Pregnancy, parturition, and lactation in familial homozygous hypercholesterolemia

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.     

Lipid and lipoprotein distributions in octo- and nonagenarians.

This study focused on 124 octogenarians and 13 nonagenarians to extend data on lipid and lipoprotein distributions into the eighth and ninth decades of life and to assess relationships between lipids, lipoproteins, and longevity. The mean (±SD) ages of the 114 women and 23 men were 85 ± 4 and 84 ± 4 yr, respectively. Mean (±SD) total plasma cholesterol and high density lipoprotein cholesterol (C-HDL) were higher in women than in men, 219 ± 41 and 198 ± 31 mg/dl, 58 ± 16 and 50 ± 13 mg/dl respectively, p<.02. Mean (±SD) low density lipoprotein cholesterol (C-LDL) levels were 132 ± 35 in women, 125 ± 26 mg/dl in men. In women, the 90th percentile levels for total plasma cholesterol, C-HDL, C-LDL, and triglyceride were respectively 269, 79, 180, and 243 mg/dl, with the 10th percentile levels being 164, 36, 85, and 77 mg/dl. For both women and men, total plasma cholesterol was closely correlated with C-LDL, r=.937, .926, p<.01. In the eighth and ninth decades of life, reductions in total plasma cholesterol are probably accounted for by reductions in C-LDL levels, while C-HDL remains stable. Subjects living into the eighth and ninth decades may have lower plasma cholesterol and C-LDL and stable C-HDL, because those with higher C-LDL and/or lower C-HDL have been removed from the distribution by coronary heart disease. Alternatively, some octo- and nonagenarians may also come from kindreds having familial hypobeta- or familial hyperalpha-lipoproteinemia, familial traits associated with increased longevity and reduced CHD morbidity and mortality.     

The effects of dietary cholesterol upon the hypercholesterolemia of pregnancy

The hypercholesterolemia which accompanies the normal human pregnancy is not known to be influenced by diet or other factors. The present experiment in fourteen pregnant women was designed to document this phenomenon under controlled metabolic conditions and to study the effect of dietary cholesterol upon this usual increase in serum cholesterol. The subjects included twelve normal subjects, one juvenile diabetic, and one type II familial hypercholesterolemic subject. They were fed controlled, nutritionally adequate diets which were equivalent except for the cholesterol content, which was cholesterol-free or 600–1000 mg from egg yolk daily. Calories were adjusted to permit weight gain of 1.4 kg per mo. The cholesterol-free diet lowered the mean serum cholesterol level in the 12 normal pregnant women from 234-187 mg/dl, a 20% decrease (?47 ± 37 S.D.) (p < 0.005). The addition of cholesterol to the diet invariably elevated the mean serum cholesterol concentrations to 223 mg/dl, a 19% increase (+36 ± 12) (p < 0.001). The mean serum triglyceride levels increased steadily throughout pregnancy regardless of diet, up to 198 ± 43 (S.D.) mg/dl at term. Both serum cholesterol and triglyceride concentrations decreased strikingly 1 wk after parturition. These serum cholesterol and triglyceride responses occurred similarly in the familial hypercholesterolemic and the diabetic women. The increased serum cholesterol levels during the high cholesterol diets occurred largely in the low density lipoprotein (LDL) fraction. Despite the inevitable alterations of cholesterol and lipooprotein homeostasis which occur in pregnancy, the results of this study indicated that the usual hypercholesterolemia of pregnancy in women eating the general American diet was greatly ameliorated by a very low cholesterol, nutritionally adequate diet.     

Effects of probucol on plasma cholesterol,high and low density lipoprotein cholesterol,and apolipoproteins A1 and A2 in adults with primary familial hypercholesterolemia

This double-blind crossover study was designed to assess the safety, utility, and effectiveness of probucol (1000 mg/day) as an agent for reduction of total and low density lipoprotein plasma cholesterol (C-LDL) in 19 adults with primary familial hypercholesterolemia. The study was also designed to evaluate the effects of probucol on high density lipoprotein cholesterol (C-HDL) and its two major apolipoproteins, Apo A1 and Apo A2. After stabilization on a diet that provided < 200 mg cholesterol/day with a $\text{P}\text{S}$ ratio of 1.2:1, the subjects were randomized into the following drug-placebo sequences: 9 subjects received 24 wk of probucol followed by 24 wk of placebo, while 10 received 24 wk of placebo followed by 24 wk of probucol, with weight maintained ± 1 kg, and dietary cholesterol and $\text{P}\text{S}$ intake stable. In all 19 subjects on probucol total plasma cholesterol was reduced 10.7% and C-LDL 8.4% beyond the effects of diet alone; plasma triglyceride, the ratio of C-HDL to Apo A1, and the ratio of Apo $\text{A1}\text{Apo}$ A2 were not significantly changed. In all 19 subjects, the $\text{C-LDL}\text{C-HDL}$ ratio during probucol therapy was 22% higher than during placebo, with an overall 26% reduction in C-HDL on probucol as compared to placebo. In the group of 9 subjects, whose plasma C-HDL levels fell 19% on probucol, mean HDL apolipoprotein A1 (Apo A1) levels fell 6%, Apo A2 levels did not change. In the group of 10 subjects whose mean plasma C-HDL levels fell 30% on probucol, mean Apo A1 fell 34%, and Apo A2 fell 20%. The probucol was well tolerated, with mean adherence of 93%. Of the 19 subjects, the only drug-related side effects were diarrhea in two subjects, and fetid perspiration in another. The relevance of the simultaneous reduction in C-HDL in the face of a mean 8.4% reduction in C-LDL is unknown. Better long-term information about the prognostic significance for atherosclerotic disease of the reductions in C-HDL, Apo A1, and Apo A2 need to be obtained, in view of the inverse association of C-HDL with coronary heart disease.     

Black--white differences in plasma lipoproteins in Cincinnati schoolchildren (one-to-one pair matched by total plasma cholesterol, sex, and age).

The suburban, biethnic Princeton School District provided a suitable population of children (ages 6–17) to test the hypothesis that black schoolchildren have higher high density lipoprotein cholesterol (C-HDL), lower low density lipoprotein cholesterol (C-LDL), and lower triglyceride levels than white schoolchildren when pair-matched by total plasma cholesterol, age, and sex. In 194 black-white pairs of male schoolchildren, black children had higher C-HDL (59.5 ± 13.5 versus 54.8 ± 12.7 mg/dl, p < .001), lower C-LDL (105.7 ± 25.8 versus 108.1 ± 26.7, p < .05), and lower triglyceride (60.7 ± 27.2 versus 71 ± 38.1, p < .001). In 222 black-white pairs of female schoolchildren, black girls had higher C-HDL (57.7 ± 13.1 versus 52.0 ± 11.6 mg/dl, p < .001), lower C-LDL (107.4 ± 24.8 versus 109.6 ± 23.3, p < .05, and lower triglyceride (64.0 ± 24.6 versus 80.2 ± 38.6, p < .001). Mean Quetelet indices (weight/height²) did not differ significantly for the black and white males or females. Since, by matching, the pairs did not differ in age, sex, or total plasma cholesterol, and also did not differ by Quetelet, any differences in C-HDL, C-LDL, and triglyceride can be imputed to racial or other unmeasured, racially related environmental differences in the cholesterol-carrying lipoprotein fractions. Persistence of these black-white differences in lipoproteins into adulthood may be associated with a relatively lower risk of coronary heart disease (CHD) in blacks than in whites, for any given total plasma cholesterol level.     

Cigarette smoking, alcohol intake, and oral contraceptives: relationships to lipids and lipoproteins in adolescent school-children.

