SLEEP DISORDERED BREATHING IN CHRONIC HEART FAILURE: CAUSES, CONSEQUENCES AND TREATMENT Dr. Angela Atalla Clinical and Academic Dept. of Sleep and Ventilation National Heart and Lung Institute Royal Brompton Hospital Imperial College, London A thesis submitted for the degree of Doctor of Philosophy August 2012 2 ABSTRACT Chronic heart failure (HF) is a prevalent clinical syndrome in which both central and obstructive sleep disordered breathing (SDB) have been described. The aim of this research was to investigate the mechanisms causing central SDB, their consequences with reference to sleep and physical activity, and the way in which treatment modalities may modify these. The first study of this thesis is the SERVE-HF study, a randomised controlled trial of adaptive servoventilation (ASV) to treat central SDB in patients with CHF. This study is ongoing and aims to test the hypothesis that patients randomised to ASV will have a reduction in mortality compared to controls. Data regarding those randomised at the Royal Brompton Hospital are presented alongside data on ventilator compliance in the ASV group. The second study investigated ventilatory control, in HF patients both with and without SDB. It tested the hypothesis that those with central SDB had heightened chemosensitivity (assessed by the hypercapnic ventilatory response, HCVR) compared to those with no SDB and older healthy controls. The third study explored the effect of treatment on ventilatory control by testing the hypothesis that the implantation of a cardiac-resynchronisation therapy pacemaker would be associated with a reduction in the HCVR from baseline to 3 months post implantation. The fourth study investigated the consequences of SDB in CHF. Physical activity, subjective sleepiness and sleep were assessed in patients with CHF and older healthy controls to test the hypothesis that physical activity would be reduced in those with central SDB compared to those without SDB, and reduced in both patient groups compared to the controls. In summary, this thesis investigated the mechanisms underlying central SDB in patients with HF, to elucidate their consequences, both by day and night and to address the ways in which treatment modalities may modify these pathophysiological mechanisms. 3 DECLARATION I declare that the work presented in this thesis is the result of my own work, except where otherwise acknowledged. The study presented in chapter 3 is an international randomised controlled trial which was conceived and designed by the SERVE-HF study steering committee. My involvement in this study was at a local level, implementing the study protocol, collecting, collating and analysing data, and coordinating study visits. The studies presented in chapters 4, 5 and 6 were created and designed by myself with the valued assistance of my supervisors. I benefited from the statistical assistance of Mr. Winston Banya for the sample size calculations in chapters 4 and 5. Data collection for the study presented in chapter 4 was the result of collaboration with my colleague Mr. Tom Carlisle using the same laboratory protocols. Tom and I both carried out the laboratory tests on HF patients and healthy subjects and pooled the resulting HCVR data. The analysis and statistical testing of the resultant data are different. No part of this thesis has previously been submitted for consideration for a higher degree. Part of the data from the study presented in chapter 6 has been presented in abstract form and the details are given in the next section. 4 PUBLICATIONS ARISING FROM THIS WORK Published abstracts Atalla A., Carlisle T.W., Ward N.W., Hastings P.C., Morrell M.J., Simonds A.K., Cowie M.R. Subjective Sleepiness And Activity Levels In Heart Failure Patients With Sleep Disordered Breathing. Am J Respir Crit Care Med 185;2012:A6707 Presentations Sleepiness in Heart Failure Patients with Sleep Disordered Breathing. 5th Annual National Heart and Lung Institute Postgraduate Research day. Winner of Best Clinical Presentation. June 2011 Sleep disordered breathing in heart failure. The next big thing? Advances in Respiratory Medicine course, National Heart and Lung Institute, Imperial College London. April 2010. Understanding Heart Failure and Sleep Disordered Breathing-The Story of Loop Gain. Physiology Society International Workshop. Imperial College, London. December 2009. 