Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects

BACKGROUND. Fatty acids that contain a trans double bond are consumed in large amounts as hydrogenated oils, but their effects on serum lipoprotein levels are unknown. METHODS. We placed 34 women (mean age, 26 years) and 25 men (mean age, 25 years) on three mixed natural diets of identical nutrient composition, except that 10 percent of the daily energy intake was provided as oleic acid (which contains one cis double bond), trans isomers of oleic acid, or saturated fatty acids. The three diets were consumed for three weeks each, in random order. RESULTS. On the oleic acid diet, the mean (+/- SD) serum values for the entire group for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were 4.46 +/- 0.66. 2.67 +/- 0.54, and 1.42 +/- 0.32 mmol per liter (172 +/- 26, 103 +/- 21, and 55 +/- 12 mg per deciliter), respectively. On the trans-fatty-acid diet, the subjects' mean HDL cholesterol level was 0.17 mmol per liter (7 mg per deciliter) lower than the mean value on the diet high in oleic acid (P less than 0.0001; 95 percent confidence interval, 0.13 to 0.20 mmol per liter). The HDL cholesterol level on the saturated-fat diet was the same as on the oleic acid diet. The LDL cholesterol level was 0.37 mmol per liter (14 mg per deciliter) higher on the trans-fatty-acid diet than on the oleic acid diet (P less than 0.0001; 95 percent confidence interval, 0.28 to 0.45 mmol per liter) and 0.47 mmol per liter (18 mg per deciliter) higher on the saturated-fat diet (P less than 0.001; 95 percent confidence interval, 0.39 to 0.55 mmol per liter) than on the oleic acid diet. The effects on lipoprotein levels did not differ between women and men. CONCLUSIONS. The effect of trans fatty acids on the serum lipoprotein profile is at least as unfavorable as that of the cholesterol-raising saturated fatty acids, because they not only raise LDL cholesterol levels but also lower HDL cholesterol levels.     

Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease

To determine the associations of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol with mortality from coronary heart disease and cardiovascular disease, we studied 2541 white men who were 40 to 69 years old at base line and followed them for an average of 10.1 years. Seventeen percent had some manifestation of cardiovascular disease at base line, whereas the others did not. Among the men who had cardiovascular disease at base line, we found, after multivariate adjustment, that those with "high" blood cholesterol levels (above 6.19 mmol per liter) had a risk of death from cardiovascular disease, including coronary heart disease, that was 3.45 times higher (95 percent confidence interval, 1.63 to 7.33) than that for men with "desirable" blood cholesterol levels (below 5.16 mmol per liter). The corresponding hazard ratios were 5.92 (95 percent confidence interval, 2.59 to 13.51) for LDL cholesterol levels above 4.13 mmol per liter as compared with those below 3.35 mmol per liter, and 6.02 (95 percent confidence interval, 2.73 to 13.28) for HDL cholesterol levels below 0.90 mmol per liter as compared with those above 1.16 mmol per liter. All three lipid levels were also significant predictors of death from coronary heart disease alone (P less than 0.005). Total cholesterol and LDL cholesterol levels were also significant predictors of death from cardiovascular and coronary heart disease in men without preexisting cardiovascular disease, although at a lower level of absolute risk of death. Thus, the 10-year risk of death from cardiovascular disease for a man with preexisting cardiovascular disease increased from 3.8 percent to almost 19.6 percent with increasing levels of total cholesterol from "desirable" to "high," whereas the corresponding risk for a man who was free of cardiovascular disease at base line increased from 1.7 percent to 4.9 percent. Our findings suggest that total, LDL, and HDL cholesterol levels predict subsequent mortality in men 40 to 69 years of age, especially those with preexisting cardiovascular disease.     

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.

BACKGROUND: Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS: We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS: The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.     

High-density lipoprotein cholesterol is positively associated with hypertension in apparently healthy Japanese men and women

