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Background  Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current ( I  Na,L ) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility.    Methods  Here, we investigated a possible role for CaMKII-dependent  I  Na,L  in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Na v 1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice).    Results  A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity.    Conclusions  These data demonstrate a novel role for CaMKII-dependent regulation of Na v 1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

international journal of obesity

Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity