Obstructive Sleep Apnea in Adults

Obstructive Sleep Apnea in Adults

Advances in Cardiology Vol. 46 Series Editor Jeffrey S. Borer New York, N.Y.

Alain Lurie Obstructive Sleep Apnea in Adults Relationship with Cardiovascular and Metabolic Disorders 95 figures in color, 37 tables, 2011 Basel Freiburg Paris London New York New Delhi Bangkok Beijing Tokyo Kuala Lumpur Singapore Sydney

To my wife Liora and my children Alexandra and David for their patience and tolerance In memory of my mother and father

Dr. Alain Lurie Laboratoire du Sommeil Centre d Exploration, de Réanimation et d Intervention Cardio-Vasculaire Centre Médico-Chirurgical Ambroise Paré 25 27 Boulevard Victor Hugo F 92000 Neuilly-sur-Seine (France) Disclosure Statement A.L. has participated in speaking engagements for Linde Healthcare and Pfizer. He has no financial conflicts of interest with the subject matter discussed in this book. Library of Congress Cataloging-in-Publication Data Lurie, Alain. Obstructive sleep apnea in adults : relationship with cardiovascular and metabolic disorders / Alain Lurie. p. ; cm. -- (Advances in cardiology, ISSN 0065-2326 ; v. 46) Includes bibliographical references and index. ISBN 978-3-8055-9645-9 (hard cover : alk. paper) -- ISBN 978-3-8055-9646-6 (e-isbn) 1. Sleep apnea syndromes. 2. Cardiovascular system--diseases. 3. Metabolism--Disorders. I. Title. II. Series: Advances in cardiology ; v. 46. 0065-2326 [DNLM: 1. Sleep Apnea, Obstructive--complications. 2. Cardiovascular Diseases--etiology. 3. Metabolic Diseases--etiology. W1 AD53C v.46 2011 / WF 143] RC737.5.L87 2011 616.2'09--dc23 2011021810 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and PubMed/MEDLINE. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2011 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0065 2326 ISBN 978 3 8055 9645 9 e-isbn 978 3 8055 9646 6

Section Title Contents Preface.......................................................................... XV Acknowledgements........................................................... XVI Chapter 1 Obstructive Sleep Apnea in Adults: Epidemiology, Clinical Presentation, and Treatment Options...................... 1 1 Definitions....................................................................... 3 2 Prevalence and Incidence of Obstructive Sleep Apnea........................ 5 3 Risk Factors for Obstructive Sleep Apnea...................................... 7 3.1 Overweight, Obesity, Metabolic Syndrome and Alterations in Glucose Metabolism....................................................................7 3.2 Age............................................................................8 3.3 Gender.........................................................................8 3.3.1 Menopause, a Risk Factor for Obstructive Sleep Apnea.....................8 3.3.2 Testosterone Levels and the Risk of Obstructive Sleep Apnea...............9 3.3.3 Polycystic Ovary Syndrome and the Risk of Obstructive Sleep Apnea.......9 3.4 Craniofacial Anatomy...........................................................9 3.5 Smoking and Alcohol Consumption...........................................10 3.6 Familial and Genetic Predisposition............................................10 4 Obstructive Sleep Apnea Symptoms and Signs............................... 11 4.1 Daytime Symptoms...........................................................11 4.1.1 Excessive Sleepiness......................................................11 4.1.2 Excessive Sleepiness in the General Population and in Patients with Obstructive Sleep Apnea..................................................12 4.1.3 Fatigue...................................................................14 4.2 Sleep-Related Symptoms......................................................15 4.2.1 Snoring, Witnessed Apneas and Nocturnal Choking............................15 4.2.2 Nocturia..................................................................16 4.3 Sequelae......................................................................17 4.3.1 Psychological Changes and Psychiatric Symptoms........................17 4.3.2 Health-Related Quality of Life.............................................18 4.3.3 Performance Alterations..................................................19 5 Characteristic Clinical Features of Obstructive Sleep Apnea in Patients with Metabolic or Cardiovascular Disorders........................ 22 VII

