# Spinal Neuraxial Modulatin of Ventricular Excitability - Mechanisms and Therapeutics

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $576,154

## Abstract

Project Summary/Abstract
 Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of death in
the United States. Dysregulation of the autonomic nervous system, specifically sympathoexcitation, plays a major
role in the pathophysiology of cardiac arrhythmias secondary to ischemic heart disease. The spinal cord serves
as a major nexus point for control of sympathetic reflexes to the heart. However, there are major gaps in the
understanding of regulation of cardiac excitability at the level of the spinal cord. Spinal neuromodulation therapies-
spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation, show promise towards reducing VTs,
but the mechanisms underlying the therapeutic benefits of these innovative approaches remain largely unknown.
The goal of this proposal is to determine how the spinal cord processes cardiac afferent impulses during
myocardial ischemia and to explain how neuromodulation therapies reduce ventricular arrhythmias, leading to
their more effective and expansive use.
 In this proposal, it is hypothesized that unique cardiospinal neural networks integrate the cardiac afferent
signals during myocardial ischemia (MI) and control sympathoexcitation, thereby modulating arrhythmogenesis.
Further, MI triggers pathologic remodeling of cardiospinal neural circuits, which increase myocardial
sympathoexcitation. SCS and DRG stimulation, reduce sympathetic output through induction of GABA signaling
pathways in the spinal cord, reducing ventricular excitability and arrhythmias after chronic MI. Importantly,
preliminary functional data shows anti-arrhythmic effects of SCS during acute I/R were abolished in the presence
of GABA receptor antagonists, supporting the hypothesis. Real Time PCR also shows expression of GABAA and
GABAB receptors is increased by SCS therapy in spinal cord during MI. Thus, modulation of cardiac afferent
neural inputs to the spinal cord presents a novel target for suppression of excessive sympathetic reflex activation
and cardiac arrhythmias. To mechanistically understand the therapeutic potential of such approaches, proposed
experiments will evaluate the effects of neuromodulation on cardiospinal neural network and ventricular excitability.
 The proposed studies will evaluate novel mechanisms of regulation of cardiac excitability at the spinal
level. Specific aims 1 is designed to provide a mechanistic understanding of the role of spinal cord processing of
afferent cardiac neural inputs. Electrophysiological and neurochemical alterations in cardiospinal neural network in
chronic MI will be compared with healthy hearts when subjected to additional cardiac stress (acute
ischemia/reperfusion). Molecular mechanisms through which chronic MI induces pathologic remodeling of the
cardiospinal neural network will be characterized. In specific aim 2 and 3, mechanisms by which SCS and DRG
stimulation reduce cardiospinal neural network remodeling and decrease myocardial sympatho...

## Key facts

- **NIH application ID:** 9975879
- **Project number:** 5R01HL136836-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JEFFREY L ARDELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $576,154
- **Award type:** 5
- **Project period:** 2018-08-02 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975879

## Citation

> US National Institutes of Health, RePORTER application 9975879, Spinal Neuraxial Modulatin of Ventricular Excitability - Mechanisms and Therapeutics (5R01HL136836-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975879. Licensed CC0.

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