# Obesity-Mediated Atrial Fibrillation: Underlying Mechanisms and Responsiveness to Antiarrhythmic Therapy

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2022 · —

## Abstract

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in Veterans, is associated with
increased risk for stroke, heart failure, and death. The number of Americans affected by AF is
expected to surge to approximately 16 million by the year 2050. Although a causal relationship
between obesity and AF was recently established, the underlying pathophysiological mechanisms and
their impact on response to antiarrhythmic drug (AAD) therapy remain unclear. Emerging evidence
supports reduced cardiac Na+ channel expression as one potential contributing mechanism. Since
Class I AADs, which block the cardiac Na+ channel (Nav1.5), are commonly used to treat AF, the
overarching goal of this proposal is to elucidate the underlying electrophysiologic (EP) and molecular
mechanisms by which obesity increases risk of AF and modulates response to Na+ channel blockers
in diet-induced obese (DIO) mice. Specific Aim 1 will test the hypothesis that obesity-induced AF is
associated with increased oxidative stress in DIO mice and this effect is in part mediated by
modulating the cardiac Na+ channel. We will measure biomarkers of atrial (4-hydroxynonenal, 4-HNE;
nitrated proteins, YNO2) and systemic (F2-isoprostanes, IsoPs) oxidative stress in DIO mice and
compare them with lean controls. This aim builds on our previous work showing that SCN5A loss-of-
function mutations increase AF risk by reducing Nav1.5 expression and current (INa), pilot data
showing that DIO mice are more prone to AF than lean controls and this risk is mediated in part by
downregulation of Nav1.5 and increased oxidative stress. Despite recent advances in catheter-based
therapies, AADs continue to be commonly used to treat symptomatic AF. However, response in an
individual patient is highly variable and membrane-active drugs are associated with serious toxicities.
Thus, a major knowledge gap is predicting which patients with AF are most likely to respond to AADs.
Our pilot data, generated in the JBVA/UIC AF Registry, not only shows that obesity modulates
response to antiarrhythmic therapy but that there is a differential response to Na+ channel versus K+
channel blocker AADs. This raises the hypothesis to be tested in Specific Aim 2 that flecainide (Na+
channel blocker) is inferior to sotalol (K+ channel blocker) in treating AF in DIO mice. Obese mice will
undergo rapid transesophageal atrial pacing to induce AF and then be treated with AADs acutely or
chronically with AF burden as the primary outcome. This aim builds on our clinical and animal data
that shows reduced efficacy of flecainide in treatment of AF in obese patients and DIO mice
respectively. Our studies have shown that obesity-mediated AF is associated with increased oxidative
stress and this is mediated in part by modulation of the cardiac Na+ channel. Specific Aim 3 will
define the underlying molecular mechanisms by which obesity increases risk of AF in DIO mice by: i)
identifying the sources and specific pathways of ROS p...

## Key facts

- **NIH application ID:** 10477286
- **Project number:** 5I01BX004268-04
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Dawood Darbar
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477286

## Citation

> US National Institutes of Health, RePORTER application 10477286, Obesity-Mediated Atrial Fibrillation: Underlying Mechanisms and Responsiveness to Antiarrhythmic Therapy (5I01BX004268-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477286. Licensed CC0.

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