Abstract WP335: Role of Sorbs2 Gene in the Development of Atrial Cardiomyopathy and Atrial Fibrillation in Mice

• Published in: Stroke (1970) 2019-02, Vol.50 (Suppl_1)
• Main Authors: Lu, Tong, Xu, Xiaolei, Lee, Hon-Chi
• Format: Article
• Language: English
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/str.50.suppl_1.WP335

Abstract only Atrial fibrillation (AF) is the most common cardiac arrhythmia and is a major cause of thromboembolic stroke in the United States. The risk of stroke is a 5-fold increase in patients with AF. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a scaffolding protein known to interact with actin and several other cytoskeletal proteins in the intercalated discs and Z band of cardiomyocytes. However, the role of Sorbs2 gene in cardiovascular diseases is largely unknown. Using the loss-of-function of Sorbs2 ( Sorbs2 e8/e8 ) mice, we found that Sorbs2 e8/e8 mice had an abnormal lifespan and die at 4 to 7 months of age. Echocardiogram examine revealed that there was a significant decrease in right ventricle (RV) and left ventricular (LV) ejection fraction (EF), increase in RV end-diastolic volume (EDV) and end-systolic volume (ESV), and progressive chamber enlargement in left atria (LA) and RV, particularly in LA with severe fibrosis and intramural thrombus formation, in Sorbs2 e8/e8 mice after 3 months of age. Surface electrocardiograph also showed a significant conduction delay and spontaneous arrhythmias including those of bifid P wave configuration, right bundle branch block (RBBB), spontaneous AF and non-sustained ventricular tachycardia (VT) in Sorbs2 e8/e8 mice. Intracellular recordings in the freshly isolated LA demonstrated that Sorbs2 e8/e8 myocardium had a delayed action potential activation in response to electrical impulse excitation, reduced amplitude and upstroke velocity (dV/dt) at phase 0, slowed repolarization at phase 1 and phase 2, prolonged atrial effective refractory period (aERP), action potential durations at 50% (APD 50 ) and 90% (APD 90 ) repolarization, and decreased resting potentials. Moreover, the mRNA and protein expressions of voltage-gated Na + channels, L-type Ca 2+ channels, transient outward K + channels and inward rectifier K + channels were significantly downregulated in the LA of Sorbs2 e8/e8 mice, compared wo those of wild type mice. Our results indicate that Sorbs2 gene plays an important role in atrial myocardium architecture and electrophysiology. Sorbs2 dysfunction leads to atrial cardiomyopathy, spontaneous AF and cardiac embolism in mice. Hence, Sorbs2 is a new genetic association with cardioembolic stroke.