# Neural Control of Myocardial Excitability at the Nerve Myocyte Interface

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $483,019

## Abstract

ABSTRACT – Project 1
Sudden cardiac death due to ventricular arrhythmias and heart failure are the leading causes morbidity and
mortality in the United States. The autonomic nervous system plays a major role in the pathophysiology of
arrhythmias and heart failure. Neuraxial modulation represents an important avenue for therapeutic
intervention. However, the structural and functional determinants of the release of neurotransmitters and
peptides in the myocardium in health and disease, which effectively govern cardiac excitability and mechanical
function, as well as propensity toward arrhythmias, remain largely unknown. Myocardial scars seen in ischemic
and nonischemic cardiomyopathy show abnormal innervation and nerve sprouting at the border zone of scars
due to neural remodeling, which have been implicated in the pathophysiology of ventricular arrhythmias. We
propose to test “The Spatiotemporal Heterogeneity of Neurotransmitter Release Hypothesis’ – which
postulates that scars alter the ultrastructure of nerves and cause non-uniform reflex-mediated neurotransmitter
release in the myocardium and represents a crucial/proximate cause of lethal arrhythmias. The major goal of
this project is to investigate the structural (myocardial) and functional (neural) changes in the heart that occur
because of heart disease and subsequently lead to ventricular arrhythmias. In aims 1 and 2, we will determine
the ultrastructure and define the nerve-myocyte stoichiometry and release profiles of neurotransmitters and
peptides in normal and diseased hearts in response to physiological stressors and specifically define areas of
non-uniform release of neurotransmitters. In aim 3, we will determine the underlying mechanism and potential
benefit of vagal nerve stimulation in mitigating the pathological remodeling related to scar formation and
autonomic innervation. Regional structural and functional changes in innervation of scar and border zone
regions will be studied using high density electrophysiological mapping and real time neurotransmitter and
neuropeptide measurements which will be correlated with structural changes at the border zones of infarcts
using tissue clearing techniques in a relevant large animal model and in human hearts. Understanding the
underlying myocardial and neural mechanisms leading to arrhythmias has the potential to develop and
precisely target therapies that inspire therapies for the prevention of sudden cardiac death and progression of
heart failure.

## Key facts

- **NIH application ID:** 10904660
- **Project number:** 5P01HL164311-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** KALYANAM SHIVKUMAR
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $483,019
- **Award type:** 5
- **Project period:** 2023-08-10 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904660

## Citation

> US National Institutes of Health, RePORTER application 10904660, Neural Control of Myocardial Excitability at the Nerve Myocyte Interface (5P01HL164311-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10904660. Licensed CC0.

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