# Mechanisms of cardiac sympathetic hyperactivity in chronic heart failure

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $376,250

## Abstract

Chronic heart failure (CHF)-induced cardiac sympathetic overactivity is involved in sudden cardiac death and is
responsible for high mortality in patients with CHF. However, the potential mechanisms concerning cardiac
sympathetic overactivity in the CHF state are unclear. Cardiac postganglionic sympathetic (CPS) neurons
located in stellate ganglia regulate cardiac function by influencing release of norepinephrine (NE) and
neuropeptide Y (NPY) from these neuronal terminals innervating the heart. Ca++ influx through voltage-gated
Ca++ channels is a key trigger for the release of NE and NPY from these neuronal terminals. Our recent study
has shown that N-type Ca++ currents and cell excitability in CPS neurons are enhanced in coronary artery
ligation-induced CHF rats, which are accompanied by cardiac sympathetic hyperactivity. Based on our
preliminary data, we hypothesize that CHF-mediated inflammation cytokines in CPS neurons evoke N-
type Ca++ channel activation via cyclin-dependent kinase (Cdk5) signaling, and N-type Ca++ channel
activation then contributes to cardiac sympathetic hyperactivity in CHF. Myocardial infarction-induced
CHF and sham (sham surgery) rats and mice will be used as the primary experimental tool in this project.
Using multi-faceted technical approaches (from whole-animal to cellular-molecular levels) in sham and CHF
rats, we will design in-vitro (cells and tissues) and in-vivo (conscious and anesthetized rats) studies to assess
this question. In specific Aim 1, we will measure whether CHF-increased N-type Ca++ currents in CPS neurons
contribute to cardiac sympathetic hyperactivity in CHF as measured by cardiac sympathetic nerve activity, in-
vivo release of NE and NPY from CPS nerve terminals, and heart rate variability. In Specific Aim 2, we will test
whether CHF-increased N-type Ca++ currents in CPS neurons trigger cardiac rhythm instability in CHF. In
Specific Aim 3, we will measure whether inflammatory cytokine-Cdk5 signaling pathway modulates N-type
Ca++ channels in CPS neurons of CHF rats. These studies will further our understanding of the cellular and
molecular mechanisms responsible for the cardiac sympathetic hyperactivity in CHF and will also explore
potential therapeutics (N-type Ca++ channel blockers and new anti-inflammatory drugs) for improving cardiac
sympathetic function and reducing mortality in the CHF state.

## Key facts

- **NIH application ID:** 9949430
- **Project number:** 5R01HL137832-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Yu-Long Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,250
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949430

## Citation

> US National Institutes of Health, RePORTER application 9949430, Mechanisms of cardiac sympathetic hyperactivity in chronic heart failure (5R01HL137832-04). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9949430. Licensed CC0.

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