Microvascular/Endothelial Dysfunction and Postoperative Atrial Fibrillation

Summary Postoperative atrial fibrillation (POAF) is the most common complication of cardiac surgery in the world, affecting 30- 50% of patients and incurring significant morbidity and mortality with elevated risk for postoperative stroke, heart failure, and death. Despite extensive research and advancements in antiarrhythmic therapy, the incidence of POAF remains high and has not changed in decades. Growing evidence indicates that endothelial dysfunction is correlated with chronic atrial fibrillation (AF). However, the direct relationship between atrial microvascular/endothelial (dys)function following cardioplegic arrest and cardiopulmonary bypass (CP/CPB) and the development of new onset of POAF is largely undefined. Moreover, the changes that occur in the atrial microvasculature/endothelium following CP/CPB and cardiac surgical procedure in patients with POAF are poorly understood. Thus, the goal of this patient- oriented proposal is to investigate how dysfunction in the cardiovascular physiology of atrial microvasculature and endothelium affects POAF. Importantly, our preliminary studies indicate that enhanced atrial arteriolar vasomotor tone and impaired atrial endothelial function following CP/CPB are associated with the new onset of POAF. Furthermore, atrial microvascular fibrosis in aged patients is significantly corelated with POAF. Therefore, we hypothesize that atrial microvascular/endothelial dysfunction and altered vascular/endothelial signaling at baseline (pre-CP/CPB) and pos-CP/CPB contribute to the development of POAF. In Aim 1, we will evaluate microvascular signaling pathways responsible for myogenic/vasomotor/endothelial dysfunction of the atrial microvasculature in patients with POAF; In Aim 2, we will investigate cellular/molecular alterations of atrial endocardial endothelial dysfunction in patients with POAF; In Aim 3, we will analyze the differential genomic expression in vascular smooth muscle cells/pericytes, endothelial cells, and fibroblasts in the harvested atrial tissue samples pre- and post-CP/CPB from patients with and without POAF. We will further analyze the impact of age, sex, diabetes, and hypertension on atrial microvascular/endothelial dysfunction correlated to POAF. To achieve these goals, we will recruit a cohort of 500 cases with and without POAF, along with human atrial tissue samples of both pre- and post-CP/CPB, atrial arterioles, atrial cardiomyocytes, and endothelial cells from patients with or without POAF. We will employ multiple cutting-edge approaches, including a human CP/CPB model, microvascular physiology, cardiovascular electrophysiology, and novel cellular/molecular approaches. This proposal will develop a novel concept that microvascular/endothelial dysfunction/signaling of atrial microcirculation play important roles in POAF; bring new insights into endocardial endothelial dysfunction related to POAF by exploring novel cellular/molecular changes of the endocardial endothelium related to POAF; and identify novel genetic mechanisms of atrial microvascular/endothelial dysfunction related to POAF. By doing so, this proposed research will provide the basis for the development of new approaches to decrease the incidence of POAF in patients undergoing cardiac surgery.