CLINICAL STUDIES
Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men
Thomas Neunteufl, MDa,
Karam Kostner, MDa,
Reinhold Katzenschlager, MDb,
Manfred Zehetgruber, MDa,
Gerald Maurer, MD, FACCa and
Franz Weidinger, MDa
a Department of Cardiology, University of Vienna, Vienna, Austria
b Department of Vascular Medicine, University of Vienna, Vienna, Austria
Manuscript received December 11, 1997;
revised manuscript received May 11, 1998,
accepted May 20, 1998.
Address for correspondence: Dr. Franz Weidinger, Department of Cardiology, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
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Abstract
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Objectives. The aim of this study was to determine whether the combination of lipid-lowering therapy and vitamin E supplementation improves peripheral endothelial function and whether it is more effective than lipid-lowering therapy alone.
Background. Endothelium-dependent vasodilation is impaired in coronary and peripheral arteries of patients with hypercholesterolemia. Coronary endothelial function has been shown to improve under lipid-lowering and antioxidant therapy, but the effect of additive vitamin E supplementation in the brachial artery is unknown.
Methods. Seven patients with hypercholesterolemia (mean ± SD; age 51 ± 10 yr) were studied. Endothelium-dependent, flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-induced dilation (NMD) were assessed in the brachial artery using high resolution ultrasound 1) at baseline (BL I), 2) after 8 weeks of simvastatin (20 mg) and vitamin E (300 IU) therapy (Comb I), 3) after withdrawal of vitamin E for 4 weeks (Statin), 4) after therapy as in #2 for 4 weeks (Comb II) and 5) after withdrawal of both drugs for 4 weeks (BL II).
Results. Combined simvastatin and vitamin E therapy reduced total cholesterol (Comb I vs. BL I: 276 ± 22 vs. 190 ± 14 mg/dl, p < 0.0001) and low-density lipoprotein (LDL)-C (197 ± 22 vs. 106 ± 22 mg/dl, p < 0.00001), augmented alpha tocopherol levels normalized to LDL (12.2 ± 4.1 vs. 4.9 ± 0.9 µg alpha-T/100 mg% LDL-C, p < 0.01) and resulted in significant improvements in FMD (16.4 ± 4.7 vs. 4.9 ± 2.5%, p < 0.001) as well as NMD (17.9 ± 4.3 vs. 11.2 ± 2.8%, p < 0.01). The ratio of FMD to NMD (0.92 ± 0.17 vs. 0.46 ± 0.24%, p < 0.05) also increased under combination therapy, indicating a greater improvement of FMD than that of NMD. After withdrawal of vitamin E, both FMD (Comb I vs. Statin: 16.4 ± 4.7 vs. 7.9 ± 4.7%, p < 0.01) and NMD (17.9 ± 4.3 vs. 10.9 ± 4.5%, p < 0.05) decreased significantly such that simvastatin alone only tended to improve FMD and did not change NMD. Results under combination therapy (Comb II vs. BL II) were reproducible.
Conclusions. Combined vitamin E and simvastatin therapy leads to an improvement of FMD and NMD in the brachial artery of patients with hypercholesterolemia. The improvement of FMD is more pronounced after combination therapy than after lipid-lowering therapy alone, similar to previous findings in the coronary circulation.
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Abbreviations and Acronyms
| | BL | = baseline | | Comb | = combined therapy | | FMD | = flow-mediated vasodilation | | LDL-C | = low-density lipoprotein-cholesterol | | NMD | = nitroglycerin-induced vasodilation | | NTG | = nitroglycerin | | Statin | = simvastatin therapy |
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Hypercholesterolemia as well as low plasma concentrations of vitamins E and C are associated with a high incidence of cardiovascular disease (1–5). Epidemiologic studies have shown that high intake of vitamin E is associated with a lower risk of coronary heart disease in men and women (6,7). Lowering the levels of total and low-density lipoprotein (LDL) cholesterol in patients with coronary artery disease resulted in a decrease in cardiac events even in patients with average serum cholesterol levels (8–12).
