Search

Apolipoprotein C-II (apoC-II) is a small exchangeable apolipoprotein found on triglyceride-rich lipoproteins (TRL), such as chylomicrons (CM) and very low-density lipoproteins (VLDL), and on high-density lipoproteins (HDL), particularly during fasting. ApoC-II plays a critical role in TRL metabolism by acting as a cofactor of lipoprotein lipase (LPL), the main enzyme that hydrolyses plasma triglycerides (TG) on TRL. Here, we present an overview of the role of apoC-II in TG metabolism, emphasizing recent novel findings regarding its transcriptional regulation and biochemistry. We also review the 24 genetic mutations in the APOC2 gene reported to date that cause hypertriglyceridemia (HTG). Finally, we describe the clinical presentation of apoC-II deficiency and assess the current therapeutic approaches, as well as potential novel emerging therapies. [ABSTRACT FROM AUTHOR]

Aims Non-HDL cholesterol represents the pro-atherogenic, apo-B-containing lipoprotein fraction of circulating lipids, and represents a secondary target for CVD prevention in people with diabetes. We therefore assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of <2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL). Methods and results Of 2674 diabetic subjects with baseline CVD in the Hungarian MULTI-GAP programme (mean age 64.8 years, mean HbA1c 7.2%), an LDL-C goal <1.8 and non-HDL-C goal <2.6 mmol/L was attained in 13.5% and 17.7% individuals, respectively. Non-HDL-C goal attainment declined at higher triglyceride concentrations; and graphically this relationship appeared to be continuously and inversely associated with triglyceride concentrations. In contrast, the relationship between LDL-C goal attainment was inversely and continuously associated with triglyceride levels up to about 2.5 mmol/L, after which the graphical appearance plateaued such that no further difference in LDL-C were observed beyond triglyceride levels of 2.5 mmol/L. With increasing triglyceride concentrations, non-HDL-C increased continuously, HDL-C decreased initially but later plateaued (at 1.5-2.0 [men] or 2.0–2.5 mmol/L [women]), LDL-C levels plateaued at about 2.0–2.5 mmol/L, and TRL-cholesterol (non-HDL-C minus LDL-C) rose continuously. In multivariable-adjusted models, elevated triglyceride concentrations, non-specialist care and uncontrolled blood pressure were inversely associated with non-HDL-C goal attainment. Triglyceride levels were more strongly associated with non-HDL-C than with LDL-C goal attainment (ORs per 1-SD increase in log-triglycerides was 0.74, 95% CI 0.61–0.89, for LDL-C goal attainment, and 0.49, 95% CI 0.38–0.61, for non-HDL-C goal attainment). Conclusion Non-HDL-C goal attainment was suboptimal in people with diabetes and co-existing CVD. This was most marked at higher triglyceride levels, possibly due to higher levels of TRL. [ABSTRACT FROM AUTHOR]

