New assay of apolipoproteins A-I and B by rate nephelometry evaluated

We evaluated new, commercially available reagents for assaying apolipoproteins (apo) A-I and B by rate nephelometry (INA). Our initial linearity studies for apoA-I indicated that use of the commercial diluent resulted in incomplete immunoreactivity. Subsequent revision of the calibration line by the manufacturer compensated for this and improved the linearity for the apoA-I assay. We observed good linearity for the apoB assay. The within-run CVs were less than 4.0% and the between-run CVs were less than 5.5% for both assays. Results were 109% for apoA-I and 101% for apoB as compared with those measured for IUIS-WHO reference materials from the Centers for Disease Control. Recovery averaged 103% for apoA-I and 105% for apoB, for duplicate assays of three concentrations of purified apoA-I and low-density lipoprotein (LDL). Assaying sera from 45 patients, we demonstrated a good correlation between INA and radial immunodiffusion for both apoA-I (r = 0.92) and apoB (r = 0.95). Correlations between apoA-I and high-density lipoprotein cholesterol, and between apoB and LDL cholesterol compared favorably with previous reports. We conclude that these assays are accurate, precise, and easily automated for clinical application.     

Lipoproteins and apolipoproteins in young nonobese Arab women with NIDDM treated with insulin

The effects of insulin on the lipid values of nonobese non-insulin-dependent diabetic (NIDDM) Arab women requiring insulin was investigated to find whether these patients have the same coronary artery risk factor related to lipid levels. In this study, 55 NIDDM women on insulin therapy (mean age 28 +/- 8.1 yr and duration of disease 5 +/- 1.2 yr) and 70 control subjects (matched for sex, age, and body mass index) were studied for their plasma levels of lipids, lipoproteins, and apolipoproteins. Concentrations of total cholesterol, very-low-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride (TG), LDL TG, high-density lipoprotein triglyceride (HDL TG), phospholipid, glucose, glycosylated hemoglobin (HbAtc), apolipoprotein B (apoB), LDL-apoB, and apoB/apoAl were significantly elevated in diabetic women compared with control subjects. There was no significant change in the levels of apoAll in plasma and lipoprotein fractions. Concentrations of HDL cholesterol (chol), HDL2-chol, HDL3-chol, plasma apoAl, HDL2-apoAl, HDL3-apoAl, and HDL-apoAl were significantly lower in diabetic women than in control subjects. There was no significant correlation between glucose or HbAtc and most of the lipids, lipoprotein lipids, and apolipoproteins measured. Despite normal body weight and insulin therapy, abnormalities in lipids, lipoprotein lipids, and apoB persisted in NIDDM patients compared with control subjects. Our data may favor an enhanced affinity toward atherosclerosis in these patients.     

Apolipoprotein E phenotypes, serum lipoproteins and apolipoproteins in angiographically assessed coronary heart disease

To determine the influence of the apolipoprotein E polymorphism on the occurrence of coronary artery disease (CAD) and on serum lipids, lipoproteins and apolipoproteins we studied 145 patients with angiographically defined CAD and compared them with 153 control subjects without history or complaints of vascular disease and with 35 subjects without significant stenosis on coronary arteriography. Subjects with hypertension, diabetes mellitus and endocrine or metabolic disorders were excluded. Covariance analysis and logistic regression analysis were performed with adjustment for age, sex, smoking habits and relative body weight. There were no significant differences for the apoE phenotypes on risk of cardiovascular disease. The CAD group had significantly higher mean values of serum cholesterol and triglycerides, very-low-density lipoprotein (VLDL)-cholesterol and VLDL-triglycerides, low-density lipoprotein (LDL)-cholesterol and apoprotein B; they had lower high-density lipoprotein (HDL)-cholesterol and apo A-I. The combination of LDL-cholesterol, apoA-I and VLDL-cholesterol was the best model in predicting cardiovascular disease. ApoE phenotype group E3/E2 had significantly lower values for serum cholesterol, LDL-cholesterol, and apoB and higher levels of apoE in comparison with the phenotype groups E3/E3 and E4/E3. The combination of LDL-cholesterol, cholesterol, apoE and VLDL-triglycerides was the best model in predicting the apoE phenotype. Thus, taking other risk factors into account, the apoE phenotype is not an independent risk factor for CAD; the apoE polymorphism influences lipoprotein levels and possibly, in that way, indirectly also the risk for CAD.     

