Showing papers by "Scott M. Grundy published in 1989"

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

Abstract: Familial defective apolipoprotein (apo) B-100 is a genetic disease that leads to hypercholesterolemia and to an increased serum concentration of low density lipoproteins that bind defectively to the apoB,E(LDL) receptor. The disorder appears to result from a mutation in the gene for apoB-100. Extensive sequence analysis of the two alleles of one subject heterozygous for the disorder has revealed a previously unreported mutation in the codon for amino acid 3500 that results in the substitution of glutamine for arginine. This same mutant allele occurs in six other, unrelated subjects and in eight affected relatives in two of these families. A partial haplotype of this mutant apoB-100 allele was constructed by sequence analysis and restriction enzyme digestion at positions where variations in the apoB-100 are known to occur. This haplotype is the same in three probands and four affected members of one family and lacks a polymorphic Xba I site whose presence has been correlated with high cholesterol levels. Thus, it appears that the mutation in the codon for amino acid 3500 (CGG----CAG), a CG mutational "hot spot," defines a minor apoB-100 allele associated with defective low density lipoproteins and hypercholesterolemia.

Familial combined hyperlipidemia workshop

Abstract: On April 17 and 18, 1986, a workshop on familial combined hyperlipidemia was held at the Battelle Conference Center, Seattle, Washington. The term familial combined hyperlipidemia (FCHL) was first used by Joseph Goldstein and associates at the University of Washington to designate families exhibiting multiple lipoprotein phenotypes. At the same time, similar families were described by Esko Nikkila in Helsinki and Herbert Rose in New York. Affected members of families with FCHL can have elevations of plasma total cholesterol, triglyceride, or both. These elevations reflect increases in very low density lipoproteins (VLDL) and/or low-density lipoproteins (LDL). Since the initial description of FCHL, many investigators have noted the occurrence of multiple lipoprotein phenotypes in single families, usually those in which there is a high frequency of premature vascular complications.

Monounsaturated Fatty Acids and Cholesterol Metabolism: Implications for Dietary Recommendations

Abstract: Dietary fat is known to affect serum concentrations of total and lipoprotein cholesterol. However, all components of dietary triglycerides--saturated, monounsaturated, and polyunsaturated fatty acids--do not have identical effects on serum cholesterol levels. Until recently, most attention has been given to saturated fatty acids, which raise cholesterol levels, and polyunsaturated fatty acids, which are thought by many to lower cholesterol levels. Monounsaturates in contrast have been given little attention. However, recent studies carried out in our laboratory and in others have shown that monounsaturates can have favorable effects when substituted for saturated fatty acids in the diet. In this exchange, the monounsaturates reduce low density lipoprotein (LDL) cholesterol levels, but do not lower high density lipoprotein (HDL) cholesterol levels. In contrast, an HDL-lowering action has been noted for polyunsaturates. Also, monounsaturates appear to alter lipoproteins more favorably than carbohydrates, which can raise triglycerides and lower HDL cholesterol levels. Therefore, monounsaturated fatty acids appear to have more potential for use in cholesterol-lowering diets than previously recognized.

The Place of HDL in Cholesterol Management: A Perspective From the National Cholesterol Education Program

Abstract: • The guidelines developed by the Adult Treatment Panel of the National Cholesterol Education Program identified low density lipoprotein (LDL) as the major atherogenic lipoprotein, and high levels of LDL-cholesterol as the primary target for cholesterol-lowering therapy. Low levels of high density lipoprotein (HDL)-cholesterol were recognized as a major risk factor for coronary heart disease. This report reexamines in depth the recommendations of the Adult Treatment Panel on HDL-cholesterol. Two major questions are discussed: (1) Should HDL-cholesterol levels be measured in all adults, as recommended for total cholesterol? (2) Should patients found to have a low serum LDL-cholesterol level (35 mg/dL [ ( Arch Intern Med. 1989;149:505-510)

Gemfibrozil alone and in combination with lovastatin for treatment of hypertriglyceridemia in NIDDM.