6 A Brief Presentation of the Strategies and Tests to Identify Obstructive Sleep Apnea and Treatment Options According to the American Academy of Sleep Medicine Guidelines........................ 22 6.1 Guidelines.....................................................................22 6.2 Diagnostic Tests...............................................................26 6.3 Treatment Options............................................................26 6.3.1 Positive Airway Pressure Administration...................................26 6.3.2 Oral Appliances...........................................................28 6.3.3 Weight Loss...............................................................28 6.3.4 Surgery...................................................................29 7 Conclusion...................................................................... 30 8 References...................................................................... 31 Chapter 2 Inflammation, Oxidative Stress, and Procoagulant and Thrombotic Activity in Adults with Obstructive Sleep Apnea..................................................................... 43 1 Inflammatory Response to Chronic Intermittent Hypoxia................... 45 1.1 Intermittent Hypoxia Activates Transcription Factors Involved in Inflammatory Processes.......................................................45 1.1.1 The Nuclear Factor κb Pathway............................................46 1.1.2 The Hypoxia- Inducible Factor Pathway....................................48 1.1.3 Tissue- Specific Effects of Chronic Intermittent Hypoxia....................50 1.2 Oxidative and Nitrosative Stress................................................51 1.2.1 Sources and Cellular Effects of Reactive Oxidative and Nitrosative Species...................................................................51 1.2.2 Oxidative and Nitrosative Stress in Obstructive Sleep Apnea...............53 2 Inflammatory Response to Sleep Loss and Fragmentation.................. 56 3 Hypercoagulability and Thrombosis........................................... 57 4 Systemic Inflammation......................................................... 58 5 Conclusions and Future Perspectives.......................................... 59 6 References...................................................................... 61 Chapter 3 Metabolic Disorders Associated with Obstructive Sleep Apnea in Adults................................................................ 67 1 Obesity and Obstructive Sleep Apnea......................................... 69 1.1 Obesity Is the Major Risk Factor for Obstructive Sleep Apnea...................69 1.1.1 Definition of Obesity......................................................69 1.1.2 Clinical and Population Studies of the Relationship between Obesity and the Risk for Obstructive Sleep Apnea.........................71 1.1.3 Impact of Treatment for Obesity on Obstructive Sleep Apnea Severity............................................................72 1.1.4 Gender Differences in Body Mass Index and the Risk for Obstructive Sleep Apnea..................................................73 VIII Contents

1.2 Visceral Obesity...............................................................74 1.2.1 Visceral Obesity May Affect the Anatomy of the Upper Airway.............75 1.2.2 Obesity and Upper Airway Collapsibility...................................75 1.3 Adipose Tissue, an Endocrine Organ...........................................81 1.3.1 Leptin....................................................................82 1.3.2 Adiponectin..............................................................84 1.3.3 Cytokines.................................................................85 1.3.4 Other Adipokines.........................................................86 1.3.5 In Summary..............................................................86 1.4 A Potentially Vicious Circle.....................................................86 1.5 Conclusion....................................................................88 2 Alterations in Glucose Metabolism and Obstructive Sleep Apnea........... 89 2.1 Assessment of the Regulation of Glucose Metabolism.........................89 2.1.1 Insulin Resistance.........................................................89 2.1.2 Diabetes Mellitus.........................................................90 2.2 Evidence for Alterations in Glucose Metabolism in Obstructive Sleep Apnea...91 2.2.1 Clinical and Epidemiological Studies......................................91 2.2.2 Therapeutic Studies.......................................................95 2.2.3 In Summary..............................................................99 2.3 Potential Mechanisms for the Development of Glucose Metabolism Alterations in Obstructive Sleep Apnea...................................... 100 2.3.1 Inflammatory Dysfunction.............................................. 100 2.3.2 Chronic Intermittent Hypoxia........................................... 102 2.3.3 Sleep Loss and Fragmentation.......................................... 105 2.4 A Potentially Vicious Circle................................................... 106 2.5 Conclusion.................................................................. 109 3 Dyslipidemia and Obstructive Sleep Apnea.................................. 110 3.1 Population and Clinical Studies of the Link between Obstructive Sleep Apnea and Dyslipidemia.............................................. 110 3.2 Effects of Continuous Positive Airway Pressure Administration on Dyslipidemia................................................................ 111 3.3 Conclusion.................................................................. 112 4 Metabolic Syndrome and Obstructive Sleep Apnea......................... 113 4.1 Definition and Prevalence of Metabolic Syndrome........................... 113 4.2 Obstructive Sleep Apnea and the Risk for Metabolic Syndrome.............. 114 4.2.1 Prevalence of Metabolic Syndrome in Obstructive Sleep Apnea Patients.......................................................... 114 4.2.2 Effects of Obstructive Sleep Apnea on the Early Signs of Atherosclerosis in Metabolic Syndrome Patients......................... 116 4.2.3 Effects of Continuous Positive Airway Pressure Administration on Metabolic Syndrome.................................................... 116 4.3 Metabolic Syndrome and the Risk for Obstructive Sleep Apnea.............. 118 4.4 Conclusion.................................................................. 118 5 Liver Injury and Obstructive Sleep Apnea.................................... 118 5.1 Characteristics of Nonalcoholic Fatty Liver Disease........................... 118 5.2 The Two- Hit Theory......................................................... 119 Contents IX