The effects of cigarette smoking, alcohol intake, and oral contraceptives on plasma cholesterol, triglyceride, high density lipoprotein cholesterol (C-HDL), and low density lipoprotein cholesterol (C-LDL) were assessed in 965 12--19-year-old school-children in the Cincinnati Lipid Research Clinic's Princeton school survey. After pair matching for age, sex, race, and total plasma cholesterol, adolescent children who smoked had mean C-HDL 6.1 mg/dl lower, and mean C-LDL 4.1 mg/dl higher, than nonsmokers (p less than 0.01). These findings for C-HDL were replicated by covariance analysis, adjusting for age, race, sex, alcohol intake, and triglyceride levels. Adolescents who drank alcohol had higher C-HDL and triglyceride levels and lower C-LDL than nondrinkers, but the differences were not significant. Adolescent females taking oral contraceptives had higher triglyceride, C-HDL, and C-LDL levels than matched controls, but the differences were not significant. If a portion of smoking's contribution to coronary heart disease risk is mediated through its inverse association with C-HDL, and if smoking habits initiated in adolescence continue into adulthood, this report provides additional physiologic data relevant to programs designed to prevent, reduce, or stop cigarette smoking in the adolescent years.     

Lipids, lipoproteins, and sexual maturation during adolescence: the Princeton maturation study.

This study encompassed a cross-sectional and longitudinal examination of schoolchildren as they entered into and passed through puberty, examining interrelationships between lipids, lipoproteins, and sexual maturation. In the first year of the study (1976), 529 schoolchildren in grades 5–12 participated; 203 were restudied in 1977, and 141 in 1978. At each yearly visit, the children's stage of sexual maturation was assessed using the Tanner scale. Plasma cholesterol and triglyceride were quantitated each year; high, low, and very low density lipoprotein cholesterol (C-HDL, C-LDL, C-VLDL) levels were measured in the second and third years of the study. In males, cross-sectional decrements in plasma cholesterol were observed with increasing sexual maturation (Tanner stages 1–4), with an increment at Tanner 5 (sexual maturity); plasma triglyceride levels rose at all stages save Tanner 4. The mid-Tanner fall in plasma cholesterol appears (longitudinally) to be accounted for by reduction in C-HDL, while the rise in plasma cholesterol at Tanner 5 may be produced by an increase in C-LDL. Changes in age and Quetelet indices did not appear to relate closely to changes in C-VLDL in 12- and 13-yr-old males, but increasing age and Quetelet indices in 14–15-yr old males accompanied increasing C-VLDL. Cross-sectional studies in females revealed that plasma cholesterol fell at Tanner stages 3 and 4 and rose at stage 5; plasma triglyceride rose during all stages except Tanner 4. Longitudinal studies suggested that the decrements in plasma cholesterol in females may be partially accounted for by reductions in C-HDL; the increase in plasma cholesterol in late sexual development may be accounted for by an increase in C-LDL. In male children, we speculate that the fall in C-HDL and late rise in C-LDL as sexual maturation progresses is associated with increased testosterone production.     

Effects of high cholesterol high fat diet on plasma lipoproteins in familial hypercholesterolemia

