# Metabolic signaling in atrial fibrillation and remodeling

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $552,114

## Abstract

Project Summary
Atrial fibrillation (AF) is a major public health problem and current therapies for its prevention are limited.
Metabolic stress is a hallmark of common conditions that predispose to AF, including aging, diabetes and
heart failure with preserved ejection fraction. Yet the origins of metabolic stress and its mechanistic link to
pathological atrial remodeling remain unknown. Our central hypothesis is that signaling via the master
metabolic regulator AMPK is a key hub in the control of atrial structural and electrophysiological (EP)
properties, and that AMPK pathway inactivation, as occurs in metabolic diseases, is a unifying mechanism for
both the triggers and substrate that promote the onset and perpetuation of AF. This application will leverage
our extensive experience in studying AMPK-regulated cardiac metabolism and metabolic signaling in the
ventricle and arrhythmia mechanisms, to elucidate novel upstream mechanisms that drive adverse atrial
remodeling and AF. Specifically, we will investigate the hypothesis that AMPK pathway inactivation causes
metabolic stress induced AF. Based on recent experimental and clinical studies, together with our new
preliminary data, we hypothesize that AMPK modulates atrial electrophysiology via direct target
phosphorylation and transcriptional regulation as well as via indirect mechanisms involving AMPK mediated
metabolic/oxidative stress in the atria. We will systematically and rigorously uncover these mechanisms using
a combination of innovative genetic models, cellular and molecular biological tools and small molecule
pharmacological AMPK activators. Our experimental design integrates advanced electrophysiological studies
with state-of–the-art cardiac imaging of structure and function, using high-resolution optical action potential
mapping and gated cardiac micro-CT imaging, to comprehensively assess the physiological and structural
remodeling of the atria both in vivo and ex vivo. Aim 1 will uncover mechanisms by which AMPK pathway
inactivation promotes early atrial ectopy and the onset of AF. Aim 2 will elucidate mechanisms by which loss
of AMPK signaling promotes disease progression forming the substrate for persistent AF. Aim 3 will
determine whether AMPK activator therapy prevents and/or reverses pathological atrial remodeling and AF
propensity without provoking ventricular pro-arrhythmia. The over-arching goal of this application is to
advance our understanding of the interface between metabolic signaling, atrial electrical and structural
remodeling, and arrhythmogenesis, in order to ultimately develop innovative therapeutic approaches for AF.
Thus, the results of the proposed experiments are expected to elucidate the fundamental atrial mechanisms
that underlie the pathogenesis of AF, and to provide the foundation for future pre-clinical and clinical studies to
test the role of AMPK activators in both the prevention and treatment of AF.

## Key facts

- **NIH application ID:** 10593102
- **Project number:** 5R01HL148008-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** FADI GABRIEL AKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $552,114
- **Award type:** 5
- **Project period:** 2021-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593102

## Citation

> US National Institutes of Health, RePORTER application 10593102, Metabolic signaling in atrial fibrillation and remodeling (5R01HL148008-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10593102. Licensed CC0.

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