Differential responses to beta-adrenergic stimulation in the long-QT syndrome type 1: Characterization and mechanisms

Long QT syndrome type 1 (LQT1) is caused by mutations that impair the function of the slow delayed rectifier potassium (I Ks ) channels. Most LQT1 patients experience arrhythmic events during beta-adrenergic stimulation (β-AS). A full description of the ionic mechanisms underlying arrhythmogenecity in LQT1 patients and their relation to β-AS is still lacking. In this study we constructed a set of stochastic human ventricular cell models reproducing experimental AP properties at baseline and following ionic inhibitions. Using the constructed models, we showed that AP duration, morphology and beat-to-beat variability in LQT1 are highly specific of the underlying ionic characteristics. Likewise, the response of individual I Ks -deficient cells to β-AS can range from negligible to as much as 200% increase in AP temporal variability, recognized as a marker of arrhythmogenesis in the setting ofLQT1. By partial correlation analysis, major ionic factors driving AP changes associated with LQT1 and β-AS were ascertained.