Remarkably high prevalence of small dense low-density lipoprotein in Japanese men with coronary artery disease, irrespective of the presence of diabetes.

To examine how prevalence of the small dense LDL phenotype (LDL particle diameter < or =25.5 nm) is associated with coronary artery disease (CAD) in type 2 diabetic and non-diabetic Japanese men, an ethnic group with a low incidence of CAD, 85 non-diabetic men and 45 type 2 diabetic men with angiographically documented CAD, and 142 control men and 76 type 2 diabetic men without CAD were studied. Mean LDL particle diameter was determined using 2-16% polyacrylamide gel electrophoresis. LDL particle diameters in CAD patients were much smaller than those in controls (25.2+/-0.7 vs. 26.0+/-0.4 nm, mean+/-S.D., P<0.0001). LDL size was smaller in diabetic subjects (25.6+/-0.6 nm) and became even smaller in diabetics with CAD (25.0+/-1.0 nm). Prevalence of small dense LDL was markedly higher in both non-diabetic and diabetic CAD patients than that in non-diabetic and diabetic patients without CAD (71, 76, 23 and 42%, respectively). CAD patients had lower HDL-cholesterol and apo A1 levels, and higher triglyceride levels than those in diabetic and non-diabetic CAD-free patients, while total- and LDL-cholesterol levels were even lower in CAD group, and remnant-like particle-cholesterol, lipoprotein (a) and insulin levels were comparable among four groups. LDL size was significantly associated with triglyceride, HDL-cholesterol and glycemic control. Logistic regression analysis revealed that the small dense LDL phenotype was significantly associated with the incidence of CAD independent of low levels of HDL-cholesterol or high levels of triglyceride in both non-diabetic and diabetic cases. These results suggest that high prevalence of small dense LDL is a leading cause of CAD in both diabetic and non-diabetic Japanese men. Type 2 diabetes shows a greater capacity to reduce LDL size, which may contribute to the high incidence of CAD in the diabetic population.     

Lipid compositional differences of small,dense low-density lipoprotein particle influence its oxidative susceptibility: possible implication of increased risk of coronary artery disease in subjects with phenotype B

An increased susceptibility of low-density lipoprotein (LDL) to lipid peroxidative modification may be a key factor in the higher risk of coronary artery disease (CAD) among subjects with phenotype B. Compositional differences in the LDL particle may also be implicated in its atherogenicity and, in particular, may be associated with varying degrees of oxidative susceptibility of LDL, although this remains unclear. We hypothesized that the oxidative susceptibility of small, dense LDL was directly influenced by its lipid composition, which may lead to an increased risk of CAD in subjects with phenotype B. To test this hypothesis, we compared the differences in lipid compositions of LDL particles from subjects with phenotype A and those with phenotype B, and investigated the direct association of lipid composition with susceptibility to lipid peroxidative modification in 102 subjects who underwent a coronary angiographic examination. Subjects with phenotype B (n = 52) had a significantly higher incidence of CAD than subjects with phenotype A (77% v 44%; P <.005). In comparing the oxidative susceptibility of LDL, the lag time was significantly reduced in subjects with phenotype B compared to phenotype A (48.7 +/- 8.6 v 41.5 +/- 5.5 minutes; P <.0001). In addition, the lag time showed a positive correlation with LDL-peak particle diameter (PPD) (r = 0.324, P <.005). Lipid composition per LDL particle was expressed as the ratio of lipid content to apolipoprotein B (apoB) content (wt/wt). Subjects with phenotype B showed a significant depletion in the contents of free-cholesterol (FC), cholesterol ester (CE), and phospholipid (PL) per particle compared to subjects with phenotype A, although there was no significant difference in the triglyceride (TG) content per LDL particle. Except for TG, the lipid content per LDL particle showed a significant positive correlation with lag time in all subjects. Moreover, increased susceptibility of small, dense LDL to lipid peroxidative modification was most strongly associated with a depleted FC content per LDL particle. In conclusion, the greater risk of CAD in subjects with phenotype B may result, in part, from increased susceptibility to lipid peroxidative modification of LDL that is depleted in lipid contents, especially FC content per LDL particle.     

Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.

The prevalence of abnormalities of lipoprotein cholesterol and apolipoproteins A-I and B and lipoprotein (a) [Lp(a)] was determined in 321 men (mean age 50 +/- 7 years) with angiographically documented coronary artery disease and compared with that in 901 control subjects from the Framingham Offspring Study (mean age 49 +/- 6 years) who were clinically free of coronary artery disease. After correction for sampling in hospital, beta-adrenergic medication use and effects of diet, patients had significantly higher cholesterol levels (224 +/- 53 vs. 214 +/- 36 mg/dl), triglycerides (189 +/- 95 vs. 141 +/- 104 mg/dl), low density lipoprotein (LDL) cholesterol (156 +/- 51 vs. 138 +/- 33 mg/dl), apolipoprotein B (131 +/- 37 vs. 108 +/- 33 mg/dl) and Lp(a) levels (19.9 +/- 19 vs. 14.9 +/- 17.5 mg/dl). They also had significantly lower high density lipoprotein (HDL) cholesterol (36 +/- 11 vs. 45 +/- 12 mg/dl) and apolipoprotein A-I levels (114 +/- 26 vs. 136 +/- 32 mg/dl) (all p less than 0.005). On the basis of Lipid Research Clinic 90th percentile values for triglycerides and LDL cholesterol and 10th percentile values for HDL cholesterol, the most frequent dyslipidemias were low HDL cholesterol alone (19.3% vs. 4.4%), elevated LDL cholesterol (12.1% vs. 9%), hypertriglyceridemia with low HDL cholesterol (9.7% vs. 4.2%), hypertriglyceridemia and elevated LDL cholesterol with low HDL cholesterol (3.4% vs. 0.2%) and Lp(a) excess (15.8% vs. 10%) in patients versus control subjects, respectively (p less than 0.05). Stepwise discriminant analysis indicates that smoking, hypertension, decreased apolipoprotein A-I, increased apolipoprotein B, increased Lp(a) and diabetes are all significant (p less than 0.05) factors in descending order of importance in distinguishing patients with coronary artery disease from normal control subjects. Not applying a correction for beta-adrenergic blocking agents, sampling bias and diet effects leads to a serious underestimation of the prevalence of LDL abnormalities and an overestimation of HDL abnormalities in patients with coronary artery disease. However, 35% of patients had a total cholesterol level less than 200 mg/dl after correction; of those patients, 73% had an HDL cholesterol level less than 35 mg/dl.     

Low-density lipoprotein particle size and coronary artery disease in a childhood-onset type 1 diabetes population

Low-density lipoprotein (LDL) cholesterol has been widely recognized as a strong predictor of coronary artery disease (CAD). Recently, studies have examined the influence of LDL particle size (an integral part of the insulin resistance syndrome) on the development of CAD in the general population. This report examines the correlates of LDL particle size and its association with CAD in a type 1 diabetes population. We evaluated the interrelationships between LDL particle size and the presence of CAD in a cohort of childhood-onset type 1 diabetic subjects using the Pittsburgh Epidemiology of Diabetes Complications (EDC) study. LDL particle size was measured in 337 subjects (mean age, 35.6 years; mean diabetes duration, 27.2 years) who underwent the 8-year follow-up examination. LDL particle size was determined by vertical polyacrylamide gel (2% to 16%) electrophoresis. Subjects with the small dense LDL particle phenotype (<235.5 angstroms) [corrected] had a longer diabetes duration, higher cholesterol, triglyceride, LDL, fibrinogen, waist to hip ratio (WHR), and hemoglobin A1 (HbA1), and lower high-density lipoprotein (HDL) cholesterol compared with subjects with the large LDL particle phenotype (>257 angstroms) [corrected]. Males were also more likely to have an increased body mass index (BMI) and CAD, while females were more likely to have hypertension and a family history of type 2 diabetes (a potential marker of insulin resistance and CAD risk). The odds ratio ([OR] 95% confidence, interval [CI]) using logistic regression analysis for LDL particle size in association with CAD was 0.79 (0.60 to 1.04). Multivariate modeling indicated that the duration of type 1 diabetes, depressive symptomatology, and triglycerides were independently associated with the presence of CAD. We conclude that although small dense LDL particle size is associated with CAD in our type 1 diabetes population, its borderline association can largely be explained by the triglyceride concentration. However, as in the general population, LDL particle size is associated with many elements of the insulin resistance syndrome, including a family history of type 2 diabetes, and is likely an important element in the contribution of insulin resistance to the development of CAD in type 1 diabetes.     

Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study

Familial combined hyperlipidemia (FCH) is characterized by a variable expression of hypercholesterolemia and/or hypertriglyceridemia. We evaluated the variability in lipid phenotype expression over a 5-year period and studied factors affecting the lipid phenotype expression. A total of 32 families (299 subjects) were studied in 1994 and in 1999. Subjects were classified as having FCH when total cholesterol and/or triglyceride levels exceeded the 90th percentile adjusted for age and sex. In 1994, 93 (31%) of the 299 subjects were affected, whereas 206 (69%) of the subjects were unaffected relatives. In 1999, a diagnosis of FCH was consistent in 69 (74%) of the 93 subjects. So, 26% of the FCH subjects in 1994 showed a sporadic normolipidemic pattern (ie, total cholesterol and/or triglycerides <90th percentile) in 1999. Among the 206 unaffected relatives in 1994, 178 (86%) remained unaffected in 1999, and 28 (14%) developed an FCH lipid phenotype. Multiple regression analysis showed that sex (odds ratio 2.03, 95% CI 1.09 to 3.87; P=0.03) and body mass index (odds ratio 1.14, 95% CI 1.05 to 1.24; P<0.01) significantly contributed to the variability in lipid phenotype expression. Thus, a diagnosis of FCH, based on plasma total cholesterol and/or triglyceride levels, is consistent in only 74% of the subjects over a 5-year period. Two other major characteristics of our FCH group, compared with the unaffected relatives, included elevated apolipoprotein B (apoB) levels and the presence of small dense low density lipoprotein (LDL), as reflected by a low value of the parameter K (apoB 1461 +/- 305 versus 997 +/- 249 mg/L, respectively [P < 0.001]; K value -0.22 +/- 0.19 versus -0.02 +/- 0.19, respectively [P < 0.001]). We now report that the apoB concentration and the K value show less variability in time and are more consistently associated with FCH, inasmuch as affected FCH subjects, compared with the unaffected relatives, persistently show a higher apoB level and a lower value of parameter K, reflecting small dense LDL, even when they present a sporadic normolipidemic pattern. In conclusion, our results emphasize the need for reevaluation of the diagnostic criteria for FCH. We demonstrate that apoB and small dense LDL are attractive new candidates for defining FCH. Further studies are indicated to evaluate the role of apoB and small dense LDL as diagnostic criteria for FCH.     

Prevalence of lipoprotein (a) [Lp(a)] excess in coronary artery disease

Lipoprotein (a) [Lp(a)] is composed of 1 low-density lipoprotein (LDL) particle, to which 1 molecule of apolipoprotein (a) is covalently linked. Elevated levels of Lp(a) have been associated with coronary artery disease (CAD) and Lp(a) has been shown to be highly heritable. Our purpose was to determine the prevalence of familial Lp(a) excess in patients with CAD. We determined plasma levels of Lp(a) in 180 patients (150 men and 30 women) with angiographically documented CAD before age 60 years, and in 459 control subjects (276 men and 183 women) clinically free of cardiovascular disease. In addition, Lp(a) levels were determined in families of 102 of the CAD probands (87 men and 15 women). No gender differences in Lp(a) levels were observed between men and women (patients or control subjects). Patients with CAD had higher Lp(a) levels than did control subjects (19 +/- 21 vs 13 +/- 15 mg/dl, p less than 0.001). The prevalence of Lp(a) excess (defined as greater than 90th percentile of controls) was 17% in patients with CAD (p less than 0.05). Lp(a) levels were not correlated with cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol or apolipoproteins A-I or B. There was a weak correlation between Lp(a) and triglycerides (r = 0.166, p less than 0.05) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was a risk factor for the presence of CAD in men, independent of smoking, hypertension, diabetes, LDL and HDL cholesterol, or apolipoprotein A-I and B levels. Family studies revealed that Lp(a) levels are strongly genetically determined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased circulating malondialdehyde-modified LDL levels in patients with coronary artery diseases and their association with peak sizes of LDL particles