Heterozygous individuals with familial hypercholesterolemia possess about half of the normal numbers of functioning receptors on their cells. This is thought to be responsible for their hypercholesterolemia. In normals, dietary cholesterol increases LDL production and decreases LDL receptor-related LDL clearance, resulting in elevations in LDL cholesterol levels of ～30 mg/dL. To assess the effects of high fat and high cholesterol diets on the lipoproteins of individuals with diminished LDL receptors, three kinds of diets, including ones high in cholesterol, were fed to four patients with familial hypercholesterolemia, in the expectation that diet effects on apoB- or apoE-containing lipoproteins would be exaggerated. The basal diet consisted of 15% protein, 30% fat, 55% carbohydrate, 300 mg/d cholesterol, $\text{P}\text{S}$ ratio 0.4; the high fat diet was identical except that fat calories were 55% and carbohydrate 30%; the high fat-high cholesterol diet was identical with the high fat diet except ～750 or ～1,500 mg/d of cholesterol were added. Each diet was eaten for five weeks at home and for the sixth week at the general Clinical Research Center. Fasting (12–14 hours) plasmas were collected every two weeks for lipoprotein-lipid and apoprotein quantitation. At the end of each period, fasting and 4-hour postprandial samples were analyzed also by zonal ultracentrifugation and gel permeation chromatography. The significant results were as follows: (1) on analysis of fasting samples on the fat + Chol diet, measures of the levels of VLDL (ie, VLDL lipids, VLDL protein on zonal ultracentrifugation, VLDL-associated lipids, and apoE on chromatography) fell; measures of LDL were not consistently changed; and measures of HDL₂ and HDL_c rose. Compositions of VLDL were altered, ie, mass % of triglycerides fell and cholesterol rose. Zonal effluent profiles of VLDL, LDL, HDL₂, and HDL₃ were not altered, nor were gel chromatographic elution patterns of cholesterol, triglycerides, apoB, apoA-I, and apoE, suggesting that the sizes and/or densities of lipoproteins were not altered. Therefore, the numbers of VLDL particles must have fallen and the numbers of HDL₂ and HDL_c must have risen. The nature and magnitude of the changes fell within the range of changes previously observed in normolipidemic subjects. The data indicate that having diminished numbers of LDL receptors did not affect the abilities of these patients to resist diet-induced qualitative or quantitative alterations of their plasma lipoproteins. Clearly other adaptive mechanisms can compensate for the diminished numbers of LDL receptors.     

New combined therapy of niceritrol and probucol on heterozygous familial hypercholesterolemia

Seventeen patients with heterozygous familial hypercholesterolemia were sequentially treated with: a low cholesterol, fat restricted diet; diet and probucol (500 mg/day); and diet, probucol and niceritrol (1500 mg/day). Concentrations of plasma cholesterol decreased from 348 + 49 mg/dl on diet alone to 304 + 32 mg/dl, to 256 + 30 mg/dl on diet and probucol, and fell to 212 + 41 mg/dl on the combined regimen with niceritrol. Concentrations of LDL-cholesterol declined 13% on diet, and 26% on diet and probucol; the subsequent addition of niceritrol resulted in a 42% fall from the baseline. Plasma concentrations of apolipoprotein B fell 37% on the combined regimen with niceritrol. As a result, normal levels of cholesterol (less than 230 mg) were achieved in thirteen subjects treated with this new combination therapy. Moreover, atherogenic index improved with the addition of niceritrol. These results suggest even a small dose of niceritrol affords opportunity to maintain normal lipid profile in heterozygous familial hypercholesterolemia when given in combination with probucol.     

Nutrient intake: Relationships with lipids and lipoproteins in 6–19-year-old children—The Princeton School District study

Relationships between nutrient intakes and plasma lipids and lipoproteins were studied in 949 randomly selected children, ages 6–19, in the biracial, suburban, Princeton School District. While nutrient intake increased with age in males, such age-associated increases in nutrient ingestion were much less consistent or were not significant for females. Primarily in the 6–9 and 10–12 yr age groups, white children ingested more total calories, more saturated fat, and a lower ratio of polyunsaturated to saturated ($\text{P}\text{S}$) fat, more total carbohydrates, sucrose, starch, and other carbohydrates, and more protein than black children. After adjusting for age, race, sex, weight, and height, several nutrient-lipid and lipoprotein partial correlation coefficients were significant, but of relatively low magnitude. There were weak but significant inverse correlations between dietary $\text{P}\text{S}$ ratios and dietary carbohydrates with both total (r = ?.07, ?0.7) and low-density lipoprotein cholesterol (C-LDL), (r = ?.07, ?.08). Plasma high-density lipoprotein cholesterol (C-HDL) was inversely and significantly correlated with dietary sucrose (r = ?.07); plasma triglyceride correlated positively with dietary sucrose (r = .08). Potential relationships between nutrients and lipids-lipoproteins were also examined in children at the extremes of, and in the middle of, lipid-lipoprotein distributions. After covariance adjustment for age, sex, race, and Quetelet index, children having the highest levels of C-HDL had the lowest intake of dietary carbohydrate and total calories. After further covariance adjustment for total calories, children at the highest end of the plasma cholesterol distribution had a greater intake of cholesterol and total protein than did children in the lowest end of the distribution. Nutrient intake may play a small but significant role relative to lipids and lipoproteins in children, and as such, may have importance relative to pediatric precursors of atherosclerosis.     