Among five components of metabolic syndrome, high-density lipoprotein (HDL) cholesterol is unique because it is not significantly associated with blood pressure. This study looks at cross-sectional relationships between HDL cholesterol and hypertension using medical check-up data from 1803 apparently healthy Japanese men aged 49.9 +/- 9.0 years, and 1150 Japanese women aged 49.5 +/- 9.0 years. Pearson's correlation coefficients between systolic blood pressure (SBP)/diastolic blood pressure (DBP) and HDL cholesterol were -0.01 (ns)/-0.01 (ns) in men and -0.04 (ns)/-0.01 (ns) in women. The standardised partial regression coefficient of HDL cholesterol for SBP/DBP (mmHg) controlling for age, body mass index (BMI), fasting plasma glucose (FPG), triglycerides, high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein (LDL) cholesterol were 0.15 (P < 0.0001)/0.15 (P < 0.0001) in men and 0.10 (P < 0.0001)/0.12 (P < 0.0001) in women. The odds ratio (OR; 95% confidence interval [CI]) of a 1 mg/dL increment of HDL cholesterol for hypertension controlling for age, BMI, FPG, triglycerides, hs-CRP, LDL cholesterol, metabolic syndrome, diabetes, exercise status, drinking status, and smoking status was 1.03 (1.02-1.04; P < 0.001) in men and 1.03 (1.01-1.05; P = 0.002) in women. Thus, HDL cholesterol was independently positively associated with hypertension in apparently healthy Japanese men and women.     

Effects of short-term melatonin administration on lipoprotein metabolism in normolipidemic postmenopausal women

OBJECTIVE: To investigate the effects of short-term administration of melatonin on lipoprotein metabolism in normolipidemic postmenopausal women. METHODS: Fifteen such women received 6.0 mg melatonin daily for 2 weeks. Blood was sampled before and after treatment. We measured concentrations of total cholesterol and total triglyceride in the plasma, as well as the levels of cholesterol, triglyceride, and protein in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Plasma apolipoprotein levels were determined by immunoturbidimetric assay. Activities of lipoprotein lipase, hepatic triglyceride lipase, and lecithin cholesterol acyltransferase were also determined by enzymatic analysis. RESULTS: Melatonin administration significantly increased the plasma levels of triglyceride by 27.2% (P < 0.05), of VLDL-cholesterol by 37.2% (P < 0.01), of VLDL-triglyceride by 62.2% (P < 0.001), and of VLDL-protein by 30.0% (P < 0.05). However, the plasma total cholesterol level and the concentration of lipid and protein in LDL and HDL were not significantly affected. Melatonin significantly increased the plasma levels of apolipoprotein C-II by 29.5% (P < 0.005), of C-III by 17.1% (P < 0.001), and of E by 7.6% (P < 0.05). The plasma levels of apolipoprotein A-I, A-II, and B were not altered. Melatonin significantly inhibited the activity of lipoprotein lipase by -14.1% (P < 0.05), but did not significantly affect the activities of hepatic triglyceride lipase or of lecithin cholesterol acyltransferase. CONCLUSIONS: Findings indicate that melatonin increases the plasma level of VLDL particles by inhibiting the activity of lipoprotein lipase, but may not affect the plasma levels of LDL and HDL particles in postmenopausal women with normolipidemia.     

Impact of hormone replacement therapy on postprandial lipoproteins and lipoprotein(a) in normolipidemic postmenopausal women

In 43 normolipidemic postmenopausal women we studied fasting and postprandial (oral fat load with 50 g fat per square meter; blood sampling for 5 h) lipoprotein components and lipoprotein(a) levels before and with the administration of conjugated equine estrogens opposed by medrogestone (on days 11–21). Data was compared intraindividually; the second testing was performed during the last 5 days of the combined estrogen/progestogen phase of the third cycle. Fasting low-density lipoprotein (LDL) and total cholesterol concentrations decreased significantly; high-density lipoprotein (HDL) cholesterol, including subfractions HDL₂ and HDL₃, was not changed. Fasting triglyceride concentrations increased. All lipoprotein fractions measured showed a postprandial elevation with the exception of chylomicron cholesterol concentrations. There was a significant effect of hormone replacement therapy on the postprandial course of total cholesterol (decrease; P < 0.001), VLDL cholesterol (increase; P = 0.025), and the triglyceride proportion in the LDL plus HDL fraction (increase; P < 0.001). With hormone replacement therapy the postprandial curve of total triglycerides was increased only 1 h after the fat load while chylomicron triglyceride concentrations were lowered after 5 h. VLDL triglycerides were not influenced. In all patients with lipoprotein(a) levels above 10 mg/dl, this parameter decreased (about 25%). Although increasing fasting triglyceride concentrations, hormone replacement therapy does not bring about an exaggerated postprandial increase in triglycerides. Postprandial chylomicron clearance is evidently promoted. Hormone replacement therapy leads to a small increase in triglycerides in the LDL plus HDL fraction by inhibiting hepatic lipase activity. Moreover, the decrease in lipoprotein(a) levels may contribute to the antiatherosclerotic effect.Abbreviations: CEE conjugated equine estrogens - HDL high-density lipoproteins - HRT hormone replacement therapy - LDL low-density lipoproteins - TG triglycerides - VLDL very low density lipoproteins Correspondence to: U. Julius     

C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

BACKGROUND: Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. METHODS: We conducted a prospective, nested case-control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (sICAM-1). We also studied homocysteine and a variety of lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronary-revascularization procedures. RESULTS: Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), sICAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), LDL cholesterol (2.4), apolipoprotein B-100 (3.4), HDL cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). CONCLUSIONS: The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events.     

