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Our specific aim was to assess within-family relationships of basal fibrinolytic activity and its determinants in hyperlipidemic probands (n = 34) with high lipoprotein (a) [Lp(a)] levels (>35 mg/dL) and their first-degree relatives (n = 74) and in hyperlipidemic probands (n = 19) with Lp(a)

Background: In 35 adolescent females (17 ± 2 years) with polycystic ovary syndrome (PCOS), median body mass index (BMI) 30.8 kg/m 2 , we assessed effeicacy of metformin-diet for 1 year for reduction of weight, insulin, HOMA insulin resistance (IR), cholesterol, triglycerides, and resumption of regular menses. Methods: Calories (26% protein, 44% carbohydrate) were targeted to 1,500-1,800/day if BMI was

Sixteen nondiabetic women with polycystic ovary syndrome (PCOS) aged 18 to 33 years were studied before and after 8 weeks on metformin (1.5 g/d) therapy to assess whether reducing hyperinsulinemia would reduce the levels of the major inhibitor of fibrinolysis, antigenic plasminogen activator inhibitor type 1 (PAI-1). Compared with six normal control women, PCOS women had a higher body mass index (BMI), waist to hip ratio, fasting insulin (Izero), insulin area under the curve during oral glucose tolerance testing (IA), glucose area under the curve during oral glucose tolerance testing (GA), IA/GA ratio, PAI-1, luteinizing hormone (LH) and ratio of LH to follicle-stimulating hormone (FSH), and free testosterone, and lower high-density lipoprotein (HDL) cholesterol (all P < .025). On metformin, BMI decreased 1.3% (P = .04), Izero 43% (P = .002), IA 31% (P = .03), GA 11% (P = .02), PAI-1 16% (P = .01), lipoprotein(a) [Lp(a)] 42% (P = .004), free testosterone 46% (P = .0006), LH 44% (P = .004), and the LH/FSH ratio 41% (P = .0001). On metformin, absolute and percent reductions in Izero correlated with absolute and percent reductions in PAI-1 (r = .60, P = .015 and r = .64, P = .008). On metformin, by stepwise multiple regression, the absolute reduction in Izero was a significant determinant of the absolute reduction in PAI-1 (partial R2 = 35%, P = .02), and the percent reduction in Izero was a significant determinant of the percent reduction in PAI-1 (partial R2 = 52%, P = .003). Metformin decreases Izero in hyperinsulinemic PCOS patients, reverses the hyperinsulinemia-driven endocrinopathy, decreases PAI-1, and decreases Lp(a), and should thus reduce the increased risk of atherothrombosis in PCOS.

In 17 men, aged 27 to 54 years, with myocardial infarction 2 to 10 months before the current exercise study, we aimed to determine whether 3 months of exercise training, at a level designed to elevate high-density lipoprotein cholesterol (HDLC), would be associated with changes in endogenous sex steroid hormones and postheparin lipoprotein and hepatic lipases, and whether the changes in sex hormones, lipids, lipoproteins, apolipoproteins, and physical activity were interrelated. Supervised bicycle ergometry, 30 minutes, 3 days per week, eliciting 75% of maximum heart rate, produced a significant training effect, with a 26% increase in the duration of the exercise test at a standardized, submaximal workload (P less than or equal to .001), and a reduction in heart rate measured at a standardized submaximal workload, P = .08. After 3 months' training, mean HDLC increased 23% (30 to 37 mg/dL), P less than or equal to .001, mean apo A2 increased 19% (43 to 51 mg/dL), P less than or equal to .001, and the ratio of total cholesterol (TC) to HDLC decreased 26% (P less than or equal to .01), while estradiol (E2) levels decreased 45% (50.1 to 27.8 pg/mL), P less than or equal to .0001. After 1 and 2 months' exercise, TC (12% [P less than or equal to .001], 11% [P less than or equal to .01]), and low-density lipoprotein cholesterol (LDLC) (13% [P less than or equal to .01], 12% [P less than or equal to .01]) were reduced. Hepatic lipase decreased 16% (P less than or equal to .01) and 16% (P less than or equal to .05) after 1 and 3 months' exercise. There were no significant changes in apo A1, lipoprotein lipase, testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), or weight. By stepwise regression analysis, after 3 months' training, 66% (P = .0025) of the variance for the increase in HDLC from baseline to day 90 was accounted for independently by a decrease in triglyceride (F = 13.2, P = .003), by reduced heart rate on a fixed submaximal load (F = 12.7, P = .0035), and by a decrease in hepatic lipase (F = 5.5, P = .036). A modest, achievable exercise program can have significant cardiovascular benefit for men after myocardial infarction by ameliorating their hyperestrogenemia, reducing TC and LDLC, improving the TC to HDLC ratio, and elevating HDLC and apo A2. The increment in HDLC was related independently to improved capacity to sustain submaximal exercise and to exercise-induced reductions in triglyceride and postheparin hepatic lipase.

