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Arrhythmia Formation in Subclinical (“Silent”) Long QT Syndrome Requires Multiple Insults: Quantitative Mechanistic Study Using the KCNQ1 Mutation Q357R as ...

T O'Hara... - Heart Rhythm, 2011 - Elsevier Background In subclinical, or silentlong QT syndrome (LQTS), the QT interval is normal under basal conditions. The hypothesis thatinsults to the repolarization reserve may cause arrhythmias insilent mutation carriers, but not in non-carriers, has been proposed as a ...

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.

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 (EA Ds) in epicardial cells with mutant I Ks, but this did not produce EA Ds in wild type. Reduced channel expression at the membrane, not I Ks kinetic differences, caused EA Ds in the silent mutant. With mutant I Ks, isoproterenol plus partial I Kr block resulted in dramatic QT prolongation in the pseudo-electrocardiogram and EA Ds formed without I Kr block in mid-myocardial cells during simulated exercise onset.