Recent establishment of a sensitive ELISA system using antibodies against malondialdehyde-modified low density lipoprotein (MDA-LDL) made it possible to determine the circulating oxidized lipoprotein levels. Here, we investigated the serum levels of MDA-LDL in 62 patients with coronary artery disease (CAD) compared with the levels in 42 patients without CAD [groups CAD(+) and CAD(-), respectively], which are adjusted for age, serum total cholesterol, LDL and high density lipoprotein cholesterol, and triglyceride levels. Serum MDA-LDL levels were 113.4+/-49.1 IU/L in CAD(+), which were significantly higher than the levels in CAD(-) (85.2+/-22.5 IU/L, P<0.0005). The ratio of MDA-LDL/LDL cholesterol was 0.95+/-0.32 in CAD(+), indicating a significant increase compared with the ratio in CAD(-) (0.68+/-0.19, P<0.0005). The positive correlation of MDA-LDL level and the ratio of MDA-LDL/LDL cholesterol with intima-media thickness in carotid arteries was observed. Age was not clearly associated with the MDA-LDL level (P=0.865). The serum MDA level was positively correlated with LDL cholesterol (P<0.0001) and with triglycerides (P<0.001) and negatively correlated with high density lipoprotein cholesterol (P<0.05). Furthermore, the MDA-LDL level was negatively correlated with the peak size of the LDL particle (P<0.01). The LDL subclasses that were identified by using the sera collected from the subjects by sequential ultracentrifugation showed that the ratios of MDA-LDL/apolipoprotein B in LDL3 and LDL4 were nearly 3-fold higher than those in LDL1 and LDL2 for CAD(+) and CAD(-). These results indicate that the circulating MDA-LDL level is increased in CAD(+), independent of the serum LDL cholesterol level but in association with the peak size of LDL particles. The measurement of serum MDA-LDL level may be useful for the identification of patients with advanced atherosclerosis.     

The small, dense LDL phenotype as a correlate of postprandial lipemia in men

The atherogenic dyslipidemia of the insulin resistance syndrome is characterized by hypertriglyceridemia (hyperTG), elevated apolipoprotein (apo) B levels, reduced high-density lipoprotein (HDL) cholesterol concentrations and by an increased proportion of small, dense low-density lipoprotein (LDL) particles. Although the hyperTG-low HDL cholesterol dyslipidemia has been associated with an impaired clearance of dietary fat, the contribution of the small, dense LDL phenotype as an independent predictor of postprandial triglyceride (TG) clearance remains uncertain. We have therefore compared the postprandial TG response among three subgroups of men characterized by small, intermediate or large LDL particles in a total sample of 69 men (mean age +/- SD; 45.1 +/- 10.5 years). To identify men with small versus large LDL particles, the first (LDL peak particle diameter < 251.9 A) and the third (> 257.6 A) tertiles of the distribution of LDL particle diameters were used as cutoff points. Men with small, dense LDL particles had the expected fasting dyslipidemic profile (high TG-low HDL cholesterol levels) compared to men with large, buoyant LDL particles. The oral lipid tolerance test revealed that men with small, dense LDL particles had significantly higher total-, large-, and medium-TG-rich lipoprotein (TRL) responses to a fatty meal than men with large LDL particles (P < 0.03). In addition, within a subgroup of normolipidemic men (TG < 2.3 mmol/l and HDL cholesterol > 0.9 mmol/l), those with small, dense LDL particles had higher levels of total-, medium- and small-TRL responses compared to men with large, buoyant LDL particles (P < 0.05). Moreover, normotriglyceridemic men with small, dense LDL had higher levels of small-TRLs measured 8 h after the ingestion of the fat meal (P < 0.05) compared to normolipidemic men with large, buoyant LDL particles. Results of the present study suggest that the dense LDL phenotype may be an additional fasting marker of an exaggerated postprandial TG response and of an impaired clearance of TRLs.     