Oxidative modification of LDL is assumed to play a key role in the pathogenesis of atherosclerosis (13–15). Oxidized LDL promotes foam cell formation (16,17), stimulates monocyte adhesion (18,19) and is cytotoxic to vascular cells (20). Moreover, in the presence of oxidized LDL the G protein-dependent stimulation of nitric oxide release is interrupted (21,22) and the physiologic action of nitric oxide is directly blocked by lipid peroxidation products (23).
Endothelium-dependent vasodilation, largely mediated by nitric oxide (24), is impaired in coronary and peripheral arteries of patients with hypercholesterolemia and coronary artery disease (25–27) and can partly be restored by lipid-lowering therapy (28–33). In coronary arteries of patients with mild hypercholesterolemia the improvement in endothelium-dependent vasodilator response to acetylcholine was more pronounced after a combined lipid lowering (lovastatin) and antioxidant therapy (probucol) (34) than after LDL-lowering therapy or dietary means alone.
Although the oral intake of vitamin E, the main lipid-soluble antioxidant in human plasma proteins and lipoproteins, restored endothelium-dependent vasodilation in cholesterol-fed rabbits (35,36), it failed to improve endothelial function in the human forearm microvasculature of patients with hypercholesterolemia (37).
The present study was performed to determine whether the combination of simvastatin therapy and vitamin E supplementation improves endothelial function of the brachial artery and whether it is more effective than lipid-lowering therapy alone.
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Methods
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Patients.
Seven patients (mean ± SD, age 51 ± 10 yr, range 36 to 64) with total serum cholesterol levels  250 mg/dl and LDL-C 150 mg/dl were enrolled in the study. All patients kept a diet for at least 6 months (American Heart Association Step I) but none of them took lipid-lowering or antioxidative drugs prior to this study. Three patients had angiographic evidence of coronary artery disease. One patient had mild mitral and aortic regurgitation. In five patients hypercholesterolemia was the only cardiovascular risk factor. In two patients borderline hypertension was also present. All patients were nonsmokers.
Assessment of FMD.
In all subjects flow-mediated endothelium-dependent vasodilation (FMD) following reactive hyperemia and endothelium-independent nitroglycerin (NTG)-induced vasodilation (NMD) were examined in the brachial artery. Ultrasound measurements were performed according to the method described by Celermajer et al. (26). Using high resolution ultrasound (Acuson 128XP/10, Mountain View, CA, with a 7.0 MHz linear array transducer), diameter measurements of the right brachial artery were taken at rest after lying quietly for at least 10 min, after cuff deflation completing suprasystolic compression (200 mm Hg for 4.5 min) of the right upper arm and after sublingual application of 0.8 mg NTG. Scans were taken of the brachial artery proximal to the bifurcation of the radial and the ulnar artery by the ultrasound operator (R.K.) who was working at a different department and blinded to the subjects’ diagnoses and therapy sequence. After optimal transducer positioning, the arm was kept in the same position and the skin was marked. Lumen diameters were measured from one media-adventitia interface to the other for at least 3 times at baseline and every 30 seconds following reactive hyperemia and after administration of NTG. The maximum FMD and NMD diameters were taken as the average of the three consecutive maximum diameter measurements following hyperemia and NTG, respectively. Vasodilation was then calculated as the percent change in diameter compared to baseline. Measurements were performed at the end of five consecutive periods: 1) at baseline (BL I), 2) after 8 weeks of a combined therapy with simvastatin and vitamin E to achieve an LDL lowering of at least 20% (Comb I), 3) after withdrawal of vitamin E (300 IU) for 4 weeks (Statin), 4) during a second combined drug period as in #2 (Comb II), and 5) after withdrawal of both drugs for 4 weeks (BL II).
Assessment of hyperemic blood flow.
To verify that suprasystolic compression of the brachial artery caused adequate increases in blood flow, flow velocity was measured at rest and within 15 s after cuff deflation. Blood flow was calculated by multiplying the velocity time integral by the heart rate and the vessel cross-sectional area (3.14 x D2/4.) Reactive hyperemia was then calculated as percent change in flow during hyperemia compared to baseline. For comparison, blood flow was also assessed 2 min after NTG administration.
Alpha-tocopherol measurements in human plasma samples.
The neutral lipid fraction (200 µl) including alpha-tocopherol, the most active form of vitamin E, was extracted in a basic extraction system consisting of 200 µl ethanol, 200 µl H2O and 200 µl hexane. The upper organic layer (20/µl) containing alpha-tocopherol was analyzed by high-performance liquid chromatography using an ExSil 100 20 x 0.46 cm silica column (mobile phase: hexane/1% ethanol, 1 ml/min) and fluorescence detection (Hitachi, E: 295nm/Em: 390nm) (38). Quantitation was performed by peak area comparison with external alpha-tocopherol standards of known concentrations. The alpha-tocopherol serum level was then normalized to LDL-C, as there is evidence that the vitamin E content in LDL-C and not in the whole plasma correlates with measures of lipid peroxidation (39) and with the susceptibility of LDL-C to oxidation (40).
Determination of lipids and lipoproteins.
Cholesterol and triglycerides were measured enzymatically using assay kits from Boehringer Mannheim (Mannheim, Germany). High-density lipoprotein-C was measured from the supernatant after precipitation with polyethylene glycol (Reagent A from Immuno A.G., Vienna, Austria). LDL-C was calculated according to the Friedewald equation.
Statistical analysis.
Results are expressed as mean ± SD. Differences between groups were analyzed using one factor analysis of variance for repeated measures followed by Scheffe’s test. Post hoc paired t tests on longitudinal changes from baseline were used to compare the improvements of FMD and NMD after different therapies. The effects of cholesterol, LDL-C, alpha-tocopherol, alpha-tocopherol/LDL, triglycerides and baseline diameter on FMD or NMD were performed with linear regression. Interactions between FMD or NMD and lipid serum levels and alpha-tocopherol serum levels were assessed using multiple stepwise regression analysis. Differences were considered significant at p < 0.05.
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Results
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Lipid and alpha-tocopherol serum levels.
In all patients simvastatin therapy (20 mg) led to a lowering of LDL-C of at least 20%. Oral intake of 300 IU vitamin E did not lead to significant increases in alpha-tocopherol serum levels. However, when the alpha-tocopherol serum level was normalized to LDL-C, a significant increase was noted under combined vitamin E and simvastatin medication compared to baseline (Table 1).
Vasodilation and blood flow responses.
As there were no differences in the baseline diameters and increases in blood flow during reactive hyperemia, the stimulus for FMD can be assumed as being similar at the end of all five study phases (Table 2). Combined lipid-lowering and vitamin E therapy reproducibly resulted in a significant improvement of FMD (Comb I vs. BL I: 16.4 ± 4.7 vs. 4.9 ± 2.5%, p < 0.001 and Comb II vs. BL II; 15.3 ± 4.2 vs. 3.7 ± 3.9%, p < 0.001) (Fig. 1, 2). After withdrawal of vitamin E for 4 weeks, FMD decreased significantly (Comb I and Comb II vs. Statin: 16.4 ± 4.7 and 15.3 ± 4.2 vs. 7.9 ± 4.7%, p < 0.05) such that simvastatin alone only tended to improve FMD and did not change NMD (Table 2).
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Figure 1 Flow-mediated vasodilation (FMD) values of seven patients with hypercholesterolemia at baseline (BL I, II) after combined lipid-lowering and antioxidant therapy (Comb I, II) and after single lipid-lowering therapy (Statin).
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Figure 2 Nitroglycerin-induced dilation (NMD) values of seven patients with hypercholesterolemia at baseline (BL I, II) after combined lipid-lowering and antioxidant therapy (Comb I, II) and after single lipid-lowering therapy (Statin).
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Similar although lesser improvement under combination therapy was found for endothelium-independent vasodilation (Fig. 3). NMD was augmented after combined lipid-lowering and vitamin E therapy compared to baseline as well as simvastatin therapy alone (Comb I vs. BL I and Statin: 17.9 ± 4.3 vs. 11.2 ± 2.8 and 10.9 ± 4.5%, p < 0.01 and Comb II vs. BL II and Statin: 16.3 ± ± 5.1 vs. 11.5 ± 2.7 and 10.9 ± 4.5%, p < 0.05). Blood flow after the application of NTG was similar at the end of all periods (BL I 100 ± 39, Comb I 87 ± 30, Statin 106 ± 30, Comb II 99 ± 41, BL II 99 ± 28 ml/min) and was also similar to blood flow at baseline (BL I 123 ± 61, Comb I 93 ± 40, Statin 123 ± 67, Comb II 115 ± 37, BL II 106 ± 28 ml/min).
