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J Am Coll Cardiol, 2008; 51:920-929, doi:10.1016/j.jacc.2007.09.069
© 2008 by the American College of Cardiology Foundation
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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*,{dagger},{ddagger},||,**,{dagger}{dagger},*, Emilio Vanoli, MD*, Lia Crotti, MD, PhD*,{dagger},{ddagger}, Carla Spazzolini, DVM*, Chiara Ferrandi, BSc{ddagger}, Althea Goosen, BSc**, Paula Hedley, MSc{ddagger}{ddagger}, Marshall Heradien, MD**, Sara Bacchini, MD*,{dagger}, Annalisa Turco, MD*,{dagger}, 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
{dagger} Department of Cardiology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
{ddagger} 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
{dagger}{dagger} Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, Cape Town, South Africa
{ddagger}{ddagger} 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 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.

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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