Smaller Low-density Lipoprotein Particle Size Research Articles

EPHA6 rs4857055 C\u2009>\u2009T polymorphism associates with hypertension through triglyceride and LDL particle size in the Korean population

BackgroundErythropoietin-producing human hepatocellular (Eph) receptors might contribute to the development of atherosclerosis. A genome-wide association study indicated that the Eph receptor A6 gene (EPHA6) associated with at least 1 blood pressure (BP) phenotype. The objective of the present study was to determine whether EPHA6 is a novel candidate gene for hypertension in a Korean population.MethodsA total 2146 study participants with normotension and hypertension were included. Genotype data were obtained using a Korean Chip. To assess the association between single-nucleotide polymorphisms (SNPs) and BP, we performed a linear regression analysis, which showed that rs4850755 in the EPHA6 gene was the SNP most highly associated with both systolic and diastolic BP.ResultsThe presence of the TT genotype of the EPHA6 rs4857055 C > T SNP was associated with a higher risk of hypertension after adjusting for age, sex, body mass index (BMI), smoking, and drinking [odds ratio 1.533, P = 0.001]. In the control group, significant associations were observed between systolic BP and the rs4857055 polymorphism and between diastolic BP and the rs4857055 polymorphism. In the hypertension group, a significant association was observed between systolic BP and the rs4857055 polymorphism. In the hypertension group, subjects with the TT genotype showed significantly higher systolic BP than CC subjects. Additionally, in the hypertension group, TT carriers showed a higher tendency of serum triglyceride (P = 0.069) and significantly higher apolipoprotein B (P = 0.015) and smaller low-density lipoprotein (LDL) particle size (P < 0.001) than either TC or CC subjects.ConclusionsThese results could suggest that the EPHA6 rs4857055 C > T SNP is a novel candidate gene for hypertension in the Korean population. Additionally, the TT genotype could be associated with hypertriglyceridemia and small LDL particle size in hypertension.

Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study.

Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. Plasma apoC-III levels were measured in baseline samples from a nested case-control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48-2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11-1.94). ApoC-III levels were positively correlated with triglyceride levels, (r=0.39), particle numbers of very-low-density lipoprotein (r=0.25), intermediate-density lipoprotein (r=0.23), small dense low-density lipoprotein (r=0.26), and high-sensitivity C-reactive protein (r=0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number (r=-0.11), P<0.001 for each. Mediation analysis indicated that the association between apoC-III and CAD risk could be explained by triglyceride elevation (triglyceride, very-low-density lipoprotein, and intermediate-density lipoprotein particles), small low-density lipoprotein particle size, and high-sensitivity C-reactive protein. ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.

Hepatic Steatosis and Insulin Resistance, But Not Steatohepatitis, Promote Atherogenic Dyslipidemia in NAFLD.

Patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk of cardiovascular disease, and atherogenic lipoproteins may play an important role. The objective of the study was to determine the contribution of the severity of steatohepatitis to atherogenic dyslipidemia in patients with NAFLD. This was a cross-sectional study. The study was conducted at a university hospital. Patients were recruited from outpatient clinics or from the general population (n = 188). Measurement of hepatic triglyceride content by magnetic resonance spectroscopy, histology (liver biopsy), metabolic profile by means of an oral glucose tolerance test, and lipoprotein analyses were performed. Outcomes measured included standard lipids, lipoprotein subfraction analysis (apolipoprotein B/A1 levels, low-density lipoprotein (LDL) particle size/phenotype, and LDL/high-density lipoprotein subfractions), and insulin resistance. Patients with NAFLD had severe insulin resistance, especially at the level of the adipose tissue, when compared with patients without NAFLD. Despite small differences in triglycerides and high-density lipoprotein-cholesterol, patients with NAFLD had a significantly higher plasma apolipoprotein B to apolipoprotein A1 ratio (0.66 ± 0.02 vs 0.58 ± 0.02, P = .01) and smaller LDL particle size (216.2 ± 0.7 vs 219.4 ± 1.1 Å, P = .01). Of note, these differences between patients with/without NAFLD were independent of the presence of obesity. Severity of steatohepatitis did not significantly influence the lipoprotein profile. Worse atherogenic dyslipidemia was best predicted by the degree of liver fat accumulation and adipose tissue and systemic insulin resistance. NAFLD was associated with a worse atherogenic lipoprotein profile, regardless of similar body mass index and other clinical parameters. We speculate that this lipoprotein profile is driven mostly by liver fat content and insulin resistance and appears not to be worsened by obesity or the severity of liver disease (nonalcoholic steatohepatitis).

