Use of Autonomic Maneuvers to Probe Phenotype/Genotype Discordance in Congenital Long QT Syndrome

Patients with congenital long QT syndrome due to potassium channel mutations (LQT1 and LQT2) may elude diagnosis due to normal electrocardiographic findings at rest, yet remain at risk of sudden death during bradycardia or sympathetic stimulation. To test the hypothesis that autonomic maneuvers can unmask long QT syndrome in genetically abnormal subjects with a normal phenotype (QTc ≤450 ms), we exposed 13 controls (33 ± 9 years; 5 men), 5 patients with LQT1 (32 ± 12 years; 3 men), and 5 patients with LQT2 (30 ± 11 years; 5 men) to phenylephrine bolus, exercise, and epinephrine infusion. The QT interval was measured at baseline and after each intervention. A substantial overlap was found in QTc among the groups at baseline and after phenylephrine. In contrast, QTc was significantly and consistently longer in subjects with LQT1 compared with controls during and after exercise (492 ± 40 vs 407 ± 14 ms, p <0.0001, at peak exercise; 498 ± 30 vs 399 ± 20 ms, p <0.0001, at 1 minute into recovery) or epinephrine (623 ± 51 vs 499 ± 51 ms, p <0.001, at peak epinephrine; 604 ± 36 vs 507 ± 54 ms, p <0.01, at 1 minute into recovery) but not in subjects with LQT2. In conclusion, sympathetic stimulation can reveal the LQT1 phenotype even in subjects with normal baseline electrocardiographic findings.