to initiate such conversations sooner, rather than later. Death from HF can be sudden, due to an ischaemic event or electric instability of the heart, or it can be slow, due to episodes of decompensation or progressive organ failure. It might be a challenge when to initiate a conversation about end

chapter 11.5  

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of life. A screening tool that can be used to aid recognition if a patient is close to the end of life and to tailor advanced palliative care to HF patients is the ‘surprise question’: would you be surprised if this patient were to die within the next year?15 If the answer to that surprise-​question is ‘no’, a discussion concerning end-​of-​life care could be initiated by health care professionals, for example by introducing a communication tool to help the patient and the family pose questions that are important to them concerning future care. If the HF trajectory is not adequately discussed, issues around end-​of-​life care tend to be addressed too late, possibly resulting in an unsatisfactory end-​of-​life care for both patients and their families.22 Critical events such as the diagnosis of HF, perceptions of a change in clinical condition (e.g. experiences of frequent exacerbations), presentation of unrealistic expectations (e.g. patient with HF seeing treatments as curative), discussions about treatment complications or decisions (e.g. ICD implantation) or referral to palliative care may all act as prompts to start end-​of-​life discussions.15,22 The impact of early discussions can also extend to those close to patients prior to death, and into bereavement allowing them to prepare for death while also maintaining hope. Maintaining hope has been identified as extremely important to patients and relatives. Hope is not necessarily incompatible with knowledge of life-​threatening disease or prognosis, and can mean more than simply survival.58 Patients seem to maintain hope while also acknowledging their prognoses, whether they continue to hope: to live longer than expected; to enjoy a good quality of life; to achieve personal goals and self-​manage themselves, or to have a peaceful death. An honest and clear communication provides and signposts clear opportunities for patients and relatives to discuss their preferences and concerns with the health care professional, including chances for them to be revisited and changed.15,50

Communication tools Tools are available to support clinicians to communicate with patients with chronic and critical illness for example the BREAKS protocol59 or the ABCDE protocol that help to prepare and structure a difficult conversation (% Table 11.5.4).60 Other protocols include the SPIKES protocol in which setting up the consultation, assessing the patient’s perception, and obtaining the patient’s invitation are considered, and in giving information to the patient and addressing the patient’s emotions with empathic responses are encouraged.61

Future directions For several decades now the literature has been replete with assertions that patients with HF have sub-​optimal care in the last stages of their illness. Palliative care should be considered throughout the HF trajectory meaning that palliative care should be offered/​available early in the disease trajectory along with life-​prolonging treatment. This means that heart failure teams must abandon the notion that they have to choose between disease-​modifying interventions and palliative care, but need to combine the two approaches.

Table 11.5.4  ABCDE protocol for delivering bad news A

Advanced preparation Review the patient’s history, mentally rehearse, and emotionally prepare. Arrange for a support person if the patient desires. Determine what the patient knows about his or her illness.

B

Build a therapeutic environment/​relationship Ensure adequate time and privacy. Provide seating for everyone. Maintain eye contact and sit close enough to touch the patient, if appropriate.

C

Communicate well Avoid medical jargon, and use plain language. Allow for silence, and move at the patient’s pace.

D

Deal with patient and family reactions Address emotions as they arise. Actively listen, explore feelings, and express empathy.

E

Encourage and validate emotions Correct misinformation. Explore what the bad news means to the patient. Be cognizant of your emotions and those of your staff.

Source data from Rabow, M.W. and S.J. McPhee, Beyond breaking bad news: how to help patients who suffer. West J Med, 1999. 171(4):260–​3.

Furthermore, optimal symptom control should be a main focus of HF management care and must be a vital part in education of professionals. Better assessment of palliative care needs supported by evidence-​based validated PROMs is advised.15 The notion that palliative care can only be delivered by palliative care specialist should also be abandoned. HF management with a palliative care approach should be provided by all professionals. Where relevant, specialist palliative care should seriously be included in the multi-​disciplinary team model with flexibility in regard to the optimal fit in different health-​care systems available resources, and the spectrum of professional competences.15

Summary and key messages ◆ Palliative care should be a vital component of HF management

% Figure 11.5.3.

◆ Palliative care can be offered in parallel with usual HF care

throughout the whole illness trajectory. core components of primary palliative care include symptom management, communication regarding the goals of care, advance care planning, and psychosocial care and care co-​ordination ◆ Successful symptom management is one of the cornerstones of palliative care in patients with HF, and it can improve the quality of life for both patients and their families during the HF trajectory. ◆ Optimal symptom control and a systematical addressing of patients’ and families’ needs and preferences for treatment should be the focus of care. ◆ The

◆ Communication to inform advanced planning and future

decision-​ making should ideally be undertaken when the patient’s HF symptoms are stable and he/​she has the ability to contribute to the conversation, rather than when death is imminent.

741

742

SECTION 11  

Advanced h eart failu re Supporting patients, families/informal caregivers CHRONIC

Iterative assessment of palliative care needs

CRISES

Optimal symptom control, drug and device management

TERMINAL

Preferences for treatment, advance care planning

Comfort care, device withdrawal, deprescription

Ensuring a good death in preferred place of care and bereavement support

Information, communication, shared decision-making

Figure 11.5.3  Palliative care in heart failure.

References 1. Alpert, C.M., et al. Symptom burden in heart failure: assessment, impact on outcomes, and management. Heart Failure Review, 2017. 22(1):25–​39. 2. Olano-​Lizarraga, M., et al.et al. The personal experience of living with chronic heart failure: a qualitative meta-​synthesis of the literature. J Clin Nurs, 2016. 25(17–​18):2413–​29. 3. Palliative care. 2020. https://​www.who.int/​news-​room/​fact-​she​ets/​ det​ail/​pal​liat​ive-​care. 4. Chow, J. and H. Senderovich. It’s time to talk: challenges in providing integrated palliative care in advanced congestive heart failure. A narrative review. Curr Cardiol Rev, 2018. 14(2):128–​37. 5. Remawi, B.N., et al. Palliative care needs-​assessment and measurement tools used in patients with heart failure: a systematic mixed-​studies review with narrative synthesis. Heart Fail Rev, 2021. 26(1):137–​55. 6. Jaarsma, T., et al. Palliative care in heart failure: a position statement from the palliative care workshop of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail, 2009. 11(5):433–​43. 7. Fitzsimons, D., et al. The challenge of patients’ unmet palliative care needs in the final stages of chronic illness. Palliat Med, 2007. 21(4):313–​22. 8. Lewin, W.H. and K.G. Schaefer. Integrating palliative care into routine care of patients with heart failure: models for clinical collaboration. Heart Fail Rev, 2017. 22(5):517–​24. 9. Quill, T.E. and A.P. Abernethy. Generalist plus specialist palliative care-​-​creating a more sustainable model. N Engl J Med, 2013. 368(13):1173–​5. 10. Diop, M.S., et al. Palliative care interventions for patients with heart failure: a systematic review and meta-​analysis. J Palliat Med, 2017. 20(1):84–​92. 11. Rogers, J.G., et al. Palliative care in heart failure: The PAL-​ HF randomized, controlled clinical trial. J Am Coll Cardiol, 2017. 70(3):331–​341. 12. Seferović, P.M., et al. The Heart Failure Association Atlas: rationale, objectives, and methods. Eur J Heart Fail, 2020. 22(4):638–​45. 13. Kavalieratos, D., et al. Palliative care in heart failure: rationale, evidence, and future priorities. J Am Coll Cardiol, 2017. 70(15):1919–​30. 14. Gelfman, L.P., et al. The state of the science on integrating palliative care in heart failure. Journal of Palliative Medicine, 2017. 20(6):592–​603. 15. Hill, L., et al. Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper. Eur J Heart Fail, 2020. 22(12):2327–​39. 16. Brännström, M., et al. Unequal care for dying patients in Sweden: a comparative registry study of deaths from heart disease and cancer. Eur J Cardiovasc Nurs, 2012. 11(4):454–​9.

17. Gadoud, A., et al. Palliative care among heart failure patients in primary care: a comparison to cancer patients using English family practice data. PLoS One, 2014. 9(11):e113188. 18. Bakitas, M.A., et al. Effect of an early palliative care telehealth intervention vs usual care on patients with heart failure: the ENABLE CHF-​ PC randomized clinical trial. JAMA Intern Med, 2020. 180(9):1203–​13. 19. Brännström, M. and K. Boman. Effects of person-​centred and integrated chronic heart failure and palliative home care. PREFER: a randomized controlled study. Eur J Heart Fail, 2014. 16(10):1142–​1151. 20. Datla, S., et al. Multi-​disciplinary palliative care is effective in people with symptomatic heart failure: A systematic review and narrative synthesis. Palliat Med, 2019. 33(8):1003–​16. 21. McIlfatrick, S., et al. ‘The importance of planning for the future’: Burden and unmet needs of caregivers’ in advanced heart failure: A mixed methods study. Palliat Med, 2018. 32(4):881–​90. 22. Fitzsimons, D., et al. Inadequate communication exacerbates the support needs of current and bereaved caregivers in advanced heart failure and impedes shared decision-​making. J Cardiovasc Nurs, 2019. 34(1):11–​19. 23. Bruera, E., et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care, 1991. 7(2):6–​9. 24. Zambroski, C.H., et al. Impact of symptom prevalence and symptom burden on quality of life in patients with heart failure. Eur J Cardiovasc Nurs, 2005. 4(3):198–​206. 25. Green, C.P., et al. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol, 2000. 35(5):1245–​55. 26. Spertus, J.A. and P.G. Jones. Development and Validation of a Short Version of the Kansas City Cardiomyopathy Questionnaire. Circ Cardiovasc Qual Outcomes, 2015. 8(5):469–​76. 27. Jaarsma, T., et al. Factors related to self-​care in heart failure patients according to the middle-​range theory of self-​care of chronic illness: a literature update. Curr Heart Fail Rep, 2017. 14(2):71–​77. 28. Riegel, B., et al. Integrating symptoms into the middle-​range theory of self-​care of chronic illness. ANS Adv Nurs Sci, 2019. 42(3):206–​15. 29. Riegel, B., T. Jaarsma, and A. Strömberg. A middle-​range theory of self-​care of chronic illness. ANS Adv Nurs Sci, 2012. 35(3):194–​204. 30. Jaarsma, T., et al. Self-​care of heart failure patients: practical management recommendations from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail, 2021:;23(1):157–​74. 31. McDonagh, T.A., et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J, 2021. 42(36):3599–​726. 32. Crespo-​Leiro, M.G., et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail, 2018. 20(11):1505–​35.

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33. Vitale, C., et al. Heart Failure Association/​ European Society of Cardiology position paper on frailty in patients with heart failure. Eur J Heart Fail, 2019. 21(11):1299–​1305. 34. Hill, L., et al. End of life decision making in patients with an implantable cardioverter defibrillator (ICD): exploring the reality. European Journal of Cardiovascular Nursing, 2014. 13(supplement 1):S9. 35. Lainscak, M., et al. General public awareness of heart failure: results of questionnaire survey during Heart Failure Awareness Day 2011. Arch Med Sci, 2014. 10:355–​360. 36. Stevenson, L.W., et al. Changing preferences for survival after hospitalisation with advanced heart failure. Journal of American College of cardiology, 2008. 52:1702–​8. 37. Lokker, M.E., et al. The prevalence and associated distress of physical and psychological symptoms in patients with advanced heart failure attending a South African medical center. Journal of Cardiovascular Nursing, 2016. 31(4):313–​22. 38. Campbell, R.T., et al. Which patients with heart failure should receive specialist palliative care? Eur J Heart Fail, 2018. 20(9):1338–​47. 39. Kane, P.M., et al. Understanding how a palliative-​specific patient-​ reported outcome intervention works to facilitate patient-​centred care in advanced heart failure: A qualitative study. Palliative Medicine, 2018. 32(1):143–​55. 40. Hjelmfors, L., et al. Using co-​design to develop an intervention to improve communication about the heart failure trajectory and end-​ of-​life care. BMC Palliative care, 2018. 17(1):85. 41. Molzahn, A.E., et al. Life and priorities before death: A narrative inquiry of uncertainty and end of life in people with heart failure and their family members. Eur J Cardiovasc Nurs, 2020. 19(7):629–​37. 42. Hill, L., et al. Patients’ perception of implantable cardioverter defibrillator deactivation at the end of life. Palliat Med 2015;29(4):310–​23. 43. Westerdahl, A.K., et al. Implantable cardioverter-​ defibrillator therapy before death high risk for painful shocks at the end of life. Circulation, 2014. 129:422–​9. 44. Padeletti, L., et al. EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy. Europace, 2010. 12(10):1480–​9. 45. Lampert, R., et al. HRS Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy. Heart Rhythm, 2010. 7(7):1008–​26.

46. Irvine, J., et al. Quality of life in the Canadian Implantable Defibrillator study (CIDS) Am.Heart J., 2002. 144:282–​9. 47. Habibović, M., et al. Posttraumatic stress and anxiety in patients with an implantable cardioverter defibrillator: Trajectories and vulnerability factors. Pacing Clin Electrophysiol., 2017. 40(7):817–​23. 48. Verdoorn, B.P., et al. Palliative medicine and preparedness planning for patients receiving left ventricular assist device as destination therapy-​challenges to measuring impact and change in institutional culture. J Pain Symptom Manage, 2017. 54(2):231–​6. 49. Scott, I.A., et al. Reducing inappropriate polypharmacy: the process of deprescribing. Jama Intern Med, 2015. 175(5):827–​34. 50. Barclay, S., et al. End-​of-​life care conversations with heart failure patients: a systematic literature review and narrative synthesis. Br J Gen Pract, 2011. 61:e49–​e62. 51. De Vleminck, A., et al. Barriers to advance care planning in cancer, heart failure and dementia patients: a focus group study on general practitioners’ views and experiences. PLoS One, 2014. 9(1):e84905. 52. Hjelmfors, L., et al. Communicating prognosis and end of life care to heart failure patients: A survey of heart failure nurses’ perspectives Eur J Cardiovasc Nurs, 2014. 13(2):152–​61. 53. Sobanski, P.Z., et al. Palliative care for people living with heart failure: European Association for Palliative Care Task Force expert position statement. Cardiovasc Res, 2020. 116(1):12–​27. 54. Kelemen, A.M., G. Ruiz, and H. Groninger. Choosing words wisely in communication with patients with heart failure and families. Am J Cardiol, 2016. 117(11):1779–​82. 55. Berkey, F.J., J.P. Wiedemer, and N.D. Vithalani. Delivering bad or life-​ altering news. Am Fam Physician, 2018. 98(2):99–​104. 56. Fallowfield, L. and V. Jenkins. Communicating sad, bad, and difficult news in medicine. Lancet, 2004. 363(9405):312–​9. 57. Cain, C.L., et al. Culture and palliative care: preferences, communication, meaning, and mutual decision making. J Pain Symptom Manage, 2018. 55(5):1408–​19. 58. Brighton, L.J. and K. Bristowe. Communication in palliative care: talking about the end of life, before the end of life. Postgrad Med J, 2016. 92(1090):466–​70. 59. Narayanan, V., B. Bista, and C. Koshy. ‘BREAKS’ protocol for breaking bad news. Indian J Palliat Care, 2010. 16(2):61–​5. 60. Rabow, M.W. and S.J. McPhee. Beyond breaking bad news: how to help patients who suffer. West J Med, 1999. 171(4):260–​3. 61. Baile, W.F., et al. SPIKES-​A six-​step protocol for delivering bad news: application to the patient with cancer. Oncologist, 2000. 5(4):302–​11.

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SECTION 12

Comorbidities and clinical conditions 12.1 Clinical aspects of chronic kidney disease in heart failure 

747

Pieter Martens and Hans-Peter Brunner-La Rocca

12.2 Dyskalaemia in heart failure 

759

João Pedro Ferreira, Kevin Damman, Wilfried Mullens, and Javed Butler

12.3 Chronic lung disease 

773

Josep Masip, Karina Portillo, and Mattia Arrigo

12.4 Ventilatory abnormalities and sleep disordered breathing 

785

Piergiuseppe Agostoni, Elisabetta Salvioni, Maria Rosa Costanzo, and Andrew JS Coats

12.5 Pulmonary hypertension associated with left heart disease 

795

Irene M Lang and Stephan Rosenkranz 12.6 Ventricular arrhythmias and sudden death in heart failure  805 Alessandro Trancuccio, Alessia Chiara Latini, Carlo Arnò, Deni Kukavica, Andrea Mazzanti, and Silvia G Priori

12.7 Management of atrial fibrillation in heart failure 

821

Andreas Metzner, Laura Rottner, Ruben Schleberger, Fabian Moser, and Paulus Kirchhof

12.8 Diabetes, prediabetes, and heart failure 

831

Giuseppe Rosano, Javed Butler, Petar M Seferović, Jelena Seferović, and Francesco Cosentino

12.9 Heart failure in systemic immune-​mediated diseases 

843

Giacomo De Luca, Luca Moroni, Alessandro Tomelleri, Renzo Marcolongo, Lorenzo Dagna, Alida LP Caforio, and Marco Matucci-Cerinic

12.10 Liver and gut dysfunction 

851

Yuri Lopatin and Gianluigi Savarese

12.11 Iron deficiency in heart failure 

857

Ewa A Jankowska, Stefan D Anker, and Piotr Ponikowski

12.12 Cognitive impairment and depression 

865

Wolfram Doehner, Cristiana Vitale, and Mehmet Birhan Yilmaz

12.13 Cancer and heart failure 

871

Dimitrios Farmakis, Alexander Lyon, Rudolf de Boer, and Yuri Belenkov

12.14 Pregnancy and heart failure 

883

Johann Bauersachs, Denise Hilfiker-Kleiner, and Karen Sliwa 12.15 Frailty in heart failure  899 Ewa A Jankowska, Cristiana Vitale, and Dong-Ju Choi

CHAPTER 12.1

Clinical aspects of chronic kidney disease in heart failure Pieter Martens and Hans-​Peter Brunner-​La Rocca Contents Introduction  747 Definition of CKD  747 Prevalence of CKD in relation to heart failure  747 Prognostic value of CKD in heart failure  748 Evaluation of the kidney in patients with heart failure  749 Biomarkers  750 Renal imaging  752

Clinical features of CKD in heart failure  752 Therapeutic approach to CKD  752

Heart failure therapies and their impact on progression of kidney dysfunction  752 Therapeutic consideration in chronic kidney disease  752 Heart failure and end-stage kidney disease  754

Future directions  755 Conclusion  755 Summary and key messages  755 References  755

Introduction Both acutely and chronically, heart failure can cause kidney failure and kidney failure can cause heart failure. In addition, underlying pathologies or pre-​existing comorbidities can result in simultaneous heart failure (HF) and kidney failure. These conditions are summarized by the term cardiorenal syndrome, and can be classified into five different groups. In individual patients, however, it can be difficult to determine if the kidneys or the heart is the (initial) trigger for the cardiorenal syndrome. Importantly, both the heart and the kidney are heavily intertwined, can worsen each other’s prognosis, and potentially lead to under-​utilization of disease modifying therapies.1 Moreover, the concomitant presence of HF and chronic kidney disease (CKD) seems to accelerate the progression of both conditions. Chapter 5.7 mainly focuses on the renal consequences of heart failure (i.e. cardiorenal syndrome types 1 and 2), while this chapter covers the effects of renal failure on the heart (cardiorenal syndrome types 3 and 4).2 This includes both diagnosis and management. In addition, this chapter provides definitions of CKD, the prognostic relevance of CKD in heart failure, assessment of kidney function, the implications of CKD on symptoms and management of heart failure as well as the management of end-​stage renal failure in relation to heart failure.

Definition of CKD In efforts to harmonize the definition of CKD, a previous consensus statement advises defining kidney function and CKD according to the Kidney Disease Improving Global Outcomes (KDIGO) classification (% Figure 12.1.1), which is based on objective measurement of specific kidney measures such as a decrease in glomerular filtration rate (GFR), and the presence of evidence of kidney damage, being most often detected by albuminuria (or abnormal urine sediment, histologic or structural abnormalities).3 While CKD is often used interchangeably for an estimated (e)GFR60mL/​min/​1.73m2 can also have CKD if albuminuria or other markers of kidney damage are present. An additional element of the definition of CKD relates to the chronicity of the findings. By definition, CKD implies the presence of kidney damage (low eGFR or albuminuria) over a time period of more than 3 months.

Prevalence of CKD in relation to heart failure The worldwide prevalence of CKD is estimated to be 697.5 million people (9.1% of the entire population).4 In heart failure patients, the prevalence of CKD is much higher, affecting around 55% of patients, with a similar high prevalence in both heart failure

SECTION 12  

C omorbidit ies and clinical c on di ti on s Albuminuria: description and range

GFR–categories (ml/min/1.73m²)

Definition of CKD-stage according to the 2012 KDIGO guidelines, with colours indicating risk to progression of CKD and guide to intensity of follow-up

G1

Normal or high

≥90

G2

Mildly decreased

60–89

Mild to moderate decreased Moderate to severely decreased

G3a G3b

A1

A2

A3

Normal to mild increase

Moderately increased

Severely increased

30mg/mmol

45–59 30–44

G4

Severely decreased

15–29

G5

Kidney failure

90mL/​min/​1.73m² ◆ Based on creatinine thus sensitive to limitation related to serum creatinine

CKD-​EPIcys 133 × (sCys/0.8)A × 0.996age × B With A and B being dependent on the gender and serum cystatine C value

◆ Based on cystatin C thus sensitive to limitation related to cystatin C

CKD-​EPIcreat-​cys A × (sCr)BC × (sCys/0.8)D × 0.995age × (1.08 if AfricanAmerican) With A,B,C, C being dependent on the gender and serum cystatine C and the serum creatinine value

◆ Based on creatinine thus sensitive to limitation related to serum creatinine ◆ Based on cystatin C thus sensitive to limitation related to cystatin C

Source data from Mullens W, Damman K, Testani JM, et al. Evaluation of kidney function throughout the heart failure trajectory -​a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020 Apr;22(4):584-​603. doi: 10.1002/​ejhf.1697.

in heart failure.37 Proximal nephron sodium and water reabsorption results in solvent drag leading to more urea reabsorption. In addition, collecting ducts reabsorb urea under situations of vasopressin stimulation.38 Therefore, it is not surprising that urea is a powerful predictor of outcomes. Other plasma biomarkers have been investigated to give information about glomerular function, but their precise role in heart failure management remain undefined (% Table 12.1.1).39 Plasma biomarkers of tubular function On a daily basis, the healthy kidneys filter 180 L of ultra-​filtrate containing 1.5 kg of NaCl. However, significantly less than 1% of this NaCl and only a tiny fraction of other solutes are excreted into the urine, which illustrates that small derangements in tubular function might have a substantial impact on volume and

electrolyte homeostasis.40 As the renal tubules consume the most oxygen in the kidney, they are sensitive to hypoxia, which is often present in HF when both renal arterial and venous flow are impeded. Currently there is no consensus on how to assess tubular function, resulting in a large number of investigated biomarkers (% Table 12.1.1).41 Most of these markers can be found in the urine as they are produced or leak out of the tubular cells, while some can also be found in the plasma and are sometimes (partly) filtered or secreted and appear in urine as well. The large majority of plasma tubular injury biomarkers have been investigated in the research setting, and many of these assays are not clinically available for bedside use. The most extensively studied plasma tubular injury biomarker is neutrophil gelatinase-​ associated lipocalin (NGAL).42 In the AKINESIS trial (Acute Kidney Injury N-​gal Evaluation of Symptomatic heart failure Study), plasma

751

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C omorbidit ies and clinical c on di ti on s

NGAL was not superior to plasma creatinine in predicting WRF or adverse in hospital outcome in patients with AHF.43 Therefore plasma biomarkers reflecting tubular function have a limited role in heart failure as yet. Urine biomarkers and diuretic response As one of the main tasks of the renal tubules is to regulate sodium and volume status, which is particularly hampered in heart failure, a more precise assessment of the tubular function might be the evaluation of urine itself.3 Urine is easily sampled and readily available in clinical practice. Due to its direct relation to the nephron, it is exquisitely useful for the evaluation of renal function. Numerous biomarkers can be measured in the urine including markers of glomerular function (e.g. urinary creatinine), glomerular integrity, and podocyte function (e.g. albuminuria) and urinary markers of tubular function and injury (e.g. urinary tubular injury markers, urinary sediment analysis, urinary electrolytes) as reflected in % Table 12.1.1. Most importantly, urine electrolyte concentrations and urinary volume can be used as a functional test to determine the tubular function, which might be of particular interest in heart failure. Indeed, heart failure is characterized by a very early loss in natriuretic responsiveness, which contributes to development of diuretic resistance and ongoing congestion.44 Numerous studies in AHF have suggested that a good diuretic response is associated with better outcome. More recently, the 2021 ESC heart failure guidelines stipulate measuring diuretic response (urinary spot sodium sample and urinary volume) after diuretic administration in AHF.20

Renal imaging Renal ultrasonography allows the measurement of kidney size (and abnormalities), which could be indicative of the chronicity of the disease. A sudden decline in renal function warrants imaging to rule out a urinary tract obstruction. Furthermore, renal artery evaluation should be considered in specific situations, such as severe decline in eGFR following initiation of a RAAS-​blocker. Detailed echocardiography allows the assessment of cardiac filling pressures non-​invasively.45,46 However, in the process towards developing haemodynamic congestion, metrics of renal venous flow might become disrupted before metrics indicative of cardiac filling pressures (e.g. e′, E/​e′, E/​ A-​ratio, systolic pulmonary artery pressure).47 Renal ultrasonography allows the clinician to assess such renal venous flow patterns, which can be measured at the bedside using an abdominal broad-​ band 2.5–​ 5 MHz echo-​ probe. A continuous venous flow-​pattern is associated with low renal venous pressures, while increased venous pressures are associated with a discontinuous renal venous flow signal.48 Examples of different possible measurements are illustrated in % Figure 12.1.4. Interestingly, a discontinuous renal venous flow in a response to volume expansion is associated with a reduced diuretic response independent of the underlying GFR.47 Although additional confirmation studies are warranted, renal venous flow pattern assessment might help to guide decongestive therapy.

