Method Profile
A coupled computational model links ventricular electrophysiology, mitochondrial energetics and ROS-dependent calcium/channel modulation.
Generate mechanistic hypotheses about oxidative cardiotoxicity, pacing rate and combined loss of repolarization reserve.
The Zukowski ECM-ROS model couples human ventricular equations with mitochondrial/ROS modules adapted from prior models and mixed-species experimental evidence.
A dimensionless doxorubicin-effect parameter and fixed IKr block are compared across pacing conditions; one population of 1,000 virtual cells is reused across five perturbations.
Model components
O’Hara–Rudy human ventricular electrophysiology with mitochondrial calcium/energetics and ROS production/scavenging modules.
Experimental comparators
Published rat/guinea-pig/rabbit and other preparations inform individual components; an independent human ventricular-slice dataset includes nine male donors.
Population design
Twelve conductance factors vary independently within ±20% of baseline; the same virtual population receives baseline, doxorubicin, block and combined conditions.
Separate calibration from comparison with external measurements. Keep the dimensionless stress parameter distinct from drug concentration and distinguish steady-state dose-effect scans from post-pause population results.
Compare one virtual-cell population under doxorubicin stress, 30%/40% IKr block and matched single-perturbation conditions.
1,000 virtual ventricular cells; the separate APD80 human-slice comparator contains nine male donors.
Baseline; full doxorubicin effect alone; full effect plus 30% or 40% IKr block; 40% block without doxorubicin.
Neither doxorubicin stress alone nor 40% IKr block alone produced early afterdepolarizations. A subset developed them with combined full stress and 40% block; 30% combined block did not.
A computational preprint couples mitochondrial ROS, calcium handling and human ventricular electrophysiology. Combined doxorubicin-like oxidative stress and 40% IKr block produce early afterdepolarizations in part of a virtual-cell population.
