# Molecular Mechanisms of HFpEF-associated Atrial Fibrillation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $410,000

## Abstract

PROJECT SUMMARY
 It is said that heart failure with preserved ejection fraction (HFpEF) is the single greatest unmet need in
cardiovascular medicine. Patients with HFpEF are uniquely predisposed to atrial fibrillation (AF), a common
rhythm disturbance that is associated with worse clinical outcomes. In other words, AF and HFpEF co-segregate,
substantially exacerbate one another, and represent a prevalent and unique clinical challenge without effective
therapies.
 Metabolic diseases, such as obesity, diabetes, and hypertension, are common comorbidities for both HFpEF
and AF, suggesting that metabolic disturbance serves as a common mechanism underlying both conditions.
 We recently developed and validated a uniquely informative murine model of HFpEF and unveiled
mechanisms never reported previously in heart disease. These animals are predisposed to AF, just as are
patients with HFpEF. Further, we have collected preliminary data revealing that AMPK signaling is impaired in
the atria of these mice and is associated with atrial remodeling similar to changes observed in HFpEF patients.
If confirmed, this is a novel mechanism of disease-triggered AF, one that does not involve tissue fibrosis, etc.
 Here, we propose to test the central hypothesis that impaired AMPK signaling contributes to pathological
atrial remodeling in HFpEF, and modulating this pathway will attenuate atrial pathology and AF predisposition in
HFpEF.
 Specifically, we will delineate the role of AMPK in HFpEF-associated atrial structural and electrical remodeling,
focusing on atrial myocyte hypertrophy, Cx40-mediated atrial myocyte communication, and HCN4-mediated
ectopic automaticity. In a translational aim, we will determine the effect of AMPK activation on attenuating atrial
remodeling and AF predisposition

## Key facts

- **NIH application ID:** 10322371
- **Project number:** 5R01HL155765-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** THOMAS G GILLETTE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322371

## Citation

> US National Institutes of Health, RePORTER application 10322371, Molecular Mechanisms of HFpEF-associated Atrial Fibrillation (5R01HL155765-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322371. Licensed CC0.

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