Intracellular calcium dynamics, shortened action potential duration, and late-phase 3 early afterdepolarization in Langendorff-perfused rabbit ventricles

Introduction: To elucidate the mechanism of late-phase 3 early after depolarization (EAD) in ventricular arrhythmogenesis, we hypothesized that intracellular calcium (Ca_i) overloading and action potential duration (APD) shortening may promote late-phase 3 EAD and triggered activity, leading to development of ventricular fibrillation (VF). Methods and Results: In isolated rabbit hearts, we performed microelectrode recording and simultaneous dual optical mapping of transmembrane potential (V_m) and Ca _i transient on left ventricular endocardium. An I_KATP channel opener, pinacidil, was used to abbreviate APD. Rapid pacing was then performed. Upon abrupt cessation of rapid pacing with cycle lengths of 60-200 milliseconds, there were APD₉₀ prolongation and the corresponding Ca_i overloading in the first postpacing beats. The duration of Ca_i transient recovered to 50% (DCaT₅₀) and 90% (DCaT ₉₀) in the first postpacing beats was significantly longer than baseline. Abnormal Ca_i elevation coupled with shortened APD produced late-phase 3 EAD induced triggered activity and VF. In additional 6 preparations, the heart tissues were treated with BAPTA-AM, a calcium chelator. BAPTA-AM significantly reduced the maximal Ca_i amplitude (26.4 ± 3.5% of the control; P < 0.001) and the duration of Ca_i transients in the mapped region, preventing the development of EAD and triggered activity that initiated VF. Conclusions: I _KATP channel activation along with Ca_i overloading are associated with the development of late-phase 3 EAD and VF. Because acute myocardial ischemia activates the I _KATP channel, late-phase 3 EADs may be a mechanism for VF initiation during acute myocardial ischemia.