Significance: The oxidative stress theory of atherosclerosis is based on the assumption that the production of reactive oxidant species (ROS) by blood, as well as resident cells of the artery wall, elicits the formation of oxidized low-density lipoproteins (ox-LDL), which, in turn, promotes a series of inflammatory responses, ultimately leading to atherosclerotic plaque. This theory prompted the development of new laboratory methodologies that aimed at assessing the relationship between oxidative stress and clinical progression of human atherosclerosis. Critical Issues: Markers assessing the oxidation of phospholipid and protein components of LDL were among the first to be developed. Clinical trials included cross-sectional as well as retrospective and prospective studies that, however, provided equivocal results. Thus, clear evidence that oxidative biomarkers add more to the risk stratification by common atherosclerotic risk factors is still lacking. Recent Advances: More recently, the analysis of oxidative stress focused on enzymatic pathways generating ROS, such as NADPH oxidase and myeloperoxidase (MPO). Experimental and clinical studies suggest that both enzymes may be implicated in promoting atherosclerotic disease. Novel laboratory methodologies have been, therefore, developed to study NADPH oxidase and MPO in patients with stable atherosclerosis as well as in patients with acute coronary and cerebro-vascular syndromes. Future Directions: This review will analyze the strengths and weaknesses of the current methodology to study these enzymes in human atherosclerosis with particular regard to their clinical application in several settings of cardiovascular disease. Clinical methodology and results of previous studies with regard to markers of LDL oxidation have also been reviewed as a useful background for the future development of clinical trials. Antioxid. Redox Signal. 23, 514–532.
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