5' ins/del and 3' VNTR polymorphisms in the apolipoprotein B gene in relation to lipids and coronary artery disease.

BACKGROUND: Studies that considered apolipoprotein B (APOB) gene polymorphisms as risk factors for coronary artery disease (CAD) have reported conflicting results. We sought to analyze the association between 5' ins/del and 3' VNTR polymorphisms of APOB, lipid parameters and CAD risk. METHODS: We recruited 251 patients with CAD, documented by coronary angiography, and 94 controls. Genotyping was performed by PCR. Lipids and apolipoproteins were measured. RESULTS: 5' ins/del (ins/ins, ins/del, del/del) and 3' VNTR (LL, SS, LS) polymorphism frequencies were significantly (p<0.05) different between controls and CAD patients. LL and del/del were significantly associated with higher levels of apolipoprotein B (apoB), total cholesterol/high-density lipoprotein cholesterol ratio and apoB/apoA-I ratio (p<0.05) and with increased risk of CAD. The odds ratio for significant coronary stenosis associated with del/del was 3.2 (95% CI 1.6-36.42) (p=0.032) and with LL was 2.2 (95% CI 1.1-5.1) (p=0.042). CONCLUSIONS: The two polymorphisms exert an impact on lipid levels and contribute to the susceptibility to the development of CAD.     

Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome

Objective: Dyslipidaemia is very common in patients with polycystic ovary syndrome (PCOS) but, beyond plasma lipids, atherogenic lipoprotein (Lp) and apolipoprotein (apo) alterations are still ill defined. Design: We measured concentrations of apoB, Lp(a) and small, dense low‐density lipoprotein (LDL) in 42 patients with PCOS [age: 28 ± 7 years, body mass index (BMI): 27 ± 5 kg/m²] vs. 37 age‐ and BMI‐matched healthy controls. Methods: Elevated Lp(a) levels considered were those > 30 mg/dl while elevated apoB concentrations were those > 100 g/l. Results: Polycystic ovary syndrome showed increased triglycerides levels (p = 0.0011) and lower high‐density lipoprotein (HDL)‐cholesterol concentrations (p = 0.0131) while total‐ and LDL cholesterol were similar. PCOS also showed smaller LDL size (p = 0.0005), higher levels of total small, dense LDL (p < 0.0001), higher concentrations of Lp(a), as considered as absolute values (p = 0.0143) and log‐transformed (p = 0.0014), while no differences were found in apoB levels. Elevated Lp(a) concentrations were found in 24% of PCOS, while elevated apoB levels were relatively uncommon (14%). Spearman correlation analysis revealed that Lp(a) concentrations were weakly correlated only with HDL‐cholesterol levels (r = ?0.378, p = 0.0431). In addition, 36% of patients with PCOS with normal plasma lipid profile showed elevated levels of Lp(a), apoB or small, dense LDL. Conclusions: Atherogenic Lp abnormalities may be found in one‐third of women with PCOS who have a normal lipid pattern. Future prospective studies are needed to test to which extent such atherogenic forms of dyslipidaemia may contribute to the increased cardiovascular risk in young women with PCOS.     

The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk.

