title: Genotype- and Sex-Specific QT-RR Relationship in the Type-1 Long-QT Syndrome.
abstract: 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.
  
  
  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.).
authors.affiliation: Center for Quantitative Electrocardiography and Cardiac Safety, Heart Research Follow-Up Program, University of Rochester Medical Center,  NY (J.-P.C., X.X., A.J.M., W.Z.).
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Couderc
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Xia
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Fabrice
authors.initials: F
authors.lastname: Extramiana
authors.forename: Pierre
authors.initials: P
authors.lastname: Maison-Blanche
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.forename: Coeli M
authors.initials: CM
authors.lastname: Lopes
keywords: KCNQ1; QT interval; QT-RR dynamicity; electrocardiogram; long-QT syndrome