K. Fred Gey

Plasma Vitamins E and A Inversely Correlated to Mortality from Ischemic Heart Disease in Cross‐Cultural Epidemiology

In eight study populations in which the medians of total plasma cholesterol did not differ significantly (mean 5.8 mM, p greater than 0.05) and therefore did not correlate with the IHD mortality (r2 = 0.05), the median of absolute plasma level of vitamin E (alpha-tocopherol) was inversely related to the IHD mortality (r2 = 0.55; p = 0.003). Vitamin A behaved similarly (r2 = 0.51; p = 0.046). The absolute levels of vitamins E and A together with cholesterol predicted (by multiple regression analysis) the IHD mortality of these eight populations fairly well (r2 = 0.81; p = 0.06). Considering all 12 study populations analyzed thus far, total plasma cholesterol correlated with the IHD mortality directly as expected (r2 = 0.51; p less than 0.01), but the median of the plasma alpha-tocopherol individually standardized for cholesterol and triglycerides (220 mg/dL + 110 mg/dL, respectively) maintained a strong inverse association with the IHD mortality (r2 = 0.49; p = 0.01). In the partial regression analysis, lipid-standardized vitamin E exhibited an even stronger inverse correlation with IHD mortality (r2 = 0.69; p less than 0.001). Again, vitamin A behaved similarly to vitamin E, that is, after lipid-standardization of individuals (r2 = 0.33; p = 0.07), as well as in the cholesterol-independent partial regression analysis (r2 = 0.74; p less than 0.001). Both vitamins may act singularly, for after lipid-standardization they vary de facto independently (rs = 0.012) in individuals. The combination of vitamins E and A as obtained by multiple partial regression predicted the actual IHD mortality to a large extent (r2 = 0.89; p less than 0.001), whereas the three-variable prediction model, with the median of total cholesterol and of individually lipid-standardized vitamins E and A, fit the actual IHD mortality of these 12 populations almost completely (r2 = 0.94; p less than 0.001). In conclusion, the plasma status of vitamins E and A are important, hitherto underrated risk factors of IHD, which may act independently, but can, if combined, predict at least 53% of the cross-cultural differences of IHD mortality. After inclusion of total cholesterol into a multivariate model, up to 94% of the IHD mortality can be predicted. The present epidemiological data are in agreement with the hypothesis that these vitamins have physiological functions in the protection of lipoproteins against peroxidation and atherogenic apo-B modifications, respectively, but that does not exclude additional beneficial effects of vitamin E and A in the arterial wall.

Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study

Plasma vitamins C, E, retinol and carotene were measured in 1971–1973 in 2,974 men working in Basel Switzerland. In 1990, the vital status of all participants was assessed. A total of 290 men had died from cancer during the 17 years of follow‐up, including 87 with lung cancer, 30 with prostate cancer, 28 with stomach cancer and 22 with colon cancer. Overall mortality from cancer was associated with low mean plasma levels of carotene (adjusted for cholesterol) and of vitamin C. Lung and stomach cancers were associated with a low mean plasma carotene level. After calculation of the relative risk, using the Cox model, with exclusion of mortality during the first 2 years of follow‐up, simultaneously low levels of plasma carotene (below quartile I) and lipid‐adjusted retinol were related to a significantly increased mortality risk for all cancers and for lung cancer. Simultaneously, low levels of plasma vitamin C and lipid‐adjusted vitamin E also were associated with a significantly increased risk for lung cancer. Additionally, low vitamin E levels in smokers were related to an increased risk for prostate cancer. It is concluded that low plasma levels of the vitamins C, E, retinol and carotene are related to increased risk of subsequent overall and lung‐cancer mortality and that low levels of vitamin E in smokers are related to an increased risk of prostate‐cancer mortality.