5.3 Obstructive Sleep Apnea and Liver Injury.................................... 119 5.3.1 Hepatic Enzyme Levels in Obstructive Sleep Apnea..................... 119 5.3.2 Histopathological Evidence Linking Obstructive Sleep Apnea and Nonalcoholic Fatty Liver Disease........................................ 120 5.3.3 Is Liver Injury in Obstructive Sleep Apnea Consistent with the Two- Hit Theory?.................................................... 121 5.4 Conclusion.................................................................. 122 6 Conclusion and Future Perspectives.......................................... 122 7 References..................................................................... 123 Chapter 4 Endothelial Dysfunction in Adults with Obstructive Sleep Apnea.................................................................... 139 1 Obstructive Sleep Apnea May Alter Vascular Structure..................... 142 1.1 Arterial Structure and Elastic Properties...................................... 142 1.2 Cell Apoptosis and Endothelial Repair Capacity.............................. 144 2 Obstructive Sleep Apnea May Adversely Affect Endothelial Regulation of the Peripheral Vasomotor Tone............................... 147 2.1 Alterations in Nitric- Oxide- Dependent Vasodilator Mechanisms.............. 147 2.1.1 Vascular Reactivity...................................................... 147 2.1.2 Nitric Oxide Availability................................................. 149 2.2 Alterations in Vasoconstriction Mechanisms................................. 152 2.2.1 Downregulation of Vascular Sympathoadrenergic Receptors............ 152 2.2.2 Endothelin 1............................................................ 154 2.2.3 Angiotensin II........................................................... 156 3 Potential Mechanisms Leading to Endothelial Dysfunction in Obstructive Sleep Apnea...................................................... 158 3.1 Chronic Intermittent Hypoxia/Reoxygenation................................ 158 3.2 Oxidative Stress............................................................. 158 3.3 Adipokines.................................................................. 159 3.4 Hypercoagulability.......................................................... 160 3.5 Sleep Loss and Fragmentation............................................... 160 3.6 Confounders and the Development of Endothelial Dysfunction in Obstructive Sleep Apnea.................................................... 161 4 Conclusion..................................................................... 161 5 References..................................................................... 163 Chapter 5 Hemodynamic and Autonomic Changes in Adults with Obstructive Sleep Apnea.................................................. 171 1 Control of Cardiovascular Function during Normal Sleep Stages........... 173 2 Hemodynamic and Autonomic Changes during the Apnea- Ventilation Resumption Cycle......................................... 177 2.1 Hemodynamic Changes..................................................... 177 2.1.1 Heart Rate and Blood Pressure.......................................... 177 2.1.2 Peripheral Resistance................................................... 177 2.1.3 Stroke Volume and Cardiac Output...................................... 178 X Contents

