Background
The Oxidative Modification Hypothesis of Atherosclerosis: Does It Hold for Humans?

https://doi.org/10.1016/S1050-1738(01)00111-6Get rights and content

Abstract

This review suggests that oxidation of LDL is an important, if not obligatory, event in atherogenesis. The important clinical corollary is that inhibition of oxidation can inhibit atherosclerosis independent of lowering plasma cholesterol levels. This article surveys the extensive data supporting the presence of oxidized LDL in vivo in animal models; the many studies demonstrating that inhibition of oxidation by pharmacologic and/or genetic manipulations retards atherogenesis; the data in humans that supports a role for oxidation of LDL; and the results of intervention trials with antioxidant vitamins. Limitations of these trials that may have led to inconclusive results to date are discussed, and what this may mean for the oxidation hypothesis. The oxidation hypothesis is still viable, but a great deal needs to be learned in order to design the appropriate clinical trials to properly test the importance of oxidation in the pathogenesis of atherosclerosis in humans.

Section snippets

Evidence for the Presence of OxLDL in vivo

There is now a large body of experimental work in animal models that strongly supports an important role for oxidative modification of LDL. This topic has been the subject of numerous reviews Chisolm and Steinberg 2000, Heinecke 1997, Navab et al. 1996, Steinberg and Witztum 1999, Tsimikas and Witztum 2000. We will not review all of these in detail again here. However, over the past several years several new lines of evidence and important studies have appeared that have continued to add to the

Does the Oxidative Hypothesis of Atherosclerosis Hold for Humans?

It is clear from the above that a wealth of evidence supports a major role for oxidative modification of LDL in a variety of animal species including nonhuman primates. Does it follow that the hypothesis will apply equally to the human disease? Not necessarily, but there are good reasons to believe that it may. In brief, and as reviewed elsewhere Steinberg 2000, Steinberg and Witztum 1999:

  • 1.

    The structure and cellular composition of lesions in experimental animal models resembles very closely that

Why Haven't the Clinical Trials Been More Effective in Humans?

First, the antioxidants used in these clinical trials may not be sufficiently potent or the doses used may be too low. As noted above, a major problem with the conduct of such clinical trials at the present time is that we do not have reliable and validated ways to identify patients who have increased rates of lipid peroxidation and importantly, we lack reliable measures to determine if there is an adequate response to a given antioxidant intervention. While vitamin E, for example, was shown to

Summary

There are a number of reasons why one would expect the oxidation of LDL to be significant in human atherosclerosis and, at the same time, there are a number of points to suggest it may not be important in all individuals, at least not to the same degree as in some experimental animal models.

To date all of the studies were carried out in patients with established, well-advanced CVD. The patients in ATBC probably received too low a dose. The patients in CHAOS, HOPE and GISSI were more or less

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