The Electrogenic Na(+)/K(+) Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study

Background: Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP) under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions. Methods and Results: Sixty two AP recordings from non-diseased human heart preparations were used to construct a population of human ventricular models with normal APs and a wide range of ion channel densities. Multichannel ionic block was applied to investigate susceptibility to repolarization abnormalities. I(Kr) block was necessary for the development of repolarization abnormalities. Models that developed repolarization abnormalities over the widest range of blocks possessed low Na(+)/K(+) pump conductance below 50% of baseline, and I(CaL) conductance above 70% of baseline. Furthermore, I(NaK) made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% I(Kr) block. Reversing intracellular Na(+) overload caused by reduced I(NaK) was not sufficient to prevent abnormalities in models with low Na(+)/K(+) pump conductance, while returning Na(+)/K(+) pump conductance to normal substantially reduced abnormality occurrence, indicating I(NaK) is an important repolarization current. Conclusions: I(NaK) is an important determinant of repolarization abnormality susceptibility in human ventricular cardiomyocytes, through its contribution to repolarization current rather than homeostasis. While we found I(Kr) block to be necessary for repolarization abnormalities to occur, I(NaK) decrease, as in disease, may amplify the pro-arrhythmic risk of drug-induced I(Kr) block in humans.