Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome

• Published in: Journal of the American College of Cardiology Vol. 51; no. 9; pp. 920 - 929
• Main Authors: Schwartz, Peter J., Vanoli, Emilio, Crotti, Lia, Spazzolini, Carla, Ferrandi, Chiara, Goosen, Althea, Hedley, Paula, Heradien, Marshall, Bacchini, Sara, Turco, Annalisa, La Rovere, Maria Teresa, Bartoli, Antonella, George, Alfred L., Brink, Paul A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.03.2008; Elsevier Limited
• Subjects: Adolescent; Adult; Age; Aged; Autonomic Nervous System - physiopathology; Baroreflex - physiology; Cardiac arrhythmia; Cardiology; Cardiovascular; Deoxyribonucleic acid; Disease; DNA; Female; Genetic Heterogeneity; Heart; Heart attacks; Heart Rate; Humans; Hypotheses; Internal Medicine; KCNQ1 Potassium Channel - genetics; Long QT syndrome; Long QT Syndrome - complications; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Male; Methods; Middle Aged; Mutation; Polymorphism, Genetic; Population; Receptors, Adrenergic - genetics; Risk Factors; Severity of Illness Index; BB; IKs; LQT1; BRS; OR; CI; MC; LQTS; ECG; HR; baroreflex sensitivity; heart rate; long QT syndrome type 1; long QT syndrome; mutation carrier; beta-adrenergic blockers; odds ratio; delayed rectifier potassium current (slow); electrocardiogram; confidence interval; I Ks
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2007.09.069

Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome Peter J. Schwartz, Emilio Vanoli, Lia Crotti, Carla Spazzolini, Chiara Ferrandi, Althea Goosen, Paula Hedley, Marshall Heradien, Sara Bacchini, Annalisa Turco, Maria Teresa La Rovere, Antonella Bartoli, Alfred L. George, Jr, Paul A. Brink There is high clinical heterogeneity in long QT syndrome (LQTS). We tested our hypothesis that autonomic responses could modulate arrhythmic risk in long QT syndrome type 1 (LQT1) patients. In an LQT1 population segregating KCNQ1-A341V, we correlated cardiac events to heart rate (HR) and baroreflex sensitivity (BRS). In 56 mutation carriers, HR and BRS were lower among asymptomatic patients (p < 0.05). A BRS in the lower tertile was associated with a lower probability of being symptomatic (odds ratio 0.13, 95% confidence interval 0.02 to 0.96, p < 0.05). Higher BRS values were more frequent (45% vs. 8%, p < 0.05) in carriers of polymorphisms predicting enhanced adrenergic responses. We have identified a first physiological modifier of LQTS, which might itself be genetically determined. 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. Some long QT syndrome (LQTS) patients experience life-threatening cardiac arrhythmias, whereas others remain asymptomatic throughout life. This clinical heterogeneity is currently unexplained. 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). 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). 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.