Abstract 14447: Increased Autophagy Flux May Underline Cardiomyocyte Remodeling in Atrial Fibrillation

Abstract

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling that impairs electrical activation of the atria. Studies have shown that mitochondrial dysfunction underlies cardiomyocyte remodeling. Here, we report a 50% reduction in total mitochondrial DNA in the atria tissue of RAP dogs as compared to control dogs, as assessed by qPCR the levels of mitochondrial DNA including mt-NT-1, mt-NT-4, mt-NT 5, mt-NT 6. This reduction in mitochondrial DNA suggests reduced mitochondria number in RAP dogs. Autophagic flux (LC3 II protein levels) was markedly increased in the atria tissue of the AF dog model (vs control dog).Furthermore, we examined autophagy flux in isolated cardiomyocytes. Results showed that LC3II was remarkably activated when subject to electrical stimulation for 6 hours under 3 Hertz condition, suggesting the direct effect of electrical stimulation on increasing autophagy. There was no change in the mRNA levels of autophagosome genes including Belin 1, ATG8, LC3, Lamp1 in the RAP dog tissue as compared to control, however, ATG7 increased by 2 fold and GNG2 increased by 5 fold. In conclusion, our study suggests that electrical stimulation-induced autophagy, and reduced mitochondria number and function, may underlie cardiomyocyte remodeling in AF. Targeting the autophagy pathway may present new therapeutic targets for AF. Ongoing AAV-mediated knockdown experiments in isolated cardiomyocytes will further elucidate the mechanism of electrical stimulation-induced autophagy.