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Biomedical subjects

R H Knopp

Publications and source records attributed to R H Knopp.

At least 73 records · Page 4Linked to original sources

Changes in plasma triacylglycerol concentrations among free-living hyperlipidemic men adopting different carbohydrate intakes over 2 y: the Dietary Alternatives Study.

We reported previously that low-fat, high-carbohydrate diets containing < 26% of energy as fat and > 57% of energy as carbohydrate induce hypertriacylglycerolemia (hypertriglyceridemia) in hypercholesterolemic but not in combined hyperlipidemic (CHL) subjects. Because subjects may not consistently adhere to an assigned diet long term, we examined the extent to which plasma triacylglycerols (triglycerides) increase at four consistently reported carbohydrate intakes at intervals of up to 2 y. Three hundred seventy-two subjects reported consistent carbohydrate intakes of < 45%, 45-51.9%, 52-59.9%, or > or = 60% of energy on food records for 3, 12, and 24 mo. Among hypercholesterolemic subjects reporting a carbohydrate intake > or = 60% of energy, triacylglycerols increased by 0.25, 0.18, and 0.27 mmol/L (22, 16, and 24 mg/dL) over baseline at 3, 12, and 24 mo, respectively (P < 0.01 in each instance), and 0.32 mmol/L (28 mg/dL) above the group with a carbohydrate intake 52-59.9% of energy (P < 0.05) after 3 mo. No statistically significant effects were observed among CHL subjects, but compared with baseline, triacylglycerols decreased during the first 3 mo (-0.29 to -0.04 mmol/L, or -26 to -4 mg/dL), were unchanged over 12 mo, and were increased after 24 mo in three of four carbohydrate intake strata (0.27-0.36 mmol/L, or 24-32 mg/dL). These data confirm our previous observation that a moderately but not extremely low-fat, high-carbohydrate diet can be used long-term without deleterious effects on plasma triacylglycerols in the management of hypercholesterolemia, whereas CHL is unaffected by the amount of carbohydrate ingested.

Body Weight↗

Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier Disease.

Tangier disease is a rare genetic disorder characterized by extremely low plasma levels of HDL and apo A-I, deposition of cholesteryl esters in tissues, and a high prevalence of cardiovascular disease. We examined the possibility that HDL apolipoprotein-mediated removal of cellular lipids may be defective in Tangier disease. With fibroblasts from normal subjects, purified apo A-I cleared cells of cholesteryl esters, depleted cellular free cholesterol pools available for esterification, and stimulated efflux of radiolabeled cholesterol, phosphatidylcholine, and sphingomyelin. With fibroblasts from two unrelated Tangier patients, however, apo A-I had little or no effect on any of these lipid transport processes. Intact HDL also was unable to clear cholesteryl esters from Tangier cells even though it promoted radiolabeled cholesterol efflux to levels 50-70% normal. Passive desorption of radiolabeled cholesterol or phospholipids into medium containing albumin or trypsinized HDL was normal for Tangier cells. Binding studies showed that the interaction of apo A-I with high-affinity binding sites on Tangier fibroblasts was abnormal. These results indicate that apo A-I has an impaired ability to remove cholesterol and phospholipid from Tangier fibroblasts, possibly because of a defective interaction of apo A-I with cell-surface binding sites. Failure of apo A-I to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles and the low plasma HDL levels in Tangier disease.

Apolipoprotein A-I↗

Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study.