Purified phosphatidylcholine exchange protein from bovine liver was used to exchange [14C]dipalmitoyl phosphatidylcholine from sonicated vesicles to human plasma very low density lipoproteins (VLDL). The exchange of [14C]-dipalmitoyl phosphatidylcholine for VLDL phospholipids was temperature dependent and linear with respect to time and amount of exchange protein. In the absence of the exchange protein, less than 10% of the [14C]dipalmitoyl phosphatidylcholine was transferred. At an initial weight ratio of [14C]-dipalmitoyl phosphatidylcholine vesicles to VLDL phospholipid (1.2 mg) of 2.2, the exchange protein (14 microgram) replaced 55% of the VLDL phospholipids with [14C]dipalmitoyl phosphatidylcholine in 15 min; VLDL protein and cholesterol content were unaltered. From these studies we conclude that the exchange protein is a useful method to alter the phospholipid composition of VLDL under conditions such that there is minimal perturbation of the lipoprotein.

Ten chlorinated hydrocarbons (tetradifon, Chlorobenzilate, Kepone, lindane, Kelthane, toxaphene, dieldrin, hexachlorobenzene, dienochlor, and Aroclor 1254; see below) were evaluated in rats to assess agents which might selectively elevate high-density lipoprotein cholesterol (C-HDL). Single, nontoxic doses of Aroclor, dieldrin, and Kepone elevated C-HDL at day 7 (31%, 26%, and 24%, respectively, p less than 0.05). The C-HDL elevations were maintained at days 21 and 60 (28% and 31%, p less than 0.01) in the Aroclor group, while C-HDL returned to baseline in the dieldrin and Kepone groups. Liver function tests were unchanged from control, suggesting that the changes in C-HDL were not the consequence of hepatotoxicity. The hepatic microsomal cytochrome P-450 content of animals receiving Aroclor, dieldrin, and Kepone was 67%, 56%, and 44% higher than control values (p less than 0.02), indicating probable hepatic enzyme induction. If HDL (an antiatherogenic lipoprotein) is also selectively elevated by chlorinated hydrocarbons in man, then analogues might potentially be developed as antiatherogenic pharmacologic agents. Alternatively, the implications of man's exposure to halogenated hydrocarbons may be better understood.

Based upon the hypothesis that endogenous testosterone plays a significant role in triglyceride and high density lipoprotein cholesterol metabolism, the specific aim of this study in 9 azoospermic and 10 oligospermic subjects (compared to 20 fertile men) was to examine potential relationships between endogenous testosterone, luteinizing hormone, follicle stimulating hormone, lipids-lipoproteins, and lipoprotein lipases. The azoospermic and oligospermic men had much higher fasting plasma triglyceride levels (mean ± SD; 479 ± 258, 295 ± 119) than did normal controls (105 ± 31 mg/dl, p p p p p p p r = .42, p r = −.50, p r = −.37, p r = .45, p

