© 2007 American Thoracic Society doi: 10.1164/rccm.200703-458ED
Obstructive Sleep Apnea and AtherosclerosisA New ParadigmUniversity of São Paulo, São Paulo, Brazil Obstructive sleep apnea (OSA) has been recognized as one of the most common respiratory diseases among the general population (1). There is now evidence that OSA is associated with increased mortality of cardiovascular origin (2), but the mechanisms are not completely understood. The research on the link between OSA and cardiovascular disease now may be divided into two paradigms. The first paradigm was based on the physiological evidence that the respiratory and cardiovascular systems are engaged in the same task of delivering oxygen and extracting carbon dioxide from the cells. The coupling between the respiratory and cardiovascular systems is remarkable. Each single breath promotes oscillations in blood pressure and heart rate, also known as respiratory sinus arrhythmia (3). Normal subjects who voluntarily breathe in a periodic pattern present profound oscillations in blood pressure and heart rate. These cardiovascular oscillations occur in concert with the breathing pattern and are independent of oxygen desaturation or arousals from sleep (4). Under the perspective that the respiratory and cardiovascular systems are coupled, the most studied link involves OSA and hypertension. In this context, animal studies anticipated and helped to direct human research. Dogs that were subjected to a model of repetitive obstructions of the airway during sleep became hypertensive not only during sleep but also while awake. Blood pressure then returned to normal levels after the repetitive obstructions were discontinued (5). Subsequently, an increased risk of developing hypertension was demonstrated in normotensive patients with OSA who were followed over a 4-year period (6). The cause-and-effect association between OSA and hypertension was recognized after well-controlled randomized studies showed that the standard treatment of OSA with continuous positive airway pressure was able to decrease blood pressure (7). There is now mounting evidence that OSA is independently associated with metabolic disorders, including insulin resistance (8) and hypercholesterolemia (9), unrelated to underlying obesity. We are now forced to extend the first paradigm (respiratory–cardiovascular coupling) by adding the metabolic system as a third major element in this integrative approach. Under the respiratory–cardiovascular–metabolic paradigm, atherosclerosis is an attractive unifying target of OSA. OSA triggers a cascade of key factors involved in the genesis of atherosclerosis, including production of reactive oxygen species, coagulation factors, and, in particular, systemic inflammation (10). Atherosclerosis may help to explain the evidence that OSA is associated with increased risk of myocardial infarction (11) and stroke (12). In this issue of the Journal (pp. 1290–1297), Savransky and colleagues extend our knowledge on the link between OSA and atherosclerosis using a rodent model of intermittent hypoxia (13). The model does not monitor sleep nor does it mimic all aspects of OSA. The model assumes that intermittent hypoxia is the most important mechanism that links OSA to cardiovascular and metabolic disorders. Keeping this potential limitation in mind, the study is a good example of a new paradigm, and provides insight into metabolic and vascular changes promoted by intermittent hypoxia. Savransky and colleagues studied male wild-type mice that are resistant to atherosclerosis. In isolation, intermittent hypoxia or a high-cholesterol diet was not capable of inducing atherosclerosis. In contrast, mice submitted to the association of intermittent hypoxia and a high-cholesterol diet developed marked atherosclerosis. It may be difficult to translate the experimental regimen to the clinical arena. We have recently studied a group of patients with OSA and well-matched control subjects who were free of comorbidities and were not receiving any medication. In contrast to the control subjects, the patients with OSA presented early signs of atherosclerosis (14). However, even in this select group, patients and control subjects had an average body mass index of 29 kg/m2 and high borderline levels of low-density lipoprotein (14). Therefore, similar to the rodent model, these patients with OSA may have been exposed to both OSA and dyslipidemia. Analogous to the study by Savransky and colleagues, we have recently shown that patients in whom OSA and hypertension coexisted presented significantly more signs of vascular stiffness and heart remodeling than patients who suffered from only hypertension or OSA (15). This evidence emphasizes that the harmful effects of OSA on the cardiovascular system may be multiplied in the presence of a second cardiovascular risk factor, such as dyslipidemia or hypertension. The study by Savransky and colleagues (13) is remarkable because it allows insights into how intermittent hypoxia induces a cascade of events, including oxidative stress, inflammation, changes in the liver metabolism, and hypercholesterolemia, which will ultimately promote marked atherosclerotic lesions. The figures of the aorta in the article are particularly illustrative. It may take a long time before some of these pathways are clarified in humans. Meanwhile, to definitively settle the link between OSA and atherosclerosis, it would be important to show reversal of atherosclerosis in animals after discontinuation of intermittent hypoxia. We also need randomized treatment studies showing reversal of atherosclerosis in patients with OSA who are free of comorbidities and who are treated with continuous positive airway pressure. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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