(P023) TARGETING TUMOR NECROSIS FACTOR (TNF) IN ATRIAL STRETCH-DEPENDENT ADVERSE ATRIAL REMODELING AND VALVULAR ATRIAL FIBRILLATION IN A MOUSE MODEL OF AORTIC REGURGITATION

Background: Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide with its incidence linked to cardiovascular (CV) disease. Most conditions linked to AF are associated with elevated atrial pressures and atrial stretch, which are powerful stimuli for atrial remodeling. We previously established that the proinflammatory and mechanosensitive cytokine, tumor necrosis factor (TNF), is a key mediator of stretch-related atrial remodeling and AF vulnerability. As TNF is critical factor mediating atrial fibrosis, hypertrophy, inflammation, and arrhythmias in heart disease, we hypothesized that targeting stretch-mediated TNF-dependent signaling may offer a novel therapeutic target in valvular AF patients.

METHODS AND RESULTS: We have developed a clinically relevant mouse model of aortic regurgitation (AR), which is characterized by acute and chronic diastolic volume overload and elevated left ventricular end-diastolic (LVEDPs) and atrial pressures. The effects of pharmacological TNF inhibition with Etanercept (Enbrel®, twice-weekly, 2.5 mg/kg) beginning early (2-days post-AR) or later (1-week post-AR) were examined. Cardiac structure and function as well as electrophysiological properties were assessed using echocardiography, telemetry hemodynamics, histology, immunohistochemistry, in vivo intracardiacs, and ex vivo optical mapping in isolated atria.

Results: Four weeks of AR resulted in progressive LV dilatation, functional impairment, and hypertrophy in the absence of ventricular arrhythmias. Moreover, LVEDPs increased acutely and remained elevated with disease progression. In the atria, AR resulted in hypertrophy, fibrosis, and macrophage infiltration as well as decreased conduction velocity, atrial effective refractory periods and action potential durations in wild-type mice. Importantly, AR increased both in vivo and ex vivo AF susceptibility. By contrast, both early and delayed TNF inhibition with Etanercept attenuated AR-induced adverse atrial remodeling and protected against AF inducibility, independent of ventricular changes.

Conclusion: Our results establish that stretch-mediated adverse atrial remodeling and AF vulnerability with AR requires TNF, suggesting TNF may offer an important therapeutic target for the prevention and treatment of valvular AF.