Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome

J Am Coll Cardiol. 2008 Mar 4;51(9):920-9. doi: 10.1016/j.jacc.2007.09.069.


Objectives: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Autonomic Nervous System / physiopathology*
  • Baroreflex / physiology
  • Female
  • Genetic Heterogeneity
  • Heart Rate*
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • Long QT Syndrome / complications*
  • Long QT Syndrome / genetics
  • Long QT Syndrome / physiopathology*
  • Male
  • Middle Aged
  • Mutation
  • Polymorphism, Genetic
  • Receptors, Adrenergic / genetics*
  • Risk Factors
  • Severity of Illness Index


  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Receptors, Adrenergic