Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea

Abstract

Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant pathophysiological disturbance in OSA-intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field.

Keywords: cardiovascular disease; intermittent hypoxia; sleep apnea; translational medicine.

Fig. 1.

Cardiovascular and respiratory responses induced by obstructive apnea in rats in one of the available models. Shown are representative recordings of arterial pressure (AP), electrocardiogram (ECG), mean arterial pressure (MAP), heart rate (HR) and thoracic pressure (TP) over an episode of apnea induced by balloon inflation in the trachea of unrestrained rats. Modified with permission from Angheben et al. (1a) and Schoorlemmer et al. (127).

Fig. 2.

Proposed pathways mediating prodiabetic effects of intermittent hypoxia (IH). IH upregulates carotid body chemoreflexes while downregulating baroreflexes. The augmented carotid sinus nerve activity excites brainstem sympathetic neurons, resulting in activation of the sympathetic nervous system efferent nerves. The enhanced sympathetic nervous system efferent output 1) increases the epinephrine efflux from the adrenal medulla, which inhibits pancreatic insulin secretion; 2) induces hypertension and endothelial dysfunction; 3) increase glycogenolysis and gluconeogenesis in the liver, augmenting the hepatic glucose output; and 4) induces adipose tissue lipolysis, increasing fatty acid flux to the liver and skeletal muscle, which causes insulin resistance. It is important to note that the impact of IH on glucose metabolism may also occur via non-carotid body pathways. FFA, free fatty acid. Modified with permission from Shin et al. (130).

Fig. 3.

Effect of chronic IH (CIH) and angiopoietin-like-4 antibodies (Ab) on the atherosclerotic plaque size in en face preparations of the entire aorta (A and B) and in cross-sections of the aortic root of apolipoprotein E^−/− mice (C–E). A: representative images of the entire aorta with atherosclerotic lesions stained in red. Sudan IV; original magnification, ×10. B: percentage of the total aortic surface covered by the atherosclerotic lesions. C: representative cross sections of the aortic root. Hematoxylin and eosin staining. Original magnification, ×100. Arrow points to plaque necrosis. D: total plaque cross-sectional area (in μm²). E: plaque necrosis area (in μm²). IA, intermittent air. *P < 0.05 for CIH vehicle vs. remaining groups. †P < 0.001 for CIH vehicle vs. remaining groups. Reprinted with permission from Drager et al. (38).