Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis?

The lipid hypothesis, despite an overwhelming body of experimental evidence in animal models and epidemiological evidence in humans, was only definitively proved after the development of effective hypolipidemic agents. Similarly, there is now a large body of experimental evidence in animal models and epidemiological data in humans to support the oxidation hypothesis, but effective antioxidant regimens have yet to be developed. With the benefit of hindsight, the decision of the 1991 National Heart, Lung, and Blood Institute workshop to give a green light to trials, even trials that use safe, naturally occurring antioxidants, may have been premature. Not knowing how LDL is oxidized in vivo, we cannot be certain which antioxidants are likely to be most effective. We lack markers that would let us evaluate the efficacy of any given antioxidant intervention, and we lack criteria for rational selection of patients under high oxidative stress. Until we have such basic information, we should put a hold on further clinical trials. Instead, we should concentrate on developing the scientific base that will enable us to design an appropriate trial to test the oxidation hypothesis.