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

Abstract

Patients with sleep disordered breathing (SDB) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of SDB, enhances sympathetic activity, depletes cardiac adrenergic reserve 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 adrenergic reserve depletion and ischemic cardiomyopathy aggravation. MI is induced in male Wistar rats by permanent ligation of the left coronary artery and CSD by ablation of the left middle cervical and stellate ganglions. After surgery, rats are exposed to 6 and 14 weeks IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia (N). Cardiac function and remodeling are evaluated by echography. Cardiac sympathetic activity is assessed by spectral analysis of heart rate variability on conscious rats (Etisense). Ultimately, hearts are withdrawn for cardiomyocyte isolation and calcium transient analysis, for assessment of calcium and adrenergic signalling pathways (western blot) and for histological analysis of fibrosis (Sirius red), hypertrophy (WGA) and cardiac sympathetic innervation (Tyrosine-hydroxylase staining). CSD prevents the IH-induced blunted cardiomyocyte response to isoproterenol challenge (ISO). ISO-induced cardiomyocyte shortening is about 78% on MI-N group, reduced to 28% in MI-IH and restored to 125% in MI-IH-CSD. Preliminary results on cardiac function indicate that CSD also improve long-term ejection fraction in MI-IH rats. Biochemical and histological analysis are on-going. These results suggest that IH-induced sympathetic activity is responsible for adrenergic reserve depletion in our rat model of ischemic cardiomyopathy. Ongoing experiments will confirm if CSD also limits the IH-induced cardiac remodeling and contractile dysfunction.