Objective: Reductions on the clearance from plasma of chylomicrons are associated with atherosclerosis. Statins improve the removal from plasma of chylomicrons in a dose dependent manner. There is controversy whether ezetimibe modifies the plasma clearance of chylomicrons. Effects of ezetimibe alone or in combination with simvastatin were compared with low and high dose of the latter, upon the kinetics of a chylomicron-like emulsion in coronary heart disease (CHD) patients. Methods: 25 CHD patients were randomized for treatment with ezetimibe 10 mg (group 1) or simvastatin 20 mg (group 2) with progression to ezetimibe + simvastatin 10/20 mg or simvastatin 80 mg, respectively. Kinetic studies were performed at baseline and after each treatment period of 6 weeks. The fractional catabolic rates (FCR) of the emulsion labeled with 14C-CE and 3H-TG, that represent respectively chylomicron remnant and triglyceride removal, were calculated. Comparisons were made by ANOVA. Results: The 14CE-FCR in group 1 were 0.005 ± 0.004, 0.011 ± 0.008 and 0.018 ± 0.005 min−1 and in group 2 were 0.004 ± 0.003, 0.011 ± 0.008 and 0.019 ± 0.007 min−1 respectively at baseline, after 6 and 12 weeks (p < 0.05 vs. baseline, and 6 vs. 12 weeks). The 3H-TG-FCR in group 1 were 0.017 ± 0.011, 0.024 ± 0.011 and 0.042 ± 0.013 min−1 and in group 2 were 0.016 ± 0.009, 0.022 ± 0.009 and 0.037 ± 0.012 min−1 at baseline, after 6 and 12 weeks (p < 0.05 vs. baseline, and 6 vs. 12 weeks). There were no differences between groups in time. Conclusion: Both treatments increased similarly the removal from plasma of chylomicron and remnants in CHD patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs. Methods: Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and triglycerides in the very low-density lipoprotein 1 and 2 (VLDL1 and VLDL2) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and triglycerides in the chylomicron, VLDL1 and VLDL2 fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting. Results: Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL1 particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial triglycerides with less accumulation of apoB100 in the VLDL1 fraction and a faster transfer of apoB100 into the VLDL2 fraction. In contrast, fasting VLDL1 secretion does not predict postprandial triglyceride accumulation. Conclusions: Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis. [Copyright &y& Elsevier]

Abstract: Objective: Elevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects. We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function, and the corresponding responses to fenofibrate treatment. Methods: Plasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM. Flow-mediated endothelium-dependent dilation (FMD) and glyceryl-trinitrate mediated dilatation (GTNMD) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique. Results: In univariate analysis, plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD (r =−0.425 and −0.423, respectively, P <0.05), but not with GTNMD. In regression models including BMI and HOMA score, plasma apoB-48 was an independent predictors (P <0.05) of brachial artery FMD (β coefficient=−0.384). Replacing HOMA-IR score with plasma triglyceride, adiponectin or CRP concentrations did not alter the findings. The subjects were then randomized to a 12-week treatment period of either 200mg micronized fenofibrate or matching placebo. Compared with the placebo group, fenofibrate treatment (200mg daily for 12weeks) achieved significant increase in FMD (+34%) and reduction in plasma triglyceride (−42%), apoB-48 (−52%) and RLP-cholesterol (−51%) concentrations. The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 (r =−0.644, P <0.02) concentrations. Conclusions: Our findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function. [Copyright &y& Elsevier]

Abstract: Chylomicron remnants bind to both their specific receptors (LRP) and to the LDL receptor (LDLR) in the liver. There is controversy whether disturbances of chylomicron metabolism occur in subjects with familial hypercholesterolemia (FH). The aim of this study was to evaluate whether there are defects on the removal from plasma of chylomicrons and their remnants in heterozygous FH patients with determined LDLR mutations. We studied 20 heterozygous FH patients (43.2±12 years old, 60% males) and 50 normolipidemic subjects matched for age and gender. FH subjects were not in use of LDL-lowering drugs for at least 6 weeks. The removal from plasma of chylomicrons and their remnants was measured by isotopic decay after venous injection of a chylomicron-like emulsion radiolabeled with 14C-cholesteryl ester (14C-CE) and 3H-triolein (3H-TO). These track respectively removal from plasma of chylomicrons and remnants and lipolysis. There was a significant reduction in the fractional catabolic rates (FCR in h−1) of 14C-CE in FH in comparison with normolipidemics: 0.048 (1.46.10−7; 0.57) vs. 0.71(0.049; 1.62), [median (25th–75th percentile)], p =0.003. No differences were found in FCR of 3H-TO between FH and controls, respectively 1.62 (1.02; 2.331) and 1.914 (1.34; 2.878), p =0.405. In conclusion heterozygous FH subjects had a significant decrease on the removal from plasma of chylomicrons and their remnants compared with normolipidemics. [Copyright &y& Elsevier]