Significance of small dense low-density lipoproteins and other risk factors in patients with various types of coronary heart disease

Background It remains unclear how closely the small dense low-density lipoprotein (LDL) (diameter ≤25.5nm) is associated with various types of coronary heart disease (CHD) in Japanese patients, an ethnic group with lower serum cholesterol levels and less massive obesity compared with Western populations. Methods and Results We measured mean LDL particle diameter by gradient gel electrophoresis in 571 patients with CHD and in 263 healthy subjects who served as control patients. Patients with CHD were classified into acute coronary syndrome (ACS), stable CHD and vasospastic angina. High-density lipoprotein cholesterol and apolipoprotein-A1 and -B were significantly different between patients with CHD and controls. LDL size in patients with CHD was markedly smaller than that in controls in both men and women (25.5 ± 0.7 vs 25.9 ± 0.4 and 25.7 ± 0.7 vs 26.0 ± 0.5 nm, respectively). LDL cholesterol was significantly higher in patients with ACS than in other groups. Plasma levels of high-density lipoprotein cholesterol decreased as the number of diseased vessels or angiographic coronary severity evaluated by Gensini score increased, but the LDL size was comparable irrespective of the type of CHD and the extent and severity of the lesions. Multiple logistic regression analysis revealed that small dense LDL was independently associated with the incidence of CHD in both sexes (odds ratio [OR] 3.5, 95% CI 2.1-5.7, and OR 2.9, 95% CI 1.5-5.6, P < .005). Conclusion Our study suggests that the small dense LDL is strongly associated with various types of CHD, independent of traditional and nontraditional coronary risk factors, but is not related to the severity and extent of the coronary lesions. (Am Heart J 2002;144:1026-35.)     

Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation

High resolution density gradient ultracentrifugation (DGUC) and non-denaturing gradient gel electrophoresis (GGE) indicate that low density lipoprotein (LDL) in both normal and hyperlipidaemic subjects is composed of overlapping particle populations. A new centrifugation procedure has been developed which permits the separation of LDL subspecies directly from plasma within 24 h. The profiles obtained were analogous to those seen on gradient gel electrophoresis. LDL was divided into 3 fractions. The plasma concentration of LDL-I seen in young females was twice that in men (85.6 +/- 28.8 vs. 42.3 +/- 25.7 mg/dl, P less than 0.005). LDL-II was not significantly different in any group while LDL-III was specifically elevated in coronary artery disease (CAD) patients (207.1 +/- 92.6 mg/dl in CAD vs. 87.4 +/- 79.6 mg/dl in normal men, P less than 0.05). The presence of small, dense LDL detected either by density gradient centrifugation or gel electrophoresis was associated with raised triglyceride (TG) and low high density lipoprotein (HDL) cholesterol and may be a risk marker for coronary artery disease.     

LDL size and risk of coronary heart disease in elderly men and women

A predominance of small, dense, low density lipoprotein (LDL) particles has consistently been associated with coronary heart disease (CHD) in young and middle-aged subjects in cross-sectional studies. Recently, 3 prospective, case-control studies showed that decreased LDL size is a predictor of CHD in middle-aged subjects. However, it is not known whether decreased LDL size is mainly associated with premature CHD or whether it continues to play a role in CHD risk at older ages also. We performed a prospective, nested case-control study in 86 subjects (58 nondiabetic and 28 type 2 diabetic) aged 65 to 74 years who were free of myocardial infarction at baseline and who then had a myocardial infarction or CHD death during a 3.5-year follow-up (cases) and in 172 controls matched for sex and diabetes status but who remained free of CHD during follow-up. LDL particle size determined by gradient gel electrophoresis (268.2+/-0.9 versus 268.5+/-0.7 A, P=0.782) and the proportion of subjects with LDL subclass phenotype B (20.9 versus 21. 5, P=0.914) were similar among cases and controls. Furthermore, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A(1), fasting glucose, fasting insulin, waist-to-hip ratio, and body mass index were not associated with CHD risk. However, smoking and increased systolic blood pressure, apolipoprotein B levels, and the total cholesterol-high density lipoprotein cholesterol ratio were significant predictors of CHD events both in univariate and multivariate analyses. Our findings indicate that LDL size is not a predictor of CHD events in elderly white subjects after controlling for diabetes status.     

