Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling.

Abstract

Although impaired AMPK signaling is a hallmark of metabolic diseases (MetD), which heighten arrhythmia risk, whether and how loss of AMPK activity per se promotes adverse electrophysiological (EP) remodeling independently of confounding factors in MetD remains unknown. We investigated the EP substrate of wildtype (WT) mice on high-fat diet (HFD) relative to those on normal diet (ND) and to mice expressing the muscle-specific AMPK kinase dead isoform (AMPK-KD). After 8-weeks of HFD, mice underwent hemodynamic analysis by echocardiography and ex vivo optical action potential (AP) mapping. While HFD-fed mice did not exhibit structural or hemodynamic changes by 8-weeks, they were more prone to pacing-induced VT than their ND counterparts (57% HFD vs 11% ND). Investigation of the EP substrate revealed a marked decrease in conduction velocity (CV) in HFD vs ND-fed mice (54.9±6.7 cm/s vs 71.6±10.2 cm/s, p<0.05) with no change in AP duration (APD). Importantly, we found similar CV slowing in AMPK-KD on ND as WT on HFD. Challenging AMPK-KD mice with HFD did not reduce CV further (45.4±10.6 cm/s HFD vs 49.0±11.1 cm/s ND). In contrast, APD was decreased exclusively in AMPK-KD mice on HFD, reflecting the importance of both factors (AMPK depletion and HFD) in the modulation of myocardial repolarization. Functionally, the subset of hearts that were prone to HFD-related VT exhibited decreased CV compared to those that were protected against VT. We examined the molecular correlates of myocardial conduction, and found a paradoxical increase in Nav1.5, total and Ser368-phosphorylated Cx43 in AMPK-KD, discounting overall protein expression as a factor in CV slowing. In conclusion, impaired AMPK signaling accounts for early CV defects in HFD prior to onset of structural or mechanical remodeling. Our findings highlight AMPK as a potentially powerful anti-arrhythmic target at early stages of MetD.