Neonatal familial hypobeta-lipoproteinemia.

A kindred with four generation vertical transmission of familial hypobeta-lipoproteinemia was ascertained by measurement of low levels of cord blood low density lipoprotein cholesterol (C-LDL) in a propositus neonate. Measurement of cord blood C-LDL in conjunction with family studies allows the neonatal diagnosis of familial hypobetalipoproteinemia.     

Homozygous familial hypercholesterolemia in Japan

Fifty-one homozygous patients with familial hypercholesterolemia, including our six patients, are described in this paper. Twenty were men and 31 were women. Their ages ranged between two and 52 years, with a mean of 16.8 years. Six patients exceeded the third decade. The mean age at death in seven patients was 17 years. The serum cholesterol levels were between 508 and 1,108 mg/dl. The mean and standard deviation (SD) of serum cholesterol were 713 ± 142 mg/dl. The serum cholesterol levels in the 35 parents (obligate heterozygotes) were between 246 and 571 mg/dl, except in one patient in whom the serum cholesterol level (936 mg/dl) was suggestive of homozygous familial hypercholesterolemia, considering the serum cholesterol level (354 mg/dl) of her heterozygous husband. The mean and SD of serum cholesterol levels of the 34 heterozygote parents were 342 ± 79 mg/dl. The mean and SD of serum cholesterol in 119 normal subjects were 187 ± 30 mg/dl. Thus, trimodai distribution was evident in the serum cholesterol levels of normal subjects, the heterozygotes and the homozygotes in Japan. The frequency of parental consanguinity was at least 33 per cent. The frequencies of ischemic heart disease in the age groups 0–9, 10–19 and above 20 years were 25 per cent (four of 16 patients), 33 per cent (six of 18 patients) and 53 per cent (nine of 17 patients), respectively. The frequency of homozygotes in Japan was in close accordance with those of Western countries. Therefore, the treatment of hypercholesterolemia and prevention of premature coronary heart disease in familial hypercholesterolemic patients are very important problems in Japan as well as in the West.     

The efficacy of cholestyramine as a hypocholesterolemic agent and its tolerance in a Mexican population

The tolerance and efficacy of cholestyramine (12-16 gr/day) was evaluated in 19 patients with primary type-IIa hyperlipoproteinemia. All patients were on an isocaloric low-cholesterol diet that began at least one month before entry, and was continued during the eight weeks of the study. Cholestyramine significantly (p less than 0.001) lowered the plasma levels of cholesterol and of low density lipoprotein cholesterol from means of 288 +/- 46 mg/dl to 244 +/- 44 mg/dl and from 221 +/- 50 mg/dl to 171 +/- 46 mg/dl respectively. These were reductions of 15 and 22%. The magnitude of response to cholestyramine was unrelated to age, sex, cause of the hypercholesterolemia (familial or polygenic) or basal cholesterol levels. The drug was well tolerated. Only one patient was excluded because gastrointestinal discomfort. Because of its safety and efficacy, cholestyramine can be recommended as a first choice drug in the treatment of hypercholesterolemia.     