OBJECTIVE: To evaluate the role of metabolic control in the progression of diabetic retinopathy during pregnancy. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of 155 diabetic women in the Diabetes in Early Pregnancy Study followed from the periconceptional period to 1 month postpartum. Fundus photographs were obtained shortly after conception (95% within 5 weeks of conception) and within 1 month postpartum. Glycosylated hemoglobin was measured weekly during the 1st trimester and monthly thereafter. RESULTS: In the 140 patients who did not have proliferative retinopathy at baseline, progression of retinopathy was seen in 10.3, 21.1, 18.8, and 54.8% of patients with no retinopathy, microaneurysms only, mild nonproliferative retinopathy, and moderate-to-severe nonproliferative retinopathy at baseline, respectively. Proliferative retinopathy developed in 6.3% with mild and 29% with moderate-to-severe baseline retinopathy. Elevated glycosylated hemoglobin at baseline and the magnitude of improvement of glucose control through week 14 were associated with a higher risk of progression of retinopathy (adjusted odds ratio for progression in those with glycohemoglobin > or = 6 SD above the control mean versus those within 2 SD was 2.7; 95% confidence interval was 1.1-7.2; P = 0.039). CONCLUSIONS: The risk for progression of diabetic retinopathy was increased by initial glycosylated hemoglobin elevations as low as 6 SD above the control mean. This increased risk may be due to suboptimal control itself or to the rapid improvement in metabolic control that occurred in early pregnancy. Excellent metabolic control before conception may be required to avoid this increase in risk. Those with moderate-to-severe retinopathy at conception need more careful ophthalmic monitoring, particularly if their diabetes was suboptimally controlled at conception.

Adult↗

Deformations in infants of diabetic and control pregnancies.

Severe and mild deformations in newborn infants of insulin dependent diabetic mothers (IDDMs) and control mothers were evaluated with respect to the types of anomalies and previously hypothesized constraint factors. Factors evaluated were gestational length, birth weight, corrected birth weight for gestation (weight ratio), maternal height and parity, and severe deformations. Newborn infants from 81 control and 133 insulin dependent diabetic pregnancies were recruited periconceptually as part of a larger study of diabetes in early pregnancy. Examinations were done at 48 to 72 hours of life by one examiner blinded to maternal status using a checklist of major and minor deformations and malformations. Mild deformations were found to be common and were present in 84% of newborn infants. Severe deformations occurred in three (1.4%) IDMs, with two of three newborn infants having major malformations involving the CNS and/or musculoskeletal system which affected fetal movement. There was no significant difference between IDMs and control newborn infants with respect to the number with deformations; however, fetal macrosomia was not present in study participants. Using the entire cohort, a significantly greater number of deformations were present in newborn infants with a gestation > 36 weeks (P < 0.001), birth weight > 3,000 g (P < 0.001), and weight ratio > or = 1.2 (P = 0.05). There was no significant association with primiparous mothers or women with a height < 165 cm and the presence of deformations. For gestational age and birth weight, mild deformations were apparent only after 33 weeks gestation (P << 0.001) and/or birth weights of 2.0 kg or more (P << 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Birth Weight↗

Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial.

BACKGROUND: Niacin and lovastatin are both effective drugs for the treatment of hypercholesterolemia and are among the drugs of first choice recommended by the adult treatment panel. To date, however, no studies have directly compared the lipoprotein-modifying effects and safety of lovastatin and niacin across their usual dosage range in patients with primary hypercholesterolemia. METHODS: The efficacy and safety of lovastatin and niacin were compared in a controlled, randomized, open-label study of 26 weeks' duration that was conducted at five lipid clinics. One hundred thirty-six patients with primary hypercholesterolemia participated in the study. Entry criteria were a low-density lipoprotein (LDL) cholesterol level greater than 4.37 mmol/L (160 mg/dL) with coronary heart disease and/or more than two coronary heart disease risk factors or an LDL cholesterol level greater than 5.19 mmol/L (190 mg/dL) in patients without coronary heart disease or less than two coronary heart disease risk factors. The study consisted of a 4-week diet run-in period after which eligible patients were randomly assigned to receive treatment with either lovastatin (20 mg/d) or niacin (1.5 g/d) for 10 weeks. On the basis of the LDL cholesterol response and patient tolerance, the doses were sequentially increased to 40 and 80 mg/d of lovastatin or 3 and 4.5 g/d of niacin after 10 and 18 weeks of treatment, respectively. RESULTS: In the two patient groups, 66% of patients treated with lovastatin and 54% of patients treated with niacin underwent full dosage titration. At all time points, lovastatin was significantly (P < .01) more effective than niacin in reducing LDL cholesterol levels (26% vs 5% at week 10, 28% vs 16% at week 18, and 32% vs 23% at week 26), whereas niacin was more effective (P < .01) in increasing high-density lipoprotein cholesterol levels (6% vs 20% at week 10, 8% vs 29% at week 18, and 7% vs 33% at week 26). Niacin reduced Lp(a) lipoprotein levels by 35% at week 26, whereas lovastatin had no effect. Cutaneous flushing was the most common side effect during treatment with niacin. CONCLUSIONS: Lovastatin and niacin both exerted favorable dose-dependent changes on the concentrations of plasma lipids and lipoproteins. Lovastatin was more effective in reducing LDL cholesterol concentrations, whereas niacin was more effective in increasing high-density lipoprotein cholesterol concentrations and reducing the Lp(a) lipoprotein level. Lovastatin was better tolerated than niacin, in large part because of the common cutaneous side effects of niacin.

