# Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $730,577

## Abstract

PROJECT SUMMARY/ABSTRACT
Cardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden death. Current therapies to
prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which
support re-entry. Here we propose to test the reverse concept, namely that boosting local tissue viability in zones
of slow conduction might eliminate slow conduction and suppress VA. We seek to do so by local injection, into
mapped areas of slow conduction, of exosomes secreted by cardiosphere-derived cells (CDCs), a
stromal/progenitor cell type from the human heart. Exosomes are extracellular vesicles laden with bioactive
cargo. Those secreted by CDCs (CDCEXO) reduce scar and improve heart function after intramyocardial delivery.
In a VA-prone porcine model of ischemic cardiomyopathy, we present preliminary data in which we injected
CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to one month post-
injection, CDCEXO, but not vehicle, decreased myocardial scar, suppressed slowly conducting electrical
pathways, and inhibited VA induction by programmed stimulation. In silico reconstruction of electrical activity
based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO. Here
we will explore alternative intracoronary delivery methods which would be more readily translatable clinically
than the intramyocardial injection approach, which requires non-approved catheters. We will also explore
mechanism of the anti-VA effects histologically and by RNA sequencing, as well as in a co-culture assay of
cardiomyocytes and fibroblasts. We will also compare directly the efficacy of exosomes versus conventional RF
ablation. In conclusion, we seek to establish biological substrate modification by exosome injection as a
nondestructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias.

## Key facts

- **NIH application ID:** 10693972
- **Project number:** 5R01HL164896-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** James F. Dawkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $730,577
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693972

## Citation

> US National Institutes of Health, RePORTER application 10693972, Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy (5R01HL164896-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693972. Licensed CC0.

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