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Biomedical subjects

J M Hoeg

Publications and source records attributed to J M Hoeg.

At least 109 records · Page 6Linked to original sources
PubMed1985

Risk factors for the development of premature cardiovascular disease.

The elucidation of the major risk factors for the development of premature atherosclerosis including plasma cholesterol, hypertension, and smoking has permitted the institution of specific therapy to reduce the risk of vascular disease. The further elucidation of LDL and HDL as positive and negative risk factors, respectively, has provided additional insights into the role of lipoproteins in cholesterol transport and atherosclerosis. Analysis of plasma apolipoproteins suggests that they may be even more effective than lipoproteins as predictors of premature vascular disease. The results of the Lipid Research Clinics Coronary Primary Prevention Trial clearly established the effectiveness of decreasing coronary risk by the reduction of LDL cholesterol in hyperlipidemic subjects. Aggressive diet and drug treatment of patients with elevated plasma levels of LDL would be anticipated to have a major impact on the development and/or progression of premature vascular disease. The implications of reduced levels of HDL on clinical practice is less certain. At present there is no evidence that interventions that change HDL levels will influence the development of vascular disease. In addition, the role of triglycerides and triglyceride-rich lipoproteins as potential risk factors for the development of premature atherosclerosis has not been firmly established. Additional epidemiological studies as well as basic research will undoubtedly provide the answers to these important unresolved questions.

Age Factors↗
PubMed1985

Characterization of plasma lipids and lipoproteins in cholesteryl ester storage disease.

Cholesteryl ester storage disease, caused by the loss of lysosomal acid ester hydrolase (EC 3.1.1.13), has been previously associated with hyperlipidemia and premature atherosclerosis. We identified a 23-month-old female with cholesteryl ester storage disease and characterized the plasma lipids and lipoproteins in the proband and her family. These studies illustrate several important points about this disease. First, a high index of suspicion is required to diagnose this disease since the major physical manifestation of the disorder, mild hepatomegaly, is subtle. Second, the Type II hyperlipoproteinemia in the proband is paralleled by a reduction in the concentration of high density lipoproteins. Third, analysis of the plasma lipids and lipoproteins in family members revealed both Type II and Type IV hyperlipoproteinemia with an inheritance pattern similar to that of familial combined hyperlipoproteinemia. Fourth, the parents and brother of this patient had 50% normal fibroblast acid ester hydrolase activity. These results raise the possibility that deficiency of the lysosomal acid ester hydrolase may be linked to familial combined hyperlipoproteinemia and that this enzyme deficiency may be more common than previously appreciated.

Biopsy↗
PubMed1985

Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment.

Total and low density lipoprotein cholesterol concentration reduction in patients with markedly increased levels of these substances, leads to a decline in the incidence of myocardial infarction and death. A unique cholesterol-rich lipoprotein, lipoprotein Lp(a), has been identified which not only can be confused with low density lipoproteins, but has also been associated with premature cardiovascular disease. Using the cholesterol-lowering drugs neomycin and niacin in 14 type II hyperlipoproteinemic subjects, we determined the effect of lipid-lowering therapy on lipoprotein Lp(a) concentrations. Neomycin (2g/day) reduced low density lipoprotein cholesterol and lipoprotein Lp(a) concentrations by 23% and 24%, respectively. Combination therapy with neomycin (2 g/day) and niacin (3 g/day) induced a 48% decline in low density lipoprotein cholesterol levels and a 45% reduction in the concentration of lipoprotein Lp(a). These changes in lipoprotein Lp(a) levels were associated with a striking decline in the intensity of the slow pre-beta-lipoprotein fraction determined Lp(a) by lipoprotein electrophoresis. This slow pre-beta-lipoprotein fraction contained Lp(a) determined by immunofixation. These observations indicate that lipoprotein Lp(a) concentrations can be altered pharmacologically and that the progression of cardiovascular disease may be altered through changes in lipoprotein (a) levels.

Adult↗
PubMed1985

Characterization of plasma lipids and lipoproteins in patients with beta 2-glycoprotein I (apolipoprotein H) deficiency.