Adult↗

Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia.

The purpose of this study was to investigate the triglyceride-lowering effect of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in the combined hyperlipidemia of non-insulin-dependent diabetes mellitus (NIDDM). In this double-blind trial, 66 patients with NIDDM (24 men and 42 women, age 37-71), with low-density lipoprotein cholesterol (LDL-C) levels of 130-300 mg/dL (3.4-7.8 mmol/L) and triglyceride (TG) levels of 200-1,000 mg/dL (2.3-11.3 mmol/L) despite an 8-week period of diet modification, were randomized to receive either fluvastatin at 20 mg once daily (at night) or placebo for 6 weeks, followed by an increase of fluvastatin to 20 mg twice daily for an additional 6 weeks of treatment. After 12 weeks, fluvastatin decreased plasma levels of total cholesterol by 19.9% (p < 0.001), LDL-C by 24.3% (p < 0.001), TG by 15.3% (p < 0.01), very low-density lipoprotein cholesterol (VLDL-C) by 19.7% (p < 0.001), apolipoprotein (apo) B by 21.3% (p < 0.001), and apo E by 18.1% (p < 0.05), whereas high-density lipoprotein cholesterol (HDL-C) levels were increased by 4.6% (p < 0.05). Within the intermediate-density lipoprotein cholesterol (IDL-C) fraction, a constituent analysis revealed a total cholesterol reduction of 35% (p < 0.01). Greater decreases in TG were seen in patients who had higher levels of TG at baseline. Slight increases in glycemic indices and body weight were seen in both treatment groups. The occurrence of clinical and laboratory abnormalities was similar with both active treatment and placebo, and no myositis was observed. Slight increases in aspartate (ASAT; mean 5.6 U/L at the higher dose) and alanine (ALAT; mean 5.1 U/L at the higher dose) aminotransferases were not clinically significant. In this first, parallel-group placebo-controlled trial of a reductase inhibitor in a free-living NIDDM population, fluvastatin safely improved the combined TG, VLDL-C, IDL-C, LDL-C, and HDL-C abnormalities associated with NIDDM.

Adult↗

Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia: preliminary report.

This randomized, double-blind, placebo-controlled study was designed to evaluate the effect of fluvastatin on the lipid profiles of patients with hypertriglyceridemia resulting from non-insulin-dependent diabetes mellitus (NIDDM). Sixty-six NIDDM patients (24 men, 42 women) with low density lipoprotein cholesterol (LDL-C) levels > 3.36 mmol/liter (130 mg/dL) and triglyceride (TG) levels of 2.3-11.3 mmol/liter (200-1,000 mg/dL) after an 8-week period of Step I diet were given fluvastatin, 20 mg every PM for 6 weeks followed by 20 mg twice daily for an additional 6 weeks, or placebo. By weeks 9-12, fluvastatin decreased plasma LDL-C levels by 24.3% (p < 0.001) and plasma TG by 15.3% (p < 0.01). High density lipoprotein cholesterol levels increased by 4.6% over the same interval (p < 0.05). Fluvastatin treatment was not associated with abnormalities in the indices of glycemic control or clinically important abnormalities in laboratory values. Fluvastatin is an effective treatment of combined elevations of TG and LDL-C in NIDDM.