Clinical features of CKD in heart failure Chronic kidney disease hardly causes any symptoms unless CKD is at an advanced stage. In addition, these symptoms are rather non-specific, such as fatigue, loss of appetite, or sleeping problems. Mild to moderate CKD cannot be detected clinically and requires blood sampling for diagnosis and to determine renal function (for details, see earlier). Despite this, patients with significant CKD may be more susceptible to fluid retention and electrolyte disturbances. For example, worsening renal function may increase the risk of fluid retention and, as a consequence, cardiac decompensation. In addition, CKD-​related hyperkalaemia may limit the use of evidence-based therapy for HF. Also, the response to diuretic therapy may be reduced in advanced CKD, where isolated thiazide treatment is less effective and the required dose of loop diuretics is often higher. Thus, changes in response to diuretic therapy might indicate deterioration of renal function or increased neurohumoral stimulation of both.

Therapeutic approach to CKD Heart failure therapies and their impact on progression of kidney dysfunction Observational data indicate that the proportion of patients using either a beta-​blocker, ACE-​I/​ARB/​ARNI, or MRA decreases with increasing severity of renal dysfunction.49 Additionally, the proportion of patients taking all three of these agents is only 15% if patients have an eGFR in the range 45–​60 mL/​min/​1.73m² and only 5% if eGFR is in the range 30–​45 mL/​min/​1.73m².49 Yet, many classes of different guideline-​directed medical therapies (GDMT) can safely be initiated in patients with lower GFR. % Table 12.1.3 shows the range of eGFR in which medical therapy can be initiated and the expected effect on eGFR, both acutely and chronically. While some agents lead to an acute drop in eGFR after initiation (% Table 12.1.3), these acute changes are most often only transient and not accompanied with persistent renal damage. Additionally, the reno-​protective effect of ACE-​I and ARB are well known in patients with CKD. Furthermore, in heart failure specifically, the classes of ARNI and SGLT2i have been shown to reduce the annual decline in eGFR slope (most pronounced for SGLT2i). None of the RCTs with the agents shown in % Table 12.1.3 found any statistical interaction between the presence of CKD and the treatment effect on the primary endpoint. Therefore, in terms of relative risk reduction, these agents are equally effective in patients with CKD. Because patients with CKD actually are at the highest baseline risk to develop cardiovascular death or heart failure hospitalization, the absolute risk reduction effect is even more pronounced in HF patients with CKD.

Therapeutic consideration in chronic kidney disease As indicated above, CKD shares many similarities with chronic heart failure, including chronic low-​ grade inflammation, and hence, the two conditions may share common treatment strategies. This is nicely demonstrated by the positive effects of SGLT2-​inhibition in heart failure and in CKD independently of other conditions. Also, the impact of associated conditions shows

chapter 12.1  

Clinica l aspects of chron i c k i dn ey di sease i n hea rt fa i lure (b) Tips for assessment

(a)

-Preference for right kidney (position patient in semi-supine left-side position) - Use dedicated abdominal (2.5–5MHz) probe -Ask patients to hold breath during registration - Place a pulse-wave doppler signal in an interlobar vessel located using colour doppler -Shift baseline of doppler signal between +and –20 cm/s

(c) Continuous venous flow pattern

(d) Measurements on flow signal (1) Resistance Index (RI) Max art. flow-Min art. flow

Rl =

Max art. flow Venous impedance index (VII) Max ven. flow-Min ven. flow

VII =

(e) Discontinuous venous flow pattern

Max ven flow

(f) Measurements on flow signal (2) Percent of cardiac cycle discontinuous venous flow

=

(g) Pattern of discontinuous venous flow

Time 1–Time 2 Time 1

X 100

(h) Pattern of the flow signal

1. Discontinuous flow pattern with biphasic signal (two red arrows) 2. Discontinuous flow pattern with monohasic signal (one blue arrow)

Figure 12.1.4  Methodology and examples of intra-​renal venous flow evaluation. Source data from Mullens W, Damman K, Testani JM, et al. Evaluation of kidney function throughout the heart failure trajectory -​a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020 Apr;22(4):584–​603. doi: 10.1002/​ejhf.1697.

significant overlap. An important example is iron deficiency, which is highly prevalent in both CKD and chronic heart failure. Not surprisingly, the risk of iron deficiency increases in the presence of both diseases, depending on the severity of each of them. The value of intravenous iron therapy has been established in patients with HFrEF, although supporting studies were of small to medium size

only and with limited follow-​up.20 Subgroup analysis suggests that the beneficial effect may be particularly present in HFrEF patients with CKD. Intravenous iron supplementation might even improve renal function. In contrast, the evidence of iron supplementation in isolated CKD is poor and limited to end-​stage CKD only. Still, a recent study suggests that more aggressive iron replacement is

753

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C omorbidit ies and clinical c on di ti on s

Table 12.1.3  Initiation of HF drugs in relation to baseline CKD-​status Drug

Evidence according to baseline eGFR enrolment criteria

Acute drop GFR

Impact on GFR slope CKD treatment in HF trial interaction

Treatment effect with CKD

Yes

No (beneficial effect No of around 1-​2mL/​min/​ 1.73m² per year in CKD trials)

Relative benefit: ~ Absolute benefit: ↑

Beta-​blockers

No

No

Yes (potentially higher Relative benefit: ~ RRR in MERIT-​HF Absolute benefit: ↑ but some conflicting results)

MRA

Yes

No

No

Relative benefit: ~ Absolute benefit: ↑

ARNI

Yes

Yes (around 0.5 mL/​ min/​1.73 m² per year)

No

Relative benefit: ~ Absolute benefit: ↑

Yes

Yes (around 1-​2 mL/​ min/​1.73 m² per year)

No

Relative benefit: ~ Absolute benefit: ↑

Ivabradine

No

No

No

Relative benefit: ~ Absolute benefit: ↑

Vericiguat

No

No

No

Relative benefit: ~ Absolute benefit: ↑

Omecamtiv mecarbil

No

No

No

Relative benefit: ~ Absolute benefit: ↑

ESRD ACE-​I/​ARB

SGLT2-​i

15–​30

Moderate evidence if dialysis, weak evidence if not on dialysis

>20

30–​60

>60

Key: Dark grey =​strong evidence, mid-grey =​moderate evidence, light grey =​no data, CKD, chronic kidney disease (eGFR < 60 mL/​min), GFR, glomerular filtration rate. RRR, relative risk reduction. Drug abbreviations as in main text.

associated with fewer cardiovascular events.50 Effects of isolated treatment of iron deficiency in CKD are, however, unknown as studies on iron replacement included erythropoiesis-​stimulating agent use for treatment of CKD related anaemia, which is standard in CKD. In contrast, erythropoiesis-​stimulating agent use is not indicated in chronic heart failure and mild to moderate anaemia as it did not improve outcome but increased the risk of thromboembolic events, as long as there is no other indication for its use.51 Anaemia related to (end-​stage) CKD could be such an indication, although the effect of erythropoiesis-​stimulating agent has not been specifically investigated in CKD patients having heart failure. Another important aspect is that CKD may limit heart failure therapy. This does not only apply to end-​stage CKD, as discussed below. In particular, hyperkalaemia may limit the use of inhibitors of RAAS including ARNI.20 Potassium-​binding drugs (patiromer and sodium zirconium cyclosilicate; others with more side-​effects) have been introduced, which may allow initiation or up-​titration of RAAS-​inhibition even in patients susceptible to hyperkalaemia. Smaller studies in patients with CKD and heart failure showed that the use of such potassium-​binding agents is safe and well tolerated (mainly patiromer). Although pathophysiologically convincing, the approach of using evidence-​based therapy in combination with potassium-​binding agents to enable this therapy has not yet been proven to improve clinical outcomes as compared to the use of less RAAS-​inhibition only. Accordingly, recent guidelines do not make clear recommendations about their use.20 An outcome study using patiromer has been conducted

(NCT03888066), although the COVID pandemic required a reduction in the number of included patients and the adjustment of the primary end point, significantly limiting the value of this study.52 With the use of patiromer, which was well tolerated, average serum potassium was lower, and the number of patients with serum potassium of >5.5 mmol/​L significantly decreased from 19.4% to 13.9%, despite higher concurrent use of MRA and RAAS. However, there was no effect at all on number of hospitalizations or mortality.52

Heart failure and end-​stage kidney disease Evidence for all drugs in patients with eGFR 5.5 mmol/​L were associated with a 1.7-​fold increase in the relative risk of death.30 In a post-​hoc analysis from the RALES trial in patients with severe HFrEF, hyperkalaemia (> 5.5 mmol/​ L) was associated with increased risk of death.57 The benefit with spironolactone was seen even when K+​ levels reached 6.0 mmol/​ L. Similar findings were reported from the EMPHASIS-​HF trial in patients with mildly symptomatic HFrEF, where eplerenone retained its survival benefits without interaction with the baseline K+​ levels.58 In the PARADIGM-​HF trial in patients with HFrEF trial fewer than 18% of the patients had K+​ levels > 5.5 mmol/​L throughout the follow-​up with no differences between the sacubitril/​valsartan and enalapril groups. Potassium levels > 6.0 mmol/​L occurred in 4% of the patients treated with sacubitril/​ valsartan and in 6% of the patients treated with enalapril, a difference that was statistically significant.32 Moreover, in patients taking an MRA the hyperkalaemia risk was attenuated by sacubitril/​valsartan.59 In the PIONEER-​ HF trial in patients with acute HF, the hyperkalaemia rates were similar to PARADIGM-​HF and were not statistically different between groups.60 In the PARAGON-​ HF trial in HFpEF, fewer than 16% of the patients had K+​ levels > 5.5 mmol/​L throughout the follow-​up. Potassium levels > 6.0 mmol/​L occurred in 3% of the patients treated with sacubitril/​ valsartan and in 4% of the patients treated with valsartan.34 Moreover, in patients taking an MRA, the hyperkalaemia risk was similar in the sacubitril/​valsartan and the valsartan groups. Even with normokalaemia, CKD is associated with sub-​optimal use of RAASi. In the RALES, EMPHASIS-​HF, and PARADIGM trials, there was no significant interaction between the treatment effect and baseline creatinine levels or CKD status (defined as eGFR < 60 mL/​min/​1.73m2). HF trials have mainly excluded patients with eGFR 15% of the average ventilation at rest. According to the American Heart Association, the EOV definition of Corrà et al. is the most reliable. Regardless of its definition, EOV can last for the entire exercise period or can end before exercise finishes. The reasons behind this phenomenon are unknown, although reduction of transit time, that is, the time needed to convey the blood gas signal from the alveoli to the chemoreceptor, seems to play a major role. Of note, in patients being treated with a left ventricular assist device (LVAD), an increase in LVAD output reduces and even cancels EOV.13 Moreover, Schmid et al.13a reported that in 50% of patients with EOV ending during exercise the VO2–​work relationship slope increases, showing that EOV increases the work of breathing. Depending on the definition applied, the prevalence of EOV varies as shown by Ingle et al.14 Regardless of the definition, EOV is more frequently observed in patients with severe heart failure and it has a strong prognostic power.15,16 Specifically, Cornelis et al.17 found a four-​fold greater risk of adverse cardiovascular events in heart failure EOV-​positive patients compared to their counterparts without EOV. In an analysis of the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score data set, Rovai et al.18 found that EOV is associated with lower survival of heart failure patients with reduced or mid-​range left ventricular ejection fraction in a 2-​year follow-​up, regardless of

age and sex (% Figure 12.4.5). Of note, the time frame of the cardiovascular risk increase between reduced and mid-​range ejection fraction patients was different and delayed by 18 months in mid-​range patients (% Figure 12.4.6). EOV is also a target of treatment. Indeed, it can be cancelled when a further respiratory stimulus is applied, such as an external dead volume or when breathing with a hypercapnic air mixture.19,20 Similarly, acetazolamide treatment reduces EOV.19 However, EOV reduction, or even disappearance, obtained via added dead space or with acetazolamide treatment, was associated with a reduction in exercise performance.19 In contrast, when severe heart failure is treated as with levosimendan, EOV disappearance is associated with exercise performance improvement.

Sleep breathing disorders The study of ventilation during sleep has a pivotal role in the analysis of respiratory abnormalities in heart failure. There are two major forms of sleep-​related breathing abnormalities seen in heart failure: central sleep apnoea (CSA) and obstructive sleep apnoea (OSA); a combination of the two can also be observed, the so-​called mixed sleep apnoea. CSA is characterized by the absence of respiratory movements due to fluctuation of the central respiratory drive. CSA occurs when PaCO2 falls below the apnoeic threshold, followed by hyperpnoea when PaCO2 rises again. A similar phenomenon has been observed at high altitude, particularly in the male sex, and it is prevented by acetazolamide.21 OSA derives from the collapse of the pharynx and upper airways leading to thoracic movements without effective air flow. The reported cause of OSA in heart failure is a shift of fluid from the legs and abdomen to central structures, including the upper airways

787

Flow, L/S

SECTION 12  

C omorbidit ies and clinical c on di ti on s

4

4

2

2

0

0

–2

–2

–4

–4 7

–10

Ptp , cm H2 O

788

5 Volume, L

3

8 –10

0

0

10

10

20

20

30

30

6

4

2

Volume, L

Figure 12.4.3  Composite tidal flow–​volume and transpulmonary pressure

(Ptp)–​volume loops at rest (dashed lines), at 40% of maximal ventilation (thin solid lines), and at maximum exercise (thick solid lines) in typical chronic heart failure (left) and normal (right) subjects. The 2 oblique lines on flow-​volume loops are partial forced expiratory flows recorded at rest (dotted line) and at maximum exercise (dashed line). Total lung capacity is at the interception of x-​and y-​axes on the flow–​volume loops. Chronic heart failure subject: at rest, EFR, i.e. the difference in flow between near end tidal expiration and forced flow at the same absolute volume, is much less than in the normal individual because of the lower functional residual capacity (FRC). At the beginning of exercise, FRC decreases and Ptp (PtpFRC) becomes slightly negative. Tidal expiratory flow near FRC encroaches on forced expiratory flow, thus suggesting initial occurrence of expiratory flow limitation (EFL). Then, FRC tends to increase above resting value at the end of exercise whereas PtpFRC becomes more negative. The increase in PtpFRC is not associated with increase in flow, thus suggesting further EFL. Forced expiratory flow at maximum exercise (dashed oblique line) is similar to resting conditions (dotted oblique line), which is consistent with lack of bronchodilatation. Normal subject: FRC decreases early during exercise and remains low through the end of exercise. PtpFRC becomes slightly negative over the second half of tidal expiration. EFL would have likely occurred at maximum exercise if forced expiratory flow had not increased. Reproduced from Agostoni P, Pellegrino R, Conca C, Rodarte JR, Brusasco V. Exercise hyperpnea in chronic heart failure: relationships to lung stiffness and expiratory flow limitation. J Appl Physiol (1985). 2002 Apr;92(4):1409-​16. doi: 10.1152/​ japplphysiol.00724.2001 with permission from American Physiological Society.

when the patient lies down to rest. In heart failure patients treated with LVADs, an increase of cardiac output is associated with a relevant reduction of CSAs but an increase of OSAs. 22 Mixed apnoea starts as a CSA episode and ends with OSA if airway collapse ensues. % Figure 12.4.7 reports an example of OSA, CSA, mixed apnoea, and hypopnoea. Cheyne–​ Stokes respiration is a type of periodic breathing characterized by hyperpnoea followed by hypopnoea or apnoea due to CSA (% Figure 12.4.8). It

is classically more regularly oscillating (with a periodicity of between 30 and 120 seconds) compared to irregularly spaced non-​ Cheyne–​Stokes forms of apnoeic CSA. Ventilation during sleep can be measured by different technologies at different levels, starting from the simple transcutaneous haemoglobin oxygen saturation and heart rate monitoring (type IV). The gold standard for sleep disease evaluation is overnight full polysomnography, which requires simultaneous and continuous monitoring of electroencephalogram, eye movements, electromyogram of the chin, ECG, body position, haemoglobin oxygen saturation, and oronasal flow as well as direct video view of patients during sleep (type I). However, type I polysomnography requires patients to be hospitalized, is extremely expensive, and does not allow recording of sleeping patterns in the place where the patient is more comfortable, for example, in their home. Type II polysomnography is similar to full polysomnography but without video recording, being continuous monitoring of physiological parameters performed outside the hospital. In contrast to type I, type II does not require the presence of a technician and can performed using portable devices. Type III is like type II but without electroencephalogram signals. At present, a type III recording is also obtainable by use of a wearable transducer based on the simultaneous recordings of at least three thoracic movements.23 In such a case, apnoea is defined as the absence of movement (central apnoea) or as the presence of contrasting movements whose sum is equal to zero (obstructive apnoea). Information on the quality of sleep can also be obtained in patients fitted with pacemakers by intrathoracic impendence changes during sleep. The most well-​known parameter to assess ventilation during sleep is the apnoea-​hypopnoea index (AHI), the number of episodes per hour. The diagnosis of sleep apnoea in heart failure requires at least type III monitoring to identify OSA and CSA and to quantify AHI. A diagnosis of OSA is made with an AHI > 15 or > 5 and concomitant presence of sleeplessness, non-​restorative sleep, fatigue, insomnia, and gasping or snoring. CSA is diagnosed when central apnoeas are predominant. The severity of sleep disorders is commonly defined by AHI frequency as light (AHI between 5 and 14 events per hour), moderate (AHI between 15 and 29), and severe in case of AHI >30. OSA can be observed even in healthy individuals with a greater prevalence in the male sex, while CSA is rarely reported.24 Many diseases are associated with OSA and CSA (% Box 12.4.1). Of note, CSA and OSA can both be frequently observed in heart failure patients and particularly in those with severe heart failure, where CSA begins to be the dominant form. Consequently, the frequency of sleep disorders varies in different reports from 28% to 82% of cases.25 Sleep disorders have been associated with a worsened heart failure prognosis. Hanly et al.26 reported a mortality of 86% in heart failure patients with Cheyne–​Stokes respiration vs 56% in patients without this type of respiratory pattern. Moreover, Cheyne–​Stokes respiration is observed combined with exercise-​induced oscillatory ventilation.27–​30 Indeed, the presence of sleep disorders, regardless OSA or CSA pattern, is associated with transient episodes of hypoxia which can lead to arrhythmias

chapter 12.4  

Ventil atory a b n or m a l i ti es a n d sl eep di s ordered b re at h i n g Kremser et al.

60

Corrà et al.

VE (L/min)

50 Leite et al./Sun et al. 40

Ben Dov et al.

20

10 Rest

0

50

100

150

200

250 300

350 400 Time (s)

450

500

550 600

650

Figure 12.4.4  EOV-​positive ventilatory pattern.

CPET, cardiorespiratory exercise test; EOV, exercise oscillatory ventilation; VE, minute ventilation; SD, standard deviation. *Visible oscillation in three or more CPET parameters.

Survival (CV death + HT + LVAD)

1.00

0.95 EOV – 0.90 EOV + 0.85

0.80 0

Follow-up (days)

0

365

730

Patients at risk EOV +

968

851

703

Patients at risk EOV –

4753

4074

3412

200

400 Follow-up (days)

600

800

Figure 12.4.5  Survival and presence of exercise oscillatory ventilation (EOV) in the total population. Kaplan–​Meier survival curves of study endpoint

(cardiovascular (CV) death, urgent heart transplant (HT), or left ventricular assist device (LVAD) implantation) according to the presence or absence of EOV (EOV+​and EOV−) in the entire study population at 2-​year follow-​up (p =​0.000; χ2 =​34.0). Reproduced from Rovai S, Corrà U, Piepoli M, Vignati C, Salvioni E, Bonomi A, Mattavelli I, Arcari L, Scardovi AB, Perrone Filardi P, Lagioia R, Paolillo S, Magrì D, Limongelli G, Metra M, Senni M, Scrutinio D, Raimondo R, Emdin M, Lombardi C, Cattadori G, et al; MECKI Score Research Group (see Appendix 1). Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-​range ejection fraction. Eur J Heart Fail. 2019 Dec;21(12):1586-​1595. doi: 10.1002/​ejhf.1595 with permission from John Wiley and Sons.

including atrial fibrillation as well as fatal arrhythmias, as shown by the increased nocturnal discharge rate of implantable defibrillators.31 Transient hypoxia is also associated with myocardial perfusion abnormalities, leading to sympathetic stimulation and myocardial ischaemia, both possible causes of myocyte apoptosis and necrosis, adrenoreceptor down regulation, and desensitization. Accordingly, polysomnography is suggested in cases of paroxysmal or recurrent atrial fibrillation, refractory hypertension,

unanticipated pulmonary hypertension with and without right ventricular failure, malignant arrhythmias, or obesity.25 Some pathophysiological aspects can help differentiate OSA from CSA. First of all, OSA is associated with negative intrathoracic pressures developing due to the respiratory muscles being stimulated and contracting against a closed airway. These muscles are not active in the apnoeic phases in CSA, and hence intrathoracic pressures do not fall. Secondly, heart failure CSA

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1.00 HFmrEF EOV –

Survival (CV death + HT + LVAD)

790

p = 0.020; χ2 = 5.4

0.95

HFmrEF EOV + HFrEF EOV –

p = 0.280; χ2 = 1.17

0.90

0.85

0.80

Follow-up (days)

0

365

730

Patients at risk HFrEF EOV +

765

666

540

Patients at risk HFrEF EOV –

3717

3211

2689

Patients at risk HFmrEF EOV +

203

185

163

Patients at risk HFmrEF EOV –

1036

863

723

0

p = 0.000; χ2 = 31.1

p = 0.000; χ2 = 9.9

p = 0.000; χ2 = 75.9 p = 0.000; χ2 = 29.7

HFrEF EOV +

200

400 Follow-up (days)

600

800

Figure 12.4.6  Surival and presence of exercise oscillatory ventilation (EOV) in patients with heart failure and reduced ejection fraction (HFrEF) and in patients

with heart failure and mid-​range ejection fraction (HFmrEF). Kaplan–​Meier survival curves of study endpoint (cardiovascular (CV) death, urgent heart transplant (HT), or left ventricular assist device (LVAD) implantation) stratified according to the presence or absence of EOV (EOV+​and EOV−) in patients with HFrEF and in patients with HFmrEF. Comparison between groups (HFmrEF EOV− vs HFmrEF EOV+​: p =​0.020, χ2 =​5.4; HFmrEF EOV− vs HFrEF EOV−: p =​0.000, χ2 =​31.1; HFmrEF EOV− vs. HFrEF EOV+​: p =​0.000, χ2 =​75.9; HFmrEF EOV+​vs HFrEF EOV−: p =​0.280, χ2 =​1.17; HFmrEF EOV+​vs. HFrEF EOV+​: p =​0.000, χ2 =​29.7; HFrEF EOV− vs. HFrEF EOV+​: p =​0.000, χ2 =​9.9). Reproduced from Rovai S, Corrà U, Piepoli M, Vignati C, Salvioni E, Bonomi A, Mattavelli I, Arcari L, Scardovi AB, Perrone Filardi P, Lagioia R, Paolillo S, Magrì D, Limongelli G, Metra M, Senni M, Scrutinio D, Raimondo R, Emdin M, Lombardi C, Cattadori G, et al; MECKI Score Research Group (see Appendix 1). Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-​range ejection fraction. Eur J Heart Fail. 2019 Dec;21(12):1586-​1595. doi: 10.1002/​ejhf.1595 with permission from John Wiley and Sons.

patients have a greater sympathetic stimulation, as shown by the high urinary and plasma norepinephrine levels.32 Thirdly, CSA is sometimes associated with heart rate oscillations, an event not observed with OSA. The combined oscillation of ventilation and heart rate has likely a further negative prognostic effect. Fourthly, CSA can be observed in severe heart failure patients during daytime in awake subjects which is not the case for OSA.33 In patients with severe heart failure, as well as at high altitude as described at the end of the nineteenth century by Angelo Mosso at Capanna Regina Margherita on top of Monte Rosa (4600 mt, Italian-​Swiss Alps), Cheyne–​Stokes respiration has also been found during daytime. This event is, however, rarer than

Apnoea obstructive (13.67s)

59s)

Apnoea central (29.16s)

night-​time Cheyne–​Stokes respiration likely due to a higher sympathetic activity. Again, daytime Cheyne–​Stokes ventilation is associated with a poor prognosis. Optimization of heart failure treatment is the first-​line treatment for both OSA and CSA in these patients. Severe OSA should be treated by continuous positive airway pressure (CPAP) which, in addition to clinical improvements in sleep quality, may be associated with positive effects on cardiac function (increases in left ventricular ejection fraction) and reductions of blood pressure, heart rate, and sympathetic tone.34–​36 A positive effect of OSA treatment by CPAP on heart failure mortality has been suggested, but no randomized double-​blind studies are at present Apnoea mixed (28.01s)

Figure 12.4.7  Example of obstructive sleep apnoea, central sleep apnoea, mixed apnoea, and hypopnoea.

Hypopnoea (44.22s)

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Apnoea central (26.20s)

Apnoea central (24.70s)

No effort No effort

No effort No effort

6.33s) [6]

Desaturation (39.67s) [6]

Apnoea central (31.60s)

Apnoea central (27.70s)

No effort No effort

Desaturation (38.67s) [5]

No effort No effort

Desaturation (37.00s) [7]

Desatu

Figure 12.4.8  Example of Cheyne–​Stokes respiration.

