Patients with obstructive sleep apnea (OSA) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of OSA, promotes sympathetic hyperactivity, hyperinsulinemia and insulin resistance, and has been identified as a major contributor to post-MI cardiac remodeling and contractile dysfunction.

We hypothesize that IH-induced sympathetic activation and insulin resistance lead to desensitization of cardiac adrenergic and insulin signaling pathways, which contribute to the progression of ischemic cardiomyopathy.

MI is induced in C57bl6 mice by permanent ligation of the left coronary artery. Mice were then randomized to IH (21–5% FiO₂, 60s cycle, 8h/day) or normoxia for up to 6weeks. Longitudinal follow-up of mice includes evaluation of systemic insulin sensitivity (dynamic insulin tolerance test), cardiac sympathetic activity, spectral analysis of heart rate variability (HRV) and determination of cardiac function/remodeling (echocardiography). Following the completion of IH protocol, cardiac interstitial fibrosis and hypertrophy are evaluated by RT-qPCR and histology (Sirius Red and WGA staining, respectively). Assessment of adrenergic and insulin signaling pathways and there cross-talk are performed by Western blot (WB).

IH worsens MI-induced cardiac contractile dysfunction in mice, resulting in a significant decrease in ejection fraction (19.4±2.1% vs. 33.3±3.9% in IH vs. N respectively, P<0.05). MI causes significant cardiac remodeling in both N and IH groups, characterized by upregulation of several markers of cardiac fibrosis (Col1a1, Col3a1) and hypertrophy (Acta1, MyH7), which tend to be higher in IH compared to N. In our MI model, IH does not induce significant systemic insulin resistance and tends to increase LF power with no significant modification of LF/HF ratio compared to N mice. Histological experiments will be performed to confirm IH-induced aggravation of post-MI cardiac remodeling and ongoing WB will determine whether IH specifically affects cardiac insulin and adrenergic signaling.

These findings demonstrate that IH is responsible for aggravation of contractile function in our ischemic cardiomyopathy mice model. Ongoing experiments will determine whether alteration of adrenergic and insulin signalling are involved as contributing mechanisms.