The fasting plasma lipids, lipoproteins, and apolipoproteins were evaluated in 5 subjects with undetectable levels of the plasma protein beta 2-glycoprotein I (apolipoprotein H). Family studies confirmed an autosomal co-dominant inheritance pattern for the concentrations of apo H. The total lack of this protein is rare and less than 0.3% of clinic patients demonstrated levels undetectable by radial immunodiffusion. Plasma lipoprotein evaluation in these subjects with beta 2-glycoprotein I absence by analytical ultracentrifugation and compositional analysis demonstrated low concentrations of HDL2b and HDL3. More striking, however, was the lack of a consistent marked effect on the plasma lipoproteins as is found in other apolipoprotein deficiency states. We conclude that the lack of apolipoprotein H does not result in a significant perturbation of normal lipoprotein metabolism as reflected by analysis of fasting plasma lipoproteins. Further study is required to evaluate the role of this glycoprotein in the metabolism of triglyceride-rich lipoproteins.

Adult↗
PubMed1985

The effect of portacaval shunt on hepatic lipoprotein metabolism in familial hypercholesterolemia.

The hyperlipidemia observed in familial hypercholesterolemia can be reduced by portacaval anastomosis. We report the effects of a portacaval shunt on hepatic morphology and biosynthetic pathways crucial to hepatic cholesterol homeostasis in homozygous receptor-negative familial hypercholesterolemia. Portacaval anastomosis was associated with a dramatic change in hepatocyte morphology, 28% reduction in plasma low-density lipoprotein concentration, and a decrease in hepatic total and free cholesterol content by 27 and 75%, respectively. Furthermore, the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase was decreased by 56%. Finally, the reduced binding of low-density lipoproteins to hepatic membranes preoperatively was increased following the portacaval shunt. These combined results indicate that the changes in circulating lipoprotein concentrations observed after portacaval shunt are due to alterations in the metabolic consequences of the defective recognition of low-density lipoproteins by the liver of familial hypercholesterolemic subjects.

Adult↗
PubMed1985

The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (FH), reveal a marked heterogeneity in plasma cholesterol levels, response to diet as well as drug treatment, and clinical course. Low-density lipoprotein (LDL) receptor activities were assessed by the rate of 14C-oleate cholesteryl ester biosynthesis in fibroblasts from 13 FH homozygotes in tissue culture. The receptor activity of the individual patients was highly correlated with initial pretreatment plasma cholesterol and LDL cholesterol levels (P less than .001, r = -0.89). In addition, the LDL receptor activity was positively correlated with the age of onset of angina based on the Cox model (P less than .035, likelihood ratio = 6.71). An association was also noted between LDL receptor activity and cholesterol reduction with drugs. These data provide direct evidence for the correlation between the heterogeneity of the LDL receptor and the expression of the clinical manifestations of homozygous FH. The determination of pretreatment plasma cholesterol level and LDL receptor activity in patients with homozygous FH provide useful parameters on which to base predictions of the clinical progression of cardiovascular disease. These parameters may also influence the selection of a program for diet and drug therapy. Patients with markedly elevated plasma cholesterol levels and very low LDL receptor activity should be considered to be candidates for multiple drug therapy, and portacaval shunt, and/or periodic plasma exchanges.

Adolescent↗
PubMed1985

Apolipoprotein B synthesis in humans: liver synthesizes only apolipoprotein B-100.

Apolipoprotein (apo) B-100 and B-48 are prominent apolipoproteins in VLDL, IDL, and chylomicrons. Organ cultures of normal adult human liver were established to ascertain the form of apo B synthesized by hepatocytes in humans. Human liver was minced and incubated in 15 mL methionine-free RPMI-1640 medium with 10% dialyzed fetal calf serum plus 250 microCi 35S-methionine for eight hours at 37 degrees C. Lipoproteins secreted by the liver were isolated by ultracentrifugation and the content of newly synthesized apo B determined by quantitation of radioactivity in the apoB-100 and apoB-48 bands after separation by 3% NaDodSO4 gel electrophoresis. In the eight-hour period, 2.5% to 3.2% of added 35S-methionine was secreted in TCA-precipitable protein of which 0.34% was apo B. Ninety-nine percent of the apo B in VLDL, IDL, and LDL was in the apo B-100 electrophoretic band. No significant radioactivity was detected in the apo B-48 electrophoretic band. Eighty-nine percent of the total radioactivity of apo B-100 was in VLDL with 3% and 8% in IDL and LDL, respectively. These results establish that adult human liver in organ culture synthesizes apo B-100 but not apo B-48.

Adult↗
PubMed1985

Impaired adrenal reserve in the Watanabe Heritable Hyperlipidemic rabbit: implications for LDL-receptor function in steroidogenesis.

The cholesterol required for steroidogenesis may be provided by the novo biosynthesis or through the delivery of cholesterol by the circulating lipoproteins. By studying adrenocortical function, structure and biosynthetic capacity in an animal model devoid of the classical, high-affinity low density lipoprotein (LDL) receptor pathway, the respective roles of de novo cholesterolgenesis and lipoprotein cholesterol delivery were investigated. The Watanabe Heritable Hyperlipemic (WHHL) rabbit lacks the LDL-receptor pathway. The activity of the rate-limiting enzyme in cholesterolgenesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was 4- to 15-fold greater than normal in the WHHL adrenal gland. The basal corticosterone concentrations were normal in the WHHL rabbit; however, the corticosterone concentration increased by less than 50% of normal after an intravenous ACTH injection. Electron-microscopic evaluation of adrenocortical cells from the WHHL rabbits disclosed significantly increased mitochondrial surface area and diminished amounts of cytosolic lipid and lysosomal area. These data indicate that the mammalian adrenal gland utilizes endogenously synthesized cholesterol as well as cholesterol delivered through the LDL-receptor pathway. Moreover, in the absence of the LDL-receptor pathway, endogenously produced cholesterol is sufficient for normal basal glucocorticoid function.

Adrenal Glands↗
PubMed1985

Perfusion studies on the formation of mural thrombi with cholesterol-modified and hypercholesterolemic platelets.

Using the Baumgartner apparatus, perfusion studies have been carried out with blood from patients with hypercholesterolemia type IIa (n = 5) and IIb (n = 9) and with reconstituted blood containing platelets in which the cholesterol/phospholipid ratio had been modified by incubation with liposomes. With cholesterol-enriched platelets (C/PL 0.869), both platelet adherence and thrombus size were doubled with respect to cholesterol-normal platelets (C/PL 0.587), which in turn had values approximately twice that in cholesterol-depleted platelets (C/PL 0.494), differences statistically significant at p less than 0.02. With blood from patients with hypercholesterolemia, statistically significant values (p less than 0.03) were seen only for increase in adherence of platelets from type IIb patients as compared with controls. These results demonstrate that changes in platelet membrane cholesterol levels can affect interaction with subendothelium in cholesterol-modified platelets but suggest that more restricted differences may occur with platelets from patients with hypercholesterolemia.

Animals↗
PubMed1984

Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients.

Familial hypercholesterolemia (FH) is characterized by an autosomal codominant inheritance, an abnormality in low-density lipoprotein (LDL) receptor function, elevated plasma cholesterol levels and premature atherosclerosis. Sixteen patients with homozygous FH were studied to correlate the extent of their atherosclerotic disease with their lipid levels and receptor function. The age range at initial presentation was 3 to 38 years (mean 12), and at the last examination, 6 to 43 years (mean 20). The mean pretreatment total plasma cholesterol concentration for all patients was 729 +/- 58 mg/dl (+/- standard error of the mean), and the mean LDL cholesterol level was 672 +/- 58 mg/dl (normal 60 to 176). High-density lipoprotein cholesterol was 28 +/- 3 mg/dl (normal 30 to 74). In the 7 patients with FH who had symptoms of myocardial ischemia (Group I), the mean pretreatment LDL cholesterol value (817 +/- 62 mg/dl) was higher than that of the 9 asymptomatic patients (Group II) (560 +/- 74 mg/dl). In Group I, 5 of 7 patients had left or right coronary ostial narrowing and 3 had significant left ventricular outflow obstruction. Most coronary arterial narrowing occurred in the right coronary and left anterior descending arteries and the least amount in the left circumflex coronary artery. A femoral bruit was the physical finding that correlated best with the Group I population; brother:sister pairs revealed a milder clinical course for the female. Seven of the 16 patients have survived into their third decade without symptoms. Comparison of these persons with those in whom angina developed reveals a marked heterogeneity in their clinical course, which appears to be associated with receptor negative/defective status.

Adolescent↗
PubMed1984

Filipin as a flow microfluorometry probe for cellular cholesterol.

