Impact of cardiac sympathetic denervation on IH-induced ischemic cardiomyopathy aggravation

Abstract

Background: Patients with sleep disordered breathing (SDB) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of SDB, enhances sympathetic activity and accelerates cardiac remodeling and dysfunction in a rat model of ischemic cardiomyopathy. In the present study, we aim at investigating whether specific cardiac sympathetic denervation (CSD) counteracts the IH-induced ischemic cardiomyopathy aggravation. Methods: MI is induced in male Wistar rats by permanent ligation of left coronary artery and CSD by ablation of the left middle cervical and stellate ganglions. After surgery, rats are exposed to IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia (N) for up to 14 weeks. Cardiac function and remodeling are evaluated by echography. Cardiac sympathetic activity is assessed by spectral analysis of heart rate variability. Hearts are withdrawn for cardiomyocyte isolation and calcium transient analysis, assessment of calcium and adrenergic signalling pathways (western blot) and histological analysis of fibrosis (Sirius red), hypertrophy (WGA) and cardiac sympathetic innervation (Tyrosine-hydroxylase staining). Results: CSD prevents the IH-induced blunted cardiomyocyte response to isoproterenol challenge (ISO). ISO-induced cardiomyocyte shortening is about 78% on MI-N group, 28% in MI-IH and 125% in MI-IH-CSD. CSD also improves long-term ejection fraction in MI-IH rats. Biochemical and histological analysis are on-going. Conclusion: These results suggest that IH-induced sympathetic activity is responsible for adrenergic reserve depletion and contractile dysfunction in our rat model of ischemic cardiomyopathy.