# Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $397,584

## Abstract

PROJECT 2 SUMMARY
Atrial fibrillation (AF) risk is increased by a variety of cardiovascular stressors, including obesity, hypertension,
coronary or valve disease, heart failure, metabolic syndrome, sleep apnea, excessive alcohol, and extreme
exertion. AF is a progressive condition, and risk of stroke and other complications increases with increasing AF
burden. Identification of drugs or interventions that can slow or reverse the progression of AF would have a
significant clinical impact. In RNA sequencing studies, we have identified mitochondrial dysfunction and
oxidative phosphorylation pathways among the most prominent pathways associated with development of
persistent AF. In Project 2, Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation
(P2), our central hypothesis is that metabolic stressors and aging increase mitochondrial oxidant production,
promoting atrial mitochondrial DNA damage, dysfunction and metabolic heterogeneity. We hypothesize that
metabolic heterogeneity underlies electrical instability, and that interventions that promote mitochondrial
resilience and limit metabolic heterogeneity will reduce atrial ectopy and slow AF progression. We propose two
specific aims. Aim 1 seeks to evaluate the role of metabolic stressors on an in vitro model of engineered heart
tissues (EHTs), derived from atrial-like cardiac myocytes differentiated from human induced pluripotent stem
cells. We will study the transcriptional and functional impact of 4 distinct metabolic stressors relevant to the
etiology of AF on EHT cellular composition and mitochondrial, contractile and electrical function of human atrial
EHTs. Stressors include: chronic exposure to isoproterenol, palmitate, ethanol and endothelin-1; the same
stressors will be used to test the protective effect of metabolic/mitochondrial targeted drugs in EHTs. In Aim 2,
we will evaluate the metabolic mechanisms that underlie progression of AF in the heterozygous CREM-IbCX
transgenic mouse model of spontaneous AF and AF progression, employing a high fat diet as a metabolic
stress with which we can study the functional and transcriptomic impact of obesity on the development and
rate of progression of AF. We hypothesize that progression of AF in this model is also caused by mitochondrial
dysfunction, resulting in metabolic, transcriptional and electrophysiologic dysfunction. We thus propose that
obese mice will develop AF more quickly, earlier, and with a greater burden than in lean transgenic mice.
Finally, using obese transgenic mice, we will evaluate the impact of drugs that protected EHTs from
mitochondrial dysfunction and downstream effects, to determine if these drugs can slow the development and
progression of AF. We expect both the atrial EHT and obese CREM-IbCX mouse models will be useful for
preclinical testing of new and existing metabolic drugs that can improve AF treatment and slow its progression.
This project is highly collaborative with the other PPG pro...

## Key facts

- **NIH application ID:** 10410649
- **Project number:** 1P01HL158502-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** David R Van Wagoner
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,584
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410649

## Citation

> US National Institutes of Health, RePORTER application 10410649, Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation (1P01HL158502-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10410649. Licensed CC0.

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