A Computational Model of Oxidative Stress in a Human Ventricular Myocyte

Mitochondrial reactive oxygen species (ROS) are implicated in cardiac dysfunction, but complex dynamic interactions between ROS, intracellular calcium, and electrophysiology make it difficult to resolve mechanisms experimentally. We developed the Zukowski excitation-contraction-mitochondrial-ROS (ECM-ROS) model, a computational model that couples human ventricular electrophysiology with mitochondrial calcium handling, energetics, ROS production, and ROS dependent modulation of the ryanodine receptor, SERCA, L-type calcium current, and late sodium current. Model predictions were evaluated against independent experimental measurements of ROS induced changes in action potential duration and intracellular calcium. We then used the model to characterize ROS calcium feedback across physiological pacing rates and applied it to doxorubicin induced oxidative stress. Increasing cytosolic calcium produced nonlinear amplification of mitochondrial activity and cytosolic ROS, with greater amplification at faster pacing rates. Moderate ROS elevation initially enhanced calcium release, whereas greater oxidative stress depleted sarcoplasmic reticulum calcium stores. During simulated doxorubicin exposure, faster pacing lowered the level of oxidative stress required to produce calcium dysregulation and action potential prolongation. Mitochondrial ROS and calcium accumulation preceded detectable electrophysiological remodeling. In populations incorporating variability in ion channel expression, neither doxorubicin induced oxidative stress nor subtle pharmacological I _Kr block alone produced early afterdepolarizations. However, early afterdepolarizations were predicted to emerge with combined perturbations. These findings establish a computational framework for investigating bidirectional coupling among mitochondrial function, ROS, calcium handling, and human cardiac electrophysiology. The model generates testable predictions regarding the early detection of oxidative cardiac injury and the physiological conditions that increase susceptibility to arrhythmia.

Hannah Zukowski is a PhD candidate in Biomedical Engineering at the University of California, Davis, where she works with Dr. Colleen E. Clancy in computational cardiovascular physiology. She earned her B.S. in Mechanical Engineering from Trinity College, where her early work in computational modeling led to an interest in applying engineering approaches to biological systems. Her doctoral research focuses on mechanistic models of mitochondrial bioenergetics, reactive oxygen species, and cardiac electrophysiology to investigate oxidative stress-induced cardiotoxicity. Her future research interests include multiscale and patient-specific cardiovascular modeling to improve the prediction of cardiac dysfunction and treatment response.

Oxidative stress can disrupt calcium regulation and electrical activity in human heart cells, but the interactions among these processes are difficult to study experimentally.We developed a computational model that connects mitochondrial function and reactive oxygen species with calcium regulation and electrical activity in human heart cells.The model predicts that increases in calcium can amplify mitochondrial activity and reactive oxygen species, particularly at faster heart rates.During simulated exposure to the chemotherapy drug doxorubicin, reactive oxygen species accumulation developed before detectable changes in electrical activity. Faster heart rates also increased the effects of oxidative stress.The model provides a framework to investigate how oxidative stress contributes to cardiac dysfunction and to identify conditions that may increase susceptibility to abnormal electrical activity.