Box 12.4.1  Clinical characteristics of obstructive and central apnoea Disease associated with obstructive sleep apnoea ◆ Unexplained daytime somnolence ◆ Abnormal sleep noises (gasping, choking, loud apnoeas) with respiratory effort witnessed by bed partners ◆ Fatigue ◆ Resistant arterial hypertension ◆ Cardiac rhythm abnormalities ◆ Obesity/​high waist and neck circumference ◆ Narrow oropharynx ◆ Heart failure symptoms, in particular peripheral oedema Disease associated with central sleep apnoea ◆ Less commonly daytime somnolence ◆ Repetitive sleep apnoeas without abnormal noises, and without respiratory effort ◆ Poor quality of sleep ◆ Possible association with periodic breathing during exercise ◆ Cardiac rhythm abnormalities ◆ Heart failure symptoms, in particular peripheral oedema Source data from Parati, G., C. Lombardi, F. Castagna, P. Mattaliano, P.P. Filardi, P. Agostoni, et al. Heart failure and sleep disorders. Nat Rev Cardiol, 2016;13:389–​403.

available.37,38 The SAVE trial, the largest trial (2717 patients) of CPAP in OSA patients with cardiovascular disease (but excluding those with NYHA (New York Heart Association) class III or IV heart failure), reported no improvement in the primary composite end point of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack after a mean follow-​up of 3.7 years. The trial reported 17.0% events in the treatment group vs 15.4% in the control group, hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; p =​0.34). CPAP did, however, significantly reduce snoring and daytime sleepiness and improved health-​related quality of life and mood.39 Pharmacological treatment of CSA has been suggested using acetazolamide and theophylline. The rationale for CSA and EOV treatment with acetazolamide is strong, but the long-​term effects are unclear.19,25 In particular, acetazolamide may be also useful in severe heart failure, not only for CSA treatment but also when a combined diuretic treatment is needed. In contrast, the arrhythmogenic action of theophylline precludes its use in heart failure, although a reduction of CSA has been reported.40 The SERVE-​HF trial used positive pressure airway masks to treat heart failure with reduced ejection fraction (HFrEF) patients with CSA, and this led to an excess in cardiovascular mortality so this form of therapy is contra-​indicated in this setting.41 An alternative of an implantable phrenic nerve stimulation device has been shown to improve sleep quality and to reduce central apnoeas and the AHI in patients with CSA.42 In a subset of these patients with heart

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failure (n =​96), improvements were reported in sleep metrics, Epworth Sleepiness Scale, patient global assessment Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters. In addition the 6-​month rate of heart failure hospitalization was 4.7% in treatment patients and 17.0% in control patients, although the trials to date have been too small to prove or disprove any effect on such major outcomes.43 Thus guidelines advise including a formal sleep study to determine the type of sleep apnoea in any HFrEF patient prior to commencing therapy and if the sleep apnoea is predominantly CSA they advise against the use of positive pressure airway masks but suggest phrenic nerve stimulation as an alternative therapy for these patients to improve symptoms.

References 1. Guazzi, M., J. Myers, M.A. Peberdy, D. Bensimhon, P. Chase, and R. Arena. Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights. Eur Heart J, 2008; 29: 2751–​2759. 2. Arena, R., J. Myers, J. Abella, et al. Development of a ventilatory classification system in patients with heart failure. Circulation, 2007; 115: 2410–​2417. 3. Wasserman, K., Y.Y. Zhang, A. Gitt, et al. Lung function and exercise gas exchange in chronic heart failure. Circulation, 1997; 96: 2221–​2227. 4. Contini, M., A. Apostolo, G. Cattadori, et al. Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. Int J Cardiol, 2013; 168: 2134–​2140. 5. Mutlu, G.M. and J.I. Sznajder. Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol, 2005; 289: L685–​695. 6. Agostoni, P., R. Pellegrino, C. Conca, J.R. Rodarte, and V. Brusasco. Exercise hyperpnea in chronic heart failure: relationships to lung stiffness and expiratory flow limitation. J Appl Physiol (1985), 2002; 92: 1409–​1416. 7. Salvioni, E., U. Corra, M. Piepoli, et al. Gender and age normalization and ventilation efficiency during exercise in heart failure with reduced ejection fraction. ESC Heart Fail, 2020; 7: 371–​380. 8. Ben-​ Dov, I., K.E. Sietsema, R. Casaburi, and K. Wasserman. Evidence that circulatory oscillations accompany ventilatory oscillations during exercise in patients with heart failure. Am Rev Respir Dis, 1992; 145: 776–​781. 9. Corrà, U., A. Giordano, E. Bosimini, et al. Oscillatory ventilation during exercise in patients with chronic heart failure: Clinical correlates and prognostic implications. Chest, 2002; 121: 1572–​1580. 10. Kremser, C.B., M.F. O’Toole, and A.R. Leff. Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy. Am J Cardiol, 1987; 59: 900–​905. 11. Leite, J.J., A.J. Mansur, H.F.G. De Freitas, et al. Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation. J Am Coll Cardiol, 2003; 41: 2175–​2181. 12. Sun, X.G., J.E. Hansen, J.F. Beshai, and K. Wasserman. Oscillatory breathing and exercise gas exchange abnormalities prognosticate early mortality and morbidity in heart failure. J Am Coll Cardiol, 2010; 55: 1814–​1823. 13. Vignati, C., A. Apostolo, G. Cattadori, et al. Lvad pump speed increase is associated with increased peak exercise cardiac output and vo2, postponed anaerobic threshold and improved ventilatory efficiency. Int J Cardiol, 2017; 230: 28–​32. 13a. Schmid, J.P., A. Apostolo, L. Antonioli, G. Cattadori, M. Zurek, M. Contini, P. Agostoni. Influence of exertional oscillatory ventilation

on exercise performance in heart failure. Eur J Cardiovasc Prev Rehabil. 2008; 15: 688–​692. 14. Ingle, L., A. Isted, K.K. Witte, J.G. Cleland, and A.L. Clark. Impact of different diagnostic criteria on the prevalence and prognostic significance of exertional oscillatory ventilation in patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil, 2009; 16: 451–​456. 15. Agostoni, P. and E. Salvioni. Exertional periodic breathing in heart failure: Mechanisms and clinical implications. Clin Chest Med, 2019; 40: 449–​457. 16. Agostoni, P., U. Corra, and M. Emdin. Periodic breathing during incremental exercise. Ann Am Thorac Soc, 2017; 14: S116–​S122. 17. Cornelis, J., J. Taeymans, W. Hens, P. Beckers, C. Vrints, and D. Vissers. Prognostic respiratory parameters in heart failure patients with and without exercise oscillatory ventilation –​a systematic review and descriptive meta-​analysis. Int J Cardiol, 2015; 182: 476–​486. 18. Rovai, S., U. Corra, M. Piepoli, et al. Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-​range ejection fraction. Eur J Heart Fail, 2019; 21: 1586–​1595. 19. Apostolo, A., P. Agostoni, M. Contini, L. Antonioli, and E.R. Swenson. Acetazolamide and inhaled carbon dioxide reduce periodic breathing during exercise in patients with chronic heart failure. J Card Fail, 2014; 20: 278–​288. 20. Gargiulo, P., A. Apostolo, P. Perrone-​Filardi, S. Sciomer, P. Palange, and P. Agostoni. A non invasive estimate of dead space ventilation from exercise measurements. PLoS One, 2014; 9: e87395. 21. Caravita, S., A. Faini, C. Lombardi, et al. Sex and acetazolamide effects on chemoreflex and periodic breathing during sleep at altitude. Chest, 2015; 147: 120–​131. 22. Apostolo, A., S. Paolillo, M. Contini, et al. Comprehensive effects of left ventricular assist device speed changes on alveolar gas exchange, sleep ventilatory pattern, and exercise performance. J Heart Lung Transplant, 2018; 37: 1361–​1371. 23. Contini, M., A. Sarmento, P. Gugliandolo, et al. Validation of a new wearable device for type 3 sleep test without flowmeter. PLoS One, 2021; 16: e0249470. 24. Levy, P., M. Kohler, W.T. McNicholas, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers, 2015; 1: 15015. 25. Parati, G., C. Lombardi, F. Castagna, et al. Heart failure and sleep disorders. Nat Rev Cardiol, 2016; 13: 389–​403. 26. Hanly, P.J. and N.S. Zuberi-​Khokhar. Increased mortality associated with Cheyne–​Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med, 1996; 153: 272–​276. 27. Oldenburg, O., B. Lamp, L. Faber, H. Teschler, D. Horstkotte, and V. Topfer. Sleep-​disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail, 2007; 9: 251–​257. 28. Corra, U., M. Pistono, A. Mezzani, et al. Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence. Circulation, 2006; 113: 44–​50. 29. Meguro, K., H. Adachi, S. Oshima, K. Taniguchi, and R. Nagai. Exercise tolerance, exercise hyperpnea and central chemosensitivity to carbon dioxide in sleep apnea syndrome in heart failure patients. Circ J, 2005; 69: 695–​699. 30. Lanfranchi, P.A., A. Braghiroli, E. Bosimini, et al. Prognostic value of nocturnal Cheyne–​Stokes respiration in chronic heart failure. Circulation, 1999; 99: 1435–​1440. 31. Bitter, T., N. Westerheide, C. Prinz, et al. Cheyne-​Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-​ defibrillator therapies in patients with congestive heart failure. Eur Heart J, 2011; 32: 61–​74. 32. Naughton, M.T., D.C. Benard, P.P. Liu, R. Rutherford, F. Rankin, and T.D. Bradley. Effects of nasal CPAP on sympathetic activity in

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patients with heart failure and central sleep apnea. Am J Respir Crit Care Med, 1995; 152: 473–​479. 33. Brack, T., I. Thuer, C.F. Clarenbach, et al. Daytime Cheyne–​Stokes respiration in ambulatory patients with severe congestive heart failure is associated with increased mortality. Chest, 2007; 132: 1463–​1471. 34. Franklin, K.A., J.B. Nilsson, C. Sahlin, and U. Naslund. Sleep apnoea and nocturnal angina. Lancet, 1995; 345: 1085–​1087. 35. Kaneko, Y., J.S. Floras, K. Usui, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med, 2003; 348: 1233–​1241. 36. Mansfield, D.R., N.C. Gollogly, D.M. Kaye, M. Richardson, P. Bergin, and M.T. Naughton. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med, 2004; 169: 361–​366. 37. Wang, H., J.D. Parker, G.E. Newton, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol, 2007; 49: 1625–​1631.

38. Kasai, T., K. Narui, T. Dohi, et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest, 2008; 133: 690–​696. 39. R.D. McEvoy, N.A. Antic, E. Heeley, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med, 2016; 375: 919–​931. 40. Javaheri, S., T.J. Parker, L. Wexler, J.D. Liming, P. Lindower, and G.A. Roselle. Effect of theophylline on sleep-​disordered breathing in heart failure. N Engl J Med, 1996; 335: 562–​567. 41. Cowie, M.R., H. Woehrle, K. Wegscheider, et al. Adaptive servo-​ ventilation for central sleep apnea in systolic heart failure. N Engl J Med, 2015; 373: 1095–​1105. 42. Costanzo, M.R., P. Ponikowski, S. Javaheri, et al. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet, 2016; 388: 974–​982. 43. Costanzo, M.R., P. Ponikowski, A. Coats et al. Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. Eur J Heart Fail 2018; 20: 1746–​1754.

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CHAPTER 12.5

Pulmonary hypertension associated with left heart disease Irene M Lang and Stephan Rosenkranz

Contents Introduction  795 Prevalence and definition  795

Prevalence of PH-LHD  795 Definition and classification of PH-LHD  796

Diagnosis  797

Non-invasive diagnosis  797 The diagnostic dilemma of PH-LHD  797 Haemodynamic variables to dissect pulmonary hypertension due to left heart disease subsets: with or without pulmonary vascular disease  798 Isolated post-capillary and combined pre and post-capillary pulmonary hypertension – are they clinical phenotypes?  799

Management of PH-LHD  800

Drug treatment of PH-LHD  800 Management of tricuspid regurgitation  800

Future directions  801 Summary and key messages  801 References  801

Introduction The commonest cause of pulmonary hypertension (PH) is left heart disease (LHD). Significant advances have occurred over the past five years in the area of pre-​capillary pulmonary hypertension (PAH) with positive findings in genetics, proteomics and metabolomics, but the understanding of PH-​LHD has remained poor. PH in heart failure with preserved ejection fraction (PH-​HFpEF) represents the most complex situation because it is usually misdiagnosed as Group 1 PH and treated as Group 1 PH. In a large cohort referred for invasive haemodynamic assessment, PH-​HFpEF was very common (46.1% of the population in1). The discussion of PH-​LHD is important within this ESC textbook because PH is an important prognostic indicator of heart failure (% Figure 12.5.1). PH-​LHD is the consequence of a 1:1 upstream transmission of elevated left atrial pressure, labeled as ‘isolated post-​capillary PH’ (Ipc-​PH). In 13% of cases with PH-​LHD an increase in mean pulmonary arterial pressure (mPAP) occurs that is disproportional to left atrial pressure due to an additional contribution of pulmonary vascular disease, with decreased right ventricular–​pulmonary vascular coupling and increased mortality, and these cases are labeled as combined post-​and pre-​capillary PH (Cpc-​PH).3 Patients with ‘pre-​capillary’ pulmonary disease can be identified by an elevated diastolic pulmonary vascular pressure gradient (DPG) ≥ 7 mmHg. At present, the prognostic relevance of DPG has been confirmed in some reports,3 but has also been refuted by others,4 and so has been the classification by the 2015 ESC/​ERS guidelines in: (1) ‘isolated post-​capillary PH’ (Ipc-​PH; DPG < 7mmHg and/​or pulmonary vascular resistance (PVR) < 3WU) and (2) ‘combined post-​and pre-​capillary PH’ (Cpc-​PH; DPG ≥ 7mmHg and/​or PVR ≥ 3WU).5 A recent analysis of a very large dataset concluded that elevated transpulmonary gradient (TPG), PVR, and DPG are all associated with mortality and cardiac hospitalizations.1 Taken together, existing data suggest that patients with an elevated DPG (roughly 16% of the population6) harbour a particularly severe pulmonary vascular disease component,6 that involves the arterial vascular bed beyond venous and intermediate vessel changes,7 while the majority of cases of PH-​LHD is classified as Ipc-​PH-​type, and may be regarded as a comorbidity of LHD % Figure 12.5.2.8 The 2022 definition of PH-LHD is shown in % Table 12.5.1.

Prevalence and definition Prevalence of PH-​LHD Globally, PH is the most common cause of right heart failure, with a prevalence estimate of 1%, increasing up to 10% in individuals aged >65 years.9 In 65–​80% of cases PH is due to left heart disease, including myocardial disease, coronary disease, valve disease, and pericardial disease. For example, in a series of patients with aortic valve

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796

0.6 0.4 0.2 0.0 –0.2

0

10

20

30

40

50

60

70

Group 1 Group 2 Group 3 Group 4

Months

Figure 12.5.1  Survival rates without urgent heart transplantation in patients grouped according to the coupling between mean pulmonary arterial pressure

(PAP) and right ventricular ejection fraction (RVEF). Group 1 =​normal PAP/​preserved RVEF (n =​73); group 2 =​normal PAP/​low RVEF (n =​68); group 3 =​high PAP/​preserved RVEF (n =​21); and group 4 =​high PAP/​low RVEF (n =​215). Reproduced from Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001 Jan;37(1):183-​8. doi: 10.1016/​s0735-​1097( 00)01102-​5 with permission Elsevier.

stenosis, a common LHD in the older population, mPAP ≥ 25 mmHg was found in 239 (48%) patients. Of those, 64 patients (13%) had Cpc-​PH, 144 (28%) had Ipc-​PH, and 31 patients (6%) had pre-​capillary PH.10 In heart failure with reduced ejection fraction (HFrEF), the prevalence of PH as assessed by right heart catherization was reported to be between 40 and 75%.11,12 In heart failure with preserved ejection fraction (HFpEF), studies utilizing either echocardiography or invasive assessments with right heart catherization indicate a PH prevalence between 36 and 83%.13–​15 However, while PH is common in HFpEF, the condition is multifaceted.16–​19 To identify distinct phenotypic subgroups in a cohort

(a)

of individuals with HFpEF unsupervised clustering analysis has recently resulted in three phenogroups based on criteria in which PH was not included.20

Definition and classification of PH-​LHD PH-​LHD denotes pulmonary hypertension due to left heart disease, meaning that PH occurs as a consequence of LHD. In the new guidelines of PH, PH-​LHD was defined as: (1) post capillary PH when mPAP > 20 mmHg and pulmonary arterial wedge pressure (PAWP) > 15 mmHg; and if (1) applies, then (2) Ipc-​PH, when PVR < 2 Wood Units (WU); and (3) Cpc-​PH when PVR

(b)

Figure 12.5.2  Schematic representation of the pulmonary circulation with corresponding pressure decay curves that arise from inflation of the Swan-​Ganz

balloon, in (a) isolated post-​capillary pulmonary hypertension (Ipc-​PH) and (b) combined post-​and precapillary pulmonary hypertension (Cpc-​PH). In Ipc-​PH there is no significant pressure difference between mean pulmonary arterial pressure (mPAP) and pulmonary arterial wedge pressure (PAWP). In contrast, in Cpc-​ PH there is a pressure difference between mPAP and PAWP due to an additional component of pulmonary vascular disease at the level of the capillary bed, both on the arterial and the venous side.

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Table 12.5.1  Haemodynamic definitions of pulmonary hypertension: 2022 ESC-ERS Guidelines on the diagnosis and treatment of pulmonary hypertension Classification

Characteristics

Clinical groups

Pre-​capillary PH

mPAP > 20 mmHg PAWP ≤ 15 mmHg PVR ≥ 3WU

1,3,4 and 5

Isolated post-​capillary PH (Ipc-​PH)

mPAP > 20 mmHg PAWP > 15mmHg PVR < 3WU

2 and 5

Combined pre-​and post-​capillary PH (Cpc-​PH)

mPAP > 20 mmHg PAWP > 15 mmHg PVR ≥ 3WU

2 and 5

Reproduced from Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019 Jan 24;53(1):1801913. doi: 10.1183/​13993003.01913-​2018 with permission from European Respiratory Society.

≥ 2 WU (% Table 12.5.1). Still, major unanswered questions are whether DPG can be substituted by PVR, and whether Cpc-​PH and idiopathic pulmonary arterial hypertension (iPAH) with comorbidities are distinct entities. Cpc-​PH occurs in fewer than 20% of cases with PH-​LHD, and is usually accompanied by other conditions, such as low DLCO,21 valve disease, or other comorbidities.6 The best way to describe the pre-​capillary component of post-​capillary PH remains controversial: none of the haemodynamic variables proposed to describe PH-​LHD are free from limitations. Future studies may employ other physical measures, e.g. pulmonary waveform analyses or right ventricular flow dynamics to discriminate pulmonary vascular disease in the context of LHD. In addition, the disease history needs to be taken into account. For example, if a patient with diagnosed iPAH survives many years on modern treatments and acquires aortic valve stenosis, amyloidosis, or coronary artery disease, adding a component of left heart disease to the haemodynamic readout, then PAH with comorbidities may be diagnosed. In contrast to this concept, nowadays, these patients and patients with Cpc-​PH are referred to by some as ‘PAH with comorbidities‘, or ‘atypical PAH’. In the new PH Guidelines, the definition of PH-​LHD has been revised as PH associated with LHD, thus including PH-​LHD, and PH occurring together with LHD.

Diagnosis Non-​invasive diagnosis Algorithms have been devised to non-​invasively and safely rule out pre-​capillary PH and diagnose post-​capillary PH without invasive right heart catheterization because this is a major unmet need in a majority of patients who are referred today for diagnostic investigation to a heart failure or PH clinic. According to a decision tree that followed the echocardiographic estimate of a pulmonary artery systolic pressure of > 36mmHg, patients were stratified by the presence or absence of an electrocardiographic right ventricular strain pattern and serum N-​ terminal brain natriuretic peptide (NT-​proBNP) levels below and above 80 pg/​

mL 100% sensitivity for pre-​capillary PH was achieved, with only one false positive case per five patients.22 Furthermore, a simple echocardiographic score for diagnosing precapillary versus post-​ capillary PH was proposed, including the ability to discriminate between Ipc-​PH and Cpc-​PH. This score23 is based on seven points (2 for E/​e’ ratio ≤ 10, 2 for a dilated non-​collapsible inferior vena cava, 1 for a left ventricular eccentricity index ≥ 1.2, 1 for a right-​ to-​left heart chamber dimension ratio > 1, and 1 for the right ventricle forming the heart apex) and was applied in 230 consecutive patients referred for evaluation of pulmonary hypertension. The data suggest that the score behaves less well for Cpc-​PH than for Ipc-​PH (AUC 73% vs 85% for Ipc-​PH). In summary, while the differentiation between pre-​and postcapillary PH is facilitated by modern echocardiography and other imaging24 providing subtle measures of left ventricular dysfunction and pulmonary hypertension, invasive right heart catheterization is still unavoidable today to differentiate Cpc-​PH from Ipc-​PH. Particularly in the presence of risk factors for Cpc-​PH, or very poor right ventricular function by echocardiography invasive assessment is clinically indicated and needs to be performed.

The diagnostic dilemma of PH-​LHD A major diagnostic dilemma is to differentiate PH-​LHD from ‘PAH with comorbidities’. The term ‘PAH with comorbidities’ was introduced at the time of the AMBITION trial, when naive patients with PAH were enrolled in a trial testing the efficacy and safety of upfront combination drug treatment against upfront monotherapy.25 Although inclusion haemodynamic thresholds were set according to the PH guidelines definition at mPAP ≥ 25 mmHg, PVR ≥ 240 dyn∙sec/​cm5, and PAWP or left ventricular end-​diastolic pressure (LVEDP) ≤ 15 mmHg, demographics of a significant proportion of enrolled patients were those of PH-​LHD, including characteristic comorbidities such as diabetes, hypertension, coronary artery disease, and obesity.26–​29 Consequently, the study leadership introduced revised criteria as per a subsequent amendment to select for patients with a more precapillary phenotype. The steering committee introduced new thresholds such as mPAP ≥ 25 mmHg, PVR ≥ 300 dyn∙sec/​cm5, PAWP or LVEDP ≤12 mmHg if PVR was ≥ 300 to < 500 dyn∙sec/​cm5 or PAWP or LVEDP ≤ 15 mm Hg if PVR was ≥ 500 dyn∙sec/​cm5. Since then it has become evident that demographics of patients with PAH have changed over recent decades, with more elderly and comorbid patients found to have ‘PAH with comorbidities‘. Whether this entity is separate and new, or a variant of PH-​LHD (CpC-​PH subtype) is unknown. Opitz et al. compared clinical phenotypes of iPAH, ‘PAH with comorbidities‘, which these authors called atypical PH, and PH-​HFpEF and found similarities, an observation which tempted them to conclude that pre-​capillary, combined post-​and pre-​capillary PH, and post-​capillary pulmonary hypertension comprised a pathophysiological continuum.30 However, differential treatment responses and diverging prognoses speak against this concept. Recently, the authors of the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) performed a cluster analysis of 841 patients with an IPAH diagnosis based on age, sex, diffusion

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capacity of the lung for carbon monoxide (DLCO; < 45% vs ≥ 45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, diabetes mellitus), and identified Cluster 1 (n =​106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥ 45%; Cluster 2 (n =​301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥ 45%; and Cluster 3 (n =​434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the two other clusters. One of the main shortfalls of the COMPERA phenomapping analysis is that there was no corelab for haemodynamic phenotyping, only selected comorbidities were collected, and the timing of the occurrence of comorbidities (from the start versus during the course of confirmed precapillary pulmonary hypertension) are unknown.31 Haemodynamic phenotyping remains at the centre of diagnosis, and right heart catheterization has been embraced by the new heart failure guidelines for heart failure types that are commonly accompanied by pulmonary hypertension, such as constrictive and restrictive disease, congenital heart disease, and high output heart failure, as well as selected cases with HFpPEF.32

TPG is calculated by subtracting mean pulmonary arterial wedge pressure (mPAWP) from mPAP, and diastolic gradient (DPG) as the difference between diastolic pulmonary arterial pressure minus PAWP.6,35,36 PVR is calculated as TPG/​cardiac output.3,4 DPG was used in the 1970s in combination with PAWP, cardiac output (or arterio-​ venous oxygen content difference) and systemic blood pressure measurements for the differential diagnosis of cardiac and pulmonary causes of acute respiratory failure.37 Recently, in a large haemodynamic database of stable patients with more than 10 years of follow-​up it was found that elevated DPG ≥ 7 mmHg was associated with more advanced pulmonary vascular remodelling and consequently, with prognosis.6 Disparity in the association of DPG with outcomes in different databases that were subsequently published (% Table 12.5.2) may be associated with sources of error in retrospectively recorded pressures, errors in PAWP (underwedging or overwedging, excessive V waves), errors in diastolic pulmonary arterial pressure due to high frequency noise, catheter whip (with underestimation of PA diastolic pressure) as well as excessive respiratory variation and/​or inadequate calibration; these errors may result in false negative values limiting clinical utility. Another factor accounting for the divergent experience with DPG as a correlate of pulmonary vascular disease6,12,38–​45,46 is the variability of patient populations Haemodynamic variables to dissect pulmonary studied with regards to heart failure aetiology, disease characterhypertension due to left heart disease subsets: with or istics, the contribution of acute heart failure, disease duration, without pulmonary vascular disease age, sex, treatment era, and contemporary practices during which Best practice suggests that right heart catherization should be the data were collected. PVR is a commonly used measure to describe the pulmonary performed in a stable clinical condition with no prior diuresis or fluid supplements (% Table 12.5.2). Proper levelling at the mid-​ vascular bed in haemodynamic terms. In the new haemodynamic chest and ‘zero-​ing’ the transducer to atmospheric pressure are definitions and updated clinical classification of pulmonary requested. Patients should be positioned supine with legs flat, hypertension,47 a PVR > 2 WU was introduced as an additional and pressures recorded during no-​ breath-​ hold-​ spontaneous-​ criterion for the definition of pre-​capillary,48 and post-​capillary breathing. All measurements, including thermodilution cardiac PH,49 and that definition was also taken up in the most recent outputs or cardiac output estimates by the direct Fick should be guidelines for adult congenital heart disease where it appears particularly useful. PVR > 2 WU as a prognostic cut-​off has been repeated in triplicate to obtain values within a 10% agreement. PAWP is the primary key haemodynamic measurement for the based on scientific evidence derived from heart failure popudiagnosis of post-​capillary disease and is assessed as stop–​flow lations.11 Most recent data from the large US Veterans Affairs pressure with the balloon inflated in the pulmonary artery at end-​ healthcare system catheterization database (2007–​2012)50 that diastole closely reflecting LVEDP or LA pressure. In the absence had supported the mPAP threshold of 20 mmHg suggest that of mitral stenosis, PAWP measured at end-​diastole (i.e. typically the effective PVR threshold may be as low as 2.2 WU in specific as the mean of the A-​wave or alternatively, a QRS-​gated approach) subsets.51 These data illustrate that disease-​specific cut-​offs may more closely approximates LVEDP. By contrast, mean PAWP emerge when more prospective large databases are analysed. In (averaged throughout the cardiac cycle) in the presence of large the preoperative evaluation of heart transplant recipients, PVR ≥3 V waves (mitral regurgitation or non-​compliant left atrium) will WU remained associated with a significant increase in hazard for be higher than end-​diastolic PAWP and will overestimate LVEDP. 30-​day mortality after cardiac transplantation, even in the presPAWP is clearly different from capillary pressure that may be esti- ence of low mPAP.52 Pulmonary vascular compliance is the stroke volume, measmated by pulmonary artery occlusion waveform analysis.33 PAWP measurements are used instead of capillary pressure values to ured in mL, needed to elevate PA pressure by 1 mmHg and is differentiate pre-​from post-​capillary disease states. While cur- calculated as stroke volume divided by the difference between rent definitions are based on a PAWP > 15 mmHg measured at systolic and diastolic pulmonary arterial pressure (also called end-​expiration, analyses of large patient-​based datasets suggest pulse pressure). Pulmonary arterial compliance calculated by that that PAWP > 12 mmHg may be a more appropriate threshold,34 formula is usually greatly overestimated, but unfortunately not in including confirmatory data from waveform analysis. The pres- a systematic fashion, with more severe overestimation in more severe disease states. ence of large V waves signifies the presence of LHD.

