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Cardiovascular Research Advance Access first published online on March 5, 2009
This version [Corrected Proof] published online on March 24, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp083
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Re-evaluating the efficacy of β-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling

Rebecca C. Ahrens-Nicklas1,2, Colleen E. Clancy2,3 and David J. Christini1,2,3,*

1 Greenberg Division of Cardiology, Weill Cornell Medical College, 1300 York Ave., Box 161, New York, NY 10065, USA
2 Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY, USA
3 Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA

* Corresponding author. Tel: +1 212 746 6280; fax: +1 212 746 8451.E-mail address: dchristi{at}med.cornell.edu

Aims: Long QT syndrome (LQTS) is a heterogeneous collection of inherited cardiac ion channelopathies characterized by a prolonged electrocardiogram QT interval and increased risk of sudden cardiac death. β-Adrenergic blockers are the mainstay of treatment for LQTS. While their efficacy has been demonstrated in LQTS patients harbouring potassium channel mutations, studies of β-blockers in subtype 3 (LQT3), which is caused by sodium channel mutations, have produced ambiguous results. In this modelling study, we explore the effects of β-adrenergic drugs on the LQT3 phenotype.

Methods and results: In order to investigate the effects of β-adrenergic activity and to identify sources of ambiguity in earlier studies, we developed a computational model incorporating the effects of β-agonists and β-blockers into an LQT3 mutant guinea pig ventricular myocyte model. β-Activation suppressed two arrhythmogenic phenomena, transmural dispersion of repolarization and early after depolarizations, in a dose-dependent manner. However, the ability of β-activation to prevent cardiac conduction block was pacing-rate-dependent. Low-dose β-blockade by propranolol reversed the beneficial effects of β-activation, while high dose (which has off-target sodium channel effects) decreased arrhythmia susceptibility.

Conclusion: These results demonstrate that β-activation may be protective in LQT3 and help to reconcile seemingly conflicting results from different experimental models. They also highlight the need for well-controlled clinical investigations re-evaluating the use of β-blockers in LQT3 patients.

KEYWORDS Arrhythmia (mechanisms); Adrenergic (ant)agonists; Long QT syndrome; Computer modelling

Time for primary review: 27 days


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