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

Abstract

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 (INa,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 INa,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Nav1.5 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 Nav1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

Sudden Cardiac Death in Diabetes and Obesity: Mechanisms and Therapeutic Strategies

“…25,39 This leads to enhanced sodium entry into the cell, elevation of intracellular sodium concentration and consequently increased calcium influx via the reverse mode of the sodium/calcium-exchanger NCX, promoting calcium-dependent proarrhythmic events. 35 Again, similar electrophysiological changes have been observed in obesity models, 31,42,43 although this has been less extensively investigated as compared to diabetes.…”

Galectin‐3 enhances atrial remodelling and arrhythmogenesis through CD98 signalling

“…The changes in calcium homeostasis in patients with AF or in AF animal models are similar to the changes in calcium dysregulation in Gal‐3‐treated HL‐1 cells; this finding suggests that Gal‐3 takes part in inflammation‐induced AF genesis. As shown in Figure 8, Gal‐3‐mediated Ca 2+ dyshomeostasis might be caused by the activation of CaMKII/RyR2 signalling, resulting in enhanced Nav1.5 and NCX and increased atrial ectopic activity 17,23,24 . Recent results revealed that a Nav1.5‐dependent elevation of sodium influx leads to CaMKII activation, which sequentially phosphorylates Nav1.5 and promotes sodium influx 25 .…”

“…5 atrial ectopic activity. 17,23,24 Recent results revealed that a Nav1.5-dependent elevation of sodium influx leads to CaMKII activation, which sequentially phosphorylates Nav1.5 and promotes sodium influx. 25 The frequency of atrial ectopic beats can predict adverse cardiovascular events and AF occurrence.…”

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

“…The diabetic, hypertrophied and failing heart is prone to atrial and ventricular arrhythmias, which are often related to activation of voltage-gated sodium channels (Na v 1.5 or Na v 1.8), facilitating the late sodium current and leading to sparks due to spontaneous release of calcium. [115][116][117][118] These abnormalities have been attributed to O-GlcNAcylation of Na v 1.5, as they are abolished following inhibition of UDP-GlcNAc. 119 Additionally, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is activated in the hypertrophied and failing heart and phosphorylates ion channels and transcription factors that are critical for hypertrophy, atrial arrhythmogenesis, oxidative stress and proinflammatory signalling.…”