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Table 12.5.2  Haemodynamic variables to define the pulmonary vascular component of PH-​LHD Parameter

TPG

DPG

PVR

Measurement

mPAP-​PAWP

dPAP-​PAWP

Strength of physiological background

-​/​+​

Dependent on quality of PAWP recording

Pulmonary wave forms

High fidelity pressure volume–​loops

(mPAP-​PAWP)/​CO SV/​(sPAP-​dPAP)

% upstream resistance

Ees/​Ea

+​+​+​

+​+​+​

+​

+​+​+​

+​+​+​+​+​

+​+​

+​+​+​

+​

-​

-​

-​

Information

Describes the pressure gradient across the lungs

Describes the degree of pulmonary vascular disease

Describes the resistance across the lungs

Describes the volume needed to elevate PA pressure by 1 mmHg, and is a measure of distensibility (capacity of all arteries and arterioles to accumulate blood in systole and release it in diastole)

Describes capillary pressure, and define the steepness of the pressure decay between the PA and PAWP

Informs about RV contractility, PA elastance and coupling

Specific limitations

Included in PVR Limited relevance

Highly dependent on quality of PAWP Small number

Interdependent numerator and denominator

Small number non-linearly overestimating PAC

Technically demanding

Technical learning curve, preload reduction necessary, by separate 8F access

Marker of disease

+​

+​+​

+​+​

–​/​+​

–​/​+​

+​

Marker of prognosis

–​/​+​

+​+​

+​+​

+​+​

+​+​

+​+​+​+​

Clinical usefulness

+​+​

+​+​+​

+​+​+​

-​

-​/​+​

–​

Conductance catheterization measures pressures and volumes simultaneously, allowing after calibration of volumes and stop–​ flow to assess right ventricle (RV) contractility as end-​systolic elastance (Ees) and arterial elastance (Ea) or RV afterload and their ratio, Ees/​Ea which describes RV–​PA coupling. While the main readout of pressure volume loops is RV contractility, RV chamber stiffness can be read from the end-​diastolic pressure–​ volume relationship of multi-​beat pressure–​volume loops with preload reduction. The arterial part describes RV afterload which is pulmonary vascular disease. Using capillary pressure estimates PVR can be partitioned into larger arterial (upstream, Rup) and small arterial plus venous (downstream, Rds) components. In healthy subjects, PVR follows an almost equal distribution across the pulmonary circulation with ~60% Rup and ~40% Rds.53 In iPAH, there is a similar PVR partitioning pattern, yet with significant elevation of mPAP and Pc’, which is increased as arteriolar pulmonary vascular remodelling extends to the capillary–​venous compartment. The discrepancy between the pulmonary artery occlusion waveform analysis estimates of capillary pressure is greatest in the presence of pulmonary vascular disease, and the magnitude of discordance is proportional to the severity of the disease. When partitioning of small vessel resistance is used for estimation of capillary pressure, the only parameter that is able to discriminate low upstream

PAC

resistance of less than 60% without performing waveform analysis is DPG ≥ 7mmHg. All these measures have been implicated as prognostic markers in PH-​ LHD, with variable importance, possibly depending on the nature and size of cohorts that were studied.54 More recently, pulmonary effective arterial elastance (Ea), calculated as ratio of mPAP to SV in mmHg/​mL, was introduced as a measure of total right ventricular afterload and prognosis of PH-​LHD.55 % Table 12.5.1 provides a summary of currently used parameters and techniques to assess the pulmonary vascular component of RV afterload, including coupling as the overall measure of energy transfer between the RV and the pulmonary vascular bed.

Isolated post-​capillary and combined pre and post-​ capillary pulmonary hypertension –​are they clinical phenotypes? The prevalence of Cpc-​PH is less than 20% of the total heart failure population.3 There is no predilection for males or females, and most patients are elderly (60 plus years) and in New York Heart Association (NYHA) functional class III at presentation. While stable ischaemic heart disease, atrial fibrillation, and body mass index are similar, arterial hypertension tends to be more common in Ipc-​PH. In Cpc-​PH associated with diastolic heart failure, mild valvular heart disease and interstitial lung disease are

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more common. In Cpc-​PH due to systolic heart failure, milder degrees of chronic obstructive pulmonary disease appear to aggravate pulmonary vascular disease. Other comorbidities of PH-​LHD include a low DLCO,21 as well as sleep apnoea,56 which occurs in approximately 50% of all heart failure patients, and has consequences such as intermittent hypoxaemia, arousal, and intra-​thoracic pressure swings leading to neurohormonal stimulation, oxidative stress, and inflammation. While sleep apnoea is a cause of PH in 10% of cases, severe PH due solely to obstructive sleep apnoea is rare. Prospective screening needs to be performed to couple sleep apnoea with a particular haemodynamic heart failure phenotype. Taken together, Ipc-​PH and Cpc-​PH clearly represent clinical phenotypes, but differential diagnosis is not possible based on the clinical presentation alone. Furthermore, several large datasets have confirmed the prognostic value of the differentiation between Ipc-​PH and Cpc-​PH. Gerges et al. and other investigators have described the dismal prognosis of Cpc-​ PH, which is similarly poor as that of iPAH.57 The 2018 WHO writing group49 has proposed to approach the diagnosis of PH-​LHD in three steps: (1) identification of a clinical phenotype taking into account all comorbid conditions to establish the characteristics of Group 2 PH; (2) assessment of a pre-​test probability to identify which patients deserve an invasive evaluation; (3) haemodynamic characterization, which could include provocative testing (e.g. exercise or fluid loading) in selected cases in whom classification is difficult despite the invasive assessment at rest.

Management of PH-​LHD Drug treatment of PH-​LHD A collective progress in pulmonary vascular and heart failure medicine reinforces the critical importance of accurate haemodynamic assessment. The proper distinction between PAH and PH-​LHD, and the distinction between Ipc-​PH and Cpc-​PH may be challenging, yet it has direct therapeutic consequences. Except for a single study,58 randomized controlled trials have failed to show evidence that PAH-​specific therapy benefits PH-​LHD.59 60 Furthermore, notwithstanding that the presence of pulmonary vascular disease may justify the use of drugs approved for PAH, the single trial that was designed to target Cpc-​PH delivered a signal of harm.61 Another signal of harm came from a randomized study of sildenafil in valvular heart disease PH.62 These data lend support to the concept of keeping drugs that are approved for the treatment of PAH away from patients with PH-​LHD. For the management of PH-​LHD it remains important to decide whether PH is the comorbidity of LHD,8 or LHD is the comorbidity of PAH.25 In the majority of patients, PH is the comorbidity of LHD and treatment of underlying left heart disease remains the best choice. Systemic light chain amyloidosis (AL) with cardiac involvement is the most common form of cardiac amyloidosis. The severity of heart disease dictates the prognosis in AL amyloidosis. Advances in chemotherapy and immunotherapy that suppress light chain production have improved outcomes. These recent

improvements in survival rates have enabled therapies such as implanted cardiac defibrillators and heart transplantation that were previously not indicated for patients with advanced AL cardiomyopathy. For transthyretin amyloidosis (ATTR), the second most common form of amyloidosis with cardiac involvement, there is also significant progress in treatment. In cardiac TTR amyloidosis, parameters of RV size and function correlated well with symptom severity.63 Therapies that stabilize transthyretin, such as tafamidis, have been successful. Tafamidis inhibits non-mutant TTR amyloidogenesis in a dose-​dependent manner and stabilizes the two most clinically significant amyloidogenic mutants with similar efficacy.64 A phase III trial of 441 patients with wild-​ type and hereditary ATTR cardiac amyloidosis tested tafamidis against placebo.65 The pooled tafamidis arms (80 mg and 20 mg doses) showed a reduction in all-​cause mortality (HR 0.70, 95% CI 0.51–​0.96) and cardiovascular hospitalization (HR 0.68, 95% CI 0.56–​0.81). Information on the regression of PH has not been published, but significant improvement in the 6-​min walk test and quality of life occurred and a smaller increase in proBNP at months 12 and 30, and tafamidis was well tolerated. Treatment of wild-​ type and hereditary ATTR cardiac amyloidosis with tafamidis is labelled as a class I guidelines recommendation.32 Similar success was made in the treatment of hypertrophic cardiomyopathy, another common cause for PH-​LHD66: in the EXPLORER-​ HCM trial, a phase 3, randomized, double-​ blind, placebo-​controlled mutlicentre trial, patients with hypertrophic cardiomyopathy with a left ventricular outflow tract gradient of 50 mmHg or greater and NYHA class II–​III symptoms were treated with placebo or mavacamten and experienced improved exercise capacity, less left ventricular outflow tract obstruction, NYHA functional class, and health status under treatment with mevacamten.67

Management of tricuspid regurgitation PH is frequently associated with RV and right atrial (RA) dilatation and functional tricuspid regurgitation (TR),68 which serves to make the diagnosis of PH5 on the one hand, but is a driver of heart failure progression. In left heart disease, functional TR can result from multiple mechanisms including dilation of the tricuspid valve annulus, RV and RA remodelling, increased RV pressures, and atrial fibrillation.69 Furthermore, presence of a pacemaker and defibrillator lead, reduced tricuspid annulus plane systolic excursion (TAPSE), and tricuspid annulus dilation are independently associated with development of significant TR.70 Primary TR caused by an anatomical abnormality of the tricuspid valve apparatus is far rarer. Moderate or severe TR is associated with an increased mortality risk, and in isolated TR an effective regurgitant orifice ≥ 40 mm2 was shown to be prognostically relevant.71 Recently, the burden of TR and its impact on mortality have become more and more evident, particularly in HFpEF.72 More interest has focused on the tricuspid valve in recent years following the advent of percutaneous tricuspid valve repair.73 In isolated severe TR, there is preliminary evidence for clinical improvement after successful transcatheter treatment with the edge-​to-​edge MitraClip technique, including improved NYHA functional class and an increase of the 6-​min walking

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distance.73 In both surgical and interventional approaches to treat TR, high mortality rates have been reported, and patient selection is crucial. It is important to bear in mind that reducing TR in situations of increased RV afterload may lead to RV failure, or not correct the underlying uncoupling of the RA from the inferior vena cava.74 In many instances, medical/​electric cardioversion or atrial fibrillation ablation may be more effective than structural intervention at the tricuspid valve.

Future directions Pathophysiology of PH-​LHD remains a research topic. Because fluid overload appears as one of the disease characteristics, the understanding of the role of SGLT-​2 inhibitors to specifically treat PH-​LHD is a goal to be achieved in the near future. Furthermore, novel imaging to understand involvement of the pulmonary vasculature (arterioles, capillaries, veins) will impact disease classification in the future, as not all PH-​LHD is the same. Finally, mechanical support of the right ventricle has been refined over the past years, with the concept to attenuate the spiral of vascular injury to the lung by lowering pulse pressure.75

Summary and key messages ◆ The commonest cause of pulmonary hypertension (PH) is left heart disease (LHD). ◆ LHD may occur in PH (PH is the first and the leading diagnosis): ● as a consequence of ageing of diagnosed PAH, e.g. coronary artery disease, or degenerative mitral or aortic valve disease. ● as a consequence of corrective heart surgery, e.g. in PH due to congenital heart disease. ● as a comorbidity, e.g. of CTEPH. ◆ PH may occur in LHD (LHD is the first and the leading diagnosis): ● as a consequence of severe chronic heart failure (all types, particularly HFmrEF and HFpEF). ● as a consequence of comorbidities such as lung disease, malignancy, chemotherapy, and other treatments including surgeries, renal impairment, and genetic disorders. ● as a consequence of concurrent causes of PH such as congenital heart disease, connective tissue disease, or hemolytic anemia. ◆ Haemodynamic phenotyping, including provocation with exercise and fluid loading remains at the centre of diagnosis. ◆ Precise aetiologic assessment is very important for treatment.

Sources of funding This manuscript was supported by FWF SFB-​ F54 ‘Cellular Mediators Linking Inflammation and Thrombosis’ and WWTF LCS 18-​090.

Disclosures IML has relationships with drug companies including AOPOrphan Pharmaceuticals, Actelion, MSD, Neutrolis, Ferrer, and United

Therapeutics. Relationships include being an investigator in trials, consultancy services, research grants, and membership of scientific advisory boards.

References 1. Vanderpool RR, Saul M, Nouraie M, Gladwin MT and Simon MA. association between hemodynamic markers of pulmonary hypertension and outcomes in heart failure with preserved ejection fraction. JAMA Cardiology. 2018;3:298–​306. 2. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. Journal of the American College of Cardiology. 2001;37:183–​8. 3. Gerges M, Gerges C, Pistritto AM, Lang MB, Trip P, Jakowitsch J, Binder T and Lang IM. Pulmonary hypertension in heart failure. Epidemiology, right ventricular function, and survival. American Journal of Respiratory and Critical Care Medicine. 2015;192:1234–​46. 4. Tedford RJ, Beaty CA, Mathai SC, et al. Prognostic value of the pre-​ transplant diastolic pulmonary artery pressure-​to-​pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension. Journal of Heart and Lung Transplantation 2014;33:289–​97. 5. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/​ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Heart Journal. 2016;37:67–​119. 6. Gerges C, Gerges M, Lang MB, Zhang Y, Jakowitsch J, Probst P, Maurer G and Lang IM. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in 'out-​of-​proportion” pulmonary hypertension. Chest. 2013;143:758–​66. 7. Fayyaz AU, Edwards WD, Maleszewski JJ et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation. 2018;137:1796–​810. 8. Tichelbäcker T, Dumitrescu D, Gerhardt F, et al. Pulmonary hypertension and valvular heart disease. Herz. 2019;44:491–​501. 9. Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respiratory Medicine. 2016;4:306–​22. 10. Weber L, Rickli H, Haager PK, et al. Haemodynamic mechanisms and long-​term prognostic impact of pulmonary hypertension in patients with severe aortic stenosis undergoing valve replacement. European Journal of Heart Failure. 2019;21:172–​81. 11. Miller WL, Grill DE and Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Failure. 2013;1:290–​9. 12. Tampakakis E, Leary PJ, Selby VN, et al. The diastolic pulmonary gradient does not predict survival in patients with pulmonary hypertension due to left heart disease. JACC Heart Failure. 2015;3:9–​16. 13. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT and Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-​based study. Journal of the American College of Cardiology. 2009;53:1119–​26. 14. Leung CC, Moondra V, Catherwood E and Andrus BW. Prevalence and risk factors of pulmonary hypertension in patients with elevated pulmonary venous pressure and preserved ejection fraction. American Journal of Cardiology. 2010;106:284–​6.

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802

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15. Shah AM, Shah SJ, Anand IS, et al. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an aldosterone antagonist trial. Circulation. Heart Failure.. 2014;7:104–​15. 16. Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-​PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). European Heart Journal. 2019;40:3297–​317. 17. Barandiarán Aizpurua A, Sanders-​van Wijk S, Brunner-​La Rocca HP, et al. Validation of the HFA-​PEFF score for the diagnosis of heart failure with preserved ejection fraction. European Journal of Heart Failure. 2020;22:413–​21. 18. Reddy YNV, Carter RE, Obokata M, Redfield MM and Borlaug BA. A simple, evidence-​based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation. 2018;138:861–​70. 19. Hwang IC, Cho GY, Choi HM, et al. H2FPEF score reflects the left atrial strain and predicts prognosis in patients with heart failure with preserved ejection fraction. Journal of Cardiac Failure. 2021;27:198–​207. 20. Segar MW, Patel KV, Ayers C, et al. Phenomapping of patients with heart failure with preserved ejection fraction using machine learning-​based unsupervised cluster analysis. European Journal of Heart Failure. 2020;22:148–​58. 21. Hoeper MM, Meyer K, Rademacher J, Fuge J, Welte T and Olsson KM. Diffusion capacity and mortality in patients with pulmonary hypertension due to heart failure with preserved ejection fraction. JACC Heart Failure. 2016;4:441–​9. 22. Bonderman D, Wexberg P, Martischnig AM, Heinzl H, Lang MB, Sadushi R, Skoro-​Sajer N and Lang IM. A noninvasive algorithm to exclude pre-​capillary pulmonary hypertension. European Respiratory Journal. 2011;37:1096–​103. 23. D’Alto M, Romeo E, Argiento P, et al. A simple echocardiographic score for the diagnosis of pulmonary vascular disease in heart failure. Journal of Cardiovascular Medicine (Hagerstown). 2017;18:237–​43. 24. Hur DJ and Sugeng L. Non-​invasive multimodality cardiovascular imaging of the right heart and pulmonary circulation in pulmonary hypertension. Frontiers in Cardiovascular Medicine. 2019;6:24. 25. Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New England Journal of Medicine. 2015;373:834–​44. 26. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. American Journal of Respiratory and Critical Care Medicine. 2012;186:790–​6. 27. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-​ US Contemporary Registries. Chest. 2011;139:128–​37. 28. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. International Journal of Cardiology. 2013;168:871–​80. 29. Rådegran G, Kjellström B, Ekmehag B, et al.Characteristics and survival of adult Swedish PAH and CTEPH patients 2000–​2014. Scandinavian Cardiovascular Journal. 2016;50:243–​50. 30. Opitz CF, Hoeper MM, Gibbs JS, et al.. Pre-​capillary, combined, and post-​ capillary pulmonary hypertension: a pathophysiological continuum. Journal of the American College of Cardiology. 2016;68:368–​78.

31. Hoeper MM, Pausch C, Grünig E, et al. Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry. Journal of Heart and Lung Transplantation. 2020;39:1435–​44. 32. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 2021;42:3599–​726. 33. Gerges C, Gerges M, Fesler P, et al. In-​ depth haemodynamic phenotyping of pulmonary hypertension due to left heart disease. European Respiratory Journal. 2018;51(5):1800067. 34. Gerges C, Gerges M, Skoro-​Sajer N, et al. Hemodynamic thresholds for precapillary pulmonary hypertension. Chest. 2016;149:1061–​73. 35. Harvey RM, Enson Y and Ferrer MI. A reconsideration of the origins of pulmonary hypertension. Chest. 1971;59:82–​94. 36. Naeije R, Vachiery JL, Yerly P and Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. European Respiratory Journal. 2013;41:217–​23. 37. Stevens PM. Assessment of acute respiratory failure: cardiac versus pulmonary causes. Chest. 1975;67:1–​2. 38. Al-​Naamani N, Preston IR, Paulus JK, Hill NS and Roberts KE. Pulmonary arterial capacitance is an important predictor of mortality in heart failure with a preserved ejection fraction. JACC Heart Failure. 2015;3:467–​74. 39. Howard C, Rangajhavala K and Safdar Z. Pulmonary artery diastolic pressure gradient as an indicator of severity of illness in patients with pulmonary hypertension related to left-​sided heart disease. Therapeutic Advances in Respiratory Disease. 2015;9:35–​41. 40. O’Sullivan CJ, Wenaweser P, Ceylan O, et al. Effect of pulmonary hypertension hemodynamic presentation on clinical outcomes in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation: insights from the new proposed pulmonary hypertension classification. Circulation Cardiovascular Interventions. 2015;8:e002358. 41. Brunner NW, Yue SF, Stub D, et al. The prognostic importance of the diastolic pulmonary gradient, transpulmonary gradient, and pulmonary vascular resistance in patients undergoing transcatheter aortic valve replacement. Catheterization and Cardiovascular Interventionss. 2017;90:1185–​91. 42. Mazimba S, Mejia-​Lopez E, Black G, et al. Diastolic pulmonary gradient predicts outcomes in group 1 pulmonary hypertension (analysis of the NIH primary pulmonary hypertension registry). Respiratory Medicine. 2016;119:81–​6. 43. Nagy AI, Venkateshvaran A, Merkely B, Lund LH and Manouras A. Determinants and prognostic implications of the negative diastolic pulmonary pressure gradient in patients with pulmonary hypertension due to left heart disease. European Journal of Heart Failure. 2017;19:88–​97. 44. Adir Y, Guazzi M, Offer A, Temporelli PL, Cannito A and Ghio S. Pulmonary hemodynamics in heart failure patients with reduced or preserved ejection fraction and pulmonary hypertension: Similarities and disparities. American Heart Journal. 2017;192:120–​7. 45. Palazzini M, Dardi F, Manes A, et al. Pulmonary hypertension due to left heart disease: analysis of survival according to the haemodynamic classification of the 2015 ESC/​ERS guidelines and insights for future changes. European Journal of Heart Failure. 2018;20(2):248–​55. 46. Ciftci O, Unal EN, Dellaloglu Z, et al. Relationship between preoperative diastolic transpulmonary gradient with pulmonary vascular resistance and 1-​ year and overall mortality rates among patients undergoing cardiac transplant. Experimental and Clinical Transplantation2019;17:231–​235. 47. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG and Souza R. Haemodynamic

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definitions and updated clinical classification of pulmonary hypertension. European Respiratory Journal. 2019;53(1):1801913. 48. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology. 2013;62:D34–​41. 49. Vachiery JL, Tedford RJ, Rosenkranz S, et al. Pulmonary hypertension due to left heart disease. European Respiratory Journal. 2019;53(1):1801897. 50. Maron BA, Hess E, Maddox TM, et al. Association of borderline pulmonary hypertension with mortality and hospitalization in a large patient cohort: insights from the veterans affairs clinical assessment, reporting, and tracking program. Circulation. 2016;133:1240–​8. 51. Maron BA, Brittan EL, Hess E, et al. Pulmonary vascular resistance and clinical outcomes in patients with pulmonary hypertension: a retrospective cohort study. Lancet Respiratory Medicine. 2020;8:873–​84. 52. Crawford TC, Leary PJ, Fraser CD, 3rd, et al. Impact of the new pulmonary hypertension definition on heart transplant outcomes: expanding the hemodynamic risk profile. Chest. 2020;157:151–​61. 53. Maggiorini M, Melot C, Pierre S, et al. High-​altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 2001;103:2078–​83. 54. Caravita S, Faini A, Carolino D’Araujo S et al. Clinical phenotypes and outcomes of pulmonary hypertension due to left heart disease: Role of the pre-​capillary component. PloS one. 2018;13:e0199164. 55. Tampakakis E, Shah SJ, Borlaug BA, et al. Pulmonary effective arterial elastance as a measure of right ventricular afterload and its prognostic value in pulmonary hypertension due to left heart disease. Circulation. Heart Failure. 2018;11:e004436. 56. Javaheri S, Javaheri S and Javaheri A. Sleep apnea, heart failure, and pulmonary hypertension. Current Heart Failure Reports. 2013;10:315–​20. 57. Naeije R, Gerges M, Vachiery JL, Caravita S, Gerges C and Lang IM. Hemodynamic phenotyping of pulmonary hypertension in left heart failure. Circulation. Heart Failure. 2017;10(9):e004082. 58. Guazzi M, Vicenzi M, Arena R and Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-​5 inhibition in a 1-​year study. Circulation. 2011;124:164–​74. 59. Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-​blind, randomized, placebo-​controlled, dose-​ ranging hemodynamic study. Circulation. 2013;128:502–​11. 60. Hoendermis ES, Liu LC, Hummel YM, et al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. European Heart Journal. 2015;36:2565–​73. 61. Vachiery JL, Delcroix M, Al-​Hiti H, Efficace M, Hutyra M, Lack G, Papadakis K and Rubin LJ. Macitentan in pulmonary hypertension due to left ventricular dysfunction. The European Respiratory Journal. 2018;51 (2):1701886.

62. Bermejo J, Yotti R, Garcia-​Orta R, et al.Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-​blind, randomized clinical trial. European Heart Journal. 2018;39:1255–​64. 63. Binder C, Duca F, Stelzer PD, et al. Mechanisms of heart failure in transthyretin vs. light chain amyloidosis. European Heart Journal Cardiovascular Imaging. 2019;20:512–​24. 64. Bulawa CE, Connelly S, Devit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proceedings of the National Academy of Sciences of the USA. 2012;109:9629–​34. 65. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. New England Journal of Medicine. 2018;379:1007–​16. 66. Musumeci MB, Mastromarino V, Casenghi M, et al. Pulmonary hypertension and clinical correlates in hypertrophic cardiomyopathy. International Journal of Cardiology. 2017;248:326–​32. 67. Olivotto I, Oreziak A, Barriales-​ Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-​ HCM): a randomised, double-​ blind, placebo-​ controlled, phase 3 trial. Lancet. 2020;396:759–​69. 68. Mentias A, Patel K, Patel H, et al. Effect of pulmonary vascular pressures on long-​ term outcome in patients with primary mitral regurgitation. Journal of the American College of Cardiology. 2016;67:2952–​61. 69. Prihadi EA, Delgado V, Leon MB, Enriquez-​Sarano M, Topilsky Y and Bax JJ. Morphologic types of tricuspid regurgitation: characteristics and prognostic implications. JACC Cardiovasc Imaging. 2019;12:491–​99. 70. Prihadi EA, van der Bijl P, Gursoy E, et al. Development of significant tricuspid regurgitation over time and prognostic implications: new insights into natural history. European Heart Journal. 2018;39:3574–​81. 71. Topilsky Y, Nkomo VT, Vatury O, et al. Clinical outcome of isolated tricuspid regurgitation. JACC Cardiovascular Imaging. 2014;7:1185–​94. 72. Borlaug BA, Kane GC, Melenovsky V and Olson TP. Abnormal right ventricular-​pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. European Heart Journal. 2016;37:3293–​302. 73. Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricuspid regurgitation with the edge-​to-​edge MitraClip technique. Circulation. 2017;135:1802–​14. 74. Marcus JT, Westerhof BE, Groeneveldt JA, Bogaard HJ, de Man FS and Vonk Noordegraaf A. Vena cava backflow and right ventricular stiffness in pulmonary arterial hypertension. European Respiratory Journal. 2019;54:1900625. 75. Gerges C, Vollmers K, Pritzker MR, Gainor J, Scandurra J, Weir EK and Lang IM. Pulmonary artery endovascular device compensates for loss of vascular compliance in pulmonary arterial hypertension. Journal of the American College of Cardiology. 2020;76:2284–​6.

