Cardiovascular Complications of Respiratory Disorders 9781849841184, 9781849841191

Table of contents :
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ERM_0_88_WEB.pdf
Preface
Guest Editors
Miguel ángel Martínez-García
Jean-Louis Pépin
Mario Cazzola
Introduction
References
Epidemiological aspects of cardiovascular and respiratory diseases
Abstract
Human disease burden
CVDs
Respiratory diseases
Epidemiological estimators
Mortality
Case fatality
Prevalence
Incidence
Disability-adjusted life years and its components
Risk factors
Costs
Discussion and challenging issues
Conclusion
References
Common pathophysiological pathways of the autonomic nervous system
Abstract
The autonomic cardiovascular system and its regulation
The autonomic cardiovascular system and its exploration
Microneurographic recording of sympathetic nerve activity
Baroreflex sensitivity
Heart rate variability
Circulating catecholamines
Other methods
The autonomic cardiovascular system and its consequences on CVDs
Autonomic stimuli in OSA and COPD
Impact of comorbidities and inflammation
High sympathetic activity and hypoxia as causes of metabolic dysfunction?
Muscle dysfunction and reduced physical activity
Autonomic activity as a potential therapeutic or adjuvant target
Conclusion
References
Murine models of cardiovascular damage in lung diseases
Abstract
Animal models of COPD
Cigarette smoke model
Elastase-induced emphysema model
Animal models of pulmonary fibrosis
Bleomycin model
Fluorescein isothiocyanate model
Silica model
Other models
Animal models of PH
MCT injury model
CH model
Combined models
Animal models of OSA
IH model
OSA model
SF model
Cardiovascular damage in OSA
Atherosclerosis
Endothelial dysfunction: functional and structural vascular remodelling
Hypertension, HF and AF
Time course and recovery
Dual effects of IH
Animal models of respiratory infections
Small-animal models
Large-animal models
Animal models of chronic lung diseases of prematurity
Hyperoxia model
Ventilation models
Inflammatory and genetically modified models
Ethical considerations
Conclusion
References
Cardiovascular disease in COPD
Abstract
Link between CVDs and COPD
Pathophysiological mechanisms leading to increased cardiovascular risk in COPD
Impact of CVD in COPD patients
Biomarkers and predictive models of cardiovascular risk in COPD patients
Teleological activities and paradoxical effects of brain natriuretic peptide in COPD
Link between COPD exacerbations and cardiovascular consequences
Conclusion
References
Management of patients with asthma or COPD and cardiovascular disease: risks versus benefits
Abstract
Choose treatment for asthma or COPD in the presence of CVD
Asthma
COPD
The impact of cardiovascular drugs on the lung
β-blockers
ACE inhibitors and AT1 receptor blockers
Statins
Antiplatelet drugs
Calcium channel blockers
Diuretics
Conclusion
References
Chronic asthma and the risk of cardiovascular disease
Abstract
Asthma and CAD
Potential mechanisms behind the association of asthma and CAD
The role of eosinophils in CAD
Sex differences and the risk of CAD in asthma
Age of onset of asthma and the risk of CAD
Smoking asthmatics and CAD
Allergic inflammation and CAD
Hyperresponsiveness of the vascular and nonvascular smooth muscle
Haemodynamic implications of severe asthma exacerbations
Asthma and hypertension
Asthma and stroke
Is asthma a hypercoagulable state?
Conclusion
References
Cardiovascular implications in bronchiectasis
Abstract
Pulmonary vessels and the diagnosis of bronchiectasis
Association between bronchiectasis and comorbid CVDs
Mechanistic links between bronchiectasis and CVDs
Pulmonary vascular disorders are prevalent in bronchiectasis
Can CVDs be identified early in bronchiectasis?
Haemoptysis and the association with vascular diseases in bronchiectasis
How best to identify bronchiectasis patients at risk of CVDs
Treatment interventions
Future research directions
References
Cardiovascular complications of cystic fibrosis
Abstract
Link between CVD and respiratory disease
Cardiovascular dysfunction in CF
PH
Cardiovascular risk factors in CF
CFTR dysfunction, inflammation and CVD
CFTR modulators, CVD and potential treatment strategies
Conclusion and the gaps in our knowledge
References
Cardiovascular consequences of sleep disordered breathing: the role of CPAP treatment
Abstract
OSA and systemic hypertension
Effects of CPAP
OSA, cardiac remodelling and HF
Effects of CPAP
OSA, atherosclerosis and CAD
OSA and atherosclerosis
Effects of CPAP
OSA and CAD
OSA and arrhythmias
AF in OSA patients
Effects of CPAP
Ventricular arrhythmias in OSA patients
Effects of CPAP
Conclusion
References
The heart in obesity hypoventilation syndrome
Abstract
Obesity and CVD
Cardiovascular morbidity and mortality in OHS
Pathophysiological mechanisms of CVD
Impact of treatment of OHS on cardiovascular risk
Role of weight loss and bariatric surgery
Role of positive airway pressure
Scientific basis of positive airway pressure
Role of oxygen therapy
Role of rehabilitation
Role of diuretics
Conclusion
References
Cardiovascular effects of innovative therapies in lung cancer
Abstract
Cardiovascular toxicities of targeted therapies: EGFR and ALK inhibitors
QT-interval prolongation and bradycardia
Thombotic events
Hypertension
Cardiac failure
Cardiovascular toxicities of anti-angiogenic agents
Hypertension and proteinuria
Pathophysiology
Prevention
Treatment
Cardiovascular toxicities of ICIs
Myocarditis
Pathophysiology
Diagnosis
Pre-therapeutic evaluation
Symptoms of cardiovascular complications
Diagnostic tests
Treatment of myocarditis
Conclusion
References
Cardiovascular implications of pulmonary hypertension due to chronic respiratory diseases
Abstract
Definition and classification
Pathophysiology
Epidemiology
COPD
IPF
CPFE syndrome
Other chronic respiratory diseases
Diagnosis
Pathological assessment
Treatment
COPD
Calcium-channel antagonists
Inhaled vasodilators
Phosphodiesterase type 5 inhibitors
Endothelin receptor antagonists
Recommendations
Chronic ILDs
Prostacyclins
Phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulators
Endothelin receptor antagonists
Recommendations
Other respiratory diseases
CPFE syndrome
LAM
OHS
Conclusion
References
Cardiovascular mortality and morbidity in pulmonary embolism
Abstract
Short-term mortality and morbidity
Mortality
Morbidity
Recurrent VTE
AF
Long-term mortality and morbidity
Mortality
Morbidity
Recurrent VTE
Post-PE syndrome
PE and specific cardiorespiratory conditions
VTE and arterial atherosclerosis
Sleep apnoea
Conclusion
References
The cardiovascular system in idiopathic pulmonary fibrosis
Abstract
Prevalence of cardiac involvement in IPF
CADs and IPF
PH in IPF
Arrhythmias in IPF
The potential cardiovascular impact of antifibrotic treatment
The impact of CVD on IPF morbidity
Challenges in the management of IPF
Conclusion
References
Cardiovascular consequences of community-acquired pneumonia and other pulmonary infections
Abstract
CAP
Epidemiology and burden disease
Type, frequency and timing of CVEs
Pathophysiological mechanisms
Systemic inflammation
Endothelial injury
Platelet activation
NETs
Direct organ damage
Other mechanisms
Risk factors and prediction tools: the role of biomarkers
Risk factors
The role of biomarkers
Other pulmonary infections
Prevention and treatment of cardiovascular complications
Vaccination
Antiplatelet agents
Statins
Macrolides
Corticosteroids
Other treatments
Future perspectives and needed studies
References
β2-adrenoceptor modulation in COPD and its potential impact on cardiovascular comorbidities
Abstract
β2-ARs in COPD
β2-ARs in COPD and in chronic CVDs
HF
Interferences with rhythm
Conclusion
References
Characterising the cardiovascular safety profile of inhaled muscarinic receptor antagonists
Abstract
Mechanisms that underlie the cardiovascular risk with inhaled mAChR antagonists
The cardiovascular risk associated with inhaled SAMAs
The cardiovascular risk associated with inhaled LAMAs
Tiotropium
Glycopyrronium
Umeclidinium
Aclidinium
The cardiovascular risk associated with inhaled dual bronchodilation
The cardiovascular risk associated with adding a LAMA to a LABA/ICS combination
Conclusion
References
Impact of inhaled corticosteroids in patients with cardiovascular disease
Abstract
Rationale for use of ICSs in COPD and asthma
Cardiovascular comorbidity in asthma and COPD
Effect of ICSs on cardiovascular risk and all-cause mortality
Observational studies
RCTs
Conclusion
References
Cardiovascular side-effects of common antibiotics
Abstract
Mechanisms of antibiotic-induced adverse CVEs
Rate-corrected QT-interval prolongation and risk of arrhythmia
Atherosclerosis
Aortic dissection or bleeding
Macrolide-induced adverse CVEs
Arrhythmia
Atherosclerosis worsening and MI
Fluoroquinolone-induced adverse CVEs
Arrhythmia
Aortic dissection or bleeding
Challenges in the current literature
Nature of the studies
Lack of adequate adjustment for confounders
Lack of animal models
Low odds ratios
Lack of data on pulmonary diseases
Limited data on long-term use of antibiotics
Weight of each risk factor
Clinical challenges and preventative strategies
Conclusion
References
The cardiovascular effects of xanthines and selective PDE inhibitors: a risk–benefit analysis
Abstract
Cardiovascular effects of xanthines
Selective PDE4 inhibitors
Cardiovascular effects of PDE4 inhibitors
Selective PDE3 inhibitors
Cardiovascular effects of PDE3 inhibitors
Bifunctional PDE3/4 inhibitors
Cardiovascular effects of bifunctional PDE3/4 inhibitors
References
Future challenges
Abstract
The traditional “one size fits all” approach to therapeutics
Precision medicine
Treatable traits
The future of cardiovascular diagnostics: the role of wearable technologies
The future of IHD detection and management
The future of HF management
Biomarkers in the management of cardiopulmonary conditions
The role of imaging in future cardiovascular assessment
AI and deep learning
Future approaches to cardiovascular comorbidities in patients with COPD and other chronic lung conditions
Future of CV management in patients with underlying chronic lung disease
Conclusion
References
Case 1
Question
Answer
References
Case 2
Question 1
Answer
Question 2
Answer
Question 3
Answer
Conclusion
References
Case 3
Answer
References

Citation preview

This Monograph provides an update on cardiovascular disease Pantone PASTEL 9081 CMJN Pantone 200 CMJN (darker) Pantone 647 CMJN complications and treatment Cyan 0for respiratory Cyan 0 Cyan 100implications Magenta 0 Magenta 100 Magenta 56 Yellow and 6 Yellow 70 Yellow 0 diseases, based on current scientific evidence considered Black 8 Black 14 Black 24 from an epidemiological, pathophysiological and clinical point of view. This book also discusses the future challenges when studying the complex relationship between these two groups of disorders.

Print ISBN: 978-1-84984-118-4 Online ISBN: 978-1-84984-119-1 June 2020 €60.00

9 781849 841184

ERS monograph 88

ISBN 978-1-84984-118-4 Print ISSN: 2312-508X Online ISSN: 2312-5098

Cardiovascular Complications of Respiratory Disorders

ERS monograph

ERS monograph Cardiovascular Complications of Respiratory Disorders

Pantone 200 CMJN (darker) Cyan 0 Magenta 100 Yellow 70 Black 14

Pantone 647 CMJN Cyan 100 Magenta 56 Yellow 0 Black 24

Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Miguel Ángel Martínez-García, Jean-Louis Pépin and Mario Cazzola

Cardiovascular Complications of Respiratory Disorders Edited by Miguel Ángel Martínez-García, Jean-Louis Pépin and Mario Cazzola Editor in Chief John R. Hurst This book is one in a series of ERS Monographs. Each individual issue provides a comprehensive overview of one specific clinical area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides factual and useful scientific detail, drawing on specific case studies and looking into the diagnosis and management of individual patients. Previously published titles in this series are listed at the back of this Monograph. ERS Monographs are available online at www.books.ersjournals.com and print copies are available from www.ersbookshop.com

Editorial Board: Mohammed AlAhmari (Dammam, Saudi Arabia), Sinthia Bosnic-Anticevich (Sydney, Australia), Sonye Danoff (Baltimore, MD, USA), Randeep Guleria (New Delhi, India), Bruce Kirenga (Kampala, Uganda), Silke Meiners (Munich, Germany) and Sheila Ramjug (Manchester, UK). Managing Editor: Rachel Gozzard European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK Tel: 44 114 2672860 | E-mail: [email protected] Production and editing: Caroline Ashford-Bentley, Claire Marchant, Kay Sharpe and Ben Watson Published by European Respiratory Society ©2020 June 2020 Print ISBN: 978-1-84984-118-4 Online ISBN: 978-1-84984-119-1 Print ISSN: 2312-508X Online ISSN: 2312-5098 Typesetting by Nova Techset Private Limited All material is copyright to ­European Respiratory Society. It may not be reproduced in any way including electronic means ­without the express permission of the company. Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editors or publishers.

ERS monograph

Contents Cardiovascular Complications of Respiratory Disorders

Number 88 June 2020

Preface

vii

Guest Editors

viii

Introduction List of abbreviations

xi xiv

1. Epidemiological aspects of cardiovascular and respiratory diseases 1 Joan B. Soriano and Roberto Elosua 2. Common pathophysiological pathways of the autonomic nervous system 12

Damien Viglino, Francois Maltais and Renaud Tamisier

3. Murine models of cardiovascular damage in lung diseases Isaac Almendros, Isabel Blanco, Maribel Marquina, Victor Ivo Peinado, Silvia Barril,

31

Ana Motos, Rosanel Amaro and Mireia Dalmases

Cardiovascular implications of specific respiratory disorders 4. Cardiovascular disease in COPD Paola Rogliani and Luigino Calzetta

47

5. Management of patients with asthma or COPD and cardiovascular disease: risks versus benefits

66

6. Chronic asthma and the risk of cardiovascular disease

82

7. Cardiovascular implications in bronchiectasis Wei-jie Guan, Yong-hua Gao, David de la Rosa-Carrillo and

96

8. Cardiovascular complications of cystic fibrosis Damian G. Downey and J. Stuart Elborn

108







Josuel Ora, Francesco Cavalli and Mario Cazzola

Franklin A. Argueta, Carlos L. Alviar, Jay I. Peters and Diego J. Maselli

Miguel Ángel Martínez-García

9. Cardiovascular consequences of sleep disordered breathing: 118 the role of CPAP treatment Maria R. Bonsignore, Salvatore Gallina and Luciano F. Drager 10. The heart in obesity hypoventilation syndrome 143 Victor R. Ramírez Molina, Juan Fernando Masa, Francisco J. Gómez de Terreros Caro,

Jaime Corral Peñafiel and Babak Mokhlesi

11. Cardiovascular effects of innovative therapies in lung cancer Anne-Claire Toffart, Hélène Pluchart and Nicolas Girard

154

12. Cardiovascular implications of pulmonary hypertension due to chronic respiratory diseases Etienne-Marie Jutant, Maria-Rosa Ghigna, David Montani and Marc Humbert

167

13. Cardiovascular mortality and morbidity in pulmonary embolism

184

14. The cardiovascular system in idiopathic pulmonary fibrosis Sy Giin Chong, Toyoshi Yanagihara and Martin R.J. Kolb

198

15. Cardiovascular consequences of community-acquired pneumonia and other pulmonary infections Raúl Méndez, Paula González-Jiménez, Laura Feced, Enrique Zaldívar and

212





Behnood Bikdeli, Carmen Rodríguez, Alberto García-Ortega and David Jiménez

Rosario Menéndez

Cardiovascular risk of pulmonary pharmacology 16. β2-adrenoceptor modulation in COPD and its potential impact on cardiovascular comorbidities

229

17. Characterising the cardiovascular safety profile of inhaled muscarinic receptor antagonists Daiana Stolz and Mario Cazzola

238

18. Impact of inhaled corticosteroids in patients with cardiovascular disease

251

19. Cardiovascular side-effects of common antibiotics

264

20. The cardiovascular effects of xanthines and selective PDE inhibitors: a risk–benefit analysis Roberta Fusco, Rosanna Di Paola, Salvatore Cuzzocrea, Maria Gabriella Matera

279







Maria Gabriella Matera and Reynold A. Panettieri Jr

Dharani Narendra and Nicola A. Hanania

Francesco Amati, Marta Di Pasquale, Marcos I. Restrepo, Judith Marin-Corral, Stefano Aliberti and Francesco Blasi



and Clive Page

The future 21. Future challenges Don D. Sin

287

Case reports

Case 1

300



Case 2

305



Case 3

314

Hirohito Sano, Taizou Hirano, Akira Koarai and Masakazu Ichinose Bruno Revol, Ingrid Jullian-Desayes, Renaud Tamisier and Marie Joyeux-Faure Samia Rached and Rodrigo Athanazio

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Preface John R. Hurst

CVD remains the most common cause of death in the world and people living with respiratory disease are at increased risk of cardiovascular events. Only by understanding the science that links both acute and chronic respiratory disease with cardiovascular events, such as myocardial infarction and stroke, and by using this knowledge to provide holistic care, can we ever hope to achieve the best outcome for our patients. It is therefore a pleasure to introduce and recommend to you this latest ERS Monograph, which focuses on the cardiovascular implications of respiratory disease, including the cardiovascular effects of drugs that we commonly use in respiratory medicine. One of the privileges of acting as Chief Editor of the Monograph, and serving on the Editorial Board, is selecting topics for future editions. We do this by considering the latest developments in respiratory medicine, reader surveys and analysing the use of previous editions. But this edition was different: the Guest Editors, Miguel Ángel Martínez-García, Jean-Louis Pépin and Mario Cazzola, came to the Editorial Board with a proposal and I congratulate and thank them for having the vision to develop the idea, and the skill and determination to deliver this excellent, state-of-the-art collection of review articles. They have assembled an impressive and authoritative collection of chapters. I would like to take this opportunity to also thank all the contributors. Whether you are a respiratory scientist or clinician, specialist or generalist, there is a topic and information for you here that is interesting and important. Read on! Disclosures: J.R. Hurst reports receiving grants, personal fees and non-financial support from pharmaceutical companies that make medicines to treat respiratory disease. This includes reimbursement for educational activities and advisory work, and support to attend meetings.

Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

https://doi.org/10.1183/2312508X.10005420

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Guest Editors Miguel Ángel Martínez-García Miguel Ángel Martínez-García is Section Head, Research Coordinator and Sleep Disordered Breathing Head of the Pulmonary Disorder Division of the University and Polytechnic La Fe Hospital in Valencia, Spain. His research mainly focuses on OSA and airway diseases, particularly bronchiectasis and COPD. Miguel Ángel is the author/co-author of six national/ international guidelines or task forces on sleep apnoea, bronchiectasis and COPD, and has had >200 peer reviewed scientific papers published. He has edited 10 books on respiratory diseases, and has received >40 grants and 12 scientific awards from national and international societies, including best reviewer of the European Respiratory Journal (ERJ) in 2014. His H-index is 36. Miguel Ángel has been a speaker at >200 invited lectures at national and international meetings. Miguel Ángel is currently a fellow of the European Respiratory Society (ERS), an Associate Editor of the ERJ and is a member of ERS’ sleep working group educational council. He is also a member of the bronchiectasias–airway disease working group of EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration). He has a Masters in airways disease, bronchiectasis and hospital management. Miguel Ángel was previous a member of the Scientific Committee of and is currently a member of the International Committee of SEPAR (Spanish Society of Pneumology and Thoracic Surgery). He is Director of the Bronchiectasis Scientific Program Project (PII) and Chair of the Spanish Bronchiectasis Registry (RIBRON) of SEPAR.

Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Jean-Louis Pépin Jean-Louis Pépin is Professor of Clinical Physiology at the University Grenoble-Alpes (UGA) (Grenoble, France). He is Head of the Clinic of Physiology, Sleep and Exercise at Grenoble University Hospital (CHUGA) (Grenoble, France), Director of the HP2 Laboratory (INSERM U1042, UGA; Hypoxia Pathophysiology), and vice-Dean of the Faculty of Medicine in charge of research and Scientific Director of clinical research at CHUGA. Jean-Louis is also the director of the UGA Chair of Excellence in e-health and integrated care and the Artificial intelligence Chair “Trajectories Medicine” (2018–2021). Jean-Louis graduated as: MD in 1987 at the University of Montpellier (Montpellier, France); MSc in 1990, in biophysiology at the University Claude Bernard, Lyon, France; and PhD in 1998, in cardiovascular adaptations induced by chronic hypoxia, at the University Joseph Fourier, Grenoble. In 1999, he was Visiting Professor at the Laboratory of Pulmonary Physiology of Harvard University (Boston, MA, USA). He achieved European certification in sleep medicine in 2013. Jean-Louis’ interests include clinical and translational research on the cardiovascular consequences of chronic and intermittent hypoxia, sleep apnoea, COPD and chronic respiratory failure. Jean-Louis runs the French National Prospective Registry of Sleep Apnea (RESAS), which has >120 000 subjects, and is involved in the European Sleep Apnea Database (ESADA). He has participated in several European and US thoracic society task forces, and is the former President of the French Sleep Research and Medicine Society. He has experience in innovation (he has >10 patents), in clinical trials and in industrial partnerships. He was the principle investigator of OPTISAS, a national telemedicine trial on sleep apnoea, and on LIFE, a transdisciplinary research program involving 70 researchers on evidence-based societal and environmental control of chronic diseases, funded by UGA-IDEX. He has been funded by EIT-Health for several European Union projects and is ranked third highest expert worldwide in the field of sleep apnea by Expertscape. Jean-Louis is an Associate Editor of Thorax, is author/co-author of >450 scientific publications and has an H-index of 58.

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Mario Cazzola Mario Cazzola is an Honorary Professor of Respiratory Medicine at the University of Rome “Tor Vergata” (Rome, Italy) and at the Sackler Institute of Pulmonary Pharmacology, GKT School of Biomedical Sciences (London, UK). Mario’s research mainly focuses on the pharmacology of airway diseases, particularly the use of bronchodilators. According to Expertscape (February 2020), he is the top-rated expert in COPD and in bronchodilator agents in the world. Mario is Chairman of the Southern Europe Chapter of Interasma and Chairman of the Med COPD Forum. He was previously: Chairman of the Airway Pharmacology and Treatment Group of the European Respiratory Society (ERS); Secretary of the Inflammatory Airway Diseases and Clinical Allergy Assembly of ERS; ERS Postgraduate Courses Director; an Internal Auditor at ERS; a member of the Steering Committee of the Airway Disorders Network and a Governor of the Italian Chapter of the American College of Chest Physicians. Mario was Co-Chair of the ERS/American Thoracic Society (ATS) Task Force “Outcomes for COPD pharmacological trials: from lung function to biomarkers”. He is a Fellow of ERS and in 2015, received a Lifetime Achievement Award from the same society. He has acted as referee/assessor for different universities and agencies worldwide. Mario founded Therapeutic Advances in Respiratory Diseases and served as its first Editor-in-Chief. He has also held the position of Editor-in-Chief of Pulmonary Pharmacology and Therapeutics, and COPD Research and Practice. He serves as an Associate Editor for Respiratory Medicine, Respiratory Research, Current Research in Pharmacology and Drug Discovery, Clinical Investigation and The Open Respiratory Medicine Journal. He is the author/co-author of almost 670 scientific papers. His H-index is 62.

x

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Introduction Miguel Ángel Martínez-García1, Jean-Louis Pépin2 and Mario Cazzola3 @ERSpublications Cardiovascular and respiratory diseases are two of the leading causes of all-cause mortality. Both are closely related. Knowing the relationship between the two groups of diseases is key to the management of the patient. https://bit.ly/3efOiN3

CVD and respiratory disease are two of the main causes of morbidity, mortality and health costs all over the world. The main organs affected by these diseases – the heart and lungs – are closely related in both physiological and pathological terms. Many CVDs, or their treatment, can affect the respiratory system, and the vast majority of lung diseases can involve or be associated with diseases of the cardiovascular system. This close relationship probably reflects two fundamental circumstances: on the one hand, the high prevalence of these groups of diseases can mean that a single patient can suffer from both simultaneously, with one acting as a comorbidity of the other. This situation will become increasingly common, due to human beings’ progressively greater longevity and the subsequent chronification of many diseases. On the other hand, both types of diseases share many of the same pathophysiological pathways and support mechanisms, as demonstrated in both murine models and human studies. A knowledge of the potential cardiovascular implications and complications inherent in the most prevalent lung diseases, and their treatment, may be crucial for clinicians as they could have therapeutic implications for a respiratory disease and influence its prognosis. Several studies have investigated the greater cardiovascular risk associated with lung diseases with a high inflammatory burden, such as COPD, asthma, and both acute and chronic respiratory infections. This situation may occur because such diseases share, or are capable of activating, some of the intermediate pathophysiological mechanisms in cardiovascular damage. Some respiratory diseases, can, in the advanced stages of their evolution, affect cardiac function as a result of changes in vascular resistance or in the structure of the vessels. This is the case in pulmonary thromboembolism, some interstitial diseases and hypoventilation syndromes.

1

Pneumology Dept, University and Politechnic La Fe Hospital, Valencia, Spain. 2Grenoble University Hospital Center, Grenoble, France. Unit of Respiratory Medicine, Dept of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy.

3

Correspondence: Miguel Ángel Martínez-García, Pneumology Dept, University and Politechnic La Fe Hospital, Bulevar Sur s/n, Valencia, 46013, Spain. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

https://doi.org/10.1183/2312508X.10005220

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Diseases such as lung cancer and the intermittent hypoxaemia or sleep fragmentation caused by OSA can influence the cardiovascular system, either by spreading or by secreting biological mediators or implementing mechanisms that have been proven to cause vascular damage. Finally, although the therapies used for the management of respiratory diseases are generally effective and safe, it is well known that many of the adverse effects of drugs, used in the management of pulmonary diseases, such as bronchodilators, corticosteroids, antibiotics, antifibrotics, anticoagulants, anti-tumoral and anti-inflammatory therapies, may incorporate a degree of cardiovascular risk, particularly in some particularly susceptible patients. In this ERS Monograph, we have tried to offer the reader a complete overview of the interaction between pulmonary diseases and CVDs, not only from an epidemiological point of view [1], but also from a pathophysiological [2], and more particularly, clinical and therapeutic point of view. Accordingly, after reviewing some basic concepts, the book has been divided into: firstly, each important group of respiratory diseases and their cardiopulmonary implications [3–14]; then to the groups of drugs most used in pulmonology and their potential cardiovascular effects [15–19]; and finally, to future diagnostic challenges in this field [20]. Three clinical cases have also been chosen to illustrate different situations taken from real life, in order to delve more fully into the concepts discussed in this book [21–23]. We hope that this Monograph provides you with some of the answers to the questions you have asked in daily practise when trying to diagnose and treat complex patients who suffer from both cardiovascular and respiratory pathology. That was our main objective.

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Soriano JB, Elosua R. Epidemiological aspects of cardiovascular and respiratory diseases. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 1–11. Viglino D, Maltais F, Tamisier R. Common pathophysiological pathways of the autonomic nervous system. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 12–30. Rogliani P, Calzetta L. Cardiovascular disease in COPD. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 47–65. Ora J, Cavalli F, Cazzola M. Management of patients with asthma or COPD and cardiovascular disease: risks versus benefits. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 66–81. Argueta FA, Alviar CL, Peters JI, et al. Chronic asthma and the risk of cardiovascular disease. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 82–95. Guan W-j, Gao Y-h, de la Rosa-Carillo D, et al. Cardiovascular implications in bronchiectasis. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 96–107. Downey DG, Elborn JS. Cardiovascular complications of cystic fibrosis. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 108–117. Bonsignore MR, Gallina S, Drager LF. Cardiovascular consequences of sleep disordered breathing: the role of CPAP treatment. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 118–142. https://doi.org/10.1183/2312508X.10005220

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Ramírez Molina VR, Masa JF, de Terreros Caro FJG, et al. The heart in obesity hypoventilation syndrome. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 143–153. Toffart A-C, Pluchart H, Girard N. Cardiovascular effects of innovative therapies in lung cancer. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 154–166. Jutant E-M, Ghigna M-R, Montani D, et al. Cardiovascular implications of pulmonary hypertension due to chronic respiratory diseases. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 167–183. Bikdeli B, Rodríguez C, García-Ortega A, et al. Cardiovascular mortality and morbidity in pulmonary embolism. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 184–197. Chong SG, Yanagihara T, Kolb MRJ. The cardiovascular system in idiopathic pulmonary fibrosis. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 198–211. Méndez R, González-Jiménez P, Feced L, et al. Cardiovascular consequences of community-acquired pneumonia and other pulmonary infections. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 212–228. Matera MG, Panettieri Jr RA. β2-adrenoceptor modulation in COPD and its potential impact on cardiovascular comorbidities. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 229–237. Stolz D, Cazzola M. Characterising the cardiovascular safety profile of inhaled muscarinic receptor antagonists. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 238–250. Narendra D, Hanania NA. Impact of inhaled corticosteroids in patients with cardiovascular disease. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 251–263. Amati F, Di Pasquale M, Restrepo MI, et al. Cardiovascular side-effects of common antibiotics. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 264–278. Fusco R, Di Paola R, Cuzzocrea S, et al. The cardiovascular effects of xanthines and selective PDE inhibitors: a risk–benefit analysis. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 279–286. Sin DD. Future challanges. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 287–299. Sano H, Hirano T, Koarai A, et al. Case 1. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 300– 304. Revol B, Jullian-Desayes I, Tamisier R, et al. Case 2. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 305–313. Rached S, Athanazio R. Case 3. In: Martínez-García MA, Pépin J-L, Cazzola M. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 314–317.

Disclosures: None declared.

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List of abbreviations AA AF AFL AHI BMI BP CAC CAD CHF CPAP CVD CVE DLCO FEV1 FVC HF ICS IHD IL ILD IPF MACE mPAP OSA PAH PAP PH RHC TNF VEGF

atrial arrhythmias atrial fibrillation atrial flutter apnoea–hypopnoea index body mass index blood pressure coronary artery calcification coronary artery disease chronic heart failure continuous positive airway pressure cardiovascular disease cardiovascular event diffusing capacity of the lung for carbon monoxide forced expiratory volume in 1 s forced vital capacity heart failure inhaled corticosteroid ischaemic heart disease interleukin interstitial lung disease idiopathic pulmonary fibrosis major adverse cardiac event mean pulmonary arterial pressure obstructive sleep apnoea pulmonary arterial hypertension pulmonary arterial pressure pulmonary hypertension right heart catheterisation tumour necrosis factor vascular-endothelial growth factor

| Chapter 1 Epidemiological aspects of cardiovascular and respiratory diseases Joan B. Soriano

1,2

and Roberto Elosua3,4,5

It is often a clinical challenge to perform a differential diagnosis of individual patients suffering from CVDs and respiratory diseases, as their causes can be coincidental, their symptoms may overlap and case definitions are often not straightforward. They are often under- or misdiagnosed and co-occur in ageing individuals with multiple comorbidities. Similar or even greater problems occur when establishing their population epidemiology. Furthermore, as global diagnostic practices and medical access are highly heterogeneous, comparing national and international epidemiology estimators is not easy. In this chapter, we aim to describe the current epidemiology and future burden of CVDs and respiratory diseases, as well as their occurrence as comorbidities. Cite as: Soriano JB, Elosua R. Epidemiological aspects of cardiovascular and respiratory diseases. In: Martínez-García MÁ, Pépin J-L, Cazzola M, eds. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 1–11 [https://doi.org/10.1183/ 2312508X.10027019].

@ERSpublications CVDs and respiratory diseases have a monumental toll on human health, and interpreting their epidemiology is challenging, as they share common causes and symptoms, there is universal underdiagnosis and case definitions are often too loose http://bit.ly/2SEaEz5

Human disease burden Compared with all other human disease conditions, the percentage of deaths caused by CVDs and respiratory diseases is huge. It was estimated that, in 2015, these two disease groups accounted for 43% of overall deaths and 49% of adult deaths [1, 2]. They also prevail in the top rankings of mortality, irrespective of regional population income strata (figure 1).

1 Servicio de Neumología, Hospital Universitario La Princesa, Madrid, Spain. 2Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 3Cardiovascular Epidemiology and Genetics Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain. 4CIBER CV, Barcelona, Spain. 5Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.

Correspondence: Joan B. Soriano, Servicio de Neumología, Hospital Universitario La Princesa, Madrid, Spain. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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CVDs Respiratory diseases Diabetes Kidney diseases Other NCDs

100 90 80

All deaths %

70 60 50 40 30 20 10 0 Global

High income

Upper middle Lower middle income income

Low income

Income status of countries Figure 1. Share of all deaths caused by CVDs, respiratory diseases and other noncommunicable diseases (NCDs), by country income, in 2015. Reproduced and modified from [1] with permission.

The Global Burden of Disease (GBD) Study framework has provided an opportunity to explore these and other issues with a worldwide view. The GBD project was born in 1991 by the New Zealand Oxford University-educated economist and Harvard-graduated physician Chris J. L. Murray and the Australian demographer Alan D. Lopez, at the World Bank and the World Health Organization (WHO), to address worldwide health-related challenges [3]. To date, it has completed seven cycles of GBD estimates published for 1999–2004, 2010, 2013, 2015, 2016, 2017 [4] and 2019 [5]. It is worth noting that we are not using the acronym CVRDs in this Monograph, which stands for cardiovascular, respiratory and related disorders, as used elsewhere [1], as it is not yet fully accepted.

CVDs As reported recently, CVDs constitute the leading cause of global mortality and morbidity [6]. CVDs caused 17.8 million deaths worldwide in 2017, and produced 330 million years of life lost and 35.6 million years lived with disability. These summary measures of health, reviewed in detail later in this chapter, should be carefully interpreted and communicated by primary care doctors, other clinicians, epidemiologists and health managers; they need to be integrated and packaged sensibly, with the aim of guiding immediate and future action for CVDs and risk factor prevention, but also in terms of targeting their treatment and control at all levels: global, national, subnational and regional. It is often stated that exploring health trends provides an insight of where in the world mortality and the burden of any disease are moving to, whether they are increasing or declining, or where incidence is at a standstill. For example, it is now known that 80% of CVD deaths occur in low- and middle-income countries (LMICs); in these countries, the CVD burden and its related risk factors are on the rise due to the ongoing epidemiological 2

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2%

4%

2%

6%

Stroke IHD Hypertensive heart disease Rheumatic heart disease

38%

Other circulatory diseases Cardiomyopathy, myocarditis, endocarditis

49%

Figure 2. Specific causes of CVD mortality in low- and middle-income countries, in 2015. Reproduced and modified from [1] with permission.

transition as the disease burden moves from mostly infectious to noncommunicable diseases, together with overall population ageing [7]. Other evidence indicates that CVD deaths are more common in middle-income countries than in high- or low-income countries [1]. Therefore, to measure the burden of all these forms of CVD, and to successfully overcome the many associated challenges, some advocate the continuous monitoring of global and regional trends by shoe-leather or field epidemiology [8], big data or other methods [9], or a combination of these [10]. The global, regional and national burdens of CVD for 10 of its causes from 1990 to 2015 have been published elsewhere [11]. It is important to highlight that due to the decrease in case-fatality rates of most CVDs on the one hand and the ageing of populations on the other, the prevalence of CVDs is expected to increase worldwide in the next decades. Therefore, preventative efforts should be implemented to decrease their burden. CVDs include IHD, stroke, HF, peripheral arterial disease and a number of other cardiac and vascular conditions (figure 2). IHD (49%) and stroke (38%) account for the largest proportion of global deaths by far [2]. However, the burden of HF is increasing and is a major public health problem [12]. A list of CVD classifications is given in table 1.

