Peak Particle Diameter Research Articles

Lipoprotein correlates of LDL particle size

Correlations of low-density lipoprotein (LDL) predominant particle diameters (PPD) were investigated in samples taken from the San Antonio Family Heart Study. A frequency histogram showed LDL PPD occurs in at least two distinct modes, at about 25.5 and 26.9 nm, with the nadir at about 26.2 nm. Triglyceride (TG) concentrations were strongly correlated with LDL PPD, accounting for nearly 50% of the variation. However, examination of the relationship between TG concentrations and LDL PPD showed considerable overlap of the two LDL size categories for samples having intermediate levels of TG (1–3 mmol/l). In order to examine the factors associated with particle size variation within this region of overlap, 163 pairs of samples, which contrasted peak particle diameters, were matched for TG concentrations and for sex and age. In this matched set, LDL-related measures (i.e. LDL-C, apoB, apoE, and TG concentrations) did not differ. However, several high-density lipoprotein (HDL) measures were significantly related to the LDL particle size category. This category predicted a substantial proportion of variation in HDL-C (9.7%) and apoAI (7.5%) concentrations, and in HDL size distributions of cholesterol (13.6%) and apoAI (10.3%). Other traits related to insulin resistance syndrome (IRS) (glucose and insulin concentrations, blood pressure, and adiposity measures) were tested for association with the LDL size category. None of these traits were related to LDL size after adjusting for TG, except fasting and postchallenge glucose concentrations which showed modest correlations ( P-values were 0.02 and 0.05, respectively). The data suggest that in addition to the strong effects of TG, there is also an aspect of LDL particle size variation that is strongly associated with variation in HDL concentration and particle size distribution, perhaps reflecting common metabolic determinants of lipoprotein size.

Visceral adipose tissue and low-density lipoprotein particle size in middle-aged versus young men.

Age is associated with increased deposition of visceral adipose tissue. We examined whether this age-related change in regional adipose tissue distribution had an impact on low-density lipoprotein (LDL) particle size. For this purpose, the plasma lipoprotein-lipid profile, including LDL peak particle diameter as determined by gradient gel electrophoresis, was assessed in 38 young men (aged 26.4 +/- 4.2 years, mean +/- SD) and compared with 40 middle-aged men (55.9 +/- 6.2 years). Middle-aged men had higher values for total body fat and visceral adipose tissue area as measured by computed tomography than young men (P < .001). Although significant differences were noted between the two age groups for plasma cholesterol, triglyceride (TG), apolipoprotein B (apo B), LDL cholesterol, and LDL apo B, as well as the cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P < .001), no difference was found for LDL peak particle size between young and middle-aged men. While visceral adipose tissue was a significant correlate of plasma lipoprotein levels, the fasting TG concentration was the best predictor of LDL particle size, and the regression of TG levels on LDL peak particle diameter was not different between the two age groups. These results suggest that middle-aged men are characterized by an increased concentration of LDL particles (reflected by increased LDL apo B levels) but not by a reduced LDL peak particle size compared with young men. It is therefore proposed that in the absence of an important age-related change in TG levels, age per se is associated with an increased concentration of atherogenic LDL particles rather than a reduction of LDL particle diameter.

Effects of troglitazone on atherogenic lipoprotein phenotype in coronary patients with insulin resistance

Insulin resistance is associated with atherogenic lipoprotein phenotype, including small dense LDL particle, hypertriglycemia and low HDL cholesterol levels. Troglitazone, a novel insulin sensitizing agent, may improve the associated lipid profile in patients with insulin resistance. We examined the effects of troglitazone (400 mg daily for 12 weeks) in 12 non-diabetic coronary patients (60±10 years), all of whom had hyperinsulinemic response to an oral glucose load. Troglitazone markedly reduced the insulin response. After the treatment, plasma triglycerides decreased by 32% ( P<0.05), HDL cholesterol increased by 11% ( P<0.05) and LDL peak particle diameter increased from 24.7±0.3 to 25.5±0.5 nm ( P<0.01). These lipidic improvements were associated with a significant rise in postheparin lipoprotein lipase levels (175±52 to 217±69 ng/ml, P<0.01). In patients with insulin resistance syndrome, troglitazone improved the atherogenic lipoprotein phenotype as well as hyperinsulinemia. Our data suggest that troglitazone therapy could reduce the atherosclerotic risk due to insulin resistance even in non-diabetic patients.