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Figure 3 Mean values of flow-mediated vasodilation (FMD), plasma cholesterol, LDL-cholesterol and alpha-tocopherol/LDL at baseline (BL I, II) after combined lipid-lowering and antioxidant therapy (Comb I, II) and after single lipid-lowering therapy (Statin).
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Improvement of the FMD/NMD ratio was observed under both combination therapy (Comb I vs. BL I: 0.92 ± 0.17 vs. 0.46 ± 0.24%, p < 0.05 and Comb II vs. BL II: 0.95 ± 0.31 vs. 0.29 ± 0.26%, p < 0.01) and lipid-lowering therapy alone (Statin vs. BL II: 0.71 ± 0.34 vs. 0.29 ± 0.26%, p < 0.05).
Post hoc paired t tests on longitudinal changes from baseline revealed a greater improvement of FMD (Comb I vs. Statin, p = 0.004; Comb II vs. Statin, p = 0.0001) and NMD (Comb I vs. Statin, p = 0.007; Comb II vs. Statin, p = 0.01) after combined lipid-lowering and vitamin E therapy compared to lipid-lowering therapy alone (Table 3).
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Table 3 Longitudinal Changes of FMD and NMD From Baseline Under Combined Vitamin E/Simvastatin Therapy vs. Simvastatin Therapy Alone
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Univariate analysis over all periods revealed significant correlations between FMD values and total cholesterol serum levels (r = –0.67, p = 0.0001), LDL-C levels (r = –0.64, p = 0.0001), alpha-tocopherol/LDL (r = 0.59, p = 0.001) and baseline diameter (r = –0.49, p = 0.002). NMD values were significantly correlated to baseline diameters (r = –0.59, p = 0.0002), total cholesterol (r = –0.43, p = 0.02), LDL-C (r = –0.39, p = 0.02) and alpha-tocopherol/LDL (r = 0.44, p = 0.02).
On multiple stepwise regression analysis over all periods, significant correlations were found between FMD values and total cholesterol levels (r = –0.62, p = 0.004) (which was the first variable to be entered), alpha-tocopherol levels (r = 0.40, p = 0.03) and baseline diameter (r = –0.45, 0.003). NMD values were independently correlated with LDL-C levels (r = –0.50, p = 0.03) and baseline diameters (r = –0.47, p = 0.02).
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Discussion
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The present study demonstrates that endothelium-dependent FMD in the brachial artery of patients with hypercholesterolemia can be improved by a combination of lipid-lowering therapy and vitamin E supplementation. This is, to the best of our knowledge, the first study revealing a beneficial effect of vitamin E on vasoreactivity in the brachial artery of hypercholesterolemic men under lipid-lowering therapy. This therapy also resulted in an improvement of endothelium-independent, nitroglycerin-induced vasodilation, albeit to a lesser extent than FMD. Our data further suggest that the combination of lipid-lowering therapy with vitamin E supplementation is more effective in restoring endothelial function in hypercholesterolemic patients than lipid-lowering therapy alone.
Endothelium-dependent dilation in hypercholesterolemia.
Endothelial function of peripheral arteries is increasingly used to assess short-term effects of therapeutic interventions. Improvement of endothelial function in the forearm vasculature of patients with hypercholesterolemia was observed within 1 month of simvastatin therapy (32) and after a single session of LDL apheresis (33). In the latter study, the authors suggested that total LDL and/or oxidized LDL may directly impair endothelial function on the basis of a close inverse correlation between oxidized LDL and acetylcholine-induced vasodilation and nitrate/nitrite production (33). In coronary arteries of patients with mild hypercholesterolemia, improvement of endothelial function was more pronounced under combination therapy of lovastatin and probucol than under lovastatin alone (34). Our study extends these findings by showing that a combined lipid-lowering and antioxidant therapy is highly effective also in the brachial artery and that vitamin E intake in addition to lipid-lowering therapy leads to further improvement in endothelial function. With regard to the effects of antioxidant vitamins alone, conflicting results have been obtained. Gilligan et al. (37) did not find a beneficial effect of vitamins C and E on endothelial function in forearm vessels of patients with hypercholesterolemia using strain gauge plethysmography. Levine et al. (41) demonstrated an acute improvement of endothelial function with the water-soluble antioxidant vitamin C given to patients with cardiovascular disease within 2 h.