Respiratory diseases Respiratory diseases are diseases of the airways and other structures of the lung [13]. They are among the leading causes of morbidity and mortality worldwide [14]. Some of the most common conditions are asthma, COPD and occupational lung diseases. The Forum of International Respiratory Societies (FIRS) considers pneumonia, asthma, COPD, lung https://doi.org/10.1183/2312508X.10027019

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Table 1. Classification of CVDs IHD Stroke (ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage) HF Hypertensive heart disease Cardiomyopathy and myocarditis Rheumatic valvular heart disease Nonrheumatic valvular heart disease AF and AFL Aortic aneurism Peripheral artery disease Endocarditis Other CVDs and circulatory diseases

cancer and tuberculosis to be the five most important lung diseases worldwide from a prevalence standpoint [15]. In spite of their extensive health and economic consequences, there is a surprising lack of comprehensive published data on the epidemiology and distribution of respiratory diseases on a global scale [16]. In this chapter, we will refer only to chronic respiratory diseases (CRDs), excluding among others infections and lung cancer. The WHO Global Alliance against Chronic Respiratory Diseases (GARD) has a vision of a world in which all people breathe freely, and it focuses on the needs of people with CRDs in LMICs [17]. Each year, it is estimated that 4 million people die prematurely from CRDs. In children 0.15 Hz), a lowfrequency (LF) band (∼0.1 Hz) and a very-low-frequency (VLF) band (0.003–0.039 Hz). The HF components reflect the respiration-driven modulation of sinus rhythm and are thought to be an index of tonic vagal drive. The LF rhythm reflects the sympathetic modulation of the heart. The LF/HF ratio is used to provide an index of the balance of the 14

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sympathovagal influence. The VLF band may reflect thermoregulation and the renin– angiotensin system. Circulating catecholamines

Although they comprise 20% of hospitalised patients with community-acquired pneumonia suffer from adverse CVEs, mainly HF, cardiac arrhythmias and myocardial infarction [76]. In this context, several animal models have been used to study this relationship [77–79]. Small-animal models

Small-animal models involving rodents consist of an intranasal or intratracheal bacterial challenge that provides multilobar confluent pneumonia associated with high mortality [80–83]. A high inflammatory response followed by neutrophil recruitment in the alveolar space has also been described in a rodent model [84]. These models are useful because of their reproducibility and limited costs. However, significant anatomical and physiological 40

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differences have been noted [85]. In addition, long-term mechanical ventilation is challenging, and the high mortality hinders the duration of the experiments [86]. Rodent models of lung infection caused by intranasal Streptococcus pneumoniae challenge have been used to study the effect of antimicrobial treatment on atherosclerotic plaque development. Interestingly, investigators found that infected animals had plaques with higher concentrations of activated macrophages than uninfected rodents [77]. Moreover, it has been shown that Chlamydia pneumoniae can disseminate through the heart, damaging cardiac function, and causing and worsening atherosclerotic lesions [79]. Large-animal models

Large animals are more similar to human species and allow mechanical ventilation, an important component for pneumonia studies. In recent decades, dog and cat models [87, 88] have been substituted by sheep and swine models [89–94]. To establish lung infection in large-animal models, three different strategies have been used: 1) spontaneous pneumonia development by endogenous flora [89], 2) intrabronchial challenge using high inoculums [91, 94], and 3) aspiration of an oropharyngeal challenge [90]. This last strategy mimics the primary pathogenic mechanism of ventilator-associated pneumonia. These models are characterised by systemic and local release of inflammatory cytokines that cause sepsis and haemodynamic impairment, as observed in relatively prolonged mechanical ventilation (i.e. up to 4 days). Moreover, nonhuman primate models have been developed and used to investigate pneumonia due to S. pneumoniae [95]. It has been shown that S. pneumoniae is capable of translocation into the myocardium, inducing apoptosis of cardiomyocytes and forming bacteria-filled microlesions. Moreover, some biomarkers of cardiac damage (troponin T and heart-type fatty acid-binding protein) were elevated in these infected nonhuman primates [78].

Animal models of chronic lung diseases of prematurity Bronchopulmonary dysplasia (BPD) is the most frequent neonatal chronic lung disease in pre-term birth, and its incidence is increasing because of the increased survival of extremely low-gestational-age newborns [96]. It is caused by an aberrant repetitive response to antenatal and post-natal injuries that leads to alveolar hypoplasia and impaired pulmonary vascular development. Inflammation has been postulated as the most common pathway implicated, but numerous genes have also been identified in murine transgenic models [97]. The animals that are most widely used to study BPD are term rodents, but pre-term sheep and primates are also used [98]. The rodent model is particularly suited because term-born rodents are born during the saccular stage of lung development (the same stage of lung development as most pre-term infants). Nevertheless, unlike pre-term infants, the term rodent has competent gas exchange. Rodent models are easily standardised and have good reproducibility and low costs; nevertheless, the translational relevance improves as the size of the animals increases. For this reason, despite concerns about costs and ethical challenges, the use of larger animals such as rabbits, pigs, sheep and apes remains important. Animal models to study lung disease in the pre-term stage have presented the following limitations: 1) a single fetal/neonatal stimulus by one factor can sometimes replicate poorly what occurs in pre-term infants who are frequently exposed several times to multiple antenatal or post-natal factors; 2) inflammatory responses in pre-term and immature lungs https://doi.org/10.1183/2312508X.10027219

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may differ from those in animals at term; and 3) it is difficult to mimic all of the different histopathological characteristics of BPD in a model. The main characteristics of animal models used in BPD and their advantages and disadvantages are described below. Hyperoxia model

The model used most for evaluating BPD is newborn rodents exposed to various amounts of oxygen for different periods of time (days to weeks). Oxidant injury delays saccular septation to alveoli, increases mesenchymal cellularity and inflammation, blocks capillary formation and can produce PH [99]. High oxygen levels could also impair endothelial proliferation and reduce the number of endothelial progenitor cells. These alterations can remain evident for some weeks. These models have some limitations that should be mentioned. First, the oxygen concentration used is very high and usually exceeds that employed in clinical practice. Second, these models lack the clinical fluctuations in oxygen concentrations that are observed in pre-term infants. Ventilation models

Mechanical ventilation alone has been demonstrated to induce BPD. The most relevant animal models for evaluating ventilation injury are pre-term sheep and primates, which can be ventilated for prolonged periods and therefore facilitate evaluation of injury progression. Although studies in large animals have been important for understanding the mechanisms involved in BPD and finding therapeutic strategies, the costs and experimental settings needed are substantial. Therefore, models in smaller animals at term (mostly rodents) have been developed because they are technically easier and less expensive. Nevertheless, these models with small animals at term also have limitations. First, it is not possible to maintain these animals for chronic ventilation. Second, animals at term may not have the same lung characteristics as pre-term infants; therefore, these animals can be less sensitive to injury induced by ventilation. Inflammatory and genetically modified models

It is well known that pre- and post-natal inflammation and infection contribute to the pathogenesis of BPD. Thus, animal models using antenatal infection, endotoxin exposure and/or transgenic rodents have been created to study inflammatory pathways. It has been reported that the antenatal administration of endotoxin arrests alveolarisation in rats and pre-term lambs [100]. Moreover, even inflammation in the absence of infection can lead to structural remodelling, impaired alveolarisation and angiogenesis. In addition, in recent years, the use of genetically modified animal models has increased. These models are useful in studying the pathways involved in lung development and may be very interesting in future studies.

Ethical considerations The development of animal models is essential for understanding the mechanisms involved in the pathophysiology of chronic respiratory diseases and the cardiovascular consequences. 42

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In fact, most of these lung diseases are accompanied by other comorbidities, such as smoking, obesity and other age-related diseases, which could hinder obtaining clear results. Therefore, the use of animal models could be useful in avoiding this limitation. However, the use of animals in scientific research must be justified accordingly, using the minimum number of animals and monitoring them frequently. Alternatively, there are also other in vitro models mimicking some pathological conditions by exposing cells to, for example, different types of hypoxia or infections, which must be considered before the use of animals in studying lung diseases.

Conclusion Animal models are used to investigate cardiovascular damage in respiratory diseases, avoiding confounding factors that are frequently present in human studies. The published evidence sheds light on the sequence of events occurring in the different respiratory disorders and furthers our understanding of the mechanisms involved. Moreover, as these models can exclude or add comorbidities in a controlled fashion, they can also assess additive effects between different components of the disorder and comorbidities usually present in patients. However, improving and developing more realistic models will be essential to better assess the relationship between lung disorders and cardiovascular damage and to make the translation from animal research to patient disease more accurate and realistic.

References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10.

11. 12. 13. 14. 15.

Wright JL, Cosio M, Churg A. Animal models of chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 2008; 295: L1–15. Tanner L, Single AB. Animal models reflecting chronic obstructive pulmonary disease and related respiratory disorders: translating pre-clinical data into clinical relevance. J Innate Immun 2019: 1–23. Churg A, Wright JL. Testing drugs in animal models of cigarette smoke-induced chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009; 6: 550–552. Wright JL, Churg A. Animal models of cigarette smoke-induced chronic obstructive pulmonary disease. Expert Rev Respir Med 2010; 4: 723–734. Reczyńska K, Tharkar P, Kim SY, et al. Animal models of smoke inhalation injury and related acute and chronic lung diseases. Adv Drug Deliv Rev 2018; 123: 107–134. Ferrer E, Peinado VI, Díez M, et al. Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pig. Respir Res 2009; 10: 76. Ferrer E, Peinado VI, Castañeda J, et al. Effects of cigarette smoke and hypoxia on pulmonary circulation in the guinea pig. Eur Respir J 2011; 38: 617–627. Paul T, Blanco I, Aguilar D, et al. Therapeutic effects of soluble guanylate cyclase stimulation on pulmonary hemodynamics and emphysema development in guinea pigs chronically exposed to cigarette smoke. Am J Physiol Lung Cell Mol Physiol 2019; 317: L222–L234. Kawut SM, Poor HD, Parikh MA, et al. Cor pulmonale parvus in chronic obstructive pulmonary disease and emphysema: the MESA COPD study. J Am Coll Cardiol 2014; 64: 2000–2009. Talukder MAH, Johnson WM, Varadharaj S, et al. Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice. Am J Physiol Heart Circ Physiol 2011; 300: H388–H396. Al Hariri M, Zibara K, Farhat W, et al. Cigarette smoking-induced cardiac hypertrophy, vascular inflammation and injury are attenuated by antioxidant supplementation in an animal model. Front Pharmacol 2016; 7: 397. Antunes MA, Rocco PRM. Elastase-induced pulmonary emphysema: insights from experimental models. An Acad Bras Cienc 2011; 83: 1385–1396. Snider GL, Lucey EC, Stone PJ. Animal models of emphysema. Am Rev Respir Dis 1986; 133: 149–169. Snider GL. Emphysema: the first two centuries – and beyond. A historical overview, with suggestions for future research: Part 2. Am Rev Respir Dis 1992; 146: 1615–1622. Oliveira M V, Abreu SC, Padilha GA, et al. Characterization of a mouse model of emphysema induced by multiple instillations of low-dose elastase. Front Physiol 2016; 7: 457.

https://doi.org/10.1183/2312508X.10027219

43

ERS MONOGRAPH | CARDIOVASCULAR COMPLICATIONS OF RESPIRATORY DISORDERS 16. 17.

18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42. 43. 44. 45. 46.

44

Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet 2017; 389: 1941–1952. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: Treatment of idiopathic pulmonary fibrosis: an update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 2015; 192: e3–e19. Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008; 294: 152–160. Umezawa H. Chemistry and mechanism of action of bleomycin. Fed Proc 1974; 33: 2296–2302. Umezawa H, Ishizuka M, Maeda K, et al. Studies on bleomycin. Cancer 1967; 20: 891–895. Muggia FM, Louie AC, Sikic BI. Pulmonary toxicity of antitumor agents. Cancer Treat Rev 1983; 10: 221–243. Degryse AL, Lawson WE. Progress toward improving animal models for idiopathic pulmonary fibrosis. Am J Medi Sci 2011; 341: 444–449. Usuki J, Fukuda Y. Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats. Pathol Int 1995; 45: 552–564. Shenoy V, Gjymishka A, Jarajapu YP, et al. Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med 2013; 187: 648–657. Rathinasabapathy A, Bruce E, Espejo A, et al. Therapeutic potential of adipose stem cell-derived conditioned medium against pulmonary hypertension and lung fibrosis. Br J Pharmacol 2016; 173: 2859–2879. Bryant AJ, Robinson LJ, Moore CS, et al. Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis. Pulm Circ 2015; 5: 681–690. Chen NY, Collum SD, Luo F, et al. Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2016; 311: 238–254. Roberts SN, Howie SEM, Wallace WAH, et al. A novel model for human interstitial lung disease: hapten-driven lung fibrosis in rodents. J Pathol 1995; 176: 309–318. Oberdorster G. Significance of particle parameters in the evaluation of exposure-dose-response relationships of inhaled particles. Inhal Toxicol 1996; 8: Suppl., 73–89. Barbarin V, Nihoul A, Misson P, et al. The role of pro- and anti-inflammatory responses in silica-induced lung fibrosis. Respir Res 2005; 6: 112. Lakatos HF, Burgess HA, Thatcher TH, et al. Oropharyngeal aspiration of a silica suspension produces a superior model of silicosis in the mouse when compared to intratracheal instillation. Exp Lung Res 2006; 32: 181–199. Zelko IN, Zhu J, Ritzenthaler JD, et al. Pulmonary hypertension and vascular remodeling in mice exposed to crystalline silica. Respir Res 2016; 17: 160. Murray RE, Gibson JE. A comparative study of paraquat intoxication in rats, guinea pigs and monkeys. Exp Mol Pathol 1972; 17: 317–325. Paun A, Kunwar A, Haston CK. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice. Radiat Oncol 2015; 10: 45. Sime PJ, Xing Z, Graham FL, et al. Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997; 100: 768–776. Stenmark KR, Meyrick B, Galie N, et al. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009; 297: L1013–L1032. Hislop A, Reid L. New findings in pulmonary arteries of rats with hypoxia induced pulmonary hypertension. Br J Exper Pathol 1976; 57: 542–554. Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001; 15: 427–438. Lalich JJ, Merkow L. Pulmonary arteritis produced in rat by feeding Crotalaria spectabilis. Lab Invest 1961; 10: 744–750. Okada K, Tanaka Y, Bernstein M, et al. Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. Am J Pathol 1997; 151: 1019–1025. Meyrick B, Gamble W, Reid L. Development of Crotalaria pulmonary hypertension: hemodynamic and structural study. Am J Physiol 1980; 239: H692–H702. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006; 99: 675–691. Morimatsu Y, Sakashita N, Komohara Y, et al. Development and characterization of an animal model of severe pulmonary arterial hypertension. J Vasc Res 2012; 49: 33–42. Nicolls MR, Mizuno S, Taraseviciene-Stewart L, et al. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis. Pulm Circ 2012; 2: 434–442. Voelkel NF, Gomez-Arroyo J. The role of vascular endothelial growth factor in pulmonary arterial hypertension. The angiogenesis paradox. Am J Respir Cell Mol Biol 2014; 51: 474–484. Vitali SH, Hansmann G, Rose C, et al. The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up. Pulm Circ 2014; 4: 619–629. https://doi.org/10.1183/2312508X.10027219

MURINE MODELS | I. ALMENDROS ET AL. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.

64. 65. 66.

67. 68.

69. 70. 71. 72. 73. 74.

de Raaf MA, Schalij I, Gomez-Arroyo J, et al. SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction. Eur Respir J 2014; 44: 160–168. Sztuka K, Jasińska-Stroschein M. Animal models of pulmonary arterial hypertension: a systematic review and meta-analysis of data from 6126 animals. Pharmacol Res 2017; 125: 201–214. Chopra S, Polotsky VY, Jun JC. Sleep apnea research in animals. Past, present, and future. Am J Respir Cell Mol Biol 2016; 54: 299–305. Almendros I, Farré R, Planas AM, et al. Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: differential effect of obstructive apneas and intermittent hypoxia. Sleep 2011; 34: 1127–1133. Tamisier R, Gilmartin GS, Launois SH, et al. A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure. J Appl Physiol 2009; 107: 17–24. Tripathi A, Melnik AV, Xue J, et al. Intermittent hypoxia and hypercapnia, a hallmark of obstructive sleep apnea, alters the gut microbiome and metabolome. mSystems 2018; 3: e00020-18. Tarasiuk A, Segev Y. Abnormal growth and feeding behavior in upper airway obstruction in rats. Front Endocrinol 2018; 9: 298. Polotsky M, Elsayed-Ahmed AS, Pichard L, et al. Effect of age and weight on upper airway function in a mouse model. J Appl Physiol 2011; 111: 696–703. Baum DM, Morales Rodriguez B, Attali V, et al. New Zealand obese mice as a translational model of obesity-related obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2018; 198: 1336–1339. Almendros I, Farré R, Torres M, et al. Early and mid-term effects of obstructive apneas in myocardial injury and inflammation. Sleep Med 2011; 12: 1037–1040. Assadi MH, Shknevsky E, Segev Y, et al. Abnormal growth and feeding behavior persist after removal of upper airway obstruction in juvenile rats. Sci Rep 2017; 7: 2730. Tarasiuk A, Levi A, Assadi MH, et al. Orexin plays a role in growth impediment induced by obstructive sleep breathing in rats. Sleep 2016; 39: 887–897. Carreras A, Wang Y, Gozal D, et al. Non-invasive system for applying airway obstructions to model obstructive sleep apnea in mice. Respir Physiol & Neurobiol 2011; 175: 164–168. Farré R, Nácher M, Serrano-Mollar A, et al. Rat model of chronic recurrent airway obstructions to study the sleep apnea syndrome. Sleep 2007; 30: 930–933. Hakim F, Wang Y, Zhang SXL, et al. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Res 2014; 74: 1329–1337. Poroyko VA, Carreras A, Khalyfa A, et al. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep 2016; 6: 35405. Bonsignore MR, Gallina S, Drager LF. Cardiovascular consequences of sleep disordered breathing: the role of CPAP treatment. In: Martínez-García MÁ, Pépin J-L, Cazzola M, eds. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Resiratory Society, 2020; pp. 118–142. Dematteis M, Godin-Ribuot D, Arnaud C, et al. Cardiovascular consequences of sleep-disordered breathing: contribution of animal models to understanding of the human disease. ILAR J 2009; 50: 262–281. Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007; 175: 1290–1297. Belaidi E, Joyeux-Faure M, Ribuot C, et al. Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. J Am Coll Cardiol 2009; 53: 1309–1317. Castro-Grattoni AL, Alvarez-Buvé R, Torres M, et al. Intermittent hypoxia-induced cardiovascular remodeling is reversed by normoxia in a mouse model of sleep apnea. Chest 2016; 149: 1400–1408. Lin M, Liu R, Gozal D, et al. Chronic intermittent hypoxia impairs baroreflex control of heart rate but enhances heart rate responses to vagal efferent stimulation in anesthetized mice. Am J Physiol Heart Circ Physiol 2007; 293: H997–H1006. Chen L, Einbinder E, Zhang Q, et al. Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med 2005; 172: 915–920. Yang X, Zhang L, Liu H, et al. Cardiac sympathetic denervation suppresses atrial fibrillation and blood pressure in a chronic intermittent hypoxia rat model of obstructive sleep apnea. J Am Heart Assoc 2019; 8: e010254. Gemel J, Su Z, Gileles-Hillel A, et al. Intermittent hypoxia causes NOX2-dependent remodeling of atrial connexins. BMC Cell Biol 2017; 18: 7. Dematteis M, Julien C, Guillermet C, et al. Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med 2008; 177: 227–235. Lavie L. Oxidative stress in obstructive sleep apnea and intermittent hypoxia – revisited – the bad ugly and good: implications to the heart and brain. Sleep Med Rev 2015; 20: 27–45. Troeger C, Blacker B, Khalil IA, et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 2018; 18: 1191–1210.