Post-heparin lipoprotein lipase (PH-LPL)-high density lipoprotein cholesterol (HDL-C) interrelationships were assessed in 9 subjects with documented familial hyperalphalipoproteinemia (FHA) and in 8 controls to focus on potential biochemical etiologies of FHA and relationships of HDL-C to triglyceride hydrolysis and PH-LPL. FHA subjects had mean HDL-C and HDL 2 -C levels > twice controls; their PH-LPL levels (X ± SEM) (3.14 ± 2.3 μmol FFA/h/ ml) were also > twice that of controls (15.0 ± 1.6) ( P P > 0.1). For all subjects (FHA and controls) PH-LPL was positively correlated with HDL-C (r = 0.79, P 2 -C (r = 0.90, P 3 -C (r = −0.02). There were no significant PH-HL and HDL-C interrelationships, P > 0.1. The amount of apo CII (the primary activator of PH-LPL) in HDL 2 was greater in the FHA (X ± SEM) (16.1 ± 2.5 μg/ml plasma) than in control subjects (4.7 ± 0.9, P 2 apo CII and both PH-LPL (r = 0.79, P 2 -C (r = 0.80, P 2 protein was higher in FHA than control subjects (X ± SEM) (1.2 ± 0.3% vs 0.5 ± 0.2%, P 3 protein was similar in FHA and control subjects. We postulate that increased turnover rate of triglyceride-rich lipoproteins due to high LPL activity may be an important factor leading to the elevation of HDL-C in FHA. The highly significant positive correlation between HDL 2 -C and PH-LPL provides strong clinical evidence for the theory that HDL 2 is formed during the hydrolysis of triglycceride-rich lipoproteins. The high concentration of HDL 2 apo CII in FHA subjects may be caused by increased catabolism of triglyceride-rich lipoproteins in the presence of high endothelial LPL, with transfer of apo CII from very low to high density lipoproteins.

Plasma lipids, lipoproteins, and anthropometric measurements were assesed in 996 Venezuelan school children (ages 13–18 years) (441 in private, 555 in public schools, Merida, Venezuela) with cross-cultural comparisons to 419 13–18-year-old. American school children from suburban Cincinnati, Ohio. Although there were no systematic differences in plasma cholesterol and triglyceride between public and private Venezuelan school children, low density lipoprotein cholesterol (LDL-C) levels were higher and high density lipoprotein cholesterol (HDL-C) levels lower in public than private school children. Within Venezuelan schools, and between sex, female children had consistently higher total plasma cholesterol, marginally higher HDL-C, and appreciably higher LDL-C than males. There were no consistent cross-sectional changes in lipids and lipoproteins in Venezuelan school children with age. Within sex, cross-cultural comparisons with Cincinnati school children revealed 2 major, consistent differences; Venezuelan children had higher fasting plasma triglyceride and lower HDL-C levels, not attributable to systematic differences in Quetelet index, laboratory methodology, subject selection, or sampling technique. Total plasma cholesterol and HDL-C were similar for Venezuelan and Cincinnati school children. Maintenance of comparable LDL-C but lower HDL-C levels by Venezuelan children into adulthood might, speculatively, be associated with augmented risk for coronary heart disease.

Lipids and lipoproteins were studied during pregnancy, parturition, and lactation in a subject homozygous for familial hypercholesterolemia and her obligate heterozygote neonate. At the end of the 1st trimester, plasma cholesterol had risen from a preconception level of 530 to 621 mg/dl, C-LDL rose from 489 to 550 mg/dl, C-HDL from 36 to 46 mg/dl, and triglyceride from 23 to 125 mg/dl. During the 2nd trimester, mean cholesterol (615 mg/dl) was significantly higher compared to preconception levels, C-LDL remained elevated at 531, C-HDL was increased to 50 mg/dl, and triglyceride had risen appreciably to 174 mg/dl. In the 3rd trimester, total cholesterol increased to 632 mg/dl, C-LDL rose to 548, triglycerides rose sharply to 275, and C-HDL fell to 30 mg/dl. The neonate's cord blood C-LDL was elevated at 52 mg/dl. Breast milk cholesterol 7 wk postpartum was 6.5 mg/g total milk fat, considerably greater than levels in 14 normals (2.4 ± 0.4). Placental lipid distribution revealed sharply reduced levels of phospholipids, triglyceride, and cholesterol, and increased free fatty acids. The linoleic acid content of the free fatty acid and triglyceride in the placenta (13.8% and 15.1%) was higher than in normal placentas, 10.0% and 10.2%, respectively. The arachidonic acid content of the triglyceride and cholesterol ester in the placenta, 3.5% and 17.8%, were considerably lower than in normal placentas (29.6% and 32.7%). Gross and microscopic examination of placental vasculature did not reveal any evidence for placental insufficiency or accelerated fetal or maternal atherosclerosis.

Effects of estrogens and the synthetic anabolic-androgenic steroid, Oxandrolone, on extrahepatic (protamine inactivated) and hepatic (protamine resistant) lipases in postheparin plasma, were assessed in 15 subjects with familial hypertriglyceridemia. In six women receiving conjugated equine estrogen (1.25 mg/day), mean (+/- SE) postheparin protemine inactivated triglyceride lipase (PI-TGL) was depressed to 0.23 +/- 0.10 mumol FFA/ml/hr, and protamine resistant lipase was depressed to 5.3 +/- 0.5 mumol FFA/ml/hr. In the 2-wk period after estrogens were discontinued, PI-TGL remained depressed, 0.54 +/- 0.24, while PR-TGL increased to 7.3 +/- 0.88, p=less than 0.05. Mean triglycerides fell insignificantly from 628 +/- 136 to 447 +/- 44 mg/100 ml when estrogens were discontinued. There was no significant correlation between changes in PR-TGL and triglycerides when estrogens were stopped. In four women with familial hypertriglyceridemia, Oxandrolone significantly increased PR-TGL in two, increased PI-TGL in three, and reduced triglycerides in two. In five men with familial hypertriglyceridemia, Oxandrolone reduced triglycerides in four, increased PR-TGL in four, but had no effect on PI-TGL. For the nine hypertriglyceridemic subjects increments in PR-TGL failed to correlate significantly with decrements in triglyceride, (r=0.309, p is greater than 0.1). Selective alteration of PR-TGL and PI-TGL by estrogens and Oxandrolone may provide an approach to better understanding of the interaction of lipases and triglycerides in familial and acquired hypertriglyceridemia.

Studies in 130 children and 45 siblings of 36 propositi with familial hypertriglyceridemia were carried out to evaluate the incidence, mechanism of transmission, and results of early therapy of hypertriglyceridemia in a pediatric-young adult population. Twenty-three of 113 children (ages 1–20) and 10 of 17 children (ages 20–35) from these kindreds had type IV hyperlipoproteinemia with primary elevations of triglycerides. Twenty-nine of the probands' 45 siblings had primary elevations of triglycerides. Although plasma cholesterol levels in the 130 children and 45 siblings were normally distributed, plasma triglycerides in both groups did not fall into a single log-normal distribution, and more nearly represented a bimodal pattern. Weight reduction and the NIH type IV diet were effective in reducing triglyceride levels to normal in most children. Complete family screening in kindreds with familial hypertriglyceridemia makes possible early diagnosis and amelioration of hypertriglyceridemia in an appreciable number of children.

To assess the relationship between altitude, atherogenic, and anti-atherogenic lipoprotein cholesterols (low- [C-LDL] and high [C-HDL] density lipoprotein cholesterols, respectively), 136 and 94 Venezuelan Mestizos living at 1,000 and 3,500 in elevation were studied. The two groups did not differ in regard to height, weight, ethnic origin, social or economic status, nutritional patterns, age, or occupation. Both groups had a high level of daily physical exertion, an imperative in their subsistence rural agricultural economy. Due to the mountainous terrain, high altitude residents were thought to have increased levels of physical activity. Males and females at high altitude had significantly lower plasma total cholesterol and C-LDL levels, and slightly lower C-HDL levels than those at low altitudes. It is speculated that reduced coronary heart disease event rates at high altitude might be related to lower levels of the atherogenic lipoprotein cholesterol, C-LDL.

