Intermittent Hypoxia Triggers Early Cardiac Remodeling and Contractile Dysfunction in the Time-Course of Ischemic Cardiomyopathy in Rats

BACKGROUND Sleep-disordered breathing is associated with a poor prognosis (mortality) in patients with ischemic cardiomyopathy. The understanding of mechanisms linking intermittent hypoxia (IH), the key feature of sleep-disordered breathing, to ischemic cardiomyopathy progression is crucial for identifying specific actionable therapeutic targets. The aims of the present study were (1) to evaluate the impact of IH on the time course evolution of cardiac remodeling and contractile dysfunction in a rat model of ischemic cardiomyopathy; and (2) to determine the impact of IH on sympathetic activity, hypoxia inducible factor-1 activation, and endoplasmic reticulum stress in the time course of ischemic cardiomyopathy progression. METHODS AND RESULTS Ischemic cardiomyopathy was induced by a permanent ligature of the left coronary artery in male Wistar rats (rats with myocardial infarction). Rats with myocardial infarction were then exposed to either IH or normoxia for up to 12 weeks. Cardiac remodeling and function were analyzed by Sirius red and wheat germ agglutinin staining, ultrasonography, and cardiac catheterization. Sympathetic activity was evaluated by spectral analysis of blood pressure variability. Hypoxia-inducible factor-1α activation and burden of endoplasmic reticulum stress were characterized by Western blots. Long-term IH exposure precipitated cardiac remodeling (hypertrophy and interstitial fibrosis) and contractile dysfunction during the time course evolution of ischemic cardiomyopathy in rodents. Among associated mechanisms, we identified the early occurrence and persistence of sympathetic activation, associated with sustained hypoxia-inducible factor-1α expression and a delayed pro-apoptotic endoplasmic reticulum stress. CONCLUSIONS Our data provide the demonstration of the deleterious impact of IH on post-myocardial infarction remodeling and contractile dysfunction. Further studies are needed to evaluate whether targeting sympathetic nervous system or HIF-1 overactivities could limit these effects and improve management of coexisting ischemic cardiomyopathy and sleep-disordered breathing.

Keywords: ER stress; hypoxia inducible factor‐1; intermittent hypoxia; ischemic cardiomyopathy; sleep‐disordered breathing; sympathetic activation.