Anticholesteremic Agents↗

Effects of estrogens on lipoprotein metabolism and cardiovascular disease in women.

Estrogen use is associated with protection from cardiovascular disease in postmenopausal women. This benefit appears to be magnified among women with pre-existing heart disease. The possible bias of intrinsically better health in women using estrogen has not been ruled out in observational studies. Therefore, two double-blind randomized clinical trials are underway in postmenopausal women. One in women with coronary disease is known as HERS (Heart Estrogen-progestin Replacement Study) and another in predominantly healthy women is the WHI (Women's Health Initiative). Several mechanisms of estrogen mediated protection from cardiovascular disease have been identified including increased HDL, lower LDL, lower VLDL-cholesterol/triglyceride ratio, increased clearance of intermediate density lipoprotein (IDL) and LDL via an upregulated LDL receptor, diminished penetration and degradation of LDL in the arterial wall, an inhibition of LDL oxidation by various estrogens and a reversal of inappropriate acetylcholine (EDRF)-mediated vasoconstriction in arteriosclerotic vessels. The predominating mechanism is not known, but estrogen replacement therapy is both likely to be beneficial to female health, pending randomized trials, as well as a tool to understand mechanisms of prevention of coronary artery disease.

Adolescent↗

Long-term developmental follow-up of infants of diabetic mothers.

The neurodevelopmental consequences of maternal insulin-dependent diabetes were studied in 109 infants of diabetic mothers and 90 control infants. The infants born to diabetic mothers included 70 "early entry" subjects and 39 "late entry" subjects. Maternal diabetes control during pregnancy was significantly better in "early entry" mothers than in late-entry mothers, as determined by glycosylated hemoglobin levels. Infants were examined by a psychologist and a developmental pediatrician unaware of group status at 6, 12, 24, and 36 months of age; 71% of the subjects completed the 3-year-study. Neurodevelopment of early-entry subjects was similar to that of control subjects, whereas late-entry subjects scored less well on language measures. Mean head size in late-entry subjects was significantly less (p = 0.03) than in either control subjects or early-entry subjects at age 3 years, and correlated negatively with glycosylated hemoglobin levels during all three trimesters. Less optimal intellectual development was associated with reduced head circumference. In addition, the presence of major congenital malformations was associated with reduced developmental performance through age 2 years. Our results indicate that mothers with insulin-dependent diabetes who maintain good control during pregnancy can expect to have infants who are neurodevelopmentally normal; mothers whose diabetes is less well controlled may have infants with less optimal neurodevelopment.

Child Development↗

Physiological levels of estradiol stimulate plasma high density lipoprotein2 cholesterol levels in normal men.

