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Early afterdepolarization (EAD) is known as a cause of ventricular arrhythmias in long QT syndromes. We theoretically investigated how the rapid ( I Kr ) and slow ( I Ks ) components of delayed-rectifier K +  channel currents, L-type Ca 2+  channel current ( I CaL ), Na + /Ca 2+  exchanger current ( I NCX ), Na + -K +  pump current ( I NaK ), intracellular Ca 2+  (Ca i ) handling via sarcoplasmic reticulum (SR), and intracellular Na +  concentration (Na i ) contribute to initiation, termination, and modulation of phase-2 EADs, using two human ventricular myocyte models. Bifurcation structures of dynamical behaviors in model cells were explored by calculating equilibrium points, limit cycles (LCs), and bifurcation points as functions of parameters. EADs were reproduced by numerical simulations. The results are summarized as follows: 1) decreasing I Ks  and/or I Kr  or increasing I CaL  led to EAD generation, to which mid-myocardial cell models were especially susceptible; the parameter regions of EADs overlapped the regions of stable LCs. 2) Two types of EADs (termination mechanisms), I Ks  activation–dependent and I CaL  inactivation–dependent EADs, were detected; I Ks  was not necessarily required for EAD formation. 3) Inhibiting I NCX  suppressed EADs via facilitating Ca 2+ -dependent I CaL  inactivation. 4) Ca i  dynamics (SR Ca 2+  handling) and Na i  strongly affected bifurcations and EAD generation in model cells via modulating I CaL , I NCX , and I NaK . Parameter regions of EADs, often overlapping those of stable LCs, shifted depending on Ca i  and Na i  in stationary and dynamic states. 5) Bradycardia-related induction of EADs was mainly due to decreases in Na i  at lower pacing rates. This study demonstrates that bifurcation analysis allows us to understand the dynamical mechanisms of EAD formation more profoundly.    NEW &amp; NOTEWORTHY We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require I Ks .

american journal of physiology. heart and circulatory physiology

Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models