Inheritance of LDL peak particle diameter: Results from a segregation analysis in Israeli families

Genetic and environmental determinants of LDL peak particle diameter (LDL-PPD) were investigated in a sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 182 males and 191 females ages 15–93 years. LDL-PPD levels were first adjusted for variability in sex and age. Commingling analysis demonstrated that a mixture of two normal distributions fit the adjusted LDL-PPD levels better than did a single normal distribution. Complex segregation analysis was first applied to these sex and age adjusted data but was not conclusive. However, when the regression model for sex and age allowed coefficients to be ousiotype (class) specific, the mixed environmental model was rejected while a major Mendelian model was not. These results suggest that the particular genotypes determined by the major gene, which are associated with different phenotypic variances, are likely to be more realistic, and that this analytic approach can contribute to improving our understanding of the genetics of LDL particle size. Genet. Epidemiol. 16:382–396, 1999. © 1999 Wiley-Liss, Inc.

Inheritance of LDL peak particle diameter: results from a segregation analysis in Israeli families.

Genetic and environmental determinants of LDL peak particle diameter (LDL-PPD) were investigated in a sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 182 males and 191 females ages 15-93 years. LDL-PPD levels were first adjusted for variability in sex and age. Commingling analysis demonstrated that a mixture of two normal distributions fit the adjusted LDL-PPD levels better than did a single normal distribution. Complex segregation analysis was first applied to these sex and age adjusted data but was not conclusive. However, when the regression model for sex and age allowed coefficients to be ousiotype (class) specific, the mixed environmental model was rejected while a major Mendelian model was not. These results suggest that the particular genotypes determined by the major gene, which are associated with different phenotypic variances, are likely to be more realistic, and that this analytic approach can contribute to improving our understanding of the genetics of LDL particle size.

Low density lipoprotein particle diameter in young, nonobese, normolipidemic Japanese men

Background: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. Methods and results: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18–20 years (mean±S.D. body mass index: 21.9±3.7 kg/m 2, total cholesterol: 180±29 mg/dl, triglyceride: 62±34 mg/dl, HDL cholesterol: 58±12 mg/dl). Men with small LDL (PPD <25.8 nm) were found in only 5.4% ( n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD <26.9 nm) had higher serum levels of LDL cholesterol (120±31 vs 104±24 mg/dl), triglyceride (72±39 vs 49±16 mg/dl) and apolipoprotein (apo) B (84±21 vs 68±14 mg/dl), and lower HDL cholesterol (54±10 vs 60±12 mg/dl). They also had greater body mass index (23.2±4.6 vs 20.9 3.1 kg/m 2) and percent body fat (21.5±7.7 vs 17.5±4.9%). LDL-PPD was positively correlated with HDL cholesterol ( R=0.20, P=0.002) and was negatively correlated with apoB ( R=0.34, P<0.001), triglyceride ( R=0.32, P<0.001), percent body fat ( R=0.26, P<0.001), body mass index ( R=0.24, P<0.001), fat mass ( R=0.23, P=0.001), total cholesterol ( R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. Conclusion: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.

Small low-density lipoproteins and vascular cell adhesion molecule-1 are increased in association with hyperlipidemia in preeclampsia.

The pregnancy disorder preeclampsia is characterized by endothelial cell dysfunction that may be promoted by abnormal increases in circulating lipids, particularly triglycerides and free fatty acids. Serum triglyceride concentration is a major regulatory determinant of low-density lipoprotein (LDL) size and density distribution. Smaller, denser LDL particles have several intrinsic properties capable of inducing endothelial dysfunction. The present nested, case-control study of gestationally matched preeclamptic and normal pregnant women tested the hypothesis that hypertriglyceridemia in preeclampsia is accompanied by decreases in LDL peak particle diameter (predominant LDL size). Plasma LDL peak particle diameter was determined by nondenaturing 2% to 16% polyacrylamide gel electrophoresis. Correlations of LDL diameter with the concentration of serum triglycerides, free fatty acids, total cholesterol, LDL-cholesterol, and apolipoprotein B (apo B) were determined. In the same individuals, we measured serum concentrations of a marker of vascular dysfunction previously reported to be increased in preeclampsia, soluble vascular cell adhesion molecule-1 (VCAM-1), and examined the association of VCAM-1 with LDL diameter and serum lipids. LDL peak particle diameter was decreased in preeclampsia relative to normal pregnancy (P < .01). The LDL-cholesterol:apo B ratio, which frequently decreases with decreasing LDL diameter, was also decreased (P < .04). Triglyceride concentrations were increased in preeclampsia (P < .0002), and there was a significant inverse relationship between LDL peak particle diameter and triglycerides (r = -.55, P < .02). Serum soluble VCAM-1 concentrations were markedly increased in preeclampsia (P < .0003). Apo B (P < .004), free fatty acids (P < .01), total cholesterol (P < .01), and LDL-cholesterol (P < .02) were also increased. VCAM-1 correlated with apo B (r = .50, P < .03) and LDL-cholesterol (r = .50, P < .03), but showed no relationship with the LDL diameter, LDL-cholesterol:apo B ratio, or other lipids. We conclude that the predominance of smaller, denser LDL, a potential contributor to endothelial cell dysfunction, is a feature of preeclampsia. However, the serum VCAM-1 level, one indicator of endothelial involvement, may be influenced more by quantitative lipoprotein changes (serum apo B or LDL-cholesterol) than by LDL particle size.