Hipercolesterolemia – uma patologia com expressão desde a idade pediátrica

IntroductionHypercholesterolemia results from an alteration, genetic or acquired, in lipoprotein metabolism. Evidence that hypercholesterolemia is associated with the atherosclerotic process from childhood justifies the screening of high-risk children and initiation of therapy at preschool ages.ObjectiveTo assess children referred for pediatric consultations due to hypercholesterolemia.MethodsChildren and adolescents referred for pediatric consultations with a diagnosis of hypercholesterolemia were enrolled. Information on family history and clinical, anthropometric and biochemical parameters was recorded and, when appropriate, molecular study was performed.ResultsA total of 168 children were assessed. Forty-six presented a familial hypercholesterolemia phenotype and in 22 of these, a mutation in the low-density lipoprotein (LDL) receptor gene was identified. The lipid profile of the group with mutations showed significantly higher values of total and non-high-density lipoprotein (HDL) cholesterol compared to the group without mutations (total cholesterol 316.5±75.9 mg/dl vs. 260.9±42,0 mg/dl; non-HDL cholesterol 268.3±72.6 mg/dl vs. 203.5±43.9 mg/dl; p<0.05). Of the total, 55 were prescribed pharmacological therapy and the others underwent diet and exercise interventions only. A greater reduction in LDL cholesterol was observed in individuals under pharmacological therapy compared to those prescribed diet and exercise only (30.3% vs. 18.1%). Drug side effects were insignificant.ConclusionIt is possible to maintain a normal lipid profile in most individuals with familial hypercholesterolemia in order to reduce the risk of early onset of atherosclerosis, which is associated with serious cardiovascular complications from childhood.     

Cholestyramine treatment during pregnancy in the rat results in hypercholesterolemia

Timed pregnant (8 days) Sprague-Dawley rats were fed ground stock diet (CON) or ground stock diet with 4% cholestyramine (CTR) until day 20 of gestation. Animals in both groups gained weight equally well during the study period (CON (n = 7), 308 +/- 7 g; CTR (n = 6), 315 +/- 7 g, mean +/- SEM). At the end of the study period, plasma cholesterol in the CTR group was significantly greater than that in the control group (CON n = 7, 91 +/- 4 mg/dl; CTR (n = 6), 108 +/- 5 mg/dl, P less than 0.05). The fecal excretion of both neutral steroids and bile acids, studied for 3 days between days 15 and 18 of gestation, was significantly enhanced by CTR treatment. (Neutral steroids: CON, 3.9 +/- 0.3; CTR, 10.4 +/- 0.3, P less than 0.05. Bile acids: CON, 7.6 +/- 0.4; CTR, 25.8 +/- 1.7, P less than 0.05, mg/100 g body wt/day). Bile acid pool size, measured at day 20 of gestation, however, was not significantly different. Consistent with these results was the finding that hepatic cholesterol 7 alpha-hydroxylase activity (the rate-limiting enzyme of bile acid biosynthesis) measured at day 20 of gestation was significantly enhanced by CTR treatment (CON (n = 4), 14.7 +/- 1.7; CTR (n = 4), 34.8 +/- 3.3, pmoles/mg/min, P less than 0.05). The atypical finding of hypercholesterolemia, despite the CTR-induced enhanced turnover of cholesterol, may be due to changes in the homeostatic mechanisms of cholesterol and bile acid metabolism during pregnancy.     

The comparative reductions of the plasma lipids and lipoproteins by dietary polyunsaturated fats: Salmon oil versus vegetable oils

The lower plasma lipid levels and lower incidence of atherosclerotic diseases in Greenland Eskimos suggested that the unusual fatty acids present in their diet of seal and fish may be anti-atherogenic. These fatty acids are eicosapentaenoic (C20:5) and docosahexaenoic (C22:6) acids and are of the omega-3 fatty acid family. We have compared a salmon oil diet containing high levels of these unique fatty acids to a control diet high in saturated fat and to a vegetable oil diet high in linoleic acid (C18:2). All diets contained 40% of the total calories as fat and 500 mg of cholesterol; they differed only in fatty acid composition. In 4 wk the salmon oil diet reduced plasma cholesterol levels from 188 to 162 mg/dl (p < 0.001) and triglyceride levels from 77 to 48 mg/dl (p < 0.005). LDL and VLDL cholesterol levels changed from 128 to 108 and 13 to 8 mg/dl (p < 0.005), respectively. HDL cholesterol levels did not change. The vegetable oil diet caused similar decreases in cholesterol levels but did not lower triglyceride levels. The omega-3 fatty acids comprised up to 30% of the total fatty acids in each plasma lipid class after the salmon diet. Fish oils contain fatty acids which may be metabolically unique and potentially useful in the control of both hypercholesterolemia and hypertriglyceridemia.     

