Reactive oxygen species imbalance in atherosclerosis: Biomarker phenotyping, residual risk, and a translational framework for precision prevention
Background: Atherosclerotic cardiovascular disease (ASCVD) leaves substantial residual risk despite intensive low-density lipoprotein-cholesterol lowering and anti-inflammatory therapy. Reactive oxygen species (ROS) have long been implicated, yet neutral broad-antioxidant trials left unclear which dimensions of ROS imbalance are causal, clinically informative, and therapeutically tractable. Aim: To critically appraise ROS imbalance in atherosclerosis through a plausibility–association–utility hierarchy and to propose a staged framework for precision cardiovascular prevention. Methods: We synthesized mechanistic, biomarker, and translational evidence from targeted PubMed/MEDLINE, Embase, and Cochrane searches (January 2000–February 2026), combining terms for ROS, oxidative stress, atherosclerosis, oxidative biomarkers, and residual cardiovascular risk, with citation chaining. Mass-spectrometry biomarker work, prospective cohorts, and randomized trials received greater interpretive weight. Systematic-review procedures were not applied. Results: Compartmentalized, source-specific ROS imbalance contributes to endothelial dysfunction, lipoprotein oxidation, inflammatory amplification, and plaque progression, particularly in high-risk cardiometabolic phenotypes. Human biomarker data are predominantly observational, assay standardization is incomplete, and risk-reclassification evidence is limited. F2-isoprostanes are a relatively mature lipid-peroxidation marker better suited to trial enrichment than treatment selection. Conclusion: Oxidative biomarkers are defensibly used for trial enrichment but not individual treatment selection. A staged precision-prevention agenda should test source-selective interventions in biomarker-enriched cohorts using vascular and mechanistic endpoints before large outcome trials. Relevance for Patients: Adults whose cardiovascular risk remains high despite cholesterol-lowering and anti-inflammatory treatment—including those with diabetes, kidney disease, smoking, obesity, or recurrent events—may eventually benefit if oxidative stress tests can identify who remains vulnerable and guide targeted prevention.