EFFECT OF AZUMOLENE ON VENTRICULAR REFIBRLLATION IN LANGENDORFF-PERFUSED RABBIT HEARTS

Abstract

During cardiopulmonary resuscitation, external shock-resistant ventricular fibrillation (VF) and re-fibrillation are common complicating factors. To determine the effects of azumolene, a modulator of ryanodine receptors (RyR), on VF, by studying re-fibrillation vulnerability and calcium transients. Following 15 minutes of global ischemia, normal saline (n=8) or 20μM azumolene (n=8) was infused during reperfusion of Langendorff-perfused rabbit hearts. To induce further stress, we induced long VF (120 seconds) twice in each heart. Those who did not stay in VF for 120 seconds were paced at 50Hz for the same duration. We then tested re-VF inducibility five times in each heart. Left ventricular (LV) epicardial calcium mapping was performed at baseline, after ischemia, after 1st and 2nd VF induction. Calcium dynamics and re-VF inducibility and organization were studied. Azumolene-treated hearts had less successful induction of re-fibrillation episodes compared to controls (32.5% vs. 67.5%, p<0.001). More calcium wavefronts (the surrogate for VF disorganization) were seen in the controls (2.88±0.05 vs. 2.14±0.13 waves per frame, p<0.01; calcium signals appeared more organized visually in azumolene-treated hearts (Panel A). Spontaneous diastolic calcium elevation (SCaE) was significantly increased in controls during post VF compared to baseline (0.117±0.029 vs. 0.052±0.010 AU, p<0.01) and SCaE was abrogated in azumolene-treated hearts (Panel B). RyR modulator, azumolene, reduces re-fibrillation vulnerability and improves calcium dynamics following VF. Dysfunctional RyR is a potential therapeutic target in VF.