Zeranol (3,4,5,6,7,8,9,10,11,12-Decahydro-7,14,16-trihydroxy-3-methyl-1H-2 - benzoxacyclotetradecin-1-one) is a synthetic oestrogenic agent used as an animal growth promoter. The effects of occupational exposure to zeranol in 11 exposed workers from a pelletising plant and 14 nonexposed subjects were assessed. A questionnaire showed that more breast symptoms were reported by male and female plant workers compared with non-exposed subjects, although the difference was not statistically significant. Clinical assessment showed no cases of gynaecomastia in all the male participants. Blood samples analysed by high performance liquid chromatography for zeranol, its precursor zearalenone, and its main metabolites did not show any of these compounds above the laboratory limit of detection. Serum levels of follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin, and oestradiol showed no striking differences between the exposed and the non-exposed subjects. Total and low density lipoprotein cholesterol (LDL cholesterol) levels did not significantly differ between the two groups but mean high density lipoprotein cholesterol (HDL cholesterol) levels were higher in the exposed group; this could be due to relatively high HDL cholesterol in two women exposed to zeranol or relatively low HDL cholesterol in three non-exposed men.

Summary: This study was designed to focus upon within-culture differences in plasma lipids and lipoproteins in Venezuelan schoolchildren having different socioeconomic and nutritional backgrounds and also to provide cross-cultural comparisons of lipids, lipoproteins, and anthropometric measurements between Venezuelan and American schoolchildren. The study was carried out in 1298 schoolchildren, ages 7 to 12 years, 428 in private and 870 in public schools in Merida, Venezuela, with comparison to 472 public schoolchildren in the (Cincinnati, OH) Princeton School District. Within Venezuelan schools, private schoolchildren were heavier, taller, had marginally higher Quetelet indices, and had considerably higher fasting plasma cholesterol, plasma high-density lipo-protein (C-HDL), and plasma low-density lipoprotein (C-LDL) levels. These lipid-lipoprotein differences were highly significant after adjusting (by covariance analysis) for Quetelet index, sex, and age. Children from private Venezuelan schools ingested more total calories, more protein, more fat, and more carbohydrate. When the diet compositions were calculated as percentage of total calories, the private schoolchildren ingested nearly twice as many calories as fat and a somewhat lower proportion of calories as carbohydrate, with a comparable proportion as protein, when compared to the public Venezuelan schoolchildren. Male-female comparisons within Venezuelan schools revealed patterns of sex-related lipoprotein differences which were qualitatively similar to those in Princeton schoolchildren. Thus, 7- to 12-year-old females had higher total plasma cholesterol and triglyceride, lower C-HDL, and higher C-LDL. Within sex, cross-cultural comparisons of lipids, lipoproteins, and Quetelet indices revealed two major differences. Venezuelan children had significantly higher fasting plasma triglyceride and lower C-HDL levels, differences not attributable to systematic differences in measures of ponderosity, because Quetelet indices in Venezuelan and Cincinnati schoolchildren did not differ appreciably. In regard to total and low-density lipoprotein cholesterol, Venezuelan and Princeton public schoolchildren were remarkably comparable, although Venezuelan private schoolchildren had somewhat higher plasma cholesterol and C-LDL levels than did Princeton public schoolchildren. We speculate that increasing "westernization" and "urbanization" of Venezuelan society is associated with convergence of Venezuelan and American pediatric plasma lipid and lipoprotein levels. Maintenance of comparable total plasma cholesterol and C-LDL levels with lower C-HDL into adulthood in Venezuela would, in fact, suggest augmented risks for coronary heart disease for Venezuela within this lipid-lipoprotein frame of reference. Speculation: We speculate that increasing "westernization" and "urbanization" of Venezuelan society is associated with convergence of Venezuelan and American pediatric plasma lipid and lipoprotein levels. Maintenance of comparable total plasma cholesterol and plasma low-density lipoprotein levels, with lower plasma high-density lipoprotein levels into adulthood in Venezuela would, in fact, suggest augmented risk for coronary heart disease in Venezuelans, within this lipid-lipoprotein frame of reference.

