Michele Emdin Alberto Giannoni Claudio Passino Editors The Breathless Heart Apneas in Heart Failure 123 The Breathless Heart Michele Emdin (cid:129) Alberto Giannoni Claudio Passino Editors The Breathless Heart Apneas in Heart Failure Editors Michele Emdin Claudio Passino Institute of Life Sciences Institute of Life Sciences Scuola Superiore Sant’Anna and Scuola Superiore Sant’Anna and Fondazione Toscana Gabriele Monasterio Fondazione Toscana Gabriele Monasterio Pisa Pisa Italy Italy Alberto Giannoni Fondazione Toscana Gabrielle Monasterio Pisa Italy ISBN 978-3-319-26352-6 ISBN 978-3-319-26354-0 (eBook) DOI 10.1007/978-3-319-26354-0 Library of Congress Control Number: 2016959210 © Springer International Publishing Switzerland 2017 T his work is subject to copyright. 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Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company is Gewerbestrasse 11, 6330 Cham, Switzerland Pref ace H eart failure is a major cause of hospitalization and mortality, despite recent advancements in diagnosis and treatment. The search for hidden pathophysiological triggers of disease evolution and potential targets of therapy has rediscovered an old, forgotten feature of the heart failure syndrome: apnea. Apneas may present themselves either as a sign or a symptom in the individual patient, but are often overlooked by clinicians, though they are both a marker of severity and a mediator of risk. Apneas are invariably associated with cyclic hyperpneas both in the asleep and in the awake subject with heart failure, possibly as an initial compensatory response. A pnea/hyperpnea phenomena oblige the clinician to reevaluate the physiology of respiration and cardiovascular function. However, is there still place for physiology in the decision-making for patients with cardiovascular diseases in the era of imag- ing, genetics, and molecular biology? T he answer is in the affi rmative, as demonstrated by the clinical value of periodic breathing/Cheyne-Stokes respiration (PB/CSR) [1, 2] in patients with heart failure (Fig. 1 ) . This abnormal breathing pattern has been known for centuries, but it is only during the last decades that its pathophysiology and its clinical meaning have been adequately investigated. In particular, the underlying derangement of neural control of respiratory cen- ters, its impact on prognosis, and the relevance of the phenomenon as a therapeutic target have been the object of an increase of interest and literature during the last decades, yet with diverse experimental fi ndings and contradictory opinions. The recent failure of two large trials testing the effectiveness of noninvasive mechanical ventilation (CANPAP and SERVE-HF) [3, 4] in improving the outcome of heart failure patients has confi rmed the need to summarize the current knowledge on this topic. For this purpose, this book has been thought for all researchers and clinicians interested in the fi eld. An international faculty has collaborated in fur- nishing a complete overview touching all aspects of the apnea phenomenon in heart failure patients. The historical background of pathophysiological alterations determining the occurrence of central apneas in different disorders will be presented. A thorough description of the visceral feedbacks and in particular of the chemorefl ex system, whose deregulation plays a key role in central apnea origin and maintenance, and the mathematical models proposed to describe PB/CSR will be presented. The role v vi Preface Fig. 1 “Record showing Cheyne-Stokes respiration (from a case of aortic and mitral insuffi ciency with atherosclerosis). The time record gives second.” Original legend in Ref. [5] and feasibility of different diagnostic approaches, including the modern recording of apneas by the implanted device, will be the object of analysis. Finally, the authors will try to defi ne the signifi cance of apneas during sleep and during wakefulness, the different pathophysiology of obstructive and central apneas, and the most advanced tools for the treatment of central apneas, including the novel technique of phrenic nerve stimulation, presented by a principal investigator of the clinical trial addressing its effi cacy. The whole matter, two thousand years after the Hippocrates’ description and two centuries after the brilliant description by the Irish physician Cheyne, is still largely debated: this book can be considered a companion for all interested in increasing their knowledge on its signifi cance, in order to improve clinical care of heart failure patients. Michele Emdin Alberto Giannoni Pisa , Italy Claudio Passino Refer ences 1. Cheyne J. Dublin hospital reports. 1818;2:216. 2. Stokes W. The diseases of the heart and the aorta. Dublin: Hodges and Smith; 1854. p. 323–6. 3 . B radley TD, Logan AG, Kimoff RJ, Sériès F, Morrison D, Ferguson K, Belenkie I, Pfeifer M, Fleetham J, Hanly P, Smilovitch M, Tomlinson G, Floras JS; CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353:2025–33. 4. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d’Ortho MP, Erdmann E, Levy P, Simonds AK, Somers VK, Zannad F, Teschler H. Adaptive servo- ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015; 373:1095–105. 5. Howell WH. Infl uence of various conditions on respiration. Modifi ed respiratory movements. In: A text book of physiology for medical students and physicians. Philadelphia/London: WB Saunders Cop; 1919. p. 717. Contents 1 Historical Background and Glossary of the Apnea Phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Michele Emdin and Alberto Aimo 2 Mechanics and Chemistry of Respiration in Health . . . . . . . . . . . . . . 