TY - JOUR
T1 - Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome
AU - Schwartz, Peter J.
AU - Vanoli, Emilio
AU - Crotti, Lia
AU - Spazzolini, Carla
AU - Ferrandi, Chiara
AU - Goosen, Althea
AU - Hedley, Paula
AU - Heradien, Marshall
AU - Bacchini, Sara
AU - Turco, Annalisa
AU - La Rovere, Maria Teresa
AU - Bartoli, Antonella
AU - George, Alfred L.
AU - Brink, Paul A.
PY - 2008/3/4
Y1 - 2008/3/4
N2 - 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 IKs, 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 ≤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 IKs is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological risk modifier, which is probably genetically determined.
AB - 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 IKs, 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 ≤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 IKs is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological risk modifier, which is probably genetically determined.
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U2 - 10.1016/j.jacc.2007.09.069
DO - 10.1016/j.jacc.2007.09.069
M3 - Article
C2 - 18308161
AN - SCOPUS:38649121254
VL - 51
SP - 920
EP - 929
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 9
ER -