# Elucidating the Origin of Sudden Cardiac Death in Dilated Cardiomyopathy: from Phenotype Predictors to Therapeutic Targets

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $727,280

## Abstract

Project Abstract
The molecular mechanisms and the clinical predictors of life-threatening arrhythmias in patients with dilated,
nonischemic cardiomyopathy (DCM) remain elusive, hampering adequate prevention and treatment of sudden
cardiac death (SCD) and malignant ventricular arrhythmias (VA) in this population. Our application will address
this unmet need. Our established team of investigators from the University of Colorado and Stanford University
has assembled preliminary data and proof-of-concept experiments to tackle three complementary aims, which
will comprehensively fill critical knowledge gaps in life-threatening VA and SCD risk in DCM. We hypothesize
that two main mechanisms are involved in VA/SCD in DCM: genetic factors (“arrhythmogenic” genes) and
cardiac fibrosis. We will address these hypotheses with three independent but complementary Specific Aims
(clinical, translational and mechanistic) designed to translate the discovery of mechanisms and delineation of
prognosis into a precision medicine approach. Specific Aim 1 will define genotype and phenotype
predictors of malignant VA and SCD in DCM. Our preliminary studies show that phenotype, such as
myocardial fibrosis, and gene mutations significantly increase the risk of VA/SCD. Thus, we hypothesize that a
clinical multidisciplinary approach including genotype and advanced imaging can precisely identify DCM patients
at risk of SCD. Using deep phenotyping, outcome measures, and NextGen sequencing in the Familial
Cardiomyopathy Registry (1,316 DCM subjects), we will generate a SCD risk prediction score for clinical use.
Specific Aim 2 will identify the transcriptome signature of VA. We found that explanted hearts of patients
with arrhythmogenic DCM have a distinct transcriptional signature. Thus, we hypothesize that, in advanced-
stage DCM, lethal arrhythmias are driven by genetically determined transcriptional signatures. We will leverage
whole genome and transcriptome sequencing data from our NIH/NHLBI TOPMed project (X01 HL139403: 1078
explanted hearts, 504 DCM, 140 controls) to identify gene-specific dysregulated pathways predicting high-risk
VA. Specific Aim 3 will elucidate the molecular mechanisms of arrhythmogenic genes. Our preliminary
data in mutant human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) show evidence of
intrinsic electrical instability. However, the role of cardiac fibroblasts and CM/CF cross-talk in arrhythmogenesis
remains unknown. We hypothesize that arrhythmogenic DCM genes activate fibroblasts and induce arrhythmia,
either directly or indirectly through their interaction with cardiomyocytes. hiPSC-CM and cardiac fibroblasts
(hiPSC-CF) will be generated from 60 patients from our Registry (Aim 1) and genome edited models with
mutations in arrhythmogenic genes (LMNA, FLNC, DSP), and 20 age/gender/ethnicity-matched healthy
individuals. Using engineered heart tissue scaffolds (EHT), we will elucidate the mechanisms of CFs activation
and arrhyth...

## Key facts

- **NIH application ID:** 10658201
- **Project number:** 1R01HL164634-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Luisa Mestroni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $727,280
- **Award type:** 1
- **Project period:** 2023-04-05 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658201

## Citation

> US National Institutes of Health, RePORTER application 10658201, Elucidating the Origin of Sudden Cardiac Death in Dilated Cardiomyopathy: from Phenotype Predictors to Therapeutic Targets (1R01HL164634-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10658201. Licensed CC0.

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