Effects of L-type calcium channel and human ether-a-go-go related gene blockers on the electrical activity of the human heart: a simulation study

AIMS: Class III and IV drugs affect cardiac human ether-a-go-go related gene (I(Kr)) and L-type calcium (I(CaL)) channels, resulting in complex alterations in repolarization with both anti- and pro-arrhythmic consequences. Interpretation of their effects on cellular and electrocardiogram (ECG)-based biomarkers for risk stratification is challenging. As pharmaceutical compounds often exhibit multiple ion channel effects, our goal is to investigate the simultaneous effect of I(CaL) and I(Kr) block on human ventricular electrophysiology from ionic to ECG level. METHODS AND RESULTS: Simulations are conducted using a human body torso bidomain model, which includes realistic representation of human membrane kinetics, anatomy, and fibre orientation. A simple block pore model is incorporated to simulate drug-induced I(CaL) and I(Kr) blocks, for drug dose = 0, IC(50), 2× IC(50), 10× IC(50), and 30× IC(50). Drug effects on human ventricular activity are quantified for different degrees and combinations of I(CaL) and I(Kr) blocks from the ionic to the body surface ECG level. Electrocardiogram simulations show that I(CaL) block results in shortening of the QT interval, ST elevation, and reduced T-wave amplitude, caused by reduction in action potential duration and action potential amplitude during the plateau phase, and in repolarization times. In contrast, I(Kr) block results in QT prolongation and reduced T-wave amplitude. When I(CaL) and I(Kr) blocks are combined, the degree of I(CaL) block strongly determines QT interval whereas the effect of I(Kr) block is more pronounced on the T-wave amplitude. CONCLUSION: Our simulation study provides new insights into the combined effect of I(CaL) and I(Kr) blocks on human ventricular activity using a multiscale computational human torso model.