BACKGROUND: The apolipoprotein B (apoB)/apoA-I ratio represents the balance of proatherogenic and antiatherogenic lipoproteins. The purpose of this study was to determine whether the apoB/apoA-I ratio was superior to any of the cholesterol ratios - total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C), low-density lipoprotein cholesterol (LDL-C)/HDL-C and non-HDL-C/HDL-C - in predicting the risk of coronary disease. Moreover, we examined whether any lipids, lipoproteins or cholesterol ratios add significant predictive information beyond that provided by the apoB/apoA-I ratio. METHODS: Plasma lipids, lipoproteins, apoB, and apoA-I were measured in 69,030 men and 57,168 women above 40 years of age. After a mean follow-up of 98 months, 1183 men and 560 women had died from a myocardial infarction in this prospective apolipoprotein-related mortality risk (AMORIS) study. RESULTS: High apoB and a high apoB/apoA-I ratio were strongly related to increased coronary risk, while high apoA-I was inversely related to risk. The apoB/apoA-I ratio was superior to any of the cholesterol ratios in predicting risk. This advantage was most pronounced in subjects with LDL-C levels <3.6 mmol/l. Addition of lipids, lipoproteins or any cholesterol ratio to apoB/apoA-I in risk models did not further improve the strong predictive value of apoB/apoA-I. CONCLUSIONS: These results indicate that the apoB/apoA-I ratio is at present the best single lipoprotein-related variable to quantitate coronary risk. Given the additional advantages apolipoproteins possess - fasting samples are not required, apoB/apoA-I is a better index of the adequacy of statin therapy than LDL-C, and the measurement of apoB and apoA-I are standardized, whereas LDL-C and HDL-C are not - there would appear to be considerable advantage to integrating apolipoproteins into clinical practice.     

ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice

The discovery of the ABCA1 lipid transporter has generated interest in modulating human plasma HDL levels and atherogenic risk by enhancing ABCA1 gene expression. To determine if increased ABCA1 expression modulates HDL metabolism in vivo, we generated transgenic mice that overexpress human ABCA1 (hABCA1-Tg). Hepatic and macrophage expression of hABCA1 enhanced macrophage cholesterol efflux to apoA-I; increased plasma cholesterol, cholesteryl esters (CEs), free cholesterol, phospholipids, HDL cholesterol, and apoA-I and apoB levels; and led to the accumulation of apoE-rich HDL1. ABCA1 transgene expression delayed 125I-apoA-I catabolism in both liver and kidney, leading to increased plasma apoA-I levels, but had no effect on apoB secretion after infusion of Triton WR1339. Although the plasma clearance of HDL-CE was not significantly altered in hABCA1-Tg mice, the net hepatic delivery of exogenous 3H-CEt-HDL, which is dependent on the HDL pool size, was increased 1.5-fold. In addition, the cholesterol and phospholipid concentrations in hABCA1-Tg bile were increased 1.8-fold. These studies show that steady-state overexpression of ABCA1 in vivo (a) raises plasma apoB levels without altering apoB secretion and (b) raises plasma HDL-C and apoA-I levels, facilitating hepatic reverse cholesterol transport and biliary cholesterol excretion. Similar metabolic changes may modify atherogenic risk in humans.     

