New mechanisms for the cardiovascular effects of sleep apnea

Abstract

Patients who develop intermittent hypoxia as a consequence of sleep apnea are believed to be at increased risk for cardiovascular diseases such as hypertension, myocardial infarction, and even stroke (1). The evidence for an association between hypertension and sleep apnea is particularly strong (2–4). Several epidemiologic studies, including a large community-based study of more than 6000 subjects (the Sleep Heart Health Study), have shown that the prevalence of hypertension is significantly greater in patients with sleep apnea, and is related to the apnea/hypopnea index (numbers of apnea and near apneas per hour) (3). These epidemiologic studies are supported by experiments in animals and by the blood pressure reduction observed in patients after treatment for sleep apnea. For example, intermittent hypoxia in sleeping rats and dogs produces sustained hypertension, as a result of carotid chemoreceptor sensitization (5). However, the evidence that myocardial infarction is a complication of sleep apnea is somewhat less compelling (6,7). Retrospective and cross-sectional studies have found a greater prevalence of a history of myocardial infarction in patients with sleep apnea, and a history of sleep apnea may be more common in patients with acute myocardial infarction (6). Other sleep complaints, including difficulty falling asleep and insomnia, have also been reported to increase the risk of heart attacks, and many of the risk factors for sleep apnea and myocardial infarction are the same, such as obesity, male sex, and older age (1). Also, patients with cardiac disease and stroke can have disordered breathing during sleep, which can be difficult to distinguish from sleep apnea. Finally, successful treatment of sleep apnea often leads to weight loss, increased activity, and better blood pressure control, which reduce the occurrence of cardiac complications. The relation between sleep apnea and myocardial infarction can be examined using another approach—measuring the effects of sleep apnea and its treatment at the molecular level (8), such as on cellular adhesion molecules. Adhesion molecules mediate the inflammatory response to injury caused by atherosclerosis or by ischemia/ reperfusion. There are several major families of adhesion molecules, including selectins, integrins, membraneassociated proteoglycans, and members of the immunoglobulin super family like intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. Selectins are responsible for the initial steps in leukocyte adherence to the endothelium. Vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 bind certain leukocyte integrins to sites of injury, and affect the adherence of leukocytes to endothelium and immunological responses such as the production of interleukin-1, which, in turn, stimulates increased formation of adhesion molecules (9). Soluble adhesion molecules arise from the shedding of these molecules from the surface of activated endothelial and other cells (9,10). Patients with atherosclerosis seem to have higher serum levels of soluble adhesion molecules (11). Ridker et al., who examined the records of more than 14,000 men (of whom 474 subsequently developed myocardial infarction), found a significant association between serum levels of soluble intercellular adhesion molecule-1 and the risk of myocardial infarction (11). In this issue of The Green Journal, Chin and colleagues report the effects of nasal continuous positive airway pressure (CPAP) on soluble adhesion molecules in patients with obstructive sleep apnea. They studied 23 patients with obstructive sleep apnea and measured serum levels of intercellular adhesion molecule-1, E-selectin and vascular cell adhesion molecule-1 before treatment and periodically for up to 6 months of treatment. Levels of soluble E-selectin and intercellular adhesion molecule-1 decreased within one month of treatment, while levels of soluble vascular cell adhesion molecule-1 were unchanged. The authors concluded that obstructive sleep apnea raises serum levels of soluble cell adhesion molecules that can be reduced by nasal CPAP treatment, and that these findings suggest that treatment of sleep apnea may decrease the risk of coronary artery disease. The patients studied by Chin et al. had fairly severe sleep apnea, with symptoms such as sleepiness and daytime fatigue and an apnea plus hypopnea index of 20 per hour (8). A substantial number of patients (9 of the 23) had some form of cardiovascular disease, which may have contributed to the increased levels of soluble adhesion molecules that were observed at baseline. While treatAm J Med. 2000;109:592–594. From the New Jersey Medical School, University of Medicine and Dentistry, Newark, New Jersey. Requests for reprints should be addressed to N. S. Cherniack, MD, New Jersey Medical School, University of Medicine and Dentistry, 185 South Orange Avenue, MSB/C-671, Newark, New Jersey, 07103.