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11. The effect of antioxidant dietary micronutrients on LDL oxidation:
Implications for atherosclerosis prevention

Jialal I.
Centre for Human Nutrition, Dept of Internal Medicine/Pathology, Univ of
Texas Southwestern Med Ctr,Dallas, TX 75235-9052 United States
Canadian Journal of Cardiology ( CAN. J. CARDIOL. ) (Canada) 1993,
9/SUPPL. B (11B-13B)

Several lines of evidence support a pro-atherogenic role for oxidized LDL and its in vivo existence. Epidemiological data suggests the decreased levels of micronutrient antioxidants such as alpha tocopherol, ascorbate and beta-carotene are associated with an increased frequency of cardiovascular disease. These micronutrient antioxidants have been shown to prevent LDL oxidation in vitro, and in addition to retard the progression of athersclerosis in animal models. Dietary supplementation studies of human subjects with ascorbate, alpha-tocopheral and beta-carotene has been shown to decrease the susceptibility of the LDL to oxidative modification without producing side effects. Thus, these micronutrient antioxidants have the potential to become an additional modality in future strategies of atherosclerosis prevention.

12. Usefulness of antioxidant vitamins in suspected acute myocardial infarction (the Indian experiment of infarct survival-3).

Am J Cardiol 1996 Feb 1;77(4):232-6
Singh RB, Niaz MA, Rastogi SS, Rastogi S
Heart Research Laboratory, Medical Hospital and Research Centre, Moradabad, India.

In a randomized, double-blind, placebo-controlled trial, the effects of combined treatment with the antioxidant vitamins A (50,000 IU/day), vitamin C (1,000 mg/day), vitamin E (400 mg/day), and beta-carotene (25 mg/day) were compared for 28 days in 63 (intervention group) and 62 (placebo group) patients with suspected acute myocardial infarction. After treatment with antioxidants, the mean infarct size (creatine kinase and creatine kinase-MB gram equivalents) was significantly less in the antioxidant group than in the placebo group. Serum glutamic-oxaloacetic transaminase decreased by 45.6 IU/dl in the antioxidant group versus 25.8 IU/dl in the placebo group (p < 0.02). Cardiac enzyme lactate dehydrogenase increased slightly (88.6 IU/dl) in the antioxidant group compared with that in the placebo group (166.5 IU/dl) (p < 0.01). QRS score in the electrocardiogram was significantly less in the antioxidant than in the placebo group. The following levels increased in the antioxidant group versus the placebo group, respectively: plasma levels of vitamin E increased by 8.8 and 2.2 mumol/L (p < 0.01), vitamin C increased by 12.6 and 4.2 mumol/L (p < 0.01), beta-carotene increased by 0.28 and 0.06 mumol/L (p < 0.01), and vitamin A increased by 0.36 and 0.12 mumol/L (p < 0.01). Serum lipid peroxides decreased by 1.22 pmol/ml in antioxidant versus 0.22 pmol/ml in the placebo group (p < 0.01). Angina pectoris, total arrhythmias, and poor left ventricular function occurred less often in the antioxidant group. Cardiac end points were significantly less in the antioxidant group (20.6% vs 30.6%, respectively). These results suggest that combined treatment with antioxidant vitamins A, E, C, and beta-carotene in patients with recent acute myocardial infarction may be protective against cardiac necrosis and oxidative stress, and could be beneficial in preventing complications and cardiac event rate in such patients

.13. Vitamin C and cardiovascular disease: a systematic review.

J Cardiovasc Risk 1996 Dec;3(6):513-21
Ness AR, Powles JW, Khaw KT
Institute of Public Health, University Forvie Site, Cambridge, UK.

BACKGROUND: Laboratory studies suggest that antioxidants, such as Vitamin C, are important inhibitors of atherosclerotic lesions. Most epidemiological reviews have considered all antioxidants together. This review seeks to clarify the current state of knowledge specifically concerned with vitamin C. METHODS: All ecological studies, case-control studies, prospective studies and trials in humans that examined the association between vitamin C intake or blood levels of vitamin C and cardiovascular disease were included. Relevant references were located by MEDLINE search for articles published from 1966 to 1996, by an EMBASE search for articles published from 1980 to 1996, by searching personal bibliographies, books and reviews and from citations in located articles. RESULTS: For coronary heart disease four of seven ecological studies, one of four case-control studies and three of 12 cohort studies found a significant protective association with vitamin C intake or status. For strokes two of two ecological studies, none of one case-control study and two of seven cohort studies found a significant protective association. For total circulatory disease, two of three cohort studies reported a significant protective association. CONCLUSIONS: The evidence, albeit limited, is consistent with vitamin C having protective effect against stroke whereas the evidence that vitamin C is protective against coronary heart disease is less consistent. The lack of an association for coronary heart disease could be explained in terms of there being a true lack of effect, dietary measurement error, a threshold effect, and effect of seasonal variations in intake, an interaction with other dietary constituents or a relatively short duration of follow-up.