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CHAPTER 12.6

Ventricular arrhythmias and sudden death in heart failure Alessandro Trancuccio, Alessia Chiara Latini, Carlo Arnò, Deni Kukavica, Andrea Mazzanti, and Silvia G Priori

Contents The impact of ventricular arrhythmias and sudden death in heart failure  805 Aetiology and pathogenesis of ventricular arrhythmias in heart failure  806 Structural abnormalities  808 Cellular remodeling  808 Metabolic abnormalities  809

Risk stratification  809

LVEF and NYHA class  809

Therapeutic approach  810

Pharmacological treatment  810 Device therapy  811 Catheter ablation  812

Conclusions  815 References  815

The impact of ventricular arrhythmias and sudden death in heart failure Ventricular arrhythmias (VAs) are highly prevalent in patients with chronic heart failure (HF),1 and range from isolated premature ventricular complexes to more severe arrhythmias, such as non-​sustained or sustained ventricular tachycardia (VTns and VTs, respectively) and, lastly, to ventricular fibrillation.2 The clinical relevance of VAs, which may cause sudden cardiac death (SCD), is related to the fact that they represent an important competing cause of death in patients with HF. Importantly, SCD has been deemed to account for approximately 50% of all deaths in HF,3 but SCD rates have been declining over time.4 A recent meta-​analysis by Shen et al.4 analyzed data from all the randomized clinical trials (RCTs) enrolling more than 1000 patients that were conducted from 1995 to 2014, including only patients without an implantable cardioverter-​defibrillator (ICD), to evaluate the impact of the increasing use of evidence-​ based pharmacotherapies able to reduce incidence of SCD in HF. Interestingly, the authors demonstrated that the SCD rates have declined by 44% over the past 20 years (% Figure 12.6.1). Accordingly, while the first trials conducted in the late 1990s5,6 reported annual rates of SCD around 6% per annum, more recent studies have found rates of approximately 3%.7,8 It is important to highlight that data deriving from RCTs may not be representative of ‘real-​world clinical practice’ because trial patients are selected by stringent criteria that often exclude older individuals and patients with co-​morbidities. Furthermore, in clinical trials compliance to the therapeutic regimen is strictly controlled. It is therefore important to highlight that the trend supporting the reduction of the incidence of SCD has been also confirmed in real-​world studies.9 Although the rates of SCD have significantly reduced over the years, recent data from the PARADIGM-​HF trial estimate the cumulative incidence in patients with HF to be 8.8% at three years.4 Additionally, another important concept that emerged from the aforementioned meta-​analysis by Shen et al.4 is that the proportion of deaths attributable to SCD remained substantially unvaried during

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Population

Slope (per decade), –1.22 per 100 patient-yr; P = 0.02 9 Annual rate of sudden death (per 100 patient-yr)

Control group

8

Experimental-therapy group

7 6 5 4 3 2

11 20

10 20

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06 20

05 20

04 20

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02 20

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95

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Figure 12.6.1  Trends in the rate of sudden cardiac death across the main trials conducted over the past 20 years.

the last 20 years, with SCD accounting for around 40% of the total number of deaths of these patients. This finding is consistent with the fact that current pharmacological therapy (beta-​ blockers (BBs), ACE-​inhibitors (ACE-​I), and mineralocorticoid receptor antagonists (MRA)) seems equally effective in reducing mortality due to arrythmias and due to worsening of HF. In patients with HF the overall risk of death is given by a combined risk of SCD and a risk of dying from other causes, cardiovascular or otherwise. The contribution of SCD as a competing cause of death in patients with HF is variable and depends on the stage of the disease. In patients with mild to moderate HF (New York Heart Association (NYHA) functional class II and III), SCD is the cause of death in 50–​60% of cases, while in the end-​stage (NYHA IV) patients are more likely to die from pump failure, with SCD being the cause of death in only 20 to 30% of the cases.10 Additionally, the proportion of deaths attributable to SCD is age-​ dependent, it competes with other causes of death, both cardiovascular and non-​cardiovascular (e.g. cancer, metabolic diseases, etc.). As shall be discussed later, the concept of competitive risk has relevant implications for the management and prognosis of patients with HF.

Aetiology and pathogenesis of ventricular arrhythmias in heart failure HF is a complex clinical syndrome resulting from several causes, often coexisting and interacting in a single patient (% Figure 12.6.2). It has been traditionally classified in post-​ischaemic and non-​ischaemic forms, with the former being the most studied by virtue of the high frequency of coronary artery disease in the

general population. However, this classification is reductive, and it disregards some important aspects. First, the prevalence of the different causes of HF varies among different geographical areas, with myocardial infarction (MI) being the leading cause in higher-​income countries, in contrast to lower-​income countries, in which hypertensive heart disease, rheumatic heart disease, and myocarditis prevail.11,12 Of note, other aetiologies, which are rare in Europe, are worthy of mention for their high arrhythmic potential (e.g. Chagas disease in South America).11 Secondly, the grouping of all other causes under the umbrella term of ‘non-​ischaemic HF’ clusters together an extremely heterogeneous spectrum of diseases. An important proof of this concept is the growing awareness of the role of inherited cardiomyopathies in HF. In fact, the increasing use of genetic analysis in clinical practice has shed light on familial cardiomyopathies as an important but underestimated cause of HF, in patients who are usually younger than those suffering from ischaemic heart disease. This is not only relevant for classification purposes but has crucial implications for the management of patients. As discussed more in detail in the section regarding risk stratification, several forms of cardiomyopathies are associated with an increased risk of SCD,2 such as those secondary to mutations in the following genes: LMNA, FLNC, PLN, RBM20, and DSP.13 These important differences notwithstanding, in the following section the general mechanisms that have been implicated in arrhythmogenesis of VAs in HF are dissected. We will inspect the arrhythmogenic mechanisms of VAs at three different levels14 (% Figure 12.6.3):

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Ventricu l a r a rrhy thm ias a n d su dden death i n hea rt fa i lure Heart failure

Congenital heart diseases

lschaemic heart disease

Primary cardiomyopathies

Genetic DCM ACM LVNC HCM Mitochondrial myopathies

Hypertensive

Acquired Tachycardia-induced Peripartum Stress-induced (Takotsubo) Substance-induced Toxin-related (e.g. anthracycline) Myocarditis Chagas HIV Viral Giant cell myocarditis

Secondary cardiomyopathies

Amyloidosis Sarcoidosis Storage disease (e.g. Fabry disease) Connective tissue disorders Thyroid disease Endomyocardial fibrosis Nutritional deficiencies Anaemia Arteriovenous fistula

Figure 12.6.2  Aetiology of heart failure. Source data from Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016 Jun;13(6):368–​78.

Figure 12.6.3  Arrhythmogenic mechanisms of ventricular arrhythmias in heart failure.

Valvular

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808

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1. Structural level: a. Replacement and interstitial fibrosis b. Left ventricle (LV) geometric remodeling and myocardial stretch 2. Cellular level (remodeling of the electrophysiological properties of the cardiomyocyte): a. Remodeling of ion channels and prolongation of action potential duration b. Altered Ca2+​ homeostasis c. Intercellular uncoupling (reduced connexin 43) 3. Metabolic level: a. Neurohormonal activation b. Electrolyte abnormalities.

Structural abnormalities Replacement and interstitial fibrosis The presence of fibrosis constitutes an anatomic substrate for the genesis of re-​entrant VAs. However, it should be emphasized that the replacement fibrosis secondary to a MI is different from fibrosis found in patients with HF of non-​ischaemic aetiology. Compared with post-​MI, in which the ischaemic wavefront of necrosis results in more endocardial than epicardial fibrosis, in HF of non-​ischaemic aetiology, the fibrosis tends to be smaller and less confluent, with less endocardial involvement and with reduced transmural extension15,16 (% Figure 12.6.3). Additionally, chronic pressure overload secondary to valvular heart disease or hypertension, as well as a consequence of hypertrophic cardiomyopathy may lead to the coexistence of replacement and interstitial fibrosis.16 The differences in the pattern of fibrosis result in the generation of different types of re-​entry. Seminal studies conducted in the 1990s demonstrated that in MI the presence of post-​infarct replacement fibrosis (i.e. confluent scar) determines sites of conduction block and anisotropic conduction leading to macro-​ reentrant VT.17,18 On the other hand, finer replacement fibrosis (typical of HF related to dilated cardiomyopathy (DCM)) tends to be associated with smaller circuits and with wandering rotors.19 Lastly, in silico studies support the hypothesis of micro-​ reentries as the sole arrhythmogenic mechanism associated with diffuse interstitial fibrosis.20 These differences have important clinical implications in terms of suitability for ablative procedures, as discussed in the section regarding the clinical management. Geometric remodeling and myocardial stretch In addition to the development of fibrosis, other structural abnormalities such as LV geometric remodeling and myocardial stretch are implicated in the arrhythmogenesis of HF. Volume and pressure overload, or a combination of both, cause different LV geometric adaptations (eccentric hypertrophy and concentric hypertrophy, respectively), which can contribute to the arrhythmogenic milieu.21,22 In fact, it is very well recognized that cardiac hypertrophy is an important pro-​arrhythmogenic factor,23 and it has been demonstrated in animal models of HF that both increased preload and afterload (i.e. increased myocardial stretch)

can promote the development of VAs.24 Additionally, myocardial stretch has been demonstrated to induce afterdepolarizations,25 which can cause triggered activity, which in turn may act as a trigger for VAs.

Cellular remodeling Ion channel remodeling and action potential prolongation A growing body of evidence deriving both from animal models26 and from studies on human tissue27,28 has shown that HF is characterized by alterations in ionic currents that determine a prolongation of the cardiac action potential (AP). These alterations include both a reduction in the outward potassium currents Ito,27,29,30 IKs,29–​31 and IK1,27,32 and an increase in the late sodium current.33,34 It has been proposed that the AP-​prolonging effects represent a compensatory mechanism, which counterbalances the loss of contraction by increasing the amplitude and/​or the duration of the Ca2+​-​transient.19 The resultant prolongation of the AP can promote the onset of early afterdepolarizations,35,36 which can be the trigger for re-​entry arrhythmias, especially when combined with an anatomical substrate predisposing to a critical degree of conduction slowing.19,37 Altered calcium homeostasis Alterations in calcium (Ca2+​) homeostasis play a pivotal role in arrhythmogenesis in patients with HF. In particular, it has been demonstrated that cardiomyocytes from patients with HF are characterized by increased diastolic cytoplasmic Ca2+​ concentration (i.e. ‘Ca2+​ overload’),38 decreased sarcoplasmic reticulum Ca2+​ content38 and decreased sarcoplasmic reticulum Ca2+​ uptake.39,40 Additionally, alterations in Na+​/​Ca2+​ exchanger (NCX), crucial for the maintenance of normal Ca2+​ homeostasis, have been reported, but their role in HF remains unclear. Although not consistently, most studies in different animal models of different forms of HF have found increased NCX expression at the mRNA and protein level.41–​43 Importantly, these findings were later confirmed in a study on explanted human hearts, where Schillinger and colleagues44 found increased protein levels of NCX by 56%, and patients with complex VAs (VTns or VTs) had significantly higher levels of NCX than patients without them. Lastly, in a recent study on a porcine model of post-​MI HF, the inward NCX current (i.e. Ca2+​ efflux) was increased during the plateau phase of action potential, consistently with an increased functional role of NCX in HF.34 According to the classical arrhythmogenic theories, the combination of all the aforementioned Ca2+​ handling abnormalities may promote the occurrence of spontaneous Ca2+​ release from the sarcoplasmic reticulum, which can ultimately lead to NCX-​ mediated delayed afterdepolarizations and triggered arrhythmias.19 Altered intercellular coupling Gap junctions mediate electrical coupling between cardiac myocytes, forming the cell-​to-​cell pathways for an orderly spread of the wave of electrical excitation responsible for synchronous contraction.45 Interestingly, both downregulation46–​48 and dephosphorylation47 of connexin-​43 (Cx43), a major gap junctional protein, have been

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described as a general feature of HF. In support of this, samples collected from human explanted hearts showed reduction of Cx43, and redistribution to other regions of the cardiomyocyte distant from their physiologic localization at the intercalated disc.48 Different studies have proposed a link between Cx43 expression and reduced sodium current amplitude in ventricular49,50 and atrial cardiomyocytes,51 while super-​resolution fluorescence localization microscopy in murine adult cardiomyocytes demonstrated that the NaV1.5 channels that conduct the inward sodium current, localization at the intercalated disks is Cx43-​dependent.52 Therefore, it is not surprising to observe a reduction of the peak sodium current density in HF cardiomyocytes.33 The role of these alterations in cell-​to-​cell communication in HF is pivotal in the arrhythmogenesis, since intercellular uncoupling, combined with a reduction of peak sodium current, results in slowed conduction, thereby increasing the susceptibility of the failing heart to re-​entrant arrhythmias.45

Metabolic abnormalities Neurohormonal activation The decreased cardiac output in HF results in a series of maladaptive compensatory mechanisms which can contribute to arrhythmogenesis. These include the activation of the adrenergic nervous system and the renin-​angiotensin system (RAS). It is well established that neurohumoral activation may influence the substrate in the failing heart and may represent a trigger for lethal VA. Both experimental evidence53 and clinical studies5,54 have demonstrated a clear association between adrenergic system and RAS activation and SCD. In 2000, Cao and colleagues demonstrated in ventricular biopsy and autopsy specimens a correlation between VAs and increased density of sympathetic nerves in patients with HF, suggesting that abnormally increased post-​injury sympathetic nerve density may contribute to the occurrence of ventricular tachyarrhythmias and SCD.55 With regards to RAS activation, it has been observed that transgenic overexpression of angiotensin-​ converting enzyme-​ related carboxypeptidase (ACE2) in mice induced connexin dysregulation, and presumably gap junction remodeling, resulting in profound electrophysiological disturbances and an increased rate of SCD.56 Electrolyte abnormalities Other metabolic alterations involved in the arrhythmogenesis of HF include electrolyte imbalance, especially alterations of serum levels of potassium and magnesium. Both hypokalaemia and hyperkalaemia can potentiate the already elevated risk of arrhythmias in patients with HF.57,58 Hypokalaemia can result from the adaptive activation of RAS or can be secondary to the use of loop diuretics, while hyperkalaemia is usually due to the use of RAS inhibitors. Additionally, patients with chronic HF frequently have clinically relevant abnormalities of the serum magnesium, which has been associated a high prevalence of VAs and an increased risk of SCD.59

Risk stratification As previously highlighted, SCD is a major cause of death in HF patients,60 and hence an appropriate arrhythmic risk stratification

is mandatory. At the same time, in the post-​DANISH trial world risk stratification represents a challenging issue for the physician. There are factors which have been extensively explored and proved to be strongly associated with SCD, such as a reduced LVEF and a higher NYHA functional class.61 However, other factors may be considered and could represent future opportunities to provide a more accurate definition of the SCD risk in these patients. Among these promising new risk stratification approaches, it is important to mention the emerging role of cardiac magnetic resonance imaging and genetic analysis, as well as the identification of novel serum and electrophysiological markers. Moreover, it should be kept in mind that patients with HF present with a wide range of comorbidities and, consequently, there are competing risks contributing to overall mortality, both cardiovascular (e.g. non-​tachyarrhythmic events such as bradyarrhythmias; non-​shockable rhythms; and vascular accidents) and non-​cardiovascular (e.g. cancer, metabolic diseases, etc.), which ought to be considered in the occurrence of SCD, making risk stratification in these patients even more difficult.62

LVEF and NYHA class An LVEF ≤ 35% in patients with a NYHA II or III functional class is a well-​established predictor of SCD, and it still represents, according to the current ESC guidelines, the main indication for ICD use in primary prevention of SCD.61 However, some studies showed that the rate of appropriate ICD shocks in these patients may be overestimated,63,64 proving that risk stratification needs to be refined. It should be considered that solid data in support of the use of LVEF ≤ 35% derive from studies like MADIT I, MADIT II, and SCD-​HeFT that were published between 1996 and 2005,65–​67 and that the pharmacological treatment has changed remarkably since then. It would be reasonable to re-​evaluate whether the currently used threshold for EF would still confirm the same predictive value in the patients of today. Unfortunately, the Class I recommendations for the use of the ICD68 have become an obstacle to the organization of a novel trial because randomizing patients to an ICD arm or to a no-​ICD arm would deprive those the subjects randomized to the no-​ICD treatment of a Class I recommended therapy (the ICD), thus constituting a legal and ethical obstacle. Serum biomarkers The identification of serum biomarkers that are indicators of patients at higher risk for SCD could provide other helpful and non-​ invasive methods to improve risk stratification in HF. Serum B-​type natriuretic peptide (BNP) or its precursor N-​ terminal prohormone of brain natriuretic peptide (NT-​pro-​BNP) could be useful prognostic tools, since higher values of these peptides have been demonstrated to be associated with an elevated risk of VAs and SCD, both in HF with reduced69 and preserved LVEF.70 Similarly, to BNP and NT-​pro-​BNP, also higher levels of cardiac troponin T have been linked to a higher risk of VAs and SCD in patients with left ventricular dysfunction of both ischaemic and non-​ischaemic aetiology.71

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Recently, circulating microRNAs (miRNAs), which are involved in the biochemical pathways underlying pathological processes such as fibrosis, apoptosis, and inflammation, have been associated for the first time with a higher risk of SCD in patients with HF.72 Imaging markers Imaging techniques such as transthoracic echocardiography and contrast-​enhanced cardiac magnetic resonance imaging could be useful for early recognition of patients at higher risk of SCD. Enlargement of both LV and left atrium in patients with DCM has been associated with a higher risk of SCD and/​or major VAs.73 Speckle-​tracking echocardiography could be another useful tool for these patients, since arrhythmic events have been shown to be associated with lower values of LV global longitudinal strain and a higher mechanical dispersion of the LV.74 Cardiac magnetic resonance imaging allows both the assessment of the function and the morphology of the myocardium. Tissue characterization allows the assessment of replacement fibrosis using late gadolinium enhancement. A recent prospective multi-​ centre study on 1,508 patients with non-​ischaemic DCM identified midwall late gadolinium enhancement in more than three wall segments as an independent predictor of both overall mortality (HR: 2.077, 95% CI: 1.211–​3.562, P =​0.008) and major adverse arrhythmic events (HR: 1.693, 95% CI: 1.084–​2.644; P =​0.021).75 All these parameters could be of great interest since they may help identify patients with a normal LVEF but who are still at high risk of experiencing potentially fatal VA. Electrophysiological markers Several ECG parameters, including QRS duration, fragmented ECG complexes, signal-​ averaged ECG, microvolt T wave alternans and heart rate variability, have been proposed as prognostic indicators of VAs and SCD in HF, both in ischaemic and non-​ischaemic aetiologies.76–​82 However, the positive predictive accuracy of these parameters is still insufficient to allow them to be used as a risk-​stratification tool.76 Studies mainly conducted on patients with ischaemic HF, which evaluated the role of invasive electrophysiological testing to stratify the risk of SCD, have yielded conflicting results.76,83–​85 Importantly, in the MADIT II study, the inducibility of VAs during the electrophysiological study was associated with an increased risk of VT but not of VF.85 It should be highlighted that the discrepancies observed between the studies can be related to the differences in patient selection and stimulation protocols. A well-​known concept is that the more aggressive the stimulation protocol, the less specific is the result in the case of inducibility. Lastly, in patients with non-​ischaemic HF, inducible VTs during programmed ventricular stimulation identified a subgroup of patients at higher risk for an SCD surrogate, defined either as appropriate ICD shock or as documented SCD.86 Genetics Patients with HF of non-​ischaemic aetiology are frequently affected by primitive forms of cardiomyopathy,11 such as DCM and arrhythmogenic cardiomyopathy (ACM), two forms of

cardiomyopathy frequently overlapping with each other and typically caused by genetic mutations in genes encoding for structural proteins of the cardiomyocyte.87 The genetic background in these cases is of great help, and it has been extensively demonstrated how certain specific genetic mutations expose patients with familial forms of cardiomyopathy to a much higher risk of developing fatal VA. For instance, mutations in Lamin A/​C (LMNA)88,89 and filamin C (FLNC)90 genes, especially if non-​missense, are associated with a particularly high risk of major VAs. Other than the aforementioned, desmosomal gene mutations are also causative of particularly arrhythmogenic phenotypes, independently from the residual LVEF.13 Among desmosomal gene mutations, truncating mutations in the desmoplakin (DSP) gene lead to a particularly arrhythmogenic phenotype, compared to plakophilin-​2 (PKP2), the most commonly found gene in ACM.91,92 Lastly, other noteworthy gene mutations associated with highly arrhythmogenic forms of DCM/​ ACM are found in genes such as phospholamban (PLN, particularly the founder mutation p.Arg14del)93 or RNA-​binding motif protein 20 (RBM20).94 Recognition of specific genetic profiles linked to a higher arrhythmic burden is critical and could represent a further step towards precision medicine in the field of HF. In clinical practice, this would translate into consideration of primary prevention of SCD for patients who do not still show an overt LV dysfunction but who are nonetheless at risk of fatal VAs based on the sole presence of specific genetic mutations. Myocardial sympathetic innervation Another risk factor which has been associated with a major risk of life-​threatening VAs in patients with ischaemic HF is an incremented inhomogeneity in myocardial sympathetic innervation, estimated by the extent of sympathetic denervation in the heart with PET imaging. Interestingly, the amount of denervated myocardium is associated with a higher risk of VAs independently from other parameters, such as LVEF or the extent of the infarcted area.95

Therapeutic approach The therapeutic approach to prevent ventricular arrhythmias and SCD in patients with HF is complicated by the multifactorial mechanisms that may generate rhythm disturbances. As described in the previous section, the aetiology of the ventricular dysfunction as well as the patient-​specific clinical characteristics, including comorbidities, concomitant therapies, and life expectancy may determine the prevailing arrhythmogenic mechanisms and therefore the most successful treatment. This section will illustrate the different therapeutic strategies available to date, including both pharmacological therapies, ablation procedures, and the implantable defibrillator.

Pharmacological treatment Optimal pharmacological therapy for HF: BBs, ACE-​I, and MRAs Current guidelines recommend the use of optimal pharmacological therapy with BBs, ACE-​I (or, when intolerant, angiotensin

chapter 12.6  

Ventricu l a r a rrhy thm ias a n d su dden death i n hea rt fa i lure

receptor blockers (ARBs)), and mineralocorticoid receptor antagonists (MRAs) titrated to the maximum tolerated dose, in all patients with HF and systolic dysfunction to reduce SCD and total mortality (Class I, level A indication).68,96 BBs constitute the cornerstone of pharmacological treatment for patients with HF and reduced ejection fraction. Several trials demonstrated their efficacy in reducing the risk of SCD, estimating the risk reduction at 40%, and overall mortality, estimating it at approximately 35%, in cohorts recruiting both ischaemic and non-​ischaemic HF patients.10,54,97–​101 At variance with BBs, beneficial effects of ACE-​I on mortality seem to be related more to a slowing of HF progression than a specific reduction of SCD.102,103 However, ACE-​ I occasionally causes worsening of renal function, hyperkalaemia, symptomatic hypotension, cough, and, rarely, angioedema. Therefore, ACE-​i should only be used in patients with adequate renal function (estimated GFR (eGFR) ≥30 mL/​min/​1.73 m2) and a normal serum potassium.104 It has been demonstrated that addition of MRAs reduce mortality and rates of SCD in patients with HF treated with ACE-​Is and BBs.68 Pitt and colleagues demonstrated in 1999 that spironolactone reduced the risk of SCD by 29% in an RCT involving patients with both ischaemic and non-​ischaemic HF.5 The same group, in 2003, demonstrated that also eplerenone, a selective aldosterone blocker, titrated to a maximum of 50 mg per day reduced the rate of SCD by 21% in patients with LV dysfunction after MI. MRAs can cause hyperkalaemia and worsening renal function, which were uncommon in the RCTs, but may occur more frequently in common clinical practice, especially in elderly and comorbid patients. Both should be used in patients with adequate renal function and a normal serum potassium.104 Angiotensin receptor neprilysin inhibitor (sacubitril/​valsartan) McMurray and colleagues8 demonstrated the superiority of sacubitril/​valsartan over enalapril in reducing the overall mortality in HF patients with elevated plasma BNP levels (BNP ≥ 150 pg/​mL or NT-​proBNP ≥ 600 pg/​mL or, if they had been hospitalized for HF within the previous 12 months, BNP ≥ 100 pg/​ mL or NT-​proBNP ≥ 400 pg/​mL), and eGFR ≥ 30 mL/​min/​1.73 m2 of body surface area, who were able to tolerate separate treatments periods with enalapril (10 mg twice a day) and sacubitril/​ valsartan (97/​103 mg twice a day) during a run-​in period. In the PARADIGM-​HF trial, Desai and colleagues105 examined the effect of sacubitril/​valsartan on the mode of death, demonstrating that the 20% reduction in cardiovascular death was attributable primarily to reductions in the incidence of both SCD (HR: 0.80, 95% CI: 0.68–​0.94, P: 0.008) and death due to progressive HF. Amiodarone The use of amiodarone in patients with HF is controversial. It has been proven that amiodarone does not have a favourable effect on survival,67,68,106 and additionally, its chronic use is profoundly limited by the presence of numerous end-​organ toxicities leading to thyroid, lung, and liver disease. The randomized double-​blind

placebo-​ controlled European Myocardial Infarct Amiodarone Trial (EMIAT)107 enrolled 1486 survivors of MI with LVEF ≤ 40%, demonstrating that amiodarone did not reduce the risk of all-​ cause mortality and cardiac mortality compared to placebo, while there was a 35% risk reduction in arrhythmic deaths. Similarly, a meta-​analysis conducted on 15 RCTs revealed that the use of amiodarone in patients with HF was neutral with respect to all-​ cause mortality, but it reduced by 26% the incidence of SCD, independently of dosage, aetiology of HF, and concomitant use of BBs.108 In the light of the aforementioned, there is no evidence for the systematic prophylactic use of amiodarone in all patients with depressed LV function, but amiodarone may be reasonably used in optimally treated HF patients with previous VTs who are not eligible for an ICD or in HF patients treated with an ICD and symptomatic VAs or recurrent shocks.2 With regards to amiodarone, its use in the context of Chagas disease merits a special mention. In fact, there is some evidence that amiodarone has a specific anti-​T. cruzi activity, disrupting parasites’ Ca2+​ homeostasis and blocking ergosterol biosynthesis.109 A recent meta-​analysis showed that amiodarone is effective in reducing VA in patients with Chagas disease, but this analysis did not identify sufficient data regarding its effect on SCD reduction.110 Class I anti-​arrhythmic drugs In 1991, a seminal study designed to test the hypothesis that suppression of ventricular ectopies after a MI would result in reducing post-​ischaemic SCD (CAST trial) showed that the use of class I anti-​arrhythmic drugs (AADs) was paradoxically associated with an increased risk of arrhythmic death.111 It is thought that the pro-​arrhythmic properties of these drugs, which are blockers of the sodium channel, in the context of HF are related to their effect on slowing of conduction velocity, which might facilitate the onset of re-​entry arrhythmias. As a consequence of this game-​changing finding, class I AADs are contraindicated in patients with HF.68,96 Two possible exceptions to this indication are represented by quinidine and mexiletine, which have been used alone or in conjunction with other class III AADs to achieve arrhythmia suppression in patients with HF, albeit this indication has never been formally evaluated in the context of RCTs.1 Diuretics and digoxin Diuretics and digoxin are still used by many patients with HF, but they do not reduce rates of all-​cause mortality or SCD,68 and provide only symptomatic relief.