Hypertriglyceridemic hyperapoB in type 2 diabetes

OBJECTIVES: Much less attention has been paid to LDL in type 2 diabetes than to VLDL or HDL. In particular, there are few data on apoB levels in these patients. Moreover, most reports have focused on mean lipoprotein levels and consequently there is little information on the frequencies of the various dyslipidemic phenotypes. RESEARCH DESIGN AND METHODS: Plasma and lipoprotein lipids, apoB and apoA1 were measured by standardized methods. LDL particle size was determined by PAGE. The total cohort was divided into phenotypes by two different methods. The first was based on triglycerides (> or = or <1.5 mmol/l) and LDL cholesterol (> or = or <4 mmol/l), whereas the second was based on triglycerides (> or = or <1.5 mmol/l) and apoB (> or = or <120 mg/dl). RESULTS: For the overall cohort, plasma triglycerides were elevated (2.13 +/- 1.6 mmol/l), total and LDL cholesterol were normal (5.34 +/- 1.1 and 3.28 +/- 0.88 mmol/l, respectively), and peak LDL size was reduced (252.9 +/- 5.8 A). HDL cholesterol was between the 25th and 50th percentiles of the general population (1.12 +/- 0.36 mmol/l). The average level of apoB was 114 +/- 29 mg/dl, a value that is between the 50th and 75th percentiles of the general population and is higher than that for LDL cholesterol, which was between the 25th and the 50th percentiles of the population. The results of the phenotyping analysis were as follows. Using the conventional approach, only 23% has abnormal LDL, i.e., an elevated LDL cholesterol level. Using the new approach, almost 40% has an elevated apoB and therefore an elevated LDL particle number. Only 12.8% has combined hyperlipidemia based on the conventional approach, whereas almost one-third had the equivalent, hypertriglyceridemic hyperapoB-based on the new algorithm. The severity of the dyslipoproteinemia in this group was noteworthy. Although the average LDL cholesterol was 3.91 mmol/l, a value just below the 75th percentile of the general population, the average apoB was 145 mg/dl, a value that approximates the 95th percentile of the population. CONCLUSIONS: The dyslipidemic profile of patients with type 2 diabetes is not uniform. A substantial group have normal lipids and normal LDL particle number and size whereas others have markedly abnormal profiles. Diagnosis based on triglycerides and apoB rather than triglycerides and LDL cholesterol revealed that more than one in five had hypertriglyceridemic hyperapoB, which is characterized by hypertriglyceridemia, marked elevation of LDL particle number, small dense LDL, and low HDL, a constellation of abnormalities that is associated with markedly accelerated atherogenesis and therefore justifies intensive medical therapy.     

Microsomal triglyceride transfer protein polymorphisms and lipoprotein levels in type 2 diabetes

BACKGROUND: Microsomal triglyceride transfer protein (MTP) regulates the assembly of chylomicrons in the intestine and very-low-density lipoprotein (VLDL) in the liver. Common polymorphisms have been described that do not affect lipoproteins in non-diabetic subjects. Their effect in diabetes has not been described in a Caucasian population. AIM: To investigate the association of these three common polymorphisms with lipoproteins in type 2 diabetes. METHODS: Eighty-two patients consumed a high-fat test meal. Chylomicron and VLDL apoB48, apoB100, cholesterol, triglycerides and phospholipids were measured fasting, and at 4 and 6 h postprandially. MTP genotyping was performed by PCR-RFLP. RESULTS: Thirty-three subjects were heterozygous for the -493 G/T substitution. These patients had significantly lower LDL cholesterol (3.0 +/- 0.2 vs. 3.5 +/- 0.1 mmol/l, p < 0.02). In the postprandial period, they had higher levels of apoB48 in the VLDL fraction (4 h, 7.0 +/- 1.4 vs. 2.9 +/- 0.4 microg/ml plasma, p < 0.002; 6 h, 6.4 +/- 1.0 vs. 3.5 +/- 0.5 microg/ml plasma, p < 0.05). In the VLDL fraction there was significantly less cholesterol at 4 and 6 h (p < 0.05). The -400 A/T substitution gave very similar lipoprotein results, but there was significant linkage dysequilibrium between the two polymorphisms. No association was found between the -164 T/C polymorphism and either plasma lipids or the postprandial lipid profile. ApoE genotype was also examined, but did not influence the above results. DISCUSSION: The common -493 G/T MTP polymorphism is associated with changes in VLDL and LDL in Type 2 diabetic patients. The importance of the changes in apoB48-containing small particles requires further investigation. The significantly lower LDL cholesterol suggests that this polymorphism may confer protection against atherosclerosis in type 2 diabetes.     