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ERS MONOGRAPH | CARDIOVASCULAR COMPLICATIONS OF RESPIRATORY DISORDERS 75.

Corrales-Medina VF, Alvarez KN, Weissfeld LA, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA 2015; 313: 264–274. 76. Violi F, Cangemi R, Falcone M, et al. Cardiovascular complications and short-term mortality risk in community-acquired pneumonia. Clin Infect Dis 2017; 64: 1486–1493. 77. Brown AO, Mann B, Gao G, et al. Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 2014; 10: e1004383. 78. Reyes LF, Restrepo MI, Hinojosa CA, et al. Severe pneumococcal pneumonia causes acute cardiac toxicity and subsequent cardiac remodeling. Am J Respir Crit Care Med 2017; 196: 609–620. 79. Campbell LA, Yaraei K, van Lenten B, et al. The acute phase reactant response to respiratory infection with Chlamydia pneumoniae: implications for the pathogenesis of atherosclerosis. Microbes Infect 2010; 12: 598–606. 80. Evans SE, Tuvim MJ, Zhang J, et al. Host lung gene expression patterns predict infectious etiology in a mouse model of pneumonia. Respir Res 2010; 11: 101. 81. Andes D, Craig WA. In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations. Antimicrob Agents Chemother 1998; 42: 2375–2379. 82. Koomanachai P, Crandon JL, Banevicius MA, et al. Pharmacodynamic profile of tigecycline against methicillin-resistant Staphylococcus aureus in an experimental pneumonia model. Antimicrob Agents Chemother 2009; 53: 5060–5063. 83. Vanderzwan J, McCaig L, Mehta S, et al. Characterizing alterations in the pulmonary surfactant system in a rat model of Pseudomonas aeruginosa pneumonia. Eur Respir J 1998; 12: 1388–1396. 84. Drusano GL, Vanscoy B, Liu W, et al. Saturability of granulocyte kill of Pseudomonas aeruginosa in a murine model of pneumonia. Antimicrob Agents Chemother 2011; 55: 2693–2695. 85. Hofmann W, Koblinger L, Martonen TB. Structural differences between human and rat lungs: implications for Monte Carlo modeling of aerosol deposition. Health Phys 1989; 57: Suppl. 1, 41–46. 86. Bielen K, ’s Jongers B, Malhotra-Kumar S, et al. Animal models of hospital-acquired pneumonia: current practices and future perspectives. Ann Transl Med 2017; 5: 132. 87. Nahum A, Hoyt J, Schmitz L, et al. Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs. Crit Care Med 1997; 25: 1733–1743. 88. Shure D, Moser KM, Konopka R. Transbronchial needle aspiration in the diagnosis of pneumonia in a canine model. Am Rev Respir Dis 1985; 131: 290–291. 89. Marquette CH, Wermert D, Wallet F, et al. Characterization of an animal model of ventilator-acquired pneumonia. Chest 1999; 115: 200–209. 90. Bassi GL, Rigol M, Marti JD, et al. A novel porcine model of ventilator-associated pneumonia caused by oropharyngeal challenge with Pseudomonas aeruginosa. Anesthesiology 2014; 120: 1205–1215. 91. Martínez-Olondris P, Sibila O, Agustí C, et al. An experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated piglets. Eur Respir J 2010; 36: 901–906. 92. Panigada M, Berra L, Greco G, et al. Bacterial colonization of the respiratory tract following tracheal intubation-effect of gravity: an experimental study. Crit Care Med 2003; 31: 729–737. 93. Enkhbaatar P, Joncam C, Traber L, et al. Novel ovine model of methicillin-resistant Staphylococcus aureus-induced pneumonia and sepsis. Shock 2008; 29: 642–649. 94. Luna CM, Baquero S, Gando S, et al. Experimental severe Pseudomonas aeruginosa pneumonia and antibiotic therapy in piglets receiving mechanical ventilation. Chest 2007; 132: 523–531. 95. Reyes LF, Restrepo MI, Hinojosa CA, et al. A non-human primate model of severe pneumococcal pneumonia. PLoS One 2016; 11: e0166092. 96. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126: 443–456. 97. Surate Solaligue DE, Rodríguez-Castillo JA, Ahlbrecht K, et al. Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2017; 313: L1101–L1153. 98. Morty RE. Recent advances in the pathogenesis of BPD. Semin Perinatol 2018; 42: 404–412. 99. Warner BB, Stuart LA, Papes RA, et al. Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol 1998; 275: L110–L117. 100. Ueda K, Cho K, Matsuda T, et al. A rat model for arrest of alveolarization induced by antenatal endotoxin administration. Pediatr Res 2006; 59: 396–400.

Disclosures: I. Blanco reports receiving personal fees from Actelion, MSD and GSK, outside the submitted work.

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| Chapter 4 Cardiovascular disease in COPD Paola Rogliani

and Luigino Calzetta

COPD is a serious public health concern and is frequently associated with CVD. When COPD is associated with CVD, there is reduced health status and increased hospitalisation rate and mortality. CVD and COPD share a common background chronic low-grade systemic inflammation, triggered by several stimuli including air pollutants and cigarette smoke. The teleological activities and paradoxical effects of polypeptide cardiac hormones further support the intimate relationship between CVD and COPD. COPD exacerbations play a pivotal role in COPD progression, and early identification of cardiac problems could help to better phenotype COPD exacerbators and ameliorate disease prognosis. In this scenario, novel predictive tools and biomarkers of cardiovascular risk specifically validated in COPD populations may help to identify pre-symptomatic subjects. Current recommendations for the management of CVD in COPD patients are limited and therefore pulmonologists and cardiologists should work together in order to reach a correct and complementary diagnosis and identify tailored therapy. Cite as: Rogliani P, Calzetta L. Cardiovascular disease in COPD. In: Martínez-García MÁ, Pépin J-L, Cazzola M, eds. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 47–65 [https://doi.org/10.1183/2312508X.10027319].

@ERSpublications CVD and COPD are comorbidities characterised by high prevalence in the population and low-grade systemic inflammation. Biomarkers to identify COPD patients with CVD could improve prognosis and reduce risk of death http://bit.ly/2SEaEz5

C

hronic obstructive pulmonary disease (COPD) is a serious public health concern, accounting for early death in individuals aged >40 years [1, 2]. In 2017, COPD was the seventh leading cause of death, but the projection for 2040 indicates that this disorder will be the fourth leading cause of premature death [3]. COPD is frequently associated with comorbidities, and a strong correlation with CVD has been demonstrated [4]. Patients suffering from COPD are at increased risk of CAD, and those with both disorders show a 2-fold increased risk of death from CVD [5]. CVD and COPD are no longer considered two separate conditions, and the presence of CVD in COPD patients is associated with reduced health status, increased hospitalisation rate and increased all-cause and CVD mortality [6].

Unit of Respiratory Medicine, Dept of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy. Correspondence: Paola Rogliani, Dept of Experimental Medicine, Via Montpellier 1, 00133, Rome, Italy. E-mail: paola.rogliani@ uniroma2.it Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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A common background of chronic low-grade systemic inflammation links CVD and COPD. Enhanced inflammatory processes are triggered by several stimuli including air pollutants and cigarette smoke, leading to worse outcomes than either condition alone [7]. The teleological activities and paradoxical effects of polypeptide cardiac hormones released in response to myocardial wall stress further support the intimate relationship between CVD and COPD [8]. To date, it has been widely recognised that primary prevention along with screening in primary care settings and cross-collaboration between specialists represent core strategies for the management of COPD patients, especially because cardiovascular conditions, as well as COPD, frequently remain underdiagnosed [9, 10]. In this scenario, novel predictive tools and biomarkers of cardiovascular risk specifically validated in COPD populations may help to identify pre-symptomatic subjects, whereas dated models set up in the general population should not be used because they usually underestimate the risk of CVEs in COPD patients [11].

Link between CVDs and COPD COPD is characterised by an enhanced inflammatory response in the airways, parenchyma and pulmonary vasculature to inhaled substances such as cigarette smoke, particulate matter and air pollutants [12]. This underlying pathophysiological process is characterised by increased levels of inflammatory markers including C-reactive protein (CRP), IL-1, -6 and -8, fibrinogen, activated leukocytes and TNF-α, with evidence of oxidative stress [13, 14]. These cytokines are increased not only in the systemic circulation but also in sputum and bronchoalveolar lavage fluid of COPD patients, suggesting that a spillover of inflammatory mediators from the peripheral lung occurs [15]. COPD and CVD share common cytokines and a similar inflammatory pathophysiology, a link that might be explained by two different views [16–20]. On the one hand, evidence indicates the presence of a “spillover” of inflammatory mediators from the peripheral lung into the circulation causing systemic inflammation [21]; on the other hand, the pulmonary manifestations in COPD might be explained as a result of a low-grade systemic inflammatory state that affects extrapulmonary organs and generates comorbid conditions in parallel with or following the development of pulmonary inflammation. Thus, it has been suggested that COPD might be included as part of a “chronic inflammatory syndrome” [15, 22, 23]. The concept of “spillover” was investigated for the first time by VERNOOY et al. [24] in patients with mild to moderate COPD; however, to date, a lack of correlation between the concentration of mediators in the airways and in the systemic circulation has failed to fully support this hypothesis, although evidence has demonstrated that this concept is somehow implicated [24, 25]. Cytokines such as IL-6 and TNF-α are released from bronchial epithelial cells into lung secretions and either diffuse into the interstitium according to their molecular weight and inflammation condition or can be directly released by monocytes, macrophages or further inflammatory cells and then enter into the lymphatic and systemic circulation [21]. Cigarette smoke and air pollutants can directly affect other organs, promoting or exacerbating systemic abnormalities [21]. In this scenario, it seems that alveolar macrophages represent the link 48

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between the inflammatory response in the lung and the systemic circulation as they initiate phagocytosis of inhaled particles [21]. Upon ingestion, macrophages produce oxidants and release pro-inflammatory cytokines that contribute to the systemic inflammatory response in COPD [21]. There is also evidence that inhaled ultrafine particles can diffuse from the lung into the systemic circulation without the need for a mediating cell [26]. Systemic inflammation could represent the pathophysiological link between COPD and CVD, and indeed is considered the major risk factor for morbidity and mortality related to CVDs [27, 28]. Elevated concentrations of inflammatory markers are present in COPD patients affected by concomitant CVD compared with those suffering from COPD alone [29]. Markers of both pulmonary and systemic inflammation can be correlated with CAC scores, which are indicators of coronary atherosclerosis [30]. Indeed, systemic inflammation may predispose to atherosclerotic plaques, which may justify the high prevalence of myocardial infarction (MI) in COPD patients [23]. Systemic inflammation and chronic or intermittent hypoxia are correlated with each other and are associated with arterial stiffness, a surrogate indicator of CVEs [31]. To date, no consensus has been reached regarding systemic inflammation in COPD: it could be related to a “spillover” of inflammatory mediators from the lung or a more general systemic inflammatory state. In both cases, a common background of chronic low-grade systemic inflammation links CVD and COPD, leading to worse outcomes than either condition alone.

Pathophysiological mechanisms leading to increased cardiovascular risk in COPD There is a growing understanding of the complex and multifaceted scenario that underpins the relationship between CVD and COPD [6]. The two diseases share several common risk factors, and chronic cigarette smoking is undoubtedly the most commonly encountered and identifiable, with ageing increasing the propensity to stroke [12, 32]. Smoking is a widely recognised risk factor for atherosclerosis and atherosclerotic plaque rupture and thus is implicated in the development of HF and CAD [33]. Besides tobacco smoke, inhalation of noxious gases and biomass fuel exposure are major factors in persistent lung and arterial wall inflammatory responses, which cause airflow obstruction and promote atherosclerosis and coronary plaque instability [12]. The lung inflammation observed in COPD patients appears to be an alteration of the normal inflammatory response in the respiratory tract to inhaled cigarette smoke and other chronic irritants, which may lead to lung parenchyma destruction, narrowing and remodelling of small airways, and progressive loss of normal mechanisms of repair and defence [12]. It has been hypothesised that a systemic inflammatory response is the possible cause of both CVD and COPD [34, 35]. Evidence shows that COPD patients with concomitant CVD have increased levels of IL-6, CRP and fibrinogen [36]. Inflammatory markers appear to be elevated during and immediately after a COPD exacerbation when CVD risk and cardiovascular mortality are increased [37]. Arterial stiffness, which is considered a putative pathophysiological condition common to both CVD and COPD, is a strong independent predictor of CVEs and a potential predictor of CVD risk in COPD patients [31]. It has been hypothesised that arterial stiffness is https://doi.org/10.1183/2312508X.10027319

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associated with elastin degradation in the vasculature and lung, where it may lead to emphysema [38, 39]. Arterial stiffness may be caused by an imbalance between matrix metalloproteases, but the precise cause remains unclear [6]. Increased arterial stiffness along with telomere shortening, senescence of endothelial cells and reduced cell proliferation are all features of COPD, especially in older patients with an emphysematous component [40–43]. Hypoxia, either sustained in severe COPD or intermittent during exercise or COPD exacerbations, is considered another important factor contributing to CVD risk [44]. Hypoxia induces systemic inflammation and oxidative stress, increases the production of foam cells, upregulates cellular adhesion molecules in endothelial cells and increases CRP levels [45–47]. Moreover, a hypoxic state was found to have a role in vascular remodelling and endothelial dysfunction of the airways and has been linked to the development of arterial stiffness [31, 48]. COPD patients show a progressive peripheral airway limitation that leads to gas trapping following exhalation, thus leading to hyperinflation [12]. Such abnormal function of the lung is thought to impair cardiac activity by increasing cardiopulmonary pressures, impairing left ventricular filling and reducing cardiac output [49–52]. Static hyperinflation is associated with emphysema, and the concomitant presence of the two conditions favours the development of hypoxaemia [53]. In COPD patients, hypoxaemia may cause pulmonary vascular remodelling and vasoconstriction, leading to right ventricular diastolic dysfunction [54]. Impairment of the right ventricle may increase pulmonary vascular resistance, which in turn may displace the interventricular septum to the left ventricle and affect ventricular filling, stroke volume and cardiac output [55, 56]. Several mechanistic pathways and factors strengthen the link between CVD and COPD, highlighting the increased chance of developing or worsening a pre-existing CVD; however, the overall picture remains complex and needs to be fully elucidated. The links and pathophysiological mechanisms leading to CVD in COPD are shown in figure 1.

Impact of CVD in COPD patients COPD and CVD share recognised risk factors such as ageing, tobacco smoke, reduced lung function and obesity [57–59], with no differences in sex for the association with all CVDs, except for angina, CAD and MI, which were found to correlate more with women than with men [4]. Therefore, it is not unusual that both diseases coexist in the same individual [6]. COPD patients have a 2–5-fold increased risk of CAD, cardiac dysrhythmia, HF, pulmonary vascular disease and peripheral vascular disease (PVD) [60]. Almost 400 million individuals suffer from COPD, with an estimated global prevalence of 11.7% [6]. Data are still lacking about the exact prevalence and impact of different CVDs in COPD patients, as most of the epidemiological studies were conducted on accurately selected patients [61, 62]. CAD, HF and PVD are CVDs that are moderately associated with COPD, while AF and hypertension are only weakly associated with COPD [63]. Epidemiological studies report high levels of prevalence of CAD in COPD patients, with values ranging between 20% and 60% [60, 64–66]. In 2017, CAD was the first leading cause 50

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Cigarette smoke Air pollutants Ageing COPD

Activated leukocytes

Oxidative stress

CVD

Spillover Airway obstruction Emphysema Epithelial dysfunction Hyperinflation Hypoxia Remodelling Small airway disease

Fibrinogen

TNF-α

Systemic inflammation CRP

IL-6

Atherosclerosis Arterial stiffness Artery calcification Endothelial dysfunction Hypoxia

IL-8

Figure 1. Links and pathophysiological mechanisms leading to CVD in COPD. The upper arrow indicates unidirectional spillover of inflammatory mediators from the lungs to the heart and vessels, while the lower arrow indicates bidirectional systemic inflammation between the lungs, heart and vessels. CRP: C-reactive protein.

of premature mortality, which accounted for more than 1 million deaths worldwide [67]. Recently, it has been demonstrated that COPD patients with ischaemic ECG changes have a significant alteration in their 6-min walk distance, Medical Research Council score and BMI. These patients may also have airflow obstruction, dyspnoea and a reduced exercise index, and a worse quality of life [68]. HF is one of the most underdiagnosed comorbidities in COPD, and its prevalence is reported to be higher in patients with COPD compared with the general population (12.3–28.3% versus 1.0–2.0%, respectively) with an annual incidence corresponding to about 3.7% [6, 66]. Conversely, the prevalence of COPD in HF patients varies between 13% and 39% [69, 70]. HF represents a significant and independent predictor of all-cause mortality [12]. Hypertension, a main risk factor for CVEs, is reported in 28.5–64.7% of COPD patients [16, 71–73], while arrhythmias occur in between 10% and 15% [60, 64–66]. AF represents the most common supraventricular arrhythmia in COPD patients and estimates report that 4.7–15% display concomitant stable COPD, with rates ranging between 20% and 30% in very severe COPD [58, 66, 74]. Stroke prevalence is generally 1.2 nmol·L−1) and day 30 (>0.83 nmol·L−1) allow the identification of patients at risk of developing early (OR 2.53) and late (OR 2.29) CVEs, respectively. Finally, soluble platelet activation markers could also be used for this purpose. Platelet activation is one of the involved biological pathways that increase cardiovascular risk in pneumonia. CANGEMI et al. [31], in 2014, published a study on the relationship of these markers and AMI during hospitalisation for CAP. Initial increased levels of thromboxane B2, P-selectin and CD40 ligand in plasma are associated with the diagnosis of silent and nonsilent AMI (adjusted for CAP severity), defined by troponin elevation and suggestive ECG signs. These findings were noted even in those patients with chronic antiplatelet agent treatment.

