Most cases of drug-induced torsades de pointe (TdP) have been associated with inhibition of the human ether-a-go-go-related gene (hERG) channel (carrying the rapid delayed rectifier IKr current); this potassium current plays an important role in the repolarization phase of the human cardiac action potential. However, not all drugs inhibit hERG channel cause TdP.
It is well appreciated that acquired or drug induced torsades de pointe (TdP), is associated with the generation of long action potential duration (APD)-related early after depolarizations (EADs) and EAD-induced triggered activity. EADs, ocurring as oscillations during phase 2 or 4 of the action potential (AP) are potentially arrhythmogenic.
In Vivo Models
A limitation of the ICH-S7B guideline is that it addresses repolarization delay with its well-known limitations to predict proarrhythmia risk and induced torsades de pointe (TdP). As a result of growing evidence against the use of QT interval as the primary endpoint for proarrhythmia liability, the interest in using clinically relevant and predictable in vivo proarrhythmia models have increased.