# Determinants of Arrhythmogenic Risk In Arrhythmogenic Cardiomyopathies and Mitral Valve Prolapse

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $395,000

## Abstract

Abstract
Arrhythmogenic cardiomyopathies are inherited or acquired abnormalities of the heart that provide substrate and
triggers that initiate and sustain ventricular arrhythmias. Ventricular arrhythmias range from infrequent premature
ventricular contractions (PVCs) to more concerning burdens of PVCs, which can then trigger sustained
ventricular tachycardia, which even if self-terminating, are harbinger of future non-terminating VT, which can be
hemodynamically unstable and fatal if not terminated by defibrillation. Diverse cellular, molecular, and
environmental etiologies have been suggested to explain the pathogenesis of arrhythmogenic cardiomyopathies
including fibrosis and scar, pathologic excitability of cardiomyocytes, and even influences from resident or bone
marrow derived myeloid cells. We hypothesize that although arrhythmogenic cardiomyopathies have distinct
origins and etiologies, they share a common set of cellular, molecular, and microenvironmental features
comprising a stereotyped arrhythmogenic niche that can be targeted for therapeutic benefit. This administrative
supplement to the funded R01 HL162369 entitled, “Uncovering Molecular Targets for Arrhythmogenic
Cardiomyopathy Therapeutics” is focused on studying arrhythmogenic cardiomyopathy with single cell spatial
resolution. The goal of this supplement is to apply these methods to dissect the cellular and molecular
microenvironment of the arrhythmogenic cardiomyopathy niche in models where fibrosis serves as a substrate
and conspires with electrical triggers, first in an arrhythmogenic cardiomyopathy mouse model from the funded
R01 and then by comparison to heart tissue from human arrhythmogenic mitral valve prolapse (MVP), where
fibrosis of the mitral valvular apparatus acts as a substrate. We aim to define: (1) the cell subsets, molecular
pathways, and potential cellular communication pathways activated by mechanically-induced arrhythmogenic
substrates using single cell/nuclei RNA-Seq and (2) the spatial location and organization of the mechanically-
induced arrhythmogenic niche by combining structural histologic analysis with spatial transcriptomics and single
cell resolution smFISH. Results generated by the proposed supplement will benefit the original arrhythmogenic
cardiomyopathy-focused R01 by identifying therapeutic targets for arrhythmogenic cardiomyopathy as well as
the CAROL Act goal of building dynamic risk assessment technologies and uncovering mechanisms underlying
arrhythmogenic MVP.

## Key facts

- **NIH application ID:** 10853894
- **Project number:** 3R01HL162369-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Farah Sheikh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,000
- **Award type:** 3
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853894

## Citation

> US National Institutes of Health, RePORTER application 10853894, Determinants of Arrhythmogenic Risk In Arrhythmogenic Cardiomyopathies and Mitral Valve Prolapse (3R01HL162369-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853894. Licensed CC0.

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