Left Ventricular Structural Adaptations to Obstructive Sleep Apnea in Dilated Cardiomyopathy

Heart failure (HF) is a debilitating condition affecting approximately 4,700,000 Americans (1). Intrinsic to the progression of HF is adverse cardiac remodeling, which involves left ventricular hypertrophy (LVH) and/or dilatation. A number of factors can contribute to the remodeling process, including hypertension, elevated sympathetic nervous system activity, and myocardial infarction (2-5). One potential stimulus to left ventricular (LV) remodeling that has received little attention is obstructive sleep apnea (OSA). A large population-based study identified OSA as an independent risk factor for HF (6). In addition, OSA often coexists with HF (7, 8), where its treatment by continuous positive airway pressure reduces blood pressure and improves LV systolic function (9, 10). These observations suggest that OSA contributes to the pathogenesis of HF in such subjects.

Obstructive apneas are accompanied by recurrent hypoxia and arousals from sleep, which activate the sympathetic nervous system, and cause repetitive surges in heart rate and blood pressure (11-13). In combination with the generation of exaggerated negative intrathoracic pressure against the occluded upper airway, this markedly increases LV afterload during sleep (14, 15). In addition, the consequent increase in myocardial oxygen demand is accompanied by a reduction in oxygen supply because of apnea-related hypoxia (12). Thus, the coexistence of OSA in patients with HF exerts unique nocturnal mechanical, adrenergic, and metabolic stresses that could result, cumulatively, in greater adaptive LV remodeling than would occur in patients with HF, but without OSA.

Furthermore, OSA places unique stresses on the interventricular septum (16, 17). These include increased pulmonary artery pressure during sleep due to hypoxic pulmonary vasoconstriction (12, 16), which increases right ventricular afterload and systolic septal wall tension without affecting posterior wall tension. Generation of exaggerated negative intrathoracic pressure during obstructive apneas increases venous return, causing distension of the right ventricle and leftward shift of the septum during diastole (11, 12, 16, 18).

We therefore hypothesized, that compared with HF patients without OSA, those with OSA would have a higher prevalence of LVH, by wall thickness criteria, and more pronounced septal thickening. To explore this hypothesis, in patients with HF, we compared LV structure between those with and those without OSA. Because myocardial infarction and ischemia can affect myocardial remodeling independently, we confined our study to subjects with nonischemic dilated cardiomyopathy, in which LV remodeling is usually eccentric (i.e., dilated and thin walled) (19). Some of the work described herein has been published in abstract form (20).

METHODS

Subjects

As part of a prospective epidemiologic study, we performed polysomnography on all newly referred patients to the Mount Sinai Hospital heart failure clinic during the 5-yr period between 1997 and 2002. For this study, we included only subjects with nonischemic dilated cardiomyopathy to avoid regional variations in LV wall thickness (LVWT) that could arise because of scarring in subjects with ischemic cardiomyopathy. Entry criteria included the following: (1) HF of at least 6 mo duration based on a history of exertional dyspnea and peripheral edema; (2) LV systolic dysfunction (LV ejection fraction = 45% by two-dimensional echocardiography); (3) nonischemic dilated cardiomyopathy based on the absence of significant coronary artery lesions on coronary angiography or absence of ischemic changes on exercise thallium scintigraphy, and an LV end-diastolic dimension by M-mode echocardiography of = 27 mm/m^sup 2^ body surface area (19); and (4) appropriate medical therapy for HF with stable medications for at least 1 mo before participation. Exclusion criteria were as follows: (1) a prior history of sleep apnea, (2) predominantly central sleep apnea (CSA), (3) ischemic cardiomyopathy, (4) primary valvular heart disease, and (5) obstructive lung disease. The protocol was approved by the Research Ethics Board of the University of Toronto and all subjects provided written, informed consent before their participation.

Echocardiography