Apolipoproteins and coronary artery disease

In this study, we compared the relative utility of plasma levels of cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoproteins in identifying men with angiographically significant coronary artery disease in a combined sample of consecutive male patients undergoing coronary angiography (N = 304) and healthy, normal male control subjects (N = 135). The plasma apolipoprotein levels were measured by using specific radioimmunoassays. We found that plasma levels of apolipoprotein A-I, followed by those of apolipoproteins A-II and B, were better discriminators than plasma cholesterol, triglycerides, or HDL cholesterol levels for identifying those with coronary artery disease. In confirmation of previous findings, the presence of coronary artery disease resulted in lower levels of apolipoproteins A-I and A-II and HDL cholesterol and higher levels of apolipoprotein B, cholesterol, and triglycerides. Linear and quadratic discriminant function analysis demonstrated that by using the age of the patients and apolipoprotein A-I, A-II, and B levels, one could correctly classify patients either as being normal or as having angiographically significant coronary artery disease in more than 75% of the cases. Thus, plasma apolipoprotein levels (especially A-I and A-II) may be considerably better markers for coronary artery disease than traditional lipid determinations.     

Differential influence of LDL cholesterol and triglycerides on lipoprotein(a) concentrations in diabetic patients

OBJECTIVE: To evaluate the relationship between plasma lipid profiles and lipoprotein(a) [Lp(a)] concentrations in diabetic patients, taking into account the Lp(a) phenotype. RESEARCH DESIGN AND METHODS: We included 191 consecutive diabetic outpatients (69 type 1 and 122 type 2 diabetic patients) in a cross-sectional study Serum Lp(a) was determined by enzyme-linked immunosorbent assay, and Lp(a) phenotypes were assessed by SDS-PAGE followed by immunoblotting. The statistical methods included a stepwise multiple regression analysis using the Lp(a) serum concentration as the dependent variable. The lipid profile consisted of total cholesterol, HDL cholesterol, LDL cholesterol, corrected LDL cholesterol, triglycerides, and apolipoproteins AI and B. RESULTS: In the multiple regression analysis, LDL cholesterol (positively) and triglycerides (negatively) were independently related to the Lp(a) concentration, and they explained the 6.6 and 7.8% of the Lp(a) variation, respectively. After correcting LDL cholesterol, the two variables explained 3.8 and 6.4% of the Lp(a) variation, respectively. In addition, we observed that serum Lp(a) concentrations were significantly lower in patients with type IV hyperlipidemia (mean 1.0 mg/dl [range 0.5-17], n = 16) than in normolipidemic patients (6.5 mg/dl [0.5-33.5], n = 117) and in type II hyperlipidemic patients (IIa 15.5 mg/dl [3.5-75], n = 13; IIb 9 mg/dl [1-80], n = 45); P < 0.001 by analysis of variance. CONCLUSIONS: Lp(a) concentrations were directly correlated with LDL cholesterol and negatively correlated with triglyceride levels in diabetic patients. Therefore, our results suggest that the treatment of diabetic dyslipemia may indirectly affect Lp(a) concentrations.     

Change in very low-, low-, and high-density lipoproteins during lipid lowering (bezafibrate) therapy: studies in type IIA and type IIb hyperlipoproteinaemia

The effects of lipid lowering therapy (bezafibrate) on plasma lipoproteins was investigated in twelve patients with familial hypercholesterolaemia (type IIA) and eight with familial combined hyperlipidaemia (type IIB). Bezafibrate caused a decrease of plasma cholesterol, plasma triglycerides, plasma apolipoprotein B, VLDL cholesterol and LDL cholesterol and an increase of HDL cholesterol. Post-heparin plasma lipoprotein and hepatic lipase activities increased in both groups (significant only in type IIB). Lipoprotein composition showed the following changes: Increased protein and phospholipids and decreased triglycerides and cholesteryl esters in VLDL. Decreased protein and triglycerides and increased free and esterified cholesterol in LDL. Decreased triglycerides and increased phospholipids in HDL. Cholesteryl ester to protein ratios decreased in VLDL and increased in LDL. The hydrated density of LDL (both groups) and of HDL3 (type IIB) decreased following bezafibrate therapy. These changes were in general similar to those observed in hypertriglyceridaemic patients and could be ascribed, at least in part, to the increase of plasma lipase activities and the decrease of lipid transfer reactions. Comparing the present data with that previously reported, it was found that bezafibrate caused decreased LDL cholesterol in types IIA and IIB but increased levels in type IV. This change was correlated with the initial plasma triglycerides (r = 0.74, P less than 0.0001) and initial plasma LDL cholesterol (r = 0.66, P less than 0.001). It is concluded that varied response of LDL to therapy reflects a complex interaction of metabolic events, including changing rates of VLDL conversion to LDL, lipoprotein compositional changes and effects of therapy on LDL degradation rates.     

