Oxidative Stress, Antioxidants, and Cardiovascular Disease
To the Editor:
Oxidative stress is believed to play a major role in the initiation and progression of atherosclerotic disease. The majority of evidence in support of the “oxidative stress theory” comes form in vitro studies and experimental models of atherosclerosis showing that antioxidants may prevent atherosclerotic disease. As outlined in a recent review by Madamanchi et al,1 interventional trials with antioxidants in human provided divergent results, which may also depend on the inability to identify a priori the patients who potentially are responders to this treatment. Concerning this last point, we have recently underscored the fact that in the interventional trials the candidates for antioxidant treatment were not accurately defined, most likely because of the application of the following syllogism:2
Oxidative stress is a common pathway for initiation and progression of atherosclerosis;
Cardiovascular complications are secondary to atherosclerosis;
All patients with or at risk of cardiovascular disease have enhanced oxidative stress and could obtain beneficial effects from antioxidant treatment.
That this syllogism has been applied to almost all trials with antioxidants is demonstrated by the fact that any patient at risk for cardiovascular disease has been indiscriminately enrolled in these trials. A typical example of the indiscriminate inclusion of patients in interventional trials with antioxidants comes from the analysis of the HPS study, which recruited patients having normal plasma values of vitamin E and probably not needing any supplementation with this vitamin.3 This interpretation is likely surprising, taking into account that the HPS study included patients with hypercholesterolemia and diabetes who have enhanced markers of oxidative stress. In another analysis, however, we noticed that these patients may have low or normal plasma values of vitamins E or C, suggesting that not all patients at risk for cardiovascular disease necessarily need a supplementation with these vitamins.2 So far the analysis of antioxidant status has not been considered as an inclusion criteria in the interventional trials with antioxidants. However, antioxidant status is an important marker of oxidative stress and may predict cardiovascular complications, as suggested by the fact that patients at high risk for cardiovascular mortality have lower plasma levels of vitamin E compared with those with low risk.2
We argue, therefore, that integration of antioxidant status as inclusion criterion in the interventional trials with antioxidants may represent another approach to better explore the role of oxidative stress and the potential efficacy of antioxidant treatment in patients at high risk for atherosclerotic progression.
Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005; 25: 29–38.
Violi F, Loffredo L, Musella L, Marcoccia A. Should antioxidant status be considered in interventional trials with antioxidants? Heart. 2004; 90: 598–602.
Violi F, Micheletta F, Iuliano L. MRC/BHF Heart Protection Study. Lancet. 2002; 360: 1782–1783.
We agree with Dr Violi et al, that a fundamental flaw in the majority of antioxidant studies has been the lack of a reliable measure for oxidative stress, either before or after therapy, making it nearly impossible to assess the success or failure of interventions such as the administration of antioxidant vitamins. There are surrogate measures that could be used, as noted in our review and in this letter, and in our opinion should be a requirement if a strong statement about antioxidant therapy efficacy is to be made. Of course, the issues of systemic versus local oxidative levels have yet to be completely understood, but even these issues would not negate the benefit of measuring systemic oxidative stress before and after purported interventions.