Abstract
Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region. However, the contribution of hypo-innervation to electrophysiological remodeling, independent from MI-induced ischemia and fibrosis, has not been comprehensively investigated. We present a novel mouse model of regional cardiac sympathetic hypo-innervation utilizing a targeted-toxin (dopamine beta-hydroxylase antibody conjugated to saporin, DBH-Sap), and measure resulting electrophysiological and Ca2+ handling dynamics. Five days post-surgery, sympathetic nerve density was reduced in the anterior left ventricular epicardium of DBH-Sap hearts compared to control. In Langendorff-perfused hearts, there were no differences in mean action potential duration (APD80) between groups; however, isoproterenol (ISO) significantly shortened APD80 in DBH-Sap but not control hearts, resulting in a significant increase in APD80 dispersion in the DBH-Sap group. ISO also produced spontaneous diastolic Ca2+ elevation in DBH-Sap but not control hearts. In innervated hearts, sympathetic nerve stimulation (SNS) increased heart rate to a lesser degree in DBH-Sap hearts compared to control. Additionally, SNS produced APD80 prolongation in the apex of control but not DBH-Sap hearts. These results suggest that hypo-innervated hearts have regional super-sensitivity to circulating adrenergic stimulation (ISO), while having blunted responses to SNS, providing important insight into the mechanisms of arrhythmogenesis following sympathetic nerve loss.
Highlights
Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region
We further showed that the hypo-innervated infarct region has supra-physiological β-adrenergic receptor (β-AR) responses, including dramatic action potential duration (APD) shortening, diastolic Ca2+ elevation, and premature ventricular complexes (PVCs) in response to circulating β-AR agonists
We previously showed that sympathetic nerve stimulation (SNS) in the normal mouse heart leads to APD prolongation and C a2+ transient duration (CaTD) shortening, while heart rates (HRs) is increased[28]
Summary
Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region. SNS produced APD80 prolongation in the apex of control but not DBH-Sap hearts These results suggest that hypo-innervated hearts have regional super-sensitivity to circulating adrenergic stimulation (ISO), while having blunted responses to SNS, providing important insight into the mechanisms of arrhythmogenesis following sympathetic nerve loss. Of the infarct was produced with either genetic deletion or pharmacologic inhibition of the neuronal receptor for CSPGs, the protein tyrosine phosphatase receptor σ (PTPRσ)[11] These data suggest an important and fundamental role for sympathetic nerve loss in post-MI arrhythmogenesis, which may be due to adrenergic super-sensitivity and subsequent supra-physiological responses of the surviving myocardium. The goal of this study was to directly investigate the role of regional sympathetic hypo-innervation on ventricular electrophysiology (EP) and C a2+ handling in the absence of infarction
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