Risks of torsade de pointes (TdP) and sudden cardiac death are increased by drug-induced hERG channel inhibition and QT interval extension. However, some medications have been found to inhibit hERG channels and lengthen QT intervals with low or intermediate TdP risk. This is most likely because these medications also inhibit late Na+ and L-type Ca2+ currents and other additional inward currents. The J-Tpeak interval is a new biomarker of the net balance between inward and outward currents was recently discovered. Recent clinical trials have demonstrated that measuring the J-Tpeak interval can be helpful for determining if a medication has caused a proportionate block from inward currents. In preclinical research, conscious telemetered dogs and monkeys serve as the gold standard for assessing in vivo QT. Given that humans and guinea pigs have similar distributions of cardiac ion channels, telemetered guinea pigs are also a good model for measuring QT interval. Furthermore, because only minimal quantities of test substances are needed, conscious telemetered guinea pigs could be good model for in vivo electrocardiogram (ECG) monitoring in preclinical studies.
In a new study published in European Journal of Pharmacology, Kyorin Pharmaceutical Co. Ltd. scientists, Dr. Hisashi Nogawa, Dr. Yukiko Muraki, Dr. Tomoyuki Kawai and Dr. Yoshiharu Kuninishi examined the possibility of using J-Tpeak interval, a novel biomarker of inward current block and TdP risk, in conscious telemetered guinea pigs. The authors tested eight reference compounds with various ion channel-blocking properties to see how they affected the J-Tpeak and Tpeak-Tend durations in awake telemetered guinea pigs.
The research team demonstrated the value of J-Tpeak interval assessment in predicting drug-induced balanced block of inward currents and the risk of TdP in conscious guinea pigs. The findings showed that the optimised correction formula’s acquired slope and R2 of linear regression were closer to zero and that the formula was appropriate for identifying drug-induced QT and J-Tpeak interval extension under experimental settings. Researchers analysed the J-Tpeakc intervals’ comprehensive relationships with the QTc interval as well as the impact of reference substances on these intervals. In conscious guinea pigs, dofetilide and sotalol increased the ΔQTcX and ΔJ-TpeakcX intervals, and the ΔΔQTcX-ΔΔJ-TpeakcX inclination appeared significant. These findings supported a clinical investigation on the impacts of dofetilide on ECG parameters. On the other hand, both quinidine and quinine prolonged the ΔQTcX and ΔJ-TpeakcX intervals, with the former having a higher impact. Similar to other potent hERG channel blockers with Ca2+ and peak/late Na+ channel-blocking action, flecainide caused a moderate increasing trend in the ΔJ-TpeakcX interval and a considerable ΔQTcX lengthening in guinea pigs. In guinea pigs, ranolazine somewhat increased ΔQTcX and ΔJ-TpeakcX intervals, though less significantly than dofetilide and quinidine.
The J-Tpeakc interval can be measured in conscious telemetered guinea pigs to assess drug-induced balanced inward current block. The authors made an excellent effort to classify reference substances in accordance with the guinea pigs’ ΔΔJ-TpeakcX and ΔΔQTcX intervals. The findings categorised dofetilide, sotalol, and quinidine as high risk, flecainide, quinine, and ranolazine as intermediate risk and verapamil, and nifedipine as low risk. According to the authors, the J-Tpeak interval in the guinea pig model may be beneficial for forecasting the risk of TdP and drug-induced balanced block of inward currents.
In conclusion, the new study showcased the value of analysing the J-Tpeakc interval for assessing the danger of TdP and drug-induced balanced block of inward currents in their conscious telemetered guinea pig model. The findings confirmed the value of examining the J-Tpeak interval in conscious guinea pigs for identifying a drug-induced balanced block of inward currents and TdP risk when evaluating in vivo ECG in early preclinical research.
Nogawa H, Muraki Y, Kawai T, Kuninishi Y. Pharmacological characterisation of electrocardiogram J-Tpeak interval in conscious Guinea pigs. European Journal of Pharmacology. 2022 May 29:175065.