Effects of continuous medroxyprogesterone acetate on lipoprotein metabolism in postmenopausal women receiving estrogen

Objective: To investigate the effects of medroxyprogesterone acetate (MPA) on the beneficial effects of estrogen therapy on lipid metabolism in postmenopausal women. Methods: Postmenopausal women were administered either conjugated equine estrogen (CEE) 0.625 mg daily for 3 months (Group 1) or CEE 0.625 mg in conjunction with MPA 2.5 mg (Group 2) or MPA 5.0 mg (Group 3) daily for 3 months. Plasma levels of cholesterol, triglyceride, lipoprotein lipids, apolipoproteins, sex steroid hormones and lecithin cholesterol acyltransferase activity (LCAT) were determined. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (H-TGL) activities were measured in postheparin plasma. Changes in the lipid concentrations and enzymatic activities were evaluated in each group. Results: Total, low-density lipoprotein (LDL) cholesterol, apolipoprotein B concentrations and LCAT activity were all significantly reduced by treatment in the three groups. The levels of high-density lipoprotein (HDL), HDL2, and HDL3 cholesterol as well as the levels of apolipoprotein AI and AII were significantly elevated in groups 1 and 2. The mean decrease in these parameters was related to the dose of MPA. Levels of triglyceride in the HDL and HDL2 were significantly increased in group 1. The levels of triglyceride in plasma, very low density lipoprotein (VLDL), LDL, HDL3 and VLDL cholesterol and LPL activity were unaffected. H-TGL activity was significantly inhibited only in groups 1 and 2. MPA produced a dose-dependent increase in H-TGL activity. A significant negative correlation was observed between the HDL cholesterol concentration and H-TGL activity (r = 0.58 P < 0.001). Conclusions: The administration of MPA 2.5 mg and 5.0 mg did not adversely affect the changes in VLDL-LDL metabolism produced by estrogen. However, MPA has dose-dependent negative effects on HDL metabolism by increasing H-TGL activity and the 5.0 mg MPA interferes with the favorable effects on lipids of estrogen in postmenopausal women.     

Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease

This study was designed to determine whether the plasma level of apolipoprotein A-I is a better discriminator of angiographically documented coronary-artery disease than the level of high-density-lipoprotein (HDL) cholesterol in male subjects. The level of plasma apolipoprotein A-I in 83 patients with coronary-artery disease was 96.7 +/- 4.2 mg per deciliter (mean +/- S.E.M.), which was significantly lower (P less than 0.0001) than the level in 25 patients without coronary-artery disease (146.9 +/- 2.1 mg per deciliter). The levels of HDL cholesterol were also lower (P less than 0.0001) in patients with coronary-artery disease (31.9 +/- 1.5 mg per deciliter) than in those without it (45.9 +/- 2.3 mg per deciliter). A stepwise discriminant analysis, however, indicated the superiority of apolipoprotein A-I over HDL cholesterol in detecting coronary-artery disease. Furthermore, a linear discriminant analysis suggested that although HDL cholesterol by itself was a discriminator of coronary-artery disease, it did not provide a substantial increase in discriminatory value over that provided by apolipoprotein A-I; in contrast, apolipoprotein A-I levels added discriminatory value to the information obtained by measuring HDL cholesterol alone. We conclude that apolipoprotein A-I by itself is more useful than HDL cholesterol for identifying patients with coronary-artery disease.     

Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease

In a randomized, double-blind five-year trial, we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein (HDL) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg per deciliter [5.2 mmol per liter] in two consecutive pretreatment measurements). One group (2051 men) received 600 mg of gemfibrozil twice daily, and the other (2030 men) received placebo. Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein (LDL), and non-HDL cholesterol and triglycerides. There were minimal changes in serum lipid levels in the placebo group. The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test). The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study. There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates. The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia.     

