Assessment of the atrial adenosinergic system in the onset of atrial fibrillation: A pre-clinical study in a mouse model with genetic susceptibility to atrial fibrillation

Abstract

Atrial fibrillation (AF) is a multifactorial sustained cardiac arrhythmia with genetic predisposition. Genome-wide association studies (GWAS) have identified loci near key cardiac transcription factors encoding genes (TBX5, GATA4, NKX2.5) associated with AF risk. Consistently, adult-specific Tbx5 knockout mice showed primary spontaneous and sustained AF, induced by calcium handling abnormalities. The adenosinergic system may be implicated in the onset of AF. We previously showed that adenosine plasma levels increase in persistent AF, and atrial adenosine receptor overexpression is associated with reentry mechanisms. While calcium signaling proteins and potassium channels are major effectors of the adenosinergic system, and also triggers of AF, the link between TBX5, AF and the adenosinergic system has not yet been studied. To assess how the intra-atrial adenosinergic system is associated with a higher susceptibility to atrial fibrillation in a mouse model. Transgenic Cx40-CreERT2::Tbx5 floxed/floxed mice allow conditional deletion of Tbx5 in atria and the ventricular conduction system. Cre-mediated recombination was induced by intraperitoneal injection of tamoxifen in control (Cx40-CreERT2::Tbx5++) and mutant newborn mice. AF was investigated by surface ECGs between 2 weeks and 3 months. The adenosinergic system was assessed by adenosine plasma measurement, in vivo pharmacological tests, immunofluorescence and western blot analyses. At 2 weeks, prolonged P wave and PR interval durations ( P < 0.001; P = 0.03, respectively) and reduced P wave amplitude ( P = 0.01) were measured in transgenic mice ( n = 9) compared to controls ( n = 8). AF episodes were more frequently observed in conditional mutant mice (33% vs. 0%; P = 0.21). Tbx5 deletion specifically in atria increases susceptibility for atrial fibrillation confirming our model as a good one to study the role of the adenosinergic system in AF.