Systemic Inflammatory Markers Are Closely Associated with Atherogenic Lipoprotein Subfractions in Patients Undergoing Coronary Angiography.

Objective. To investigate the relationship between inflammatory markers and atherogenic lipoprotein subfractions. Methods. We studied 520 eligible subjects who were not receiving any lipid-lowering therapy. The inflammatory markers including white blood cell (WBC) count, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR), and D-dimer were measured. A multimarker inflammatory index was developed. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) separation processes were performed using Lipoprint System. Results. In age- and sex-adjusted analysis, several inflammatory markers (WBC count, hs-CRP, fibrinogen, and ESR) were positively related to circulating non-HDL cholesterol and remnant cholesterol (p < 0.05, all). Among lipoprotein subfractions, we observed a positive association of inflammatory markers with very low-density lipoprotein cholesterol, small LDL cholesterol, and LDL score (p < 0.05, all). Meanwhile, a negative association was detected between inflammatory markers and mean LDL particle size (p < 0.05) or large HDL cholesterol (p < 0.05). Moreover, we found that the relationships between multimarker index quartiles and small LDL cholesterol, LDL score, and mean LDL particle size were slightly stronger in patients with CAD. Conclusions. Systemic inflammatory markers are positively correlated with small LDL cholesterol and LDL score while being negatively linked with mean LDL particle size and large HDL cholesterol, highlighting the potential contribution to increased cardiovascular risk.

SMITH-LEMLI-OPITZ syndrome, caused by deficiency in the last step of cholesterol biosynthesis: The bristol UKGTN DHCR7 mutation service

SMITH-LEMLI-OPITZ syndrome, caused by deficiency in the last step of cholesterol biosynthesis: The bristol UKGTN DHCR7 mutation service

Low-density lipoprotein subfraction, carotid artery intima-media thickness, nitric oxide, and tumor necrosis factor alpha are associated with newly diagnosed ischemic stroke

Objectives:Small dense (sd) low-density lipoprotein (LDL), tumor necrosis factor (TNF) alpha (α), and nitric oxide (NO) have recently emerged as important stroke risk factors. The aim of the study was to investigate the effects of increased levels of small LDL particle size, TNF-α and NO on the developed ischemic stroke and increased carotid artery intima-media thickness (CIMT).Materials and Methods:A total of 29 women and 25 men (a total of 54 ischemic stroke patients) and a similar age group of 50 controls (29 females and 21 males) were included in the study. CIMT, C-reactive protein (CRP), TNF-α, NO, and lipid subfraction test of the two groups were measured.Results:The mean LDL particle size was smaller in patients with stroke than in the controls (26.8 ± 0.31 nm vs. 27.0 ± 0.31 nm, P = 0.003). sd-LDL, TNF-α, NO, CRP, right CIMT, and left CIMT were higher in patients with stroke than in the controls (respectively; 8.2 ± 7.8 mg/dL vs. 3.3 ± 3.5 mg/dL, P < 0.001;75.6 ± 25.0 pg/mL vs. 65.4 ± 9.1 pg/mL, P = 0.009;76.4 ± 53.3 mmol/L vs. 41.5 ± 27.0 mmol/L, P < 0.001;1.9 ± 2.6 mm vs. 0.4 ± 0.3 mm P < 0.001;0.97 ± 0.38 mm vs. 0.83 ± 0.15 mm, P = 0.007;1.04 ± 0.44 mm vs. 0.87 ± 0.19 mm, P = 0.010).Conclusion:These results show that sd-LDL is independently associated with the incidence of stroke and may be a risk factor in the development of stroke. In addition, TNF-α, NO, right CIMT, and left CIMT may be a risk factor in the development of ischemic stroke.