Lipid and apolipoprotein levels in patients with nephrotic syndrome

Plasma lipids and 6 plasma apolipoproteins (apoA-I, apoA-II, apoB, apoC-I, apoC-II and apoC-III) were studied in 23 patients with nephrotic syndrome. The elevated total cholesterol, triglyceride and apoB levels in nephrotic patients decreased gradually, after the disappearance of proteinuria. During the acute stage high density lipoprotein cholesterol, as well as the sum of apoA-I and apoA-II were similar in the patients and the controls. ApoA-I and apoA-II were transiently elevated during the recovery stage. All three apoC proteins (apoC-I, apoC-II and apoC-III) were elevated during the acute stage. A significant decrease in apoC-I, apoC-II and apoC-III was observed during the first 3 weeks after normalization of the urine protein. The ratio of apoC-II/apoC-III was reduced during the first 4 weeks after normalization of urine protein and then returned to the control level. The results suggest that as far as total levels are concerned, changes of apoC-II, apoC-III and the ratio of apoC-II/apoC-III appear to have no effect on the development of hyperlipidemia in th nephrotic syndrome.     

High-density lipoprotein apolipoprotein A-I kinetics: comparison of radioactive and stable isotope studies

To compare the kinetic determinants of high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I) concentration in lean normolipidaemic subjects using radioisotope and stable isotope studies. We pooled data from 16 radioisotope and 13 stable isotope studies to investigate the kinetics of apoA-I in lean normolipidemic individuals. We also examined the associations of HDL kinetic parameters with age, sex, body mass index (BMI) and concentrations of apoA-I, triglycerides, HDL cholesterol and low-density lipoprotein (LDL) cholesterol. Lean subjects from radioisotope and stable isotope studies were matched for age, gender, BMI and lipid profile. The apoA-I concentration was significantly lower in the radioisotope group than the stable isotope group (P = 0.031). There was no significant difference in HDL apoA-I fractional catabolic rate (FCR) and production rate (PR) between the groups. In the radioisotope group, HDL apoA-I FCR was significantly associated with apoA-I and HDL cholesterol concentrations (r = -0.681, P < 0.001 and r = -0.542, P < 0.001, respectively), whereas in the stable isotope group, only HDL apoA-I PR was significantly associated with apoA-I concentration (r = 0.455, P = 0.004). Our findings suggest that HDL apoA-I FCR is the primary determinant of apoA-I concentrations in lean subjects in studies using radiotracer techniques. By contrast, HDL apoA-I PR is the primary determinant of apoA-I concentration in lean subject in studies employing stable isotope methods. These discrepancies may be reconciled by differences in methodologies and/or study population characteristics.     