Endothelium-independent dilation in hypercholesterolemia.
An unexpected finding in this study was that lipid-lowering and antioxidant (vitamin E) therapy also improved NMD in the brachial artery. This is in contrast to the findings of Anderson et al. (34) in coronary arteries, who used probucol as an antioxidant together with lovastatin. Other possible explanations for the discrepancy between that study and ours include higher mean cholesterol (276 ± 22 vs. 217 ± 32 mg/dl) and LDL-C serum levels (276 ± 22 vs. 145 ± 37 mg/dl) in our study and the fact that different arteries were investigated.
In coronary arteries of hypertensive patients (42) and in the brachial artery of patients with coronary disease (41), the water-soluble antioxidant vitamin C failed to improve endothelium-independent vasodilation. However, as the primary antioxidant mechanisms of vitamin C and E are distinct, different effects of these substances on the vascular wall cannot be excluded (43).
The mechanism of improved endothelium-independent vasodilation in the brachial artery by vitamin E is unclear. As blood flow in response to NTG was similar at the end of all periods and comparable to blood flow at baseline, the improvement of NMD under combination therapy cannot be explained by altered shear stress.
If an antioxidant effect of vitamin E is assumed, our findings of an improvement in NMD are supported by a study of Galle et al. (44) who revealed an inhibition of cyclic adenosine monophosphate- and cyclic guanosine monophosphate-mediated vasodilation in isolated deendothelialized human mammary and rabbit femoral arteries by oxidized LDL. The authors suggested that oxidized LDL could decrease the efficacy of endogenous as well as exogenous vasodilators either by direct inactivation of the dilators or by affecting the signal cascade in the smooth muscle cells. The concept that oxygen-derived free radicals inactivate the enzymes involved in the release of nitric oxide from NTG is also supported by findings of Watanabe et al. (45,46), who demonstrated that vitamin E as well as vitamin C prevents the development of nitrate tolerance. Furthermore, Rajagopalan et al. (47) demonstrated that enhanced angiotensin II activity resulted in increased vascular superoxide production via activation of the membrane associated nicotinamide-adenine dinucleotide oxidase, which inhibits the vasodilator effect of NTG-derived nitric oxide.
Study limitations.
As we did not compare combined vitamin E and statin therapy with vitamin E alone, we cannot exclude that the beneficial effect of vitamin E on endothelial function is at least partly bound to a concomitant LDL-lowering therapy. Recent studies, however, support the contention that antioxidants improve vascular function independent of their ability to inhibit the oxidation of LDL (48,49). Data from simple linear regression analyses and multiple stepwise regression analyses need to be interpreted with caution as measurements were repeatedly performed in the same patients. However, additional influences on vasodilation by gender, age and body mass index can be widely excluded as only men at similar age (51 ± 10 yr) were enrolled in the study and body mass index did not influence FMD as well as NMD in previous studies (27).
Conclusions.
The combination of vitamin E supplementation and lipid-lowering therapy leads to a marked improvement of endothelial function of the brachial artery within 8 weeks. As previously shown in the coronary circulation, the combination of antioxidant and lipid-lowering therapy is more effective than lipid-lowering therapy alone, underscoring the potential utility of noninvasive testing of peripheral endothelial function as a surrogate for the coronary artery. The improvement of endothelium-independent vasodilation was an unexpected finding which, due to the small number of patients, requires further investigation.
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March 1, 2007;
1(2):
110 - 112.
[Abstract]
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D. Tousoulis, C. Antoniades, C. Vassiliadou, M. Toutouza, C. Pitsavos, C. Tentolouris, A. Trikas, and C. Stefanadis
Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure
Eur J Heart Fail,
December 1, 2005;
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[Abstract]
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M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning
Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response
Eur. Heart J.,
February 2, 2005;
26(4):
363 - 368.
[Abstract]
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R. Stocker and J. F. Keaney Jr.