Lipids and lipoproteins in adolescents with prediabetes

There is concern in both adults and adolescents about diabetes as a cardiovascular disease risk equivalent. This means that the risk for cardiovascular disease in a patient with diabetes is similar to that in patients with already extant cardiovascular disease. There also is concern that clustering of traditional cardiovascular disease risk factors leads to accelerated atherosclerosis. In this issue of The Journal, Magge et al report on the lipoprotein profile of obese adolescents with prediabetes. The authors found that those with prediabetes (impaired fasting glucose) had higher concentrations of small low-density lipoprotein (LDL) particles and smaller LDL particle size, as well as higher concentration of small high-density lipoprotein (HDL) particles and smaller HDL particle size compared with youth with a normal concentration of glucose normoglycerinic youth. These results demonstrate that obese adolescents with prediabetes already have a more atherogenic lipoprotein profile. This emphasizes the need for early intervention to prevent obesity and for those who are obese to prevent the development of prediabetes. Article page 881▶ Prediabetic Obese Adolescents have a More Atherogenic Lipoprotein Profile Compared with Normoglycemic Obese PeersThe Journal of PediatricsVol. 161Issue 5PreviewTo compare lipoprotein profiles of prediabetic to normoglycemic obese adolescents. Full-Text PDF

Surrogate Lipid Markers for Small Dense Low-Density Lipoprotein Particles in Overweight Youth

To determine if the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL) and non-HDL cholesterol concentration could identify youth with small dense low-density lipoprotein (LDL). One hundred forty-one (75 black and 66 white) overweight adolescents (9 to <18 years) had a fasting measurement of plasma lipids and LDL particle concentrations and size. Receiver operating characteristic curves were used to indicate the ability of different TG/HDL ratios and non-HDL cholesterol concentrations to identify overweight youth with atherogenic LDL concentration and size. Youth with a TG/HDL ratio of ≥3 vs <3 had higher concentrations of small dense LDL (1279.5 ± 60.1 vs 841.8 ± 24.2 nmol/L, P < .001) and smaller LDL particle size (20.3 ± 0.1 vs 21.2 ± 0.1 nm, P < .001). In receiver operating characteristic analyses a TG/HDL cut-point of 3 best predicted LDL concentration in white youth, and 2.5 in black youth. Non-HDL cholesterol cut-point of 120 mg/dL and 145 mg/dL predicted LDL particle concentration in white and in black youth, respectively. TG/HDL ratio with body mass index or waist circumference explained 71% and 79% of the variance, respectively, in total small LDL. TG/HDL ratio and non-HDL cholesterol can identify overweight youth with atherogenic LDL particles. These easily obtained clinical lipid markers, in combination with body mass index and waist circumference, could be cost effective, in observational or interventional studies, for screening and follow-up of youth at heightened risk for atherogenic LDL.

Higher levels of serum triglyceride and dietary carbohydrate intake are associated with smaller LDL particle size in healthy Korean women

The aim of this study was to investigate the influencing factors that characterize low density lipoprotein (LDL) phenotype and the levels of LDL particle size in healthy Korean women. In 57 healthy Korean women (mean age, 57.4 ± 13.1 yrs), anthropometric and biochemical parameters such as lipid profiles and LDL particle size were measured. Dietary intake was estimated by a developed semi-quantitative food frequency questionnaire. The study subjects were divided into two groups: LDL phenotype A (mean size: 269.7Å, n = 44) and LDL phenotype B (mean size: 248.2Å, n = 13). Basic characteristics were not significantly different between the two groups. The phenotype B group had a higher body mass index, higher serum levels of triglyceride, total-cholesterol, LDL-cholesterol, apolipoprotein (apo)B, and apoCIII but lower levels of high density lipoprotein (HDL)-cholesterol and LDL particle size than those of the phenotype A group. LDL particle size was negatively correlated with serum levels of triglyceride (r = -0.732, P < 0.001), total-cholesterol, apoB, and apoCIII, as well as carbohydrate intake (%En) and positively correlated with serum levels of HDL-cholesterol and ApoA1 and fat intake (%En). A stepwise multiple linear regression analysis revealed that carbohydrate intake (%En) and serum triglyceride levels were the primary factors influencing LDL particle size (P < 0.001, R2 = 0.577). This result confirmed that LDL particle size was closely correlated with circulating triglycerides and demonstrated that particle size is significantly associated with dietary carbohydrate in Korean women.

Apolipoprotein B, oxidized low-density lipoprotein, and LDL particle size in predicting the incidence of metabolic syndrome: the Cardiovascular Risk in Young Finns study

To test whether serum apolipoprotein B (apoB) and low-density lipoprotein (LDL) particle characteristics (oxidation and mean particle size) predict the incidence of metabolic syndrome (MetS). The 6-year follow-up study included 1429 adults (baseline mean age 31.5). Lipids, apoB, and apoA1 were measured at baseline in 2001. LDL oxidation was measured with monoclonal antibody-based enzyme-linked immunosorbent assay (oxLDL-prot) and with a method measuring oxidized lipids in LDL (oxLDL-lipids). Mean LDL particle size was calculated from proton nuclear magnetic resonance spectroscopy data. Increased concentrations of both oxLDL-measures were associated with increased apoB levels but not with LDL particle size. The odds ratios (95% confidence intervals) for MetS incidence during a 6-year follow up by quartiles of apoB were 2.0 (1.0-3.8) for the second quartile, 3.1 (1.7-5.7) for the third quartile, and 4.2 (2.3-7.6) for the fourth quartile. This association remained after adjusting for age, sex, body mass index, homeostasis model assessment for insulin resistance, C-reactive protein, smoking, LDL cholesterol, oxidized LDL measures (p ≤ 0.01) in addition to risk factors comprising the MetS (p = 0.03). OxLDL-prot and oxLDL-lipids levels were not independently associated with incident MetS after adjusting for apoB. Mean LDL particle size was not associated with the incidence of MetS. ApoB is associated with increased risk of MetS incidence. We found no clear evidence to suggest that increased LDL oxidation or small mean LDL particle size would facilitate the development of MetS.

LDL-associated apolipoprotein J and lysozyme are associated with atherogenic properties of LDL found in type 2 diabetes and the metabolic syndrome

Exchangeable low-density lipoprotein (LDL)-associated proteins can affect the atherogenic properties of LDL. Our aim was to analyse the protein composition of LDL from individuals with or without type 2 diabetes and the metabolic syndrome (T2DM) in relation to other LDL particle characteristics, to assess whether certain proteins associate more with certain subclasses of LDL typical for T2DM, such as small, apoCIII-rich LDL. Low-density lipoprotein from two cohorts of 61-year-old men (n = 19 and 64) with or without T2DM was isolated using size-exclusion chromatography or deuterium oxide-based ultracentrifugation. LDL-associated proteins were identified using mass spectrometry and quantified using two-dimensional gel electrophoresis or enzyme-linked immunosorbent assay. Differently expressed LDL-associated proteins apolipoprotein (apo)J and lysozyme were also measured in serum from a third cohort of women (n = 71) with or without T2DM. Lysozyme binding to advanced glycation end product (AGE)-LDL was examined in vitro. ApoJ and lysozyme were increased in LDL particles with increased apoCIII content and decreased cholesterol content. When isolated with size-exclusion chromatography, LDL from individuals with T2DM contained more apoJ and lysozyme and less apoA1 than LDL from control individuals. LDL content of apoJ correlated with a smaller LDL particle size. Serum levels of lysozyme, but not apoJ, were increased in individuals with T2DM. In vitro, lysozyme associated more with AGE-LDL than with unmodified LDL. Our results indicate that apoJ and lysozyme are increased in LDL with characteristics of small dense LDL in T2DM. Small dense LDL is easily glycated, and the increased affinity of lysozyme for AGE-LDL provides a possible partial explanation for an increase lysozyme in LDL from those with type 2 diabetes.

LDL Species Heterogeneity in the Atherogenic Dyslipidemia of Polycystic Ovary Syndrome

One of the important risk factors for coronary heart disease is dyslipidemia. Several lipid abnormalities have been studied in patients with polycystic ovary syndrome (PCOS), but the relationship between PCOS and low-density lipoprotein (LDL) subclass pattern is not clear. A case-control study was designed to look into lipid differences, and LDL size was analyzed by a newly developed polyacrylamide tube gel electrophoresis method. Results indicated that only PCOS status and serum triglyceride levels were independently associated with LDL particle size. The apolipoprotein (Apo)A-I level was higher in PCOS patients with small dense LDL (sdLDL). PCOS seems to result in smaller LDL particle size and higher ApoA-I levels independent of triglyceride levels. After adjusting for triglyceride levels, other traits of insulin resistance syndrome (IRS) were not associated with LDL size phenotype, suggesting that the IRS-related sdLDL is linked most strongly to alterations in triglyceride levels.

Dietary polyunsaturated fat intake is associated with low-density lipoprotein size, but not with susceptibility to oxidation in subjects with impaired glucose metabolism and type II diabetes: the Hoorn study

A high monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) intake is associated with lower plasma low-density lipoprotein (LDL)-cholesterol. However, PUFA may increase the susceptibility of LDL to undergo oxidative modifications. The aim of this study was to analyze the association of habitual dietary fat intake with LDL size and oxidizability. Cross-sectional. Cohort study. Seven hundred and fifty-eight subjects with normal, impaired glucose metabolism and type II diabetes. Mean LDL size was measured by high-performance gel-filtration chromatography. In vitro oxidizability of LDL was determined by measuring lag time, reflecting the resistance of LDL to copper-induced oxidation. Information about dietary fat intake was obtained by a validated food frequency questionnaire. PUFA intake (energy percent) was significantly and negatively associated with LDL size in subjects with type II diabetes (standardized beta (95% confidence interval) -0.17 (-0.28;-0.06)) and impaired glucose metabolism - although not statistically significant - (-0.09 (-0.24;0.05)), but not in subjects with normal glucose metabolism (0.01 (-0.10;0.12)) (P-value for interaction=0.02). No significant associations were observed for total, saturated fat and MUFA intake with LDL size. Intake of fat was associated with lag time; however, the small magnitude of the associations suggested that the composition of dietary fat is not a major factor affecting lag time. The same association with lag time was observed in all three glucose metabolism categories. In individuals with abnormal glucose metabolism, higher PUFA intake is associated with smaller LDL particle size, but does not alter the susceptibility of LDL to in vitro oxidation. Dutch Diabetes Research Foundation, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).

Tu-P10:446 Relationship between C-reactive proteine and cerebrovascular stenosis

The fasting atherogenic dyslipidemia of visceral obesity, which includes the presence of small, dense low-density lipoprotein (LDL) particles, is predictive of an increased risk of coronary heart disease (CHD). It has also been suggested that progression of atherosclerosis may be accelerated in the presence of postprandial hyperlipidemia independently from the fasting dyslipidemic state. Studies have shown that the best predictor of postprandial hyperlipidemia and of the small, dense LDL phenotype is fasting triglyceride (TG) concentration. In the present study, we evaluated the impact of postprandial hypertriglyceridemia on the variation in LDL particle size. Fasting (0 hour) and postprandial changes (2, 4, 6, and 8 hours) in LDL particle size were measured by nondenaturing 2% to 16% polyacrylamide gel electrophoresis in a sample of 49 men (mean age ± SD: 46.6 ± 9.2 years) who underwent a standardized breakfast with a high-fat (64% calories as fat) content. The postprandial increase in TG levels was associated with a transient reduction in LDL particle size, the most substantial reduction being observed 4 hours (−1.0 ± 2.4 Å) after the oral fat load. Although there were strong correlations between TG-rich lipoprotein (TRL)-TG levels and LDL particle size in the fasting state (r = −0.71, P < .0001) as well as 4 hours after the oral fat load (r = −0.70, P < .0001), changes in TRL-TG concentrations during the postprandial state (from time 0 to 4 hours) were not associated with changes in LDL particle size during this period (r = −0.04, not significant [NS]). However, among subgroups of men matched for similar fasting TRL-TG levels (n = 12), subjects with the highest total area under the curve (AUC) of TRL-TG after the fat load were characterized by smaller LDL particle size at 6 and 8 hours compared with men with the lowest AUC TRL-TG (P < .02). Men displaying the highest postprandial AUC TRL-TG were also characterized by the greatest accumulation of visceral adipose tissue (AT) (P < .05). These results indicate that the hypertriglyceridemic (hyperTG) state induced by a high-fat meal is associated with a transient reduction in LDL peak particle diameter, which is not proportionate, however, to the level of TG achieved in the postprandial state. Furthermore, despite similar TG levels at baseline, viscerally obese men with an impaired postprandial lipemia had smaller LDL particles at the end of the oral fat load than obese men with a lower accumulation of visceral AT.

Diacylglycerol oil ingestion in type 2 diabetic patients with hypertriglyceridemia

Objective Coronary arteriosclerotic heart disease frequently develops in patients with diabetes. Decreased serum high-density lipoprotein cholesterol concentration and low-density lipoprotein (LDL) particle size, accompanied by hypertriglyceridemia, are associated with the onset of atherosclerosis. We recently reported that hypertriglyceridemia was significantly improved in patients with type 2 diabetes who ingested diacylglycerol (DAG) oil. The effect on variables, including LDL particle size related to lipid metabolism, however, was not examined. The present study investigated the effects on these variables in more detail. Methods Patients with type 2 diabetes ( n = 24) were assigned to receive DAG oil or triacylglycerol oil, and a 3-mo, single-blind, controlled study was performed. Patients replaced cooking oil in their daily diet with DAG or triacylglycerol oil, and anthropometry and blood sampling were performed at monthly intervals. Results There were no significant differences in calorie intake or amount of test oil ingested between groups. Waist circumference and serum triacylglycerol concentrations were significantly lower and serum concentrations of high-density lipoprotein cholesterol and apolipoprotein-AI were significantly higher in the DAG oil group than in the triacylglycerol oil group. Plasma plasminogen activator inhibitor-1 concentrations were significantly lower in the DAG oil group. LDL particle size tended to increase in the DAG oil group and was significantly larger in patients who had a small initial LDL particle size (<25.5 nm). There were no significant differences in variables related to glucose metabolism or in serum concentration of free fatty acids or total ketone bodies. Conclusions These results indicate that DAG oil may be useful for patients who have type 2 diabetes in the management of obesity and lipid abnormalities.

Usefulness of low-density lipoprotein particle size measurement in cardiovascular disease prevention

Cardiovascular disease is largely explained by the traditional risk factors, but there are several novel risk factors that have been shown to predict cardiovascular morbidity. The measurement of low-density lipoprotein particle size (LDLPS) is a novel cardiovascular risk factor, yet it is unknown whether this measurement provides additional information that may influence the subsequent medical treatment of patients. The measurement of LDLPS provides additional information that may influence preventive treatment for cardiovascular disease. In an observational study of 82 patients referred to a tertiary care preventive cardiology clinic, LDLPS was dichotomized as either small or large and was determined by either the NMR LipoProfile test, the Vertical Auto Profile (VAP) cholesterol test, or gradient gel electrophoresis. Lipid profiles were obtained and Framingham risk scores were calculated. Patients were stratified by Adult Treatment Panel guidelines as being at low, intermediate, or high risk. The study included 56 men and 26 women with a mean age of 54 +/- 11 years. In the entire cohort of 82 patients, only 31 (38%) were at non-high-density lipoprotein (HDL) goal, only 21 (26%) were at goals for both non-HDL and HDL, and only 18 (22%) were at goal for non-HDL, HDL, and triglycerides. When considering each of the risk factor strata, 19 of 43 (44%) low-risk patients were at non-HDL goal and 12 of these also had a small LDLPS. Only 8 of 18 (44%) intermediate-risk patients were at non-HDL goal and 7 of these (88%) had small LDLPS. Finally, only four high-risk patients were at non-HDL goal and three of these (75%) had small LDLPS. Knowing the LDLPS could alter subsequent therapeutic recommendations for most patients who have reached target lipid values.

Tobacco smoking, estrogen receptor α gene variation and small low density lipoprotein level

High levels of small low density lipoprotein (LDL) particles are a major risk factor for cardiovascular morbidity and mortality. Both estrogens and smoking, with known anti-estrogenic effects, alter the atherogenic lipid profile. We tested for a role of interaction between smoking and estrogen receptor alpha gene (ESR1) variation in association with plasma concentration of atherogenic small LDL particles and LDL particle size. We studied 1727 unrelated subjects, 854 women and 873 men, mean age 51 years (SD 10), from the population-based Framingham Heart Study. After covariate adjustment, women who smoked and had the common ESR1 c.454-397 TT genotype (in 30% of women, T was present on both chromosomes at position 397 prior to the start of exon 2) had >1.7-fold higher levels of small LDL particles than women with the alternative genotypes (P-value for smoking-genotype interaction was 0.001). Similar results were obtained for three other ESR1 variants including c.454-351A > G, in the same linkage disequilibrium block. A similar substantial gender-specific result was also evident with a fifth variant, in a separate linkage disequilibrium block, in exon 4 (P = 0.003). Women who smoked and had specific, common ESR1 genotypes had a substantially higher plasma concentration of atherogenic small LDL particles. Significant results revealed a dose-dependent effect of smoking and were evident in both pre- and postmenopausal women. The reported association has the potential to explain the risks associated with estrogen use in certain women and a recent report of association between an ESR1 haplotype comprised of c.454-397 T and c.454-351 A alleles with increased myocardial infarction and ischaemic heart disease, independent of the standard, established cardiovascular risk factors.

Oxidized LDL and small LDL particle size are independently predictive of a selective defect in microcirculatory endothelial function in type 2 diabetes

To explore the associations of LDL (low-density lipoprotein) particle size and oxidized LDL with endothelium-dependent function of the forearm microcirculation in diabetes. Endothelium-dependent function was examined in 43 middle-aged men and women with type 2 diabetes and 10 age-matched controls. All received aspirin to inhibit endothelial cyclo-oxygenase. Forearm blood flow (FBF) was measured using venous occlusion plethysmography with separate administration of acetylcholine (ACh) and bradykinin (BK) into the brachial artery. Endothelium-independent function was assessed using sodium nitroprusside (SNP). N(G)-monomethyl-L-arginine (L-NMMA) was co-infused with ACh (ACh + L-NMMA) and BK (BK + L-NMMA) to assess non-NO-mediated contributions to endothelium-dependent function. Subjects with diabetes had impaired endothelium-dependent and endothelium-independent function compared with controls (p < 0.01 for ACh, BK and SNP). In multivariate regression analysis, LDL size (r = 0.41 and p = 0.007), oxidized LDL (r = -0.41 and p = 0.007) and duration of diabetes (r = -0.37 and p = 0.02) predicted FBF response to ACh independently of age, gender and systolic blood pressure. There were no associations between LDL size, oxidized LDL, duration of diabetes and FBF response to BK, SNP, ACh + L-NMMA or BK + L-NMMA. In type 2 diabetes, small dense LDL particles, duration of diabetes and oxidized LDL may independently contribute to endothelial dysfunction of the microcirculation. These disturbances may occur via a selective defect, because ACh and BK activate endothelial NO synthase via different G-protein signal transduction pathways.

Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes

The atherogenic lipoprotein phenotype is characterized by an increase in plasma triglycerides, a decrease in high-density lipoprotein (HDL), and the prevalence of small, dense low-density lipoprotein (LDL) particles. The present study investigated the clinical significance of LDL size and subclasses as markers of atherosclerosis in diabetes type 2. Thirty-eight patients with type 2 diabetes, total cholesterol of less than 6.5 mmol/L, and hemoglobin A 1c (HbA1c) of less than 9% were studied. Median age was 61 years, mean (±SD) body mass index 29 ± 4.3 kg/m 2, and mean HbA1c 7.1 ± 0.9 %. Laboratory parameters included plasma lipids and lipoproteins, lipoprotein (a), apolipoprotein (apo) A-I, apo B-100, apo C-III, and high-sensitivity C-reactive protein. Low-density lipoprotein size and subclasses were measured by gradient gel electrophoresis and carotideal intima media thickness (IMT) by duplex ultrasound. By factor analysis, 10 out of 21 risk parameters were selected: age, body mass index, systolic blood pressure, smoking (in pack-years), HbA1c, high-sensitivity C-reactive protein, lipoprotein (a), LDL cholesterol, HDL cholesterol, and LDL particle size. Multivariate analysis of variance of these 10 risk parameters identified LDL particle size as the best risk predictor for the presence of coronary heart disease ( P = .002). Smaller LDL particle size was associated with an increase in IMT ( P = .03; cut-off >1 mm). Within the different lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apo B, apo A-I, apo C-III, LDL particle size), LDL particle size was most strongly associated with the presence of coronary heart disease ( P = .002) and IMT ( P = .03). It is concluded that LDL size is the strongest marker for clinically apparent as well as non-apparent atherosclerosis in diabetes type 2.

Low-density lipoprotein particle number and risk for cardiovascular disease.

The key role played by low-density lipoprotein (LDL) particles in the pathogenesis of coronary heart disease (CHD) is well accepted, as is the benefit of lowering LDL in high-risk patients. What remains controversial is whether we are using the best measure(s) of LDL to identify all individuals who would benefit from therapy. Many studies have shown that, at a given level of LDL cholesterol, individuals with predominantly small LDL particles (pattern B) experience greater CHD risk than those with larger-size LDL. However, it is not clear from this observation that small LDL particles are inherently more atherogenic than large ones because, at a given level of LDL cholesterol, individuals with small LDL have more LDL particles in total. The phenotype of small LDL particle size co-segregates with a cluster of metabolic factors, including elevated triglycerides and reduced HDL cholesterol, and in multivariate analyses has generally been found not to be independently associated with CHD risk. In contrast, LDL particle number measured by nuclear magnetic resonance has consistently been shown to be a strong, independent predictor of CHD.