In silico study on the effects ofIKurblock kinetics on prolongation of human action potential after atrial fibrillation-induced electrical remodeling

Pharmacological treatment with various antiarrhythmic agents for the termination or prevention of atrial fibrillation (AF) is not yet satisfactory. This is in part because the drugs may not be sufficiently selective for the atrium, and they often cause ventricular arrhythmias. The ultrarapid-delayed rectifying potassium current (I(Kur)) is found in the atrium but not in the ventricle, and it has been recognized as a potentially promising target for anti-AF drugs that would be without ventricular proarrhythmia. Several new agents that specifically block I(Kur) have been developed. They block I(Kur) in a voltage- and time-dependent manner. Here we use mathematical models of normal and electrically remodeled human atrial action potentials to examine the effects of the blockade kinetics of I(Kur) on atrial action potential duration (APD). It was found that after AF remodeling, an I(Kur) blocker with fast onset can effectively prolong APD at any stimulus frequency, whereas a blocker with slow onset prolongs APD in a frequency-dependent manner only when the recovery is slow. The results suggest that the voltage and time dependence of I(Kur) blockade should be taken into account in the testing of anti-AF drugs. This modeling study suggests that a simple voltage-clamp protocol with a short pulse of approximately 10 ms at 1 Hz may be useful to identify the effective anti-AF drugs among various I(Kur) blockers.