Synchronizing systolic calcium release with azumolene in an experimental model

BACKGROUND: Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca(2+)) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). OBJECTIVE: In the present study, we explored the effects of RyR2 stabilization by azumolene on systolic Ca(2+) release synchrony and myocardial contractility. METHODS: After completion of baseline optical mapping, Langendorff-perfused rabbit hearts were subjected to global ischemia followed by reperfusion with azumolene or deionized distilled water (vehicle). Following reperfusion, LDVF was induced with burst pacing. In the first series of experiments (n = 16), epicardial Ca(2+) transient was analyzed for Ca(2+) transient amplitude alternans and dispersion of Ca(2+) transient amplitude alternans index (CAAI). In the second series of experiments following the same protocol (n = 12), ventricular contractility was assessed by measuring the left ventricular pressure. RESULTS: Ischemic LDVF led to greater CAAI (0.06 ± 0.02 at baseline vs 0.12 ± 0.02 post-LDVF, P < .01) and magnitude of dispersion of CAAI (0.04 ± 0.01 vs 0.09 ± 0.01, P < .01) in control hearts. In azumolene-treated hearts, no significant changes in CAAI (0.05 ± 0.01 vs 0.05 ± 0.01, P = .84) and dispersion of CAAI (0.04 ± 0.01 vs 0.04 ± 0.01, P = .99) were noted following ischemic LDVF. Ischemic LDVF was associated with reduction in left ventricular developed pressure (100% vs 36.8% ± 6.1%, P = .002) and dP/dt(max) (100% vs 45.3% ± 6.5%, P = .003) in control hearts, but these reductions were mitigated (left ventricular developed pressure: 100% vs 74.0% ± 8.1%, P = .052, dP/dt(max): 100% vs 80.8% ± 7.9%, P = .09) in azumolene-treated hearts. CONCLUSION: Treatment with azumolene is associated with improvement of systolic Ca(2+) release synchrony and myocardial contractility following ischemic LDVF.