Association of apolipoprotein B gene variants with plasma apoB and low density lipoprotein (LDL) cholesterol levels.

The contribution of the variants of the apolipoprotein (apo) B locus to the total variance in plasma apoB and cholesterol levels was examined in four independent populations, two that were composed of normal controls (n = 77 and 85) and two with coronary heart disease (n = 115 and 159). A correlation between genotype at the apoB-XbaI locus and apoB levels was observed. The effects of the (+; presence of restriction site) and (-) alleles were to increase or decrease the apoB and cholesterol levels by approximately 3.5 mg/dl, respectively. None of the 274 individuals in the coronary heart disease (CHD) groups was found to be a carrier of the apoB allele Arg3500----Gln, previously shown to be associated with an apoB protein defective in binding to the low density lipoprotein receptor (LDL-R). No DNA sequence variants were found in the region encoding amino acid residues 3129-3532 within the putative LDL-R binding domain among 35 individuals with apoB levels above the 94th percentile (141 mg/dl).

Effects of n-3 and n-6 fatty acid-enriched diets on plasma lipoproteins and apolipoproteins in heterozygous familial hypercholesterolemia.

Polyunsaturated fatty acids in vegetable (n-6) and marine (n-3) oils have been shown to reduce cholesterol levels in normolipidemic individuals. However, there is relatively little information available on the lipoprotein responses to dietary n-6 and n-3 fatty acids in individuals with genetic forms of hyperlipidemia at risk for premature cardiovascular disease. We studied five subjects with heterozygous familial hypercholesterolemia (FH), as well as five normal controls, on three rigidly controlled diets differing primarily in their fatty acid composition. FH subjects reduced their total plasma cholesterol by 34% during the n-3 diet and by 26% with the n-6 diet (both p less than 0.001) when compared with values while on a butter diet. In addition, low density lipoprotein (LDL) cholesterol fell 31% and 29% (both p less than 0.001), and apolipoprotein B (apo B) levels dropped 28% and 27% (both p less than 0.01) during the n-3 and n-6 diets, respectively. A significant reduction of total and LDL cholesterol as well as of apo B was also noted in normal controls during n-3 and n-6 diets. Total plasma triglyceride and high density lipoprotein cholesterol fell significantly during n-3 diets in normal and FH subjects. Thus, FH and normal subjects respond in a similar fashion to diets low in saturated fatty acids and rich in n-3 and n-6, with decreased LDL cholesterol and apo B concentrations.

The effects of omega 3 and omega 6 fatty acid-enriched diets on plasma lipoproteins and apoproteins in familial combined hyperlipidemia.

There is abundant evidence that dietary omega 3 fatty acids effect a favorable change in lipoprotein profiles of normolipidemic individuals. However, there is relatively little information available on the lipoprotein responses of hyperlipidemic individuals at risk for premature coronary artery disease. We studied a group of subjects with familial combined hyperlipidemia (FCHL), as well as a group of normal controls, on three rigidly controlled diets differing primarily in their fatty acid composition. The normal subjects demonstrated significant reductions in total cholesterol, low density lipoprotein (LDL) cholesterol, and total apolipoprotein B (apo B) levels on both an omega 3 (salmon) and omega 6 (safflower) fatty acid-enriched diet when these were compared with a basal diet high in saturated fat. The primary difference in response to the polyunsaturated diets was the potent triglyceride-lowering effect of the salmon diet. The FCHL subjects demonstrated a response to the safflower diet similar to that observed in normals and also manifested a marked triglyceride lowering with the salmon diet. However, total cholesterol and total apo B levels were not lowered by the salmon diet, and LDL cholesterol and apo B levels exhibited an upward trend. Thus, individuals with FCHL, a common disorder associated with premature coronary artery disease, do not appear to have a favorable lipoprotein response to diets enriched in omega 3 fatty acids.

Metabolic consequences of genetic heterogeneity of lipoprotein composition (lipoprotein heterogeneity).

