Introduction: To elucidate the mechanism of late-phase 3 early after depolarization (EAD) in ventricular arrhythmogenesis, we hypothesized that intracellular calcium (Cai) 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 (Vm) and Ca i transient on left ventricular endocardium. An IKATP 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 Cai overloading in the first postpacing beats. The duration of Cai transient recovered to 50% (DCaT50) and 90% (DCaT 90) in the first postpacing beats was significantly longer than baseline. Abnormal Cai 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 Cai amplitude (26.4 ± 3.5% of the control; P < 0.001) and the duration of Cai transients in the mapped region, preventing the development of EAD and triggered activity that initiated VF. Conclusions: I KATP channel activation along with Cai 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.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- Physiology (medical)