Abstract:
This study hypothesized that 1) a reduction of electromechanical window (EMW) to negative value in rabbit’s model of long QT syndrome type 2 is associated with torsade de pointes (TdP) and an increase of EMW from baseline value in rabbit’s model of short QT syndrome is associated with ventricular fibrillation (VF); 2) the EMW is a reliable marker for predicting ischemia-induced VF in rabbit model; 3) the value of EMW may be less negative in rabbits receiving calcium channel blocker before administration of dofetilide to induced TdP; and 4) EMW is a marker that may not be affected by changing of preload, heart rate (HR), blood pressure (BP) and contractility. In order to test these hypotheses, the study was divided into 4 parts. The study part 1 aimed to evaluate the characteristics of EMW in animal models of LQT and SQT syndromes. The results showed that EMW can be used as a biomarker for drug safety evaluation as it was negative during infusion of known QT prolonging agents while it became more positive during infusion of known QT shortening drugs. The study part 2 aimed to determine the use of EMW for predicting ischemia-induced VF in anesthetized rabbits produced by coronaries ligation. The results suggested that the increasing of EMW >64 ms as well as the elevation of STVQT >5.31 ms can potentially be used as biomarkers for predicting of VF in anesthetized rabbits with myocardial ischemia. The study part 3 aimed to assess the characteristic of EMW in the rabbit model of dofetilide-induced TdP. The results showed that dofetilide decreased EMW to negative values both in rabbits with (TdP+) and without (TdP-) TdP development in which it decreased more for TdP+ group. The purpose of study part 4 was to determine the effect of preload, HR, BP and contractility on EMW. The results indicated that, in the anesthetized rabbit model, EMW was affected by changing of HR and contractility but not preload and BP. Therefore, interpretation of changes of EMW in this model should be cautious. In conclusion, EMW can be used as a surrogate marker for predicting the TdP and VF in LQT, SQT anesthetized rabbit models and in ischemia-induced VF rabbit model. However, the EMW was affected by extremely changes of HR and contractility.