The polyene antibiotic filipin, which forms specific complexes with 3 beta-hydroxysterols, displays spectral properties compatible with its use in flow microfluorometry (FMF). The purpose of this study was to test the suitability of filipin as an FMF probe for unesterified cellular cholesterol. The following experimental conditions appeared optimal for cells with an average unesterified cholesterol content of less than 3 nmol per 10(6) cells: 2 X 10(6) fixed cells (1-4% p-formaldehyde, 30 min, 21 degrees C) stained for 2-4 h with 100 micrograms/ml filipin and excited at 350.7/356.7 nm. Fluorescence emission (Em) was measured above 510 nm. Less suitable conditions involved excitation at 488 nm or using cells which had not been fixed. Fixation preserved the live-dead cell discrimination provided by forward light scatter measurements, so that dead cells could be excluded from the FMF analysis of cellular cholesterol. Under the above conditions FMF analysis of a variety of murine cell types showed that in all cases the fluorescence intensity of filipin-stained cells was clearly increased above autofluorescence levels of the unstained control cells. The increase in fluorescence signal in different filipin stained cell types correlated (P less than or equal to .001) with the cellular content of unesterified cholesterol determined by an independent enzymatic assay. The sensitivity of the FMF assay was in the femtomole (10(-15) ) range. Mixing experiments with cells of different cholesterol levels showed that the technique distinguishes cell populations with distinctive levels of unesterified cholesterol. We therefore concluded that filipin is a useful FMF probe for determining relative levels of unesterified cholesterol in cells.

Animals↗
PubMed1984

Neomycin and plasma lipoproteins in type II hyperlipoproteinemia.

Neomycin, a nonabsorbable aminoglycoside antibiotic, has been shown to exert a hypocholesterolemic effect in man. In a 9-mo, double-blind, randomized, crossover, placebo-controlled clinical trial, the effect of neomycin, 2 gm/day, on plasma lipoproteins, as well as its safety, was described in 20 subjects with type II hyperlipoproteinemia. A 15% (50 mg%) decline in plasma cholesterol concentration was observed with neomycin. Most of this effect resulted from a 41 mg% (16%) decrease in low-density lipoprotein cholesterol concentration. No significant or consistent effect on the concentration of high-density lipoprotein cholesterol was observed. Monthly audiologic and renal evaluation disclosed no oto- or nephrotoxicity. Neomycin treatment in patients with type II hyperlipoproteinemia is an inexpensive and effective means of lowering the concentration of low-density lipoproteins and is free of significant side effects over a 3-mo period.

Adult↗
PubMed1984

Normalization of plasma lipoprotein concentrations in patients with type II hyperlipoproteinemia by combined use of neomycin and niacin.

The oral administration of neomycin or niacin as single-drug therapy can significantly lower total and low-density lipoprotein cholesterol concentrations in patients with type II hyperlipoproteinemia. However, in the majority of patients treated with one of these drugs as sole therapy plasma lipid and lipoprotein concentrations do not normalize. The effect of combined neomycin (2 g/day) and niacin (3 g/day) treatment on the plasma lipoprotein concentrations was determined in 25 type II hyperlipoproteinemic patients in a double-blind, randomized, placebo-controlled, crossover clinical trial. Treatment with neomycin was well tolerated by all 25 study patients and significantly reduced total and low-density lipoprotein cholesterol concentrations by 23% and 29%, respectively (p less than .05). In contrast to the well-tolerated neomycin regimen, 11 patients (44%) were unable to continue niacin treatment because of adverse side effects. In the 14 patients treated with both neomycin and niacin, niacin further lowered the concentrations of total and low-density lipoprotein cholesterol by 18% and 25%, respectively, and increased high-density lipoprotein cholesterol by 32% (p less than .05) compared with that in the patients receiving neomycin plus niacin placebo. Compared with diet-only therapy, combined treatment with neomycin plus niacin reduced the total plasma cholesterol concentration by 36%, low-density lipoprotein cholesterol by 45%, and the low-density lipoprotein/high-density lipoprotein ratio by 46% and it increased plasma high-density lipoprotein concentrations by 24% (p less than .001). During the study, 80% of all the study patients and 92% of the patients who complied with the combined regimen normalized their total and low-density lipoprotein concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Characterization of hepatic low density lipoprotein binding and cholesterol metabolism in normal and homozygous familial hypercholesterolemic subjects.

