© 2007 American Thoracic Society doi: 10.1164/rccm.200706-926ED
Pathogenesis of AtherosclerosisIs Obstructive Sleep Apnea the New Kid on the Block?Sleep Research Laboratory of the Toronto Rehabilitation Institute, Toronto, Canada
Sleep Research Laboratory of the Toronto Rehabilitation Institute and Toronto General Hospital of the University Health Network, Toronto, Canada Growing evidence from epidemiological studies suggests that obstructive sleep apnea (OSA) may be a treatable risk factor for hypertension as well as for atherosclerotic diseases (1–3). OSA elicits a cascade of noxious cardiovascular stimuli during sleep characterized by repetitive apnea-induced hypoxia, generation of exaggerated negative intrathoracic pressure, arousals from sleep, surges in blood pressure, sympathetic nervous system activation and parasympathetic withdrawal, as well as production of reactive oxygen species, vascular endothelial growth factors, and inflammatory mediators (4). Downstream, these factors promote trophic stimulation of the myocardium, vascular endothelial dysfunction, increased platelet aggregability and blood coagulability, and insulin resistance (4, 5). Several of these factors are atherogenic and participate in the pathogenesis of cardiovascular and cerebrovascular diseases. The quest to determine whether OSA itself is atherogenic, however, has been fraught with difficulties because the majority of the patients with OSA share several risk factors for atherosclerosis, including obesity, hypertension, hypercholesterolemia, insulin resistance, and hyperglycemia (4, 5). Nevertheless, intermittent hypoxemia induces atherosclerosis in susceptible mice and, compared with subjects without OSA, those with OSA have greater carotid artery intima-medial thickness (IMT) and carotid–to–femoral artery pulse-wave velocity (PWV), two early signs of atherosclerosis (6). These findings, however, fall short of proving a cause–effect relationship between OSA and atherosclerosis. A further impediment to assessing the atherogenic potential of OSA has been the dearth of studies to determine whether treating OSA prevents or reverses markers of atherosclerosis. Yet, the stakes in determining whether such a cause–effect relationship exists are high, and have been fueled by some intriguing data from observational studies. For example, Marin and colleagues (7) found, in an observational study, that severe, untreated OSA is associated with an elevated cardiovascular event rate. In contrast, the cardiovascular event rate of patients whose severe OSA was treated by continuous positive airway pressure (CPAP) was no different than in subjects without OSA. It is therefore tempting to conclude that OSA increases the risk for atherosclerotic diseases, and that its treatment prevents them. However, caution must be exercised before embracing such conclusions, because the results of nonrandomized, observational studies are often not confirmed by more rigorous randomized trials (8, 9). Patients who accepted CPAP may have been more health conscious or compliant with other treatments, and this might have had a beneficial effect on outcomes independently of OSA therapy. Thus, whereas physiological studies suggest that OSA provides a substrate for the development of atherosclerosis, and epidemiological and observational studies suggest an association between OSA and odds of having atherosclerotic diseases, there remains a gap between cause and effect yet to be filled. In this issue of the AJRCCM (pp. 706–712), Drager and colleagues (10) provide evidence that begins to fill this gap. From 400 patients with severe OSA, they enrolled 24 patients free of cardiovascular comorbidities. Subsequently, they performed a randomized trial of CPAP versus no CPAP. After 4 months, the 12 patients randomized to CPAP experienced a reduction in plasma concentrations of norepinephrine and C-reactive protein accompanied by regression of early signs of atherosclerosis (i.e., a 9% reduction in carotid IMT and a 10% reduction in carotid–to–femoral artery PWV). These findings were all the more remarkable because there was no concurrent change in weight, lipid levels, or blood pressure. However, because no carotid plaques were visualized, the question remains, How robust are reductions in IMT and PWV as signs of regression of early atherosclerosis? A good marker of atherosclerosis should be noninvasive and capable of identifying subclinical disease, and provide prognostic information for risk stratification. How well do IMT and PWV stack up to this standard? As it turns out, quite well. Carotid IMT can be measured noninvasively by ultrasonography, and correlates well with histological evidence of subclinical atherosclerosis (11). Increased IMT is also associated with an increased risk of atherosclerotic cardiovascular and cerebrovascular diseases, and therefore with the severity of generalized atherosclerosis (12). On the other hand, the primary ill effect associated with increased IMT may not be carotid artery thickness itself but rather the increase in the stiffness of the vessel resulting from increased IMT. The risk of stroke increases with increasing IMT and stiffness (13). Because of their superficial location, the carotid and femoral arterial pulse waveforms, and thus their PWV, are readily measurable noninvasively. As the arteries become stiffer, PWV increases, and the reflected pressure wave from the periphery returns in systole, thereby augmenting pressure during ventricular contraction. This increase in pressure raises left ventricle afterload and contributes to its hypertrophy (14), a potent risk factor for heart failure, ischemic heart disease, and sudden cardiac death. Accordingly, arterial PWV is an important independent predictor of cardiovascular events. What are the implications of Drager and colleagues' findings? First, they provide the best evidence to date that OSA can contribute to the causation of subclinical atherosclerosis in the absence of other contributing factors. Second, they indicate that treatment of OSA by CPAP can cause regression of subclinical atherosclerosis in the absence of changes in blood pressure or lipid profile, but in association with reduced sympathetic activity and systemic inflammation. Third, the magnitude of these reductions in IMT and PWT was as great or greater than that due to lipid-lowering agents, which have been shown to reduce the incidence of strokes and acute coronary events (15, 16). Thus, these findings imply that treating OSA could prevent atherosclerosis, and consequently lower the risk of ischemic cardiovascular and cerebrovascular events. Because OSA affects approximately 10% of the adult population (1–3), these results may have important public health implications for prevention of atherosclerotic diseases. The findings of Drager and colleagues are subject to some limitations. First, the sample size was small, and consisted of a highly selected subset of patients with OSA free of comorbidities. Thus, their findings may not be applicable to the overall OSA population. Second, because of the small sample size, and short study duration, they were unable to determine whether treating OSA actually reduced cardiovascular and cerebrovascular events. It is therefore premature to recommend screening for, and treatment of, OSA as a strategy for prevention of atherosclerosis and its consequences. OSA may be the "new kid on the block" of atherogenesis, but before it can take its place with traditional atherogenic factors as a target for risk reduction, large-scale randomized trials that will determine whether treatment of OSA prevents ischemic cardiovascular and cerebrovascular events should be undertaken. FOOTNOTES Conflict of Interest Statement: D.Y. is supported by an unrestricted research fellowship from Respironics, Inc., a manufacturer of CPAP devices. T.D.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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