Sudden cardiac death (SCD) due to ventricular fibrillation (VF) is a major world-wide health problem. Common triggers of VF are abnormal repolarizations of the cardiac action potential, known as early afterdepolarizations (EADs). Here we used a hybrid biological-computational approach to investigate the dependence of EADs on the biophysical properties of the L-type Ca(2+) current (I(Ca,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 ?mol/L H(2)O(2) (oxidative stress) or lowering the external [K(+)] from 5.4 to 2.0-2.7 mmol/L (hypokalemia). The role of I(Ca,L) in EAD formation was directly assessed using the dynamic clamp technique: the paced myocyte’s Vm was input to a myocyte model with tunable biophysical parameters, which computed a virtual I(Ca,L), that was injected into the myocyte in real time, replacing the endogenous I(Ca,L) which was suppressed with nifedipine. Injecting a current with the native I(Ca,L) biophysical properties restored EAD occurrence in myocytes challenged by H(2)O(2) or hypokalemia. 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 that modifying I(Ca,L) biophysical properties has potential as a powerful therapeutic strategy for suppressing EADs and EAD-mediated arrhythmias.