Cell-to-ECG modeling and clinical trial ECG evaluation of ECG J-to-T peak interval

Drug induced prolonged QT is associated with torsade de pointes (TdP), and therefore has been under a thorough investigation by FDA for the last 10 years. The main focus has been on the rapid delayed outward rectifier potassium current (Ikr) effects on the ECG QT interval. Lately, multi-ion channel effects like late-sodium and calcium currents have also been investigated, and the new ECG parameters like Tpeak-to-Tend (TpTe) and J-to-Tpeak (JTp) have been shown to correlate with multiple ion-channel changes. This study used a newly modified Cell-to-ECG whole heart model to simulate multi-ion channel effects on QT, TpTe and JTp intervals. The heart model combined the modified ion-channel with added Late Sodium current (I
_naL
) and a human ventricle heart geometry. The simulation induced the blockage of I
_kr
, I
_naL
, separately, and combined. The clinical data was from an FDA sponsored clinical trial with 22 healthy subjects who each received a single dose of a pure hECG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. The modeling results showed the I
_kr
-only-block prolongs QT by prolonging both TpTe and JTp intervals. The combination of I
_kr
and I
_naL
block caused QT and TpTe prolongation, but to a lesser extent; the JTp interval was shortened. The clinical trial data verified that for hECG blocker dominant drugs like dofetilide and quinidine, QT, TpTe and JTp were all prolonged with the increase of drug concentration; while balanced I
_kr
and I
_naL
by ranolazine had no effect on JTp. The modeling simulation predicted the trend of clinical results. I
_naL
block can shorten the JTp prolongation caused by Ikr block.