Mechanisms Involved In The Deleterious Impact Of Intermittent Hypoxia On Ischemic Cardiomyopathy

Background Chronic intermittent hypoxia (IH) is the hallmark feature of sleep-disordered breathing and clinical studies underlie a poor prognosis in severe apneic patients post-myocardial infarction (MI). Thus, it is necessary to understand specific mechanistic pathways involved in this post-MI aggravation, in order to improve the management of patient. Previous studies showed that IH activates myocardial HIF1-endoplasmic reticulum (ER) stress axis. Thus, we aimed at highlighting: 1 the impact of IH on the development of ischemic cardiomyopathy; 2 to determine the involved mechanisms, in particular the role of IH on HIF1-ER stress axis, sympathetic activation and calcium (Ca 2+ ) homeostasis perturbations. Methods MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Then, rats were exposed to IH (21–5% FiO 2 , 60 s cycle, 8 h/day) or normoxia (N) for 1 to 12 weeks. Cardiac function was evaluated by ultrasonography and cardiac catheterization. Ultimately, hearts were withdrawn for biochemical and histological analysis, as well as Ca 2+ transient imaging after cardiomyocytes isolation. Results We observed more important alterations in ejection fraction, dP/dtmax, and dP/dtmin in IH rats compared to N. These IH rats exhibited sympathetic hyperactivation (i.e. increased LF/HF ratio and adrenal gland hypertrophy), which was associated with an increased HIF1 expression post-MI. Expressions of GRP78, CHOP and caspase 12 proteins were also increased by IH, suggesting a pro apoptotic ER stress. Except from phospholamban that was hyper-phosphorylated, Ca 2+ handling protein expressions were not different between N and IH. Finally, Ca 2+ transient analysis is ongoing. Conclusion As in severe apneic patients, we showed that IH is deleterious on ischemic cardiomyopathy development. Besides, HIF1, sympathetic activity, ER stress and Ca 2+ homeostasis are disturbed. Further studies are needed to better understand the relationship between these mechanisms.