# Ventricular arrhythmias and mechanisms of parasympathetic dysfunction following myocardial infarction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $678,343

## Abstract

ABSTRACT
Ventricular arrhythmias (VT/VF) due to cardiac disease and myocardial infarction (MI) lead to sudden cardiac
death. To prevent sudden cardiac death, implantable cardiac defibrillators (ICD) are used. Although
defibrillators save lives by aborting dangerous arrhythmias, they neither prevent recurrence of VT/VF nor
progression of the underly disease. Recurrent ICD shocks are associated with increased mortality and
hospitalizations, and decreased quality of life. Despite our current therapies, including catheter ablation, 60-
75% of patients have recurrence of their VT/ICD shocks at 2 years. Additional therapies are desperately
needed. Chronic sympathetic activation and reduced parasympathetic function increase risk of VT/VF and
recurrent ICD shocks. MI leads to amplification of sympathetic afferent signaling, which increases sympathetic
outflow to the heart and causes release of not only, norepinephrine, but several co-transmitters, including
neuropeptide Y and galanin. These neuropeptides have much longer half-lives than norepinephrine, and
elevated sympathetic neuropeptide levels in MI and heart failure are associated with increased mortality. It has
also been known for decades that MI reduces parasympathetic function, the body's own anti-arrhythmic drug,
increasing risk of VT/VF. However, clinical trials that attempted to increase vagal outflow by stimulating mixed
nerves (vagal nerve stimulation, spinal cord stimulation) have had disappointing results, likely because the
reasons behind chronic parasympathetic “withdrawal” remain unknown. In order develop new targeted
therapies, it is critical to understand mechanisms underlying parasympathetic dysfunction and sympathetic and
parasympathetic interactions that occur in the setting of cardiac disease. In this proposal, we aim to test the
novel hypotheses that (1) persistent efferent sympathetic activation due to MI inhibits parasympathetic
function at the nerve-myocyte interface (the neuro-effector junction) due to release of sympathetic co-
transmitters and (2) sympathetic afferent activation reduces central vagal tone. In specific aim 1, we will
test whether inhibition of sympathetic neuropeptides, neuropeptide Y and galanin, improves vagal tone and
prove anti-arrhythmic. In aim 2, we will test whether sympathetic afferent blockade improves parasympathetic
function and decreases ventricular arrhythmias. For aims 1 and 2, we will utilize hemodynamic and multi-
electrode array neural recordings simultaneously with high-density electrophysiological mapping and direct
interstitial norepinephrine measurements in a large animal model. Aim 3 will evaluate whether disruptions of
sympathetic signaling via cardiac sympathetic denervation, the only current therapy that interrupts sympathetic
afferent fibers and potentially reduces co-transmitters levels, will improve parasympathetic function in patients
with scar-mediated VT. Understanding these fundamental autonomic pathways has the potential to ...

## Key facts

- **NIH application ID:** 10652988
- **Project number:** 5R01HL148190-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Marmar Vaseghi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $678,343
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652988

## Citation

> US National Institutes of Health, RePORTER application 10652988, Ventricular arrhythmias and mechanisms of parasympathetic dysfunction following myocardial infarction (5R01HL148190-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10652988. Licensed CC0.

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