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.

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.

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).

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.

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.

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.

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.