# Multiomics and Functional Characterization Establish Druggable Targets for PVC-Driven Idiopathic VF

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $749,641

## Abstract

PROJECT ABSTRACT
Sudden cardiac death (SCD) claims >300,000 lives yearly in the US and despite aggressive attempts at
phenotype-genotype correlations, ~50% of patients with primary electrical SCD do not meet diagnostic criteria
for any SCD syndrome and are labeled Idiopathic Ventricular Fibrillation (IVF). This “catch-all” diagnosis of
exclusion encompasses a cohort of individuals that are undefined phenotypically with arrhythmia that is
mechanistically unexplored. Moreover, without defined genotype-phenotype characterization, clinical practice
guidelines for IVF suggest homogenous treatment for a heterogenous disorder. Recognizing that genetic linkage
studies have failed for IVF, we propose a paradigm shift to address these challenging gaps in knowledge. We
propose to integrate computational modeling of comprehensive electrophysiologic and multiomic outputs to
identify the mechanistic underpinnings of an emerging IVF subphenotype related to Purkinje-triggered VF (PVC-
IVF). In collaboration with the Bordeaux group Deep Phenotype efforts, who originally described these emerging
subphenotypes of IVF, PVC-IVF patients have been recruited to create induced pluripotent stem cells (iPSCs)
from UW and Bordeaux. Our iPSC experimental system has distinct advantages including integration of PVC-
IVF iPS-cardiomyocytes (iPS-CMs) with a mixed (ventricular myocyte and Purkinje) cell population with
computational myocyte models reflecting region-specific phenotypes. Our group’s design for iPSCs experiments
combine innovation of platforms that promote electrical and functional maturity, including incorporation of iPS-
cardiac fibroblasts (iPS-CFs), and analysis by computational modeling of iPS-CMs and in silico adult human
myocytes and tissue. In our pilot data we demonstrate the effectiveness of using iPSCs to differentiate IVF with
experimental evidence and integrate this data into computational modeling approaches to gain mechanistic
insight into cellular arrhythmic perturbations. Our overarching goal is to examine the mechanistic underpinning
of PVC-IVF and identify specific complementary and synergistic therapeutic targets. In Aim 1 we will integrate
experimental functional readouts from our advanced model system designed to recapitulate native cardiac milieu
with a combination of micro and nanoscale cues with “bottom-up” computational modeling to unravel the specific
cellular perturbations that cause the observed functional PVC-IVF readout. The focus of Aim 2 is to incorporate
a broad, unbiased data-driven dataset from multiomic characterization of PVC-IVF patient-specific iPS-CMs into
a computational systems pharmacology framework to define synergistic arrhythmogenic pathways and
antiarrhythmic polytherapy, which we predict to be safer and more effective than monotherapy approaches.
Finally, computational cross-cell translators will predict responses in the adult heart. With completion of our aims,
we will define the cellular arrhythmic signature; unrav...

## Key facts

- **NIH application ID:** 10873297
- **Project number:** 5R01HL170521-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Lee Lochbaum Eckhardt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $749,641
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873297

## Citation

> US National Institutes of Health, RePORTER application 10873297, Multiomics and Functional Characterization Establish Druggable Targets for PVC-Driven Idiopathic VF (5R01HL170521-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873297. Licensed CC0.

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