05. The electro-mechanical window as Torsade de Pointes risk marker in conscious and anaesthetised dogs after IKS blockade.

The electro-mechanical window (EMw) is a recently proposed biomarker describing the temporal difference between electrical and mechanical events in beating hearts and is a precursor to identify Torsade de Pointes (TdP) risk in the anaesthetised dog. In follow-up studies, conscious dogs (n=6; telemetered) showed comparable baseline values to anaesthetised dogs (n=20): QT=250 vs 252⇔…ms, QLVPend=347 vs 339⇔…ms and EMw=+96 vs +87⇔…ms, respectively. To compare the EMw in conscious and anaesthetised dogs after IKs blockade. Six conscious dogs were orally treated with JNJ303 (20⇔…mg/kg) and four anaesthetised dogs received infusions of JNJ303 (cumulative 2.5⇔…mg/kg). In both conditions JNJ303 induced QT prolongation, a large negative EMw and TdP appeared in 50% of the dogs in each condition (pause-dependent and adrenergic-dependent). In the conscious dogs significant differences in maximum plasma levels (PL), QT and EMw were observed between dogs that induced TdP and those without TdP: PL (4950 vs 1473⇔…ng/ml), QT (427 vs 351⇔…ms) and EMw (⇔'150 vs ⇔'68⇔…ms), without differences in RR (642 vs 654⇔…ms) and QLVPend (273 vs 287⇔…ms), respectively. Also in anaesthetised dogs long QT (766⇔…ms) and large negative EMw (⇔'445⇔…ms) at similar PL (5743⇔…ng/ml) were observed. In conclusion a potent IKs blocker (JNJ303) can cause TdP in conscious and anaesthetised dogs, coupled with a large negative EMw. [ABSTRACT FROM AUTHOR]