Other pulmonary infections Although this chapter has focused on pneumonia, there are other pulmonary infections, such as influenza, with significant cardiovascular consequences. Influenza infection is a recognised trigger for the occurrence of CVEs. This happens especially in the most vulnerable, such as the elderly or those with chronic pathologies such as CVDs [111, 116, 117]. Influenza infection stimulates cardiovascular damage due to endothelial damage [118, 119], atherosclerosis progression or inflammatory infiltration of atheroma plaques, whose biological pathways have been described [101]. Finally, given the current Public Health Emergency of International Concern (PHEIC) and the pandemic situation declared by the World Health Organization (WHO) due to COVID-19, a rapid review of its cardiovascular consequences is mandatory [120]. This 220

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novel virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appears to most severely affect the most vulnerable populations, such as people with chronic heart disease [121]. Severe patients have more cardiac injury compared with nonsevere patients [122, 123]. SARS-CoV-2, as with previous coronaviruses, has deleterious cardiovascular effects [124]. Early data show that up to 10% of critically ill patients had cardiac comorbidities, and up to 23% of these critically ill patients developed cardiac injury [122, 125, 126]. One of the mechanisms by which the virus is thought to affect the cardiovascular system is through angiotensin-converting enzyme 2 (ACE2) [127]. ACE2, which has a determinant role in the cardiovascular system and is widely expressed in the heart, endothelium and lungs, is a functional receptor for SARS-CoV-2. This fact has generated a debate regarding the safety of antihypertensive drugs. However, preliminary data advise against removing renin–angiotensin system blockers [128]. Other potential mechanisms of myocarditis secondary to COVID-19 could be related to hypoxia, vascular inflammation, a cytokine storm and the infiltration of interstitial mononuclear inflammatory cells [124, 129]. It is, however, still early to provide more data about cardiovascular damage in these patients. In the near future, new studies will determine the short- and long-term magnitude of these complications, as well as providing more information about the pathophysiological mechanisms involved.

Prevention and treatment of cardiovascular complications The therapeutic alternatives recommended by clinical guidelines for CAP are limited to antibiotic therapy and support measures beyond preventative measures such as vaccination and modification of exercise, hygienic and toxic habits [130]. In recent years, the development and study of adjuvant treatments has been limited, and their impact on cardiovascular risk is unknown. In this section, some preventative and therapeutic measures such as vaccination, macrolides, antiplatelet agents, statins, corticosteroids and other factors that are even more novel concerning cardiovascular risk in CAP are analysed. Despite drugs already being available, more treatments are coming in the future. Vaccination

One of the most important preventative strategies is vaccination. Influenza and S. pneumoniae are commonly related to cardiovascular consequences. Influenza vaccination has shown a protective effect against cardiovascular risk in CAP, especially in the elderly and in those with previous coronary disease [131, 132]. Regarding pneumococcal vaccination, we only have data from the 23-valent polysaccharide vaccine, and these are somewhat more controversial. Although its protective effect against pneumonia is not under debate, there has only been one meta-analysis that found beneficial cardioprotective effects, and the current evidence is insufficient [133–137]. Further prospective RCTs and mechanistic studies are needed. Antiplatelet agents

Another current area of great interest is antiplatelet drugs, such as aspirin and ticagrelor. In observational studies of patients with CAP who are receiving aspirin, lower mortality has been observed [138, 139]. However, there have been no observational or interventional https://doi.org/10.1183/2312508X.10028419

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studies that have analysed the impact of antiplatelet drugs on the cardiovascular risk of CAP. Only a small nonblinded RCT has been published, which found a decreased risk of CVD in patients with CAP [140]. More recently, a trial with ticagrelor in CAP showed a decrease in thromboinflammatory markers [141]. These data will have to be confirmed in larger trials evaluating the incidence of cardiovascular complications. Statins

Statins, which affect the activity of neutrophils and the inflammatory response, constitute another alternative as an adjunctive treatment in CAP. Various observational studies seem to demonstrate a potential beneficial effect on CAP in terms of mortality, although there are also contrary studies [142, 143]. A first pilot clinical trial has shown that 7-day treatment with simvastatin improved neutrophil function, reduced NET formation, decreased systemic inflammation and increased 1-year survival in CAP [144]. These findings offer a new area of research aimed at reducing cardiovascular risk dependent on the inflammatory response and the damage caused by NETs. However, there are no double-blinded RCTs currently available that assess the neutralisation of cardiovascular risk in CAP. Macrolides

The role of macrolides is controversial. There are studies that seem to attribute a protective effect against mortality, especially in the most severe patients, but others dispute this aspect [145–147]. However, macrolides can increase cardiovascular risk by prolonging QT intervals and other mechanisms [148]. Nevertheless, in the context of CAP, the data are again contradictory, with some studies that suggest a decrease in cardiovascular risk during CAP while others suggest an increase [147, 149]. Corticosteroids

Corticosteroids are potent anti-inflammatory drugs. Corticosteroids have been studied in CAP due to their potential effect in reducing mortality and treatment failure. Recently, their probable protective effect on the cardiovascular risk of CAP [150] and their ability to decrease platelet thromboxane production in CAP [151] have been analysed. Their antithromboinflammatory properties are believed to exert a protective effect at the cardiovascular level. Currently, a clinical trial (the Colosseum trial) is about to start with the objective of evaluating whether treatment with methylprednisolone versus placebo during the acute phase of CAP reduces myocardial damage measured by troponin T [152]. As secondary outcomes, it will analyse platelet activation markers and oxidative stress, mortality and CVEs in the short and long term. Other treatments

Other treatments are being evaluated as adjuvants in pneumonia, although their benefits are not being analysed in relation to cardiovascular risk. An example is immunoglobulins, and the first findings suggest a beneficial effect in severe pneumonia [153]. Finally, very recently, an experimental model with ex vivo human lungs has been published in which hyaluronic acid perfusion reduced bacterial load and acute inflammation and increased the phagocytosis capacity of monocytes [154]. These and other treatments may be available in the future with the hope of reducing cardiovascular risk and improving the overall prognosis in CAP. 222

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Future perspectives and needed studies Epidemiological and mechanistic studies have demonstrated that CAP should be considered a cardiovascular risk factor. To date, there is a lack of evidence on how to minimise the incidence of CVEs in this population. More prospective trials and RCTs are needed to assess the frequent cardiovascular consequences. Improving the identification of patients with increased cardiovascular risk during and after pneumonia is essential for the design of new clinical trials. An interesting approach is to recognise enduring cardiac residual damage and inflammation in CAP survivors [155]. Measurement of the initial and residual injury could be promising for this purpose. Potential drugs being evaluated for this purpose are statins, corticosteroids, antiplatelets and others. In the future, more novel data will provide new tools for the attending physicians to identify, prevent and treat these complications.

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388: 1459–1544. Dela Cruz CS, Wunderink RG, Christiani DC, et al. Future research directions in pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med 2018; 198: 256–263. Cillóniz C, Liapikou A, Martin-Loeches I, et al. Twenty-year trend in mortality among hospitalized patients with pneumococcal community-acquired pneumonia. PLoS One 2018; 13: e0200504. Shah FA, Pike F, Alvarez K, et al. Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med 2013; 188: 586–592. Corrales-Medina VF, Alvarez KN, Weissfeld LA, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA 2015; 313: 264–274. Feldman C, Anderson R. Community-acquired pneumonia: still a major burden of disease. Curr Opin Crit Care 2016; 22: 477–484. Schnoor M, Hedicke J, Dalhoff K, et al. Approaches to estimate the population-based incidence of community acquired pneumonia. J Infect 2007; 55: 233–239. Saba G, Andrade LF, Gaillat J, et al. Costs associated with community acquired pneumonia in France. Eur J Health Econ 2018; 19: 533–544. Rozenbaum MH, Mangen MJJ, Huijts SM, et al. Incidence, direct costs and duration of hospitalization of patients hospitalized with community acquired pneumonia: a nationwide retrospective claims database analysis. Vaccine 2015; 33: 3193–3199. Kolditz M, Ewig S, Klapdor B, et al. Community-acquired pneumonia as medical emergency: predictors of early deterioration. Thorax 2015; 70: 551–558. Baek MS, Park S, Choi JH, et al. Mortality and prognostic prediction in very elderly patients with severe pneumonia. J Intensive Care Med 2019: 885066619826045. Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012; 67: 71–79. Menéndez R, Torres A, Zalacaín R, et al. Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome. Thorax 2004; 59: 960–965. Eurich DT, Marrie TJ, Minhas-Sandhu JK, et al. Ten-year mortality after community-acquired pneumonia. A prospective cohort. Am J Respir Crit Care Med 2015; 192: 597–604. Mortensen EM. Potential causes of increased long-term mortality after pneumonia. Eur Respir J 2011; 37: 1306–1307. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update. Circulation 2015; 131: e29–e322. Menéndez R, Méndez R, Aldás I, et al. Community-acquired pneumonia patients at-risk for early and long-term cardiovascular events are identified by cardiac biomarkers. Chest 2019; 156: 1080–1091. Violi F, Cangemi R, Falcone M, et al. Cardiovascular complications and short-term mortality risk in community-acquired pneumonia. Clin Infect Dis 2017; 64: 1486–1493. Cangemi R, Calvieri C, Falcone M, et al. Relation of cardiac complications in the early phase of communityacquired pneumonia to long-term mortality and cardiovascular events. Am J Cardiol 2015; 116: 647–651.

https://doi.org/10.1183/2312508X.10028419

223

ERS MONOGRAPH | CARDIOVASCULAR COMPLICATIONS AND RESPIRATORY DISORDERS 20. 21.

22. 23. 24. 25. 26.

27.

28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

45. 46. 47. 48.

224

Corrales-Medina VF, Musher DM, Wells GA, et al. Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality. Circulation 2012; 125: 773–781. Aldás I, Menéndez R, Méndez R, et al. Eventos cardiovasculares tempranos y tardíos en pacientes ingresados por neumonía adquirida en la comunidad. [Early and late cardiovascular events in patients hospitalized for community-acquired pneumonia.] Arch Bronconeumol 2020, in press [DOI: https://doi.org/10.1016/j.arbres.2019. 10.009]. Corrales-Medina VF, Suh KN, Rose G, et al. Cardiac complications in patients with community-acquired pneumonia: a systematic review and meta-analysis of observational studies. PLoS Med 2011; 8: e1001048. Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med 2019; 380: 171–176. Moret I, Lorenzo MJ, Sarria B, et al. Increased lung neutrophil apoptosis and inflammation resolution in nonresponding pneumonia. Eur Respir J 2011; 38: 1158–1164. Chalmers JD, Singanayagam A, Hill AT. C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am J Med 2008; 121: 219–225. Kosmas EN, Baxevanis CN, Papamichail M, et al. Daily variation in circulating cytokines and acute-phase proteins correlates with clinical and laboratory indices in community-acquired pneumonia. Eur J Clin Invest 1997; 27: 308–315. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–140. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–979. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836–843. Cangemi R, Della Valle P, Calvieri C, et al. Low-grade endotoxemia and clotting activation in the early phase of pneumonia. Respirology 2016; 21: 1465–1471. Cangemi R, Casciaro M, Rossi E, et al. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol 2014; 64: 1917–1925. Yende S, d’Angelo G, Mayr F, et al. Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths. PLoS One 2011; 6: e22847. Bastarache JA, Wang L, Geiser T, et al. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax 2007 Jul; 62: 608–616. Maris NA, de Vos AF, Bresser P, et al. Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers. Thromb Haemost 2005; 93: 1036–1040. Aras O, Shet A, Bach RR, et al. Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. Blood 2004; 103: 4545–4553. Lay AJ, Donahue D, Tsai MJ, et al. Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency. Blood 2007; 109: 1984–1991. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115–126. Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 2009; 27: 165–197. Randolph GJ. The fate of monocytes in atherosclerosis. J Thromb Haemost 2009; 7: Suppl. 1, 28–30. Newby LK. Inflammation as a treatment target after acute myocardial infarction. N Engl J Med 2019; 381: 2562–2563. Chen QM, Tu VC, Wu Y, et al. hydrogen peroxide dose dependent induction of cell death or hypertrophy in cardiomyocytes. Arch Biochem Biophys 2000; 373: 242–248. Panaro MA, Cianciulli A, Gagliardi N, et al. CD14 major role during lipopolysaccharide-induced inflammation in chick embryo cardiomyocytes. FEMS Immunol Med Microbiol 2008; 53: 35–45. Comstock KL, Krown KA, Page MT, et al. LPS-induced TNF-α release from and apoptosis in rat cardiomyocytes: obligatory role for CD14 in mediating the LPS response. J Mol Cell Cardiol 1998; 30: 2761–2775. Spallarossa P, Altieri P, Aloi C, et al. Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am J Physiol Circ Physiol 2009; 297: H2169–H2181. Yende S, d’Angelo G, Kellum JA, et al. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008; 177: 1242–1247. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116: 1793–1801. Mathieu P, Lemieux I, Després JP. Obesity, inflammation, and cardiovascular risk.. Clin Pharmacol Ther 2010; 87: 407–416. Newby DE, McLeod AL, Uren NG, et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation 2001; 103: 1936–1941. https://doi.org/10.1183/2312508X.10028419

COMMUNITY-ACQUIRED PNEUMONIA | R. MÉNDEZ ET AL. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79.

Lim HS, Lip GYH, Blann AD. Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. Atherosclerosis 2005; 180: 113–118. Menéndez R, Méndez R, Almansa R, et al. Simultaneous depression of immunological synapse and endothelial injury is associated with organ dysfunction in community-acquired pneumonia. J Clin Med 2019; 8: E1404. Schuetz P, Stolz D, Mueller B, et al. Endothelin-1 precursor peptides correlate with severity of disease and outcome in patients with community acquired pneumonia. BMC Infect Dis 2008; 8: 22. Gutbier B, Neuhauß AK, Reppe K, et al. Prognostic and pathogenic role of angiopoietin-1 and -2 in pneumonia. Am J Respir Crit Care Med 2018; 198: 220–231. Bermejo-Martin JF, Martín-Fernandez M, López-Mestanza C, et al. Shared features of endothelial dysfunction between sepsis and its preceding risk factors (aging and chronic disease). J Clin Med 2018; 7: E400. Cho JG, Lee A, Chang W, et al. Endothelial to mesenchymal transition represents a key link in the interaction between inflammation and endothelial dysfunction. Front Immunol 2018; 9: 294. Vos IHC, Briscoe DM. Endothelial injury: cause and effect of alloimmune inflammation. Transpl Infect Dis 2002; 4: 152–159. Cotran RS, Pober JS. Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol 1990; 1: 225–235. Lee WL, Liles WC. Endothelial activation, dysfunction and permeability during severe infections. Curr Opin Hematol 2011; 18: 191–196. Qi H, Yang S, Zhang L. Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front Immunol 2017; 8: 928. Loffredo L, Cangemi R, Perri L, et al. Impaired flow-mediated dilation in hospitalized patients with community-acquired pneumonia. Eur J Intern Med 2016; 36: 74–80. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111–1115. Vazzana N, Ganci A, Cefalù AB, et al. Enhanced lipid peroxidation and platelet activation as potential contributors to increased cardiovascular risk in the low-HDL phenotype. J Am Heart Assoc 2013; 2: e000063. Abbate R, Cioni G, Ricci I, et al. Thrombosis and acute coronary syndrome. Thromb Res 2012; 129: 235–240. Zucoloto AZ, Jenne CN. Platelet-neutrophil interplay: insights into neutrophil extracellular trap (NET)-driven coagulation in infection. Front Cardiovasc Med 2019; 6: 85. Anderson R, Feldman C. Pneumolysin as a potential therapeutic target in severe pneumococcal disease. J Infect 2017; 74: 527–544. Lê VB, Schneider JG, Boergeling Y, et al. Platelet activation and aggregation promote lung inflammation and influenza virus pathogenesis. Am J Respir Crit Care Med 2015; 191: 804–819. Modica A, Karlsson F, Mooe T. Platelet aggregation and aspirin non-responsiveness increase when an acute coronary syndrome is complicated by an infection. J Thromb Haemost 2007; 5: 507–511. Deppermann C, Kubes P. Start a fire, kill the bug: the role of platelets in inflammation and infection. Innate Immun 2018; 24: 335–348. Amison RT, O’Shaughnessy BG, Arnold S, et al. Platelet depletion impairs host defense to pulmonary infection with Pseudomonas aeruginosa in mice. Am J Respir Cell Mol Biol 2018; 58: 331–340. Gaertner F, Ahmad Z, Rosenberger G, et al. Migrating platelets are mechano-scavengers that collect and bundle bacteria. Cell 2017; 171: 1368–1382.e23. de Stoppelaar SF, van ’t Veer C, Claushuis TAM, et al. Thrombocytopenia impairs host defense in Gram-negative pneumonia-derived sepsis in mice. Blood 2014; 124: 3781–3790. Fitzgerald JR, Foster TJ, Cox D. The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 2006; 4: 445–457. Schattner M. Platelet TLR4 at the crossroads of thrombosis and the innate immune response. J Leukoc Biol 2019; 105: 873–880. Andonegui G, Kerfoot SM, McNagny K, et al. Platelets express functional Toll-like receptor-4. Blood 2005; 106: 2417–2423. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 2017; 544: 105–109. Mirsaeidi M, Peyrani P, Aliberti S, et al. Thrombocytopenia and thrombocytosis at time of hospitalization predict mortality in patients with community-acquired pneumonia. Chest 2010; 137: 416–420. Prina E, Ferrer M, Ranzani OT, et al. Thrombocytosis is a marker of poor outcome in community-acquired pneumonia. Chest 2013; 143: 767–775. Cangemi R, Pignatelli P, Carnevale R, et al. Low-grade endotoxemia, gut permeability and platelet activation in community-acquired pneumonia. J Infect 2016; 73: 107–114. Brinkmann V. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532–1535. Gupta AK, Joshi MB, Philippova M, et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett 2010; 584: 3193–3197.

https://doi.org/10.1183/2312508X.10028419

225

ERS MONOGRAPH | CARDIOVASCULAR COMPLICATIONS AND RESPIRATORY DISORDERS 80.

81. 82.

83. 84.

85. 86. 87. 88. 89. 90.

91. 92. 93.

94.

95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106.

