Abstract 363: Dantrolene Decreases Susceptibility to Refibrillations by Restoring Vf Dependent Cardiac Calcium Handling Dysfunction

Abstract

Background: Ventricular refibrillation frequently occurs after successful defibrillation of Ventricular Fibrillation (VF) and negatively affects outcomes. Diastolic elevation in cytosolic calcium and dysfunction in calcium handling is proposed to underlie post-shock arrhythmias. Ryanodine Receptor 2 (RyR2) is the major calcium handling protein in cardiomyocytes. its dysfunction causes diastolic calcium leak from sarcoplasmic reticulum and calcium transient amplitude alternans (Ca-Alt), which can lead to arrhythmias. We hypothesized Dantrolene protects against refibrillations by restoring cardiac calcium handling and stabilizing RyR2 after VF. Methods and Results: Hearts from 14 healthy New-Zealand rabbits were excised and perfused using Langendorff method; VF(+ISO) was induced by burst pacing and left untreated for 4 min. Hearts received either Dantrolene (20μM) or saline during VF. Upon defibrillation, 4 more VF episodes were attempted. Sustainability (VF≥60 sec) and inducibility of refibrillations (VF≥10 sec) was evaluated. Calcium mapping using RhoD-2 was performed to assess Ca-Alt and diastolic Spontaneous Calcium Elevation (SCaE). Ca-Alt was defined as ≥10% variability in Calcium transient amplitudes. SCaE amplitude was measured during diastolic pause after termination of pacing. In total, 83.33% of attempts to induce refibrillation in controls were successful compared to 41.18% in Dantrolene-treated hearts. (P=0.007) Dantrolene (20μM) significantly decreased SCaE amplitude post VF. (Table 1) Ca-Alt emerged at shorter PCL in Dantrolene-treated hearts with 10% decrease from 195±9.5ms at baseline to 173±6.7ms post-VF compared to 11% increase in controls from 215±20ms to 235±8ms. (P=0.05) Conclusion: Dantrolene ameliorated arrhythmogenic diastolic SCaE caused by VF and increased calcium alternans threshold and may be the basis for the decreased susceptibility of treated hearts to refibrillations.