BACKGROUND: Pharmacological challenge with class I antiarrhythmic drug is a recommended diagnostic test in patients with unexplained syncope only in the presence of bundle branch block, when non-invasive tests have failed to make the diagnosis. Its role in patients with minor or no conduction disturbances on 12-leads ECG has not been evaluated yet. It is also not clear which are the values of His-Ventricular interval to be considered diagnostic. We sought to evaluate the role of ajmaline challenge in unmasking the presence of an infrahisian disease in patients with recurrent and unexplained syncope, regardless of the existence of conduction disturbances on surface ECG. MATERIALS AND METHODS: Patients with history of recurrent syncope, preserved EF and a negative first level workup were enrolled. Conduction disturbances on ECG were not considered as an exclusion criteria. During EPS, basal HV conduction was determined. In the presence of a HV >70 msec the study was interrupted and the patient was implanted with a pacemaker. If the HV was ≤ 70 msec, ajmaline was infused and HV was reassessed. The maximum value of HV was considered. A prolongation ≥ 100 msec was considered as diagnostic and indicative of conduction disease, and the patient underwent pacemaker implantation. Patients with an HV <100 msec were implanted with an ILR. RESULTS: Sixteen consecutive patients were studied (age 76±5.2 years). Nine patients had conduction disturbances at baseline ECG (group ECG+). Among them, 5 had a basal diagnostic HV interval and 4 had a non-diagnostic HV interval. In the latter group, abnormal response to ajmaline was observed in 3 patients. In this group only one patient was implanted with an ILR, 8 patients were implanted with a pacemaker. Among the seven patients without conduction disturbances (group ECG-), no one had a diagnostic basal HV interval. After drug administration, 4 patients had a non-diagnostic response and were implanted with an ILR, while 3 patient had a pathological response and were implanted with a pacemaker. No difference was found in the values of maximum HV interval prolongation after ajmaline between the two groups (P = 0.89). During a mean follow up of 13±3 months, no patient has developed a syncopal episode. One patient in group ECG- and negative drug test was implanted after 3 months with a permanent pacemaker because of a two to one asymptomatic AV block at ILR interrogation. CONCLUSIONS: Ajmaline challenge is a useful tool to unmask the presence of a infrahisian disease in patients with preserved EF, unexplained syncope and negative workup, even in the absence of conduction disturbances on 12-leads ECG. It is a simple and safe test that may disclose the detection of the disease. In these patients, an earlier pacemaker implantation of a pacemaker, may avoid the consequences of a syncopal recurrence. Values of HV interval > 70 msec in basal conditions and ≥ 100 msec after ajmaline administration seem appropriate to unmask infrahisian disease. Larger population is required to validate this hypothesis.