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J Am Coll Cardiol. 2015 Feb 3;65(4):367-374. doi: 10.1016/j.jacc.2014.11.015.

Autonomic control of heart rate and QT interval variability influences arrhythmic risk in long QT syndrome type 1.

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Department of Biomedical Sciences for Health, University of Milan, Milan, Italy; IRCCS Galeazzi Orthopedic Institute, Milan, Italy. Electronic address:
Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy.
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee.
Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa.
Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.



A puzzling feature of the long QT syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes.


This study tested the hypothesis that vagal and sympathetic control, as assessed by spectral analysis of spontaneous beat-to-beat variability of RR and QT intervals from standard 24-h electrocardiogram Holter recordings, could modulate the severity of LQTS type 1 (LQT1) in 46 members of a South-African LQT1 founder population carrying the clinically severe KCNQ1 A341V mutation.


Nonmutation carriers (NMCs) (n = 14) were compared with mutation carriers (MCs) (n = 32), 22 with and 10 without major symptoms. We assessed the effect of circadian rhythm and beta-blocker therapy over traditional time and frequency domain RR and QT variability indexes.


The asymptomatic MCs differed significantly from the symptomatic MCs and from NMCs in less vagal control of heart rate and more reactive sympathetic modulation of the QT interval, particularly during daytime when arrhythmia risk for patients with LQT1 is greatest.


The present data identified an additional factor contributing to the differential arrhythmic risk among patients with LQT1 carrying the same mutation. A healthy autonomic control confers a high risk, whereas patients with higher sympathetic control of the QT interval and reduced vagal control of heart rate are at lower risk. This differential "autonomic make-up," likely under genetic control, will allow refinement of risk stratification within families with LQTS, leading to more targeted management.


QT variability; autonomic nervous system; beta-blocker therapy; cardiovascular control; heart rate variability

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