Abstract
AimsLong 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 resultsIn 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.ConclusionThese 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.
Original language | English (US) |
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Pages (from-to) | 439-447 |
Number of pages | 9 |
Journal | Cardiovascular Research |
Volume | 82 |
Issue number | 3 |
DOIs | |
State | Published - Jun 2009 |
Externally published | Yes |
Keywords
- Adrenergic (ant)agonists
- Arrhythmia (mechanisms)
- Computer modelling
- Long QT syndrome
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
- Physiology