Cellular mechanisms of radiation-induced myocyte dysfunction: effects on calcium handling, ion channel regulation and...

Ionizing radiation induces a range of cellular responses in cardiomyocytes that vary with the dose, duration of exposure and metabolic state. Although historically attributed to microvascular injury and fibrosis, radiation-induced cardiac dysfunction is now recognized to originate from direct perturbations of myocyte calcium handling, ion channel regulation and mitochondrial energetics. Low to moderate radiation doses generate sustained reactive oxygen species (ROS) that activate oxidation-dependent calcium/calmodulin-dependent protein kinase II (CaMKII) signalling, leading to disrupted sarcoplasmic reticulum calcium cycling, altered sodium and calcium currents and increased susceptibility to early and delayed after-depolarizations. Mitochondrial structural and energetic instability further amplifies ROS-CaMKII feedback, promoting a pro-arrhythmic electrophysiological substrate. High-dose radiation exposures, such as those used in cardiac stereotactic body radiotherapy, lead to a distinct electrical reprogramming phenotype characterized by coordinated upregulation of sodium channels, calcium channels, potassium channels and gap junction proteins. The resulting emergent effects are to enhance conduction velocity and electrical homogeneity that together provide a mechanistic explanation for the rapid anti-arrhythmic effects observed clinically, even independent of fibrosis. Across the radiation dose spectrum, the mitochondria serve as key integrators of redox stress and calcium overload, shaping the transition from reversible signalling alterations to persistent remodelling. This review synthesizes mechanistic patterns underlying radiation-induced myocyte dysfunction, highlights unresolved discrepancies across experimental models and discusses how computational modelling might be the ideal tool to predict optimal therapeutic radiation delivery while mitigating long-term cardiotoxicity.