Low-density lipoprotein particle size decreases during normal pregnancy in association with triglyceride increases.

To characterize the changes in low-density lipoprotein (LDL) peak particle diameter (diameter of the predominant LDL subclass) in relation to changes in serum triglyceride concentration during successive stages of normal gestation and postpartum. Nonfasting venous blood was obtained longitudinally during and after uncomplicated primiparous pregnancy from 10 nonsmoking women with no history of metabolic disorders. Plasma LDL diameter was determined by nondenaturing polyacrylamide gel electrophoresis. Serum concentrations of total cholesterol, triglyceride, apolipoprotein B, apolipoprotein A-I, and LDL-cholesterol were measured. Gestational changes were analyzed by one-way repeated-measures analysis of variance and the paired multiple comparison Student-Newman-Keuls test. Pearson coefficients were computed for correlation of serum lipids and LDL diameter. Low-density lipoprotein diameter decreased progressively with advancing gestation, evident by 16-20 weeks relative to 5-12 weeks. Seven of 10 cases were subclass pattern B (diameter less than 255 A) by term, indicating that small, dense particles predominated. The average diameter decrease from early to late gestation was 13 A. All subjects reverted to subclass pattern A (diameter 255 A or more) by 6-12 weeks postpartum, indicating prevalence of large, buoyant LDL. Low-density lipoprotein diameter correlated inversely with concentrations of serum triglyceride (r = -.61, P < .0001), apo B (r = -.66, P < .0001), cholesterol (r = -.53, P < .001), LDL cholesterol (r = -.45, P < .005), and apo A-I (r = -.39, P < .02). Gestational triglyceride increases are accompanied by progressive decreases in LDL diameter in a majority of cases. These changes undergo reversal postpartum and therefore are transient. Small, dense LDL particles have a number of properties capable of altering vascular function. However, the consequences of the gestational LDL size decrease for maternal and fetal metabolism remain unknown.

Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men

We tested whether nutrient intakes estimated from 4-d diet records were associated with plasma lipoprotein subclasses in 103 men who were randomly assigned to a low-fat (24% fat) and a high-fat (46% fat) diet for 6 wk each in a crossover design. Postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities were also determined in a subset of 43 men. Changes in intake (ie, high fat minus low fat) of total saturated fatty acids, as well as myristic (14:0) and palmitic (16:0) acids, were positively correlated (P < 0.01) with increases in mass of large LDL particles [measured by analytic ultra-centrifugation as mass of lipoproteins of flotation rate (Sf) 7-12] and with LDL peak particle diameter and flotation rate, but not with changes in LDL-cholesterol concentration. Changes in total saturated fatty acids as well as myristic and palmitic acids were also inversely associated with changes in HL activity (P < 0.05). With the high-fat diet only, variation in dietary total saturated fatty acid intake was inversely correlated (P < 0.01) with concentrations of small, dense LDL of Sf 0-5. This correlation was significant specifically for myristic acid (P < 0.001). Stearic acid (18:0), monounsaturates, and polyunsaturates showed no significant associations with lipoprotein concentrations. These data indicate that a high saturated fat intake (especially 14:0 and 16:0) is associated with increased concentrations of larger, cholesterol-enriched LDL and this occurs in association with decreased HL activity.

Influence of apoE content on receptor binding of large, bouyant LDL in subjects with different LDL subclass phenotypes.

