Regional cardiac denervation produces supersensitivity of myocardial Ca2 + handling to β-adrenergic stimulation

Abstract

Rationale: Myocardial infarction (MI) can result in chronic loss of sympathetic nerve fibers in the infarct region (denervation). Heterogeneity of sympathetic transmission combined with ischemic damage and fibrosis are all likely contributors to post-MI arrhythmogenesis. However, the precise contribution of denervation to arrhythmogenesis – independent from ischemic damage - has not been systematically investigated. Objective: To create a novel mouse model of regional myocardial sympathetic denervation and measure resulting electrophysiological and Ca2+ handling dynamics. Methods and Results: A targeted toxin (anti-dopamine beta hydroxylase [DBH] conjugated to saporin [Advanced Targeting System, San Diego, CA]) was applied to the apical/anterior region of the ventricle during survival surgery. Untargeted anti-IGg-saporin was applied as a control. At 5 days post-surgery, action potential and Ca2+ handling parameters were measured in Langendorff-perfused hearts using optical mapping with voltage- and Ca2+-sensitive indicators at baseline and in response to isoproterenol (ISO, 1μM). Action potential durations (APD80) were similar in the denervated versus normally innervated regions both before and after ISO (baseline: 51.26 ± 3.36 vs. 48.93 ± 9.17ms, p=NS; ISO: 30.69 ± 14.89 vs. 31.88 ± 13.94ms, p=NS, denervated vs. innervated). At baseline, Ca2+ handling parameters were also similar between denervated and innervated regions. However, following ISO, spontaneous diastolic Ca2+ elevation was frequently observed in the denervated region (14.25 ± 2.23% vs. 5.41 ± 1.43%, p=0.001, denervated vs. innervated). Additionally, an approximate 4-fold reduction in sympathetic fibers in the denervated region was observed. Conclusions: Local application of anti-DBH-saporin produces regional cardiac sympathetic denervation. At 5 days post-denervation, spontaneous Ca2+ elevation was observed in response to ISO in the denervated region, which may indicate catecholaminergic supersensitivity and an increased likelihood for triggered activity. These findings may have important implications for understanding the specific role of denervation in contributing to post-MI remodeling and arrhythmogenesis.