# Identification of Novel Cellular/Molecular Mechanisms and Arrhythmia Targets in Heart Failure

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2024 · —

## Abstract

ABSTRACT
Arrhythmogenic cardiovascular disease, which disproportionately affects individuals in the VA population with
acquired cardiac and metabolic diseases, particularly heart failure, is associated with increased morbidity and
mortality. The mechanisms contributing to increased risk of sudden cardiac death in individuals suffering
arrhythmogenic cardiovascular disease, however, remain very poorly understood, hampering our ability to risk
stratify patients and to develop novel, targeted therapeutic strategies. Although numerous experimental
(animal/cellular) heart failure models have been developed and extensively studied, only limited insights into
human arrhythmia mechanisms have been provided. Motivated to bridge this knowledge gap and advance the
field, we have initiated a comprehensive research effort aimed at defining the mechanisms involved in the
physiological regulation of membrane excitability in the human heart and the pathophysiological electrical
remodeling associated with human heart failure. To enable direct molecular/biochemical and functional studies
on human ventricular myocardium/myocytes, we developed the infrastructure to acquire non-failing and failing
human hearts and we established robust, reliable methods for the isolation, in vitro maintenance, adenovirus-
mediated transduction, and electrophysiological characterization of human ventricular myocytes. Here, we utilize
these unique resources in experiments designed to define the molecular and cellular mechanisms controlling
the expression, the properties and the remodeling of critical ionic currents that impact action potential
repolarization, the late component of the voltage-gated Na+ (Nav) current, INa,L, and the novel non-inactivating K+
(Kv) current, IK,L, that we have recently identified in non-failing human left ventricles. We will define the roles of
channel accessory subunits and post-translational modifications in controlling the cell surface expression and
the biophysical and pharmacological properties of native human ventricular INa,L (aim #1) and IK,L (aim #2). In
aim #2, we shall also explore the hypothesis that there are actually two, functionally and molecularly distinct
components of human ventricular IK,L. Additional experiments (aim #3) will elucidate the molecular mechanisms
underlying in INa,L and IK,L remodeling in failing human ventricles.
These studies will provide new, clinically relevant insights into the cellular/molecular mechanisms contributing to
the physiological regulation and pathophysiological remodeling of native human ventricular Ito,f, Iss and INa
channels. These insights will transform the refinement of human cardiac myocyte and whole heart models and
translate to novel, mechanism-based strategies to target specific cell types to reduce the risk of life-threatening
ventricular arrhythmias in VA patients suffering heart failure.

## Key facts

- **NIH application ID:** 11076175
- **Project number:** 5I01BX005001-05
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** C. William Balke
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11076175

## Citation

> US National Institutes of Health, RePORTER application 11076175, Identification of Novel Cellular/Molecular Mechanisms and Arrhythmia Targets in Heart Failure (5I01BX005001-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11076175. Licensed CC0.

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