Arrhythmia formation in subclinical ("silent") long QT syndrome requires multiple insults: Quantitative mechanistic study using the KCNQ1 mutation Q357R as example

Background: In subclinical or silent long QT syndrome, the QT interval is normal under basal conditions. The hypothesis that insults to the repolarization reserve may cause arrhythmias in silent mutation carriers but not in noncarriers has been proposed as a general principle, yet crucial aspects remain descriptive, lacking quantification. Objective: To utilize accurate mathematical models of the human action potential and β-adrenergic stimulation to quantitatively investigate arrhythmia-formation mechanisms peculiar to silent long QT syndrome, using mutation Q357R in KCNQ1 (α subunit of slow-delayed rectifier I_Ks) as a paradigm. Methods: Markov models were formulated to account for altered I_Ks kinetics in Q357R compared with wild type and introduced into a detailed model of the human ventricular myocyte action potential. Results: Dominant negative loss of I _Ks available reserve accurately represents Q357R. Action potential prolongation with mutant I_Ks was minimal, reproducing the silent phenotype. Partial block of rapid delayed rectifier current (I_Kr) was needed in addition to fast pacing and isoproterenol application to cause early afterdepolarizations (EADs) in epicardial cells with mutant I_Ks, but this did not produce EADs in wild type. Reduced channel expression at the membrane, not I_Ks kinetic differences, caused EADs in the silent mutant. With mutant I_Ks, isoproterenol plus partial I_Kr block resulted in dramatic QT prolongation in the pseudo-electrocardiogram and EADs formed without I_Kr block in mid-myocardial cells during simulated exercise onset. Conclusion: Multiple severe insults are needed to evince an arrhythmic phenotype in silent mutation Q357R. Reduced membrane I _Ks expression, not kinetic changes, underlies the arrhythmic phenotype.