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The QT interval is a predictor of sudden death. Many drugs prolong the QT, primarily through IKr block. Autonomic tone directly affects heart rate and ventricular repolarization, but its effects in the setting of IKr block are unknown.Determine the effects of autonomic tone on heart rate and QT interval after IKr block.Healthy adults (n = 9) were administered ibutilide with ECGs obtained at regular intervals. On a separate day, subjects were administered intravenous propranolol and atropine to induce autonomic block, resulting in intrinsic heart rate and QT interval; ibutilide was administered again, with serial ECGs obtained at regular intervals. No differences in baseline RR, QT, or QTc intervals were seen between the two study days. Ibutilide in the setting of intact autonomic tone prolonged QTc by 43 ± 8 msec (P = 0.001) and prolonged RR interval by 93 ± 39 msec (P = 0.04). Autonomic block alone on the second day prolonged QTc by 16.7 ± 9.4 msec (P = 0.02). An additional 68 ± 5 msec prolongation of QTc was seen with ibutilide in the setting of double autonomic block (P = 0.036). There was no effect of ibutilide on intrinsic heart rate (P = 0.125).Autonomic block results in an exaggeration of drug-induced QT prolongation by ibutilide. IKr block has no effect on intrinsic heart rate. QT-prolonging drugs may have more deleterious effects in those with underlying autonomic dysfunction, thus increasing the risk for sudden death.