2.2 Autonomic Changes........................................................ 178 2.2.1 Levels of PaO 2 and PaCO 2................................................ 179 2.2.2 Lung Inflation........................................................... 180 2.2.3 Blood Pressure.......................................................... 180 2.3 Pulmonary Arterial Pressure Changes during the Apnea- Ventilation Resumption Cycle........................................................... 181 3 Chronic Autonomic Cardiovascular Dysfunction............................ 184 3.1 Daytime Sympathetic Overactivity........................................... 184 3.2 Downregulation of Vascular Sympathoadrenergic Receptors................. 187 3.3 Polymorphisms in α- and β- Adrenergic Receptor Genes...................... 187 3.4 Chemoreflex Changes....................................................... 187 3.5 Cardiac Vagal Dysfunction and Baroreflex Changes........................... 187 3.6 Relationship between Nighttime Chronic Intermittent Hypoxia and Daytime Autonomic and Blood Pressure Changes............................ 189 4 Conclusion..................................................................... 191 5 References..................................................................... 191 Chapter 6 Cardiovascular Disorders Associated with Obstructive Sleep Apnea.................................................. 197 1 Limitations of Studies Found in the Literature............................... 199 2 Obstructive Sleep Apnea and the Risk of Mortality from Cardiovascular Causes......................................................... 200 2.1 Clinical and Epidemiological Studies......................................... 200 2.2 Day- Night Pattern of Death in Obstructive Sleep Apnea Patients............. 202 2.3 Effect of Continuous Positive Airway Pressure Treatment on Mortality from Cardiovascular Causes.................................................. 204 2.4 Key Points.................................................................. 206 3 Systemic Hypertension........................................................ 206 3.1 Clinical and Epidemiological Studies......................................... 206 3.2 Blood Pressure Profile Abnormalities Associated with an Increased Risk of Obstructive Sleep Apnea............................................. 210 3.3 Effects of Treatment for Obstructive Sleep Apnea on Blood Pressure.......... 211 3.3.1 Effect of Continuous Positive Airway Pressure Therapy................... 211 3.3.2 Effect of a Mandibular Advancement Device............................ 213 3.4 Effects of Antihypertensive Drugs in Obstructive Sleep Apnea Patients....... 214 3.5 Mechanisms Potentially Involved in the Development of Sustained Hypertension in Obstructive Sleep Apnea................................... 214 3.6 Key Points................................................................... 215 4 Heart Failure................................................................... 215 4.1 Obstructive Sleep Apnea Prevalence in Patients with Heart Failure........... 215 4.2 Characteristic Clinical Features of Obstructive Sleep Apnea in Patients with Chronic Heart Failure................................................... 216 4.3 Effects of Continuous Positive Airway Pressure Therapy...................... 218 4.4 Mechanisms Potentially Involved in the Development of Heart Failure in Obstructive Sleep Apnea Patients............................................ 219 4.4.1 Increased Blood Pressure and Other Cardiac Disorders................... 219 4.4.2 Chronic Intermittent Hypoxia........................................... 220 4.4.3 Sympathetic Overactivation............................................. 221 Contents XI

4.4.4 Fluid Retention and Obstructive Sleep Apnea Severity................... 221 4.4.5 Ventricular Hypertrophy................................................ 222 4.4.6 Recurrent Exaggerated Negative Intrathoracic Pressure during Apnea- Ventilation Resumption Cycles................................... 222 4.5 Diagnosis of Obstructive Sleep Apnea in Patients with Heart Failure.......... 223 4.6 Key Points................................................................... 223 5 Stroke.......................................................................... 223 5.1 Prevalence of Obstructive Sleep Apnea in Patients with Stroke............... 223 5.1.1 Clinical Studies.......................................................... 223 5.1.2 Population Studies...................................................... 224 5.1.3 Meta- Analysis of the Frequency of Sleep Apnea in Stroke and Transient Ischemic Attack............................................... 226 5.2 Effects of Obstructive Sleep Apnea on Stroke Outcome...................... 226 5.2.1 Effects of Untreated Obstructive Sleep Apnea on Stroke Outcome....... 226 5.2.2 Effects of Treated Obstructive Sleep Apnea on Stroke Outcome......... 226 5.3 Characteristic Clinical Features of Obstructive Sleep Apnea in Patients with Stroke: Diagnosis of Obstructive Sleep Apnea in the Poststroke Period............................................................ 228 5.4 Key Points................................................................... 229 6 Coronary Artery Disease...................................................... 230 6.1 Clinical and Epidemiological Studies......................................... 230 6.2 Day- Night Pattern of Myocardial Ischemia and Infarction in Obstructive Sleep Apnea Patients........................................................ 230 6.2.1 Myocardial Ischemia.................................................... 230 6.2.2 Myocardial Infarction................................................... 231 6.3 Coronary Artery Calcification in Obstructive Sleep Apnea Patients............ 231 6.4 Effect of Obstructive Sleep Apnea Treatment on Nonfatal Coronary Events............................................................. 234 6.5 Mechanisms Potentially Linking Obstructive Sleep Apnea and Coronary Artery Disease..................................................... 235 6.6 Assessment of Obstructive Sleep Apnea in Coronary Artery Disease Patients............................................................. 235 6.7 Key Points................................................................... 235 7 Pulmonary Hypertension and Right Ventricular Dysfunction............... 236 7.1 Pulmonary Hypertension.................................................... 236 7.1.1 Definition of Pulmonary Hypertension.................................. 236 7.1.2 Clinical Studies.......................................................... 236 7.1.3 Therapeutic Studies..................................................... 237 7.2 Right Ventricular Dysfunction................................................ 238 7.2.1 Clinical Studies.......................................................... 238 7.2.2 Therapeutic Studies..................................................... 238 7.3 Potential Mechanisms That May Lead to Pulmonary Hypertension and Right Ventricular Dysfunction in Obstructive Sleep Apnea............... 239 7.4 Key Points................................................................... 240 8 Arrhythmias.................................................................... 240 8.1 Atrial Fibrillation............................................................. 240 8.1.1 Clinical, Epidemiological and Therapeutic Studies....................... 240 8.1.2 Mechanisms Potentially Linking Obstructive Sleep Apnea with Atrial Fibrillation........................................................ 243 8.1.3 Key Points.............................................................. 246 XII Contents