14. Oral vitamin C reduces arterial stiffness and platelet aggregation in humans.

J Cardiovasc Pharmacol 1999 Nov;34(5):690-3
Wilkinson IB, Megson IL, MacCallum H, Sogo N, Cockcroft JR, Webb DJ
Clinical Pharmacology Unit & Research Centre, University of Edinburgh, Western General Hospital, Scotland.

Atherosclerosis is associated with stiffening of conduit arteries and increased
platelet activation, partly as a result of reduced bioavailability of nitric oxide (NO), a mediator that normally has a variety of protective effects on blood vessels and platelets. Increased levels of oxygen free radicals are a feature of atherosclerosis that contributes to reduced NO bioavailability and might lead to increased arterial stiffness and platelet activation. Vitamin C is a dietary antioxidant that inactivates oxygen free radicals. This placebo-controlled, double-blind, randomized study was designed to establish whether acute oral administration of vitamin C (2 g), would reduce arterial stiffness and in vitro platelet aggregation in healthy male volunteers. Plasma vitamin C concentrations increased from 428 to 1048 microM at 6 h after oral administration, and were associated with a significant reduction in augmentation index, a measure of arterial stiffness (by 9.63.0%; p = 0.016), and ADP-induced platelet aggregation (by 3513%; p = 0.046). There was no change in these parameters after placebo. Vitamin C, therefore, appears to have beneficial effects, even in healthy subjects. The mechanism responsible is likely to involve protection of NO from inactivation by oxygen free radicals, but this requires confirmation. If similar effects are observed in patients with atherosclerosis or risk factors, vitamin C supplementation might prove an effective therapy in cardiovascular disease.

15. Vitamin C intake and mortality among a sample of the United States population.

Epidemiology 1992 May;3(3):194-202
Enstrom JE, Kanim LE, Klein MA

School of Public Health, University of California, Los Angeles 90024.

We examined the relation between vitamin C intake and mortality in the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study cohort. This cohort is based on a representative sample of 11,348 noninstitutionalized U.S. adults age 25-74 years who were nutritionally examined during 1971-1974 and followed up for mortality (1,809 deaths) through 1984, a median of 10 years. An index of vitamin C intake has been formed from detailed dietary measurements and use of vitamin supplements. The relation of the standardized mortality ratio (SMR) for all causes of death to increasing vitamin C intake is strongly inverse for males and weakly inverse for females. Among those with the highest vitamin C intake, males have an SMR (95% confidence interval) of 0.65 (0.52-0.80) for all causes, 0.78 (0.50-1.17) for all cancers, and 0.58 (0.41-0.78) for all cardiovascular diseases; females have an SMR of 0.90 (0.74-1.09) for all causes, 0.86 (0.55-1.27) for all cancers, and 0.75 (0.55-0.99) for all cardiovascular diseases. Comparisons are made relative to all U.S. whites, for whom the SMR is defined to be 1.00. There is no clear relation for individual cancer sites, except possibly an inverse relation for esophagus and stomach cancer among males. The relation with all causes of death among males remains after adjustment for age, sex, and 10 potentially confounding variables (including cigarette smoking, education, race, and disease history).

16. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering.

Circulation 1996 Nov 15;94(10):2369-72
Azen SP, Qian D, Mack WJ, Sevanian A, Selzer RH, Liu CR, Liu CH, Hodis HN
Statistical Consultation and Research Center, University of Southern California, Los Angeles 90033, USA.

BACKGROUND: There is accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis. METHODS AND RESULTS: CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of > or = 100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of > or = 250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P = .03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found. CONCLUSIONS: Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

17. Combination oral antioxidant supplementation reduces blood pressure.

Clin Sci (Colch) 1997 Apr;92(4):361-5
Galley HF, Thornton J, Howdle PD, Walker BE, Webster NR
Clinical Oxidant Research Group, St James's University Hospital, Leeds, UK.