Premenopausal women have a lower risk of coronary artery disease than men or postmenopausal women; estrogens are thought to contribute to this lower risk. Administration of exogenous estrogen to post-menopausal women increases plasma high density lipoprotein (HDL) cholesterol and may reduce mortality from coronary disease in users. Although many investigations have examined the roles of estrogen in the regulation of lipoproteins in women, little attention has been directed to estrogen regulation of lipids in men. We designed a paradigm to study the role of physiological levels of estradiol (E2) on plasma lipoproteins in healthy men. We used a GnRH antagonist, Nal-Glu, to suppress endogenous steroid hormones in healthy men. We then administered testosterone (T) enanthate (100 mg, im, weekly) to restore T levels to the baseline range, and we administered an aromatase inhibitor, testolactone (Teslac), to prevent the normal conversion of T to E2, thereby producing a selective estrogen deficiency state in normal young men. As controls, we administered Nal-Glu and T along with placebo Teslac to a separate group of men; a third group of men received all placebo medications. We found that in men who received Nal-Glu plus T plus Teslac, E2 levels were profoundly suppressed during treatment, whereas T levels remained in the baseline range. Plasma HDL cholesterol, particularly, the HDL2 fraction, decreased significantly in response to the low serum E2 level. Plasma apoprotein-AI levels also decreased significantly. Plasma LDL and triglyceride levels did not change. All hormone and lipoprotein parameters returned to baseline within 4 weeks after treatment ended. In men who received Nal-Glu plus T, plasma HDL and apoprotein-AI decreased, but these decreases did not achieve statistical significance. Only a small decrease in HDL2 cholesterol was seen in these men. There were no hormonal or lipid changes in the placebo group. We conclude that in men, physiological levels of E2 are important in maintaining plasma levels of HDL cholesterol, especially the HDL2 fraction. These observations suggest that estrogen, in the amount normally produced in men, may offer some degree of protection against cardiovascular disease in males, as they do in women.

Adult↗

Efficacy and safety of fluvastatin in hyperlipidaemic patients with non-insulin-dependent diabetes mellitus.

In this preliminary report of a 20-week trial, 66 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hyperlipidaemia who remained eligible after an 8-week dietary stabilization phase were randomly allocated to receive 20 mg of fluvastatin or placebo once daily for 6 weeks. Fluvastatin was subsequently increased to 20 mg twice daily and administered according to the same schedule, versus placebo, for a further 6 weeks. Both dosages of fluvastatin substantially improved serum lipid profiles compared with baseline and placebo. Both dosages of fluvastatin significantly reduced low-density- and very-low-density-lipoprotein (LDL, VLDL), cholesterol and triglyceride (TG) compared with placebo, and both dosages significantly elevated high-density-lipoprotein (HDL) cholesterol. The ratio of LDL to HDL was also significantly decreased. Amongst the 58 patients who completed the study, there was no evidence either of myopathy or of hepatotoxicity; mean creatine kinase values remained stable in the fluvastatin arm. Fasting glucose, glycosylated haemoglobin, and fructosamine levels were not markedly affected by active treatment. No serious adverse events attributable to the drug were reported. In conclusion, both dosages of fluvastatin appear to be effective and safe in the management of hyperlipidaemia in this outpatient, maturity-onset, diabetic population.

Adult↗

Once-daily, extended-release gemfibrozil in patients with dyslipidemia. The Lopid SR Work Group I.

This randomized, parallel-group, multicenter clinical trial compared a newly developed, once-daily, extended-release formulation of gemfibrozil (Lopid SR) and gemfibrozil twice daily (Lopid) in terms of lipid-regulating effects and toxicity. Patients were men and women with elevations of low-density lipoprotein cholesterol and low levels of high-density lipoprotein cholesterol. The trial consisted of a 1-week screening period, an 8-week diet baseline period (Step One Diet), and a 24-week double-blind treatment period (extended-release gemfibrozil 1,200 mg once daily vs gemfibrozil 600 mg twice daily). At the end of the trial, the 2 treatment groups showed comparable improvements in all primary lipid factors: mean percent changes in triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were -32, +10 and -10% for extended release (n = 325) and -36, +11 and -10% for twice daily (n = 330). The 90% confidence interval for the relative difference between the treatment means fell within the equivalence bounds of +/- 35% for all 3 factors, demonstrating equivalence of efficacy. Adverse events were reported at low rates and were similarly distributed in frequency and intensity between treatment groups; they were preponderantly mild or moderate, and gastrointestinal effects were the most frequent. The once-daily formulation of gemfibrozil may afford better control of dyslipidemia through improved compliance by patients who have this asymptomatic disease.

Adolescent↗

Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation.