8.2 Ventricular Arrhythmias...................................................... 246 8.2.1 Clinical, Epidemiological and Therapeutic Studies....................... 246 8.2.2 Key Points.............................................................. 247 8.3 Bradyarrhythmias............................................................ 247 8.3.1 Clinical, Epidemiological and Therapeutic Studies....................... 247 8.3.2 Atrial Pacing and Treatment of Obstructive Sleep Apnea................. 248 8.3.3 Key Points.............................................................. 249 9 Conclusions and Future Directions........................................... 249 10 References..................................................................... 249 Subject Index.................................................................. 267 Contents XIII

Preface The relationship between obstructive sleep apnea (OSA) and cardiovascular and metabolic diseases is a topical subject of concern to a wide range of specialists and general practitioners. In the last 2 decades, significant advances have been made in the understanding of factors contributing to, and the complications of, OSA. With the increase in the population levels of obesity (the greatest risk factor for OSA), the effects of OSA are likely to increase in the coming years; therefore, there is a corresponding need for wider education concerning this disease. The goal of this peer- reviewed book is, therefore, to provide a comprehensive and clear review of the current knowledge of the relationship between OSA and cardiovascular and metabolic diseases. Separate chapters describe the definition, symptoms and sequelae of OSA in adults, and the diagnostic strategies and treatment options for adults with OSA according to the American Academy of Sleep Medicine (chapter 1). The pathogenic mechanisms by which OSA may contribute to the development and progression of cardiovascular and metabolic disorders, including inflammation, oxidative stress and thrombosis, are also explored (chapter 2). In addition, special emphasis has been given to the relationship between OSA and obesity, alterations in glucose metabolism, and metabolic syndrome and liver injury (chapter 3). The evidence for a relationship between OSA, endothelial dysfunction, autonomic dysfunction and cardiovascular disorders is also presented, and the results of studies investigating the effect of treatment for OSA on the concomitant cardiovascular disease are discussed (chapters 4 6). The chapters tend to emphasize human rather than basic animal data; nevertheless, animal data are cited, particularly, for example, with reference to the difficulties associated with unraveling the mechanisms of metabolic dysfunction in obese populations, in which the prevalence of comorbidities and potential confounding factors is high. Each chapter summarizes the essential information and is illustrated by tables and figures, many of which are drawn from the articles cited in the text. It is my hope that these easy- to- read tables and figures will aid the readers in their understanding of the complex systemic interactions involved in this disease. Alain Lurie, Paris XV

Acknowledgements To Dr. Pierre Squara and the reviewers for their insightful comments and fruitful suggestions that have critically contributed towards the writing of this book. To the sleep technicians Bérengère Guillaume Beulé, for her helpful assistance in editing the manuscript, and Theo Sokphon Teng and Caroline Lafif, for their assistance during the writing of this book. To editor L.C. (www.editage.com) for his efforts in providing excellent-quality English editing assistance. XVI