© 2004 American Thoracic Society
ProSleep Apnea Causes Cardiovascular DiseaseLloyd Rigler Sleep Apnea Research Laboratory B. Rappaport Faculty of Medicine Technion-Israel Institute of Technology Haifa, Israel The association between sleep apnea syndrome and cardiovascular morbidity has been evident since the first apneic patients were investigated in the laboratory: these anecdotal observations were dramatic. In one of the first documentations of tracheostomy in sleep apnea, Coccagna and coworkers (1) observed the complete disappearance of a severe "atrial flutter" the day after the tracheostomy, and a rapid postoperative decrease in systemic blood pressure. Likewise, Guilleminault, Eldridge, and Dement (2) reported that blood pressure in two hypertensive children with severe sleep apnea was normalized within 24 hours after a tracheostomy! These are no longer exotic anecdotes. Since then, it has been repeatedly demonstrated that sleep apnea syndrome is causally linked with cardiovascular morbidity, and impressive progress has been made in delineating how sleep apnea causes cardiovascular diseases. The first line of evidence came from cross-sectional and case-control studies, revealing high rates of sleep apnea in unselected cardiovascular patients on the one hand, and high rates of cardiovascular morbidity in sleep apnea patients on the other (3). A fundamental problem confronting such studies is the notorious contribution of confounders. Both sleep apnea and cardiovascular diseases share similar risk factors such as male gender, obesity and middle age; therefore, skeptics have raised doubts as to how much can be attributed to these confounders. The fitting response to this valid criticism appeared in the form of larger studies that allowed a better control over confounding variables. The year 2000 was particularly prolific, with eight studies, all relying on very large cohorts, providing supporting evidence for an independent association between sleep apnea and cardiovascular morbidity (4). This association was evident in both sleep laboratory cohorts as well as in general population cohorts. Further support came from studies demonstrating that effective treatment of sleep apnea with nasal continuous positive airway pressure (CPAP) reduced daytime and night time blood pressure (5). Animal models contributed when Brooks and coworkers (6) induced sleep apnea in dogs by intermittent airway occlusion, which resulted in sustained daytime hypertension. Here, obviously, there were no "confounding variables" that could account for these results.
Still, skeptics would demand mechanisms by which sleep apnea could give rise to cardiovascular diseases and insist on knowing the natural history of this association. Several mechanisms were proposed to mediate the effects of sleep apnea on the cardiovascular system, including sustained sympathetic activation (7), swings in intrathoracic pressure (8) and, more recently, oxidative stress and consequently vascular inflammation resulting from the nocturnal hypoxia/reoxygenation cycles (9). This latter mechanism that has been the focus of intense research in our laboratory in recent years allows to chart the natural history of this association. What is the evidence that oxidative stress is a major contributor to cardiovascular morbidity in sleep apnea? Increased production of oxygen reactive species was found in granulocytes and monocytes obtained from sleep apnea patients (10–11). This was associated with increased expression of adhesion molecules and proinflammatory cytokines, which resulted in increased avidity of monocytes and lymphocytes and increased cytotoxicity of lymphocytes against endothelial cells in culture (11–12). Moreover, the increased adhesion and cytotoxicity of sleep apnea patients' monocytes and lymphocyes to endothelial cells in culture could be blocked by employing antibodies against selectins and tumor necrosis factor- Collectively, the above evidence implicates exaggerated oxidative stress in initiating a cascade of events which culminates in atherogenesis and diverse cardiovascular morbidities in sleep apnea. This has far reaching clinical implications for diagnosis and treatment of the syndrome. From the above chain of events, it appears likely that atherogenesis starts at a very early stage after sleep apnea onset, perhaps even during the very first night in which patients experience apneic events. By the time they are diagnosed with the syndrome, usually at the age of 47–50 years when symptoms become apparent, they have already accumulated substantial atherosclerotic insults which may be irreversible. Diagnosis at this age may be too late. This can explain why so many sleep apnea patients exhibit cardiovascular morbidity at the time of diagnosis. Furthermore, starting treatment years after atherogenesis has been initiated may slow it down or abort its progress but not necessarily reverse it. Thus, to prevent cardiovascular morbidity, sleep apnea diagnosis and treatment should be made as early as possible. To conclude, there is no real debate if sleep apnea causes cardiovascular morbidity: not only do we know for sure that it does, we even have convincing evidence regarding the underlying mechanisms and the natural history of these relationships. The challenge, however, is entirely different. With the help of PubMed, I retrieved 250 editorial papers that include in their title the key term "sleep apnea." None appeared in a leading cardiovascular journal, and only 14 were published in major general medical journals! Thus, the medical community, and cardiologists in particular, are yet to embrace the idea that sleep apnea syndrome causes cardiovascular morbidity, which is crucial to any change in the diagnosis and treatment of the syndrome. This is the real challenge facing the medical sleep community today, and not to prove what is so clearly evident. Acknowledgments Critical reading and thoughtful comments made by Dr. Lena Lavie are greatly appreciated. FOOTNOTES Conflict of Interest Statement: P.L. is a consultant and board member of Itamar Medical Ltd. and SLP Ltd. that produce medical devices for diagnosis of sleep apnea and is a board member of Sleep Medicine Center, Israel, and Sleep HealthCenters, U.S., that provide diagnostic and treatment services to patients with sleep disorders. In 2001, he received $40,000, in 2002 $40,000, and $20,000 in 2003 as consultant fees and owns options in these companies and has five patents relevant to the subject matter of this article and some of his research was supported by grants from Itamar Medical and SLP for a total of approximately $50,000 and in the last three years he participated as a speaker in scientific meetings and courses organized and financed by industrial companies (Itamar Medical, Respironics, ResMed). REFERENCES
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, suggesting the active involvement of adhesion molecules and inflammatory cytokines in endothelial cell injury and dysfunction (