Longitudinal studies of the effects of a cholesterol-free diet and a less rigid 300 mg/day low cholesterol diet, both with a polyunsaturated to saturated fatty acid ratio of 1.8/1, were carried out preconception, during gestation, and postpartum in a women heterozygous for familial hypercholesterolemia. On the cholesterol-free diet, during weeks 8-14 of gestation, plasma cholesterol was lowered 25% (from 310 to 230mg/dl), and plasma low density lipoprotein cholesterol (C-LDL) (from 240 to 160 mg/dl), 33%. The 25% reduction in plasma cholesterol was slightly more than previously reported decrements of 19% in 14 normal women during pregnancy, also receiving a cholesterol-free diet. The 300 mg cholesterol diet was not as hypocholesterolemic as the cholesterol-free diet. Its maintenance throughout gestation limited the within-pregnancy increments of total plasma cholesterol and C-LDL to 21% (352-426 mg/dl) and 14% (286-326 mg/dl) respectively. Both the cholesterol-free and the 300 mg cholesterol diet were well tolerated, and should be nutritionally adequate for pregnant women, since they contain more than the recommended amounts of high quality protein, vitamins, minerals, and calories for pregnant women. Cholesterol restricted diets during pregnancy in familial hypercholesterolemics should reduce the physiologic hypercholesterolemia of pregnancy, and potentially reduce the increased risk of coronary heart disease relative to the degree and duration of elevations of total and LDL cholesterol.

Interrelationships between pregnancy, hypertriglyceridemia, and pancreatitis were assessed in three women with familial hypertriglyceridemia. One subject had known familial hypertriglyceridemia, familial type V hyperlipoproteinemia, prior to conception. In this woman a progressive increase in triglyceride levels to more than 3,000 mg/dl during the first two trimesters required dietary intervention and hospitalization at 28 weeks' gestation. Use of an isocaloric National Institutes of Health type V diet reduced triglyceride levels to less than 900 mg/dl; the pregnancy was uneventful with term delivery of a healthy neonate. The familial hypertriglyceridemia was covert in the other two women until term. In one subject, subsequently shown to have familial type V, acute hemorrhagic pancreatitis with a pancreatic pseudocyst, shock, and hypocalcemia developed at 39 weeks' gestation; the neonate was safely delivered, and the mother survived. In the second, entirely asymptomatic subject, triglyceride levels greater than 5,000 mg/dl were discovered incidentally at term cesarean section during delivery of a healthy neonate. With a fat restricted diet, plasma triglyceride levels abruptly fell post partum to less than 500 mg/dl, and subsequent studies revealed familial type III hyperlipoproteinemia. Routine quantitation of plasma cholesterol and triglyceride levels or simple visual examination of fasting plasma for triglyceride-induced opacity or “milky” appearance should be done during early pregnancy. This would allow the obstetrician to identify women with severe familial hypertriglyceridemia prior to the superimposition of the physiologic hyperlipidemia of pregnancy upon familial hypertriglyceridemia with resultant, and often catastrophic, acute pancreatitis.

Lipid and lipoprotein levels were evaluated in 33 kindreds where the proband had primary elevations of cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride (combined hyperlipoproteinemia). Fifty-eight of 74 living siblings and 95 of 103 living children from the 33 kindreds were studied. The siblings and children of affected probands had either normal cholesterol and triglyceride levels or one of the following combinations: (1) elevated cholesterol, elevated LDL cholesterol, and normal triglyceride; (2) elevated cholesterol, elevated LDL cholesterol, and elevated triglyceride; (3) normal to slightly elevated cholesterol, normal LDL cholesterol, and elevated triglyceride. It appeared that a single autosomal dominant gene with variable expression of phenotype might account for some of the kindred data, particularly in siblings of the propositi.