Abstract Body (Do not enter title and authors here): Background: Sudden cardiac death (SCD) is a major complication of diet-induced obesity. Whether early metabolic stress from nutrient overload per se, prior to overt obesity or related remodeling, can independently promote arrhythmias remains unclear. Fatty acids can allosterically stimulate AMP-activated protein kinase (AMPK), a key metabolic sensor that preserves myocardial function following ischemia-reperfusion (I/R). We hypothesized that AMPK signaling modulates the electrophysiological (EP) response to high-fat diet (HFD)-induced metabolic stress.
Methods: Wild-type (WT) and AMPK kinase-dead (AMPK-KD) mice were placed on HFD for 8 weeks beginning at 4 weeks of age; controls remained on a normal diet (ND). This regimen led to minimal weight gain (<5g), no plasma lipid changes and preserved LV function. Arrhythmia susceptibility was assessed ex vivo using rapid pacing and I/R challenge. EP properties were evaluated via high resolution optical mapping; mechanisms were examined by western blotting, confocal, and electron microscopy.
Results: HFD-fed WT hearts showed no increase in arrhythmia risk (ND WT: 0/7; HFD WT: 1/9; p>0.99) and exhibited improved post-ischemic conduction recovery (CV recovery >90%: ND WT 1/6 vs HFD WT 5/5; p=0.015), with increased phosphorylation of AMPK targets (ACC, raptor). In contrast, AMPK-KD hearts were arrhythmia-prone regardless of diet (ND KD: 4/9; HFD KD: 5/8), due to slowed (~30%, p<0.001) and aberrant conduction. These abnormalities, arising in structurally normal hearts, occurred despite Cx43 and Nav1.5 upregulation and were linked to impaired ULK1 phosphorylation and autophagic turnover, leading to unphosphorylated Cx43 accumulation at intercalated discs. AMPK-KD hearts also exhibited mitochondrial fragmentation, reduced fusion proteins, and elevated ROS under HFD, which accelerated repolarization (APD75: ND KD 46.7 ms vs HFD KD 33.8 ms; p<0.001) and promoted sustained VT (VT duration: ND KD 5.6 min vs HFD KD 18.7 min; p=0.011).
Conclusions: AMPK preserves EP stability during early nutrient stress by coordinating redox balance, mitochondrial integrity, and conduction-related protein homeostasis. Its loss in aging and advanced metabolic disease may be a key link between HFD and increased SCD risk.