Reactive oxygen species (ROS) production in cardiac myocytes plays a crucial role in the pathophysiology of various cardiac diseases by altering calcium dynamics and consequently, excitation-contraction coupling. Clinical and experimental studies suggest that oxidative stress is a major common pathway in response to radiation, anticancer drugs, and aging, leading to disruptions in calcium dynamics and ultimately causing arrhythmia or cell death. While the mechanisms underlying ROS-induced cardiac dysfunction have been the subject of many studies, the intersection and coupling of the many pathways involved creates a complex system difficult to address with traditional experimental approaches. Computational modeling and simulation overcome many limitations, allowing for prediction, sensitivity analysis, and component dissection. To identify the primary disease-causing mechanisms, we developed a computational model integrating the O’Hara-Rudy human ventricular action potential model with a simplified model of mitochondrial bioenergetics and ROS production. Our mitochondrial component includes membrane potential, calcium uptake through the calcium uniporter, and calcium efflux through the permeability transition pore and sodium-calcium exchanger. ROS generation is modeled as a fraction of mitochondrial NADH production, and cytosolic ROS scavenging is adapted from the Cortassa 2004 mitochondrial ROS model. Simulations predict that elevated ROS levels lead to greater calcium release through the ryanodine receptor, reduced calcium reuptake by the sarcoplasmic reticulum calcium-ATPase pump, and changes to the L-type calcium current and late sodium current. The resulting disruption of calcium homeostasis alters the mitochondrial membrane potential and further increases ROS production. The positive feedback loop sustains elevated intracellular calcium, producing prolonged action potential duration and afterdepolarizations that may promote arrhythmia. The model predictions are validated by experimental data, indicating plausible mechanisms of oxidative stress effects on myocyte electrophysiology. The model can used to identify therapeutic targets for managing ROS-induced calcium dysfunction.
Zukowski et al. (Sun,) studied this question.