Influence of lovastatin plus gemfibrozil on plasma lipids and lipoproteins in patients with heterozygous familial hypercholesterolemia

We investigated the hypocholesterolemic effects of lovastatin alone and in combination with gemfibrozil on plasma lipids and lipoproteins in 12 adult patients with well-characterized heterozygous familial hypercholesterolemia. Plasma concentrations of low density lipoprotein (LDL) cholesterol decreased from 321 +/- 14 mg/dl on diet only to 207 +/- 8 mg/dl (-35.5%) on single-drug therapy with lovastatin at a dose of 40 mg twice daily, whereas triglyceride concentrations fell by 27.6% (from 145 +/- 20 to 105 +/- 20 mg/dl). Subsequent addition of gemfibrozil at a dose of 600 mg twice daily resulted in a nonsignificant further reduction in LDL cholesterol to 194 +/- 7 mg/dl (-39.6% change from baseline), whereas triglycerides decreased to 80 mg/dl (-44.8%, p less than 0.05 vs. single-drug therapy with lovastatin). Plasma concentrations of high density lipoprotein (HDL) increased slightly during lovastatin and combined drug therapy (from 45 +/- 4 mg/dl at baseline to 46 +/- 4 mg/dl on lovastatin to 48 +/- 4 mg/dl on lovastatin plus gemfibrozil). The response to combination drug therapy in individual patients was heterogeneous and clinically significant decreases in LDL cholesterol concentrations were noted in two of the 12 patients, whereas in three patients LDL cholesterol concentrations increased on the combined drug regimen. One patient developed an asymptomatic increase in creatine kinase on monotherapy with lovastatin and a more pronounced and symptomatic increase during combination drug therapy with lovastatin plus gemfibrozil.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of niceritrol (pentaerythritoltetra-nicotinate) and clofibrate upon hyperlipemia and atherosclerosis induced in rabbits by cholesterol-free semisynthetic diets

Hyperlipemia and atherosclerosis were induced in rabbits by cholesterol-free semisynthetic diets containing 8–15% coconut oil or 8% butter.

The coconut oil diet increased the levels of plasma cholesterol and triglycerides (TG) and also produced moderate lipid infiltration of the aorta. Addition of 0.5% niceritrol to the diet significantly inhibited the increase of cholesterol and TG in total plasma and in the “VLD”- and “LD”-fractions. The lipid-infiltrated area and the contents of total cholesterol and cholesterol esters of the aorta were reduced by niceritrol. Clofibrate in a concentration of 0.33% gave no significant reduction of the lipid levels in the plasma or aorta. Niceritrol combined with clofibrate did not protect the aorta to a higher degree than niceritrol alone.

The butter diet induced a more moderate hypercholesterolemia with a mean level of about 300 mg/100 ml but with no increase of plasma TG. Addition of niceritrol resulted in somewhat lower mean values of plasma cholesterol but the reduction was not significant. The butter diet induced a slight atherosclerosis of a variable degree. After addition of niceritrol to the diet the mean level of aortic cholesterol lay within the normal region.     

Bile sequestrant therapy alters the compositions of low-density and high-density lipoproteins.