Effects on lipids and lipoproteins in women treated with oestradiol and progesterone

Thirty women with climacteric symptoms were treated for 4 months with 2 mg 17β-oestradiol and different doses of progesterone (50, 100 or 200 mg). The concentrations of total and free cholesterol, phospholipids, triglycerides (TG), apoprotein A1 and apoprotein B were determined in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions and in serum. HDL levels increased and LDL levels decreased, while TG levels in VLDL remained unchanged, which indicates that the lipoprotein pattern is oestrogen-induced and that progesterone exerts little or no influence.     

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 μg/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 ± 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.     

Changes in lipid and lipoprotein profile in postmenopausal women receiving low-dose combinations of 17beta-estradiol and norethisterone acetate

OBJECTIVE: To evaluate the modification of lipid and lipoprotein by use of low doses of continuous-combined formulations of 17beta-estradiol (E ) and norethisterone acetate (NETA) in healthy postmenopausal women. DESIGN: The study was designed as a double-blind, randomized, placebo-controlled trial. A total of 120 healthy postmenopausal women were randomized to one of three treatment arms: (1) placebo group ( = 40); (2) E /NETA 0.25-mg group-subjects receiving oral continuous-combined E 1 mg and NETA 0.25 mg ( = 40); (3) E /NETA 0.5-mg group-women who were treated with E 1 mg and NETA 0.5 mg ( = 40). The duration of study was 12 months. Plasma levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL) cholesterol, triglycerides, lipoprotein(a), apolipoprotein A and apolipoprotein B were determined on four occasions (i.e., baseline, 3-, 6-, and 12-month visits). RESULTS: There were no differences in the baseline characteristics among the three groups. A total of 102 women completed the study, resulting in a compliance rate of 85%. There was a significant reduction of total cholesterol, LDL cholesterol, and lipoprotein(a) in both combined groups when compared with placebo. The level of apolipoprotein B declined significantly only in the E /NETA 0.25-mg group. Decrements were observed within 3 months of treatment and maintained thereafter. No significant changes were found in triglycerides, VLDL cholesterol, HDL cholesterol, apolipoprotein A, and LDL/HDL ratio. Between the two active combined groups, no statistically significant differences were noted. CONCLUSION: Favorable changes in lipids and lipoproteins were associated with the low dose of E /NETA combinations. These effects may contribute to the reduction or prevention of atherogenesis in postmenopausal women.     

Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B

BACKGROUND AND METHODS. The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2 1/2-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated). RESULTS. The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7 and +5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-32 and +43 percent). In the conventional-therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; P less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77). CONCLUSIONS. In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.     

Changes in lipid and lipoprotein levels and body weight in Tarahumara Indians after consumption of an affluent diet

BACKGROUND. Major new public health problems occur in developing countries as they become more affluent and change their traditional dietary patterns. To study this phenomenon in microcosm, we substituted an "affluent" diet for the traditional diet of a group of Tarahumara Indians, a Mexican people known to consume a low-fat, high-fiber diet and to have a very low incidence of risk factors for coronary heart disease. METHODS. Thirteen Tarahumara Indians (five women and eight men [including one adolescent]) consumed their traditional diet (2700 kcal per day) for one week, and were then fed a diet typical of affluent societies, which contained excessive calories (4100 kcal per day), total fat, saturated fat, and cholesterol, for five weeks. RESULTS. After five weeks of consuming the affluent diet, the subjects' mean (+/- SE) plasma cholesterol level increased by 31 percent, from 121 +/- 5 to 159 +/- 6 mg per deciliter (3.13 +/- 0.13 to 4.11 +/- 0.16 mmol per liter, P less than 0.001). The increase in the plasma cholesterol level was primarily in the low-density lipoprotein (LDL) fraction, which rose 39 percent, from 72 +/- 3 to 100 +/- 4 mg per deciliter (1.86 +/- 0.08 to 2.59 +/- 0.10 mmol per liter, P less than 0.001). High-density lipoprotein (HDL) cholesterol, usually low in this population, increased by 31 percent, from 32 +/- 2 to 42 +/- 3 mg per deciliter (0.83 +/- 0.05 to 1.09 +/- 0.08 mmol per liter). Consequently, the ratio of LDL to HDL levels changed little (2.25 with the base-line diet and 2.38 with the affluent diet). Plasma triglyceride levels increased by 18 percent, from 91 +/- 8 to 108 +/- 11 mg per deciliter (1.03 +/- 0.09 to 1.22 +/- 0.12 mmol per liter, P less than 0.05), with a significant increase in the very-low-density lipoprotein triglyceride fraction. All the subjects gained weight, with a mean increase of 3.8 kg (7 percent). CONCLUSIONS. When Tarahumara Indians from a population with virtually no coronary risk factors consumed for a short time a hypercaloric diet typical of a more affluent society, they had dramatic increases in plasma lipid and lipoprotein levels and body weight. If sustained, such changes might increase their risk of coronary heart disease.     

Combined oral estradiol valerate-norethisterone treatment over 3 years in postmenopausal women: effect on lipids,coagulation factors,haematology and biochemistry

OBJECTIVE: To determine the effect of continuous estradiol valerate 2 mg and norethisterone 0.7 mg daily as hormone replacement on lipid profiles, coagulation factors, haematology and biochemistry over 3 years. METHODS: An open label trial with 107-133 postmenopausal women assessed pre-treatment and at annual visits with extensive lipid and coagulation profiles, and observation of circulatory adverse events. Standard haematology and biochemical profiles were also analysed. Results were compared at point of entry and at 36 months. RESULTS: Total cholesterol (TC) and HDL and LDL fractions fell significantly (P=0.0001) and there was a significant decline in favourable ratios as well as a rise in VLDL mass (P=0.0001). Lipoprotein (a) (Lp(a)) decreased significantly (P=0.0053). Fibrinogen, free protein, prothrombin time and thrombin increased (P=0.0001) while platelets and KPTT were unchanged. Protein C, antithrombin III and total protein S decreased (P=0.0001) and there was a rise in the frequency of lupus anticoagulant positivity. Significant but small changes were seen in haematology and biochemical parameters although this did not raise safety issues and their clinical significance was uncertain. CONCLUSION: The direction of lipid and coagulation factors move in competing ways, emphasising the complexity of metabolic change and making interpretation of outcome for venous and arterial thrombosis or atherosclerosis difficult to predict. Eight patients developed thromboembolic or ischaemic events over the 3 year period of this study but these patients had lipid changes normally considered beneficial to cardiovascular disease and coagulation changes not thought to be associated with thromboembolism. Decrease in lipoprotein 'a' levels might be an indicator of long-term decreases in atherosclerotic events.     

The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism

BACKGROUND. Oral contraceptives can induce changes in lipid and carbohydrate metabolism similar to those associated with an increased risk of coronary heart disease, including increased serum triglyceride, low-density lipoprotein (LDL) cholesterol, and insulin levels and decreased high-density lipoprotein (HDL) cholesterol levels. In this study, we examined whether modification of the type or dose of progestin in oral-contraceptive preparations diminishes these changes. METHODS. We measured plasma lipoprotein levels and performed oral glucose-tolerance tests in a cross section of 1060 women who took one of nine types of oral contraceptives for at least three months and 418 women who took none. Seven of the contraceptive formulations contained various doses and types of progestin: levonorgestrel in low (150 micrograms), high (250 micrograms), and triphasic (50 to 125 micrograms) doses; norethindrone in low (500 micrograms), high (1000 micrograms), and triphasic (500 to 1000 micrograms) doses; and a new progestin, desogestrel, in one dose (150 micrograms). All seven contained 30 to 40 micrograms of ethinyl estradiol. Two additional formulations contained progestin alone. RESULTS. As compared with controls, women taking combination drugs did not have increased serum total cholesterol levels but did have increases of 13 to 75 percent in fasting triglyceride levels. Levels of LDL cholesterol were reduced by 14 percent in women taking the combination containing desogestrel and by 12 percent in those taking low-dose norethindrone. Levels of HDL cholesterol were lowered by 5 percent and 16 percent by the combinations containing low-dose and high-dose levonorgestrel, respectively; these decreases were due to reductions of 29 percent and 43 percent, respectively, in the levels of HDL subclass 2. The combination pill containing high-dose norethindrone did not affect HDL cholesterol levels, whereas that containing low-dose norethindrone increased HDL cholesterol levels by 10 percent. The desogestrel combination increased HDL cholesterol levels by 12 percent. Levels of apolipoproteins A-I, A-II, and B were generally increased by combination drugs. Depending on the dose and type of progestin, combination drugs were associated with plasma glucose levels on the glucose-tolerance test that were 43 to 61 percent higher than in controls, insulin responses 12 to 40 percent higher, and C-peptide responses 18 to 45 percent higher. Progestin-only formulations had only minor metabolic effects. CONCLUSIONS. The appropriate dose and type of progestin may reduce the adverse effects of oral contraceptives on many metabolic markers of risk for coronary heart disease. Progestin-only formulations or combinations containing desogestrel or low-dose norethindrone were associated wtih the most favorable profiles.     

Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause

To elucidate the effect of smoking on estrogen metabolism, we examined 136 postmenopausal women treated for one year with one of three different doses of combined estrogen-progestogen or placebo. The women were grouped according to smoking status, and serum levels of estrone and estradiol were measured before and after treatment. The results showed reduced levels of both estrogens in smokers as compared with nonsmokers in all three dosage groups. This reduction was most pronounced in the high-dose group (4 mg of estradiol), in which the serum levels of estrone and estradiol in smokers were only 50 per cent of those in nonsmokers (P less than 0.001 and less than 0.05, respectively). In contrast, no significant changes could be demonstrated in the corresponding placebo groups. Moreover, it was possible to demonstrate significant inverse correlations between the number of cigarettes smoked daily and the changes in the levels of serum estrone and estradiol, respectively, (P less than 0.001). This study suggests that an increased hepatic metabolism of estrogens results in lower estrogen levels among postmenopausal smokers. This may contribute to the reported risk of osteoporosis among smokers.     

Effect of Synthetic Truncated Apolipoprotein C-I Peptide on Plasma Lipoprotein Cholesterol in Nonhuman Primates

The present studies were conducted to determinewhether a synthetic truncated apoC-I peptide thatinhibits CETP activity in baboons would raise plasmaHDL cholesterol levels in nonhuman primates with lowHDL levels. We used 2 cynomolgus monkeys and 3baboons fed a cholesterol- and fat-enriched diet. Incynomolgus monkeys, we injected synthetic truncatedapoC-I inhibitor peptide at a dose of 20mg/kgand, in baboons, at doses of 10, 15, and 20mg/kgat weekly intervals. Blood samples were collected 3times a week and VLDL + LDL and HDL cholesterolconcentrations were measured. In cynomolgus monkeys,administration of the inhibitor peptide caused arapid decrease in VLDL + LDL cholesterolconcentrations (30%–60%) and an increase in HDLcholesterol concentrations (10%–20%). VLDL + LDLcholesterol concentrations returned to baselinelevels in approximately 15days. In baboons,administration of the synthetic inhibitor peptidecaused a decrease in VLDL + LDL cholesterol (20%–60%)and an increase in HDL cholesterol (10%–20%). VLDL+ LDL cholesterol returned to baseline levels byday 21, whereas HDL cholesterol concentrationsremained elevated for up to 26days. ApoA-Iconcentrations increased, whereas apoE andtriglyceride concentrations decreased. Subcutaneousand intravenous administrations of the inhibitorpeptide had similar effects on LDL and HDLcholesterol concentrations. There was no change inbody weight, food consumption, or plasma IgGlevels of any baboon during the study. Thesestudies suggest that the truncated apoC-I peptide canbe used to raise HDL in humans.     

Lipids and clotting factors during low dose transdermal estradiol/norethisterone use

OBJECTIVE: To demonstrate the effects of 2-year transdermal continuous combined low-dose estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) on lipid/lipoprotein profile and coagulation/fibrinolysis. METHODS: A double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years post menopause. Patients received either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo transdermally. One hundred and thirty five women completed a second year open follow-up (96 had used Estragest TTS, 39 placebo during the first year), where all women had the estradiol/norethisterone patch. Lipid/lipoprotein profile and coagulation/fibrinolysis parameters were studied at 0, 24, 48, 72 and 96 weeks. RESULTS: In women on estradiol/norethisterone total cholesterol, Lp(a) and VLDL cholesterol decreased significantly more than in the placebo group after 24 weeks and LDL cholesterol after 48 weeks. Women on estradiol/norethisterone had no change in HDL, triglycerides or Lp(a), an increased HDL/total cholesterol ratio and decreased LDL, VLDL and total cholesterol at 48 weeks compared to placebo. Women with active treatment also showed a significant reduction compared with the placebo group of Factor VII and antithrombin III at 24 and 48 weeks and a reduction of fibrinogen at 24 weeks. These changes persisted over the second year. CONCLUSIONS: A continuous combined low-dose transdermal patch daily delivering 0.025 mg estradiol and 0.125 mg norethisterone acetate provided beneficial effects on lipid/lipoprotein profile and coagulation/fibrinolysis. The changes were similar to those previously described after higher dose oral and transdermal estrogen/progestogen regimens.