We investigated the influence of apolipoprotein (apo) E-containing particles on LDL receptor binding of large, buoyant LDL subfractions (LDL I) from subjects with predominantly large (phenotype A) and small (phenotype B) LDL particles. Direct binding by human fibroblast LDL receptors was tested at 4 degrees C before and after removal of apoE-containing particles by immunoaffinity chromatography. The binding affinity of total LDL I in phenotype B was greater than that in phenotype A (Kd of 1.83+/-0.3 and 3.43+/-0.9 nmol/L, respectively, P<.05). LDL I from phenotype B subjects had a higher apoE to apoB molar ratio than did that from phenotype A (0.16+/-0.04 versus 0.06+/-0.02, P<.05). Nondenaturing gradient gel electrophoresis of apoE-containing LDL I isolated by immunoaffinity chromatography revealed a substantially larger peak particle diameter than in apoE-free LDL I, and comparison of LDL I composition before and after immunoaffinity chromatography suggested an increase in triglyceride content of apoE-containing particles. After removal of these particles, there was a greater than twofold reduction in LDL receptor affinity of phenotype B LDL (Kd of 1.83+/-0.3 to 3.76+/-0.6, P<.01), whereas in phenotype A no change was observed (Kd of 3.43+/-0.9 to 3.57+/-0.4, respectively). The receptor affinity of apoE-free LDL I from phenotype A and B subjects did not differ. These findings confirm that large, buoyant LDL particles from phenotype B subjects have a higher LDL receptor affinity than does LDL I from phenotype A subjects and suggest that this difference is due to an increased content of large, triglyceride-enriched, apoE-containing lipoproteins. It is possible that the accumulation of these particles reflects abnormalities in the metabolism of remnant lipoproteins that contribute to atherosclerosis risk in phenotype B subjects.

冠動脈疾患におけるLDLの被酸化性とその粒子径の関連およびLDL分画中構成脂質成分についての検討

Oxidative modification of LDL is considered to play an important role in the pathogenesis of coronary atherosclerosis. However, LDL is heterogeneous in size, density, and chemical composition and these differences may be responsible for some of the variability in the atherogenicity of LDL in different subjects.We evaluated the association between oxidative susceptibility and particle size or lipid composition of LDL obtained from patients with or without CAD.The subjects were 102 patients who underwent coronary angiography:62 patients with significant coronary artery stenosis ≥50% defined as CAD and 40 patients without CAD. Susceptibility to oxidative modification was assessed by TBARS in plasma and LDL and the monitoring curve of copper-induced oxidation of LDL was separated by an ultracentrifugal method. Peak particle diameter (PPD) was measured by 2.5-16% nondenaturing polyacrylamide gradient-gel and lipid compositions were investigated by the enzymatic method.Patients with CAD had a higher prevalence of hypertension, diabetes mellitus and body mass index (BMI) than patients without CAD. When comparing plasma lipid levels, total cholesterol and apo B were higher, and HDL-C and apo A-I were lower in patients with CAD. LDL in patients with CAD showed significantly higher levels of TBARS(1.37±0.75 vs. 1.10±0.35nmol MDA/mg, p<0.05) and reduced lag time (43.3±6 vs. 48.5±9分, p<0.005) compared to those without CAD. Moreover, their LDL was significantly smaller (25.59±0.51 vs. 26.02±0.71nm, p<0.005) and diminished in lipid contents such as free cholesterol (FC), cholesterol ester (CE), and phospholipid (PL) except for triglycerides. In all patients, we found that LDL-PPD showed a significantly positive correlation with lag time and lipid contents including FC, CE, and PL. In particular, the content of FC per particle had a significantly positive correlation with LDL-PPD and lag time even after adjusting for age, BMI, and plasma lipids.We conclude that increased susceptibility to oxidative modification of small LDL may contribute to the development of coronary atherosclerosis. The lipid composition of LDL per particle associated with size, especially FC, may be responsible for increased susceptibility to oxidative modification and the atherogenicity.