Bile sequestrant resins are used to lower the levels of low-density lipoprotein cholesterol in plasma because this may ameliorate atherosclerosis. Yet the levels and compositions of all the lipoproteins may affect atherogenesis. We have previously shown alterations in very-low-density lipoprotein (VLDL) metabolism in response to one of these agents, colestipol HCl. Here we report the effects of colestipol on the composition of low-density and high-density lipoproteins (HDL). Eighteen subjects with type II hyperlipoproteinemia were studied during baseline, diet, and drug periods lasting 2–3 mo. Lipoprotein lipids and apolipoproteins A-I, A-II, and B were measured, and indices of lipoprotein composition were calculated. Colestipol produced significant changes in all lipoproteins. VLDL-triglyceride rose transiently, the magnitude and duration both correlated with pretreatment values (r = 0.84 and 0.76, respectively, both p < 0.001). Low-density (density 1.006–1.063) lipoprotein cholesterol fell below the dietary mean by 28%, but low-density triglyceride fell by only 13% and apolipoprotein B by 17%. Thus, low-density lipoprotein cholesterol/apolipoprotein B ratios decreased (1.9 versus 1.6, p < 0.005). Low-density and very-low-density cholesterol/apoprotein B ratios also decreased significantly. Thus, all the apolipoprotein-B-containing lipoproteins had less cholesterol relative to apolipoprotein B. High-density lipoprotein cholesterol remained unchanged, although transient increases in high-density lipoprotein triglyceride occurred. Apolipoprotein A-I levels remained constant (∼105 mg/dl), but A-II levels fell (from 55 to 45 mg/dl); therefore, $\text{A-I}\text{A-II}$ ratios rose (2.0 versus 2.5, p < 0.001). Thus, alterations in the composition of both high-density and low-density lipoproteins occurred. Colestipol produced changes in lipoprotein composition that may have effects on atherogenesis independent of its effects on lowering plasma cholesterol. Further studies will be needed to determine whether or not these changes are beneficial.     

Hypercholesterolemia due to elevated low density lipoprotein-cholesterol in newborns with anencephaly and adrenal atrophy

In the present investigation, we evaluated the relationship between plasma lipoprotein-cholesterol and adrenal steroid production in abortuses and newborns in whom the adrenal was expected to be atrophic, i.e. in anencephalics. We found that umbilical cord plasma levels of dehydroepiandrosterone sulfate (DS) in 23 anencephalics delivered between 13.5 and 45.5 weeks of gestation (mean +/- SE, 176 +/- 37 ng/ml) were significantly lower than those in normal newborns of similar gestational ages; the umbilical cord plasma concentrations of cortisol in many anencephalics, however, were within normal limits. The levels of total cholesterol (134 +/- 10 mg/dl) and low density lipoprotein (LDL)-cholesterol (94 +/- 8 mg/dl) were substantially higher (up to 4-fold) in umbilical cord plasma of anencephalics than in umbilical cord plasma of normal newborns. The mean level of high density lipoprotein-cholesterol in umbilical cord plasma of anencephalic abortuses and newborns (38 +/- 4 mg/dl) was approximately 50% higher than that in normal newborns. The lowest plasma cholesterol level (56 mg/dl) and a concentration of DS (480 ng/ml) that was among the highest seen in the group of anencephalics were found in an anencephalic newborn in whom adrenals were of near-normal weight. Plasma cholesterol levels were inversely correlated to adrenal weights and plasma DS levels, and plasma DS levels were correlated to adrenal weight. Whereas the estimated plasma pool of DS in normal newborns increased to over 300 micrograms during the latter part of gestation, that of anencephalic newborns was much lower (less than 1 to 26 micrograms) and did not appear to increase as a function of gestational age. Conversely, the estimated plasma pool of cholesterol in normal newborns appeared to decline slightly during the last 10 weeks of gestation (80 mg at term), whereas that of anencephalic newborns expanded greatly near term; levels (approximately 200 mg) were attained that were about 3 times those in normal newborns. We conclude that the hypercholesterolemia in anencephalic newborns, due primarily to extremely elevated plasma levels of LDL-cholesterol, is a result of decreased uptake and utilization of plasma LDL-cholesterol for steroid biosynthesis by the adrenals. Since hypercholesterolemia is apparently early in gestation in anencephalic abortuses, we speculate that in normally developing fetuses, plasma LDL-cholesterol is used as substrate for adrenal steroidogenesis early in gestation as well as near term when the rates of growth and steroid production by the adrenals accelerate markedly.