11 Claudio Passino , Elisabetta Cacace , Daniele Caratozzolo , Federico Rossari , and Luigi Francesco Saccaro 3 Hypopneas and Apneas as Physiological and Pathological Phenomena Throughout the Life Span . . . . . . . . . . . . . . . . . . . . . . . . . 35 Alberto Giannoni , Chiara Borrelli , and Valentina Raglianti 4 Pathophysiology of Central Apneas in Heart Failure . . . . . . . . . . . . . 91 Alberto Giannoni, Maria Sole Morelli, and Darrel Francis 5 The Importance of Visceral Feedbacks: Focus on Chemoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Alberto Giannoni , Alberto Aimo , Francesca Bramanti , and Massimo F. Piepoli 6 The Apneas Before and After Heart Failure . . . . . . . . . . . . . . . . . . . . 147 Jens Spießhöfer and Olaf Oldenburg 7 Not Only Sleep Apnea: The “Awake” Apneas of the Failing Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Maria Teresa La Rovere , Roberto Maestri , and Gian Domenico Pinna 8 Exertional Oscillatory Ventilation and Central Sleep Apnea in Heart Failure: Siblings, Cousins, or What Else? . . . . . . . . . 183 Piergiuseppe Agostoni , Anna Apostolo , and Ugo Corrà 9 To Breathe, or Not to Breathe: That Is the Question . . . . . . . . . . . . . . 203 Gianluca M irizzi , Alberto Giannoni , Claudio Passino , and Michele Emdin vii viii Contents 10 Diagnostic Tools: The Easier, the Better . . . . . . . . . . . . . . . . . . . . . . . . 219 Roberta Poletti , Alberto Aimo , Vincenzo Castiglione , Alessandro Di Gangi , Giovanni Iudice , Mauro Micalizzi , Claudio Passino , and Michele Emdin 11 Diagnostic Tools: Messages from Implanted Devices (Pacemakers as Diagnostic Tools) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Margherita Padeletti , Fabrizio Bandini , Edoardo Gronda , and Luigi Padeletti 12 Targeting and Treating Apneas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Claudio Passino , Alberto Giannoni , Alberto Aimo , Gianluca M irizzi , and Michele Emdin 13 Novel Tools for Treating Central Apneas . . . . . . . . . . . . . . . . . . . . . . . 271 Maria Rosa Costanzo 14 Breathless Heart: Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Michele Emdin , Alberto Giannoni , and Claudio Passino 1 Historical Background and Glossary of the Apnea Phenomenon Apneas and Heart Disease Michele Emdin and Alberto Aimo Abbreviations AHI Apnea-hypopnea index CSR Cheyne-Stokes respiration EEG E lectroencephalogram/electroencephalography HF Heart failure OSAS Obstructive sleep apnea syndrome PB Periodic breathing PSG Polysomnography RDI Respiratory disturbance index 1.1 Introduction “ A remarkable abnormal rhythm of respiration, fi rst observed by Cheyne but after- wards more fully studied by Stokes and hence called by their combined names, occurs in certain pathological cases. The respiratory movements gradually decrease both in extent and rapidity until they cease altogether, and a condition of apnoea, lasting it may be for several seconds, ensues. This is followed by a feeble M. Emdin (*) Institute of Life Sciences, Scuola Superiore Sant’Anna , Pisa , Italy Division of Cardiology and Cardiovascular Medicine , Fondazione Toscana Gabriele Monasterio, Pisa , Italy e-mail: [email protected] A. Aimo Institute of Life Sciences, Scuola Superiore Sant’Anna , Pisa , Italy e-mail: [email protected] © Springer International Publishing Switzerland 2017 1 M. Emdin et al. (eds.), The Breathless Heart, DOI 10.1007/978-3-319-26354-0_1 2 M. Emdin and A. Aimo Fig. 1.1 Typical example of Cheyne-Stokes respiration (Source: Hartridge H, 1940 [6 ]) respiration, succeeded in turn by a somewhat stronger one, and thus the respiration returns gradually to the normal, or may even rise to hyperpnoea or slight dyspnea after which it again declines in a similar manner (Fig. 1 .1) . The cause of the phe- nomena is not thoroughly understood. Stokes connected it with a fatty condition of the heart, but it has been met with in various maladies. Schiff observed it as the result of compression of the medulla oblongata; and closely similar phenomena have been observed during sleep, under perfectly normal conditions” [ 1 ]. This report summarizes the state of the art about Cheyne-Stokes respiration (CSR) in 1879. The oscillatory respiratory pattern named CSR or periodic breathing (PB) (according to the presence or absence of apneas, respectively) has stimulated the curiosity of physicians for centuries. 1.2 From Hippocrates to Hunter, Cheyne and Stokes: Watching the Ill Breathing Interestingly, the condition now known as obstructive sleep apnea syndrome (OSAS) was described only in 1889, while PB/CSR was noted long before, being easily recognizable and most of all occurring also during wakefulness. The very same father of medicine Hippocrates (460–379 BC) is thought to have provided the fi rst account of PB/CSR: “His respiration was rare and large, l ike a person who forgot for a time the need of breathing and then suddenly remembered ” [2 ]. We must wait until 1781 to fi nd another account of PB/CSR. Describing the case history of a Mr. Boyed, who apparently suffered from atrial fi brillation and congestive heart failure, the British surgeon John Hunter wrote: “The pulse was irregular, as usual, and quick; but his breathing was very particular: he would cease breathing for twenty or thirty seconds, and then begin to breathe softly, which increased until he breathed extremely strong, or rather with violent strength, which gradually died away till we could not observe that he breathed at all. He could not lie down without running the risk of being suffocated, therefore he was obliged to sit up in his chair” [ 3 ].