Low-Density Lipoprotein Particle Size Distribution in Subjects with Coronary Artery Disease

Background:Low-density lipoprotein (LDL cholesterol has been shown to be a major risk factor for coronary artery disease (CAD in animal studies, clinical trials, and observational epidemiologic studies. It has a hydrated density of 1.019 to 1.063 kg/L, a diameter of 20 to 30 nm, and displays β -mobility on paper or agarose gel electrophoresis. With technique such as density gradient ultracentrifugation and gel electropho- resis, it is possible to separate lipoproteins accurately on the basis of their density, charge, and particle size. Further, it has been shown that a smaller LDL is associated with an increased risk of coronary artery disease, even when total cholesterol level is only slightly raised. The aim of this study was to analyze LDL particle size distribution in patients with angiographically confirmed coronary artery disease and in control subjects, using nondenaturating gradient polyacrylamide gel electrophoresis, and to investigate the relationship between LDL particle size and the other traditional coronary risk factors. Methods:Baseline characteristics such as age, sex, body mass index, history of hypertension or NIDDM, smoking habits, and plasma lipoprotein profiles were obtained in 33 and 27 subjects with and without CAD angiographically confirmed, respectively. We determined LDL peak particle diameter (LDL-PPD using nondenaturating gradient polyacrylmide gel electrophoresis in CAD and control group. 4% to 12% polyacrylamide gradient gels were used for this assay, and the diameters of LDL subclass peaks were calculated by comparison with a standard calibration curve. This procedure permits the assignment according to distribution of particle diameters as exhibiting pattern A, B, or INT. Results:Traditional coronary risk factors(age, sex, body mass index, history of hypertension or NIDDM, smoking habits, plasma triglyceride, HDL-cholesterol, and total to HDL-cholesterol ratio were found to be significantly different between two groups, except the plasma total cholesterol and LDL- cholesterol. The mean value of LDL-PPD in patients with CAD wassignificantly lower than that in control subjects(26.110.4 nm versus 27.011.9 nm, p=0.006. LDL-PPD showed relatively strong associations with plasma triglyceride (r=-0.536, p<0.01), HDL-cholesterol (r=0.497, p<0.01, and total to HDL-cholesterol ratio (r=-0.516, p<0.01, but showed no relation to total cholesterol (r=-0.168 or LDL-cholesterol (r=-

Insulin resistance is not a major determinant of low-density lipoprotein particle size

The relationship between low-density lipoprotein (LDL) peak particle diameter and insulin sensitivity, very—low-density lipoprotein (VLDL) + intermediate-density lipoprotein (LDL) triglyceride, cholesterol, and apoprotein B, postprandial lipemia, and LDL + high-density lipoprotein (HDL) triglyceride was assessed. The subjects were 101 healthy males aged 15 to 45 years. Sixty-one subjects (60.4%) were offspring of a parent with coronary artery disease before age 60, and 40 subjects (39.6%) had no parental history of coronary artery disease. LDL peak particle diameter was measured following polyacrylamide gradient gel electrophoresis. An insulin sensitivity index (S i) was determined from a frequently sampled intravenous glucose tolerance test using a minimal modeling method. A fat tolerance test was performed with a test meal containing 70 g/m 2 fat, with triglyceride concentrations measured hourly for 12 hours. LDL peak particle diameter was significantly correlated with body mass index (BMI) ( r = −.282, P < .01), waist to hip ratio ( r = −.291, P < .01), fasting triglyceride (logarithmically [log] transformed) ( r = −.556, P < .001), area under the postprandial triglyceride (log transformed) ( r = −.562, P < .001), VLDL + IDLL triglyceride (log transformed) ( r = −.321, P < .001), LDL + HDLL triglyceride (log transformed) ( r = .583, P < .001), and HDL cholesterol ( r = .347, P < .001), but there was no significant correlation with S i. Using stepwise regression analysis, LDL + HDL triglyceride showed the strongest relationship to LDL peak particle diameter, accounting for 34% of the variation in size. S I was not an independent predictor of LDL particle size. In conclusion, insulin sensitivity appears to have little influence on LDL particle size. The importance of LDL + HDL triglyceride should be ocnsidered a preliminary finding warranting varification in this and other populations.

