Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice

Abstract

Patients with obstructive sleep apnea, who experience episodic hypoxia and hypercapnia during sleep, often demonstrate increased inflammation, oxidative stress, and dyslipidemia. We hypothesized that sleep apnea patients would be predisposed to the development of atherosclerosis. To dissect the mechanisms involved, we developed an animal model in mice whereby we expose mice to intermittent hypoxia/hypercapnia (IHH) in normobaric environments. Two- to three-month-old low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were fed a high-fat diet for 8 or 16 wk while being exposed to IHH for either 10 h/day or 24 h/day. Plasma lipid levels, pulmonary artery and aortic atherosclerotic lesions, and cardiac function were then assayed. Surprisingly, atherosclerosis in the aorta of IHH mice was similar compared with controls. However, in IHH mice, atherosclerosis was markedly increased in the trunk and proximal branches of the pulmonary artery of exposed mice; even though plasma cholesterol and triglycerides were lower than in controls. Hemodynamic analysis revealed that right ventricular maximum pressure and isovolumic relaxation constant were significantly increased in IHH exposed mice and left ventricular % fractional shortening was reduced. In conclusion, 1) Intermittent hypoxia/hypercapnia remarkably accelerated atherosclerotic lesions in the pulmonary artery of Ldlr(-/-) mice and 2) increased lesion formation in the pulmonary artery was associated with right and left ventricular dysfunction. These findings raise the possibility that patients with obstructive sleep apnea may be susceptible to atherosclerotic disease in the pulmonary vasculature, an observation that has not been previously recognized.

Intermittent Hypoxia and Hypercapnia Accelerate Atherosclerosis, Partially via Trimethylamine-Oxide

“…In Ldlr 2/2 mice, IHC had no impact on the progression of aortic atherosclerosis, in contrast to what was observed for ApoE 2/2 mice. Although a marked increase in plasma lipids was noted in response to HFD in Ldlr 2/2 mice, there were no differences in total plasma cholesterol or triglyceride levels between IHC and RA controls after 8 weeks of treatment (9). It is interesting to note that mice exposed to IHC, even with reduced body weights and less high-fat food intake, formed more lesions in the PA than the RA control mice.…”

“…Both ApoE and Ldlr play important roles in the clearance of cholesterol and triglyceride-rich lipoprotein particles from the blood. We recently reported that 8 and 16 weeks of IHC exposure remarkably accelerated the formation of atherosclerosis in the pulmonary artery (PA) of Ldlr 2/2 mice on a high-fat diet (HFD), which was accompanied by hemodynamic changes consistent with early pulmonary hypertension and right-ventricular strain (9). However, IHC did not cause more lesion formation in the aorta after either 8 or 16 weeks of exposure, although the absolute extent of the lesions was increased after 16 weeks.…”

“…Atherosclerosis was quantified by computer-assisted image analysis (ImageJ, NIH Image) (22) in Sudan Red-stained en face preparations of the aorta and PAs as previously described (9). Briefly, the heart was perfused with cold PBS plus EDTA, followed by fixation with 4% paraformaldehyde.…”

Role of Oxidized Lipids in Pulmonary Arterial Hypertension

“…Intermittent hypoxia/hypercapnia resulted in marked increase in atherosclerotic lesions in the pulmonary artery, accompanied by RV and left ventricular dysfunction. 127 In addition, pulmonary artery atheroscelerosis is accelerated in patients with hypertensive pulmonary disease and shows significant correlation with RV dilation and hypertrophy. 128 It has been reported that pulmonary artery atherosclerosis is also characterized by increased lipid peroxidation in pulmonary artery lesions.…”

Tissue Doppler Imaging predicts central sleep apnea in patients with chronic heart failure: data from the Daunia Registry

“…LV hypertrophy, myocardial fibrosis, atrial dilatation, and LV systolic and diastolic dysfunction in patients with OSA explain the association of the disease with these clinical outcomes. Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low-density lipoprotein receptor-deficient mice [21]. According to other authors, LV wall stress may represent the link between HF and SDB [22].…”