1. Hypertension affects 30% of adults and low intakes of antioxidants have been associated with increased risk of hypertension and cardiovascular disease. To investigate the effect of short-term high-dose antioxidant supplementation on blood pressure in hypertensive and normotensive outpatients, we undertook a randomized, double-blind, crossover design placebo-controlled study. 2. Forty subjects were recruited from medical outpatient clinics, of whom 38 completed the study. Twenty-one were attending for treatment of hypertension and 17 were normotensive, attending for minor gastrointestinal complaints. Subjects were randomly assigned to receive either 8 weeks placebo followed by 2 weeks washout then 8 weeks antioxidants or vice versa. The combination of antioxidants consisted of 200 mg of zinc sulphate, 500 mg of ascorbic acid, 600 mg of alpha-tocopherol (sodium succinate salt) and 30 mg of beta-carotene daily. 3. Systolic blood pressure fell at the end of the antioxidant phase compared with the placebo phase both in subjects receiving anti-hypertensive therapy (P < 0.01) and those who were normotensive (P = 0.067). Circulating levels of beta-carotene and alpha-tocopherol increased in all subjects during
supplementation (P < 0.01) and urine nitrite increased in hypertensive patients (P < 0.05). 4. Short-term oral high-dose combination antioxidant therapy reduces blood pressure, possibly via increased availability of nitric oxide. This study may have implications for the innovative use of antioxidants as an adjunct to anti-hypertensive therapy.

18. Antioxidant nutrient supplementation reduces the susceptibility of low density lipoprotein to oxidation in patients with coronary artery disease.

J Am Coll Cardiol 1997 Aug;30(2):392-9
Mosca L, Rubenfire M, Mandel C, Rock C, Tarshis T, Tsai A, Pearson T
University of Michigan Preventive Cardiology Program, Department of Medicine, Ann Arbor 48106-0363, USA.

OBJECTIVE: This study sought to determine the effect of antioxidant
supplementation on the susceptibility of low density lipoprotein (LDL) to oxidation in patients with established cardiovascular disease (CVD). BACKGROUND:
Data are inconsistent regarding the role of antioxidant nutrients in the prevention of CVD. METHODS: The study design was a 12-week, double-blind, placebo-controlled clinical trial. Patients with CVD (n = 45) were randomized to 1) placebo control; 2) 400 IU of vitamin E, 500 mg of vitamin C, 12 mg of beta-carotene (mid-dose); or 3) 800 IU of vitamin E, 1,000 mg of vitamin C, 24 mg of beta-carotene (high dose) daily. Reduced susceptibility of LDL to oxidation was estimated by an increase in lag phase (minutes). Baseline and 6- and 12-week measurements of lipoproteins and lag phase were obtained. Plasma levels of antioxidants were measured at baseline and 12 weeks. RESULTS: Concentrations of alpha-tocopherol, vitamin C and beta-carotene significantly increased in the mid- and high dose groups during the trial. Lag phase significantly increased from baseline (190.1 63.8 min [mean SD]) to 12 weeks (391.1 153.0 min) in the high dose group (p < 0.01). A nonsignificant increase in lag phase in the mid-dose group was observed during the same time interval. A dose response was found for mean percent change from baseline to 12 weeks for lag phase for the placebo, mid- and high dose groups (p = 0.004 for trend). CONCLUSIONS: A high dose combination of antioxidant nutrients reduces the susceptibility of LDL to oxidation in patients with CVD and may be useful in secondary prevention.

19. The nature of prooxidant activity of vitamin C.

Life Sci 1999;64(23):PL 273-8
Paolini M, Pozzetti L, Pedulli GF, Marchesi E, Cantelli-Forti G
Department of Pharmacology, University of Bologna, Italy.

It was recently reported that vitamin C (500 mg/day for 6 weeks) administered as< a dietary supplement to healthy humans exhibits a prooxidant, as well as an antioxidant effect in vivo. Here we show that high intakes of vitamin C (500 mg/kg b.w. for 4 days) in the rat are able to markedly induce hepatic cytochrome P4502E1-linked monooxygenases, measured as p-nitrophenol hydroxylase activity and corroborated by means of Western blot analyses. Furthermore, using Electron Paramagnetic Resonance Spectroscopy (EPR) coupled to a spin-trapping technique, we have also found that this induction generates large amounts of the anion radical superoxide (O2-). Therefore we can conclude that the adverse prooxidant outcomes (i.e. oxidative DNA damage) associated to vitamin C supplementation, being associated to a typical reversible boosting effect (i.e. enzymatic induction), may be easily controlled by a discontinuous supply. However, since the induced P4502E1 isoforms by vitamin C are responsible for ethanol metabolism to highly reactive radicals, care should be taken even in moderate drinkers.

20. [The antioxidant protection of the heart by coenzyme Q10 in stable stenocardia of effort].

Patol Fiziol Eksp Ter 1999 Oct-Dec;(4):16-9
Kogan AKh, Syrkin AL, Drinitsina SV, Kokanova IV

It was found that patients with angina of effort (functional class II and III) exhibit enhanced generation of active oxygen forms by leukocytes, higher concentration of malonic dialdehyde in plasma and lower antiperoxide resistance of plasma. These changes increase with increasing severity of the disease. Adjuvant use of coenzyme Q10 in combined antianginal therapy suppresses generation of active oxygen forms by leukocytes, lipid peroxidation. Antiperoxide plasma resistance rises. In this way clinical improvement of effort angina is achieved.