Predicting critical drug concentrations and torsadogenic risk using a multiscale exposure-response simulator.

ABSTRACT: Torsades de pointes is a serious side effect of many drugs that can trigger sudden cardiac death, even in patients with structurally normal hearts. Torsadogenic risk has traditionally been correlated with the blockage of a specific potassium channel and a prolonged recovery period in the electrocardiogram. However, the precise mechanisms by which single channel block translates into heart rhythm disorders remain incompletely understood. Here we establish a multiscale exposure-response simulator that converts block-concentration characteristics from single cell recordings into three-dimensional excitation profiles and electrocardiograms to rapidly assess torsadogenic risk. For the drug dofetilide, we characterize the QT interval and heart rate at different drug concentrations and identify t

SUBMITTER: Sahli Costabal F 

PROVIDER: S-EPMC6483901 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature