Low-density Lipoprotein Peak Particle Size Research Articles

Heparin induces an accumulation of atherogenic lipoproteins during hemodialysis in normolipidemic end-stage renal disease patients.

Dyslipidemias may account for the excess of cardiovascular mortality in end-stage renal disease (ESRD). Lipoprotein studies in ESRD patients are usually relative to prehemodialysis samples even if significative changes may occur after dialysis. In this study, we aimed to investigate the effects of ESRD on triglyceride-rich lipoproteins (TRL) subpopulations distribution and acute change following hemodialytic procedures, including the relative contribution of heparin administration. We selected a group of normolipidemic male middle-aged ESRD patients free of any concomitant disease affecting lipoprotein remnant metabolism compared with controls. We separated TRL subfractions according to density and apoE content and evaluated the changes of these particles after hemodialytic procedures with or without heparin. ESRD subjects had higher TRL subfractions, with the exception of apoE-rich particles, lower high-density lipoprotein (HDL) largest subclasses, and a smaller low-density lipoprotein peak particle size than controls. After a hemodialytic standard procedure with heparin, we demonstrated a significant reduction of triglyceride, an increase of HDL-cholesterol levels, and a raise of small very-low-density lipoprotein, intermediate-density lipoproteins (IDL), apoE-rich particles, and non-HDL-cholesterol levels. When hemodialysis was performed without heparin, no significant changes were observed. In the absence of concomitant hyperlipidemic triggers, ESRD patients show significant lipoprotein abnormalities before dialysis, but without any increased remnant particles concentrations. We speculate that hemodialysis, in particular heparin administration during this procedure, leads to a massive atherogenic TRLs production because of the acute stimulation of the dysfunctional lipolytic system not followed by an efficient removal, determining a recurrent lipoprotein remnant accumulation.

Low-density lipoprotein particle size in hepatic steatosis and metabolic syndrome

BackgroundHepatic steatosis (HS), the most frequent liver disorder, was reported to be an independent predictor of cardiovascular disease. HS, if combined with the metabolic syndrome (MetS), might have a synergistic effect on low-density lipoprotein (LDL) particle size.MethodsCarotid intima-media thickness (IMT) and plaque formation, and HS were diagnosed ultrasonographically, and the MetS was diagnosed using the ATP III criteria in 274 healthy workers (mean age ± SD, 43.5 ± 7.1 yrs). LDL particle size was measured with density gradient ultracentrifugation, and subfractions were classified as large, buoyant LDL I (27.2~28.5 nm) and small, dense LDL III (24.2~25.5). All participants were grouped into three categories: control, subjects with HS alone and those with both HS and the MetS.ResultsThe subjects with HS alone were 84 (30.7%), whereas those with HS and the MetS were 46 (16.8%). LDL peak particle sizes showed significant negative correlations with carotid mean IMTs. LDL peak particle size and LDL I (%) decreased significantly in the HS, showing the lowest values in the subjects with both HS and the MetS, and their association was independent, even adjusted for potential confounders. LDL III also showed independent associations across the groups.ConclusionHS alone was more prevalent than HS combined with the MetS in general population. For the patients with HS alone, LDL particle size and carotid atherosclerosis were found to fall in the middle of the control and those with both HS and the MetS.

Serum Folate and Low-Density Lipoprotein Particle Size

Nutritional parameters, such as B-vitamins, have not been studied for an association with low-density lipoprotein (LDL) particle size. The present study explored whether serum vitamin levels, including folate and vitamin B-12, could be associated with LDL particle size. Using a randomly selected population of 255 hospital workers, we collected detailed lipid profiles, including triglyceride (TG), high-density lipoprotein (HDL) cholesterol, and LDL particle sizes. The peak particle size of LDL was measured by density gradient ultracentrifugation and a pore gradient lipoprotein system. Serum folate and vitamin B-12 levels were measured about 1 year later and analyzed. Carotid intima-media thickness (IMT) and hepatic steatosis were diagnosed ultrasonographically, and metabolic syndrome was diagnosed using ATP III criteria. LDL peak particle size was significantly correlated with carotid mean IMT (r=-0.16, p=0.010). Serum folate levels were significantly and positively correlated with HDL cholesterol and negatively with TG, although the latter showed borderline significance. With increasing serum folate levels, the LDL peak particle size showed a gradual independent increase, even when adjusted for age, sex, hepatic steatosis, metabolic syndrome, and the TG/HDL cholesterol ratio. Folate may act to enhance LDL particle size. Future clinical and research work should include a study of the safe application and manipulation of folate levels in order to control LDL particle size.

Regional body fat distribution and metabolic profile in postmenopausal women

The aim of the study was to examine how body fat distribution variables were associated with metabolic parameters in a sample of 113 postmenopausal women not receiving hormone therapy (56.9 ± 4.4 years, 28.4 ± 5.1 kg/m 2). Body fat distribution variables (visceral adipose tissue [AT], subcutaneous AT, and total midthigh AT) were measured using computed tomography; body fat mass was assessed by hydrostatic weighing; insulin sensitivity was determined with the euglycemic-hyperinsulinemic clamp; fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPG) concentrations were measured by a 75-g oral glucose load; and (high-sensitivity) C-reactive protein (hs-CRP) was measured using a highly sensitive assay. After controlling for fat mass, visceral AT was positively associated with plasma triglyceride, hs-CRP, FPG, and 2hPG, and negatively associated with high-density lipoprotein cholesterol (HDL-C) and insulin sensitivity. Total midthigh AT was negatively associated with apolipoprotein B, FPG, and 2hPG, and positively associated with insulin sensitivity. Stepwise multiple regression analyses including abdominal visceral AT, subcutaneous AT and total midthigh AT as independent variables showed that abdominal visceral AT best predicted the variance in plasma triglyceride, HDL-C, low-density lipoprotein peak particle size, hs-CRP, FPG, 2hPG, and insulin sensitivity. Abdominal subcutaneous AT was a significant predictor of only insulin sensitivity, whereas total midthigh AT predicted HDL-C, low-density lipoprotein peak particle size, and apolipoprotein B. These multivariate analyses also indicated that total midthigh AT was favorably related to these outcomes, whereas abdominal visceral AT and subcutaneous AT were unfavorably related. These results confirmed that abdominal visceral fat is a critical correlate of metabolic parameters in postmenopausal women. In addition, a higher proportion of AT located in the total midthigh depot is associated with a favorable metabolic profile.

Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia

Coadministration of fenofibrate and ezetimibe (FENO + EZE) produced complementary and favorable effects on the major lipids and lipoproteins, low-density lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C), and non–HDL-C levels, and was well tolerated in patients with mixed hyperlipidemia. The current analysis evaluates the effects of FENO and EZE, as monotherapies and in coadministration, on lipoprotein subfractions and LDL particle size distributions in these patients. In a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients with mixed hyperlipidemia were randomized in a 1:3:3:3 ratio to one of 4 treatment groups: placebo, FENO 160 mg/day, EZE 10 mg/day, or FENO 160 mg/day + EZE 10 mg/day. At baseline and study end point, the Vertical Auto Profile II method was used to measure the cholesterol associated with 2 very low-density lipoprotein (VLDL) subfractions (VLDL-C1 + 2 and VLDL-C3), intermediate-density lipoproteins (IDL-C), and 4 LDL subfractions (LDL-C1 through LDL-C4, from most buoyant to most dense), lipoprotein (Lp) (a), and 2 HDL-C subfractions (HDL-C2 and HDL-C3). The LDL particle size was determined using segmented gradient gel electrophoresis. Fenofibrate reduced cholesterol mass within VLDL, IDL, and dense LDL (primarily LDL-C4) subfractions, and increased cholesterol mass within the more buoyant LDL-C2 subfraction, consistent with a shift to a more buoyant LDL peak particle size. Ezetimibe reduced cholesterol mass within all of the apolipoprotein B–containing particles (eg, VLDL-C, IDL-C, and LDL-C) but did not lead to a shift in the LDL particle size distribution profile. Coadministration of FENO and EZE promoted more pronounced reductions in VLDL-C, IDL-C, and LDL-C, and a preferential decrease in dense LDL subfractions. Fenofibrate and FENO + EZE promoted similar increases in HDL-C2 and HDL-C3. Coadministration of FENO + EZE produced complementary and favorable changes in lipoprotein fractions and subfractions, as assessed by the Vertical Auto Profile II method, in patients with mixed hyperlipidemia. These changes reflected the combined effects of FENO in reducing triglycerides-rich lipoproteins and promoting a shift in the LDL particle distribution profile toward larger, more buoyant particles and of EZE in promoting reductions in cholesterol mass across the apolipoprotein B particle spectrum.

Myeloperoxidase gene sequence variations are associated with low-density-lipoprotein characteristics

The small, dense low-density-lipoprotein (LDL) phenotype is associated with an increased atherosclerosis risk. A genome-wide scan performed on 236 nuclear families of the Quebec Family Study (QFS) revealed a quantitative trait locus (QTL) for LDL peak-particle size (LDL-PPD) on the 17q21 region. This region encodes the myeloperoxidase (MPO) gene. MPO is able to oxidize LDL by its reactive intermediates. To test the associations between MPO gene polymorphisms and LDL-PPD as well as plasma lipid levels, we performed direct sequencing of the coding regions, exon-intron splicing boundaries, and the regulatory regions on 25 subjects to identify new genetic variants. Genotyping was performed either by TaqMan or direct sequencing on 680 subjects in the QFS. LDL-PPD was measured by gradient gel electrophoresis (GGE) on nondenaturing 2-16% polyacrylamide gradient gels. MPO gene sequencing revealed 16 polymorphisms. The c.-653G > A MPO polymorphism was associated with lower plasma total cholesterol, LDL cholesterol (LDL-C), and LDL apolipoprotein B (LDL-apoB) levels (P = 0.026, 0.042 and 0.014, respectively). No significant association with a gene-dosage effect were observed for LDL-PPD. The MPO gene variants are not associated with LDL-PPD and thus are unlikely to be responsible for the quantitative trait locus reported on 17q21. However, the c.-653G > A is associated with plasma LDL-C and LDL-apoB concentrations.

Autoantibodies against modified apolipoprotein B-100 in relation to low-density lipoprotein size and the metabolic syndrome in otherwise healthy men

The role of inflammation in atherosclerotic disease is well established, but the role of autoantibodies against modified apolipoprotein (apo) B-100 remains unclear. The metabolic syndrome is associated with a proinflammatory state, a predominance of small dense low-density lipoprotein (LDL) particles, and an increased risk for atherosclerotic diseases. Previous studies have shown specific autoantibodies against modified apo B-100 (within LDL) to be related to human atherosclerotic disease. The objective of the present study was to investigate whether autoantibodies against modified apo B-100 are related to parameters of the metabolic syndrome, such as small dense LDL. Two hundred ninety-one healthy men were investigated for different metabolic, anthropometric, and inflammatory variables; LDL peak particle size; and distribution of LDL in 4 subfractions. Subjects were grouped according to LDL peak size ≥23.5 nm (pattern A, n = 230) or <23.5 nm (pattern B, n = 61). Immunoglobulin (Ig) G and IgM antibodies against 2 aldehyde-modified peptide sequences, denoted as 45 and 210, within apo B-100 were quantified. Levels of IgG 45, but not the other autoantibodies, were significantly higher in pattern B individuals (with a predominance of small dense LDL particles) compared with pattern A ( P < .01). Relationships for both IgG 45 and IgG 210 with parameters typically associated with the metabolic syndrome were found. Only IgG 45 tended to be higher in individuals with the metabolic syndrome compared with those without ( P = .07). We conclude that subjects with a predominance of small dense LDL particles have elevated concentrations of IgG 45 in the circulation, which reflect an activated immune response to a specific epitope of modified apo B-100.

Flaxseed on cardiovascular disease markers in healthy menopausal women: a randomized, double-blind, placebo-controlled trial

Objective Due to its high content of lignans, α-linolenic acid and fiber, flaxseed may reduce cardiovascular disease risk in humans. The present study evaluated the effect of flaxseed on markers of cardiovascular disease risk in healthy menopausal women. Methods One hundred ninety-nine women were randomly assigned to consume 40 g daily of flaxseed or wheat germ placebo for 12 mo. Fatty acids, apolipoproteins A-1 and B, lipoprotein(a), low-density lipoprotein particle size, fibrinogen, C-reactive protein, insulin, and glucose were measured at baseline and at 12 mo. Results In total 179 women were available for the intention-to-treat analysis. Flaxseed increased plasma α-linolenic ( P < 0.0001), docosapentaenoic ( P = 0.001), and total ω-3 fatty ( P = 0.0004) acids. Differences between flaxseed and wheat germ were observed for apolipoprotein A-1 (−0.10 ± 0.26 g/L, P = 0.011) and apolipoprotein B (−0.05 ± 0.16 g/L, P = 0.047). From baseline, flaxseed raised apolipoproteins A-1 and B by 4.4% ( P = 0.006) and 3% ( P = 0.054), whereas wheat germ increased these apolipoproteins by 11.6% ( P < 0.0001) and 7% ( P = 0.0001), respectively. Both treatments increased lipoprotein(a) ( P < 0.0001) and decreased low-density lipoprotein peak particle size ( P < 0.0001). Conclusion In this large, long-term, placebo-controlled trial in healthy menopausal women, flaxseed increased some ω-3 fatty acids in plasma and had a limited effect on apolipoprotein metabolism.

Atherogenic lipid phenotype in a general group of subjects.

Abstract Context.—The atherogenic lipid phenotype is a major cardiovascular risk factor, but normal values do not exist derived from 1 analysis in a general study group. Objective.—To determine normal values of all of the atherogenic lipid phenotype parameters using subjects from a general study group. Design.—One hundred two general subjects were used to determine their atherogenic lipid phenotype using polyacrylamide gradient gels. Results.—Low-density lipoprotein (LDL) size revealed 24% of subjects express LDL phenotype B, defined as average LDL peak particle size 258 A or less; however, among the Chinese subjects, the expression of the B phenotype was higher at 44% (P = .02). For the total group, mean LDL size was 265 ± 11 A (1 SD); however, histograms were bimodal in both men and women. After excluding subjects expressing LDL phenotype B, because they are at increased cardiovascular risk and thus are not completely healthy, LDL histograms were unimodal and the mean LDL size was 270 ± 7 A. A small, de...

Atherogenic Lipid Phenotype in a General Group of Subjects

The atherogenic lipid phenotype is a major cardiovascular risk factor, but normal values do not exist derived from 1 analysis in a general study group. To determine normal values of all of the atherogenic lipid phenotype parameters using subjects from a general study group. One hundred two general subjects were used to determine their atherogenic lipid phenotype using polyacrylamide gradient gels. Low-density lipoprotein (LDL) size revealed 24% of subjects express LDL phenotype B, defined as average LDL peak particle size 258 A or less; however, among the Chinese subjects, the expression of the B phenotype was higher at 44% (P = .02). For the total group, mean LDL size was 265 +/- 11 A (1 SD); however, histograms were bimodal in both men and women. After excluding subjects expressing LDL phenotype B, because they are at increased cardiovascular risk and thus are not completely healthy, LDL histograms were unimodal and the mean LDL size was 270 +/- 7 A. A small, dense LDL concentration histogram (total group) revealed skewing; thus, phenotype B subjects were excluded, for the rationale described previously, and the mean value was 13 +/- 9 mg/dL (0.33 +/- 0.23 mmol/L). High-density lipoprotein (HDL) cholesterol histograms were bimodal in both sexes. After removing subjects as described previously or if HDL cholesterol levels were less than 45 mg/dL, histograms were unimodal and revealed a mean HDL cholesterol value of 61 +/- 12 mg/dL (1.56 +/- 0.31 mmol/L). HDL 2, HDL 2a, and HDL 2b were similarly evaluated. Approximate normal values for the atherogenic lipid phenotype, similar to those derived from cardiovascular endpoint trials, can be determined if those high proportions of subjects with dyslipidemic cardiovascular risk are excluded.

Accumulation of apoE-enriched triglyceride-rich lipoproteins in patients with coronary artery disease

Triglycerides (TGs) are vehicled by multiple particles with different abilities to promote atherosclerosis. Among plasma TG-rich lipoproteins (TRLs), subspecies may or may not contain apolipoprotein E (apoE) molecules: in this study, we evaluated the relative contribution of apoE-rich and apoE-poor TRLs to coronary atherosclerosis. We selected a group of males with premature coronary artery disease (CAD) without any of the classical nonlipid risk factors and/or high plasma lipid levels and evaluated the plasma concentration of TRL subspecies in comparison with healthy controls. Patients with CAD and controls had total cholesterol and TG levels within the normal range (despite slightly, even if significantly, higher TG levels in patients with CAD) and low-density lipoprotein cholesterol levels near optimal values. Nevertheless, patients with CAD had significantly lower high-density lipoprotein cholesterol, smaller low-density lipoprotein peak particle size, and a reduced HDL2b subfraction than controls. In addition, we observed higher concentrations of total TRL in patients with CAD together with a selective increase in apoE-rich particles. All these data were confirmed after correction for TG levels. We also investigated which parameters were associated with the spread of coronary atherosclerosis. Subjects with a single-vessel disease had selectively lower levels of apoE-rich fractions than patients with a multivessel disease. This was confirmed by multivariate analysis. Patients with a premature CAD free of nonlipid conventional risk factors, despite not having elevated lipid levels, show several lipoprotein abnormalities. Besides known atherogenic alterations, the accumulation of apoE-rich TRL subfractions may represent an additive factor that can potentially promote and initiate the atherosclerotic process.

Visceral adipose tissue accumulation, secretory phospholipase A2-IIA and atherogenecity of LDL

The aim of the present study was to investigate the combined impact of visceral adipose tissue (VAT) and secretory group IIA phospholipase A(2) (sPLA(2)-IIA) concentrations on the atherogenicity of low-density lipoprotein (LDL) particles among men. Analyses were conducted in 74 mid-obese healthy men (age: (mean+/-s.d.) 37.9+/-11.7 years). Plasma levels of sPLA(2)-IIA were measured with a commercial ELISA and VAT levels were assessed by computed tomography. Distinct subpopulations of LDL particles were characterized from whole plasma using nondenaturating 2-16% gradient gel electrophoresis. Data indicated that plasma sPLA(2)-IIA levels were approximately 29% (P=0.007) higher among men characterized by a higher accumulation of VAT (>142 vs < or =142 cm(2)). Men having high plasma sPLA(2)-IIA levels (> or =127.2 ng/dl, the median value), were characterized by higher levels of plasma cholesterol (C) and apolipoprotein (apo) B, LDL-C, LDL-apoB, oxidized LDL (OxLDL) and by smaller LDL particles compared to men with sPLA(2)-IIA<127.2 ng/dl. Multiple regression analyses showed that plasma triglycerides and sPLA(2)-IIA levels explained 22.7 and 11.8% of the variance in LDL peak particle size, respectively. Levels of VAT and of sPLA(2)-IIA were the strongest correlates of OxLDL levels explaining, respectively, 15.0 and 5.5% of their variability. Both VAT and sPLA(2)-IIA levels modulate the atherogenecity of LDL by accounting for the reduction in their size and their susceptibility to oxidation.

The Triglyceride/High-Density Lipoprotein Cholesterol Ratio, the Small Dense Low-Density Lipoprotein Phenotype, and Ischemic Heart Disease Risk

This study investigated the relevance of using the plasma triglyceride to high-density lipoprotein cholesterol ratio (Log TG/HDL-C) for the prediction of the small dense lowdensity lipoprotein (LDL) phenotype and the risk of ischemic heart disease (IHD). Analyses were based on data from the Quebec Cardiovascular Study in a cohort of 2072 men free of IHD at baseline, among whom 262 had a first IHD event (coronary death, non fatal myocardial infarction and unstable angina) during a 13-year follow-up period. LDL particle size phenotype was characterized using 2-16% polyacrylamide gradient gel electrophoresis (PAGGE) of whole plasma. There were significant associations between the Log TG/HDL-C ratio and features of LDL size phenotype such as the proportion of LDL with a diameter <255A (r = 0.43, p < 0.001) and LDL peak particle size (r = -20.55, p < 0.001). However, the Log TG/HDL-C ratio brought no additional value (p â yen 0.1) in predicting the small dense LDL phenotype (area under the receiver operating curve (AUROC = 71.9%) compared to TG alone (AUROC = 71.2%) or to a combination of Log TG and HDL-C (AUROC = 72.4%) after multivariate adjustment for non lipid risk factors. Finally, elevations in the Log TG/HDL-C ratio did not improve the discrimination of incident IHD cases from non IHD cases compared to the use of plasma TG levels alone (p = 0.5) or a combination of the individual TG and HDL-C values (p = 0.5). The Log TG/HDL-C ratio does not improve our ability to identify individuals with the small dense LDL phenotype compared to plasma TG levels alone. The Log TG/HDLC is also not superior to plasma TG levels alone in predicting IHD risk in men of the QuA(c)bec Cardiovascular Study.

The Triglyceride/High-Density Lipoprotein Cholesterol Ratio, the Small Dense Low-Density Lipoprotein Phenotype, and Ischemic Heart Disease Risk

This study investigated the relevance of using the plasma triglyceride to high-density lipoprotein cholesterol ratio (Log TG/HDL-C) for the prediction of the small dense lowdensity lipoprotein (LDL) phenotype and the risk of ischemic heart disease (IHD). Analyses were based on data from the Quebec Cardiovascular Study in a cohort of 2072 men free of IHD at baseline, among whom 262 had a first IHD event (coronary death, non fatal myocardial infarction and unstable angina) during a 13-year follow-up period. LDL particle size phenotype was characterized using 2–16% polyacrylamide gradient gel electrophoresis (PAGGE) of whole plasma. There were significant associations between the Log TG/HDL-C ratio and features of LDL size phenotype such as the proportion of LDL with a diameter <255Å (r = 0.43, p < 0.001) and LDL peak particle size (r = -20.55, p < 0.001). However, the Log TG/HDL-C ratio brought no additional value (p ≥ 0.1) in predicting the small dense LDL phenotype (area under the receiver operating curve (AUROC = 71.9%) compared to TG alone (AUROC = 71.2%) or to a combination of Log TG and HDL-C (AUROC = 72.4%) after multivariate adjustment for non lipid risk factors. Finally, elevations in the Log TG/HDL-C ratio did not improve the discrimination of incident IHD cases from non IHD cases compared to the use of plasma TG levels alone (p = 0.5) or a combination of the individual TG and HDL-C values (p = 0.5). The Log TG/HDL-C ratio does not improve our ability to identify individuals with the small dense LDL phenotype compared to plasma TG levels alone. The Log TG/HDLC is also not superior to plasma TG levels alone in predicting IHD risk in men of the Québec Cardiovascular Study.

Effect of Plasma C-Reactive Protein Levels in Modulating the Risk of Coronary Heart Disease AssociatedWith Small, Dense, Low-Density Lipoproteins in Men(The Quebec Cardiovascular Study)

This purpose of this study was to investigate how plasma C-reactive protein (CRP), a nonspecific acute-phase reactant, modulates the risk of coronary heart disease (CHD) associated with the small, dense, low-density lipoprotein (LDL) phenotype. LDL particle size and plasma CRP were measured in the Quebec Cardiovascular Study cohort of 2,025 men free of CHD at baseline, among whom 103 had a first CHD event during a 5-year follow-up period. Plasma CRP levels were measured using the Behring Latex-Enhanced (highly sensitive) CRP assay. LDL particle size phenotype was characterized using 2% to 16% polyacrylamide gradient gel electrophoresis. There were weak but significant associations between plasma CRP levels and features of LDL size, such as the proportion of LDL with a diameter <255 Å (r = 0.09, p <0.001) and LDL peak particle size (r = −0.09, p <0.001). Variations in plasma CRP levels modulated the risk of CHD associated with small LDL peak particle size (relative risk 4.3 vs 2.5 in men with high vs low plasma CRP levels, respectively) and with an elevated proportion of LDL <255 Å (relative risk 6.6 vs 3.0). Thus, increased plasma CRP levels further elevate the risk of CHD associated with having small, dense LDL particles.

Influence of common variants in the CETP, LPL, HL and APO E genes on LDL heterogeneity in healthy, middle-aged men

Low density lipoprotein (LDL) particle size is a genetically influenced trait associated with coronary heart disease (CHD). This study investigates the effects of genetic variation in plasma factors with important roles in lipoprotein metabolism on LDL heterogeneity. Common variants in the cholesteryl ester transfer protein (CETP-629C/A), lipoprotein lipase (LPL S447X), hepatic lipase (HL-480C/T) and apolipoprotein E (apoE e2/e3/e4) genes were studied in relation to LDL particle size distribution in 377 healthy, middle-aged men. A high-resolution polyacrylamide gradient gel electrophoresis technique was used to measure plasma concentrations of four LDL subfractions. The CETP-629A and LPL 447X alleles were associated with moderately increased LDL peak particle size. In contrast, the apoE e4 allele was associated with a marked reduction in LDL peak particle size and an increased relative proportion and plasma concentration of small, dense LDL. An interaction between the HL-480C/T and apo E polymorphisms contributed significantly to increased plasma concentration of small, dense LDL (LDL-III) in HL-480T carriers. In summary, the investigated polymorphisms were associated with diverse effects on the LDL particle size distribution, consistent with respect to protein function and proposed association with CHD risk. The observed associations were further modulated by gene–gene and gene–environment interactions.

Low-density-lipoprotein peak particle size in a Mediterranean population.

The predominance of small, dense low-density lipoprotein (LDL) particles ('LDL phenotype B') has been associated with a three-fold increased risk of myocardial infarction, but the feasibility of the identification of small, dense LDL as independent predictors of coronary artery disease risk in population studies remains questioned. Design We evaluated the LDL peak particle size and its relation with other established risk factors for coronary heart disease in a group of 156 randomized subjects living on the Mediterranean island of Ustica (71 males and 85 women, range of age 20-69 years), representing approximately 30% of the total population. The prevalence of LDL phenotype B subjects was low (approximately 15% in both men and women) and there was a clear trend for both genders in reducing the LDL peak particle size with age. Moreover, LDL phenotype B subjects had higher BMI values, prevalence of diabetes and plasma triglyceride (TG) levels and lower plasma HDL-C concentrations in comparison with LDL phenotype A individuals; in a multivariate analysis, plasma TG levels were the only variable independently associated with LDL peak particle size. In this population, which appears to be somewhat protected by premature coronary artery disease, a low prevalence of the LDL pattern B was found in both men and women, and plasma TG could have a key role in regulating the LDL peak particle size. The follow up, still ongoing, will provide useful information on the predictive role of LDL peak particle size on cardiovascular risk, at least in a low-risk population.

Effects of prednisone withdrawal on the new metabolic triad in cyclosporine-treated kidney transplant patients

