Re-evaluating the efficacy of beta-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling.
OBJECTIVE
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. Beta-adrenergic blockers are the mainstay of treatment for LQTS. While their efficacy has been demonstrated in LQTS patients harbouring potassium channel mutations, studies of beta-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 beta-adrenergic drugs on the LQT3 phenotype.


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


CONCLUSIONS
These results demonstrate that beta-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 beta-blockers in LQT3 patients.
Ahrens-Nicklas
Rebecca C
RC
Greenberg Division of Cardiology, Weill Cornell Medical College, 1300 York Ave., Box 161, New York, NY 10065, USA.
Clancy
Colleen E
CE
Christini
David J
DJ
D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D003198:Computer Simulation; D006168:Guinea Pigs; D006801:Humans; D007545:Isoproterenol / Q000627:therapeutic use*; D008133:Long QT Syndrome / Q000188:drug therapy*; D008955:Models, Cardiovascular; D010641:Phenotype; D011433:Propranolol / Q000008:administration & dosage*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D007545:Isoproterenol