Abstract P3016: Role Of AMPK/Sirtuin3 Signaling In HFpEF-associated Atrial Myopathy

Abstract

Background: Patients with heart failure with preserved ejection fraction (HFpEF) are uniquely predisposed to atrial fibrillation (AF), which significantly worsens clinical outcomes. Pathological atrial remodeling, i.e. atrial myopathy, usually precedes clinical AF and is deemed to be an underlying cause of AF. However, little is known about its molecular features, and no effective treatments have been identified. Method: Wild type C57Bl6 mice were fed a high fat diet (HFD) and received L-NAME via drinking water (5-8 weeks). Atrial morphology and function were assessed by echocardiography. AF was induced by transesophageal pacing. Results: We discovered that HFpEF mice manifest prominent sinoatrial node (SAN) dysfunction and are highly susceptible to pacing-induced AF, suggesting that this is an ideal model for studying HFpEF-associated atrial changes. Our findings revealed that atrial hypertrophy, contractile dysfunction, and conduction abnormalities are key features of HFpEF-associated atrial myopathy. Interestingly, we did not observe significant atrial fibrosis in this model, a prominent feature of other AF models. Importantly, we discovered impaired AMPK/Sirt3 signaling in the atria of HFpEF mice, and similar atrial defects were observed in mice with cardiomyocyte-specific loss of sirtuin3 (Sirt3) or AMPK, indicating a critical role of AMPK/Sirt3 signaling in HFpEF-associated atrial myopathy. Lastly, we found that metformin, a widely used clinical AMPK agonist, significantly attenuated AF inducibility and SAN dysfunction in HFpEF mice. Conclusion: Our “two-hit” HFpEF model successfully recapitulates HFpEF-associated atrial phenotypes. Using this model, we unveiled molecular features of a distinct atrial myopathy. We identified a critical role of AMPK/Sirt3 signaling in HFpEF-associated atrial remodeling and demonstrated the therapeutic effect of metformin. As next steps, confirming this benefit in a clinical trial is warranted.