Abstract: Objective: Postprandial hyperlipemia has been shown to impair endothelial function and contribute to the development of atherosclerosis. We investigated the association between postprandial lipid profiles and endothelial function, and we examined the effects of ezetimibe on postprandial hyperlipemia and lipemia-induced endothelial dysfunction. Methods: A randomized prospective trial in which 10mg/day of ezetimibe was administered to 10 subjects for 4 weeks and not administered to 10 subjects (control group) was performed. Lipid profiles and endothelial function, assessed by brachial artery flow-mediated dilation (FMD) during a fasting state and at 2, 4, 6 and 8h after an oral cookie loading test, were determined before and after treatment for 4 weeks. Results: In all subjects before treatment, the maximum reduction in postprandial %FMD was significantly correlated with the maximum increases in postprandial triglyceride (TG) (r =−0.499, P <0.05) and apolipoprotein B-48 (apoB-48) concentrations (r =−0.551, P <0.05). Ezetimibe treatment for 4 weeks significantly suppressed postprandial elevation in TG (area under the incremental curve, from 1419±594 to 968±321mgh/dl, P <0.05), remnant lipoprotein cholesterol (from 66.9±27.6 to 38.9±15.4mgh/dl, P <0.01) and apoB-48 (from 58.8±27.5 to 36.2±17.0μgh/ml, P <0.05) concentrations, and postprandial endothelial dysfunction assessed by %FMD (maximum reduction in %FMD, from −2.6±1.1% to −1.2±0.8%, P <0.05), whereas no significant changes were observed in the control group. Conclusion: Postprandial hyperlipemia is closely correlated with transient endothelial dysfunction. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction. [Copyright &y& Elsevier]

Abstract: Introduction: Type 2 diabetes is associated with atherogenic abnormalities of postprandial triglyceride-rich lipoproteins. This study evaluated whether ezetimibe, by inhibiting intestinal cholesterol absorption, influences chylomicrons and VLDL particles at fasting and after a standard meal. Methods: By a double blind cross-over design 15 subjects with type 2 diabetes and hypercholesterolaemia followed in random order a 6-week treatment with ezetimibe 10mg+simvastatin 20mg (EZE+S) or placebo+simvastatin 20mg (P+S) and, after a 6-week wash-out period, crossed over to the other treatment (NCT00699023). At the end of each period lipids, apoB-48, and apoB-100 concentrations in plasma and lipoprotein fractions (separated by discontinuous density gradient ultracentrifugation) were determined before and over 6h following a high-fat test meal. Results: Compared with P+S, EZE+S induced, (a) beside a greater decrease in LDL cholesterol, (b) a significant decrease in chylomicron lipid content both at fasting and postprandially (4.4±2.7 vs. 8.3±8.7mg/dl×6h total AUC for cholesterol, p <0.05; 18±12 vs. 29±24mg/dl triglyceride concentrations at 6h, p <0.05), (c) a significant decrease in chylomicron postprandial apoB-48 (0.03±0.03 vs. 0.09±0.08mg/l at 4h, p <0.05), and (d) significant fasting and postprandial decreases in the cholesterol content of VLDL, IDL, and LDL, as shown by the significant reduction of the cholesterol/triglyceride ratio in these lipoproteins. Conclusions: A 6-week treatment with ezetimibe and simvastatin, compared to simvastatin alone, positively influences lipoprotein profile both at fasting and postprandially in type 2 diabetic patients by favouring the production of cholesterol-poor chylomicrons and VLDL particles that have less atherogenic potential. [Copyright &y& Elsevier]

