Atrial Deletion Of AMPK Promotes Atrial Oxidative Stress And The Formation Of Delayed Afterdepolarizations Within The Interatrial Pulmonary Vein Junction

Atrial specific AMPK deletion leads to spontaneous onset of AF. Electrophysiological mechanisms underlying this heightened propensity remain unknown. We hypothesized that AMPK inactivation forms atrial triggered activity leading to atrial ectopy and AF initiation, in large part, by promoting atrial oxidative stress. Methods: We performed detailed ex vivo atrial optical action potential (AP) mapping on the posterior surface of hearts from mice with atrial deletion of AMPK a1/a2 (AMPK-dKO) (via Cre recombinase driven by sarcolipin) vs littermate controls (Ctrl), both during steady state pacing and following challenge with right atrial stimulus trains designed to promote calcium overload. Mitochondrial (mito) ultrastructure and markers of atrial oxidative stress were measured. To assess the functional impact of atrial oxidative stress, AMPK-dKO mice underwent chronic in vivo treatment with EUK-134 (EUK, 25mg/Kg SQ, 3X/wk) for 16 wks. Results: AMPK-dKO (7/11) but not Ctrl (0/5) hearts exhibited subthreshold delayed afterdepolarizations (DAD) that were consistently localized within a discrete inter-atrial region corresponding with the pulmonary veins (PV) junction. These triggers coincided with atrial oxidative stress indexed by a significant (p<0.05) decrease in GSH/GSSG, PRDX3, SOD2, and increase in nitrotyrosine expression along with atrial mito swelling, decreased count and loss of cristae density. Chronic EUK treatment of AMPK-dKO suppressed the incidence (83% to 40%) and frequency (1.81±0.98/s to 0.083±0.08/s) of PV triggers abrogating the genesis of post-pacing atrial AP ectopy originating from the PV (4/5 vs 0/5). Serial in vivo ECG recordings in a subset of AMPK-dKO mice showed reorganization of the RR vs RR+1 relationship following 16 wks of EUK treatment consistent with decreased incidence of premature atrial complexes. Expression of total and S368 phosphorylated Cx43 were both reduced in the atria of AMPK-dKO mice vs Ctrl and restored by EUK reflecting reversal of pathological molecular remodeling by in vivo ROS scavenging. Conclusions: AMPK deletion promotes formation of left atrial ectopy from DAD sources within the PV region. AMPK plays a central role in the prevention of atrial oxidative stress and associated arrhythmias.