Abstract Fri094: Increased Ventricular Arrhythmia Burden and Prolong QTc with Preserved Conduction Velocity Hallmark Electrical Heart Disease and Increased Risk of Sudden Death in Melanocortin Type 4 Receptor Knockout Mice

Background: Obesity (OB) is an independent risk factor for arrhythmias and sudden death (SD) which accounts for ~50% of deaths in OB population, predominantly affecting men (75%). Yet, the mechanisms involved remain poorly defined. We hypothesized that OB creates a proarrhythmogenic substrate that increases the risk to develop malignant ventricular arrhythmias leading to SD. Aim: To characterize the electrical ventricular phenotype in severely obese melanocortin type 4 receptor knockout (MC4R KO) male mice. Methods: In-vivo ECGs were obtained from anesthetized MC4R KO and c57bl/6 lean (WT) adult male mice. Ventricular conduction velocity (CVv) was measured by optically mapping Langendorff perfused hearts (Di-4-ANEPPS) with simultaneous ECGs recording. Spontaneous and triggered arrhythmias were quantified using a ventricular arrhythmia severity score (VASs) ranging from zero (no arrhythmia) to five (Torsade de point, TdP). QT intervals were quantified from ECGs and corrected applying Mitchell’s formula (QTc). Experiments were done at 37°C with blebbistatin to prevent contraction. Data is reported as mean±SEM. Unpaired T-test was used. Results: Averaged weights: MC4R KO: 59±1.2 g (N=8), WT: 30±1.3 g (N=7). At 60 weeks of age MC4R KO survival rate was 55% vs 100% in WT (N=40/group). ECGs from MC4R KO showed a prolonged QTc compared to WT (44.7±0.9 [N=8] vs 28.6±1.7 ms [N=7]; p<0.01). On average, QTc in MC4R KO was lengthened by 36% respect to WT (p<0.01). While 50% of MC4R KO showed an increased incidence of complex arrhythmias including fragmented QRS (f-QRS ≥3 peaks), alternans (f-QRS/QRS), ventricular tachycardia and fibrillation, and TdP (total arrhythmia burden increased), WT only exhibited isolated PVCs and 2 peaks f-QRS. On average, MC4R KO hearts spend 15.4% of total experimental time (N=6) in arrhythmia vs 0.1% in WT (N5) (p<0.03). Both cumulative (C) and average (A) VASs were increased in MC4R KO compared to WT (C: 25 vs 2; A: 8.3 vs 1; p<0.02). Although we did not find differences in transversal (T) and longitudinal (L) CV between MC4R KO and WT (CVT: 35.2±4.5 vs 36.9±1.4 cm/s; CVL: 59.7±7.5 vs 72.4±4.8 cm/s; N=6, 5), dispersion increased by 3.7 (CVT) and 1.7 (CVL) folds respectively in MC4R KO, suggesting a rise in CVv heterogeneity. Conclusion: Obese MC4R KO mice exhibit increased arrhythmia burden with prolonged QTc and unchanged CVv, suggesting that a delayed ventricular repolarization plays a key role in increasing the risk of SD in these mice.