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.     

Small dense low‐density lipoprotein cholesterol is a promising biomarker for secondary prevention in older men with stable coronary artery disease

Aim

The study objective was to investigate whether small dense low‐density lipoprotein cholesterol (sdLDL‐C) is superior to low‐density lipoprotein cholesterol (LDL‐C) and other biomarkers to predict future cardiovascular events (CE) in secondary prevention.

Methods

sdLDL‐C measured by a homogeneous assay, remnant lipoprotein cholesterol, LDL particle diameter and other biomarkers were compared in 345 men aged ≥65 years with stable coronary artery disease. Baseline LDL‐C was 100.5 ± 30.1 mg/dL. CE including cardiovascular death, onset of acute coronary syndrome, need for arterial revascularization, hospitalization for heart failure, surgery procedure for cardiovascular disease and hospitalization for stroke were monitored for 5 years.

Results

CE occurred in 96 patients during the study period. LDL‐C, sdLDL‐C non‐high‐density lipoprotein cholesterol, apolipoprotein B, remnant lipoprotein cholesterol, glucose, glycated hemoglobin and brain natriuretic peptide were significantly higher; LDL particle diameter and apolipoprotein A‐1 were significantly lower in patients with than in those without CE. Age‐adjusted Cox regression analysis showed that sdLDL‐C per 10 mg/dL, but not LDL‐C, was significantly associated with CE (HR 1.206, 95% CI 1.006–1.446). A significant association of sdLDL‐C and incident CE was observed in statin users (HR 1.252, 95% CI 1.017–1.540), diabetes patients (HR 1.219, 95% CI 1.018–1.460), patients without diabetes (HR 1.257, 95% CI 1.019–1.551) and patients with hypertriglyceridemia (HR 1. 376, 95% CI 1.070–1.770).

Conclusions

sdLDL‐C was the most effective predictor of residual risk of future CE in stable coronary artery disease patients using statins and in high‐risk coronary artery disease patients with diabetes or hypertriglyceridemia. Geriatr Gerontol Int 2018; 18: 965–972 .     

Cardiovascular risk factors and LDL subfraction profile in Type 2 diabetes mellitus subjects with good glycaemic control

Objectives: To compare cardiovascular risk factors and LDL particle size in well-controlled Type 2 diabetes mellitus and normal subjects. Methods: Ninety-three Type 2 diabetic males and 186 age-matched, male controls were studied. Glycaemic control was stable for at least 3 months prior to recruitment. None were on insulin or lipid lowering therapy. Anthropometric indices, blood pressure, lipids, glucose, insulin, apolipoprotein A1 and B, LDL subfraction by density ultracentrifugation were obtained after an overnight fast of 10 h. Results: Diabetic subjects (mean HbA(1c) 6.6%+/-0.10) did not differ from controls in total cholesterol levels (5.04+/-0.08 vs. 5.16+/-0.05 mmol/l, respectively) but had lower serum HDL cholesterol (0.98+/-0.03 vs. 1.12+/-0.02 mmol/l, P<0.001), higher serum triglyceride (2.38+/-0.16 vs. 1.80+/-0.08 mmol/l, P<0.001), lower LDL(1) and LDL(2) and higher LDL(3) concentration. An LDL(3) concentration exceeding 100 mg/dl was found in 59.1% of diabetics and 39.1% of non-diabetics (P<0.001). Diabetic subjects also had higher body mass index, waist to hip ratio and insulin resistance (HOMA). Difference in LDL subfraction between groups disappeared after adjustments were made for either triglyceride or HDL cholesterol. Conclusion: Well controlled Type 2 diabetes mellitus subjects exhibit an increased cardiovascular burden through low HDL cholesterol and predominance of small, dense LDL particles.     

