# Cellular Basis for Autonomic Regulation of Cardiac Arrhythmias

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $382,466

## Abstract

PROJECT SUMMARY/ABSTRACT - Project 2
Sudden cardiac death (SCD) describes the abrupt onset of ventricular arrhythmias that kills more Americans
than any other disease. These life-threatening changes in electrical activity are most often observed in people
who have suffered a prior myocardial infarction (MI). Unfortunately, our ability to prevent SCD is limited by an
incomplete understanding of what actually triggers the underlying arrhythmias. The surviving tissue
surrounding the infarcted area of the heart, known as the border zone, is the primary sight of reentrant
electrical activity that sustains these events. Electrical heterogeneities in myocytes found in the border zone
and more remote areas of the myocardium create a substrate for reentry. However, the generation of
arrhythmias associated with SCD is also linked to an increase in sympathetic tone and a decrease in
parasympathetic tone. In fact, chronic vagal nerve stimulation (cVNS) has been shown to reduce the incidence
of ventricular arrhythmias following an MI. Yet, it is not known how myocytes found in different areas of the
infarcted heart respond to autonomic neurotransmitters such as norepinephrine (NE) and acetylcholine (ACh).
Furthermore, there is evidence the incidence of arrhythmias is also affected by the release of co-transmitters
such as neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). Our working hypothesis is that the
sympathetic neurotransmitters NE and NPY, as well as the parasympathetic neurotransmitters ACh and VIP,
alter the arrhythmogenic potential of the infarcted heart by regulating electrical heterogeneity as well as
triggered activity in different areas. In this Project, we will address the following questions: 1) how do NPY and
VIP affect the electrical properties of ventricular myocytes, 2) do sympathetic and parasympathetic
neurotransmitters affect electrical heterogeneity and triggered activity of myocytes in the border zone and
remote areas of the infarcted heart differently, and 3) does cVNS reduce arrhythmogenesis by remodeling the
electrical and pharmacological properties of myocytes in the infarcted heart. A combination of single cell
electrophysiology, molecular biology, immunocytochemistry, and biochemical techniques will be used to
answer these questions. Changes occurring at the cellular level identified in this Project will be integrated with
information about changes in the distribution and function of autonomic nerves observed at the whole heart
level in Projects 2 and 3 of this Program Project by using a computational modeling approach to investigate the
mechanistic basis for autonomic regulation of arrhythmias. The results of this project will provide the foundation
from which the efficacy of targeted neuromodulation can be mechanistically assessed, leading to improved
therapeutic strategies for preventing SCD.

## Key facts

- **NIH application ID:** 10904663
- **Project number:** 5P01HL164311-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ROBERT D HARVEY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,466
- **Award type:** 5
- **Project period:** 2023-08-10 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904663

## Citation

> US National Institutes of Health, RePORTER application 10904663, Cellular Basis for Autonomic Regulation of Cardiac Arrhythmias (5P01HL164311-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10904663. Licensed CC0.

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