Abstract: Mannose binding lectin (MBL) is one of the three initiators of complement activation and is therefore closely linked to inflammation. MBL deficiency has been associated with the generation of atherosclerosis. Since atherosclerosis, the complement system and postprandial lipemia are linked to inflammation, we studied postprandial lipoprotein metabolism in MBL deficiency. An observational study was carried out in 107 volunteers (21% MBL deficient). Classical cardiovascular risk factors were not different between subjects with and without MBL deficiency. Oral fat loading tests in 8 MBL deficient and 14 MBL sufficient subjects showed similar postprandial triglyceride, free fatty acid, hydroxybutyric acid and complement component 3 concentrations. MBL deficient subjects had 2.4 times lower postprandial Sf>400 (chylomicron)–apoB48 concentrations, but in contrast a 2–3.5 times increased Sf 60–400 (VLDL1–TG) and Sf 60–400–apoB100 response. MBL activity was inversely related to the postprandial Sf 60–400–TG increase. Despite lower postprandial Sf>400–apoB48 concentrations, MBL deficient subjects show an accumulation of Sf 60–400 lipoproteins. [Copyright &y& Elsevier]

Abstract: Aim: Postprandial lipaemia is a significant contributor to the development of dyslipidaemia and cardiovascular disease, which has more recently been shown as a potential risk factor for obesity and pre-diabetes. Clinically however, the diagnosis of early insulin-resistance remains confounded due to the fact that aberrations in lipid metabolism are not often readily identified using classic indicators of hypercholesterolemia (i.e. LDL). Methods: In this study, we assessed the metabolism of apolipoprotein-B48 (apoB48)-containing lipoproteins in an animal model of obesity and insulin-resistance, the JCR:LA-cp rat. The contribution of lipoproteins from the intestine was assessed by measuring plasma apoB48 concentration in the postprandial period following an oral fat load. Plasma apoB48 was measured by improved enhanced chemiluminescent detection and other biochemical parameters measured by established analysis. Results: Fasting concentrations of plasma apoB48, postprandial apoB48 area under the curve (AUC), as well as incremental-AUC (iAUC), were all significantly greater in the obese phenotype compared to lean controls. Fasting apoB48 correlated significantly with apoB48-iAUC, triglyceride (TG)-iAUC and insulin-iAUC. In addition, there was a highly significant association with fasting insulin and the postprandial ratio of TG:apoB48, a relationship not often detected in humans during insulin-resistance. Conclusions/interpretation: We conclude that the JCR:LA-cp rat can be used as a model of postprandial lipemia to explore chylomicron metabolism during the onset and development of insulin-resistance, including the increased cardiovascular complications of the metabolic syndrome. [Copyright &y& Elsevier]

Abstract: Background and methods: Hepatic lipase (HL) is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of triglyceride-rich lipoprotein remnants and high density lipoproteins. The search described here concentrated on the description of the double invalidation of the HL and LDL receptor genes in mice in order to better understand the possible role of HL in combined hyperlipidemia/hyperalphalipoproteinemia and development of atherosclerosis. Results: We show here that mice lacking both endogenous HL and LDL receptor (HL−/−:LDLR−/−) dramatically increased their plasma triglyceride-rich lipoproteins and their remnants as a consequence of reduced liver uptake. This result is strenghthened by the fact that HL−/−:LDLR−/− were found to overexpress LRP, LSR, and apoE genes. Interestingly, HL−/−:LDLR−/− mice showed premature spontaneous atherosclerosis and aortic lesions from 1-year-old animals were two-fold larger than those of LDLR−/− single mutants. We confirmed that HL−/− and wild-type mice did not develop atherosclerosis lesion even 1 year after birth. Conclusions: Analysis of this double HL–LDLR knockout mouse model provides in vivo evidence that HL has a major role in the clearance of TRL remnants when LDLR is deficient and in the reduction of the development of atherosclerosis. [Copyright &y& Elsevier]