The effect of PPARgamma-agonism on LDL subclass profile in patients with type 2 diabetes and coronary artery disease

Patients with type 2 diabetes (T2DM) often present a preponderance of small, dense LDL particles (small-LDL), which are associated with a high risk of myocardial infarction. Some studies suggest that PPARgamma-agonists increase LDL cholesterol but have divergent effects on various LDL subclasses in T2DM patients. We studied the effect of rosiglitazone on the LDL subclass profile in T2DM patients with verified coronary artery disease (CAD). 58 patients with T2DM (HbA1c < 8.5%) and CAD were enrolled in a 16-week, randomized, double-blind and placebo-controlled trial with rosiglitazone 8 mg/day (n = 29) or placebo (n = 29). The LDL subclass profile was measured with gel electrophoresis. Rosiglitazone improved insulin sensitivity and glycemic control. Total cholesterol did not change after rosiglitazone treatment (p = 0.062, ANCOVA adjusted for gender and baseline values), whereas LDL (including IDL) cholesterol increased from 2.33 +/- 0.48 to 2.67 +/- 0.61 mmol/l (p = 0.002 vs. baseline, p = 0.0497 vs. placebo) and large buoyant LDL (large-LDL < 250A) increased from 1.31 +/- 0.36 to 1.46 +/- 0.42 mmol/l (p = 0.010 vs. baseline, p = 0.044 vs. placebo) in the rosiglitazone group. No significant changes occurred to the concentration of small-LDL (< 250A), the average LDL particle size, or HDL or triglyceride concentrations. Whole-body insulin sensitivity was associated with the average LDL particle size after intervention in the whole population (r = 0.40, p = 0.002) and in the rosiglitazone group (r = 0.43, p = 0.020). In conclusion, in T2DM patients with CAD, rosiglitazone treatment significantly increases the concentration of large (buoyant) LDL cholesterol, but not of small dense LDL cholesterol. The long term consequences of this divergent effect of rosiglitazone on LDL subfractions require further exploration.     

High-density lipoprotein cholesterol in coronary artery disease patients: is it as low as expected?

OBJECTIVE: Epidemiological studies demonstrated that the high-density lipoprotein (HDL) cholesterol levels in Turkish people are lower compared to other populations. In the present study, the HDL cholesterol levels in subjects with or without angiographically documented coronary artery disease (CAD) were compared to assess whether HDL cholesterol levels were as low as expected. METHODS: A total of 420 consecutive patients with age of > or =40 years (160 female, 260 male) undergoing coronary angiography were included in the study. Patients receiving fibric acid derivatives or niacin were excluded. Coronary artery disease group consisted of those patients with any atherosclerotic lesions in coronary angiography, and non-CAD group consisted of patients with no such lesions. RESULTS: Average HDL cholesterol levels were 45.0+/-10.5 mg/dl (44.4+/-10.9 mg/dl in men, 46.5+/-9.6 mg/dl in women) in CAD group, and 47.7+/-9.0 mg/dl (45.5+/-8.4 mg/dl in men, 48.9+/-9.2 mg/dl in women) in non-CAD group (p<0.05). CONCLUSION: Compared to non-CAD patients, patients with CAD had lower HDL cholesterol levels, but in general HDL cholesterol levels were not as low as to be expected from epidemiological studies.     

A functional polymorphism in the promoter region of the microsomal triglyceride transfer protein (MTP -493G/T) influences lipoprotein phenotype in familial hypercholesterolemia

The microsomal triglyceride transfer protein (MTP) has a key function in intracellular apolipoprotein (apo) B lipidation and secretion of very low density lipoprotein (VLDL). A recently discovered functional polymorphism in the promoter of the MTP gene (-493G/T) affects the plasma concentration of low density lipoprotein (LDL) cholesterol and the VLDL distribution between large and small particle species in healthy men. This phenotype is likely to be explained by an effect on VLDL synthesis. Against this background, we studied the effect of the MTP-493G/T polymorphism in a large cohort (217 men and 211 women) with heterozygous familial hypercholesterolemia (FH). A 40% to 50% lower serum triglyceride level was observed in homozygous carriers of the MTP-493 T allele (T/T, 0.93+/-0.34; G/T, 1.54+/-1.40; and G/G, 1.56+/-1.24 mmol/L; T/T vs G/T P=0.04, T/T vs G/G P=0.02). In contrast to the situation in healthy subjects, the MTP promoter polymorphism did not have a significant effect on the LDL cholesterol levels in FH subjects, although the same trend was observed (T/T, 7.31+/-1.87; G/T, 7. 80+/-2.12; and G/G, 7.91+/-2.31 mmol/L, NS). Adjustment for the apo E gene polymorphism by inclusion of subjects homozygous for the apo E3 allele only revealed a reciprocal high density lipoprotein cholesterol-elevating effect (T/T, 1.41+/-0.73; G/T, 1.18+/-0.27; and G/G, 1.16+/-0.29 mmol/L; T/T vs G/T P=0.06, T/T vs G/G P=0.04). This effect seemed to be sex-specific because it was accounted for by the female patients. In conclusion, the LDL cholesterol-lowering effect of the rare MTP gene promoter variant (MTP-493T) present in healthy subjects is shifted to a triglyceride-lowering effect in FH. These data suggest that the MTP gene has a role in modulating the clinical phenotype of FH.     

Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects

BACKGROUND: The metabolic syndrome (MS) is often accompanied by atherogenic dyslipidemia, which is characterized by elevated triglycerides (TG), reduced high-density lipoprotein cholesterol (HDL-C), and elevated numbers of small, dense low-density lipoprotein (LDL) particles. HYPOTHESIS: It was hypothesized that a threshold exists for the circulating TG level needed to produce changes in LDL subclass distribution. METHODS: Hypertriglyceridemic (TG > or =300 and <1000 mg/dl) subjects with the MS were randomly assigned to placebo (n=50) or 130 mg/day of micronized fenofibrate-coated microgranules (n=96) for 8 weeks. RESULTS: In the overall analysis, fenofibrate treatment resulted in significant (p < 0.05) changes versus placebo in TG (-36.6%), non-HDL-C (-7.5%), very low-density lipoprotein-C (-32.7%), LDL-C (15.0%), HDL-C (14.0%), remnant lipoprotein-C (-35.1%), apolipoprotein B (-6.0%), apolipoprotein A-I (5.3%), and apolipoprotein C-III--29.7%). Changes in LDL particle diameter in the fenofibrate group were significantly inversely associated with the TG level achieved on treatment (p = 0.019). When individually matched for percent change in TG, subjects with on-treatment TG < 200 mg/dl, in contrast to those with on-treatment values > or =200 mg/dl, had significantly different median responses (p < 0.05) in LDL size (0.79 vs. -0.06 nm) and cholesterol carried by small (-35 vs. 21 mg/dl) and large (31 vs. 11 mg/dl) particles. CONCLUSION: These data support the view that a threshold exists below which the TG level must be lowered to produce shifts in LDL particle size.     

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 A1c (HbA1c) of less than 9% were studied. Median age was 61 years, mean (+/-SD) body mass index 29 +/- 4.3 kg/m2 , 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 diameter in normal pregnancy and preeclampsia

We investigated the changes of low-density lipoprotein (LDL) size and serum lipids during pregnancy and postpartum not only in normal pregnant women but also in preeclampsia. Serum triglyceride (TG) and total cholesterol levels as well as serum high-density lipoprotein (HDL)-cholesterol, apolipoprotein (Apo) A1, B, E and remnant-like particle (RLP)-cholesterol levels were increased in normal pregnant women. The LDL peak particle diameter (PPD) in normal pregnant women was decreased during pregnancy and that at 37 weeks of gestation showed significant decrease compared with the women at 4 weeks after delivery (25.8 +/- 1.0 vs.26.8 +/- 0.7 nm, p < 0.05). The LDL-PPD in the preeclamptic women at admission (mean gestational age: 36 +/- 2.4 weeks) was significantly lower than that in normal pregnancy at 37 weeks of gestation (24.7 +/- 1.2 vs. 25.8 +/- 1.0 nm, p < 0.05). Moreover, the LDL-PPD in the preeclamptic women was significantly higher after delivery compared with the level at admission (27. +/- 0.7 vs. 24.7 +/- 1.2 nm, p < 0.05) accompanied by an improvement in plasma lipids profile. These findings suggest that the predominance of small, dense LDL, a potential contributor to endothelial dysfunction, may be a possible predictor of preeclampsia.