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

Frontiers in Physiology
Oliver J BrittonBlanca Rodriguez

Abstract

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. IKr 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 ICaL conductance above 70% of baseline. Furthermore, INaK made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% IKr block....Continue Reading

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Citations

Feb 23, 2020·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Dominic G WhittakerGary R Mirams
Feb 25, 2020·Alternatives to Laboratory Animals : ATLA·Blanca Rodriguez
Sep 4, 2020·Investigative Ophthalmology & Visual Science·Soufien SghariLena Gunhaga
Sep 8, 2017·Frontiers in Physiology·Sara DuttaZhihua Li
Aug 7, 2018·Frontiers in Physiology·Haibo NiEleonora Grandi
Mar 1, 2021·Journal of Electrocardiology·John JurkiewiczPeter Hinow
Mar 26, 2021·Cell Reports Medicine·Polina MamoshinaAlfonso Bueno-Orovio
Sep 9, 2021·Proceedings of the National Academy of Sciences of the United States of America·Meera VarshneyaEric A Sobie

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