Genetically Defined Therapy of Inherited Long-QT Syndrome

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Abstract
Background Many members of families with inherited long-QT (LQT) syndrome have mutations in HERG, a gene encoding a cardiac potassium channel that is modulated by extracellular potassium. We hypothesized that an increase in serum potassium would normalize repolarization in these patients. Methods and Results We studied seven subjects with chromosome 7–linked LQT syndrome and five normal control subjects. Repolarization was measured by ECG and body surface potential mapping during sinus rhythm, exercise, and atrial pacing, before and after serum potassium increase. Potassium administration improved repolarization in the LQT syndrome. At baseline, LQT subjects differed from control subjects: resting corrected QT interval (QTc, 627±90 versus 425±25 ms, P=.0007), QTc dispersion (133±62 versus 36±9 ms, P=.009), QT/RR slope (0.35±0.08 versus 0.24±0.07, P=.04), and global root-mean-square QT interval (RMS-QTc; 525±68 versus 393±22, P=.002). All LQT subjects had biphasic or notched T waves. After administration of potassium, the LQT group had a 24% reduction in resting QTc interval (from 617±92 to 469±23 ms, P=.004) compared with a 4% reduction among control subjects (from 425±25 to 410±45 ms, P>.05). The reduction was significantly greater in LQT subjects (P=.018). QT dispersion became normal in LQT subjects and did not change in control subjects. The slope of the relation between QT interval and cycle length (QT/RR slope) decreased toward normal. T-wave morphology improved in six of seven LQT subjects. The LQT group had a greater reduction in RMS-QTc than control subjects (P=.04). Conclusions An increase in serum potassium corrects abnormalities of repolarization duration, T-wave morphology, QT/RR slope, and QT dispersion in patients with chromosome 7–linked LQT.