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Objective-Oxidative stress is believed to play a pivotal role in the initiation and progression of atherosclerosis. We analyzed whether vitamin E supplementation influences oxidative stress in plasma and atherosclerotic plaques of patients with severe atherosclerosis. Methods and Results-In 16 patients who were candidates for carotid endarterectomy and in 32 age-and sex-matched controls, plasma levels of 7␤-hydroxycholesterol, 7-ketocholesterol, cholesterol, and vitamin E were measured. Patients were randomly allocated to standard treatment with or without 900 mg/d vitamin E. After 6 weeks of treatment, the reported variables were measured in plasma and plaques. The plasma vitamin E/cholesterol ratio was significantly lower in patients than in controls (3.05Ϯ0.6 versus 6.3Ϯ1.7 mol/mmol cholesterol, PϽ0.001). Plasma 7␤-hydroxycholesterol was significantly higher in patients than in controls (5.0Ϯ1.04 versus 4.4Ϯ0.6 ng/mL, PϽ0.05). Patients who were given vitamin E supplementation showed a significant increase of plasma vitamin E with concomitant decrease of 7␤-hydroxycholesterol. Conversely, no treatment dependence was observed in oxysterol or vitamin E content of plaques. Conclusions-An imbalance between oxidative stress and antioxidant status is present in patients with advanced atherosclerosis. Vitamin E supplementation improves this imbalance in plasma but not in plaques. Key Words: atherosclerosis Ⅲ oxidative stress Ⅲ vitamin E Ⅲ oxysterols Ⅲ carotid plaques T here is considerable interest in the role of oxidative stress in several disease settings, including atherosclerosis. 1,2 A large number of clinical trials with antioxidants, mainly vitamin E, in patients with or at risk for cardiovascular disease was performed, but in most cases no effect of vitamin E on the incidence of cardiovascular events was noted. 3 Consequently, the usefulness of antioxidants in cardiovascular diseases has been a matter for debate in the scientific community. 4 Several hypotheses have been put forward to explain the discordant results of interventional trials based on antioxidant treatment, including the compliance, design of the trials, and dosage and source of vitamin E used. 5,6 An important argument of debate is the striking difference of vitamin E effects in experimental and clinical studies. In contrast to clinical trials with antioxidants, there is compelling evidence in favor of the antiatherosclerotic effect of vitamin E in experimental models of atherosclerosis. 7 One possible explanation for this discrepancy is that in experimental models, vitamin E treatment has been able to affect the early stage of atherosclerosis, whereas clinical trials enrolled patients with advanced atherosclerosis who are not sensitive to antioxidant treatment. The demonstration that antioxidants are ineffective in advanced human atherosclerosis could help to interpret the negative results of clinical trials and also to modify the design of future trials. To specifically address this issue, we studied candidates for carotid endarterectomy, be...

Oxidative stress is implicated in the pathogenesis of hepatic ischemia-reperfusion injury, a major determinant of initial poor graft function (IPGF) after orthotopic liver transplantation (OLT). We prospectively investigated the association between the recipient plasma preoperative oxidative stress and the occurrence of IPGF after deceased-donor OLT and indirectly studied the sourcehepatic or extra-hepatic-of systemic oxidative stress in vivo in cirrhosis. We used a recently developed specific and sensitive mass spectrometry assay to measure 7␤-hydroxycholesterol and 7-ketocholesterol (oxysterols), markers of oxidative stress, in biological matrices. At univariate analysis, preoperative recipient 7␤-hydroxycholesterol plasma concentration was significantly higher in transplants with subsequent IPGF (n ‫؍‬ 9) compared with those with initial good graft function (IGGF; n ‫؍‬ 23) [mean ؎ SD: 30.63 ؎ 26.42 and 11.57 ؎ 15.76 ng/mL, respectively] (P ‫؍‬ 0.017). In a logistic regression model, which included also the Model for End-Stage Liver Disease (MELD) score, 7␤-hydroxycholesterol plasma concentration was an independent predictor of IPGF with an odds ratio of 1.17 (95% CI, 1.02-1.33, P ‫؍‬ 0.028). Patients with cirrhosis (n ‫؍‬ 32) had increased oxysterol plasma levels compared with healthy controls (n ‫؍‬ 49); livers with cirrhosis (n ‫؍‬ 21), however, had oxysterol content comparable with normal livers obtained from organ donors (n ‫؍‬ 19). Oxysterols persisted elevated in plasma 1 month after OLT (n ‫؍‬ 23). In conclusion, cirrhosis presents upregulated systemic oxidative stress likely of extrahepatic source that is associated with graft failure after OLT. (Liver Transpl 2005;11:1494-1504.)