Abstract: Background: Microsomal triglyceride transfer protein (MTP) is responsible for the assembly of the triglyceride-rich lipoproteins (TRLs) and is increased in diabetic animal models. Human intestinal MTP expression has not been previously reported. This study examined the relationship between intestinal MTP gene expression and postprandial TRL composition in diabetic and non-diabetic subjects. Since the MTP promoter region has a sterol response element the effect of statins on intestinal MTP mRNA was analysed. Methods: Twenty-seven diabetic and 24 non-diabetic subjects were examined. Duodenal biopsies were taken during gastroscopy and MTP mRNA was measured by RNase protection assay. Postprandial lipoprotein composition was determined. Results: Diabetic subjects had significantly higher MTP mRNA than non-diabetic subjects. Statin therapy was associated with lower MTP mRNA in both groups. In the untreated diabetic patients compared to the untreated non-diabetic patients MTP mRNA was 25.0±25.1amol/μg versus 13.1±5.6amol/μg total RNA (p <0.05). In the statin-treated diabetic group compared to statin-treated non-diabetic group MTP mRNA was 17.7±8.6amol/μg versus 5.8±4.1amol/μg total RNA (p <0.05). In the whole group there was a positive correlation between the MTP mRNA and postprandial chylomicron cholesterol/B48 (r =0.36, p <0.01). Conclusions: This is the first study to demonstrate increased MTP expression in diabetic subjects. MTP mRNA expression was lower in statin-treated patients confirming the suggestion that the insulin and sterol response elements of the MTP gene are important regulators of MTP transcription in diabetes. Our results show that MTP plays a central role in regulating the cholesterol content of the chylomicron particle. [Copyright &y& Elsevier]

Abstract: It is well known that raised plasma triglycerides (TG) are positively linked to the development of coronary heart disease. However, triglycerides circulate in a range of distinct lipoprotein subfractions and the relative atherogenicity of these subfractions is not clear. In this study, three fractions of triglyceride rich lipoprotein (TRL) were isolated from normolipidaemic males according to their differing Svedberg flotation (S f) rates: chylomicron (CM, S f >400), very low-density lipoprotein (VLDL)-1 (S f 60–400) and VLDL-2 (S f 20–60). These fractions were incubated with THP-1 monocyte-derived macrophages for determination of cholesterol and TG accumulation, in the presence and absence of the lipoprotein lipase (LPL) inhibitor orlistat. Expression of LDL receptor related protein (LRP) and apolipoprotein B48 receptor (apoB48R) was also examined in both differentiating monocytes, and monocyte-derived macrophages, incubated with TRL. VLDL-1 caused a significantly greater accumulation of TG within macrophages compared to VLDL-2. Binding studies also tended to show a greater preference for VLDL-1. No change in expression of LRP or apoB48R was observed in fully differentiated macrophages incubated with VLDL-1, VLDL-2 or CM, although a greater expression of LRP mRNA was observed in differentiating monocytes exposed to VLDL-1, compared to those incubated with CM or VLDL-2. TG loading in response to all three TRL fractions was blocked by orlistat, suggesting that it is likely that the major pathway for uptake of TG was hydrolysis by LPL. Calculations suggested that direct uptake of particles accounts for between 12 and 25% of total TAG uptake. In conclusion, THP monocyte-derived macrophages demonstrate a preference for VLDL-1, both through the LPL pathway and by direct uptake of whole particles. [Copyright &y& Elsevier]

Abstract: The effects of diacylglycerol ingestion on postprandial lipid metabolism in non-diabetic subjects with and without insulin resistance were investigated. This was single dose ingestion study, in a double blind cross over manner and postprandial lipid concentrations were compared between diacylglycerol oil (DAG) and triacylglycerol oil (TAG) ingestion. The subjects were 18 male volunteers and homeostasis model assessment (HOMA-R) was used to classify them into insulin sensitive (IS, n =10, HOMA-R&#60;2.0) and insulin resistant (IR, n =8, HOMA-R≥2.0) groups. Fasting serum triglycerides (TG) and remnant-like particle cholesterol (RLP-C) correlated with HOMA-R and were significantly higher in the IR as compared to the IS group. Postprandial increments of TG and RLP-C after DAG ingestion were significantly lower as compared to those after TAG ingestion. In a case of TAG ingestion, their increments positively correlated with HOMA-R and were significantly higher in the IR as compared with the IS group. In contrast, their increments remained constant after DAG ingestion in both groups. In the IR group, the postprandial lipidemia were reduced after DAG ingestion to about half of those after TAG ingestion. In conclusion, DAG reduced postprandial lipidemia especially in subjects with insulin resistance and may be beneficial in preventing atherosclerosis and related diseases. [Copyright &y& Elsevier]