Low-density lipoprotein particle size is not a discriminating marker for atherogenic risk in male offspring of parents with early coronary artery disease

The aim of this study was to assess the importance of low-density lipoprotein (LDL) particle size as a marker of atherogenic risk in male offspring of a parent with early coronary artery disease (CAD) before the age of 60 years. CAD-positive (CAD +) offspring were recruited into two groups based on age, 15 to 30 years (In = 20) and 31 to 45 years in = 41), and matched to CAD-negative (CAD −) offspring by age and body mass index (BMI) (n = 20 and 21 per group). LDL peak particle diameter was assessed by polyacrylamide gradient gel electrophoresis. There was no significant difference in LDL peak particle diameter between CAD + and CAD − offspring (26.2 ± 0.1 v 26.2 ± 0.1 nm, mean ± SE). There was also no difference between CAD + offspring and CAD offspring when comparisons were made within their own age group (26.5 ± 0.1 nm in younger CAD + offspring v 26.2 ± 0.1 nm in younger CAD − offspring, and 26.0 ± 0.1 nm in older CAD + offspring v 26.1 ± 0.2 nm in older CAD − offspring. Peak particle diameter was significantly greater in younger CAD + offspring than in older CAD + offspring (26.5 ± 0.1 v 26.0 ± 0.1 nm, P < .05). We conclude that small LDL particle size is not a discriminating marker for early atherogenic risk, and that measurement of LDL particle size has limited value in the assessment of coronary risk, at least in the age ranges we studied.

Effect of fluvastatin on low-density lipoprotein peak particle diameter

In this investigation, there was no appreciable effect on LDL particle diameter and there was no greater or lesser effect in patients classified at baseline as LDL pattern A, B, or I. This investigation indicates that fluvastatin, a 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, can significantly reduce LDL cholesterol, but has no effect on LDL particle diameter and no differential effect on patients characterized by differences in LDL subclass pattern. This contributes additional information on the lack of a differential effect of this statin medication in patients classified at baseline as LDL pattern A, B, or I.

Low‐density lipoprotein subfraction profiles in dialysis patients

Summary: Uraemic dyslipidaemia is a major risk factor for cardiovascular disease in end‐stage renal failure patients. In patients without renal failure, high levels and qualitative abnormalities of low‐density lipoprotein (LDL) are known to be atherogenic. Recently, LDL subfraction analysis has associated premature coronary artery disease with a high prevalence of small, dense LDL particles characterizing the LDL subclass phenotype B. We therefore examined the lipid profiles, LDL subfraction distribution and phenotypes in our population of haemodialysis (HD; n= 30) and peritoneal dialysis patients (PD; n= 17), and compared them to 40 asymptomatic, non‐uraemic volunteers. Dialysis patients had significantly higher triglyceride and VLDL cholesterol concentrations and lower HDL cholesterol and smaller LDL peak particle diameters. PD patients had significantly higher total cholesterol, glycated haemoglobin and fasting blood glucose levels with smaller LDL peak particle diameters (24.4 [0.1] vs 24.8 [0.1 nm] than HD. Both groups showed significant negative correlations between plasma triglyceride and LDL peak particle diameter, and positive correlations between HDL cholesterol and LDL peak particle diameter. All the PD patients expressed the B phenotype (LDL peak diameter ± 25.5 nm) compared to 73% of HD patients. This study demonstrates that HD and especially PD patients have atherogenic lipid profiles which are associated with a predominance of small dense LDL particles and the highly atherogenic LDL subclass phenotype B.

Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study.

Case-control studies have reported that patients with ischemic heart disease (IHD) have a higher proportion of small, dense LDL particles than do healthy control subjects. The extent to which the risk attributed to small LDL particles may be independent of concomitant variations in plasma lipoprotein-lipid concentrations remains to be clearly determined, however, particularly through prospective studies. Baseline characteristics were obtained in 2103 men initially free of IHD, among whom 114 developed IHD during a 5-year follow-up period. These 114 case patients were matched with healthy control subjects for age, body mass index, smoking habits, and alcohol intake. LDL peak particle diameter (PPD) was measured a posteriori in 103 case-control pairs by nondenaturing gradient gel electrophoresis of whole plasma. Conditional logistic regression analysis of the case-control status revealed that men in the first tertile of the control LDL-PPD distribution (LDL-PPD < or = 25.64 nm) had a 3.6-fold increase in the risk of IHD (95% CI, 1.5 to 8.8) compared with those in the third tertile (LDL-PPD > 26.05 nm). Statistical adjustment for concomitant variations in LDL cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B concentrations had virtually no impact on the relationship between small LDL particles and the risk of IHD. These results represent the first prospective evidence suggesting that the presence of small, dense LDL particles may be associated with an increased risk of subsequently developing IHD in men. Results also suggest that the risk attributed to small LDL particles may be partly independent of the concomitant variation in plasma lipoprotein-lipid concentrations.

Heritability of factors of the insulin resistance syndrome in women twins.