OBJECTIVE: To examine the relationship between caffeine consumption during pregnancy and the occurrence of spontaneous abortion and intrauterine growth retardation. DESIGN, SETTING, AND PATIENTS: A cohort of 431 women, enrolled in a multicenter study within 21 days of conception, was monitored throughout pregnancy to determine (1) caffeine exposure, (2) exposure to other risk factors, (3) fetal growth as assessed by ultrasonography, and (4) pregnancy outcome. OUTCOME MEASURES: Spontaneous abortion, intrauterine growth, birth weight, and head circumference. RESULTS: The mean (+/- SD) first-trimester caffeine consumption was not significantly higher in women who aborted (125.9 +/- 123.1 mg) than in women who delivered liveborn infants (111.6 +/- 107.0 mg) (P = 34). The adjusted odds ratio (OR) for spontaneous abortion was 1.15 (95% confidence interval [CI], 0.89 to 1.49). Early fetal growth, assessed by crown-rump length on ultrasonographic examination, was not affected by caffeine. Although the group consuming the most caffeine (> 300 mg/d) had a significantly higher proportion of babies with birth weights and head circumferences below the 10th percentile in the crude analysis, the association with caffeine was no longer significant when other risk factors (notably smoking) were taken into account. The adjusted ORs were 1.11 (95% CI, 0.88 to 1.40) for decreased birth weight and 1.09 (95% CI, 0.86 to 1.37) for smaller head circumference. CONCLUSIONS: Close monitoring of a cohort identified very soon after conception enabled us to identify all abortions after 21 days postconception, monitor intrauterine growth prospectively, and track caffeine use. Despite this intensive surveillance, we found no evidence that moderate caffeine use increased the risk of spontaneous abortion, intrauterine growth retardation, or microcephaly after accounting for other risk factors.

Abortion, Spontaneous↗

Influence of diagnostic criteria on the incidence of gestational diabetes and perinatal morbidity.

OBJECTIVE: To determine the incidence of gestational diabetes and its associated maternal and infant morbidity by two sets of 3-hour glucose tolerance test criteria, those recommended by the National Diabetes Data Group or the lower, modified criteria of Carpenter and Coustan. DESIGN: Prospective, observational outcome cohort study. SETTING: Prepaid health maintenance organization. SUBJECTS: A total of 2019 pregnant women preregistered in a health maintenance organization were screened for a plasma glucose of 7.77 mmol/L (140 mg/dL) or greater, 1 hour after ingestion of a 50-g glucose drink administered after an overnight fast. Positive subjects received a 3-hour glucose tolerance test interpreted by the two criteria. Data are presented for 521 randomly selected negative screenees; 264 positive screen, negative glucose tolerance test subjects; and 101 subjects with gestational diabetes mellitus. OUTCOME MEASURES: Maternal risk factors for diabetes, infant birth weight corrected for gestational age (birth-weight ratio), umbilical cord serum insulin levels, and 33 maternal and infant perinatal morbidities assessed from chart review. RESULTS: Gestational diabetes incidence was 5.0% overall based on the modified criteria and 3.2% by the recommended criteria. Maternal age and family history of diabetes were higher in both modified and recommended groups. Birthweight ratio was 1.05 in negative screenees, 1.09 in gestational diabetes overall (P < .05 when only diet-treated subjects were considered), and 1.11 in modified and 1.08 in recommended criteria groups. Cord serum insulin levels in infants of gestational diabetic mothers by both criteria were 40% above those of negative screenees (P < .001). The average percentage incidence of 33 possible perinatal morbidities was 41% higher in gestational diabetic pregnancies by the modified criteria. The cumulative number of morbidities was higher in both modified and recommended criteria groups (P < .01 in both instances). In contrast, subjects having a positive glucose screening test but a negative glucose tolerance test by modified criteria had none of the characteristics of gestational diabetes with the single exception of greater age. CONCLUSIONS: Fifty percent more cases of gestational diabetes were identified using the more inclusive, modified criteria. These cases had as much excess in maternal diabetes risk factors, infant macrosomia, and cord hyperinsulinemia and nearly as much increase in perinatal morbidity as subjects diagnosed by the recommended criteria. The incidence and perinatal impact of gestational diabetes may be greater than previously appreciated. The modified criteria deserve wider verification and use.

