OBJECTIVES The aim of this study was to assess the response of refractoriness in normal and diseased human bundle branches to changes in cycle length, as well as during a long period of continuous overdrive pacing. BACKGROUND The anterograde refractory period of the bundle branches in patients with functional bundle branch block shortens as the rate is increased. The rate-dependent response of refractoriness in diseased bundle branches is quite different. However, this difference has not been precisely delineated, and its physiologic meaning is uncertain. METHODS Refractoriness of the bundle branches was measured by the extrastimulus technique in 16 patients with tachycardia-dependent bundle branch block and 10 patients with functional bundle branch block, both after basic trains of 8 atrial-paced impulses at different cycle lengths and during a 10-min period of continuous overdrive pacing. RESULTS The baseline refractory period in the bundle branches of patients with functional bundle branch block measured 430 +/- 32 ms (mean +/- SD) and shortened to 368 +/- 30 ms at the shortest cycle length. The maximal effect was reached within the 1st min of overdrive pacing. The baseline refractory period of the bundle branches was significantly longer in patients with tachycardia-dependent bundle branch block (611 +/- 184 ms) and demonstrated a cumulative overdrive prolongation in 15 (83%) of 18 studies with typical manifestations of fatigue. In two other studies, this occurred only after ajmaline administration. CONCLUSIONS A rate- and time-dependent prolongation of refractoriness frequently occurs in diseased human bundle branches. When absent, this response may be induced under the effects of sodium channel blockers. This would suggest that an abnormality in the recovery from inactivation of the sodium channel might underlie the early stages of bundle branch disease.