Cardiovascular disease is a major cause of morbidity and mortality after renal transplantation. Prednisone (Pred) maintenance therapy is associated with risk factors for atherosclerosis. Therefore, we were interested in quantifying the effects of Pred withdrawal on body weight and waist circumference as well as on metabolic markers of coronary heart disease risk. Twenty-six cyclosporine-treated renal transplant patients (13 men and 13 women) were evaluated before and after at least 11 months (16 +/- 2.9 months) of Pred withdrawal. A complete fasting lipoprotein-lipid profile as well as anthropometric measurements were obtained from each patient. Pred withdrawal was associated with a 6.0% reduction of body weight (-4.34 +/- 5.40 kg; P < 0.05) and with a 7.7% decrease in waist girth (-7.13 +/- 5.75 cm; P < 0.005) in women, whereas no change in these variables were observed in men. In both genders, plasma low-density lipoprotein (LDL) cholesterol and triglyceride concentrations were unaffected by Pred withdrawal, whereas plasma high-density lipoprotein (HDL) cholesterol levels decreased by 14.0% in women (-0.22 +/- 0.22 mmol/L; P < 0.005) and 22.0% in men (-0.36 +/- 0.28 mmol/L; P < 0.005). Pred withdrawal was associated with a significant reduction in plasma apolipoprotein B concentrations in both women (-0.28 +/- 0.15 g/L; -24.6%; P < 0.0001) and men (-0.22 +/- 0.19 g/L; -20.5%; P < 0.005). A significant reduction in fasting insulin was observed in both women (-27.8 +/- 27.9 pmol/L; -25.3%; P < 0.005) and men (-25.0 +/- 32.8 pmol/L; -21.4%; P < 0.05), whereas the LDL peak particle size was unaffected by Pred withdrawal. Pred withdrawal modifies several anthropometric and metabolic cardiovascular risk factors in renal transplant patients. Furthermore, female patients may derive further benefits of Pred withdrawal resulting from the concomitant loss of body weight and abdominal fat.

Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia.

The nature of the genetic and environmental factors influencing low density lipoprotein (LDL) particle size in patients with familial combined hyperlipidaemia (FCHL) is under debate. We measured LDL peak particle size in 553 subjects belonging to 48 Finnish FCHL families. Individuals with high triglyceride (TG) concentrations (phenotype IV) or combined hyperlipidaemia (phenotype IIB) had significantly smaller LDL particles than those with hypercholesterolaemia (phenotype IIA) or unaffected subjects (P<0.001). In stepwise regression analyses, serum TGs (r(2)=43%, P<0.001) and high density lipoprotein cholesterol (HDL-C) (r(2)=4.5%, P<0.001) were the only significant predictors of LDL peak particle size. Familial correlations support the conclusion that LDL peak particle size is familial, and most probably influenced by genes in these families. Segregation analysis of LDL peak particle size, a quantitative trait, was performed to model this genetic influence. Our results suggest a polygenic background for LDL size with a recessive major gene that may contribute to large LDL peak particle size in women. Serum TG and HDL-C concentrations predict the majority of variations in LDL particle size.

A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients

Objective: The objective of the present study was to compare the effects of a 16-week pharmacotherapy with fenofibrate (200 mg) or pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) on low density lipoprotein (LDL) particle size assessed by gradient gel electrophoresis among patients with type IIa dyslipidemia. Methods: For that purpose, type IIa dyslipidemic patients (cholesterol, 7.45±1.18 (S.D.) mmol/l; LDL cholesterol, 5.57±1.16 mmol/l; triglycerides (TGs), 1.66±0.43 mmol/l) were randomized to either fenofibrate ( n=36) or pravastatin ( n=43) therapy for 16 weeks. Fasting plasma lipoprotein levels as well as the LDL peak particle size (using 2–16% polyacrylamide gel electrophoresis) were assessed at baseline and after the 16-week treatment period. Results: Whereas significant improvements in the plasma lipoprotein–lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased with fenofibrate therapy (+2.11±5.18 Å, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size ( r=−0.54, P<0.0007), whereas no such association was found in pravastatin-treated patients. The prevalence of patients with small, dense LDL particles (as defined by LDL particle diameter <255.5 Å) was reduced from 69.4 to 30.6% ( P<0.05) among fenofibrate-treated patients as opposed to 81.4 to 72.1% (NS) in patients who received pravastatin. Conclusion: As pravastatin treatment had no effect on LDL size, it is suggested that the additional effect of fenofibrate therapy on LDL size may contribute to reduce the risk of coronary heart disease (CHD) beyond what can be expected from the reduction in LDL cholesterol concentration in type IIa dyslipidemic patients.