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

Public Health Relevance

Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence worldwide. HFpEF patients are predisposed to atrial fibrillation (AF), a rhythm disturbance that exacerbates HFpEF and is associated with worse clinical outcomes. We have uncovered evidence of a novel mechanism of HFpEF-associated AF, and we propose here to define and manipulate underlying mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL155765-01
Application #
10097363
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2021-01-01
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390