Introduction: Alterations in metabolic signaling may impact atrial remodeling and predispose to atrial fibrillation (AF). AMPK activation is altered in human AF, and global cardiac deletion of AMPK leads to heart failure and AF. To avoid confounding ventricular dysfunction with global cardiac deletion, we developed a novel atrial-specific model of AMPK deletion to study its autonomous role in atrial homeostasis.
Results: Atrial AMPK α1/α2 subunits knockout (aKO, n=12) vs. control (CON, n=9) mice had P-wave prolongation (16.6±0.5 vs. 7.7±0.6 ms, p<0.001), with frequent atrial ectopy at 1 week of age with later spontaneous AF. Echocardiograms showed similar left atrial (LA) sizes at 4 weeks (3.33±0.32 vs. 3.28±0.52 mm2, n=7/group), and there was no histologic evidence of fibrosis or differences in hydroxyproline content (1.05±0.06 vs. 0.92±0.17 μg/mg of atrial mass, n=5/group) at the time of AF onset. Determinants of intra-atrial conduction (ion channel and gap junction protein transcripts) were altered in both RA and LA. In aKO mice, SCN5A (voltage-gated sodium channel 1.5) showed a 70% reduction in RA and LA (p<0.001), while GJA5 (connexin-40) displayed a 50% decrease in LA (p<0.001). Further, HCN4, gene encoding funny current channels, was increased by twofold in LA (p<0.05). In aKO LA, the transcription factor responsible for left-right atrial asymmetry, PITX2C, was reduced by 60% (p<0.001) while myocyte-specific MEF2C was reduced by 40% compared to CON (p<0.05). In vitro siRNA double knockdown of α1/α2 AMPK subunits in primary LA myocytes resulted in a 42% decrease in PITX2C (p<0.05), a twofold increase in HCN4 (p<0.05) vs. scrambled siRNAs. siRNA knockdown of MEF2C in LA myocytes led to 52% reduction in GJA5 (p<0.01).
Conclusions: Selective atrial deletion of AMPK leads to spontaneous atrial fibrillation in the absence of heart failure or atrial fibrosis. AMPK regulates Pitx2c and Mef2c in the LA and their downstream targets HCN4 and GJA5, with induction of atrial ectopy and conduction abnormalities. These results provide a direct link between AMPK and atrial molecular remodeling that modulates arrhythmogenesis.