Oxidative stress and endothelial dysfunction: therapeutic implications.

In a previous issue of Annals of Medicine, we presented evidence in support of the concept that an abnormally increased production of reactive oxygen species plays a central role in the genesis and progression of cardiovascular disease. While a number of preclinical lines of evidence support this concept, and despite the results of many studies suggesting a beneficial impact of antioxidant drugs on endothelial function, large clinical trials have failed to demonstrate a benefit of antioxidants on cardiovascular outcomes. Studies exploring the possibility that classical antioxidants such as vitamin C, vitamin E, selenium, or folic acid may improve the prognosis of patients with cardiac disease have substantially reported neutral-and occasionally negative-results. In contrast, medications such as statins, ACE inhibitors, certain β-blockers, or angiotensin I receptor blockers, which possess indirect 'ancillary' antioxidant properties, have been associated with beneficial effects in both preclinical studies and large clinical trials. The reasons for the failure of the 'direct' approach to antioxidant therapy, and for the success of the therapy with these drugs, are discussed in the present review.