The present randomized, placebo controlled study demonstrates that antioxidant supplementation with vitamin C, vitamin E, coenzyme Q10 and selenium significantly increased large and small artery elasticity in patients with multiple cardiovascular risk factors. This beneficial vascular effect was associated with an improvement in glucose and lipid metabolism as well as significant decrease in blood pressure.
Assessment of arterial function and structure can serve as a surrogate endpoint for prediction of morbid events and for estimation of success of treatment. Pulse wave contour analysis using the modified Windkessel model is one of several noninvasive methods for estimation of arterial properties. Numerous studies performed with the HDI CR-2000 equipment have shown good correlation to age, cardiovascular risk factors and markers of disease [13
]. Therapeutic interventions with medications like statins, angiotensin II receptor blocking agents as well as weight loss, have also shown improvement in LAEI and SAEI which may suggest lowering of cardiovascular risk. Nevertheless, no major prospective study associating arterial elasticity with cardiovascular events has been performed. Although PWA using the modified Windkessel model has some limitations, this method provides complementary information about vascular health.
The favorable vascular effect of antioxidants has been observed in vitro
and in animal models of atherosclerosis [14
]. However, data on long-term vascular impact of antioxidant supplementation in humans are limited and controversial. The findings of the present study concur with those of previous study that has shown substantial reduction in the progression of common carotid atherosclerosis during three year treatment with combined supplementation of both vitamin E and vitamin C [17
]. Additionally, the beneficial effect of antioxidant supplementation on LDL oxidation and endothelial flow has been demonstrated [18
]. Moreover several prospective randomized controlled clinical trials such as Cambridge Heart Antioxidant Study, Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage Renal Disease study and Cholesterol Lowering Atherosclerosis Study reported that the administration of antioxidants reduced the risk of cardiovascular disease [20
]. Nevertheless, subsequent large interventional studies do not support a benefit from antioxidant supplementation [23
]. These clinical trials have demonstrated that vitamin E alone or in combination has no effect on the risk of death or prevention of cardiovascular disease. Moreover, a dose-response meta-analysis has shown that high-dosage vitamin E supplementation was associated with a small but statistically significant increased risk for mortality [25
]. The lack of benefit seen in these clinical trials does not disprove the central role of oxidative stress in atherosclerosis and justify investigating the overall clinical impact of antioxidant treatment.
Although the anti-atherogenic effect of antioxidants has been assessed in several experimental studies, the mechanisms by which these agents inhibit atherosclerosis remain to be clarified. Combined supplementation of vitamin E and C have been shown to inhibit DNA oxidation by H2
in human lymphocytes, to enhance endogenous plasma and tissue antioxidant defenses and restore endothelium-dependent vasoactivity [18
]. Coenzyme Q10
which plays an essential role as an electron carrier in mitochondrial oxidative phosphorylation, improves endothelial dysfunction in diabetic patients [28
]. Finally, selenium as a determinant of antioxidative glutathione peroxidase 1 expression and activity, provides significant protection of the coronary artery endothelium against damage by oxidative stress [29
The findings of the present study concur with those of previous studies that have shown substantial reduction in blood pressure and improvement in long-term glycaemic control with oral CoQ supplementation, reduction in plasma glucose and insulin resistance with high doses of vitamin E supplementation and significant reduction in blood pressure levels with vitamin E as well as vitamin C in hypertensive patients [30
]. Nevertheless, which particular antioxidant or combination of antioxidants is responsible for the favorable metabolic effect in the present study remains uncertain. Additionally, we cannot exclude the possibility that specific antioxidant combination which was used in the present study, has a contributory effect of on blood pressure, glucose and lipid homeostasis as well as on improvement of vascular elasticity.
In the present study, we did not observe significant changes in humoral factors such as homocystein, endothelin, aldosterone and renin in subjects received antioxidant supplementation. Levels of urine cathecholamines also did not change during the treatment period. These findings emphasize a previously published data which have shown that patophysiologic mechanism of antioxidants action is independent of the changes in plasma concentration of blood pressure modulators, such as renin, aldosterone, endothelin [34
], although the precise mechanism for antioxidant action on the vasculature remains to be elucidated.
Our study has several limitations. First, the present study contains relatively small number of participants and larger studies are required to establish the beneficial vascular effect of antioxidant supplementation. Second, we did not measure plasma levels of the antioxidants which would have added the information regarding treatment compliance and would have elucidated the pathophysiology for vascular action of antioxidants. Furthermore, since the present study has focused on patients with multiple cardiovascular risk factors, the application of our findings to other patient populations remains uncertain.