Importance of Intracellular Calcium-Membrane Voltage Coupling Gain in Post-Shock Ventricular Arrhythmias

Abstract

Objective: Ventricular tachycardia/fibrillation (VT/VF) can recur repeatedly after defibrillation (i.e. electrical storm). We tested the hypothesis that intracellular Ca²⁺ (Ca_i) overload during VF and sensitivity of membrane voltage (Vm) to Ca_i (Ca_i-Vm coupling gain) is important for post-shock arrhythmias. Methods and Results: We simultaneously mapped Ca_i and Vm on epicardial (n=14) or endocardial (n=14) surfaces of Langendorff-perfused rabbit ventricles. Spontaneous Ca_i elevation (SCaE) was noted after defibrillation in 32% of VT/VF at baseline, 83% during isoproterenol infusion. SCaE was reproducibly induced by rapid ventricular pacing and inhibited by ryanodine. We found triggered activities (TAs) originating from 6 of 14 endocardial surfaces but none from epicardial surfaces, despite similar SCaEs between epicardial and endocardial surfaces. This was because delayed afterdepolarizations induced by SCaEs were larger on endocardial surfaces due to higher Ca_i-Vm coupling gain. Purkinje-like potentials preceded the TAs. /_K1 suppression with CsCl or BaCl₂ enhanced Ca_i-Vm coupling gain and enabled epicardium to also generate TAs. Further enhancement of Ca_i overload and Ca_i-Vm coupling gain by low [K⁺]_o induced post-shock VTs and spontaneous VF recurrences leading to electrical storm. Conclusions: Ca_i-Vm coupling gain is important for the genesis of post-shock VT/VF and electrical storm. Purkinje fibers serve as arrhythmogenic substrate because of its higher Ca_i-Vm coupling gain. /_K1 is a major determinant for Ca_i-Vm coupling gain.