Device therapy Implantable cardioverter defibrillator in secondary prevention of SCD An ICD is recommended to reduce the risk of SCD and all-​cause mortality in patients with HF who have recovered from a VA causing haemodynamic instability, and who are expected to survive for > 1 year with good functional status.96 This recommendation is supported by the data that ICD implantation reduces by 28% the risk of death, due to a 50% reduction in SCD risk.112

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C omorbidit ies and clinical c on di ti on s

Implantable cardioverter defibrillator in primary prevention of SCD The current risk stratification scheme for the prediction of life-​ threatening VAs in patients with HF is based mainly on the degree of systolic dysfunction of the LV, with LVEF < 35% set as the high-​risk threshold for SCD, based on the results of RCTs. Current guidelines recommend the use of an ICD in patients with symptomatic HF (NYHA class II–​III) and LVEF ≤ 35% after ≥ 3 months of optimal medical therapy who are expected to survive for at least 1 year with good functional status, with a class I level A indication in patient with ischaemic aetiology and class I level B indication in patients with non-​ischaemic aetiology.68 While there are more data to support the use of ICDs in ischaemic HF, in patients with non-​ischaemic aetiologies reduction in all-​cause mortality and arrhythmic mortality is supported as well (% Table 12.6.1). The recent DANISH trial119 conducted on 1,116 patients with symptomatic non-​ischaemic HF (LVEF≤35%) demonstrated that prophylactic ICD implantation was associated with a significant reduction of SCD, but it was not associated with a significant reduction in the long-​term overall mortality. However, it is remarkable that the subgroup analyses in the DANISH trial revealed that age was the only factor showing a significant interaction with the treatment (ICD or not ICD). Indeed, the rate of death from any cause was significantly lower among patients younger than 68 years than among patients 68 years of age or older (HR: 0.64, 95% CI: 0.45–​0.90, P =​0.01). Put together, these data highlight the pressing need to consider the competitive risks of death when managing patients with HF. Therefore, when evaluating the role of the ICD in reducing the overall mortality, it must be considered that the greater the competitive risk of dying suddenly, the greater the utility of ICD. In other words, it is not a mere question of establishing whether the ICD itself would be effective or not, but rather of identifying the patients in which the competitive risk of dying suddenly is greater than other causes of death, and who could hence benefit the most from the implant. A recent meta-​analysis (% Figure 12.6.4) collected all available RCTs comparing the role of ICD in primary prevention of SCD. Although ICD therapy was associated with a statistically significant reduction in SCD in all three groups studied (i.e. patients with acute MI, ischaemic HF, non-​ischaemic HF), the effects on overall mortality were consistently different. Two RCTs114,115 did not demonstrate a beneficial role of ICD implanted within 40 days after an MI in reducing the overall mortality and, accordingly, an ICD is contraindicated in this time period. In a meta-​ analysis of 11 trials, the authors demonstrated a significant and quantitatively reproducible reduction in death from any cause in patients with HF and reduced ejection fraction resulting from both ischaemic and non-​ischaemic disease (HR 0.76), thus providing strong support for the role of ICD implant primary prevention of SCD also in patients with non-​ischaemic aetiologies.121 However, when dealing with patients with non-​ischaemic HF, the underlying cause of the disease needs to be considered in the therapeutic choice, particularly in the case of inherited cardiomyopathies. Both DCM and ACM can progress to HF, sometimes

with overlapping phenotypes between the two. In particular, the growing use of genetic analysis in clinical practice in the last decade has brought increasingly strong evidence about the existence of subgroups of patients with inherited cardiomyopathies who are at higher risk of SCD. Although genotype–​phenotype correlations in the literature are still scarce, the emerging issue is that the use of LVEF ≤ 35% as the only risk marker for patients with cardiomyopathy-​related HF is not sufficient to assist the physicians in selecting the patients most likely to benefit from an ICD implantation in primary prevention of SCD. Consequently, current guidelines suggest the use of LVEF < 45% as the threshold for ICD implantation in patients with mutations in LMNA, FNLC, and PLN.68,122 Moreover, as a general concept, patients with inherited cardiomyopathies should be referred to highly specialized tertiary centers and undergo there an evaluation specifically tailored on their phenotype and risk factors. Cardiac resynchronization therapy Two RCTs (COMPANION, CARE-​HF)120,123 randomized patients with moderate to severe symptomatic HF (NYHA class III or IV) and QRS duration ≥ 120 ms to either optimal medical therapy or optimal medical therapy plus cardiac resynchronization therapy (CRT). The COMPANION trial120 demonstrated that CRT-​ pacemaker (CRT-​P) and CRT-​defibrillator (CRT-​D) reduced the all-​cause mortality by 24% and 36%, respectively, but only CRT-​D reduced the rate of SCD. The CARE-​HF trial123 demonstrated that CRT-​P reduced both the overall mortality by 40% and the risk of SCD by 46%. Other two RCTs124,125 enrolled patients with mild or moderate symptoms and showed that CRT-​D was superior to ICD alone in reducing the overall mortality. Importantly, different meta-​analyses126,127 conducted on these RCTs revealed that CRT was beneficial only in patients with left bundle branch block, and not in patients with other types of conduction defects. Accordingly, current guidelines recommend CRT for patients with HF and LVEF ≤ 35% who have a life expectancy with good functional status of > 1 year if they are in sinus rhythm and have a markedly prolonged QRS duration (≥ 130 ms) and an ECG that shows left bundle branch block, irrespective of symptom severity.

Catheter ablation Although ICDs effectively terminate life-​threatening VAs, they do not prevent arrhythmia recurrence. For the purpose of prevention of arrhythmic recurrence, catheter ablation is used in patients with recurrent ICD shocks due to sustained VT.68 Nonetheless, the available evidence does not support a benefit of VT catheter ablation to reduce mortality, as confirmed also by a recent meta-​ analysis.128 Therefore, it is important to highlight that catheter ablation cannot be considered as an alternative to ICD implantation. As previously highlighted, in patients with ischaemic HF, scar-​ mediated macro-​ re-​ entry is the common pathophysiological mechanism and catheter ablation targets the isthmus of slow conduction (critical isthmus) within VT re-​entry circuit. Several studies have evaluated the role of catheter ablation in the treatment of VTs, in different populations: (1) patients with recurrent ICD shocks, (2) patients with a first episode of VT, and (3) patients with electrical storms.

196 1232 674 898

Moss, 1996

Moss, 2002

Hohnloser, 2004

Steinbeck, 2009

MADIT-​I

MADIT-​II

DINAMIT

IRIS

104 103 458 1116

Bänsch, 2002

Strickberger, 2003

Kadish, 2004

Køber, 2016

CAT

AMIOVIRT

DEFINITE

DANISH

1520 1676

Bristow, 2004

Bardy, 2005

COMPANION

SCD-​HeFT

ICD vs SMT

CRT-​D vs SMT

Randomized Study groups (N)

Author, year

Colonna1

Heart failure with both ischaemic and non-​ischaemic heart disease

ICD vs SMT

ICD vs SMT

ICD vs SMT

ICD vs SMT

Randomized Study groups (N)

Author, year

ICD vs SMT

ICD vs SMT

ICD vs SMT

ICD vs SMT

Colonna1

Heart failure without ischaemic heart disease

900

Bigger, 1997

CABG-​Patch

ICD vs SMT

Randomized Study groups (N)

Author, Year

Colonna1

Heart failure with ischaemic heart disease

45.5

15.8

Follow-​up (months)

67.6

29

24

66

Follow-​up (months)

37

30

20

27

32

Follow-​up (months)

NYHA 2-​3, OMT

NYHA 3-​4, recent HF hospitalization

Inclusion criteria

NYHA 2-​4, raised NT-​proBNP

Symptomatic DCM, ambient arrhythmias

NYHA 1-​3, asymptomatic

NYHA 2-​3, recent DCM diagnosis

Inclusion criteria

Recent MI

Recent MI

NYHA 1-​3, MI

NYHA 1-​3, MI, NSVT

Undergoing CABG, abnormal ECG

Inclusion criteria

-​

-​

Exclusion criteria

-​

NYHA 4, familial cardiomyopathy

Syncope

Valvular, HCM or restrictive, prior MI

Exclusion criteria

NYHA 4, VA before or ≥ 48 h after

NYHA 4

MI within 1 month

CA, syncopal VT

Sustained VT or VF

Exclusion criteria

Overall mortality

Death from or hospitalization for HF

Primary endpoint

Overall mortality

Overall mortality

Overall mortality

Overall mortality

Primary endpoint

Overall mortality

Overall mortality

Overall mortality

Overall mortality

Overall mortality

Primary Endpoint

0.77 (0.62–​0.96)

0.80 (0.68–​0.85)

HR (95% CI)

0.87 (0.68–​1.12)

0.65 (0.40–​1.06)

0.87 (0.32–​2.42)

0.80 (0.39–​0.64)

HR (95% CI)

1.04 (0.81–​1.35)

1.08 (0.76–​1.55)

0.69 (0.51–​0.93)

0.46 (0.26–​0.82)

1.07 (0.81–​1.42)

HR (95% CI)

Table 12.6.1  Randomized clinical trials conducted in primary prevention of SCD in patients with HF, divided by ischaemic or non-​ischaemic aetiology.

67

120

Reference

119

118

117

116

Reference

115

114

66

65

113

Reference

814

SECTION 12  

C omorbidit ies and clinical c on di ti on s HF with ischaemic heart disease Weight

ICD (N) | No ICD (N)

HR [95% Cl]

MADIT I 1996

95 | 101

12.85% 0.46 [0.26, 0.82]

MADIT II 2002

742 | 490

27.83% 0.69 [0.51, 0.93]

COMPANION 2004

325 | 331

26.28% 1.01 [0.74, 1.40]

SCD–HeFT 2005

431 | 452

33.04% 0.79 [0.62, 1.00]

100.00% 0.76 [0.60, 0.96]

Summary, random effects (p = 0.02)

0.25 0.50 1.00 2.00 ICD better Hazard ratio ICD worse

HF without ischaemic heart disease ICD (N) | No ICD (N)

Weight

HR [95% Cl]

CAT 2002

50 | 54

5.59%

0.80 [0.39, 1.64]

AMIOVIRT 2003

52 | 51

2.78%

0.87 [0.32, 2.42]

DEFINITE 2004

229 | 229

11.95%

0.65 [0.40, 1.06]

COMPANION 2004

270 | 285

12.28%

0.55 [0.34, 0.89]

SCD–HeFT 2005

398 | 394

24.91%

0.73 [0.52, 1.02)

DANISH 2016

556 | 560

42.49%

0.87 [0.68, 1.12]

100.00%

0.76 [0.64, 0.90]

Summary, random effects (p = 0.01) 0.25 0.50 1.00 2.00 4.00 ICD better Hazard ratio

ICD worse

Figure 12.6.4  Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-​analysis of 8567 patients in 11 trials.

Reproduced from Shun-​Shin MJ, Zheng SL, Cole GD, Howard JP, Whinnett ZI, Francis DP. Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-​analysis of 8567 patients in the 11 trials. Eur Heart J. 2017 Jun 7;38(22):1738-​1746. doi: 10.1093/​eurheartj/​ehx028 with permission from Oxford University Press.

The most extensively studied population is that of patients with ischaemic HF who experienced multiple ICD interventions. In the Cooled RF trial (2000) the elimination of all inducible VTs was achieved in 41% of patients and the rate of recurrence during 243 ± 153 days of follow-​up was 46%.129 The Multicenter Thermocool Ventricular Tachycardia Ablation Trial (2008) showed that catheter ablation abolished all inducible VTs in 49% of patients and freedom from recurrent VT at 6-​month follow-​up was achieved for 53% of patients.130 The EURO-​VT multicentre study (2009) assessed the efficacy and safety of electro-​ anatomical mapping in combination with irrigated ablation technology for ablation of recurrent VT after MI.131 Ablation was acutely successful in 81% of patients, and 49% of patients experienced VT recurrence after a mean follow-​up of 12 ± 3 months. The Post-​Approval THERMOCOOL VT Trial (2016)132 showed that 62% of patients were free from sustained VT recurrences at 6-​month follow-​up, with 41.3% of patients

reported being free of any VT at the 3-​year mark. The recent multicentre, randomized VANISH trial133 enrolled 259 patients with ischaemic cardiomyopathy and an ICD who continued to experience VT despite the use of AADs to compare the strategies of escalating anti-​arrhythmic therapy versus catheter ablation. Notably, there was a significant reduction of the composite primary outcome (i.e.,death, VT storm, or appropriate ICD shock) among patients undergoing catheter ablation than among those receiving an escalation in AAD therapy (HR: 0.72, 95% CI: 0.53–​0.98, P =​0.04). Consequently, according to the recent HRS/​EHRA/​APHRS/​LAHRS expert consensus statement,134 in patients with ischaemic HF who experience recurrent monomorphic VT despite chronic amiodarone therapy, catheter ablation is recommended in preference to escalating AAD therapy. Catheter ablation is also recommended in patients with recurrent symptomatic monomorphic VT despite AAD therapy, or when AAD therapy is contraindicated or not tolerated.134

chapter 12.6  

Ventricu l a r a rrhy thm ias a n d su dden death i n hea rt fa i lure

Other studies focused on the role of catheter ablation in patients who experienced their first episode of VT. In 2007, Reddy et al.135 conducted a RCT in which ablation was performed with the use of a substrate-​based approach in which the myocardial scar is mapped and ablated while the heart remains predominantly in sinus rhythm (i.e. without the need for VT induction). Interestingly, the authors observed a significant reduction of ICD therapy from 33% in the control group to 12% in the ablation group. The VTACH trial (2010)136 evaluated the role of prophylactic VT ablation before ICD implantation in patients with previous MI, reduced ejection fraction, and haemodynamically stable VT. Although catheter ablation did not affect mortality, the rate of survival free from recurrent VT over 2 years was higher in the ablation group (47%) compared with the control arm (29%). The CALYPSO pilot study found an increased time to first VT recurrence with ablation versus AADs,137 but on the other hand, the Substrate Modification Study (SMS) failed to meet its primary endpoint of time to first VT/​VF recurrence.138 However, in the SMS study catheter ablation reduced the total number of ICD interventions.138 Therefore, in patients with ischaemic heart disease and an ICD who experience a first episode of monomorphic VT, catheter ablation may be considered (Class IIb indication) to reduce the risk of recurrent VT or ICD therapies.134 Several studies evaluated the application of catheter ablation in patients with ICDs and with electrical storm, demonstrating that catheter ablation can terminate potentially life-​threatening electrical storms with high acute success rate, but with a significant mortality.139–​141 Therefore, in patients with ischaemic heart disease and VT storm refractory to AAD therapy, catheter ablation is currently recommended.134 While the role of catheter ablation has been well elucidated in patients with myocardial infarction and scar, the different structural substrate between patients with ischaemic or non-​ischaemic HF profoundly influences the outcome of the ablation procedure. In fact, areas of scar in non-​ischaemic cardiomyopathy (e.g. DCM, ACM) tend to be smaller and more often located in the mid-​myocardium or epicardial layers142 as compared to patients with ischaemic HF, and therefore, patients with VT related to post-​myocardial scar tend to have a better outcome following catheter ablation than patients with VT due to non-​ischaemic cardiomyopathy.15,142 Another intrinsic limit of ablative procedures in patients with non-​ischaemic cardiomyopathy is the progressive nature of the disease, which renders them non-​resolutive in the long run. Nonetheless, several studies have shown good results of ablation in patients with non-​ischaemic aetiology, with VT-​free survival ranging from 40% to 70% at 1 year post catheter ablation.143–​147 Given the presence of epicardial substrate and VT circuits that cannot be successfully ablated from the endocardium, in patients with non-​ischaemic cardiomyopathy epicardial mapping and catheter ablation can significantly reduce VT recurrence.148 However, due to an increased risk of complications or late adhesions preventing future pericardial access, current guidelines state that epicardial ablation may be reserved to first-​ line endocardial approach failures, except when ECG or imaging suggests a predominant epicardial substrate.134

Conclusions The clinical relevance of VAs in HF is related to the fact that they are a frequent cause of SCD, which, in turn, accounts for almost half of the deaths of these patients. When dealing with VAs and SCD in HF, the issue is complex and multifaceted, since HF is not a unitary clinical entity, but it rather represents the evolution of many heterogeneous cardiac conditions. Consequently, the arrhythmogenic mechanisms leading to VAs and SCD in HF are equally varied, involving several abnormalities at different levels: structural, metabolic, and cellular. In addition, associated comorbidities are a common feature of patients with HF and may have substantial influence on arrhythmias, their complications, treatment, prognosis, and mortality of patients with HF. Therefore, the clinical management of these patients is arduous, and synergistic combinations are often required to reach the goal of a personalized therapy. Current pharmacological therapies are effective in reducing the risk of life-​threatening VAs but do not abolish it and therefore SCD still remains a major cause of death in patients affected by HF. A difficult challenge for the clinician is to identify subjects who are at the highest risk of dying suddenly and who may benefit most from ICD implantation. The only risk factor which has been consistently and independently associated with SCD is represented by the reduction of LVEF. It is clear, however, that a single parameter cannot be the only guide for prevention of SCD and more refined risk stratification strategies are urgently needed.

References 1. Santangeli P, Rame JE, Birati EY, Marchlinski FE. Management of ventricular arrhythmias in patients with advanced heart failure. J Am Coll Cardiol. 2017;69:1842–​1860. 2. Lip GYH, Heinzel FR, Gaita F, et al. European Heart Rhythm Association/​ Heart Failure Association joint consensus document on arrhythmias in heart failure, endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. Eur J Heart Fail. 2015;17:848–​874. 3. Kannel WB, Plehn JF, Cupples LA. Cardiac failure and sudden death in the Framingham Study. Am Heart J. 1988;115:869–​875. 4. Shen L, Jhund PS, Petrie MC, et al. Declining risk of sudden death in heart failure. N Engl J Med. 2017;377:41–​51. 5. Pitt B, Zannad F, Remme WJ, Cody R, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–​717. 6. Eichhorn EJ, Domanski MJ, Krause-​Steinrauf H, Bristow MR, Lavori PW. A trial of the beta-​blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:1659–​1667. 7. Zannad F, McMurray JJ V, Krum H, et al. Eplerenone in pa tients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–​21. 8. McMurray JJ V, Packer M, Desai AS, et al. Angiotensin-​neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–​1004. 9. Cubbon RM, Gale CP, Kearney LC, et al. Changing characteristics and mode of death associated with chronic heart failure caused by left ventricular systolic dysfunction: a study across therapeutic eras. Circ Heart Fail. 2011;4:396–​403.

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C omorbidit ies and clinical c on di ti on s

10. 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–​2007. 11. Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13:368–​378. 12. Roger VL. Epidemiology of heart failure. Circ Res. 2013;113:646–​659. 13. Gigli M, Merlo M, Graw SL, et al. Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2019;74:1480–​1490. 14. Masarone D, Limongelli G, Rubino M, et al. Management of arrhythmias in heart failure. J Cardiovasc Dev Dis. 2017;4.(1):3 15. Nakahara S, Tung R, Ramirez RJ, et al. Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia. J Am Coll Cardiol. 2010;55:2355–​2365. 16. Eijgenraam TR, Silljé HHW, de Boer RA. Current understanding of fibrosis in genetic cardiomyopathies. Trends Cardiovasc Med. 2020;30:353–​361. 17. Pogwizd SM, Hoyt RH, Saffitz JE, Corr PB, Cox JL, Cain ME. Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart. Circulation. 1992;86:1872–​1887. 18. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation. 1993;88:1647–​1670. 19. Coronel R, Wilders R, Verkerk AO, Wiegerinck RF, Benoist D, Bernus O. Electrophysiological changes in heart failure and their implications for arrhythmogenesis. Biochim Biophys Acta. 2013;1832:2432–​2441. 20. Balaban G, Costa CM, Porter B, et al. 3D electrophysiological modeling of interstitial fibrosis networks and their role in ventricular arrhythmias in non-​ischemic cardiomyopathy. IEEE Trans Biomed Eng. 2020;67:3125–​3133. 21. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011;4:98–​108. 22. Verma A, Meris A, Skali H, et al. Prognostic implications of left ventricular mass and geometry following myocardial infarction: the VALIANT (VALsartan In Acute myocardial iNfarcTion) Echocardiographic Study. JACC Cardiovasc Imaging. 2008;1:582–​591. 23. Aronow WS, Epstein S, Schwartz KS, Koenigsberg M. Correlation of complex ventricular arrhythmias detected by ambulatory electrocardiographic monitoring with echocardiographic left ventricular hypertrophy in persons older than 62 years in a long-​term health care facility. Am J Cardiol. 1987;60:730–​732. 24. Zabel M, Koller BS, Sachs F, Franz MR. Stretch-​induced voltage changes in the isolated beating heart: importance of the timing of stretch and implications for stretch-​ activated ion channels. Cardiovasc Res. 1996;32:120–​130. 25. Franz MR. Mechano-​ electrical feedback. Cardiovasc. Res. 2000;45:263–​266. 26. Aiba T, Tomaselli G. Electrical remodeling in dyssynchrony and resynchronization. J Cardiovasc Transl Res. 2012;5:170–​179. 27. Beuckelmann DJ, Näbauer M, Erdmann E. Alterations of K+​currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73:379–​385. 28. Vermeulen JT, McGuire MA, Opthof T, et al.Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts. Cardiovasc Res. 1994;28:1547–​1554. 29. Tsuji Y, Opthof T, Kamiya K, et al. Pacing-​induced heart failure causes a reduction of delayed rectifier potassium currents along with

decreases in calcium and transient outward currents in rabbit ventricle. Cardiovasc Res. 2000;48:300–​309. 30. Li G-​R, Lau C-​P, Ducharme A, Tardif J-​C, Nattel S. Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol. 2002;283:H1031–​41. 31. Tsuji Y, Zicha S, Qi X-​Y, Kodama I, Nattel S. Potassium channel subunit remodeling in rabbits exposed to long-​term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-​rectifier changes. Circulation. 2006;113:345–​355. 32. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-​ calcium exchange, inward rectifier potassium current, and residual beta-​ adrenergic responsiveness. Circ Res. 2001;88:1159–​1167. 33. Valdivia CR, Chu WW, Pu J, et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol. 2005;38:475–​483. 34. Hegyi B, Bossuyt J, Griffiths LG, et al. Complex electrophysiological remodeling in postinfarction ischemic heart failure. Proc Natl Acad Sci U S A. 2018;115:E3036–​E3044. 35. Nattel S, Maguy A, Le Bouter S, Yeh Y-​H. Arrhythmogenic ion-​ channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87:425–​456. 36. Weiss JN, Garfinkel A, Karagueuzian HS, Chen P-​S, Qu Z. Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm. 2010;7:1891–​1899. 37. Michael G, Xiao L, Qi X-​Y, Dobrev D, Nattel S. Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis. Cardiovasc Res. 2009;81:491–​499. 38. Baartscheer A, Schumacher CA, Belterman CNW, Coronel R, Fiolet JWT. SR calcium handling and calcium after-​transients in a rabbit model of heart failure. Cardiovasc Res. 2003;58:99–​108. 39. Zarain-​Herzberg A, Afzal N, Elimban V, Dhalla NS. Decreased expression of cardiac sarcoplasmic reticulum Ca(2+​)-​pump ATPase in congestive heart failure due to myocardial infarction. Mol Cell Biochem. 1996;163–​164:285–​290. 40. Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res. 1993;72:463–​469. 41. Yoshiyama M, Takeuchi K, Hanatani A, et al. Differences in expression of sarcoplasmic reticulum Ca2+​-​ATPase and Na+​-​Ca2+​exchanger genes between adjacent and remote noninfarcted myocardium after myocardial infarction. J Mol Cell Cardiol. 1997;29:255–​264. 42. Winslow RL, Rice J, Jafri S, Marbán E, O’Rourke B. Mechanisms of altered excitation-​contraction coupling in canine tachycardia-​ induced heart failure, II: model studies. Circ Res. 1999;84:571–​586. 43. Wang Z, Nolan B, Kutschke W, Hill JA. Na+​ -​ Ca2+​exchanger remodeling in pressure overload cardiac hypertrophy. J Biol Chem. 2001;276:17706–​17711. 44. Schillinger W, Schneider H, Minami K, Ferrari R, Hasenfuss G. Importance of sympathetic activation for the expression of Na+​-​ Ca2+​exchanger in end-​stage failing human myocardium. Eur Heart J. 2002;23:1118–​1124. 45. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008;80:9–​19. 46. Wiegerinck RF, van Veen TAB, Belterman CN, et al. Transmural dispersion of refractoriness and conduction velocity is associated with heterogeneously reduced connexin43 in a rabbit model of heart failure. Hear Rhythm. 2008;5:1178–​1185.

