Synchronizing systolic calcium release with azumolene in an experimental model

Daoyuan Si; Praloy Chakraborty; Mohammed Ali Azam; Madhav Krishna Kumar Nair; Stéphane Massé; Patrick F H Lai; Christopher Labos; Sheila Riazi; Kumaraswamy Nanthakumar

doi:10.1016/j.hroo.2022.06.001

Synchronizing systolic calcium release with azumolene in an experimental model

Heart Rhythm O2. 2022 Jun 15;3(5):568-576. doi: 10.1016/j.hroo.2022.06.001. eCollection 2022 Oct.

Authors

Daoyuan Si^{1

2}, Praloy Chakraborty¹, Mohammed Ali Azam¹, Madhav Krishna Kumar Nair¹, Stéphane Massé¹, Patrick F H Lai¹, Christopher Labos³, Sheila Riazi⁴, Kumaraswamy Nanthakumar¹

Affiliations

¹ The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Canada.
² Department of Cardiology, China-Japan Union Hospital, Jilin University, Changchun, China.
³ Queen Elizabeth Health Complex, McGill University, Montréal, Canada.
⁴ Malignant Hyperthermia Investigation Unit, Department of Anesthesia and Pain Management, University Health Network, Toronto, Canada.

Abstract

Background: Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca²⁺) 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 Ca²⁺ 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 Ca²⁺ transient was analyzed for Ca²⁺ transient amplitude alternans and dispersion of Ca²⁺ 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 Ca²⁺ release synchrony and myocardial contractility following ischemic LDVF.

Keywords: Azumolene; Ca2+ release synchrony; LDVF; Postresuscitation myocardial stunning; Ryanodine receptor.