L-type calcium current reactivation contributes to arrhythmogenesis associated with action potential triangulation

Calcium Current Reactivation Contributes to Arrhythmogenesis. Introduction: The morphology of the mammalian cardiac action potential (AP) is an important factor in the susceptibility to drug-induced early afterdepolarizations (EADs) that may initiate Torsade de Pointes (TdP). AP triangulation has been shown to be an important predictor of drug-induced TdP. Methods and Results: APs from guinea pig and rabbit left ventricular single myocytes were recorded using a microelectrode-recording technique. ICa-L currents were recorded in ventricular myocytes of guinea pig and rabbit using patch-clamping technique. At a stimulus frequency of 0.5 Hz, guinea pig ventricular myocytes displayed a square-like AP, whereas rabbit ventricular myocytes exhibited a triangle-like AP. Dofetilide-induced EADs were observed only in rabbit ventricular myocytes. Under the guinea pig AP clamping condition, the normalized ICa-L instant reactivation currents in guinea pig and rabbit myocytes at voltages of -40 mV were 0.13 +/- 0.01 and 0.14 +/- 0.01, respectively. However, when rabbit AP served as the first clamping voltage, the normalized ICa-L reactivation currents at -40 mV in guinea pig and rabbit myocytes were 0.20 +/- 0.01, 0.21 +/- 0.01, respectively, indicating that the ICa-L recovery from inactivation in the rabbit triangular AP condition was significantly faster than in the guinea pig square AP condition. Comparison of the voltage clamp using the triangular waveform with the square waveform further confirmed that triangulation accelerates ICa-L recovery from inactivation. Conclusions: In rabbit ventricular myocardium, AP triangulation accelerates ICa-L channel recovery from inactivation, leading to instability of the cell membrane potential during repolarization, which is capable of initiating TdP.