chapter 12.6  

Ventricu l a r a rrhy thm ias a n d su dden death i n hea rt fa i lure

47. Ai X, Pogwizd SM. Connexin 43 downregulation and dephosphorylation in nonischemic heart failure is associated with enhanced colocalized protein phosphatase type 2A. Circ Res. 2005;96:54–​63. 48. Kostin S, Rieger M, Dammer S, et al. Gap junction remodeling and altered connexin43 expression in the failing human heart. Mol Cell Biochem. 2003;242:135–​144. 49. Danik SB, Rosner G, Lader J, Gutstein DE, Fishman GI, Morley GE. Electrical remodeling contributes to complex tachyarrhythmias in connexin43-​deficient mouse hearts. FASEB J Off Publ Fed Am Soc Exp Biol. 2008;22:1204–​1212. 50. Jansen JA, Noorman M, Musa H, et al. Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice. Heart Rhythm. 2012;9:600–​607. 51. Desplantez T, McCain ML, Beauchamp P, et al. Connexin43 ablation in foetal atrial myocytes decreases electrical coupling, partner connexins, and sodium current. Cardiovasc Res. 2012;94:58–​65. 52. Agullo-​ Pascual E, Lin X, Leo-​ Macias A, et al. Super-​resolution imaging reveals that loss of the C-​terminus of connexin43 limits microtubule plus-​end capture and NaV1.5 localization at the intercalated disc. Cardiovasc Res. 2014;104:371–​381. 53. Yamada C, Kuwahara K, Yamazaki M, et al. The renin-​angiotensin system promotes arrhythmogenic substrates and lethal arrhythmias in mice with non-​ischaemic cardiomyopathy. Cardiovasc Res. 2016;109:162–​173. 54. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-​II): a randomised trial. Lancet. 1999;353:9–​13. 55. Cao JM, Fishbein MC, Han JB, et al. Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. Circulation. 2000;101:1960–​1969. 56. Donoghue M, Wakimoto H, Maguire CT, et al. Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol. 2003;35:1043–​1053. 57. Nolan J, Batin PD, Andrews R, Lindsay SJ, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-​heart). Circulation. 1998;98:1510–​1516. 58. Sarwar CMS, Papadimitriou L, Pitt B, et al. Hyperkalemia in Heart Failure. J Am Coll Cardiol. 2016;68:1575–​1589. 59. Gottlieb SS, Baruch L, Kukin ML, Bernstein JL, Fisher ML, Packer M. Prognostic importance of the serum magnesium concentration in patients with congestive heart failure. J Am Coll Cardiol. 1990;16:827–​831. 60. Alvarez CK, Cronin E, Baker WL, Kluger J. Heart failure as a substrate and trigger for ventricular tachycardia. J Interv Card Electrophysiol.. 2019;56:229–​247. 61. Priori SG, Blomström-​Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace 2015;17:1601–​1687. 62. Packer M. Nonarrhythmic sudden cardiac death in chronic heart failure –​a preventable event? JAMA Cardiol. 2019;4:721–​722. 63. Chen C-​Y, Stevenson LW, Stewart GC, et al. Real world effectiveness of primary implantable cardioverter defibrillators implanted during hospital admissions for exacerbation of heart failure or other acute co-​morbidities: cohort study of older patients with heart failure. BMJ. 2015;351:h3529. 64. Sabbag A, Suleiman M, Laish-​Farkash A, et al. Contemporary rates of appropriate shock therapy in patients who receive implantable

device therapy in a real-​world setting: From the Israeli ICD Registry. Heart Rhythm. 2015;12:2426–​2433. 65. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:1933–​1940. 66. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–​883. 67. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-​defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–​237. 68. Priori SG, Blomström-​Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death –​Web Addenda.. Europace. 2015;17:1601–​1687. 69. Levine YC, Rosenberg MA, Mittleman M, et al. B-​type natriuretic peptide is a major predictor of ventricular tachyarrhythmias. Heart Rhythm. 2014;11:1109–​1116. 70. Adabag S, Langsetmo L. Sudden cardiac death risk prediction in heart failure with preserved ejection fraction. Heart Rhythm. 2020;17:358–​364. 71. Nakamura H, Niwano S, Fukaya H, et al. Cardiac troponin T as a predictor of cardiac death in patients with left ventricular dysfunction. J Arrhythm. 2017;33:463–​468. 72. Silverman MG, Yeri A, Moorthy MV, et al. Circulating miRNAs and risk of sudden death in patients with coronary heart disease. JACC Clin Electrophysiol. 2020;6:70–​79. 73. Stolfo D, Ceschia N, Zecchin M, et al. Arrhythmic risk stratification in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2018;121:1601–​1609. 74. Haugaa KH, Goebel B, Dahlslett T, et al. Risk assessment of ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy by strain echocardiography. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2012;25:667–​673. 75. Guaricci AI, Masci PG, Muscogiuri G, et al. CarDiac magnEtic Resonance for prophylactic Implantable-​cardioVerter defibrillAtor ThErapy in Non-​ Ischaemic dilated CardioMyopathy: an international Registry.. 2021; Europace 2021;23:1072–​1083. 76. Goldenberg I, Huang DT, Nielsen JC. The role of implantable cardioverter-​ defibrillators and sudden cardiac death prevention: indications, device selection, and outcome. Eur Heart J. 2020;41:2003–​2011. 77. Hartikainen JE, Malik M, Staunton A, Poloniecki J, Camm AJ. Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signal-​ averaged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction. J Am Coll Cardiol. 1996;28:296–​304. 78. Bailey JJ, Berson AS, Handelsman H, Hodges M. Utility of current risk stratification tests for predicting major arrhythmic events after myocardial infarction. J Am Coll Cardiol. 2001;38:1902–​1911. 79. Huikuri H V, Raatikainen MJP, Moerch-​ Joergensen R, et al. Prediction of fatal or near-​fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J. 2009;30:689–​698. 80. Hombach V, Merkle N, Torzewski J, et al. Electrocardiographic and cardiac magnetic resonance imaging parameters as predictors of a worse outcome in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2009;30:2011–​2018. 81. Kitamura H, Ohnishi Y, Okajima K, et al. Onset heart rate of microvolt-​level T-​wave alternans provides clinical and prognostic value in nonischemic dilated cardiomyopathy. J Am Coll Cardiol. 2002;39:295–​300.

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82. Salerno-​Uriarte JA, De Ferrari GM, Klersy C, et al. Prognostic value of T-​wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol. 2007;50:1896–​1904. 83. Bourke JP, Richards DA, Ross DL, McGuire MA, Uther JB. Does the induction of ventricular flutter or fibrillation at electrophysiologic testing after myocardial infarction have any prognostic significance? Am J Cardiol. 1995;75:431–​435. 84. Roy D, Marchand E, Théroux P, Waters DD, Pelletier GB, Bourassa MG. Programmed ventricular stimulation in survivors of an acute myocardial infarction. Circulation. 1985;72:487–​494. 85. Daubert JP, Zareba W, Hall WJ et al. Predictive value of ventricular arrhythmia inducibility for subsequent ventricular tachycardia or ventricular fibrillation in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients. J Am Coll Cardiol. 2006;47:98–​107. 86. Gatzoulis KA, Vouliotis A-​I, Tsiachris D, et al. Primary prevention of sudden cardiac death in a nonischemic dilated cardiomyopathy population: reappraisal of the role of programmed ventricular stimulation. Circ Arrhythm Electrophysiol. 2013;6:504–​512. 87. McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res. 2017;121:731–​748. 88. van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Meta-​analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/​C mutations portend a high risk of sudden death? J Mol Med (Berl). 2005;83:79–​83. 89. van Rijsingen IAW, Arbustini E, Elliott PM, et al. Risk factors for malignant ventricular arrhythmias in lamin a/​c mutation carriers a European cohort study. J Am Coll Cardiol. 2012;59:493–​500. 90. Ortiz-​Genga MF, Cuenca S, Dal Ferro M, et al. Truncating FLNC mutations are associated with high-​risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol. 2016;68:2440–​2451. 91. López-​ Ayala JM, Gómez-​ Milanés I, Sánchez Muñoz JJ, et al. Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype. Europace. 2014;16:1838–​ 1846. . 2014;16:1838–​1846. 92. Smith ED, Lakdawala NK, Papoutsidakis N, et al. Desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy. Circulation. 2020;141:1872–​1884. 93. van der Zwaag PA, van Rijsingen IAW, Asimaki A, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14:1199–​1207. 94. van den Hoogenhof MMG, Beqqali A, Amin AS, et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling. Circulation. 2018;138:1330–​1342. 95. Fallavollita JA, Heavey BM, Luisi AJJ, et al. Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. J Am Coll Cardiol. 2014;63:141–​149. 96. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–​2200. 97. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-​ release metoprolol on total mortality, hospitalizations, and well-​being in patients with heart failure: the Metoprolol CR/​XL Randomized Intervention Trial in congestive heart failure (MERIT-​HF). JAMA. 2000;283:1295–​1302. 98. Packer M, Coats AJ, Fowler MB, et al.. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–​1658.

99. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–​1355. 100. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–​2199. 101. Flather MD, Shibata MC, Coats AJS, et al.. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–​225. 102. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–​1435. 103. Garg R, Yusuf S. Overview of randomized trials of angiotensin-​ converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450–​1456. 104. McMurray JJ V, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–​1847. 105. Desai AS, McMurray JJ V, Packer M, et al. Effect of the angiotensin-​receptor-​neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015;36:1990–​1997. 106. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival trial of antiarrhythmic therapy in congestive heart failure. N Engl J Med. 1995;333:77–​82. 107. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-​ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet. 1997;349:667–​674. 108. Piccini JP, Berger JS, O’Connor CM. Amiodarone for the prevention of sudden cardiac death: a meta-​analysis of randomized controlled trials. Eur Heart J. 2009;30:1245–​1253. 109. Benaim G, Sanders JM, Garcia-​Marchán Y, et al. Amiodarone has intrinsic anti-​Trypanosoma cruzi activity and acts synergistically with posaconazole. J Med Chem. 2006;49:892–​899. 110. Stein C, Migliavaca CB, Colpani V, et al.. Amiodarone for arrhythmia in patients with Chagas disease: A systematic review and individual patient data meta-​analysis. PLoS Negl Trop Dis. 2018;12:e0006742. 111. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781–​788. 112. Connolly SJ, Hallstrom AP, Cappato R, et al. Meta-​analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg . Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21:2071–​2078. 113. Bigger JTJ. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-​ artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med. 1997;337:1569–​1575. 114. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-​defibrillator after acute myocardial infarction. N Engl J Med. 2004;351:2481–​2488. 115. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med. 2009;361:1427–​1436.

chapter 12.6  

Ventricu l a r a rrhy thm ias a n d su dden death i n hea rt fa i lure

116. Bänsch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002;105:1453–​1458. 117. Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-​defibrillator:randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia—​AMIOVIRT. J Am Coll Cardiol. 2003;41:1707–​1712. 118. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151–​2158. 119. Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221–​1230. 120. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-​resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–​2150. 121. Shun-​Shin MJ, Zheng SL, Cole GD, Howard JP, Whinnett ZI, Francis DP. Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-​analysis of 8567 patients in the 11 trials. Eur Heart J. 2017;38:1738–​1746. 122. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16:e301–​e372. 123. Cleland JGF, Daubert J-​C, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–​1549. 124. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-​resynchronization therapy for the prevention of heart-​failure events. N Engl J Med. 2009;361:1329–​1338. 125. Tang ASL, Wells GA, Talajic M, et al. Cardiac-​resynchronization therapy for mild-​ to-​ moderate heart failure. N Engl J Med. 2010;363:2385–​2395. 126. Sipahi I, Chou JC, Hyden M, Rowland DY, Simon DI, Fang JC. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-​analysis of randomized controlled trials. Am Heart J. 2012;163:260–​7.e3. 127. Cunnington C, Kwok CS, Satchithananda DK, et al. Cardiac resynchronisation therapy is not associated with a reduction in mortality or heart failure hospitalisation in patients with non-​left bundle branch block QRS morphology: meta-​analysis of randomised controlled trials. Heart. 2015;101:1456–​1462. 128. Martinez BK, Baker WL, Konopka A, et al. Systematic review and meta-​analysis of catheter ablation of ventricular tachycardia in ischemic heart disease. Heart Rhythm. 2020;17:e206–​e219. 129. Calkins H, Epstein A, Packer D, et al. Catheter ablation of ventricular tachycardia in patients with structural heart disease using cooled radiofrequency energy: results of a prospective multicenter study. J Am Coll Cardiol. 2000;35:1905–​1914. 130. Stevenson WG, Wilber DJ, Natale A, et al. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial. Circulation. 2008;118:2773–​2782. 131. Tanner H, Hindricks G, Volkmer M, et al.. Catheter ablation of recurrent scar-​related ventricular tachycardia using electroanatomical mapping and irrigated ablation technology: results of the prospective multicenter Euro-​VT-​study. J Cardiovasc Electrophysiol. 2010;21:47–​53. 132. Marchlinski FE, Haffajee CI, Beshai JF, et al. Long-​term success of irrigated radiofrequency catheter ablation of sustained ventricular

tachycardia: Post-​approval THERMOCOOL VT Trial. J Am Coll Cardiol. 2016;67:674–​683. 133. Sapp JL, Wells GA, Parkash R, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med. 2016;375:111–​121. 134. Cronin EM, Bogun FM, Maury P, et al. 2019 HRS/​EHRA/​APHRS/​ LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias.. Europace. 2019;21:1143–​1144. 135. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med. 2007;357:2657–​2665. 136. Kuck K-​H, Schaumann A, Eckardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet. 2010;375:31–​40. 137. Al-​Khatib SM, Daubert JP, Anstrom KJ, et al. Catheter ablation for ventricular tachycardia in patients with an implantable cardioverter defibrillator (CALYPSO) pilot trial. J Cardiovasc Electrophysiol. 2015;26:151–​157. 138. Kuck K-​H, Tilz RR, Deneke T, et al. Impact of substrate modification by catheter ablation on implantable cardioverter-​defibrillator interventions in patients with unstable ventricular arrhythmias and coronary artery disease: results from the multicenter randomized controlled SMS ( (Substrate Modification Study). Circ Arrhythm Electrophysiol. 2017;10.e004422 139. Carbucicchio C, Santamaria M, Trevisi N, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-​defibrillators: short-​and long-​term outcomes in a prospective single-​center study. Circulation. 2008;117:462–​469. 140. Deneke T, Shin D, Lawo T, et al. Catheter ablation of electrical storm in a collaborative hospital network. Am J Cardiol. 2011;108:233–​239. 141. Muser D, Liang JJ, Pathak RK, et al. Long-​term outcomes of catheter ablation of electrical storm in nonischemic dilated cardiomyopathy compared with ischemic cardiomyopathy. JACC Clin Electrophysiol. 2017;3:767–​778. 142. Mathuria N, Tung R, Shivkumar K. Advances in ablation of ventricular tachycardia in nonischemic cardiomyopathy. Curr Cardiol Rep. 2012;14:577–​583. 143. Proietti R, Essebag V, Beardsall J, et al. Substrate-​guided ablation of haemodynamically tolerated and untolerated ventricular tachycardia in patients with structural heart disease: effect of cardiomyopathy type and acute success on long-​term outcome.. Europace. 2015;17:461–​467. 144. Muser D, Santangeli P, Castro SA, et al. Long-​ term outcome after catheter ablation of ventricular tachycardia in patients with nonischemic dilated cardiomyopathy. Circ Arrhythm Electrophysiol. 2016;9:e004328. 145. Dinov B, Fiedler L, Schönbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-​VT) Study. Circulation. 2014;129:728–​736. 146. Tokuda M, Tedrow UB, Kojodjojo P, et al. Catheter ablation of ventricular tachycardia in nonischemic heart disease. Circ Arrhythm Electrophysiol. 2012;5:992–​1000. 147. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: An International VT Ablation Center Collaborative Group study. Heart Rhythm. 2015;12:1997–​2007. 148. Cano O, Hutchinson M, Lin D, et al. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol. 2009;54:799–​808.

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CHAPTER 12.7

Management of atrial fibrillation in heart failure Andreas Metzner, Laura Rottner, Ruben Schleberger, Fabian Moser, and Paulus Kirchhof Contents Introduction  821 Diagnostic approach to atrial fibrillation  822

Diagnostic algorithm  822 Specific aspects in patients with atrial fibrillation and heart failure  823

Therapeutic approach to atrial fibrillation  824

Treatment algorithm of the ESC atrial fibrillation guidelines 2020  824 Early rhythm control: The emerging treatment standard for patients with AF and heart failure  825 Antiarrhythmic medication or catheter ablation  825 Specific aspects of atrial fibrillation treatment in patients with heart failure  825

Future perspectives  828 Summary and key messages  828 References  828

Introduction Heart failure and atrial fibrillation are two of the epidemics in cardiovascular medicine and their incidences are expected to further rise in the future.1 Their prevalence in the USA is projected to increase to >770,000 newly diagnosed patients with heart failure in 2040,2 and from 3.3 million in 2020 to >5.1 millions of patients with atrial fibrillation in 2040.3,4 Approximately one in three patients with heart failure has atrial fibrillation, and vice versa.5–​7 One explanation is that both entities share identical risk factors. Arterial hypertension, diabetes mellitus, obesity, smoking, sleep apnoea, kidney disease, coronary artery disease, and valvular heart disease are conditions that may cause or contribute to both heart failure and atrial fibrillation.8 In addition, all inherited cardiomyopathies have a high incidence of concomitant atrial fibrillation, thus reflecting shared genetic causes and shared genomic traits.9 Heart failure and atrial fibrillation also sustain and aggravate each other. Heart failure may lead to left atrial enlargement, increasing left atrial pressure and functional mitral regurgitation, thus increasing the risk for atrial fibrillation. Atrial fibrillation reduces cardiac output and can even lead to tachycardia-​mediated cardiomyopathy.10 Some degree of tachycardiomyopathy can be detected in 20–​30% of patients suffering from atrial fibrillation.10 Patients with prevalent atrial fibrillation have a significantly higher risk for additional development for both, heart failure with preserved or reduced ejection fraction.11 Patients with heart failure also have a significantly higher risk of developing atrial fibrillation compared to patients without heart failure. It is more likely that atrial fibrillation antedates rather than follows heart failure. It was also shown that new onset atrial fibrillation in patients with heart failure and reduced or preserved ejection fraction significantly increases mortality when compared to patients with new onset of atrial fibrillation and without heart failure.11 These numbers and interrelations also demonstrate the highly relevant socioeconomic impact as well as present and future challenges for medical systems. Regarding treatment of atrial fibrillation in the setting of heart failure important trials were performed and published over recent years and improved our understanding of interactions of both conditions and, at the same time, challenged previous treatment recommendations. Studies such as the Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial12 or the Catheter Ablation of Atrial Fibrillation with Heart Failure13 trial randomized patients with atrial fibrillation and concomitant heart failure with reduced ejection fraction into antiarrhythmic drug-​ based and interventional ablation arms. While the first study defined recurrence of atrial fibrillation as the primary endpoint, the latter study defined a composite endpoint of death from any cause or worsening heart failure as the primary endpoint. Both studies found significant benefits for ablation of atrial fibrillation demonstrating the rising

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Confirm and characterize atrial fibrillation (‘CC’)

Therapeutic approach (‘ABC') Avoid stroke - Identify low-risk patients: CHA2DS2-VASc 0 (m)/1 (w) - Consider stroke prevention: CHA2DS2-VASc ≥1 (m)/≥2 (w) - Decide on: NOAC or Vit. K antagonist (TTR >70%) - Evaluate bleeding risk (HAS-BLED Score): risk reduction

Confirm - 12-lead ECG or 1-/3-lead ECG - AF with ≥30 sec duration

Better rhythm and rate control - Optimize rate control - Consider rhythm control: Antiarrhythmic drug/catheter ablation

Characterize – the 4S-AF Scheme - Stroke risk CHA2DS2-VASc score EHRA-symptom score - Symptom severity paroxysmal, persistent - Severity of AF burden Echo/MRI, biomarkers - Substrate severity

Comorbidities -Therapy of comorbities: Art. hypertension, diabetes mellitus, obstructive sleep apnoea syndrom etc. - Modify life style factors/risk factors: Weight loss, physical exercise, reduction of alcohol and nicotine consumption

Figure 12.7.1  The CC to ABC algorithm of the 2020 ESC atrial fibrillation guidelines. Based on more recent data, ‘B’ may refer to ‘Better rhythm and rate control’ in patients with atrial fibrillation and heart failure. The emphasis on rhythm control is emerging based on new evidence. AF, atrial fibrillation; Art., arterial; ECG, electrocardiogram; f, female; m, male; MRI, magnetic resonance imaging; NOAC, direct oral anticoagulant; TTR, time in therapeutic range.

importance of interventional treatment strategies. More recently, the EAST–​AFNET 4 trial showed that systematic rhythm control therapy, given to all patients irrespective of LV function (800/​ 2789 patients in that trial had heart failure), improves outcomes in patients with recently diagnosed atrial fibrillation compared to usual care.7,14 These favourable outcomes with regard to reduction of cardiovascular outcomes have been confirmed for the main cohort of the EAST-AFNET 4 trial and in several subgroup analyses.14a,14b The effectiveness of early rhythm control is mediated by the presence of sinus rhythm at 12 months in the EASTAFNET 4 trial.14c A recently published substudy of the CABANA trial suggests that atrial fibrillation ablation may have better outcomes than rhythm control using antiarrhythmic drugs in patients with heart failure.15 The sub-​analysis of patients with atrial fibrillation and heart failure randomized in the EAST—​AFNET 4 trial also underpins that systematic initiation of rhythm control therapy improves outcomes in patients with atrial fibrillation and heart failure across the spectrum of left ventricular functions.35 This chapter proposes a contemporary approach to the management of patients with atrial fibrillation and heart failure.

therapeutic approach to atrial fibrillation (CC: Confirm and characterise, ABC: Avoid stroke/​anticoagulation; better symptom control; cardiovascular risk factors and concomitant diseases; % Figure 12.7.1).16 Confirmation and characterization of atrial fibrillation are mainly based on widely available diagnostic tools and clinical scores. For in-​depth information about the underlying conditions and the myocardial substrate, especially in the context of heart failure, more specialized imaging tools like cardiac magnetic resonance imaging and laboratory markers might be necessary.

Diagnostic approach to atrial fibrillation

Confirmation of diagnosis To establish the diagnosis of atrial fibrillation, ECG documentation (> 30 seconds) is required. Implanted devices can detect atrial high-​rate episodes which might represent subclinical atrial fibrillation and require confirmation by conventional ECG. In addition, the ECG provides valuable information on the type of heart failure, e.g. showing bundle branch block, signs of ischaemia, and/​or of cardiomyopathies. The latter are of particular relevance in patients with atrial fibrillation and heart failure as all inherited cardiomyopathies can present with atrial fibrillation.

The symptoms of atrial fibrillation and heart failure often overlap and the two diseases often occur together. Screening for atrial fibrillation should thus be part of the work-​up of all patients with heart failure, and work-​up for heart failure is necessary in all patients with atrial fibrillation.

