Following myocardial infarction (MI), patients have an increased risk of ventricular arrhythmias and sudden cardiac death. Remodeling of the cardiac sympathetic nervous system (SNS) occurs post-MI and recent experimental and clinical studies suggest that both sympathetic hyperinnervation and denervation are associated with ventricular arrhythmias. Adverse electrophysiological (EP) remodeling also occurs post-MI and includes changes to ion channels, gap junctions, and Ca2+ handling that can lead to both the trigger and substrate for ventricular arrhythmia. Individually, many SNS and EP factors have been linked to ventricular arrhythmias. However, the precise mechanisms by which post-MI SNS remodeling contributes to ? and interacts with ? EP remodeling have never been systematically investigated. The overall objective of this project is to determine the individual and interacting roles of SNS and EP remodeling in producing the triggers and substrate for ventricular arrhythmias post-MI, which may unveil novel anti-arrhythmic strategies. To meet this objective, an innovative set of methodologies has been developed, including novel approaches for modulation of cardiac innervation combined with dual optical mapping of Vm and intra-sarcoplasmic reticulum (SR) Ca2+ in the intact, fully innervated Langendorff-perfused rabbit heart.
Aim 1 will focus on acute effects of SNS stimulation in the normal heart and how SR and intracellular Ca2+ handling play a role in mediating arrhythmogenic changes. Experiments will address the hypothesis that SNS-dependent effects on SR Ca2+ and Ca2+i generate triggers for arrhythmia and modulate repolarization to create the substrate for reentry. The impact of non-classical neurotransmitters in mediating these effects will also be examined.
Aim 2 will determine the impact of chronic SNS remodeling (hyper- or denervation) on arrhythmogenesis, including the role of Ca2+ handling in mediating these effects. Here, hyper- or denervation will be created independent of MI, allowing for the separation of MI-induced changes from SNS remodeling. The contributions of acute SNS stimulation and circulating catecholamines to hyper- or denervation-induced arrhythmias will be examined.
Aim 3 will focus on the interplay between SNS remodeling and EP remodeling in the post-MI rabbit heart and novel anti-arrhythmic strategies aimed at preventing SNS remodeling will be tested. The results of this study will provide unprecedented mechanistic insight into the individual and synergistic contributions of SNS and EP remodeling in post-MI arrhythmogenesis and will determine whether targeting key nerve-heart interactions represents a novel therapeutic approach.
Myocardial infarction (MI, also known as a heart attack) predisposes patients to deadly cardiac arrhythmias (disturbances of the normal heart rhythm). Following MI, the sympathetic nerves in the heart undergo changes to their structure and function and these changes are known to be associated with arrhythmias. But how exactly sympathetic nerve activity leads to arrhythmias and the interaction between nerve activity and other changes that occur in the heart after MI are unknown. The goal of this project is to determine the role of sympathetic nerve activity in leading to arrhythmias, which may lead to new anti-arrhythmic treatments.
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