Talk abstracts
Talk on Friday 01:45-02:05pm submitted by Revati Dewal
Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity
Revati S. Dewal (MCDB), Amara Greer-Short, Cemantha Lane, Shinsuke Nirengi, Pedro Acosta Manzano, Diego Hernndez-Saavedra, Katherine Wright, Drew Nassal, Lisa A. Baer, Peter J. Mohler, Thomas J. Hund, Kristin I. Stanford (OSU Wexner Medical Center)
Abstract:
Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity 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.
Here, we tested a possible role for CaMKII-dependent INa,L in obesity-induced AF. The effects of diet-induced obesity on AF were investigated using wild-type (WT) and whole-body knock-in mice that ablate phosphorylation of the Nav1.5 sodium channel and prevent augmentation of the late sodium current (S571A; SA mice). 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 a reduction in food consumption compared to WT mice. When food consumption was controlled by pair feeding, both reduced weight gain and partial rescue of AF susceptibility were observed in WT mice, while only SA mice showed improved metabolic capacity. This indicates that improved metabolic health in HFD-fed SA mice is independent of body weight. Overall, 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.
Keywords: Obesity, Atrial Fibrillation, pathogenic late sodium current