226

Demyanets S, Stojkovic S, Mauracher LM, et al. Surrogate markers of neutrophil extracellular trap formation are associated with ischemic outcomes and platelet activation after peripheral angioplasty and stenting. J Clin Med 2020; 9: E304. Nel JG, Durandt C, Theron AJ, et al. Pneumolysin mediates heterotypic aggregation of neutrophils and platelets in vitro. J Infect 2017; 74: 599–608. Ullah I, Ritchie ND, Evans TJ. The interrelationship between phagocytosis, autophagy and formation of neutrophil extracellular traps following infection of human neutrophils by Streptococcus pneumoniae. Innate Immun 2017; 23: 413–423. Gould TJ, Lysov Z, Liaw PC. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost 2015; 13: S82–S91. Ebrahimi F, Giaglis S, Hahn S, et al. Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial. Eur Respir J 2018; 51: 1701389. Gould TJ, Vu TT, Swystun LL, et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 2014; 34: 1977–1984. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107: 15880–15885. Alhamdi Y, Abrams ST, Cheng Z, et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med 2015; 43: 2094–2103. Meegan JE, Yang X, Beard RS, et al. Citrullinated histone 3 causes endothelial barrier dysfunction. Biochem Biophys Res Commun 2018; 503: 1498–1502. Franck G, Mawson TL, Folco EJ, et al. Roles of PAD4 and NETosis in experimental atherosclerosis and arterial injury. Circ Res 2018; 123: 33–42. Zhou Z, Zhang S, Ding S, et al. Excessive neutrophil extracellular trap formation aggravates acute myocardial infarction injury in apolipoprotein E deficiency mice via the ROS-dependent pathway. Oxid Med Cell Longev 2019; 2019: 1209307. Stakos DA, Kambas K, Konstantinidis T, et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 2015; 36: 1405–1414. Mangold A, Hofbauer TM, Ondracek AS, et al. Neutrophil extracellular traps and monocyte subsets at the culprit lesion site of myocardial infarction patients. Sci Rep 2019; 9: 16304. Mangold A, Alias S, Scherz T, et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 2015; 116: 1182–1192. Eghbalzadeh K, Georgi L, Louis T, et al. Compromised anti-inflammatory action of neutrophil extracellular traps in PAD4-deficient mice contributes to aggravated acute inflammation after myocardial infarction. Front Immunol 2019; 10: 2313. Brown AO, Mann B, Gao G, et al. Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 2014; 10: e1004383. Brown AO, Millett ERC, Quint JK, et al. Cardiotoxicity during invasive pneumococcal disease. Am J Respir Crit Care Med 2015; 191: 739–745. Reyes LF, Restrepo MI, Hinojosa CA, et al. A non-human primate model of severe pneumococcal pneumonia. PLoS One 2016; 11: e0166092. Reyes LF, Restrepo MI, Hinojosa CA, et al. Severe pneumococcal pneumonia causes acute cardiac toxicity and subsequent cardiac remodeling. Am J Respir Crit Care Med 2017; 196: 609–620. Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res 2004; 95: 754–763. Keller TT, van der Meer JJ, Teeling P, et al. Selective expansion of influenza A virus-specific T cells in symptomatic human carotid artery atherosclerotic plaques. Stroke 2008; 39: 174–179. Naghavi M, Wyde P, Litovsky S, et al. Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation 2003; 107: 762–768. Gupta S. Chronic infection in the aetiology of atherosclerosis – focus on Chlamydia pneumoniae. Atherosclerosis 1999; 143: 1–6. Almeida NCC, Queiroz MAF, Lima SS, et al. Association of Chlamydia trachomatis, C. pneumoniae, and IL-6 and IL-8 gene alterations with heart diseases. Front Immunol 2019; 10: 87. Iriz E, Cirak MY, Engin ED, et al. Effects of atypical pneumonia agents on progression of atherosclerosis and acute coronary syndrome. Acta Cardiol 2007; 62: 593–598. Ngeh J, Anand V, Gupta S. Chlamydia pneumoniae and atherosclerosis – what we know and what we don’t. Clin Microbiol Infect 2002; 8: 2–13. Vita JA, Treasure CB, Yeung AC, et al. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines. Circulation 1992; 85: 1390–1397. https://doi.org/10.1183/2312508X.10028419

COMMUNITY-ACQUIRED PNEUMONIA | R. MÉNDEZ ET AL. 107. Moammar MQ, Ali MI, Mahmood NA, et al. Cardiac troponin I levels and alveolar–arterial oxygen gradient in patients with community-acquired pneumonia. Heart Lung Circ 2010; 19: 90–92. 108. Merx MW, Weber C. Sepsis and the heart. Circulation 2007; 116: 793–802. 109. Sibila O, Mortensen EM, Anzueto A, et al. Prior cardiovascular disease increases long-term mortality in COPD patients with pneumonia. Eur Respir J 2014; 43: 36–42. 110. Musher DM, Rueda AM, Kaka AS, et al. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007; 45: 158–165. 111. Kwong JC, Schwartz KL, Campitelli MA, et al. acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018; 378: 345–353. 112. Méndez R, Aldás I, Menéndez R. Biomarkers in community-acquired pneumonia (cardiac and non-cardiac). J Clin Med 2020; 9: E549. 113. Matsuo A, Nagai-Okatani C, Nishigori M, et al. Natriuretic peptides in human heart: novel insight into their molecular forms, functions, and diagnostic use. Peptides 2019; 111: 3–17. 114. Papassotiriou J, Morgenthaler NG, Struck J, et al. Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem 2006; 52: 1144–1151. 115. Wanecek M, Weitzberg E, Rudehill A, et al. The endothelin system in septic and endotoxin shock. Eur J Pharmacol 2000; 407: 1–15. 116. Warren-Gash C, Blackburn R, Whitaker H, et al. Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland. Eur Respir J 2018; 51: 1701794. 117. Warren-Gash C, Smeeth L, Hayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis 2009; 9: 601–610. 118. Madjid M, Awan I, Ali M, et al. Influenza and atherosclerosis: vaccination for cardiovascular disease prevention. Expert Opin Biol Ther 2005; 5: 91–96. 119. Harskamp RE, van Ginkel MW. Acute respiratory tract infections: a potential trigger for the acute coronary syndrome. Ann Med 2008; 40: 121–128. 120. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727–733. 121. Li B, Yang J, Zhao F, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol 2020; 109: 531–538. 122. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506. 123. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323: 1061–1069. 124. Madjid M, Safavi-Naeini P, Solomon SD, et al. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol 2020; in press [DOI: https://doi.org/10.1001/jamacardio.2020.1286]. 125. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: a systematic review and meta-analysis. Int J Infect Dis 2020; 94: 91–95. 126. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; in press [DOI: https://doi.org/10.1016/S2213-2600(20)30079-5]. 127. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17: 259–260. 128. Danser AHJ, Epstein M, Batlle D. Renin–angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin–angiotensin system blockers. Hypertension 2020; in press [DOI: https://doi. org/10.1161/HYPERTENSIONAHA.120.15082]. 129. Clerkin KJ, Fried JA, Raikhelkar J, et al. Coronavirus disease 2019 (COVID-19) and cardiovascular disease. Circulation 2020; in press [DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.046941]. 130. Menéndez R, Cilloniz C, España PP, et al. Community-acquired pneumonia. Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) Guidelines. 2020 update. Arch Bronconeumol 2020; 56: Suppl. 1, 1–10. 131. Chiang MH, Wu HH, Shih CJ, et al. Association between influenza vaccination and reduced risks of major adverse cardiovascular events in elderly patients. Am Heart J 2017; 193: 1–7. 132. Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients. JAMA 2013; 310: 1711–1720. 133. Binder CJ, Hörkkö S, Dewan A, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003; 9: 736–743. 134. Ren S, Newby D, Li SC, et al. Effect of the adult pneumococcal polysaccharide vaccine on cardiovascular disease: a systematic review and meta-analysis. Open Hear 2015; 2: e000247. 135. Hung IFN, Leung AYM, Chu DWS, et al. Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study. Clin Infect Dis 2010; 51: 1007–1016. https://doi.org/10.1183/2312508X.10028419

227

ERS MONOGRAPH | CARDIOVASCULAR COMPLICATIONS AND RESPIRATORY DISORDERS 136. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, et al. Ineffectiveness of pneumococcal vaccination in cardiovascular prevention: the CAPAMIS study. JAMA Intern Med 2013; 173: 1918–1920. 137. Tseng HF, Slezak JM, Quinn VP, et al. Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men. JAMA 2010; 303: 1699–1706. 138. Falcone M, Russo A, Shindo Y, et al. A hypothesis-generating study of the combination of aspirin plus macrolides in patients with severe community-acquired pneumonia. Antimicrob Agents Chemother 2018; 63: e01556-18. 139. Falcone M, Russo A, Cangemi R, et al. Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin. J Am Heart Assoc 2015; 4: e001595. 140. Oz F, Gul S, Kaya MG, et al. Does aspirin use prevent acute coronary syndrome in patients with pneumonia. Coron Artery Dis 2013; 24: 231–237. 141. Sexton TR, Zhang G, Macaulay TE, et al. Ticagrelor reduces thromboinflammatory markers in patients with pneumonia. JACC Basic Transl Sci 2018; 3: 435–449. 142. Troeman DPR, Postma DF, van Werkhoven CH, et al. The immunomodulatory effects of statins in community-acquired pneumonia: a systematic review. J Infect 2013; 67: 93–101. 143. Havers F, Bramley AM, Finelli L, et al. Statin use and hospital length of stay among adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2016; 62: 1471–1478. 144. Sapey E, Patel JM, Greenwood H, et al. Simvastatin improves neutrophil function and clinical outcomes in pneumonia: a pilot randomised controlled trial. Am J Respir Crit Care Med 2019; 200: 1282–1293. 145. Martin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med 2010; 36: 612–620. 146. Vardakas KZ, Trigkidis KK, Falagas ME. Fluoroquinolones or macrolides in combination with β-lactams in adult patients hospitalized with community acquired pneumonia: a systematic review and meta-analysis. Clin Microbiol Infect 2017; 23: 234–241. 147. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA 2014; 311: 2199–2208. 148. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366: 1881–1890. 149. Postma DF, Spitoni C, van Werkhoven CH, et al. Cardiac events after macrolides or fluoroquinolones in patients hospitalized for community-acquired pneumonia: post-hoc analysis of a cluster-randomized trial. BMC Infect Dis 2019; 19: 17. 150. Cangemi R, Falcone M, Taliani G, et al. Corticosteroid use and incident myocardial infarction in adults hospitalized for community-acquired pneumonia. Ann Am Thorac Soc 2019; 16: 91–98. 151. Cangemi R, Carnevale R, Nocella C, et al. Glucocorticoids impair platelet thromboxane biosynthesis in community-acquired pneumonia. Pharmacol Res 2018; 131: 66–74. 152. Violi F, Calvieri C, Cangemi R. Effect of corticosteroids on myocardial injury among patients hospitalized for community-acquired pneumonia: rationale and study design. The Colosseum trial. Intern Emerg Med 2020; 15: 79–86. 153. Welte T, Dellinger RP, Ebelt H, et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). Intensive Care Med 2018; 44: 438–448. 154. Liu A, Park JH, Zhang X, et al. Therapeutic effects of hyaluronic acid in bacterial pneumonia in the ex vivo perfused human lungs. Am J Respir Crit Care Med 2019; 200: 1234–1245. 155. Brack MC, Lienau J, Kuebler WM, et al. Cardiovascular sequelae of pneumonia. Curr Opin Pulm Med 2019; 25: 257–262.

Disclosures: None declared. Acknowledgements: We thank Arash Javadinejad, La Fe Health Research Institute, Spain, for help with editing the English.

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| Chapter 16 β2-adrenoceptor modulation in COPD and its potential impact on cardiovascular comorbidities Maria Gabriella Matera1 and Reynold A. Panettieri Jr2 COPD and chronic CVDs often coexist and pharmacological modulation of β2-adrenoceptor (β2-AR) function remains a critical issue in the management of these diseases. Activation of the β2-AR, a requisite mechanism of action, promotes bronchodilation that improves COPD-related health-outcome measures, such as quality of life, dyspnoea, exercise capacity and, mainly, the number and severity of exacerbations. Nevertheless, recent findings suggest that β2-AR stimulation induces physiological and pathological signals in the lung. β-AR found in the heart play an important role in the control of the cardiovascular system, but the changes in cardiac autonomic function in CVDs may contribute to an increased cardiac risk associated with inhaled β2-AR agonist treatment. New insights on the mechanism of action of β2-AR agonists have engendered rethinking of the efficacy and safety of β2-AR activation in the management of CVD and COPD. The future development of novel synthetic β2-AR agonists could avoid adverse reactions by modulating tertiary and quaternary conformations that alter β2-AR phosphorylation and desensitisation. Cite as: Matera MG, Panettieri RA Jr. β2-adrenoceptor modulation in COPD and its potential impact on cardiovascular comorbidities. In: Martínez-García MÁ, Pépin J-L, Cazzola M, eds. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 229–237 [https://doi.org/10.1183/2312508X.10028519].

@ERSpublications β2-adrenoceptor agonists can induce both physiological and pathological signals in the lungs and in the heart http://bit.ly/2SEaEz5

lthough ephedrine, a nonselective α-adrenoceptor (AR) and β-AR agonist, was derived from the Chinese herb Ma Huang over 5000 years ago, the history of β2-AR agonist really started with the discovery of salbutamol by Sir David Jack and colleagues. By starting with nonselective β-AR agonists, specific β2-AR agonists were developed; today there are selective drugs that, based on their half-life, are classified as short-acting β2-AR agonists, twice daily long-acting β2-AR agonists (LABAs) and once daily ultra long-acting β2-AR agonists (U-LABAs) [1–3].

A

1 Dept of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy. 2Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ, USA.

Correspondence: Maria Gabriella Matera, Experimental Medicine, University of Campania Luigi Vanvitelli, via Costsntinopoli 16, Naples, 80135, Italy. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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The half-life of a β2-AR agonist with its receptor is dependent on molecular structure (figure 1). Hydrophilic compounds, such as short-acting β2-AR agonists, access the active site of the β2-AR directly from the extracellular aqueous compartment, and show a rapid onset and a short duration of action (4–6 h). LABAs, such as salmeterol, a drug that is >10 000 times more lipophilic than salbutamol, interacts with an auxiliary binding site (exosite) of the β2-AR, a domain of highly hydrophobic amino acids. Salmeterol manifests a long activity, which is concentration-independent and has a slower onset (>30 min) compared with salbutamol. Unlike salmeterol, formoterol intercalates into the membrane, forms a depot that progressively releases the drug, which then interacts with the active site of the β2-AR. Compared with salbutamol, formoterol shows a slower onset and a longer concentrationdependent duration of action. Indacaterol, a U-LABA, uniquely interacts with the lipid membrane and the β2-ARs. Indacaterol and salmeterol have a similar steady state and both demonstrate kinetic interactions with lipid membranes; however, indacaterol has a higher partitioning into the microenvironment of the receptor, which contributes to its faster onset and longer duration of therapeutic action. The longer duration of indacaterol compared with salmeterol can be also explained as the drug has a two-fold higher affinity for lipid rafts, and caveolae, areas of cell membranes where β2-ARs are held together in close contact with signalling molecules and effectors, in airway smooth muscle (ASM). Unlike salmeterol, which drastically increases membrane fluidity and reduces the intrinsic efficacy of the molecule, indacaterol has little effect on membrane fluidity [1, 2, 4, 5]. Contemporary thought in the 1990s suggested that when a ligand binds the receptor (R), a binary complex occurs that enhances its affinity for downstream effectors (like G proteins). This ligand is then termed an agonist; if the binary complex that is formed by the ligand YY

YY

YY

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Salbutamol

Salmeterol Figure 1. β2-agonist–β2-adrenoceptor interaction. U-LABA: ultra long-acting β2-adrenoceptor agonist.

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lacks an affinity for downstream effectors, it is termed an antagonist. Further, COSTA and HERZ [6] suggested that all G protein-coupled receptors (GPCRs) oscillate between two forms: an inactive state R and an activated conformation of the receptor R* that was capable of signalling in the absence of the ligand and GPCRs, being in equilibrium with the rest (figure 2). These observations refined the ligand-receptor theory, which suggests that a receptor ligand can be classified as an antagonist (also termed a “neutral antagonist”), which has relatively equal affinity for both conformations R and R*, does not alter the equilibrium, and blocks the effects of agonists and inverse agonists. An agonist binds and temporarily stabilises receptors in their activated state but with a different efficacy. Accordingly, β2-AR agonists can be characterised in three classes: full agonists, such as isoproterenol or formoterol, which completely move the equilibrium in the activated conformation, shifting the equilibrium towards R*; partial agonists, such as salmeterol or U-LABAs, which less frequently stabilise a different conformation of the receptor and induce a relatively higher affinity for R* (this affinity is lower than that of a full agonist); inverse agonists, which bind to the receptor in the inactive state and thus shift the equilibrium away from the R* towards R [6–8]. In ASM, there are sufficient numbers of spare β2-ARs, and a full or partial agonist can elicit similar downstream effects. Full agonists offer therapeutic advantages over partial agonists during an exacerbation in which there could be a reduced number of spare receptors [8].

β2-ARs in COPD Compelling evidence suggests that inhaled LABA and U-LABA play an important role in the management of stable COPD. In patients suffering from COPD, these drugs induce a prolonged bronchodilation and improve clinically important outcomes such as quality of life, dyspnoea, exercise capacity and exacerbations [1, 2, 9]. Inverse agonist

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Active receptor state (R*) Figure 2. Schematic representation of the effects of a full agonist, a partial agonist and an inverse agonist. Highly efficacious drugs (full agonists) have a much higher affinity for R* than R, while agonists with low intrinsic efficacy (partial agonists) have a relatively small affinity preference for R* relative to R. R: receptor. Thicker arrows represent a higher affinity.

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The effects of β2-ARs in the airways depend on β2-AR distribution in ASM. Direct adrenergic innervation of ASM is sparse in humans, but β2-ARs are densely expressed on this cell type, with a density that increases from central to peripheral airways, including the alveolar airspace [1, 2, 10]. The relaxation induced by these drugs depends on the binding to the β2-AR, which, like all GPCRs, has seven transmembrane-spanning α-helices predominantly coupled to the stimulatory Gs protein, a trimeric complex consisting of an α-subunit (which stimulates adenylate cyclase) and βγ-subunits (which transduce other signals) (figure 3). The activation of the β2-AR stimulates, through the subunit α of Gs, adenylyl cyclase (AC) to catalyse the conversion of adenosine triphosphate into cyclic adenosine monophosphate (cAMP); cAMP induces the phosphorylation of protein kinase A, which, in turn, phosphorylates key regulatory proteins, leading to the inhibition of calcium ion (Ca2+) release from intracellular stores, a reduction of membrane Ca2+ entry, sequestration of

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Figure 3. Mechanism of action of β2-adrenoceptor agonist. AC: adenylyl cyclase; AMP: adenosine monophosphate; BK: large-conductance potassium; Ca2+: calcium ion; [Ca2+]i: cytoplasmic free Ca2+ concentration; cAMP: cyclic AMP; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal-regulated kinase; Ggust: gustducin; GPCR: G protein-coupled receptor; GRK: GPCR kinase; IP3: inositol-3-phosphate; MAPK: p38 mitogen-activated protein kinase; MLCP: myosin light chain phosphatase; NO: nitric oxide; PDE: phosphodiesterase; PI3K: phosphatidylinositol 3-kinase; PLC: phospholipase C; PKA: protein kinase A; PKC: protein kinase C; PKD: protein kinase D; PLC: phospholipase C; ROCK: Rho-associated coiled-coil-containing protein kinases; TAS2R: taste type 2 receptor. Reproduced and modified from [11] with permission.