Adult↗

Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia.

UNLABELLED: The HMG-CoA reductase inhibitor class of cholesterol-lowering agents reduces very low density lipoproteins (VLDL) and low density lipoproteins (LDL) and slightly increases high density lipoproteins (HDL). However, the effects of these agents on subclasses within the LDL and HDL fractions are not well understood. We have employed an HMG-CoA reductase inhibitor, pravastatin, to determine if LDL subclass phenotypes, as determined by gradient gel electrophoresis, and HDL particles containing both apolipoprotein (apo) A-I and A-II, Lp(AI w AII), and those containing apo A-I but not A-II, Lp(AI w/o AII) are affected by pravastatin (10 mg daily). Twenty-four subjects with LDL-cholesterol (LDL-C) > 160 mg/dl, triglyceride (TG) < 350 mg/dl and no recent myocardial infarction or secondary causes of hypercholesterolemia were enrolled. Compared with an age- and sex-matched normolipidemic reference group (controls), the hypercholesterolemic subjects had reduced levels of Lp(AI w/o AII) and increased levels of Lp(AI w AII) at baseline. In addition, both of their HDL subpopulations had significantly more small (7.0-8.2 nm) particles (P < 0.02 and 0.0001) but significantly fewer large (9.2-11.2 nm) particles (P < 0.002 and 0.0001). Pravastatin induced statistically significant (P < 0.001) reductions in plasma total C (15%), LDL-C (18%), and apo B (16%). While apo A-I and A-II levels increased 5% (P < 0.001) and 6% (P < 0.05), respectively, concentration, composition, and size abnormalities in Lp(AI w AII) and Lp(AI w/o AII) persisted. Lp(a), apo E and cholesteryl ester transfer protein (CETP) levels also did not change. Although changes in LDL subclass phenotypes were observed, all changes involved the intermediate phenotype, and no significant changes in LDL peak particle diameter were seen in either group. Interrelationships between CETP, LDL subclass phenotypes and HDL subpopulations were also seen. CONCLUSIONS: Although pravastatin decreased plasma apo B and LDL lipid concentrations, no major changes were seen in LDL subclass phenotypes or HDL subpopulations even in the presence of abnormalities associated with arteriosclerosis. Similarly, CETP, which is believed to play a role in HDL and LDL particle size distribution, did not change with pravastatin treatment. Further research is needed to determine the pathophysiological basis of abnormal HDL and LDL subclasses in hypercholesterolemia and explore methods of rectifying the abnormalities.

Adult↗

Contraception and dyslipidemia.

The risks of cardiovascular disease associated with dyslipidemia differ in women and men, being more strongly associated with triglyceride/high-density lipoprotein in middle-aged women than in men. Although the incidence of heart disease is lower in women because they live longer, over a lifetime, cardiovascular disease in women is equal to that in men, with the greatest incidence after age 65 years. Major coronary events are rare among reproductive-age women who use oral contraceptives and are related to the concomitant effects of age, smoking, diabetes, hypertension, and obesity. Low estrogen-progestin dose oral contraceptives appear not to promote cardiovascular disease and can be used in women with controlled cholesterol elevations. Alternative contraceptive measures should be considered for patients with severe uncontrolled hypercholesterolemia or a lipid disorder that carries a high risk of coronary heart disease. In these conditions, thrombotic propensity associated with supraphysiologic doses of estrogen in oral contraceptives might accelerate coronary thrombosis should an arteriosclerotic plaque rupture. Treatment of hypercholesterolemia should follow the guidelines of the National Cholesterol Education Program and emphasize hygienic measures. Contraceptive selection in hyperlipidemic patients should reflect a balance between the risks--and their management--of developing cardiovascular disease versus the risks of pregnancy.

