Proarrhythmic effects of flecainide acetate have been reported during exercise, but the mechanism for the arrhythmogenic interaction between flecainide and exercise is unknown. We hypothesized that the sinus tachycardia of exercise may enhance flecainide-induced conduction slowing by increasing use-dependent sodium channel blockade, thereby facilitating the occurrence of ventricular reentry. To evaluate the modulation of flecainide's effects by exercise, we studied 19 patients who were receiving therapeutic doses of flecainide for the treatment of cardiac arrhythmias. Sixteen patients underwent treadmill exercise testing by a modified Bruce protocol. During exercise, QRS duration increased progressively from 94 +/- 22 msec (mean +/- SD) at rest to 116 +/- 25 msec (p less than 0.001) at a mean heart rate increase of 84 +/- 32 beats/min. The patient with the greatest QRS increase developed a monomorphic ventricular tachycardia at peak exercise. At rest, the QRS duration after treatment with flecainide increased 12.1 +/- 10.0% compared with the pretreatment value, and with exercise, the QRS duration increased by a further 28.1 +/- 17.0% compared with the predrug value. We found that the best predictor of further exercise-induced QRS slowing was the change in QRS duration produced by flecainide at rest (r = 0.76, p = 0.001). In an age- and disease-matched control group, the QRS duration did not change during exercise that caused a similar heart rate increase.(ABSTRACT TRUNCATED AT 250 WORDS)