Abstract: Hypertriglyceridemic patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased risk of coronary heart disease (CHD) and acute pancreatitis. To examine the potential of hypolipidemic drugs for therapy of lipoprotein abnormalities in NIDDM, 10 patients maintaining marked (plasma triglycerides greater than 500 mg/dl) and 6 with moderate (plasma triglycerides 250-500 mg/dl) hypertriglyceridemia, despite good glycemic control, were studied in two phases. In the first phase, gemfibrozil alone (600 mg twice daily) was compared with a placebo, and in the second phase a combination of gemfibrozil and lovastatin (20 mg twice daily) was compared with gemfibrozil alone in a randomized, double-blind, placebo-controlled crossover study. In markedly hypertriglyceridemic patients, gemfibrozil reduced plasma triglycerides by 52% and very-low-density lipoprotein cholesterol (VLDL-chol) by 55% and increased high-density lipoprotein cholesterol by 23% compared with a placebo. However, low-density lipoprotein cholesterol (LDL-chol) levels increased (42%), and LDL apolipoprotein B (apoB) levels remained unchanged. Addition of lovastatin to gemfibrozil effectively reduced total cholesterol (25%), LDL-chol (30%), and LDL-apoB (19%). Lovastatin further reduced plasma triglycerides (11%) and VLDL-chol (27%). However, in moderately hypertriglyceridemic patients, gemfibrozil or the combination therapy did not seem to offer benefits over the previously reported study with lovastatin alone. Glycemic control was maintained throughout the study. In conclusion, the beneficial effects of the combination therapy on lipoprotein levels in markedly hypertriglyceridemic NIDDM patients could decrease the risk of development of both acute pancreatitis and CHD.

Intestinal absorption of stearic acid after consumption of high fat meals in humans

Abstract: The intestinal absorption of stearic acid (18:0), relative to other fatty acids, was evaluated in a group of 10 normal volunteers. Subjects were fed two types of high fat meals; one contained a relatively high content of stearic acid and the other a relatively low content. Plasma chylomicrons were isolated at 2, 4, 6 and 8 h after ingestion of the meals. Fatty acid patterns of chylomicron lipids were determined, and relative intestinal absorption rates of each fatty acid were estimated by comparing the fatty acid composition of chylomicron lipids with that of the fat in the meals. Overall, for both meals the fatty acid pattern of chylomicron lipids was very similar to that of ingested fat. Percentages of palmitic acid (16:0) and stearic acid, relative to other fatty acids, were only slightly lower in chylomicron lipids than in the meal fat. These data suggest that intestinal absorbability of stearic acid is similar to that of palmitic acid, and both saturated fatty acids appear to be absorbed almost as well as oleic acid (16:1).

Influence of plasma triglycerides on lipoprotein patterns in normal subjects and in patients with coronary artery disease

Abstract: This study examined the correlation of plasma triglyceride levels with concentrations of intermediate, low and high density lipoproteins (IDL, LDL, and HDL, respectively) and to particle sizes of LDL in 93 normal men and 106 men with coronary artery disease. Plasma triglyceride concentrations were in the normal range for all persons in both groups. Analysis of lipoproteins of density f for LDL as well as an indication of heterogeneity of particle sizes in the density range of LDL. In both normal subjects and patients with coronary artery disease, a positive correlation was found between peak S f for LDL and concentrations of plasma triglycerides. Plasma triglyceride levels also were correlated positively with concentrations of S f 20 to 60 lipoproteins and total IDL mass, and inversely with HDL cholesterol levels. Furthermore, the value for peak S f for LDL correlated inversely with the IDL mass concentration and IDLLDL mass ratio, and positively with the HDL cholesterol levels. The results indicate that the lipoprotein pattern, including lipoprotein concentrations and particle sizes, is sensitive to concentrations of plasma triglycerides even when the latter are within the normal range.

Comparison of lovastatin and gemfibrozil in normolipidemic patients with hypoalphalipoproteinemia.

Abstract: This study compared lovastatin and gemfibrozil therapy for effects on lipid and lipoprotein levels in 22 normolipidemic patients with reduced high-density lipoprotein cholesterol levels. Most patients had coronary heart disease. A randomized, crossover design consisted of two drug phases (lovastatin and gemfibrozil) alternating with placebo. Lovastatin reduced total and low-density lipoprotein cholesterol and apolipoprotein B levels by 28%, 34%, and 24%, respectively. These were unaffected by gemfibrozil. Both drugs reduced very low—density lipoprotein and intermediate-density lipoprotein cholesterol levels by 30% to 40%. Both caused small but significant increases in high-density lipoprotein cholesterol, but not in apolipoproteins A-I or A-II. Both significantly lowered ratios of total (and low-density lipoprotein) cholesterol—to—high-density lipoprotein cholesterol, but lovastatin more than gemfibrozil. Thus, for normolipidemic patients with low levels of high-density lipoprotein cholesterol, neither drug markedly raised high-density lipoprotein levels, but lovastatin produced the better overall change in lipoprotein cholesterol and apolipoprotein B levels. (JAMA. 1989;262:3148-3153)