Effect of atorvastatin on apolipoprotein B100 containing lipoprotein metabolism in type-2 diabetes

Seven hypertriglyceridemic patients with type-2 diabetes were treated with atorvastatin (40 mg/day) for 2 months. Kinetics of apolipoprotein B100 (apoB100)-containing lipoproteins were determined before and after atorvastatin treatment and compared with data obtained in five normolipidemic volunteers. ApoB100 metabolism was studied using stable isotopes and multicompartmental modeling. Compared with normolipidemic obese subjects, type-2 diabetic patients had a higher apoB100 concentration in very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and low-density lipoproteins (LDL) (P < 0.005). Kinetic analysis showed an increase in the total apoB100 production rate (P < 0.005) related to VLDL apoB100 overproduction (P < 0.005). Patients were also characterized by a lower fractional catabolic rate (FCR) in VLDL (not significant) or IDL (P < 0.005) mainly related to a decrease in VLDL and IDL delipidation rate (P < 0.005). Catabolism of LDL was also lower in diabetic patients (P < 0.05). Atorvastatin treatment significantly decreased plasma triglycerides (P < 0.05), total and LDL cholesterol (P < 0.05), apoB100 in LDL, IDL, and VLDL (P < 0.05). Treatment significantly decreased total apoB100 production rate (P < 0.05), but only for VLDL (P < 0.05). Treatment normalized FCR in IDL and LDL (P < 0.05). We concluded that atorvastatin improved lipid abnormalities in type-2 diabetic patients not only by increasing the clearance of apoB100-containing lipoproteins but also by decreasing VLDL production.     

Ratio of triglycerides to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels

OBJECTIVE: In patients with type 2 diabetes, a normal HDL cholesterol level does not rule out that LDL particles may be small. Although techniques for analyzing LDL subfractions are not likely to be used in clinical practice, a prediction of LDL size based on a regular lipid profile may be useful for assessment of cardiovascular risk. RESEARCH DESIGN AND METHODS: Sixty patients with type 2 diabetes with acceptable glycemic control and an HDL cholesterol level > or = 1 mmol/l were recruited after cessation of lipid-altering treatments. LDL size was determined by 2-20% PAGE; patients having small LDL (n = 30) were compared with those having intermediate or large LDL (n = 30). RESULTS: Clinical characteristics, pharmacological therapies, lifestyle, and prevalence of diabetes-related complications were similar in both patient groups. LDL size correlated negatively with plasma triglycerides (TGs) (R2 = 0.52) and positively with HDL cholesterol (R2 = 0.14). However, an inverse correlation between the TG-to-HDL cholesterol molar ratio and LDL size was even stronger (R2 = 0.59). The ratio was > 1.33 in 90% of the patients with small LDL particles (95% CI 79.3-100) and 16.5% of those with larger LDL particles. A cutoff point of 1.33 for the TG-to-HDL cholesterol ratio distinguishes between patients having small LDL values better than TG cutoff of 1.70 and 1.45 mmol/l. CONCLUSIONS: The TG-to-HDL cholesterol ratio may be related to the processes involved in LDL size pathophysiology and relevant with regard to the risk of clinical vascular disease. It may be suitable for the selection of patients needing an earlier and aggressive treatment of lipid abnormalities.     

Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications

Abstract. We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day^-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% ( P = 0.002), triglycerides by 27% ( P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% ( P = 0.002); high-density lipoprotein cholesterol increased by 17% ( P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of l-[¹³C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a mono-exponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day^-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007mgkg^-1day^-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0)mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration ( P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol. This effect does not appear to be directly related to the inhibition of cholesterol synthesis and may be due to decreased hepatic delivery of cholesterol esters via the LDL receptor-independent pathway, but these mechanisms require further investigation.     

Genetic risk factors and ischaemic cerebrovascular disease: role of common variation of the genes encoding apolipoproteins and angiotensin-converting enzyme

