The role of endothelial dysfunction in atrial fibrillation

Project: Research project

Project Details

Description

Atrial fibrillation (AF) is the most common sustained arrhythmia. It is associated with significant morbidity and mortality, being a leading cause of stroke. As age is a major risk factor for AF, this arrhythmia is becoming an epidemic, with significant socioeconomic burden. Unfortunately, current therapies for AF are suboptimal: pharmacologic therapies and catheter ablation have <50% efficacy, particularly in persistent AF. A better understanding of the molecular mechanisms of AF will be crucial for the development of new therapies. AF is a multifactorial disease, with chronic insults leading to progressive changes in the myocardium with electrical, structural and autonomic remodeling. Endothelial dysfunction is a hallmark of most risk factors for AF including heart failure, hypertension and diabetes. While multiple studies showed an association between endothelial dysfunction and AF, the causal relationship remains unknown. We propose to investigate the role of endothelial dysfunction in atrial fibrillation using clinically relevant large animal models of AF, and harnessing novel gene therapy tools with high translational potential. In Aim 1, we propose to first characterize the temporal and spatial relationship between endothelial dysfunction and AF, with a particular focus on the transition from paroxysmal to persistent AF. In addition, this work will aim to determine the mechanisms by which Endothelin-1, a major effector of endothelial dysfunction, creates an AF substrate by promoting autonomic, electrical and structural atrial remodeling. Aim 2 will focus on the role of Endothelin-1 in autonomic remodeling in AF, evaluating the mechanisms by which it promotes increased autonomic nerve firing and nerve growth. Aim 3 will be centered on the molecular mechanisms by which Endothelin-1 promotes both arrhythmogenic calcium signaling and fibrosis in the context of heart failure. In summary, this proposal will expand our knowledge on the mechanisms leading to atrial remodeling and AF, with a significant translational potential.
StatusActive
Effective start/end date4/1/223/31/25

Funding

  • American Heart Association (AHA Award Number: 941300)

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