Effects of Replacing Saturated Fat With Complex Carbohydrate in Diets of Subjects With NIDDM

Abstract: This study examined the safety of an isocaloric high-complex carbohydrate low-saturated fat diet (HICARB) in obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Although hypocaloric diets should be recommended to these patients, many find compliance with this diet difficult; therefore, the safety of an isocaloric increase in dietary carbohydrate needs assessment. Lipoprotein cholesterol and triglyceride (TG, mg/dl) concentrations in isocaloric high-fat and HICARB diets were compared in 7 NIDDM subjects (fat 32 +/- 3%, fasting glucose 190 +/- 38 mg/dl) and 6 nondiabetic subjects (fat 33 +/- 5%). They ate a high-fat diet (43% carbohydrate; 42% fat, polyunsaturated to saturated 0.3; fiber 9 g/1000 kcal; cholesterol 550 mg/day) for 7-10 days. Control subjects (3 NIDDM, 3 nondiabetic) continued this diet for 5 wk. The 13 subjects changed to a HICARB diet (65% carbohydrate; 21% fat, polyunsaturated to saturated 1.2; fiber 18 g/1000 kcal; cholesterol 550 mg/day) for 5 wk. NIDDM subjects on the HICARB diet had decreased low-density lipoprotein cholesterol (LDL-chol) concentrations (107 vs. 82, P less than .001), but their high-density lipoprotein cholesterol (HDL-chol) concentrations, glucose, and body weight were unchanged. Changes in total plasma TG concentrations in NIDDM subjects were heterogeneous. Concentrations were either unchanged or had decreased in 5 and increased in 2 NIDDM subjects. Nondiabetic subjects on the HICARB diet had decreased LDL-chol (111 vs. 81, P less than .01) and unchanged HDL-chol and plasma TG concentrations).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on mechanisms for enhanced clearance of low-density lipoproteins in patients with primary hypertriglyceridaemia.

Abstract: Patients with primary hypertriglyceridaemia usually have increased clearance rates for plasma low-density lipoproteins (LDL). To evaluate the mechanisms for this effect, simultaneous turnover rates for autologous and normal homologous LDL were determined in 12 patients with primary hypertriglyceridaemia. On average, the autologous LDL was cleared more rapidly than the normal homologous LDL. Fractional catabolic rates (FCRs) for autologous LDL averaged 0.61 +/- 0.06 (SEM) pools d-1, whereas FCRs for homologous LDL averaged 0.49 +/- 0.04 pools d-1. In eight of the 12 patients the FCRs for 'hypertriglyceridaemic' LDL were found to be significantly higher than for normal LDL; in four others both forms of LDL were cleared at essentially the same rate. In all cases, however, both for the normal and 'hypertriglyceridaemic' LDL, clearance rates were higher than normal. Thus, besides the variability in LDL affinity for removal pathways, hypertriglyceridaemic patients appear to have an increased availability of LDL receptors for removal of circulating LDL.

Treatment of diabetic dyslipidaemia

Abstract: Lipid evaluation in a diabetic paticnt begins with averaging several measurements of blood sugar, total cholesterol. triacylglycerol and high-density lipoprotein (HDL) cholesterol after a 1 2 h fast. Patients with non-insulin-dependent diabetes may have any one of several of lipid disorders [ 1 I, but typically diabetic dyslipidaemias share the characteristics of high very-low-density lipoprotein (VLDL) cholesterol levels and low HDL cholesterol levcls [ 2 ] . Lipid disorders can be classified as in Table 1. Aggressive, appropriate treatment of thcse disorders may be crucial because of this population's increased risk of cardiovascular discasc. Diabetics may not respond to the usual diet and drug regimens useful in non-diabetics [3] (Table 2). This paper briefly outlines a treatmcnt approach to these disorders, including diet and drug therapy.