DNA polymorphisms in genes encoding apolipoproteins (apo) A-I, C-III, B and E and angiotensin-converting enzyme (ACE) have been proposed to be associated with the risk of coronary artery disease (CAD). We studied whether the same genetic markers would also be associated with the occurrence and extent of atherosclerosis in cervical arteries. DNA samples from 234 survivors of stroke or a transient ischaemic attack aged 60 years or less were examined. The presence of atherosclerosis was assessed using aortic arch angiograms. The SstI polymorphism of apoA-I/C-III gene locus, the Xbal polymorphism of apoB gene, common apoE phenotypes and the insertion/deletion polymorphism of the ACE gene were analysed. The allele frequencies of the apoA-I/C-III, apoB, apoE or ACE gene did not differ between the groups with (n = 148) or without (n = 85) cervical atherosclerosis. However, when patients with at least one apoE4 allele and one X2 allele of apoB were combined and compared with those without either of them (E2E3 or E3E3 and X1X1), a significant association with the presence of cervical atherosclerosis was found (P = 0.03). The patients having the E2E3 phenotype had a significantly elevated serum triglyceride level compared with those with the E3E3 phenotype (P = 0.03). Serum high-density lipoprotein (HDL) cholesterol was lower in the patients with the E2E3 phenotype than in those with the E3E3 and E3E4 (P = 0.01 and P = 0.06, respectively). The apoB or ACE genotypes were not significantly associated with serum lipid or lipoprotein levels. There was no association between the ACE gene polymorphism and the occurrence of hypertension. In conclusion, the interaction of common apoB and apoE alleles may increase the risk of atherosclerosis in cervical arteries.     

糖耐量受损的冠心病患者血浆同型半胱氨酸和血脂水平的变化

目的探讨糖耐量受损的冠心病患者血浆总同型半胱氨酸（tHcy）和血脂水平的变化。方法采用高效液相层析技术测定45例糖耐量受损的冠心病患者（糖耐量受损组）和51例糖耐量正常的冠心病患者（糖耐量正常组）血浆tHcy水平,同时测定常规血脂。结果糖耐量受损组血浆tHcy、总胆固醇（TC）、载脂蛋白B（apo B）、低密度脂蛋白胆固醇（LDL-C）、水平高于糖耐量正常组（P〈0.05、P〈0.01）;而三酰甘油（TG）、载脂蛋白A-I（apo A-I）、高密度脂蛋白胆固醇（HDL-C）2组差异无统计学意义（P〉0.05）。tHcy水平和患者年龄、apo A-I相关（P〈0.05）,而与其他血脂指标不相关（P〉0.05）。结论血浆tHcy水平的增高与糖耐量受损和冠心病的发生密切相关。     

Effect of moxonidine on lipid subfractions in patients with hypertension

Moxonidine is centrally acting imidazoline type-1 receptor agonist that significantly lowers blood pressure and has some insulin-sensitising actions. Its effects on plasma lipid profiles are uncertain. This study examined the effects of moxonidine on detailed lipid and lipoprotein profiles in 12 patients with hypertension and type 2b Fredricksen hyperlipidaemia. Treatment with moxonidine in six patients who completed the study resulted in a 10/5 mmHg reduction in 24-h ambulatory blood pressure (p = 0.01). A significant reduction in total and low-density-lipoprotein cholesterol (LDL-C) of 10% (p = 0.04) and 18% (p = 0.03), respectively, was seen. Triglycerides were reduced non-significantly by 23%, and high-density-lipoprotein cholesterol (HDL-C) was increased by 16%. There were no significant changes in apolipoprotein (apo) A-1 and B concentrations. No significant shifts were seen in HDL-C, LDL-C, very-low-density-lipoprotein cholesterol (VLDL-C) or apolipoprotein peak positions with therapy. Analysis of area under curve for each subfraction showed that moxonidine therapy resulted in a redistribution within the apoB profile. A slight non-significant reduction in VLDL apoB was seen. There was a reduction in the dense LDL apoB peak (p = 0.02) but less in the buoyant LDL apoB peak (p = 0.17) with a countervailing increase in LDL-C in the buoyant fraction (p = 0.01). The HDL-C and apoA-1 profile showed a shift from dense HDL apoA-1 (p = 0.01) to a buoyant HDL apoA-1sub-species (p = 0.01). These changes are consistent with a tendency for moxonidine to improve atherogenic lipid and lipoprotein profiles by actions on insulin-sensitisation and possibly through a direct cholesterol-reducing effect as seen with other imidazoles.