B-AB01-02 EPICARDIAL ADIPOSITY MEDIATED LOCAL INFLAMMATION PROMOTES ARRHYTHMOGENESIS IN OBESE DONOR HEARTS

Abstract

Epicardial adiposity has emerged as an independent risk factor for VT/VF. However, the molecular mechanisms by which the accumulation of epicardial fat contributes to VT/VF development remains unelucidated. We hypothesized that epicardial adipose tissue (EAT) paracrine signaling promotes local inflammation mediated arrhythmogenesis in obese human hearts. To test our hypothesis, we characterized transcriptome profile of the EAT and the underlying myocardial tissue in normal, overweight, and obese hearts as well as their susceptibility to arrhythmias. Tissue samples from the right ventricle (RV) EAT as well as the underlying myocardium were collected from donor hearts (N=9) and processed for RNA sequencing as well as western blotting studies. Arrhythmia susceptibility was investigated in the same hearts using optical mapping studies on RV wedge preparations. Briefly, the tissue was paced using a dynamic restitution protocol (S1S1) after intervention with isoproterenol (100nM). Optical action potentials (OAPs) and electrograms (EGMs) were recorded to track EADs, DADs, and the premature ventricular complexes (PVCs). The pro-inflammatory markers (IL-6, IL-1β, TLR-2, NLRP-3) were upregulated in EAT of obese hearts when compared with EAT in normal hearts. Additionally, the fibrotic markers (TGFβ, MMP2) were also upregulated in myocardial tissue from obese hearts in comparison with normal hearts. Tissue wedge preparations from obese hearts (2.45±1.4) registered higher incidence of PVCs per min when compared with normal (0.6±0.3) and overweight (0.96±0.2) hearts in presence of β-adrenergic stimulation. Moreover, CaMKII protein expression was higher in obese hearts (1.57±0.46) compared to normal hearts (0.89±0.29) (p<0.05). Our results suggest that EAT paracrine signaling promotes arrhythmias in obese hearts via local inflammation mediated functional and structural remodeling of the underlying cardiac tissue.