Yaowalak Panyasing

Assessment of ECG interval and restitution parameters in the canine model of short QT syndrome

INTRODUCTION The short QT syndrome (SQTS) is characterized by a short QT interval resulting from accelerated ventricular repolarization, and may be associated with ventricular fibrillation but not torsades de pointes. There are abundant data on the adverse effects of long QT, but knowledge of SQTS is sparse. The aim of this study was to examine whether analyses of several ECG biomarkers (QT, QTcB, QTcF, QTcV, QT(btb), and QT(RR1000)) and dynamic restitution of the beat-to-beat QT-TQ relationship (TQ(min), %QT/TQ ratio>1, QT/TQ ratio(max)) can be used to assess ECG changes in conscious dogs. METHODS Sling-trained dogs were infused with escalating concentration of levcromakalim (0, 1.0, 3.3, and 10.0 microg/kg/min), pinacidil (0, 3.3, 10.0, and 33.3 microg/kg/min), and nicorandil (0, 0.03, 0.1, and 0.3 mg/kg/min), drugs known to shorten QT. The RR, QT, QTcB, QTcF, QTcV, QT(RR1000), and TQ were measured before and after each concentration of the QT shortening test compounds. RESULTS Levcromakalim, pinacidil, and nicorandil but not vehicle significantly shortened RR, QT, QT(btb), QT(RR1000), and TQ but not QTc(B,F,V). The QT-RR cloud also shifted to the lower bounds of the normal QT-RR boundary by the test compounds. The percentage of beats with a QT/TQ ratio>1 was significantly increased in a dose response manner with levcromakalim and pinacidil and the lower TQ interval boundary (5th percentile) was decreased when compared to baseline or vehicle. DISCUSSION QT(btb), QT(RR1000), and dynamic beat-to-beat measurements of restitution constitute clinically applicable ECG biomarkers for assessment of changes associated with arrhythmogenic risk of ventricular fibrillation due to QT abbreviation.

Uni- or bi-ventricular hypertrophy and susceptibility to drug-induced torsades de pointes

INTRODUCTION Cardiac hypertrophy is an independent risk factor for torsades de pointes (TdP), a polymorphic ventricular tachycardia that is often drug-induced, that may evolve into ventricular fibrillation and sudden death. Therefore this study was designed to determine if right (RVH), left (LVH), or biventricular (BVH) hypertrophy increases susceptibility to drug-induced TdP. METHODS Rabbits were separated into 4 groups: control or RVH, LVH, BVH (studied 8weeks after banding of one or both great arteries). ECGs were recorded continuously under anesthesia after baseline and after rabbits received escalating doses of torsadogens (dofetilide, clofilium and terfenadine) or non-torsadogens (cilobradine, diltiazem and vehicle). The following parameters were measured [RR, PQ, QRS and QT] or calculated [QTc (F), short term variability of QT interval]. RESULTS Generally, torsadogenicity for the compounds tested was dofetilide>clofilium>terfenadine, and there was no TdP following cilobradine, diltiazem or vehicle. In general the susceptibility to TdP was RVH>BVH>LVH>control. Rabbits with RVH developed TdP much more prevalently than for those with either LVH or BVH (p<0.05). At the low dose of dofetilide, LVH was actually protective. CONCLUSION Rabbits with any form of hypertrophy develop prolongation of QT, QTc and increased QT instability. Rabbits with any form of hypertrophy are more prone to arrhythmia than normals in response to known torsadogens.