Relationship of Plasma Level of Vitamin C to Mortality from Ischemic Heart Disease

The present epidemiological data support and extend previous evidence in men and animals. Thus, a poor plasma status of vitamin C (less than 23 microM = 0.4 mg/dl) and/or of cholesterol-standardized vitamin E (less than 20-21.5 microM = 9 mg/l) occurs in westernized countries with an increased risk of IHD. A poor status in the major essential antioxidants may be a hitherto underrated, at least permissive, risk factor of IHD that could, at least in some European countries, substantially complement the previously established risk factors such as hypercholesterolemia.

Low plasma vitamins E and C. Increased risk of angina in Scottish men.

Cross-cultural studies suggest that low plasma antioxidant levels contribute to the high incidence of coronary heart disease (CHD) in Scotland. One hundred twenty-five cases of angina without reported history were identified by a postal WHO chest pain questionnaire from a systemic population sample of 6000 Edinburgh men (35-54 years). Classical CHD risk factors (lipids, blood pressure, smoking, and relative weight), plasma vitamins, and a new independent CHD risk factor, adipose tissue linoleate, were measured in angina (n = 125) and healthy controls (n = 430). Cigarette smoking was common in angina (46% vs. 29%, p less than 0.01), and adipose tissue linoleate was lower (8.77 +/- 0.18% vs. 9.81 +/- 0.14% (p less than 0.01). Classical CHD risk factors were not different. Vitamin E/cholesterol molar ratio (micron/mM) was lower in angina than in controls: 1.58 +/- 0.03 vs. 1.66 +/- 0.02 (p less than 0.01). Plasma vitamin C was also lower in angina than in controls: 23.6 +/- 1.7 vs. 30.5 +/- 1.1 microM (p less than 0.001). The relative risk of angina for those in the lowest versus those in the highest quintile of the vitamin E/cholesterol ratio distribution was 2.2:1, irrespective of other risk factors (p less than 0.009). Adipose tissue linoleate removed the association between vitamin E and angina. The relative risk of angina for those in the lowest versus those in the highest quintile of plasma vitamin C was 2.6:1 (p less than 0.01), and the increased risk was also independent of classical risk factors, but closely related to a smoking habit. Low plasma vitamin E or adipose linoleate predisposes to angina, and smoking may increase the risk of angina by lowering plasma vitamin C levels in Scottish men.

Decreased Essential Antioxidants and Increased Lipid Hydroperoxides Following High-Dose Radiochemotherapy

The blood from 19 patients having bone marrow transplantation was examined for the essential antioxidants alpha-tocopherol and beta-carotene as well as lipid hydroperoxides before, at and after bone marrow transplantation (BMT). Conditioning therapy, preceding BMT in order to achieve marrow ablation and immunosuppression, consists of high-dose chemotherapy which is mostly combined with total body irradiation (TBI). In order to see a possible difference between patients with and without additional TBI, we divided the patients up into two groups; patients receiving TBI (RT+) and patients without TBI (RT-). All patients required total parenteral nutrition beginning one week prior to BMT. After conditioning therapy plasma levels of absolute and lipid-standardized alpha-tocopherol and beta-carotene decreased in both groups, presumably as a result of an enhanced breakdown of these antioxidants. The loss of these lipid-soluble antioxidants has to be considered as a possible cause for early post-transplant toxicity. Lipid hydroperoxides increase significantly in the group of patients with additional TBI, whereas the other group, receiving no additional TBI, showed no significant change. We suggest high-dose supplementation of essential antioxidants for patients undergoing BMT.

Effect of etoposide (VP16-213) on lipid peroxidation and antioxidant status in a high-dose radiochemotherapy regimen.

SummaryA total of 13 patients receiving bone marrow transplants (BMT) for treatment of different haematological diseases were investigated. Conditioning therapy preceding BMT consisted of fractionated total-body irradiation (12 Gy) and high-dose chemotherapy with cyclophosphamide (2±60 mg/kg). Patients stratified to be at high risk for relapse (6/13) were additionally treated with etoposide (30 mg/kg). Plasma concentrations of absolute and lipid-standardized antioxidants (α-tocopherol and β-carotene) decreased following conditioning therapy, presumably as the result of an enhanced breakdown of these antioxidants. Etoposide treatment did not amplify the loss of essential anti-oxidants but significantly increased lipid hydroperoxide concentrations in serum. We suggest that the abnormal generation of lipid hydroperoxides is the result of free radical formation.

