Abstract 13985: Targeting the Activin Receptor Type IIA for Therapeutics in Atrial Fibrillation

Abstract

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia and a leading cause of stroke and heart failure. However, limited treatment options are available. The adipo-fibrokine Activin-A has been associated with AF in humans, and genome-wide association studies have implicated the Activin receptor type IIA (ActRIIA) in AF. Hypothesis: Our aim was to investigate the potential functional role of ActRIIA in AF pathophysiology. Methods: We used an Activin-A overexpression murine model (AOE) to determine if Activin-A/ActRII signaling increases AF inducibility and explored potential mechanisms by performing RNA sequencing. Comparative studies between the Activin-A binding receptors, ActRIIA and ActRIIB, were then conducted in vitro using siRNA knockdown (KD) in isolated cardiomyocytes and in vivo using cardiac specific ActRIIA or ActRIIB mouse knockouts (KO) in a high fat diet (HFD)-induced model of AF. Results: AOE mice displayed increased cardiac ActRII signaling, including increased FSTL3 mRNA expression (3.4-fold; p=0.005) and SMAD3 phosphorylation (2.7-fold; p=0.005). AF inducibility was markedly increased in AOE mice (75% versus 0% in controls), and was associated with decreased atrial conduction velocity (RA: 0.46±0.07 vs 0.61±0.09 m/s, p=0.005; LA: 0.54±0.18 vs 0.73±0.14 m/s, p=0.06). Pathway analysis of the cardiac transcriptome in AOE mice identified gap junctions as one of the most downregulated pathways (normalized enrichment score -2.8, FDR<0.001) with 50% decreased expression of the AF-associated connexin, CX43 (p adj =1.2x10 -9 ). Conversely, ActRIIA KD increased CX43 expression in cardiomyocytes (mRNA: 2-fold; p=0.005; protein: 1.8-fold; p=0.07), which was not observed with ActRIIB KD (mRNA: 1-fold; p=0.9; protein: 0.9-fold; p=0.3). ActRIIA KO mice also displayed lower AF inducibility rates (67%) to HFD, compared to ActRIIB KO mice (80%) and controls (αMHCcre 83%, ActRIIA flox/flox 89%, ActRIIB flox/flox 100%). Conclusions: Activin-A/ActRII signaling increases AF inducibility in part by decreasing cardiomyocyte CX43 expression and atrial conduction. This effect is specifically mediated through the ActRIIA, not ActRIIB, suggesting Activin receptor specificity in AF pathophysiology.