Patients with familial hypercholesterolemia have elevated levels of plasma low density lipoproteins (LDL), increased hepatic synthesis of apolipoprotein B-containing lipoproteins, defective binding of low density lipoproteins to fibroblasts, and premature atherosclerosis. The role of a hepatic low density lipoprotein receptor in normal man and its importance in the pathogenesis of familial hypercholesterolemia have not been previously determined. In the present study, direct comparison was made of the binding of LDL to hepatic membranes from normal and receptor-negative homozygous familial hypercholesterolemic subjects. The effects of calcium, EDTA, and temperature on the binding of lipoproteins to the hepatic membranes were also evaluated. At 4 degrees C, no significant difference in specific binding of LDL to hepatic membranes from normal and familial hypercholesterolemic subjects was observed. At 37 degrees C, both total and specific binding of LDL were significantly reduced in patients with familial hypercholesterolemia. Hepatic membrane binding of LDL from the two patients homozygous for receptor-negative familial hypercholesterolemia was 53 and 59% of normal. The activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase was normal; however, the total hepatic cholesterol and cholesteryl ester content was significantly increased from 53 to 129%. These results indicate that patients with familial hypercholesterolemia have a defect in the interaction of hepatic membranes with low density lipoproteins. This defect may lead to accelerated atherosclerosis by decreasing the cellular catabolism of LDL and enhancing the production of LDL, which is characteristic of patients homozygous for familial hypercholesterolemia.

Adult↗
PubMed1984

Cholesteryl ester storage disease and Wolman disease: phenotypic variants of lysosomal acid cholesteryl ester hydrolase deficiency.

The lysosomal enzyme responsible for cholesteryl ester hydrolysis, acid cholesteryl ester hydrolase, or acid lipase (E.C.3.1.1.13) plays an important role in cellular cholesterol metabolism. Loss of the activity of this enzyme in tissues of individuals with both Wolman disease and cholesteryl ester storage disease is believed to play a causal role in these conditions. The objectives of our studies were not only to directly compare and contrast the clinical features of Wolman disease and cholesteryl ester storage disease but also to determine the reasons(s) for the varied phenotype expression of acid cholesteryl ester hydrolase deficiency. Although both diseases manifest a type II hyperlipoproteinemic phenotype and hepatomegaly secondary to lipid accumulation, a more malignant clinical course with more significant hepatic and adrenal manifestations was observed in the patient with Wolman disease. However, the acid cholesteryl ester hydrolase activity in cultured fibroblasts in both diseases was virtually absent. In addition, fibroblasts from both Wolman disease and cholesteryl ester storage disease were able to utilize exogenously supplied enzyme, suggesting that neither disease was due to defective enzyme delivery by the mannose-6-phosphate receptor pathway. Coculture and cell fusion of fibroblasts from Wolman disease and cholesteryl ester storage disease subjects did not lead to correction of the enzyme deficiency, indicating that these disorders are allelic. However, the activities of the hepatic acid and neutral lipase in these two clinical variants were quite different. Hepatic acid lipase activity was only 4% normal in Wolman disease, but the activity was 23% normal in cholesteryl ester storage disease. The hepatic neutral lipase activity was normal in Wolman disease but increased more than twofold in cholesteryl ester storage disease. These combined results indicate that the clinical heterogeneity in acid cholesteryl ester hydrolase deficiency can be explained by a varied hepatic metabolic response to an allelic mutation.

Adrenal Cortex Hormones↗
PubMed1983

Initial diagnosis of lipoprotein lipase deficiency in a 75-year-old man.

Lipoprotein lipase deficiency, characterized by recurrent pancreatitis, profound hypertriglyceridemia, and delayed clearance of chylomicrons, is generally first diagnosed in childhood. Although patients with this condition have died during episodes of acute pancreatitis in the fourth and fifth decades, no patient older than 50 years has been previously reported. The de novo diagnosis of lipoprotein lipase deficiency in a 75-year-old man illustrates important points about this disease. This inborn error in metabolism may have a relatively benign clinical course resulting in normal life span, particularly if there is strict adherence to a low-fat diet and abstinence from alcohol. Moreover, measurement of lipoprotein lipase activity in persons with severe hypertriglyceridemia and recurrent abdominal pain, even in elderly patients, should lead to the correct diagnosis and treatment of this condition.

Abdomen↗
PubMed1983

CT findings in acid lipase deficiency: wolman disease and cholesteryl ester storage disease.

Acid lipase deficiency leads to the abnormal accumulation of cholesteryl esters and triglycerides in many tissues. It is manifested clinically in two forms: Wolman disease, which is usually fatal in infancy, and cholesteryl ester storage disease (CESD), which is clinically milder. One case of each is presented. In the patient with Wolman disease, computed tomography (CT) showed an enlarged liver of diminished density and enlarged adrenals with cortical calcification. Computed tomography of the patient with CESD showed an enlarged liver of normal density and normal adrenals. In vitro CT density is inversely related to cholesterol content. However, CT is unreliable in assessing liver cholesterol in these patients due to their poor nutrition and concomitant changes in liver glycogen and fat.

Adrenal Gland Diseases↗