# Sympathetic remodeling and ventricular arrhythmia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $453,266

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 9846232
- **Project number:** 5R01HL111600-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Crystal May Ripplinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,266
- **Award type:** 5
- **Project period:** 2012-04-16 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846232

## Citation

> US National Institutes of Health, RePORTER application 9846232, Sympathetic remodeling and ventricular arrhythmia (5R01HL111600-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9846232. Licensed CC0.

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