Sling-trained dogs were infused with escalating concentration of levcromakalim (0, 1.0, 3.3, and 10.0 µg/kg/min), pinacidil (0, 3.3, 10.0, and 33.3 µg/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, QTRR1000, and TQ were measured before and after each concentration of the QT shortening test compounds.
Levcromakalim, pinacidil, and nicorandil but not vehicle significantly shortened RR, QT, QTbtb, QTRR1000, 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.
QTbtb, QTRR1000, 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.