Review of human studies on oxidative damage and antioxidant protection related to cardiovascular diseases.

Under oxidative stress, which is associated with atherosclerosis, oxidative modifications of LDL take place. A major effect of antioxidants in the LDL environment is to prevent the formation of oxidized LDL during atherogenesis. The question that arises is what are the body's capabilities to inhibit LDL oxidation and to remove and/or to neutralize atherogenic Ox-LDL when formed. Strategies to reduce LDL oxidation and atherogenesis can involve the enrichment of the LDL and arterial cells with potent antioxidants that can prevent oxidative damage to the arterial wall. There seems to be a clear cause and effect relationship between LDL oxidation and atherosclerosis. Atherosclerosis is a multifactorial disease and LDL is oxidized by all major cells of the arterial wall during the development of atherosclerosis via more than one mechanism. The various LDL oxidation pathways produce several lipid peroxidation products such as isoprostanes from arachidonic, eicosapentaenoic and docosahexaenoic acids, oxysterols from unesterified and esterified cholesterol, hydroxy fatty acids, lipid peroxides and aldehydes. Thus, one single assay of lipid peroxidation is probably not sufficient to serve as a marker for cardiovascular risk and there is a need for measurements of several markers. The use of biomarkers provides a logical scientific basis for major intervention trials of antioxidants; such trials will, in turn, eventually validate or disprove the biomarker concept. Any intervention trial that does take place should be accompanied by measurements of one or more relevant biomarkers at intervals during the study. If the endpoint of the trial is disease incidence or mortality, such studies will help to validate or disprove the biomarker concept. They might also help to explore the possibility that in vivo levels of oxidative lipid damage are early predictors of subsequent development of cardiovascular disease. In addition, specific antioxidants in serum, as well as serum paraoxonase activity can provide very useful information on the risk for cardiovascular diseases. For vascular disease risk, in addition to the markers in use for lipid peroxidation, there is a need to include also markers for endothelial dysfunction, monocyte adhesion, macrophage uptake of lipoproteins, thrombotic, and inflammatory processes.