5 ACKNOWLEDGEMENTS Sincerest thanks are due to my supervisors, Professor Martin Cowie, Professor Mary Morrell and Professor Anita Simonds for their advice and encouragement. Thanks are due also to the patients and subjects who took part in this research. I benefited enormously from the help of the Sleep and Ventilation Team and wish to thank Steve Heather, Anna Hanak, Vitor Roldao, Rachel Pickersgill and the entire team for their time and help, not to mention entertainment, along the way. I would also like to thank the heart failure specialist nurses Laura Fallon and Hayley Pryse-Hawkins for their advice and assistance with recruitment. My thanks to Lisa Trembath for her friendship, particularly in the early days of my research, and to Professor Doug Corfield for his encouragement and assistance. I was part of the Health Services Research Group and am grateful to the other researchers in that group. Particular thanks must go to Zarrin Shaikh, Jay Jaye, Lizzy Goff, Lydia Paniccia, Neil Ward, and Thomas Carlisle; you witnessed the recruitment dance, shared in the endless Haribos, and offered much needed and appreciated help and advice throughout. I salute you. Thanks also to Alison McMillan, Martin Glasser, Julia Kelly, Alana Hare and Annette Woods. I would also like to extend my deepest thanks to Pam Copeland from the Chelsea and Westminster hospital, for her help and friendship during my research time; to Dr. Emma Watson, for her help and encouragement and to Professor John Trinder, for showing me that sleep research and jazz are, happily, not mutually exclusive. As I have moved around the UK during the last few years I have been cheered on by friends at South West London Vineyard church, Bristol Vineyard Church and Belfast City Church to whom I am enormously grateful. Particular thanks to my close friends Liesl Wandrag, Sarah Bennett, Fiona Hunter, Michael Hunter and Rebecca Dunlop. My family share this achievement with me, as without the love and support of my brothers Ash and Andrew, of whom I am immensely proud, and that of my parents, Albert and Adele, none of this would have been possible. Thank you, thank you, thank you. And finally, to my husband, Chris. You have been my tower of strength and my best friend. There are simply no words sufficient to thank you. I dedicate this thesis to my parents, my brothers and my husband; with all my love. 6 Now, upon what has been said, the physicians may determine whether sleep be so necessary that our lives depend upon it: for we read that King Perseus of Macedon, being prisoner at Rome, was killed by being kept from sleep; but Pliny instances such as have lived long without sleep. Herodotus speaks of nations where the men sleep and wake by half-years, and they who write the life of the sage Epimenides affirm that he slept seven-and-fifty years together. Montaigne, Michel de. “Of sleep.” Trans. Charles Cotton. 1574. Quotidiana. Ed. Patrick Madden. 23 Sep 2006. 25 Aug 2012 <http://essays.quotidiana.org/montaigne/sleep/>. 7 8 TABLE OF CONTENTS ABSTRACT 3 DECLARATION 4 PUBLICATIONS ARISING FROM THIS WORK 5 ACKNOWLEDGEMENTS 6 TABLE OF CONTENTS 9 LIST OF TABLES 17 LIST OF FIGURES 20 ABBREVIATIONS 23 CHAPTER ONE: GENERAL INTRODUCTION 26 1.1 Heart failure 27 1.1.1 Definition of heart failure 27 1.1.2 Classification of heart failure 28 1.1.3 Epidemiology of heart failure 29 1.1.4 Aetiology of heart failure 31 1.1.5 Pathogenesis of heart failure 34 1.1.6 Diagnosis of heart failure 42 1.1.7 Management of heart failure 48 1.1.8 Prognosis of heart failure 53 1.1.9 Summary 56 1.2 Sleep disordered breathing 57 1.2.1 The classification of sleep disordered breathing 57 1.2.2 Obstructive sleep disordered breathing 58 1.2.3 Central sleep disordered breathing 60 1.3 Sleep disordered breathing in patients with heart failure 61 1.3.1 Prevalence of sleep disordered breathing in heart failure 62 1.3.2 Variability in severity and type of sleep disordered breathing 65 1.3.3 Summary 66 1.4 Symptoms of sleep disordered breathing in heart failure 67 1.4.1 The effect of ageing on sleep, sleepiness and daytime activity 68 1.4.2 The effect of heart failure on sleep and daytime activity 69 9 1.4.3 The effect of sleep on the failing heart 70 1.4.4 Subjective and objective sleepiness in patients with HF and SDB 71 1.4.5 Sympathetic nerve activity and subjective sleepiness 72 1.5 Breathing during sleep in healthy subjects 74 1.5.1 Changes in breathing during sleep 74 1.5.2 The effect of sleep on the upper airway 74 1.5.3 The apnoeic threshold 75 1.5.4 The model of loop gain 75 1.5.5 Controller, plant and feedback gains 78 1.5.6 Summary 80 1.6 Pathophysiology of sleep disordered breathing in heart failure 82 1.6.1 The effect of heart failure on controller gain 82 1.6.2 The effect of heart failure on plant and feedback gains 83 1.6.3 The effect of heart failure on the upper airway 83 1.6.4 Summary 85 1.7 The treatment of central SDB in heart failure 86 1.7.1 Continuous positive airways pressure 86 1.7.2 The use of CPAP for the treatment of CSA in patients with HF 87 1.7.3 The CANPAP Study 87 1.7.4 Adaptive servoventilation 89 1.7.5 Nocturnal oxygen, carbon dioxide and other treatments 92 1.7.6 Cardiac