EARLY AFTERDEPOLARIZATIONS IN CARDIAC MYOCYTES - MECHANISM AND RATE DEPENDENCE

A model of the cardiac ventricular action potential that accounts for dynamic changes in ionic concentrations was used to study the mechanis m, characteristics, and rate dependence of early afterdepolarizations (EADs). A simulation approach to the study of the effects of pharmacol ogical agents on cellular processes was introduced. The simulation res ults are qualitatively consistent with experimental observations and h elp resolve contradictory conclusions in the literature regarding the mechanism of EADs. Our results demonstrate that: 1) the L-type calcium current, I-Ca, is necessary as a depolarizing charge carrier during a n EAD; 2) recovery and reactivation of I-Ca is the mechanism of EAD fo rmation, independent of the intervention used to induce the EADs (cesi um, Bay K 8644, or isoproterenol were used in our simulations, followi ng similar published experimental protocols); 3) high [Ca2+](i) is not required for EADs to develop and calcium release by the sarcoplasmic reticulum does not occur during the EAD; 4) although the primary mecha nism of EAD formation is recovery of I-Ca, other plateau currents can modulate EAD formation by affecting the balance of currents during a c onditional phase before the EAD take-off; and 5) EADs are present at d rive cycle lengths longer than 1000 ms. Because of the very long activ ation time constant of the delayed rectifier potassium current, I-K, t he activation gate of I-K does not deactivate completely between conse cutive stimuli at fast rates (drive cycle length < 1000 ms). As a resu lt, I-K, plays a key role in determining the rate dependence of EADs.