# Sympathetic remodeling and ventricular arrhythmia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $502,382

## Abstract

ABSTRACT
Autonomic remodeling is a major contributor to the initiation and maintenance of lethal ventricular arrhythmias.
Following myocardial infarction (MI), sympathetic drive is increased and parasympathetic tone is reduced.
There is also structural and functional remodeling of the cardiac sympathetic nerves, including regional
denervation, and altered neuropeptide and neurotransmitter content. Due to the intimate relationship between
cardiomyocytes and neurons, any change in nerve activity brings about adaptive changes in nearby cardio-
myocytes. These changes are in addition to ischemia-driven electrophysiological and structural remodeling.
The combined effects of post-MI autonomic, electrophysiological, and structural remodeling are critically
important but not well understood, in part because investigating the role of the autonomic nervous system in
contributing to emergent cardiac arrhythmias in the complex MI setting requires integrative, multi-scale and
multi-organ approaches. Using novel methodologies developed in our lab, our goal is to determine cardiac
signaling responses to normal and pathological autonomic activity, how this activity provokes arrhythmias in
the post-MI heart, and the anti-arrhythmic effects of restoring nerve structure or function. We have recently
developed a novel whole-heart multi-parametric optical imaging system capable of high-sensitivity fluor-
escence resonance energy transfer (FRET) imaging of cardiomyocyte signaling activity in parallel with high-
speed optical mapping of resulting electrophysiological responses in the intact heart. We have also generated
a novel cardiomyocyte-specific cyclic AMP (cAMP) reporter mouse with a large dynamic range. We will
combine these new tools with our established innervated heart approach and pharmacological and electrical
neuromodulation to precisely connect physiological autonomic activity, cardiomyocyte signaling responses,
and resulting arrhythmogenic behavior. Aim 1 will focus on how gradients in nerve density drive the spatio-
temporal kinetics of cAMP responses throughout the heart, the effective doses of neurotransmitters required to
produce nerve-evoked responses, and how cAMP activity is transduced into functional Vm and Cai changes.
Aim 2 will discern cellular mechanisms responsible for denervation super-sensitivity, and the role of nerve
structure vs. function in driving adrenergic responsiveness. Aim 3 will determine the mechanisms and anti-
arrhythmic effects of post-MI neuromodulatory therapies. These studies will provide unprecedented insight into
how autonomic dysfunction contributes to post-MI arrhythmias from cellular signaling up to macro-scale multi-
organ interactions.

## Key facts

- **NIH application ID:** 10652490
- **Project number:** 5R01HL111600-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Crystal May Ripplinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $502,382
- **Award type:** 5
- **Project period:** 2012-04-16 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652490

## Citation

> US National Institutes of Health, RePORTER application 10652490, Sympathetic remodeling and ventricular arrhythmia (5R01HL111600-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10652490. Licensed CC0.

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