Ischemia enhances use-dependent sodium channel blockade by pilsicainide, a class IC antiarrhythmic agent

The aim of this study was to elucidate whether the electrophysiologic properties of pilsicainide, a novel class IC drug with slow kinetic properties, could be altered in the presence of acute myocardial ischemia.

An increase in the rate of sudden death in patients taking flecainide and encainide has been reported by the Cardiac Arrhythmia Suppression Trial (CAST), implying a proarrhythmic effect that may be due to the interaction between ischemia and class IC antiarrhythmic drugs.

Thirty-five patients and 16 age-matched control patients performed a treadmill exercise test and were assigned to four study groups: group A = 16 control patients; group B = 15 patients with ischemic ST segment depression; group C = 11 patients receiving pilsicainide without ST segment depression; and group D = 9 patients receiving pilsicainide with ischemic ST segment depression. The QRS duration was measured at rest and at heart rates of 80, 100 and 120 beats/min.

There were no changes in the QRS duration as heart rates increased to 120 beats/min in the control patients. Ischemia, however, independently caused a significant increase in QRS duration at a heart rate of 120 beats/min. Pilsicainide produced a rate-dependent prolongation of the QRS duration in patients without ST segment depression as the heart rate increased to 100 beats/min. The combination of ischemia and pilsicainide led to a much greater rate-dependent prolongation of the QRS duration.

Combination of a class IC drug and acute ischemia could lead to additive rate-dependent ventricular conduction slowing. This may be one plausible mechanism for the induction of proarrhythmias noted in the CAST study.