Abstract 15442: Pharmacological and Atrial Cardiomyocyte-Specific Inhibition of Tumor Necrosis Factor (TNF) Protects Against Adverse Atrial Remodeling and Valvular Atrial Fibrillation an a Mouse Model of Aortic Regurgitation

• Published in: Circulation (New York, N.Y.) Vol. 146; no. Suppl_1
• Main Authors: Lakin, Robert, Liu, Xueyan, CHEN, WENLIANG, DEBI, RYAN, Yakobov, Simona, Polidovitch, Nazari, Backx, Peter
• Format: Journal Article
• Language: English
• Published: 08.11.2022
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.15442

Abstract only Introduction: Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide. Most conditions linked to AF, such as cardiovascular (CVD) and valvular disease, are linked to elevated atrial pressures and atrial cardiomyocyte (CM) stretch, which are powerful stimuli for atrial remodeling. We have shown that the proinflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) is a key mediator of stretch-related atrial remodeling and AF. Hypothesis: As TNF is a critical factor mediating fibrosis, hypertrophy, inflammation, and arrhythmias in CVD, we hypothesized that targeting TNF-dependent signaling may offer a novel therapeutic target in AF patients. Methods: We created an aortic regurgitation (AR) mouse model of volume overload characterized by elevated left ventricular end diastolic (LVEDPs) and atrial pressures. To examine TNF-dependent AF pathogenesis in AR, the impact of Tnf excision in atrial CMs (Cre-recombinase expression controlled by an Nppa promoter) and pharmacological TNF inhibition with Etanercept (twice-weekly, 2.5 mg/kg) beginning 2-days (early) or 1-week (delayed) post-AR in CD1 mice were examined. Cardiac structural, functional, and electrophysiological properties were assessed using echo, pressure telemetry, immunohistochemistry, in vivo intracardiacs, and ex vivo optical mapping of AF. Results: Four weeks of AR resulted in chronically elevated LVEDPs and progressive LV dilatation, functional impairment, and hypertrophy in the absence of ventricular arrhythmias with or without TNF inhibition compared to SHAM mice. In atria, AR resulted in both in vivo (8/11, 73%) and ex vivo (5/8, 63%) AF inducibility, which was associated with hypertrophy, fibrosis, and macrophage infiltration (F4/80 + ) as well as decreased conduction velocity and atrial effective refractory periods. Importantly, atrial CM-specific Tnf excision (n=10) and both early (n=8) and delayed (n=6) pharmacological TNF inhibition attenuated AR-induced adverse atrial remodeling and protected against AF inducibility. Conclusions: AF pathogenesis and vulnerability with AR requires TNF, suggesting TNF is an important therapeutic target for the prevention and treatment of AF linked to elevated atrial pressures.