Shaping a new Ca2+ conductance to suppress early afterdepolarizations in cardiac myocytes

Sudden cardiac death (SCD) due to ventricular fibrillation (VF) is a major world-wide health problem. A common trigger of VF involves abnormal repolarization of the cardiac action potential causing early after depolarizations (EADs). Here we used a hybrid biological-computational approach to investigate the dependence of EADs on the biophysical properties of the L-type Ca2+ current (I-Ca,I-L) and to explore how modifications of these properties could be designed to suppress EADs. EADs were induced in isolated rabbit ventricular myocytes by exposure to 600 mu mol l(-1) H2O2 (oxidative stress) or lowering the external [K+] from 5.4 to 2.0-2.7 mmol l(-1) (hypokalaemia). The role of I-Ca,I-L in EAD formation was directly assessed using the dynamic clamp technique: the paced myocyte's V-m was input to a myocyte model with tunable biophysical parameters, which computed a virtual I-Ca,I-L, which was injected into themyocyte in real time. This virtual current replaced the endogenous I-Ca,I-L, which was suppressed with nifedipine. Injecting a current with the biophysical properties of the native I-Ca,I-L restored EAD occurrence in myocytes challenged by H2O2 or hypokalaemia. A mere 5 mV depolarizing shift in the voltage dependence of activation or a hyperpolarizing shift in the steady-state inactivation curve completely abolished EADs in myocytes while maintaining a normal Ca-i transient. We propose thatmodifying the biophysical properties of I-Ca,I-L has potential as a powerful therapeutic strategy for suppressing EADs and EAD-mediated arrhythmias.