# Arrhythmogenic Cardiomyopathy is an Inflammatory Disease

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $503,423

## Abstract

Project Summary/Abstract
The goal of this project is to define the role of inflammation in the pathogenesis of arrhythmogenic
cardiomyopathy (ACM), a familial non-ischemic heart muscle disease that causes sudden death in the young
and especially in athletes. Exercise accelerates disease penetrance, and increases arrhythmic risk and
adverse cardiac events in ACM patients, but how exercise exacts this terrible toll is not known. We now report
substantial new data showing that ACM disease alleles activate NFκB signaling in cardiac myocytes and that
inhibition of this signaling pathway prevents the full ACM disease phenotype in a robust, well characterized
mouse model. We also show that exercise greatly intensifies inflammatory signaling, thus providing a new
mechanistic explanation for accelerated disease progression in athletes. These observations suggest that
targeted anti-inflammatory therapy could be a powerful, truly mechanism-based approach to reduce adverse
events in ACM patients. Accordingly, we will test the hypotheses that 1) activation of an innate immune
response in cardiac myocytes mediated by NFκB causes arrhythmias and myocardial damage in ACM; and 2)
exercise accelerates progression of ACM by stimulating production of injurious inflammatory mediators via
activation of NFκB signaling in cardiac myocytes. In Aim 1, we will use genetic approaches in defined mouse
models to elucidate the relative contributions to the ACM disease phenotype of activation of an immune
response in cardiac myocytes vs. the actions of infiltrating inflammatory cells. In Aim 2, we will characterize
effects of exercise on inflammation in ACM and define new mechanisms by which exercise promotes
myocardial injury and arrhythmias. And in Aim 3, we will test the efficacy of selected FDA-approved drugs to
prevent clinically important features of the ACM disease phenotype and mitigate the dangerous effects of
exercise. We will also characterize expression of miRNAs that regulate NFκB and GSK3β signaling to identify
RNA-based strategies to turn off inflammatory signaling. Such preclinical testing, we hope, will provide a
pathway to future clinical trials in patients with ACM.

## Key facts

- **NIH application ID:** 10132387
- **Project number:** 5R01HL148348-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** JEFFREY E SAFFITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $503,423
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132387

## Citation

> US National Institutes of Health, RePORTER application 10132387, Arrhythmogenic Cardiomyopathy is an Inflammatory Disease (5R01HL148348-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132387. Licensed CC0.

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