Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

BACKGROUND Short QT syndrome (SQTS) is a primary electrical disease of the heart associated with a high risk of sudden cardiac death. A gain-of-function in I-Kr, due to a mutation in KCNH2, underlies SQT1. OBJECTIVE This study sought to examine the cellular basis for arrhythmogenesis in an experimental model of SQT1 created using PD-118057, a novel I-Kr, agonist. METHODS Transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions of arterially perfused canine left ventricular (LV) wedge preparations, together with a pseudo-electrocardiogram. RESULTS PD-118057 (10 [mu mol/l[) abbreviated the OT interval from 267 +/- 4 to 232 +/- 4 ms and increased transmurat dispersion of repotarization (TOR) from 33.7 +/- 2.0 to 49.1 +/- 3.1 ms (P <.001). T-wave amplitude increased from 18.0% +/- 1.4% to 23.1% +/- 1.7% of R-wave amplitude (P =.027). Reversing the direction of activation of the LV wall (epicardial pacing) resulted in an increase in QT interval from 269 +/- 5 to 282 +/- 5 ms and an increase in TOR from