The insulin resistance syndrome (IRS) is characterized by a combination of interrelated coronary heart disease (CHD) risk factors, including low high-density lipoprotein cholesterol (HDL-C) levels, obesity and increases in triglyceride (TG), blood pressure, small low-density lipoprotein particles (LDL), and both fasting and postload plasma insulin and glucose. Using factor analysis, we previously identified 3 uncorrelated factors that explained 66% of the variance among these variables, based on data from women participating in examination 2 of the Kaiser Permanente Women Twins Study in Oakland, CA during 1989-1990. The factors were interpreted as: 1) body mass/fat distribution, 2) insulin/glucose, and 3) lipids: TG, HDL-C, LDL peak particle diameter. In this analysis, heritability of each of the factors was estimated based on data from 140 monozygotic and 96 dizygotic pairs of non-diabetic women twins. Heritability estimates were calculated using the classical approach, the analysis of variance (ANOVA) approach, and the maximum likelihood approach. For the body mass/fat distribution factor heritability estimates suggest moderate genetic influences; 0.61 (P < 0.001), 0.14 (P > 0.05), and 0.71 (P < 0.001), respectively. The insulin/glucose factor appeared to be highly heritable, with estimates of 0.87, 0.92, and 0.57 (all P < 0.001), respectively. The heritability estimates for the lipid factor were moderate and consistent across methods: 0.25 (P < 0.10), 0.32 (P < 0.05), and 0.30 (P < 0.05), respectively. These results are consistent with genetic influences on each of the 3 "factors," and suggest that both genetic and environmental effects are involved in the clustering of IRS risk factors.

Association of Small Low-Density Lipoprotein Particles With the Incidence of Coronary Artery Disease in Men and Women

To investigate the prospective association of low-density lipoprotein (LDL) particle diameter with the incidence of fatal and nonfatal coronary artery disease (CAD). A nested case-control study. Cases and controls were identified from a population-based sample of men and women combining all of the 5 cross-sectional surveys conducted from 1979 to 1990 of the Stanford Five-City Project (FCP). Incident CAD cases were identified through FCP surveillance between 1979 and 1992. Controls were matched by sex, 5-year age groups, survey time point, ethnicity, and FCP treatment condition. The sample included 124 matched pairs: 90 pairs of men and 34 pairs of women. LDL peak particle diameter (LDL size) was determined by gradient gel electrophoresis on plasma samples collected during the cross-sectional surveys (stored at 70 degrees C for 5-15 years). Established CAD risk-factor data were available from FCP baseline measurements. LDL size was smaller among CAD cases than controls (mean +/- SD) (26.17 +/- 1.00 nm vs 26.68 +/- 0.90 nm; P<.001). The association was graded across control quintiles of LDL size. The significant case-control difference in LDL size was independent of levels of high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), triglyceride, smoking, systolic blood pressure, and body mass index, but was not significant after adjusting for the ratio of total cholesterol (TC) to HDL-C (TC:HDL-C). Among all the physiological risk factors, LDL size was the best differentiator of CAD status in conditional logistic regression. However, when added to the physiological parameters above, the TC:HDL-C ratio was found to be a stronger independent predictor of CAD status. LDL size was significantly smaller in CAD cases than in controls in a prospective, population-based study. These findings support other evidence of a role for small, dense LDL particles in the etiology of atherosclerosis.

Increase in plasma high-density lipoprotein 2b subclass protein concentration after pravastatin treatment in patients with hypercholesterolemia

To determine the effects of pravastatin on plasma lipid levels, on low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle size and HDL subclass protein concentration, we studied 31 patients with hypercholesterolemia (9 men and 22 women, aged 36 to 79 years [mean age, 61.5 ± 10.3 years]). Patients were treated with pravastatin 10 mg daily for 12 weeks. After treatment, plasma levels of LDL cholesterol were significantly reduced (from 197 ± 60 to 149 ± 56 mg/dL), plasma levels of total cholesterol were significantly reduced (from 281 ± 58 to 237 ± 51 mg/dL), and levels of HDL 2b subclass protein were significantly increased (from 1.24 ± 0.24 to 1.35 ± 0.23 mg/protein/mL). Significant differences were not noted in the level of HDL cholesterol, LDL peak particle diameter, and the activity of lecithin-cholesterol acyltransferase and cholesteryl-ester transfer protein before and after treatment. The effect of pravastatin on lipoprotein concentration and particle size will need to be confirmed in studies with larger numbers of patients with various lipoprotein abnormalities.