Abstract 258: Elucidating Sex Differences in Stress-related Atrial Remodeling and AF Risk in a Mouse Model of Atrial Dysfunction

Abstract

Atrial fibrillation (AF) is the most common arrhythmia and a major risk factor for cardiovascular mortality and stroke. Despite significant advances in AF diagnosis and management, major gender discrepancies in treatment and clinical outcomes remain. It is unclear if these are related to treatment disparities or to underlying differences in the structure and biochemical makeup of the female versus male heart. How lifestyle, diet, comorbidities and risk factors contribute to this clinical dimorphism are not well understood. My laboratory has recently developed a double-transgenic mouse line that recapitulates this gender dimorphism. These mice were generated by crossing lines with cardiac expression of an amino and carboxyl terminal fragment, βARKnt (residues 50-145) and βARKct (residues 495-689), of the prototypical G protein-coupled receptor (GPCR) kinase GRK2 (originally βARK1). This line was created to investigate the therapeutic potential of dual regulation of β-adrenergic receptor signaling independent of canonical GRK2 activity. Since preliminary data demonstrate atrial dysfunction in both genders, but structural remodeling in females only, this model presents a unique tool to investigate sex differences in the molecular and cellular mechanisms of atrial remodeling. Masson’s trichrome staining of 4-chamber paraffin sections demonstrated an increase in wall thickness in the βARKnt and βARKnt/βARKct mice in agreement with the increased heart weight. Interestingly, these data revealed a significant increase in left and right atrial size in the double transgenic female hearts only, with no apparent alteration in the male atria. Preliminary echo recordings demonstrated significant alterations in E/A ratio (ventricular relaxation/atrial contraction) in the βARKnt and even more pronounced in the βARKnt/βARKct male and female mice. These data suggest that although no remodeling is evident at baseline, the male βARKnt/βARKct mice have underlying atrial dysfunction that may be more susceptible to additional cardiovascular stress. A better understanding of gender differences in the underlying mechanisms of atrial susceptibility may facilitate the development of safer and more effective approaches for AF management and prevention.