Role of Endothelin-1 signaling in the development and progression of atrial fibrillation

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SUMMARY 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. Dr Pfenniger proposes to investigate the role of endothelial dysfunction, and specifically of its major effector Endothelin-1, in AF using two clinically relevant large animal models of AF, and harnessing novel gene therapy tools with high translational potential. This proposal aims 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 creates an AF substrate by promoting autonomic, electrical and structural atrial remodeling. The objective of this proposal aligns closely with NHLBI's identified strategic vision to investigate newly discovered pathobiological mechanisms important to the onset and progression of heart, lung, blood, and sleep (HLBS) health. This Career Development Award will support Dr. Pfenniger's transition to an independent physician-scientist. Dr. Pfenniger is currently an Assistant Professor at Northwestern University, with the support of a KL2 Mentored Career Development Award and an AHA Career Development Award. Dr. Pfenniger will carry out this work at the Feinberg Cardiovascular and Renal Research Institute at Northwestern University under the primary mentorship of Dr. Rishi Arora. As a physician-scientist in electrophysiology, Dr. Pfenniger will uniquely benefit from the support of her mentoring team led by Dr. Arora, an internationally recognized physician-scientist with specialization in basic, translational and clinical electrophysiology, who possesses expertise in large animal models of AF. The combination of mentors with distinct expertise – EC coupling (Dr. Wasserstrom), high-throughput cellular electrophysiology (Dr. George), vascular biology (Dr. Vaughan), translational AF research (Dr. Passman), advanced cardiovascular imaging (Drs. Lee and Shah), and cardiovascular genetics (Dr. Roy-Puckelwartz) will allow Dr. Pfenniger to build on her current skills and help her carve out her own niche in the field of heart rhythm disorders. Near the end of the award period, Dr. Pfenniger will apply for a NIH R01 award, using the results of this proposal to develop an independent research program to further study the role of endothelial dysfunction in AF.