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intracellular Ca2+, and, at the end, ASM relaxation and bronchodilation. cAMP levels are then regulated through the activity of phosphodiesterase isozymes/isoforms, which degrade it to 5′-AMP [12–16]. More recently, JOHNSTONE et al. [17] characterised a phosphodiesterase subtype, PDE8A, colocalised in lipid raft microdomains β2-AR-AC6 signals; the discriminating inhibition of this enzyme selectively increases cAMP formation in isoproterenol-stimulated responses. Other bronchodilatory mechanisms mediated by β2-AR suggest a direct interaction of Gs with potassium channels that are expressed on the ASM cell membranes and that could mediate β2-agonist effects in a through cAMP-independent manner [18]. Despite β2-AR efficacy, evidence suggests that some COPD patients treated with inhaled β2-AR agonists have poor disease control related to a decrease in receptor responsiveness (i.e. desensitisation) from prolonged β2-AR activation [19]. β2-AR desensitisation may occur through varied GPCR intracellular signalling pathways. Biased agonism (or functional selectivity) refers to a subset of responses that affect β2-AR agonists’ efficacy. In particular, GPCR interaction with β-arrestin proteins, which are members of a small family of multifunctional GPCR regulatory or adaptor proteins, can markedly effect β2-AR desensitisation. β-arrestin activation desensitises GPCRs through the receptor phosphorylation induced by a G protein-coupled receptor kinase (GRK); subsequent to its recruitment and receptor desensitisation, β-arrestin evokes receptor internalisation and degradation. This homologous desensitisation is an autoregulatory process to prevent overstimulation of β2-AR. Furthermore, β2-AR-mediated β-arrestin signalling can drive pathogenic features (mucus production, inflammation) in COPD [1, 15–17, 19, 20]. To overcome the lack of efficacy due to desensitisation, functional studies from primary human ASM have proposed the modulation of β2-AR interaction with G proteins, GRKs and β-arrestins using pepducins, cell penetrating palmitoylated peptides [21, 22]; these peptides induce cAMP production without the recruitment of β-arrestins. Moreover, the modulation of PDE8A could be a relevant target to moderate β2-AR-induced bronchodilation, and to avoid long-term desensitisation [21]. Indeed, the β2-AR phosphorylation induced by β-arrestin could switch β2-AR-G protein coupling from Gs to Gi. This effect decreases cAMP levels and activates other distinct signalling pathways, which involve the activation of the Rho kinase responsible for inactivation of actin-myosin phosphatase. In some cell types, including ASM, β2-AR activation can also trigger a non-canonical pathway via β-arrestin, which involves the activation of ERK, cJun N-terminal kinase, p38 mitogen-activated protein kinase, phosphoinositide-3-kinase, Akt and RhoA. This non-canonical pathway is responsible for deleterious effects, such as increased ASM contractility, airway hyperresponsiveness, mucus metaplasia and pro-inflammatory mediator release, playing an important role in orchestrating inflammation and remodelling, and disease progression [23–27]. Finally, a cross-talk also exists amongst β2-ARs and other GPCRs, particularly on Gq-protein coupled receptors; these signalling pathways can also contribute to β2-AR heterologous desensitisation and, consequently, to airway hyperresponsiveness [14]. In the near future, pharmacologists should be forced to rethink their concepts of agonism. The idea that new agonists may well induce receptor conformations that activate signalling https://doi.org/10.1183/2312508X.10028519

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proteins in a biased manner could lead to the development of therapeutically better molecules. These new molecules could preferentially confine their activity in stabilising the receptor to a conformation that enhances clinical efficacy while decreasing adverse reactions (figure 4) [11, 28, 29].

β2-ARs in COPD and in chronic CVDs COPD and chronic CVDs often coexist; their prevalence is known to range 20–32%, with a large incidence of mortality; this incidence is not surprising, because COPD and CVDs share smoking as a common risk factor, but also older age and unhealthy lifestyle choices. Pharmacological modulation of β2-AR function is one of the critical issues in the treatment of these patients [30]. β-AR found in the heart plays an important role in the control of the cardiovascular system. It has been documented that the proportions of β1-AR and β2-AR coexist on the atria and ventricles, being 77% and 23%, respectively, in normal hearts [31]. The β1-AR subtype predominates in both regions; however, the density of β2-AR is ∼2.5-fold higher in the sinoatrial node than in the right atrial myocardium. This is consistent with the results of

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Figure 4. Biased various G protein-coupled receptor (GPCR) signalling. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signalling. GRK: GPCR kinase. Reproduced and modified from [11] with permission.

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physiological studies, which suggest that this receptor regulates cardiac chronotropism [32]. β2-ARs can also be round in the heart’s adrenergic nerve terminals, where they facilitate noradrenaline release [30, 33, 34]. HF

In the failing heart, the systemic response of increasing adrenergic stimulation, a compensatory mechanism to overcome the reduced inotropism, induces desensitisation of cardiac β1-ARs, with an impairment transduction signal, and myocardial apoptosis. This sustained cardiac sympathetic drive was seen to be responsible for the progression of left ventricular dysfunction. However, there are no changes in β2-AR proportion because of the protective mechanism to counteract the deleterious effects of sympathetic overdrive. Consequently, the failing heart becomes more dependent on the β2-ARs for inotropic support, which can alter the cardiac electrical stability, increasing the propensity for the formation of malignant arrhythmias in the diseased heart [33]. Although the functional responses mediated by β1-ARs and β2-ARs are not necessarily different, the recent knowledge on cardiac β2-AR signal and function demonstrated that the increased β2-AR phosphorylation by GRK2 in the failing heart exacerbates the Gi signalling that can activate GRK2, the most abundant and best-characterised GRK in the heart, associated in β-AR defective signalling and cardiac dysfunction [34]. These pathways seem to be involved in cardiac remodelling. Receptor downregulation and desensitisation are considered to be protective responses against excessive sympathetic stimulation during CHF. However, desensitisation of β1-AR by GRK2 and the resultant increase in Gi-biased β2-AR signalling are responsible for the CHF pathogenesis because of maladaptive remodelling, failure and cardiodepression due to the activation of signalling pathways such as the phosphoinositide 3-kinase cascades [30, 33–35]. Therefore, in patients with HF, β2-ARs can improve lung function, cardiovascular haemodynamics and reabsorption of pulmonary oedema [33]. In a preclinical study carried out in an experimental model of CHF, an additive interaction was documented between indacaterol and metoprolol in normalising and reversing cardiac remodelling, reducing infarct size even more than these drugs administered alone, lowering BP and heart rate, reversing the decrease in ejection fraction, normalising left ventricular systolic and diastolic internal diameters, normalising the decreased β1-AR messenger RNA expression as well as cardiac cAMP levels, and reducing cardiac G protein-coupled GRK2 expression [36]. Synergistic β2-AR stimulation and β1-AR blockade together may be efficacious for cardiac progenitor cell expansion in the failing heart [37]. Collectively, these findings might be of clinical interest, paving the way for a novel therapeutic modality to treat patients suffering from CHF and COPD [38]. Interferences with rhythm

Changes to cardiac autonomic function may contribute to an increased cardiac risk associated with treatment with inhaled β2-AR agonists. Even in healthy subjects, inhalation of a therapeutic dose of salbutamol will cause significant haemodynamic changes, accompanied by a shift in CV autonomic tone towards increased sympathetic outflow. In https://doi.org/10.1183/2312508X.10028519

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patients suffering from COPD, a mild tachycardia that can be recorded in both the left and the right ventricle after the first dose of a β2-AR agonist is a common occurrence. Torsade de pointes, hypokalaemia and QTc prolongation are possible adverse events in a patient on usual-dose β2-AR agonist [33, 39]. It should, however, be emphasised that the heart is a non-target tissue with a lower β2-AR density than target tissues, such as ASM, and this can justify the better side-effect profile of partial agonists such as salmeterol and newer β2-AR agonists. In non-target tissues, β2-ARs desensitise more quickly during the first few days of regular use, with a faster resolution of tachycardia. Consequently, a full β2-AR agonist with high intrinsic efficacy has more adverse effects than partial β2-AR agonists. This has been demonstrated in COPD patients with coexisting CVDs, in whom formoterol increased arterial pressure and cardiac rhythm but salmeterol did not [8, 22, 33]. Current evidence remains confusing; some studies suggest a high risk of CVEs after initiation of long-acting bronchodilators in patients with coexisting CVDs; others showed that LABA or U-LABA were safe and significantly improve CVD outcomes even in patients at heightened CVD risk [33, 40].

Conclusion These findings collectively suggest that that of β2-AR agonists can induce both physiological and pathological signals in the lungs and heart. To date, there is no direct evidence that COPD should be treated differently in the presence of CVD; however, no studies have been designed to evaluate the effectiveness/safety ratio of such a therapeutic approach. Therefore, while we are waiting for specific studies, a degree of caution is necessary in the choice of therapy used in patients with coexisting COPD and CVDs.

References 1.

Matera MG, Page C, Calzetta L, et al. Pharmacology and therapeutics of bronchodilators revisited. Pharmacol Rev 2020; 72: 218–252. 2. Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med 2013; 187: 690–696. 3. Patel AR, Patel AR, Singh S, et al. Global Initiative for Chronic Obstructive Lung Disease: the changes made. Cureus 2019; 11: e4985. 4. Ringdal N, Derom E, Wåhlin-Boll E, et al. Onset and duration of action of single doses of formoterol inhaled via Turbuhaler. Respir Med 1998; 92: 1017–1021. 5. Lombardi D, Cuenoud B, Krämer SD. Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties? Eur J Pharm Sci 2009; 38: 533–547. 6. Costa T, Herz A. Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci USA 1989; 86: 7321–7325. 7. Onaran HO, Costa T, Rodbard D. Subunits of guanine nucleotide-binding proteins and regulation of spontaneous receptor activity: thermodynamic model for the interaction between receptors and guanine nucleotide-binding protein subunits. Mol Pharmacol 1993; 43: 245–256. 8. Hanania NA, Dickey BF, Bond RA. Clinical implications of the intrinsic efficacy of beta-adrenoceptor drugs in asthma: full, partial and inverse agonism. Curr Opin Pulm Med 2010; 16: 1–5. 9. Calzetta L, Rogliani P, Matera MG, et al. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest 2016; 149: 1181–1196. 10. Ikeda T, Anisuzzaman AS, Yoshiki H, et al. Regional quantification of muscarinic acetylcholine receptors and β-adrenoceptors in human airways. Br J Pharmacol 2012; 166: 1804–1814. 11. Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators. Eur Respir Rev 2019; 28: 190095. 12. Lefkowitz RJ. Seven transmembrane receptors: something old, something new. Acta Physiol 2007; 190: 9–19. 236

https://doi.org/10.1183/2312508X.10028519

b2-ADRENOCEPTOR MODULATION | M.G. MATERA AND R.A. PANETTIERI JR 13. Mueller L, Prosser RS, Kobilka BK. The dynamic process of β2-adrenergic receptor activation. Cell 2013; 152: 532–542. 14. Panettieri RA Jr. Bronchodilators, receptors and cross-talk: together is better? Postgrad Med 2015; 127: 771–780. 15. Pera T, Penn RB. Bronchoprotection and bronchorelaxation in asthma: new targets, and new ways to target the old ones. Pharmacol Ther 2016; 164: 82–96. 16. Chung KY, Rasmussen SG, Liu T, et al. Conformational changes in the G protein Gs induced by the β2 adrenergic receptor. Nature 2011; 477: 611–615. 17. Johnstone TB, Smith KH, Koziol-White CJ, et al. PDE8 is expressed in human airway smooth muscle and selectively regulates cAMP signaling by β2-adrenergic receptors and adenylyl cyclase 6. Am J Respir Cell Mol Biol 2018; 58: 530–541. 18. Calzetta L, Matera MG, Cazzola M. Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy. Curr Opin Pharmacol 2018; 40: 95–103. 19. Oehme S, Mittag A, Schrödl W, et al. Agonist-induced β2-adrenoceptor desensitization and downregulation enhance pro-inflammatory cytokine release in human bronchial epithelial cells. Pulm Pharmacol Ther 2015; 30: 110–120. 20. Kobilka BK, Deupi X. Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci 2007; 28: 397–406. 21. Panettieri RA, Pera T, Liggett SB, et al. Pepducins as a potential treatment strategy for asthma and COPD. Curr Opin Pharmacol 2018; 40: 120–125. 22. Cazzola M, Imperatore F, Salzillo A, et al. Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia. Chest 1998; 114: 411–415. 23. Giembycz MA, Newton R. Beyond the dogma: novel beta2-adrenoceptor signalling in the airways. Eur Respir J 2006; 27: 1286–1306. 24. Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the adrenergic receptor to different G-proteins by protein kinase A. Nature 1997; 390: 88–91. 25. Matera MG, Page C, Rinaldi B. β2-adrenoceptor signaling bias in asthma and COPD and the potential impact on the comorbidities associated with these diseases. Curr Opin Pharmacol 2018; 40: 142–146. 26. Cassier E, Gallay N, Bourquard T, et al. Phosphorylation of β-arrestin2 at Thr383 by MEK underlies β-arrestin-dependent activation of Erk1/2 by GPCRs. eLife 2017; 6: e23777. 27. Kenakin BMC. The potential for selective pharmacological therapies through biased receptor signaling. BMC Pharmacol Toxicol 2012; 13: 3. 28. Shonberg J, Lopez L, Scammells PJ, et al. Biased agonism at G protein-coupled receptors: the promise and the challenges - a medicinal chemistry perspective. Med Res Rev 2014; 34: 1286–1330. 29. Luttrell LM, Maudsley S, Bohn LM. Fulfilling the promise of “biased” G protein-coupled receptor agonism. Mol Pharmacol 2015; 88: 579–588. 30. Cazzola M, Rogliani P, Matera MG. Cardiovascular disease in patients with COPD. Lancet Respir Med 2015; 3: 593–595. 31. Matera MG, Calzetta L, Cazzola M. β-adrenoceptor modulation in chronic obstructive pulmonary disease: present and future perspectives. Drugs 2013; 73: 1653–1663. 32. Rodefeld MD, Beau SL, Schuessler RB, et al. β-adrenergic muscarinic cholinergic receptor densities in the human sinoatrial node: identification of a high β2-adrenergic receptor density. J Cardiovasc Electrophysiol 1996; 7: 1039–1049. 33. Cazzola M, Calzetta L, Rinaldi B, et al. Management of chronic obstructive pulmonary disease in patients with cardiovascular diseases. Drugs 2017; 77: 721–732. 34. Woo AYO, Xiao R. β-adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin 2012; 33: 335–341. 35. Woo AYO, Song Y, Xiao RP, et al. Biased β2-adrenoceptor signaling in heart failure: pathophysiology and drug discovery. Br J Pharmacol 2015; 172: 5444–5456. 36. Rinaldi B, Donniacuo M, Sodano L, et al. Effects of chronic treatment with the new ultra-long-acting β2-adrenoceptor agonist indacaterol alone or in combination with the β1-adrenoceptor blocker metoprolol on cardiac remodelling. Br J Pharmacol 2015; 172: 3627–3637. 37. Khan M, Mohsin S, Avitabile D, et al. β-adrenergic regulation of cardiac progenitor cell death versus survival and proliferation. Circ Res 2013; 112: 476–486. 38. Cazzola M, Matera MG. Combining dual bronchodilation and β-blockade in patients with an overlap between COPD and cardiovascular diseases. Chest 2018; 153: 1289–1291. 39. Cekici L, Valipour A, Kohansal R, et al. Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study. Br J Clin Pharmacol 2009; 67: 394–402. 40. Rogliani P, Ora J, Matera MG, et al. The safety of dual bronchodilation on cardiovascular serious adverse events in COPD. Expert Opin Drug Saf 2018; 17: 589–596.

Disclosures: None declared.

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| Chapter 17 Characterising the cardiovascular safety profile of inhaled muscarinic receptor antagonists Daiana Stolz1 and Mario Cazzola2 Long-acting muscarinic receptor (mAChR) antagonists (LAMAs) are likely to be the main drugs used to treat patients with COPD. They are generally considered “safe” but concerns have been raised about the possible association of their use with cardiovascular morbidity and mortality. Evidence suggests that suppressed parasympathetic nervous system function can lead to tachycardia and arrhythmia. In effect, when cardiac vagal tone is blocked, β2-adrenergic-mediated increases in heart rate are greater. A review of the available literature on the cardiovascular adverse events of LAMAs indicates that they must be considered safe even in cardiac patients when compared with other active therapies or placebo. However, much of the available information has been generated through pivotal clinical trials and the adverse event rates of a drug observed in a clinical trial may not reflect the rates observed in daily practice. There is a need for studies in a real-world setting to identify high-risk patients that may benefit from ECG surveillance because there may be a different cardiovascular response to mAChR blockages in individual patients. Cite as: Stolz D, Cazzola M. Characterising the cardiovascular safety profile of inhaled muscarinic receptor antagonists. In: Martínez-García MÁ, Pépin J-L, Cazzola M, eds. Cardiovascular Complications of Respiratory Disorders (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 238–250 [https://doi.org/10.1183/2312508X.10028619].

@ERSpublications LAMAs do not increase the risk of severe cardiovascular adverse events compared with other active therapies or placebo. However, real-world studies are needed to identify high-risk patients due to the individual cardiovascular response to vagal blockage. http://bit.ly/2SEaEz5

A

n important concern when treating a patient with COPD and concomitant CVD arises from the possibility that the drugs prescribed to treat COPD have a negative impact on CVD. Bronchodilators still represent the core treatment for COPD [1], but both long-acting β2-agonists (LABAs) and long-acting muscarinic receptor (mAChR) antagonists

1 Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital of Basel, Basel, Switzerland. 2Unit of Respiratory Medicine, Dept of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy.

