In Response:Kontush and colleagues claim that vitamin E is not deficient in advanced atherosclerotic plaques of our patient cohort. 1 They suggest that our conclusion should not be based on the comparison of vitamin E/cholesterol ratios in plaque versus control plasma nor on the use of 7hydroxy-cholesterol/vitamin E ratios.As we pointed out in our study aimed at understanding the striking differences of vitamin E effects in experimental and clinical studies, this is the first report on lipid peroxidation, colloquially oxidative stress, and vitamin E tenure in patients with advanced atherosclerosis at both plasma and tissue level. Lipid peroxidation and vitamin E are strictly linked, thus the simultaneous assay of their levels should show the current free radical flux in vivo and the related consumption of protective antioxidants. With regard to our findings, the plasma level of 7hydroxy-cholesterol, a marker of lipid peroxidation, is significantly higher in patients with carotid atherosclerosis compared with healthy subjects, whereas plasma vitamin E concentration is reduced by Ϸ50%. This pattern resembles the kinetics of LDL oxidation in vitro, which shows the rise of lipid peroxidation products after a large consumption of vitamin E carried in the LDL molecule. 2,3 Thus, vitamin E is unambiguously reduced in the plasma of our patients with advanced carotid atherosclerosis. On the other hand, the analysis at tissue level showed increased oxysterols in plaque compared with normal vessels, but inconsistent differences were found in vitamin E levels between plaque and normal vessels. Because there is no "normal" plaque to serve as a reference, we used normal vessels and plasma considered as compartments. In addition, we chose the ratio 7hydroxy-cholesterol/vitamin E to have further details of the relative amounts in these compartments, and we measured a 200-fold gradient of 7hydroxy-cholesterol/vitamin E ratio between plaque and plasma compartments. Therefore, any antioxidant therapy should affect this gradient. Consistent with the oxidative stress/antioxidant imbalance in patients with carotid atherosclerosis, we found that lipid peroxidation and antioxidant status in plasma were affected positively by vitamin E supplementation. The novel information which emerged from our study is that vitamin E supplementation does not affect the levels of oxysterols and vitamin E in the plaque. These findings suggest that supplemental vitamin E did not reach the carotid plaque, which might be because of the inadequate dosage and/or period of supplementation or on the involvement of unknown mechanisms. Therefore, a cautionary note should be sounded with the conclusion by Kontush that we "have consistently documented the absence of a deficit of vitamin E in human plaque tissue, even at advanced stages of atherosclerosis." In fact, the absence of a deficit implies that the "optimal" vitamin E concentration in the plaque has been well established, and that this value coincides with the value we measured. Thus, the only conclus...