Role of Oxidative Modifications in Atherosclerosis
Physiol Rev,
October 1, 2004;
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[Abstract]
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S. Y. Chan, G. B. J. Mancini, L. Kuramoto, M. Schulzer, J. Frohlich, and A. Ignaszewski
The prognostic importance of endothelial dysfunction and carotid atheromaburden in patients with coronary artery disease
J. Am. Coll. Cardiol.,
September 17, 2003;
42(6):
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[Abstract]
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M. M. Engler, M. B. Engler, M. J. Malloy, E. Y. Chiu, M. C. Schloetter, S. M. Paul, M. Stuehlinger, K. Y. Lin, J. P. Cooke, J. D. Morrow, et al.
Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial
Circulation,
September 2, 2003;
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[Abstract]
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G. D. Plotnick, M. C. Corretti, R. A. Vogel, R. Hesslink Jr, and J. A. Wise
Effect of supplemental phytonutrients on impairment of the flow-mediated brachialartery vasoactivity after a single high-fat meal
J. Am. Coll. Cardiol.,
May 21, 2003;
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[Abstract]
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J. H. Stein, C. M. Carlsson, K. Papcke-Benson, S. E. Aeschlimann, A. Bodemer, M. Carnes, and P. E. McBride
The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia
J. Am. Coll. Cardiol.,
December 1, 2001;
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[Abstract]
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J. T. Kuvin, A. R. Patel, K. A. Sliney, N. G. Pandian, W. M. Rand, J. E. Udelson, and R. H. Karas
Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease
J. Am. Coll. Cardiol.,
December 1, 2001;
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[Abstract]
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M. A van de Ree, M. V Huisman, F. H de Man, J. C van der Vijver, A.E. Meinders, and G. J Blauw
Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin
Cardiovasc Res,
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[Abstract]
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F. Visioli
Effects of vitamin E on the endothelium: equivocal? {alpha}-tocopherol and endothelial dysfunction
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A. C. Carr, B.-Z. Zhu, and B. Frei
Potential Antiatherogenic Mechanisms of Ascorbate (Vitamin C) and {alpha}-Tocopherol (Vitamin E)
Circ. Res.,
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[Abstract]
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D. Tomasian, J. F. Keaney Jr., and J. A. Vita
Antioxidants and the bioactivity of endothelium-derived nitric oxide
Cardiovasc Res,
August 18, 2000;
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R. A. P. Skyrme-Jones, R. C. O'Brien, K. L. Berry, and I. T. Meredith
Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study
J. Am. Coll. Cardiol.,
July 1, 2000;
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[Abstract]
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K. J. Williams, R. Scalia, K. D. Mazany, W. V. Rodrigueza, and A. M. Lefer
Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport
Arterioscler. Thromb. Vasc. Biol.,
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[Abstract]
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T. Neunteufl, U. Priglinger, S. Heher, M. Zehetgruber, G. Soregi, S. Lehr, K. Huber, G. Maurer, F. Weidinger, and K. Kostner
Effects of vitamin E on chronic and acute endothelial dysfunction in smokers
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[Abstract]
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K. K. Koh, A. Blum, L. Hathaway, R. Mincemoyer, G. Csako, M. A. Waclawiw, J. A. Panza, and R. O. Cannon III
Vascular Effects of Estrogen and Vitamin E Therapies in Postmenopausal Women
Circulation,
November 2, 1999;
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[Abstract]
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J. H. Stein, J. G. Keevil, D. A. Wiebe, S. Aeschlimann, and J. D. Folts
Purple Grape Juice Improves Endothelial Function and Reduces the Susceptibility of LDL Cholesterol to Oxidation in Patients With Coronary Artery Disease
Circulation,
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[Abstract]
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J. F. KEANEY JR., D. I. SIMON, and J. E. FREEDMAN
Vitamin E and vascular homeostasis: implications for atherosclerosis
FASEB J,
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K. Kugiyama, T. Motoyama, H. Doi, H. Kawano, N. Hirai, H. Soejima, Y. Miyao, K. Takazoe, Y. Moriyama, Y. Mizuno, et al.
Improvement of endothelial vasomotor dysfunction by treatment with alpha-tocopherol in patients with high remnant lipoproteins levels
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[Abstract]
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Abstract
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