Genotype- and Sex-Specific QT-RR Relationship in the Type-1 Long-QT Syndrome.

Background: Genotype-phenotype investigations have revealed significantly larger risk for cardiac events in patients with type 1 long-QT syndrome (LQT-1), particularly in adult females, with missense mutation in the cytoplasmic loop (C-loop) regions of the α subunit of the KCNQ1 gene associated with an impaired ion channel activation by adrenergic stimulus. We hypothesize that the impaired response to increases in heart rate leads to abnormal QT-RR dynamic profiles and is responsible for the increased cardiac risk for these patients.
Methods and Results: We measured the QT-RR slope in 24-hour Holter ECGs from LQT-1 patients with the mutations associated with impaired adrenergic stimulus (C-loop, n=18) and compared to LQT-1 patients with other mutations (non-C-loop, n=48), and to a healthy control group (n=195). The diurnal QT-RR slope was less steep in C-loop mutation patients (0.10±0.05) than in the ECGs from non-C-loop mutation patients (0.17±0.09, P=0.002). For female patients, slower heart rates were associated with prolonged QT and increased QT-RR slope. Male patients with C-loop mutations showed an impaired repolarization for shorter range of heart rates than in females, which is consistent with gender differences in triggers for events in this syndrome.
Conclusions: Our observations suggest that the C-loop LQT-1 patients have specific impaired adrenergic regulation of the ventricular repolarization. This response to heart rate increases may be useful in identification of high-risk patients with inherited prolonged QT and may help select an optimal antiarrhythmic therapeutic strategy. (J Am Heart Assoc. 2012;1:e000570 doi: 10.1161/JAHA.112.000570.).