Cardiovascular Diseases↗

Characterization of apolipoprotein A-I- and A-II-containing lipoproteins in a new case of high density lipoprotein deficiency resembling Tangier disease and their effects on intracellular cholesterol efflux.

A 48-yr-old Caucasian female of central European origin (subject IM) with low plasma cholesterol and normal plasma triglyceride (TG) had extremely low apo A-I (6 mg/dl), A-II (5 mg/dl), and HDL cholesterol (2 mg/dl) levels. She had most of the clinical symptoms typically associated with Tangier disease, including early corneal opacities, yellow-streaked tonsils, hepatomegaly, and variable degrees of peripheral neuropathy, but had no splenomegaly. She had a myocardial infarction at age 46. Since HDL are postulated to be involved in the transport of excess cholesterol from peripheral tissues to the liver for degradation, and the ability of an HDL particle to promote cellular cholesterol efflux appears to be related to its density, size, and apo A-I and A-II contents, we isolated and characterized the HDL particles of this patient and all her first degree relatives (mother, a brother, and two children). The plasma A-I, A-II, and HDL cholesterol levels of all five relatives were either normal or high. Using anti-A-I and anti-A-II immunosorbents, we found three populations of particles in IM: one contained both apo A-I and A-II, Lp(AI w AII); one contained apo A-I but no A-II, Lp(AI w/o AII); and the third (an unusual one) contained apo A-II but no A-I, Lp(AII). Two-thirds of her plasma A-I and A-II existed in separate HDL particles, i.e., in Lp(AI w/o AII) and Lp(AII), respectively. Only Lp(AI w AII) and Lp(AI w/o AII) were present in the plasma of the relatives. All three populations of the patient's HDL particles had a normal core/surface lipid ratio, but the cores were enriched with TG. The apo A-I-containing particles, however, were considerably smaller and contained much less lipid than Lp(AII). Despite these unusual physicochemical characteristics, the apo A-I-containing particles and Lp(AII) were effective suppressors of intracellular cholesterol esterification in cholesterol-loaded human skin fibroblast. The patient's plasma apo D and lecithin cholesterol acyltransferase levels were reduced, with an increased proportion located in non-HDL plasma fractions. These findings are discussed in light of Tangier disease and other known HDL-deficiency cases, and the role of HDL in the maintenance of cell cholesterol homeostasis.

Adolescent↗

Effect of insulin-dependent diabetes on plasma lipoproteins in diabetic pregnancy.

A reduction in total plasma cholesterol concentration has been reported in insulin-dependent diabetic (IDDM) pregnant women in early gestation. To determine if this reduction extends throughout gestation and which lipoprotein fractions may be responsible, we measured plasma triglyceride, cholesterol (C), high density lipoprotein cholesterol (HDL-C) and HDL2 and HDL3-C subfractions between 6 and 36 weeks' gestation in normal and IDDM women. Total plasma C was significantly lower in IDDM pregnant subjects between 20 and 36 weeks' gestation as compared to nondiabetic controls, while plasma triglyceride concentrations were not significantly different in this interval. Very low and low density lipoprotein (VLDL, LDL) C concentrations were not statistically significantly different from controls at any of the times studied, while HDL-C was lower throughout diabetic pregnancy as compared to controls, significantly so between 20 and 36 weeks' gestation. The lower HDL-C in IDDM women was associated with a significantly lower HDL3-C level. Plasma apoprotein A-I and A-II concentrations, markers of the HDL2 and HDL3 subclasses, respectively, were measured to corroborate the HDL subfraction changes. Apo A-I and A-II increased significantly between 12 and 28 weeks' gestation in control but not in diabetic pregnant subjects, consistent with a higher HDL3 in normal than in diabetic pregnant subjects. It appears that plasma triglyceride, VLDL and LDL-C, and HDL2-C concentrations are similar in IDDM and normal pregnancy, while total-C, HDL-C and HDL3-C and its associated apoproteins are lower than in normal subjects in late gestation. The mechanism of these changes and their significance for fetal growth and development deserve further study.

Adult↗