Diagnostic algorithm The current ESC atrial fibrillation guidelines contain the ‘CC to ABC pathway’ that offers guidance for the diagnostic and

Screening Although screening for atrial fibrillation is technically feasible using several different technical tools (e.g. Holter ECG and blood pressure monitors, implantable loop recorders, wrist bands, smart watches, and phones), data on screening benefit and optimal strategy are scarce. The guidelines recommend opportunistic screening in a population > 65 years (IB) and consideration of systematic screening in patients at high risk (e.g. > 75 years, IIaB). Based on the recently published STROKESTOP outcomes study, population-​based ECG screening could prevent strokes in the long term.16a

chapter 12.7  

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Characterization of atrial fibrillation The guidelines contain the mnemonic ‘4S-​AF-​Scheme’ (stroke risk; symptoms; severity of burden; substrate) for a comprehensive characterization of atrial fibrillation. The keywords can be addressed using the CHA2DS2-​VASc Score for stroke risk and the EHRA symptom score for symptom evaluation. For assessment of the substrate severity (e.g. atrial enlargement, dysfunction, and fibrosis), imaging technics like echocardiography and cardiac magnetic resonance imaging or biomarkers are helpful. Echocardiography Transthoracic echocardiography is the most useful, widely available tool in patients with suspected heart failure to establish the diagnosis and it provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, valve function, and pulmonary hypertension. Differentiation of patients with heart failure based on left ventricular ejection fraction, usually measured using echocardiography, is important in establishing the diagnosis and in determining appropriate treatment. The diagnosis of heart failure with preserved ejection fraction is more challenging than the diagnosis of heart failure with reduced ejection fraction. Left ventricular diastolic dysfunction is thought to be the underlying pathophysiological abnormality in patients with heart failure with preserved ejection fraction, thus its assessment plays an important role in diagnosis. Although echocardiography is at present the only imaging technique that can allow for the diagnosis of diastolic dysfunction, no single echocardiography variable is sufficiently accurate to be used in isolation to make a diagnosis of left ventricular diastolic dysfunction. Therefore, a comprehensive echocardiography examination incorporating all relevant two-​dimensional and Doppler data is recommended. In patients with atrial fibrillation transthoracic echocardiography is essential in the assessment of structural and functional changes (i.e. left atrial size, valvular abnormalities) and to guide treatment. Cardiac magnetic resonance imaging Magnetic resonance imaging is the gold standard for evaluation of cardiac morphology and measurements of volume, mass, and cardiac function. It is the best modality for patients with non-​ diagnostic echocardiographic studies, to visualize the right heart, and is the method of choice in patients with congenital heart disease.17 Magnetic resonance imaging also allows characterization of myocardial structure using late gadolinium enhancement along with T1 mapping. It thereby allows differentiation between ischaemic and non-​ischaemic origins of heart failure. In addition, it is useful to identify the presence of myocarditis and to diagnose specific cardiomyopathies, such as infiltrative processes or left ventricular non-​compaction. Patients with heart failure with reduced ejection fraction and atrial fibrillation without late gadolinium enhancement exhibited significantly greater improvement in systolic function after restoration of sinus rhythm. Further stratification with magnetic resonance imaging may identify patients who benefit from the restoration of sinus rhythm and certain therapies, such as catheter ablation.18 Although imaging of the ventricular myocardium is well

established, there are important limitations related to the spatial resolution of the thin atrial myocardium. Assessment of left atrial fibrosis with late gadolinium enhancement has been described but only rarely applied and reproduced in clinical practice.19 Further clinical limitations include lower availability and higher costs compared with echocardiography as well as safety issues in patients with certain implanted pacemakers or defibrillators. Biomarkers Natriuretic peptides, in particular B-​ type natriuretic peptide and its pro-​hormone fragment, are markers of cardiac load and stress, including end-​diastolic left ventricular pressure as they are released from cardiomyocytes in response to stretch. Elevated natriuretic peptides help establish an initial working diagnosis and to identify those who require further cardiac investigation. Patients with normal plasma concentrations are unlikely to have heart failure (high negative predictive value). Therefore, the use of natriuretic peptides is recommended for ruling-​out heart failure, but not to establish the diagnosis. Their plasma concentrations are elevated in patients with atrial fibrillation as well. Furthermore, natriuretic peptides provide prognostic information in patients with atrial fibrillation.20,20a Circulating biomarkers provide quantifiable measures of clinical or subclinical disease states in patients with atrial fibrillation and enable prediction of atrial fibrillation when long-​term monitoring or even an ECG is not feasible.21 Furthermore, biomarkers (e.g. troponin, natriuretic peptides, growth differentiation factor 15, von Willebrand factor, or bone morphogenic protein-​10) can help to estimate prognosis and assess risk once atrial fibrillation has been diagnosed. Clinical scores including biomarkers (e.g. the ABC-​stroke risk score considering age, previous stroke/​transient ischaemic attack, high-​sensitivity troponin T, and N-​terminal-​ prohormone B-​type natriuretic peptide) can improve stroke risk prediction significantly over clinical scores.22

Specific aspects in patients with atrial fibrillation and heart failure The diagnostic evaluation of patients presenting with atrial fibrillation and heart failure with preserved ejection fraction can be particularly challenging. It might be unclear which condition is predominantly responsible for the symptoms. In those cases, a stepwise approach has been suggested by the 7th AFNET/​EHRA consensus conference (% Figure 12.7.2).23 The first overtly presenting condition may stratify patients with primary and secondary causes, possibly enabling differential therapy. It has been proposed to observe the initial response to diuretics and a ‘diagnostic cardioversion’. This information can define the further management pathway including a potentially more aggressive rhythm control management. Those who respond well to diuretics may have heart failure with preserved ejection fraction as their predominant condition, while in those who respond well to cardioversion, atrial fibrillation may be the main driver of symptoms. The patients with predominant heart failure with preserved ejection fraction might potentially benefit more from identification and treatment of underlying risk factors. Patients predominantly suffering from atrial fibrillation may benefit from

823

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C omorbidit ies and clinical c on di ti on s

Cardioversion in specific symptomatic populations

Manage concomitant diseases and drivers Maintain sinus rhythm with AAD/ablation

Assess contribution of AF-related symptoms Focus on addressing underlying conditions

Cardioversion HFpEF predominant

AF predominant

Diuretic response test Specifically consider hypertension and ischaemia

Anticoagulation Heart rate control

Identify any initiating or precipitating factors Assess underlying comorbidities to ascertain temporality

Risk factor and comorbidity treatment

Figure 12.7.2  Acute management of patients presenting with atrial fibrillation and heart failure with preserved ejection fraction. This proposal for a sequence of acute interventions is based on expert consensus from the 7th AFNET/​EHRA consensus conference. This approach is expected to improve patient wellbeing and reduce incidence of adverse events. The lower staircase is a common to both management of heart failure with preserved ejection fraction and atrial fibrillation, the upper staircases illustrate separate management priorities. The approach may be adjusted in patients with early atrial fibrillation. AAD, antiarrhythmic drugs; AF, atrial fibrillation; HFpEF, heart failure with preserved ejection fraction.

antiarrhythmic drugs, cardioversion, or ablation to improve symptoms, disease substrate, and possibly even prognosis. Tachymyopathy Some patients with persistent atrial fibrillation and otherwise unexplained left ventricular systolic dysfunction suffer from an arrhythmia-​mediated cardiomyopathy, sometimes even despite adequate ventricular rate control. The left ventricular dysfunction is partially or even completely reversible in these patients. Frequently the clinical history cannot determine the temporal relationship of the two conditions. The restoration of sinus rhythm, and especially rhythm control therapy using catheter ablation, can lead to considerable improvements in left ventricular ejection fraction, cardiac remodelling, and functional capacity.18 Of note, systematic rhythm control therapy and symptom-​restricted rhythm control therapy have similar long-​term effects on left ventricular function in patients with recently diagnosed atrial fibrillation and heart failure, while systematic rhythm control improves outcomes.35 Coronary angiography is recommended in patients with heart failure and intermediate to high pre-​test probability of coronary artery disease in the presence of probable ischaemia in non-​ invasive stress test. Coronary angiography is also recommended in patients with a history of symptomatic ventricular arrhythmia or aborted cardiac arrest. In patients with a low pre-​test probability, the use of computed tomography is reasonable to determine whether an obstructive coronary artery disease is present.17

Therapeutic approach to atrial fibrillation Treatment algorithm of the ESC atrial fibrillation guidelines 2020 The Atrial Fibrillation Better Care (ABC) approach is part of the ESC guidelines as a recommendation for structured atrial fibrillation treatment.24 The acronym stands for Avoid stroke/​ anticoagulation, Better symptom control and Cardiovascular risk factors and concomitant diseases (% Figure 12.7.1). The approach has recently been evaluated in a post-​hoc analysis of the AFFIRM trial and achieved an improved outcome with less major adverse events in patients with multiple comorbidities.25 1. Acute atrial fibrillation therapy The ABC approach can generally be applied in the acute and long-​term care of patients with atrial fibrillation. In case of rapid ventricular response with haemodynamic instability, emergency electrical cardioversion might be necessary.16 Anticoagulation should be started as soon as possible and underlying heart failure as well as precipitating factors should be treated according to the respective guidelines. 2. Anticoagulation/​avoid stroke The CHA2DS2-​VASc score offers a compromise between practicability and accuracy making it an essential tool for stroke-​risk assessment, stroke prevention, and anticoagulation management. In individuals with CHA2DS2-​VASc score 2 (male) or 3

chapter 12.7  

M a nag em en t of atria l fi b ri l l ati on i n hea rt fa i lure

(female), oral anticoagulation is recommended. Frequent re-​ evaluations are important, as unknown risk factors may come to light during the time after first diagnosis of atrial fibrillation. The HAS-​BLED score should be applied in all patients before the beginning of anticoagulation to determine the bleeding risk, but it is generally recommended to modify risk factors and intensify surveillance instead of withholding anticoagulation. Direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) remain the preferred treatment. Dose reduction apart from evidence-​based recommendations should be avoided. 3. Rhythm and rate control therapy Rate control should be applied in every patient. The target heart rate is 30 seconds) was not associated to the primary endpoint, whereas an atrial fibrillation burden of 6% or less predicted freedom from the primary endpoint, compared to those with atrial fibrillation burden > 6%.42 Upcoming trials, such as RAFT-​AF (Randomized Ablation-​ based atrial Fibrillation rhythm control versus rate control Trial in patients with heart failure and high burden Atrial Fibrillation), will provide additional information on the effect of atrial fibrillation burden on post-​ablation outcome in patients with atrial fibrillation and heart failure.43 In their seventh EHRA/​AFNET 4 Consensus Statement, Fabritz et al. offer a recurrence-​risk-​based therapy selection (% Figure 12.7.3): patients at low risk of recurrence are offered initial therapy with antiarrhythmic drugs, patients at higher risk of recurrence would benefit from atrial fibrillation ablation, and those at highest risk of recurrent atrial fibrillation might benefit from initial combination therapy with ablation and antiarrhythmic drugs.23 Traditionally, the electrophysiology community has sought to treat the ‘ideal patient’ with the highest likelihood of acute and long-​term procedural success, i.e. a younger patient with recent-​ onset heart failure, recent-​onset atrial fibrillation, fast ventricular rates, idiopathic cardiomyopathy, absence of ventricular late gadolinium enhancement, lower ejection fraction, minimal to moderate left atrial enlargement (45 years)

Rotterdam (55–94 years)

Italy (>65 years)

Reykjavik (33–84) years

Prevalence of T2DM in HF

Copenhagen (mean 69 years)

USA, Olmsted County (mean 77 years)

Prevalence of T2DM without HF

Figure 12.8.1  Prevalence of T2DM in patients with heart failure in the general population. Reproduced from Pfeffer MA, Swedberg K, Granger CB, et al; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-​Overall programme. Lancet. 2003 Sep 6;362(9386):759-​66. doi: 10.1016/​s0140-​6736(03)14282-​1 with permission from Elsevier.

A meta-​analysis of 31 registries and 12 clinical trials with 381,725 patients with acute and chronic HF demonstrated that T2DM is an independent predictor of adverse long-​term outcomes, including all-​cause death (random-​effects hazard ratio,

1.28), cardiovascular death (random-​effects hazard ratio, 1.34) and HF hospitalizations (random-​ effects hazard ratio 1.35). In addition to known T2DM, pre-​diabetes and unrecognized T2DM also confer an increased risk of adverse clinical outcomes

Selected clinical trials of patients with HFrEF 1.79 (1.06–3.03) 2.08 (1.29–3.36)

Echo-CRT SOLVD

1.56 (1.30–1.83) 1.46 (1.26–1.70) 1.29 (1.1–1.5)

SENIORS

1.25 (0.99–1.58)

SHIFT

1.05 (0.91–1.20) 1.10 (0.96–1.25)

PARAGIGM-HF

MERIT-HF

1.08 (0.80–1.47) 0.97 (0.78–1.20)

HF-ACTION 0

0,5

1

1,5

2

2,5

Adjusted hazard ratios with 95% confidence intervals CV mortality All-cause mortality

Selected clinical trials of patients with HFpEF 1.59 (1.28–1.96) 1.59 (1.33–1.91)

I-Preserve TOPCAT DIG Preserved

1.51 (1.14–1.99) 1.48 (1.10–1.99)

1,4 1,45 1,5 1,55 1,6 Adjusted hazard ratios with 95% confidence intervals CV mortality All-cause mortality

Figure 12.8.2  The association of T2DM and all-​cause and cardiovascular mortality in clinical trials of patients with heart failure. Reproduced from Pfeffer MA, Swedberg K, Granger CB, et al; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-​Overall programme. Lancet. 2003 Sep 6;362(9386):759-​66. doi: 10.1016/​s0140-​6736(03)14282-​1 with permission from Elsevier.

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(albeit lower than known T2DM), both in patents with HFrEF and HFpEF.22,34 Not only does T2DM adversely affect morbidity and mortality in HF, but it also has unfavourable impact on symptoms, functional status, and quality of life, and increases the risk of complications, such as vascular events (myocardial infarction and stroke).35,36 In patients with HFpEF, the presence of T2DM was associated with increased markers of inflammation, fibrosis, and endothelial dysfunction, and echocardiographic evidence of greater LV hypertrophy, and elevated filling pressures.14,37 These patients also had more comorbidities (hypertension, renal dysfunction, obesity) and more pronounced congestion.14,15,38

Underlying mechanisms of HF in T2DM Despite long-​standing scientific research and much epidemiological evidence linking T2DM with HF, the mechanisms responsible for the development of HF in T2DM have not been fully elucidated.39 Among the most important and well understood contributors to HF in T2DM are myocardial ischaemia and infarction.40 Indeed, hyperglycaemia, hyperinsulinaemia, and proatherogenic dyslipidaemia in T2DM are associated with accelerated atherosclerosis, extensive epicardial coronary artery disease, and microvascular endothelial dysfunction. HF that develops in this setting of myocardial ischaemia and infarction usually takes the phenotype of HFrEF.40,41] However, HF in T2DM can occur in the absence of significant coronary artery stenosis, and most commonly manifests as HFpEF.40,41 In this setting, it was postulated that several complex and interrelated mechanisms, in combination with the effect of comorbidities (obesity, hypertension chronic kidney disease), underlie the pathophysiology of HF. These mechanisms may also contribute to the severity of HF in patients with concomitant myocardial ischaemia and vice versa. Hyperglycaemia leads to excessive production of advanced glycated end-​products (AGEs), which were associated with increased myocardial interstitial fibrosis, reduced LV compliance42,43 and the development of diastolic dysfunction.44 The interaction between AGEs and the vascular vessel wall leads to endothelial dysfunction, increased vascular permeability, leukocyte adhesion, activation of fibroblastsand promotion of vascular wall remodelling, which results in increased vascular stiffening.45 Hyperinsulinaemia and insulin resistance were associated with profound changes in myocardial metabolism, characterized by a shift away from glucose utilization towards increased use of free fatty acids.46,47 The metabolic shift is produced by impaired glucose uptake into the cardiomyocytes, and simultaneous increase in the availability of free fatty acids, triglycerides, and non-​esterified fatty acids abundantly produced by the liver. Since the uptake of free fatty acids is not insulin-​dependent, they become the preferred metabolic fuel for the myocardial energy production, at an expense of increased myocardial oxygen consumption, fragmentation of cellular mitochondrial network, and greater production of free oxygen species. Mitochondrial dysfunction and augmentation of oxidative stress directly contribute to the cardiac contractile

dysfunction in T2DM.48 In addition, increased uptake of non-​ esterified fatty acids, which are not a substrate for beta-​oxidation, results in their accumulation in the cardiomyocytes and perturbation in several cellular signalling processes, which is referred to as lipotoxicity.49,50 Cardiac magnetic resonance imaging was used to document that impaired insulin signalling is associated with a significant increase in cardiac lipid content.49 This leads to the activation of proinflammatory and profibrotic cytokines, excessive collagen deposition, and cardiomyocyte loss due to apoptosis, with a resultant increase in myocardial wall stiffness and impaired diastolic function. Diastolic dysfunction is further aggravated by the alteration in the expression and phosphorylation of titin protein in the cardiomyocytes. Impaired insulin signalling is responsible for a switch towards the more ‘stiffer’ titin isoform,51 which, in combination with titin hypo-​phosphorylation,52 leads to higher passive myocardial tension and impaired diastolic relaxation. In addition, inflammation and oxidative stress in T2DM foster the development of microvascular endothelial dysfunction.53 Lower bioavailability of nitric oxide in the myocardium, hampers titin phosphorylation and results in the activation of signalling pathways responsible for cardiomyocyte hypertrophy. Collectively, the pathological processes in T2DM portend the occurrence of myocardial contractile dysfunction, LV remodelling, and diastolic dysfunction, and the resulting HF phenotype depends on the prevailing pathophysiological mechanism. In addition, extra-​cardiac abnormalities associated with T2DM, such as obesity, impaired vascular stiffness, systemic endothelial dysfunction, autonomic nervous system perturbations and excessive kidney sodium and water retention, contribute to an increase in cardiac preload and afterload and the development of overt HF.54,55

Prevention of HF in T2DM SGLT2 are the first class of glucose-​lowering medications that have proven effective in reducing the risk of HF-​related events in patients with T2DM. They exert their glucose-​lowering effect by promoting urinary glucose excretion and have an additional modest diuretic, natriuretic, and uricosuric effects.56 However, cardiovascular benefits of SGLT2 inhibitors extend beyond glucose lowering and include several postulated mechanisms, which have not yet been conclusively proven. These include a reduction in plasma volume without neurohormonal activation, a decrease in blood pressure, favourable impact on cardiac and systemic metabolism, anti-​ inflammatory effects, improvement in endothelial function, increased erythropoiesis, and modulation of autophagy.57–​60 The favourable effect of SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, sotagliflozin) on risk reduction in HF hospitalization has been consistently demonstrated in patients with T2DM across a spectrum of cardiovascular risk and regardless of earlier HF history 61–​ 64 (% Table 12.8.1). Furthermore, SGLT2 inhibitors (canagliflozin, dapagliflozin and sotagliflozin) have also proven beneficial in reducing HF hospitalizations in patients with diabetic nephropathy65 or chronic kidney disease66,67 (% Table 12.8.1).

7,020 10,142

4,401

17,160

4,094

8246 10,584

EMPA-​REG OUTCOME61

CANVAS Program62

CREDENCE65

DECLARE TIMI-​5863

DAPA-​CKD66

VERTIS-​CV64

SCORED67

Empagliflozin

Canagliflozin

Canagliflozin

Dapagliflozin

Dapagliflozin

Ertugliflozin

Sotagliflozin

T2DM and Chronic kidney disease and established CV risk factors

T2DM and Established CVD

Chronic kidney disease and T2DM ~67%

T2DM and Established CVD (41%) CV risk factors (59%)

T2DM and Albuminuric chronic kidney disease

T2DM and Established CVD (66%); CV risk factors (34%)

T2DM and Established CVD

Patient characteristics

8.3%

8.2%

-​-​-​

8.3%

8.3%

8.2%

8.1%

HbA1c (mean)

31%

~24%

~11%

10%

~15%

14%

10%

History of HF

1.3 years

3.5 years

2.4 years

4.2 years

2.62 years

3.2 years

3.1 years

Follow-​up (mean or median)

*Coprimary efficacy outcomes. ** Composite of death from cardiovascular causes or hospitalization for heart failure. CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HbA1c, glycosylated haemoglobin A1c; HF, heart failure; HR, hazard ratio.

Patients, n

Trial

Medication

Table 12.8.1  Effect of SGLT2 inhibitors on risk reduction in CV outcomes and HF hospitalization

Total no. of deaths from CV causes, HF hospitalizations and urgent visits for HF 0.74 (0.63–​0.88); p7.5%) and T2DM-​related end-​organ damage, except for non-​ proliferative retinopathy, are relative contraindications for heart transplantation.93 In selected patients with uncontrolled T2DM, MCS may be considered as a bridge to candidacy.93 According to the US United Network of Organ Sharing database, concomitant T2DM is present in 18.1% of adult heart transplant recipients.94 Median survival following heart transplantation was similar in patients with uncomplicated T2DM (9.3 years) and those without T2DM (10.1 years), but when stratified by disease severity, heart transplant recipients with more severe T2DM (i.e. one of more T2DM-​related complications) had significantly worse survival compared to individuals without T2DM.94 Although acute rejection and the incidence of transplant coronary artery disease were similar in patients with and without T2DM, the risk of renal failure and severe infections was higher in patients with T2DM and inversely related to the number of T2DM-​related complications.94 There is also a risk of worsening glycaemic control with the use of immunosuppressive agents.

Glycaemic targets and the choice of glucose-​lowering medications in patients with HF and T2DM Although intensive glycaemic control provides long-​term benefits in the prevention of microvascular complications (retinopathy,

Dia b etes , predia b etes , a n d hea rt fa i lure

nephropathy, and peripheral neuropathy), it was not proven effective in reducing the risk of HF or cardiovascular mortality in patients with T2DM. A meta-​analysis of eight clinical trials, with a total of 37,229 patients with T2DM, did not show a significant difference in the risk of HF between intensive glycaemic control and standard of care treatment.95 Observational data suggest that in patients with HF receiving glucose-​lowering medications, the association between glycaemic control (i.e. HgA1c levels) and mortality appears to be U-​shaped,96, with the lowest mortality risk associated with modest glycaemic control (i.e. HbA1c levels 7.0–​7.9%). More recently, a focus has been put on cardiovascular outcomes and the associated risk of HF with several glucose-​lowering medications (dipeptidyl peptidase-​4 (DPP4) inhibitors, glucagon like peptide-​1 receptor agonists (GLP-​1 RA), and SGLT2 inhibitors). DPP-​4 inhibitors demonstrated non-​inferiority compared with placebo with respect to cardiovascular outcomes, but a concern has been raised about a significantly higher risk of HF hospitalizations with saxagliptin,97 a non-​significant increase in HF risk with alogliptin98 (% Table 12.8.2), as well as a non-​significant increase in mortality with vildagliptin in a small trial of patients with T2DM and HFrEF.99 GLP-​ 1 RA proved to be effective in reducing cardiovascular outcomes and likely have a neutral effect on the risk of HF in the general population of patients with T2DM (% Table 12.8.3). However, in two small, randomized trials of patients with HFrEF, the use of liraglutide led to more adverse CV events compared with placebo,100,101 which raised a safety issue for patients with HF. Although SGLT2 inhibitors had a varied effect on cardiovascular outcomes depending on the study medication and patient characteristics, all SGLT2 inhibitors have proven effective in reducing the risk of HF hospitalization in their respective trials, regardless of CV risk burden or a history of HF (% Table 12.8.1). Possible risks and recommendations on the use of DPP4 inhibitors, GLP-​1 RA, SGLT2 inhibitors and other glucose lowering medications for the treatment of T2DM in patients with HF are summarized in % Table 12.8.4.4.

Table 12.8.2  Risk of HF hospitalization associated with the use of PDD4 inhibitors compared with placebo in the pivotal cardiovascular outcome trials Medication

Trial

Patients, n

Patient characteristics

HbAic (mean)

History of HF

Follow-​up (mean or median)

HF hospitalization (HR, 95% CI)a

P-​value

Saxagliptin

SAVOR-​TIMI 5397,104*

16,492

Established CVD; multiple

8.0%

2105 (13%)

2.1 years

1.27 (1.07–​1.51)

0.007

CV risk factors 98

Alogliptin

EXAMINE

Sitagliptin

TECOS105

Linagliptin

106

CARMELINA

5380

Recent acute coronary syndrome

8.0%

1533 (28%)

1.5 years

1.07 (0.79–​1.46)

0.66

14,671

Established CVD

7.2%

2643 (18%)

3 years

1.00 (0.83–​1.20)

0.98

6991

High CV and renal risk 7.9%

1876 (27%)

2.2 years

0.90 (0.74–​1.08)

0.26

CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HbA1, glycated haemoglobin; HF, heart failure; HR, hazard ratio. *Treatment vs. placebo. Seferović PM, Coats AJS, Ponikowski P, et al. European Society of Cardiology/​Heart Failure Association position paper on the role and safety of new glucose-​lowering drugs in patients with heart failure. Eur J Heart Fail. 2020 Feb;22(2):196-​213. doi: 10.1002/​ejhf.1673. (C) European Society of Cardiology reproduced by Oxford University Press.

837

LEADER

SUSTAIN-​6

PIONEER 6’

EXSCEL

Harmony

Liraglutide

Semaglutide (subcutaneous)

Semaglutide (oral)

Exenatide

Albiglutide

REWIND

9901

9463

14,752

3183

3297

9340

6068

Patients, n

CV risk factors (68.5%)

Established CVD (31.5%)

Established CVD

CV risk factors (37%)

Established CVD (73%)

≥ 60 years and CV risk factors

Age > 50 years and established CVD; Age

≥ 60 years and CV risk factors

Age > 50 years and established CVD Age

> 60 years and CV risk factors

Age > 50 years and established CVD Age

Recent acute coronary syndrome

Patient characteristics

∼7.3%

∼8.7%

8.0%

8.2%

8.7%

853 (8.6%)

1922 (20%)

2389 (16%)

388 (12%)

777 (24%)

1667 (18%)

1358 (22%)

∼7.7% 8.7%

History of HF

HbA1c (mean)

5.4 years

1.5 years

3.2 years

1.3 years

2.1 years

3.8 years

2.1 years

Follow-​up (mean or median)

0.93 (0.77–​1.12) ‡

0.85 (0.70–​1.04)†

0.94 (0.78–​1.13)

0.86 (0.48–​1.55)

1.11 (0.77–​1.61)

0.87 (0.73–​1.05)

0.96 (0.75–​1.23)

HF hospitalization (HR, 95% CI)*

0.46

0.11

-​

-​

0.57

0.14

0.75

P-​value

CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HbAk, glycated haemoglobin; HF, heart failure; HR, hazard ratio. *Treatment vs placebo; †A composite of CV death or HF hospitalization. ‡HF hospitalization or urgent HF visit. Seferović PM, Coats AJS, Ponikowski P, et al. European Society of Cardiology/​Heart Failure Association position paper on the role and safety of new glucose-​lowering drugs in patients with heart failure. Eur J Heart Fail. 2020 Feb;22(2):196-​213. doi: 10.1002/​ejhf.1673. (C) European Society of Cardiology reproduced by Oxford University Press.

Dulaglutide

ELIXA

Lixisenatide

Outcome

Trial

Medication

Table 12.8.3  Risk of HF hospitalization associated with the use of GLP1 RA inhibitors compared with placebo in the pivotal cardiovascular outcome trials.

chapter 12.8  

Dia b etes , predia b etes , a n d hea rt fa i lure

Table 12.8.4  Risks, precautions, and recommendations for the use of glucose-​lowering medications in accordance with the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Medication

Risks and cautions

Recommendations for use

DPP4 inhibitors

Increase risk of HF hospitalization with saxagliptin.

Not recommended to reduce cardiovascular events in patients with HF

GLP-​1 RA

May be associated with increased risk of adverse events in HFrEF (liraglutide)

Not recommended to prevent HF events in patients with HF

SGLT2 inhibitors

Consistently lower risk of HF hospitalization

Recommended to prevent hospitalizations for HF, major cardiovascular events, end-​stage renal dysfunction, and cardiovascular death

Metformin

Increased risk of lactic acidosis in patients with eGFR 400

Kidney Heart

>200

>150