title: Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome.
abstract: OBJECTIVE
  The purpose of this study was to test the hypothesis that differences in autonomic responses might modify clinical severity in long QT syndrome type 1 (LQT1) patients, those with KCNQ1 mutations and reduced I(Ks), in whom the main arrhythmia trigger is sympathetic activation.
  
  
  BACKGROUND
  Some long QT syndrome (LQTS) patients experience life-threatening cardiac arrhythmias, whereas others remain asymptomatic throughout life. This clinical heterogeneity is currently unexplained.
  
  
  METHODS
  In a South African LQT1 founder population segregating KCNQ1-A341V, we correlated major cardiac events to resting heart rate (HR) and to baroreflex sensitivity (BRS) on and off beta-adrenergic blockers (BB).
  
  
  RESULTS
  In 56 mutation carriers (MCs), mean HR was lower among asymptomatic patients (p < 0.05). Among MCs with a QT interval corrected for heart rate <or=500 ms, those in the lower HR tertile were less likely to have suffered prior cardiac events (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.04 to 0.79, p < 0.02). The BRS was lower among asymptomatic than symptomatic MCs (11.8 +/- 3.5 ms/mm Hg vs. 20.1 +/- 10.9 ms/mm Hg, p < 0.05). A BRS in the lower tertile was associated with a lower probability of being symptomatic (OR 0.13, 95% CI 0.02 to 0.96, p < 0.05). A similar trend was observed during BB. The MCs in the lower tertile for both HR and BRS were less frequently symptomatic than MCs with different patterns (20% vs. 76%, p < 0.05). Subjects with either ADRA2C-Del322-325 or homozygous for ADRB1-R389, 2 polymorphisms predicting enhanced adrenergic response, were more likely to have BRS values above the upper tertile (45% vs. 8%, p < 0.05).
  
  
  CONCLUSIONS
  Lower resting HR and "relatively low" BRS are protective factors in KCNQ1-A341V carriers. A plausible underlying mechanism is that blunted autonomic responses prevent rapid HR changes, arrhythmogenic when I(Ks) is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological risk modifier, which is probably genetically determined.
authors.affiliation: Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Emilio
authors.initials: E
authors.lastname: Vanoli
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.forename: Althea
authors.initials: A
authors.lastname: Goosen
authors.forename: Paula
authors.initials: P
authors.lastname: Hedley
authors.forename: Marshall
authors.initials: M
authors.lastname: Heradien
authors.forename: Sara
authors.initials: S
authors.lastname: Bacchini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Turco
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: La Rovere
authors.forename: Antonella
authors.initials: A
authors.lastname: Bartoli
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brink
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001341:Autonomic Nervous System / Q000503:physiopathology*; D017704:Baroreflex / Q000502:physiology; D005260:Female; D018740:Genetic Heterogeneity; D006339:Heart Rate; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000150:complications* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011941:Receptors, Adrenergic / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D011941:Receptors, Adrenergic