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CLINICAL RESEARCH: HEART RHYTHM DISORDER

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

Peter J. Schwartz, MD, FACC^{_*,,,||,_**,,_*}, Emilio Vanoli, MD^_*,¶, Lia Crotti, MD, PhD^_*,,, Carla Spazzolini, DVM^_*, Chiara Ferrandi, BSc, Althea Goosen, BSc^_**, Paula Hedley, MSc, Marshall Heradien, MD^_**, Sara Bacchini, MD^_*,, Annalisa Turco, MD^_*,, Maria Teresa La Rovere, MD^#, Antonella Bartoli, PharmD, Alfred L. George, Jr, MD and Paul A. Brink, MD^_**

^_* Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy
Department of Cardiology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
Molecular Cardiology Laboratory, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
Clinical Pharmacokinetics Laboratory, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
^|| Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico, Milan, Italy
^¶ Department of Cardiology, Policlinico di Monza, Monza, Italy
^# Centro Medico di Montescano, IRCCS Fondazione "Salvatore Maugeri," Montescano, Italy
^_** Department of Medicine, University of Stellenbosch, Stellenbosch, South Africa
Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, Cape Town, South Africa
US/MRC Centre for Molecular and Cellular Biology, University of Stellenbosch, Stellenbosch, South Africa
Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee.

Manuscript received June 6, 2007; revised manuscript received August 31, 2007, accepted September 20, 2007.

^_* Reprint requests and correspondence: Dr. Peter J. Schwartz, Professor and Chairman, Department of Cardiology, IRCCS Fondazione Policlinico S. Matteo, Viale Golgi 19 - 27100 Pavia, Italy. (Email: pjqt{at}compuserve.com).

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 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.

Abbreviations and Acronyms   BB = beta-adrenergic blockers   BRS = baroreflex sensitivity   CI = confidence interval   ECG = electrocardiogram   HR = heart rate   IKs = delayed rectifier potassium current (slow)   LQT1 = long QT syndrome type 1   LQTS = long QT syndrome   MC = mutation carrier   OR = odds ratio

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