Conclusion and future trends reconciling the evidence

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On the basis of these considerations we can conclude that there is compelling evidence that enhanced oxidative stress is detectable in patients with classic risk factors for atherosclerosis, but its impact in the context of atherosclerosis, progression is still unclear. The reason for this uncertainty is due to the lack of clear evidence indicating that markers of oxidative stress, such as blood lipid peroxides or urinary F2-isoprostane, are of some value for predicting the progression of atherosclerosis, even if there is some evidence suggesting that antibodies against oxidized LDL may be of some utility.67 Conversely epidemiological studies seem to indicate that low antioxidant status increases the risk of cardiovascular disease.

Clinical characteristics of patients with low antioxidant status have not been defined and should be studied in the near future. So far, clinical trials with antioxidants included patients without evaluating either oxidative stress or antioxidant status and such indiscriminate enrolment could perhaps account for the negative results of antioxidant trials recently emphasized by meta-analysis.68 A recent report by Meagher et al.69 is highly relevant to this discussion. They fed normal subjects doses of vitamin E ranging from 200 to 2000 mg/day for 8 weeks. The highest dose increased plasma vitamin E levels 5-fold, but urinary excretion of isoprostanes and 4-hydroxynonenal (breakdown products of fatty acid auto-oxidation) was unaffected. The results suggest that in normally nourished subjects, additional vitamin E will not necessarily confer any additional antioxidant protection. Earlier studies in cigarette smokers, in contrast, did show a vitamin E effect on plasma isoprostane levels, suggesting that only in subjects under some oxidative stress will a vitamin E effect be obtained.70 The protective effect of vitamin E against coronary events in the SPACE study may reflect the fact that the subjects were under the oxidant stress known to accompany haemodialysis.59 In the same way, other people under increased oxidative stress (such as smokers, diabetics) could be also constitute a population more likely to benefit from antioxidants.

Moreover, as Steinberg and Witzum suggested,5 the antioxidants might be effective in inhibiting the initial stages of human atherosclerosis and yet ineffective or much less effective in reducing plaque instability and rupture. If this were the case, it might be necessary to find some way to assess early stages of lesion development (e.g. high-resolution ultrasound or magnetic resonance imaging) rather than relying on the usual late clinical endpoints. Of course, if the development of early lesions were successfully inhibited, there should eventually be a decrease in the frequency of clinical events, but in that case, the trials might need to extend beyond the conventional 5 years.

Another issue that deserves further attention is the choice of appropriate antioxidant treatment. So far several mechanisms, including enzymatic and nonenzymatic oxidation of LDL, have been proposed, but the exact process leading to LDL accumulation within vessel wall is still unclear. This fact creates uncertainty in the type of antioxidants that could be relevant for inhibiting atherosclerotic progress. Thus future trials with antioxidants should not be discouraged; conversely better identification of criteria identifying potential candidates for antioxidant treatment, together with the choice of an adequate daily regimen of antioxidants, should be studied.

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