Lipoprotein composition varies among different genetic forms of hyperlipidemia. An increase in hepatic triglyceride (TG) synthesis in subjects with familial hypertriglyceridemia (FHTG) is associated with secretion of large, TG-enriched, very low-density lipoproteins (VLDL), which have an increased affinity for lipoprotein lipase (LPL) in vivo as compared with VLDL from subjects with familial combined hyperlipidemia (FCHL) or from normal subjects. Elevated levels of plasma low-density lipoprotein (LDL) apoprotein B in FCHL are associated with high apoprotein B production rates. The LDL in FCHL is heterogeneous, with a preponderance of an LDL subfraction, which is denser, smaller, and lipid poor as compared with LDL from normal subjects. The more buoyant LDL subfraction in FCHL seems to be catabolized more rapidly than this dense LDL subfraction.

Evidence for kinetic heterogeneity among human low density lipoproteins.

The kinetics of low density lipoprotein apolipoprotein B (LDL apo B) metabolism are usually determined using turnover techniques in which radioiodinated LDL apo B is injected as a bolus into plasma, and serial plasma and urinary radioactivity samples are taken. The metabolic parameter of interest usually estimated from such data is the fractional catabolic rate (FCR). Two methods are normally employed to obtain an estimate of the FCR. One, the so-called Matthews' analysis, assumes plasma LDL apo B metabolism can be described by a single plasma pool while the other is determined by calculating the ratio of urinary radioactivity excreted to mean plasma radioactivity per day. Both of these methods assume LDL apo B is kinetically homogeneous, thus ignoring the evidence that LDL is biochemically heterogeneous in some individuals. If this biochemical heterogeneity manifests itself as kinetic heterogeneity, then the use of these data to estimate the FCR will not permit the resolution of the finer details of potential metabolic defects. This paper addresses the question of kinetic homogeneity and heterogeneity of LDL apo B within the context of several integrated kinetic models of increasing complexity. Each model fits reasonably the turnover data and hence cannot be rejected on the basis of failure to be compatible with the data. However, the models have strikingly different physiologic interpretations while providing essentially the same estimate for the FCR. Thus LDL apo B metabolism appears to be more complex than originally believed, and the models provide a framework within which to design new experiments to distinguish among them.

Low density lipoprotein metabolism in familial combined hyperlipidemia and familial hypercholesterolemia: kinetic analysis using an integrated model.

Several models for low density lipoprotein (LDL) apo B metabolism were applied to LDL turnover data from subjects with two distinct genetic forms of hyperlipidemia, familial hypercholesterolemia (FH), and familial combined hyperlipidemia (FCHL). Of the first two models tested, there was good agreement between the observed and predicted data for FH in one (model A), and for FCHL in the other (model B). The major difference between these two models is that LDL is kinetically homogeneous in model A and heterogeneous in model B, raising the possibility that LDL subspecies differences may occur between these two disorders. The findings are consistent with LDL homogeneity in FH and LDL heterogeneity in FCHL. Two other integrated models (models C and D) provided good agreement between observed and predicted data in both disorders. Although neither could be rejected outright on the basis of known physiology, parameter estimates were more variable with model D. Analysis of the data using model C was consistent with the known pathophysiologic defect in LDL catabolism in FH and suggests that individuals with FH as well as FCHL have more than one LDL subpopulation in plasma. The urine/plasma (U/P) ratio was shown to be constant from day 4 to day 14 of the study in FH, while in FCHL this value declined in all cases. Thus, determination of LDL fractional catabolic rates (FCR) by the U/P ratio method may be invalid in certain groups of patients. The other traditional method for calculating LDL FCR, the Matthews' analysis, overestimated FCR in some instances, and could lead to systematic errors when used to determine LDL FCR and production rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Screening for hypertension in the emergency department.

Review of emergency department charts at three university-affiliated hospitals showed that less than half of all patients who had elevated blood pressure (BP) recorded were recognized by physicians to be hypertensive. At the primary teaching hospital, less than one third of patients with the greatest BP elevation (greater than 20 mm Hg above normal) were sent for some type of hypertension follow-up care.