Plasma vitamin E, apolipoprotein B and HDL-cholesterol in middle-aged men from Southern Italy

Plasma vitamin E, HDL-cholesterol, apolipoprotein B and triglycerides were measured in an apparently healthy, male, random population sample (n = 74) from Southern Italy. Plasma vitamin E concentration was positively correlated to that of serum cholesterol, non-HDL cholesterol, triglycerides and apolipoprotein B (all P less than 0.001). The results of partial correlation analysis showed that apo B, the apolipoprotein constituent of LDL, was related to vitamin E independently of serum triglycerides, a fairly accurate marker of VLDL. On the other hand, triglycerides were related to vitamin E independently of apo B. Both correlations were much weaker if an adjustment was performed for non-HDL-cholesterol. No independent relationship was demonstrated between plasma vitamin E and HDL-cholesterol.

Decrease of Alpha‐Tocopherol and Beta‐Carotene by High‐Dose Radiochemotherapy Preceding Bone Marrow Transplantation

Conditioning regimens preceding bone marrow transplantation (BMT) consist of high-dose chemotherapy, generally in combination with total body irradiation (TBI). These regimens approach the limit of tolerance for several tissues. Lipid peroxidation has been suggested as one of the main causes of radiation damage. Cyclophosphamide (CP), frequently used in conditioning chemotherapy, depletes hepatic glutathione, thus potentially initiating peroxidative processes and enhancing radiation-induced tissue damage. Therefore, we measured lipid hydroperoxides (LOOH) in blood and investigated whether an abnormal breakdown of antioxidants, such as alpha-tocopherol (TOC) and beta-carotene (CAR), follows the conditioning therapy, which may be involved in the pathogenesis of severe and early posttransplant complications.

Cancer Mortality Inversely Related to Plasma Levels of Antioxidant Vitamins

Aggressive oxygen species (such as superoxide anion, hydroxyl radical, singlet oxygen and longer-lived reaction products (e.g. hydroperoxides, alkenals) have been implicated in cancerogenesis but it is very difficult to show their direct role in vivo. Indirect evidence can be obtained from the inspection of the body’s multilevel defense system against oxygen radicals which includes essential antioxidants, i.e. β-carotene and the vitamins A, C and E. Since the dietary supply of the latter can vary considerably cancerogenesis might, at least in part, be inversely related to the status of antioxidant vitamins. There is growing evidence in animals and humans in favour of this concept. In animals vitamin A deficiency results in metaplasia whereas experimentally induced tumors can be diminished by β-carotene, vitamins A, C and E. In the human many dietary surveys have convincingly shown that the intake of fresh fruits and leafy green-yellow vegetables as well as the calculated consumption of the above mentioned essential antioxidants is inversely related to the mortality from cancers (1–4). Dietary surveys have, however, inherent weaknesses and thus require confirmation by the measurement of plasma antioxidants in prospective studies.

Plasma-Vitamine A und E invers zur Koronarmortalität korreliert

All essential plasma antioxidants were measured in representative samples of apparently healthy males from 12 European study populations the coronary mortality of which differed by the factor 4. Lipid-standardized vitamins A and E showed a strong inverse correlation to the age-specific coronary mortality (r2 = 0.33 and r2 = 0.49, resp.; combined r2 = 0.53) and thus complemented substantially the direct correlation of coronary mortality with total cholesterol (r2 = 0.51). Multiple regression analysis with these three variables predicted the actual mortality almost completely (r2 = 0.94). In conclusion, a fair plasma status of vitamins A and E could be a quantitatively important, hitherto underrated protective factor of coronary heart disease. These antioxidant vitamins presumably protect lipoproteins against peroxidation and atherogenic modification, respectively, but might still have additional antiarteriosclerotic effects in the arterial wall.