Correspondence: Daiana Stolz, Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel and University Basel, Petersgraben 4, Basel, Switzerland. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-118-4. Online ISBN: 978-1-84984-119-1. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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(LAMAs) can potentially affect cardiac function [2]. In fact, it has been noted that in patients with COPD who start to use LABAs or LAMAs, there is a 1.5-fold increased cardiovascular risk within 30 days of therapy initiation [3]. Both short-acting mAChR antagonists (SAMAs) and LAMAs are likely to be the main drugs used to treat patients with COPD. They are generally considered “safe” [4] but concerns have been raised about the possible associations of mAChR antagonists with cardiovascular morbidity and mortality. In effect, although results regarding the effects of mAChR antagonists on cardiovascular risk and mortality in COPD are inconsistent, both SAMAs and LAMAs have been associated with cardiovascular adverse events (AEs), such as cardiac arrhythmias, in both observational studies and in clinical trials [5]. In effect, a large meta-analysis of randomised controlled trials (RCTs) of any inhaled mAChR antagonist treatment of COPD that had ⩾30 days of treatment and reported on CVEs, found an increased risk of myocardial infarction (MI) (relative risk or risk ratio (RR) 1.53) and cardiovascular death (RR 1.80) in patients treated with these agents [6].

Mechanisms that underlie the cardiovascular risk with inhaled mAChR antagonists Cardiac parasympathetic innervation is mediated by the vagus nerves. Parasympathetic nerves densely innervate the atria, sinoatrial and atrioventricular nodes and conducting tissue. There are also cardiac vagus nerves that course throughout the ventricles [7]. However, the density of parasympathetic innervation is heterogeneous across both the epicardial and the endocardial surfaces of the heart [8]. Activation of the vagal nerves induces hyperpolarisation in the sinoatrial and atrioventricular nodal cells, which results in a reduction in action potential duration and conduction velocity of cardiac muscle and, consequently, in inhibition of the pacemaker activity of the sinoatrial node with a decrease in heart rate, reduced atrioventricular conduction and decreased excitability of the His-Purkinje system [9]. Furthermore, there is experimental evidence that vagus nerve stimulation decreases infarct size and inflammatory markers, and prevents myocardial remodelling by inducing antioxidant effects [10]. These actions are mediated by the binding of acetylcholine (ACh) to M2 mAChRs in myocytes that are coupled to Gi proteins [9, 10]. One of the mechanisms inhibits adenylyl cyclase via the αi subunit of Gi proteins, causing a reduction in 3′,5′-cyclic monophosphate (cAMP) (figure 1). The changes in cAMP affect the targets of protein kinase A-dependent phosphorylation, such as troponin I and phospholamban, and reduce the activity of If (the pacemaker current which is a cAMP-dependent current) and the L-type Ca2+ (ICa,L) current [10]. Decreases in cAMP also directly regulate pacemaker channels, which are permeable to both Na+ and K+ [11]. They increase the activity of the rapid delayed rectifier potassium channel (IKr), which promotes repolarisation from the plateau phase of cardiac action potential [12]. The inhibition of IKr prolongs action potential duration [13]. This favours a hyperpolarising shift in the voltage dependence of these channels, which reduces their contribution to the spontaneous depolarisation rate [9]. Another mechanism involves direct activation of inwardly rectifying ACh-sensitive potassium channels (G protein-gated inwardly rectifying K+/Kir3) also known as IK,ACh, https://doi.org/10.1183/2312508X.10028619

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NOR

ACh K+ β1-AR

M2 mAChRs

Na+ IK,ACh

Ca2+ IKr

ICa,L

K+

GDs E J

GDi

E J

AC cAMP PKA

Tnl

PLM

Figure 1. Actions mediated by the binding of acetylcholine (ACh) to M2 muscarinic receptors (mAChRs) in myocytes. One mechanism involves the direct inhibition of adenylyl cyclase (AC) via the α subunit (αi) of Gi proteins, resulting in a decrease in 3′,5′-cyclic monophosphate (cAMP). Changes in cAMP affect targets of protein kinase A (PKA)-dependent phosphorylation, such as troponin I (TnI) and phospholamban (PLM), and reduce the activity of the L-type Ca2+ (ICa,L) current. Decreases in cAMP also directly regulate pacemaker channels, which are permeable to both Na+ and K+. Another mechanism involves direct activation of inwardly rectifying ACh-sensitive potassium channels, also known as IK,ACh, with potassium efflux. Stimulation of M2 mAChRs by ACh slows the conduction of electrical impulses and results in dissociation of Gi proteins in Gαi and Gβγ subunits with the latter activating IK,ACh in sinoatrial nodal cells, atrial cells and atrioventricular nodal cells. NOR: noradrenaline; β1-AR: adrenergic receptor β1.

with potassium efflux (figure 1) [14]. Stimulation of M2 mAChRs by ACh slows the conduction of electrical impulses and results in dissociation of Gi proteins in Gαi and Gβγ subunits, with the latter activating IK,ACh in sinoatrial nodal cells, atrial cells and atrioventricular nodal cells [15], although recent data suggest that Gq-coupled M1mAChRs regulate human atrial IK,ACh [16]. It has been documented that stimulation of M2 mAChRs by ACh also activates extracellular signal-regulated kinases 1/2 and phosphoinositide 3-kinase/protein kinase B pathway to inhibit endoplasmic reticulum stress-induced cell apoptosis, resulting in attenuation of cardiac ischaemia/reperfusion injury [17]. In addition, it increases the nitric oxide synthase/ nitric oxide cyclic guanosine-3′,5′-monophosphate (cGMP) pathway, and by activating the cGMP/cGMP-dependent protein kinase type I pathway offers cardioprotection via mitochondrial BK channels located at the inner mitochondrial membrane of cardiomyocytes [18]. There is evidence for a possible role of other subtypes, particularly the M3 mAChRs. M3 mAChRs influence cardiac function coupling to Gαq to activate the Gq-phospholipase C-protein kinase C (PKC) pathway [19] and inositol trisphosphate (IP3) and diacylglycerol production. Then, IP3 promotes the release of Ca2+ from endoplasmic reticulum stores via 240

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binding to specific IP3 receptors, whereas diacylglycerol participates in the activation of various PKC isoforms [15, 20]. M3 mAChRs also influence the delayed rectifying potassium current IK,M3 [19, 21], thus directly participating in cardiac membrane repolarisation and negative chronotropic actions [22]. To date, IK,M3 is the only identified K+ channel activated by Gαq. The waveform is similar to that of IKr; however, it is insensitive to the IKr blockers [23]. It is noteworthy that the role of M3 mAChRs might become prominent in pathological situations, such as cardiac ischaemia, pathological cardiac hypertrophy, cardiac arrhythmias and HF [24]. Obviously, suppressed parasympathetic nervous system function can lead to tachycardia and arrhythmia (table 1). It is noteworthy that when cardiac vagal tone is blocked with a mAChR antagonist, β2-adrenergic-mediated increases in heart rate are greater [25], which may be a result of the lack or reduction of the blunting effect of vagal tone on the adrenergic response in the heart.

The cardiovascular risk associated with inhaled SAMAs A body of evidence suggests the possible existence of a link between the use of inhaled SAMAs and cardiovascular risk, although sometimes other evidence denies the existence of this link. Over the 5 years of the Lung Health Study, patients treated with ipratropium bromide had a 3.7-fold increase in the risk of arrhythmia, a 26% increase in the risk of CVEs and a 2.7-fold increase in fatal CVEs compared with placebo [26]. However, when the Lung Health Study data were evaluated to compute morbidity and mortality rates according to inhaler use as obtained from subjects at regular visits, it was observed that the RR of supraventricular tachycardia was higher among the most compliant subjects, whereas the RRs of overall cardiovascular morbidity and mortality and of cardiovascular mortality specifically were higher in subjects who did not use their inhaler than in those who used more than four puffs per day [27]. When the arrhythmogenic effects of ipratropium bromide were assessed in a cohort of patients with COPD from Saskatchewan, Canada, it was found that the new use of this agent was associated with an increased risk of cardiac arrhythmia mainly among patients with severe COPD [28]. However, in a second Canadian study that used data from the much-larger province of Quebec, resulting in nine times the number of cases, the previously suggested increase in risk associated with ipratropium bromide was not substantiated [29].

Table 1. Physiological function of M2 and M3 muscarinic receptor (mAChR) subtypes

Slowing of heart rate Shortening of cardiac action potentials Cardiac contraction Smooth muscle contraction

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M2 mAChR

M3 mAChR

+++ +++ ↓↓ ↑↑

+ ++ ↑ ↑↑↑

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A study of administrative databases reported increased CVEs associated with the use of ipratropium bromide within the past 6 months [30]. A nested case–control study in patients with recently diagnosed COPD that used the US Veterans Health Administration healthcare system databases found that ipratropium was associated with a 34% increase in the risk of cardiovascular death [31]. However, it is impossible to exclude that this information was biased by severity of COPD since the analysis could not be appropriately adjusted for severity as smoking status and FEV1 were not available. In fact, RINGBAEK and VISKUM [32] found no increase in the risk of cardiovascular-related deaths with the use of ipratropium bromide in patients with COPD, even though there was a 1.6-fold increased risk of all-cause mortality in ipratropium bromide users, compared with nonusers. This finding contrasts with the conclusion of a retrospective cohort Canadian study that did not find an association between ipratropium bromide and mortality in COPD patients after adjustment for potential confounders [33].

The cardiovascular risk associated with inhaled LAMAs Cardiovascular safety and mortality remain a potential risk for LAMAs, with cardiovascular risks peaking at around the 30th day after new initiation of LAMA therapy, although the risk seems to be absent, or even reduced, with prevalent use of these agents [3]. Analyses of individual CVD outcomes revealed increased risks of CAD, HF and cardiac arrhythmias with LAMA therapy. There is evidence that glycopyrronium [34], umeclidinium [35] and aclidinium [36] display a greater M3 mAChR versus M2 mAChRs selectivity than tiotropium, from which they also differ in faster dissociation from M2 mAChRs. Furthermore, at least aclidinium is quickly hydrolysed in plasma into an acid and an alcohol metabolite, neither of which binds to mAChRs [36]. Tiotropium

Until 2008, there were no real concern regarding the cardiovascular safety of tiotropium bromide, the first LAMA to have been developed and marketed. In fact, a pooled analysis of AE data from 19 pre-approval and post-approval tiotropium clinical trials performed in 2006 revealed no significant increase in the risk of cardiovascular AEs with this inhaled LAMA, although an association with supraventricular arrhythmias was observed [37] and the results of a meta-analysis of nine randomised trials indicated that the frequency of arrhythmia was significantly higher with tiotropium than with placebo when adjusted for statistical heterogeneity [38]. However, in March 2008, the Food and Drug Administration (FDA) issued a warning about a potential increased risk of stroke in patients using tiotropium [39], and in September 2008, SINGH et al. [6] published a systematic review and meta-analysis conducted to ascertain the cardiovascular risks of inhaled mAChR antagonists, including cardiovascular death, MI and stroke. Tiotropium significantly increased the risk of cardiovascular death, and MI, and showed a trend towards increased risk of stroke, with RRs higher than those observed for ipratropium bromide. Although these data raised concerns for physicians and patients, the study by SINGH et al. [6] did not include data from UPLIFT (Understanding Potential Long-Term Impacts on Function with 242

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Tiotropium), which compared tiotropium with placebo in 5993 patients who were followed for 4 years [40]. In that study, which was published in October 2008, the occurrence of cardiovascular AEs was significantly reduced with tiotropium, although those of angina, cardiac failure and stroke were not significantly higher with tiotropium compared with placebo. The availability of data from the UPLIFT study generated several critical analyses of the potential cardiovascular risk of tiotropium, but the definitive documentation of its inconsistency resulted from the study by CELLI et al. [41], a meta-regression analysis of 30 double-blind RCTs comprised of 10 846 (tiotropium) and 8699 ( placebo) patients, with 4 weeks to 4 years of follow-up. Tiotropium showed a trend toward a reduced risk for a cardiac or vascular fatal AE. There was a 17% reduction in the risk of a major CVE in the tiotropium group relative to the placebo group, and a 23% reduction for fatal CVEs, with both values being statistically significant. Furthermore, tiotropium was superior in reducing MI, cardiac failure and stroke events (22%, 18% and 3%, respectively) compared with placebo. Interestingly, a post hoc analysis also demonstrated through that in patients who suffered from cardiac arrhythmia, MI or cardiac failure during the UPLIFT trial and completed the study, tiotropium did not increase the risk of a major or even fatal CVE after the occurrence of the cardiac episode [42]. Nonetheless, the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial noted an excess of angina pectoris (nine out of 3707 versus five out of 3669), myocardial ischaemia (11 out of 3707 versus six out of 3669) and MI (20 out of 3707 versus 13 out of 3669) with tiotropium compared with salmeterol; it must be noted that the trial excluded patients with MI or congestive HF within a year, severe CVD, cardiac arrhythmias or moderate-to-severe renal failure (creatinine clearance >50 mL) [43, 44]. All the data described were, however, related to tiotropium delivered at a dose of 18 μg by the HandiHaler Dry Powder Inhaler (Boehringer Ingelheim, Ingelheim, Germany). Subsequently, tiotropium delivered using the Respimat Soft Mist Inhaler (Boehringer Ingelheim, Ingelheim, Germany) (5 μg once daily or 10 μg) became available and controversy surrounding long-term safety soon arose [45]. In a large real-life study, VERHAMME et al. [46] showed that use of the tiotropium Respimat Soft Mist Inhaler was associated with an increase in mortality of ∼30% compared with HandiHaler; the association was the strongest for cardiovascular/cerebrovascular death, although patients given tiotropium Respimat had more severe COPD and underlying cardiovascular comorbidities in comparison with patients given the tiotropium HandiHaler. Consequently, and in the presence of the results of the massive Tiotropium Safety and Performance in Respimat (TIOSPIR) trial (which documented that when administered via Respimat at 5 μg, tiotropium is not less safe than HandiHaler at 18 μg but shows a trend towards an increased incidence of MI [47]), MATHIOUDAKIS et al. [48] suggested that the administration of tiotropium via the Respimat Soft Mist Inhaler should be avoided in patients with pre-existing cardiovascular comorbidities. This was mainly because of the exclusion of patients with pre-existing unstable CVD in the TIOSPIR trial. This opinion fits well with the recent documentation that tiotropium alters calcium signalling in the heart through modulation of intracellular calcium release and enhanced activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) in naïve hearts, resulting in cell damage within the heart but without significantly affecting haemodynamic function [49]. Nevertheless, a pooled analysis of AE data from 28 tiotropium HandiHaler 18 μg and seven Respimat 5 μg RCTs with a duration of ⩾4 weeks in patients with COPD indicated that the https://doi.org/10.1183/2312508X.10028619

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risk of cardiac AEs was numerically lower in the tiotropium group [50]. No increased risk was observed with the tiotropium HandiHaler and Respimat groups separately, with the exception of an increased risk of IHD in the tiotropium Respimat group. However, since this pooled analysis did not include data from the studies of BOULOUKAKI et al. [51], ICHINOSE et al. [52] and the TIOSPIR trial [47], a systematic review and network meta-analysis of all available studies that allowed a safety assessment of the tiotropium HandiHaler 18 μg compared with the tiotropium Respimat Soft Mist Inhaler 5 μg and 2.5 μg was performed. The results of this systematic review showed a low absolute risk of cardiovascular AEs with both devices, although there was a modest but not statistically significant advantage in favour of the tiotropium HandiHaler [53]. This finding was confirmed by data generated in routine clinical practice through a population-based cohort study [54]. LAMAs do not increase the risk of cardiovascular severe adverse events compared with other active therapies or placebo. However, since it is possible that vagal blockage may cause a different cardiovascular response in individual subjects, there is a pressing need for studies in real-world settings to identify those patients who are potentially at high cardiovascular risk [53]. In any case, there is documentation that tiotropium improves cardiac function, and reduces the severity of HF in patients with mild-to-moderate COPD and concomitant compensated HF with reduced ejection fraction [55]. Glycopyrronium

In an integrated rat pharmacokinetic, pharmacodynamic and safety model, which predicted significantly higher M2 mAChR blockade at effective dose (ED50) doses with tiotropium than with glycopyrronium, there was an improved safety profile for glycopyrronium when compared with tiotropium [56]. In fact, a supra-therapeutic dose of glycopyrronium had a favourable cardiovascular safety profile with no clinically relevant effect on QT interval in healthy subjects [57]. Pooled data of GLOW1 (GLycopyrroniuim bromide in chronic Obstructive pulmonary disease airWays clinical study 1) (6 months) and GLOW2 (12 months) demonstrated that glycopyrronium was well tolerated, with a low frequency of cardiac effects, which was comparable with that of placebo and open-label tiotropium 18 μg once daily [34]. In the GLOW5 study, in which glycopyrronium was compared with blinded tiotropium, the proportion of patients with newly occurring or worsening clinically notable QTcF values was slightly higher with tiotropium (5.8%) than with glycopyrronium (4.0%) [58]. In the glycopyrronium group, two patients had QTcF values >480 ms, compared with none in the tiotropium group. The percentage of patients with an increase in QTcF of 30−60 ms from baseline was similar between the treatment groups (glycopyrronium 3.4% and tiotropium 3%). No patient had an increase from baseline in QTcF >60 ms. Pooled safety data from RCTs with a duration of ⩾12 weeks and the available data from post-marketing surveillance have shown that in RCTs, the CVE rate was low and similar for glycopyrronium and placebo, although AF was seen more often with glycopyrronium [59]. However, the post-marketing surveillance data indicated that there was no increase in the severity or incidence of AF. 244

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Umeclidinium

In healthy subjects, there was no clinically significant effect on QTcF following 10 days’ treatment with umeclidinium (UMEC) 500 μg compared with placebo [60]. As reported by BABU and MORJARIA [61], the clinical development programme of UMEC regarding safety included eight completed monotherapy studies of a duration of >4 weeks. Both UMEC 62.5 μg and 125 μg caused cardiac-related side-effects compared with placebo, mainly AA (supraventricular tachycardia, AF and atrial ectopics). However, there was no evidence of an increased risk of major cardiovascular AEs with either dose of UMEC compared with placebo. In a 52-week trial in COPD patients, the incidence of some individual CVEs was ⩾2% greater with UMEC 125 μg than placebo: sinus tachycardia (UMEC 3%; placebo