High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an independent risk factor for coronary artery disease. Here, we show that TGRL inhibit the efflux of cholesterol from ‘foam cell’ macrophages to lipid-poor apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions. Human (THP-1) monocyte-derived macrophages were pre-incubated (48 h) with acetylated low-density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to apoA1. Pre-incubation of macrophage ‘foam cells’ with TGRL (0–200 μg/ml, 0–24 h) inhibited the efflux of exogenously radiolabelled ([3H]), endogenously synthesised ([14C]) and cellular cholesterol mass to lipid-poor apoA1, but not control medium, during a (subsequent) efflux period. This inhibition is dependent upon the length of prior exposure to, and concentration of, TGRL employed, but is independent of changes in intracellular triglyceride accumulation or turnover of the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol efflux, major proteins involved in this process—namely apoE, ABCA1, SR-B1 and caveolin-1—were unaffected by TGRL pre-incubation, suggesting that exposure to these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic pathway. [Copyright &y& Elsevier]

Objectives: To explore the therapeutic potential of fibrates to attenuate premature atherosclerosis and cardiovascular disease in the atherogenic dyslipidemias typical of Type II diabetes, Metabolic Syndrome, and the Type IIB (mixed) lipid phenotype; such dyslipidemias frequently feature peripheral insulinoresistance. Background: Recent epidemiological data reveal that a marked increase in the prevalence of Type II diabetes, obesity and the Metabolic Syndrome has occurred on a worldwide scale. Dyslipidemia is an integral component of the metabolic perturbations which characterise these disorders, and is intimately associated with premature atherosclerosis and elevated cardiovascular risk. The atherogenic dyslipidemias of Type II diabetes, the Metabolic Syndrome and mixed (IIB) hyperlipidemia feature moderate to marked elevation of triglyceride-rich lipoproteins, low HDL-C cholesterol levels, and a dense LDL phenotype; equally, they feature an inflammatory state. Fibrates, agonists of PPARα, act to modulate the expression of key genes of lipid transport and metabolism in organs such as the liver and adipose tissue; equally, they exert pleiotropic, anti-inflammatory effects downregulating expression of genes encoding acute phase proteins and inflammatory cytokines. By inducing elevation of HDL-C levels, reduction in triglyceride-rich lipoproteins and a shift in the dense LDL phenotype to receptor-active, buoyant LDL, and by diminishing the inflammatory state, fibrates act to attenuate the atherosclerotic burden in atherogenic dyslipidemia. Such actions translate into significant clinical benefit as demonstrated by the reduction in cardiovascular morbi-mortality observed in both primary and secondary intervention trials (VA-HIT, Helsinki Heart Study, SENDCAP, DAIS, BECAIT). Conclusions: Fibrate therapy represents a cost effective approach to the clinical management of a wide spectrum of atherogenic dyslipidemias involving low HDL-C and elevated TGRL levels, and which include Type II diabetes and the Metabolic Syndrome. Optimised clinical application of these lipid modulating, anti-inflammatory drugs in these disorders in the context of either monotherapy or in combination with low dose statin is, therefore, warranted. [Copyright &y& Elsevier]

Background: Evidence linking cardiovascular risk factors to aortic valve sclerosis (AVS) has led to the assumption that the latter is an atherosclerosis-like process. However, triglyceride (TG)-rich lipoproteins, an important risk factor for atherosclerosis, have been rarely investigated in connection with AVS. Methods: A cross-sectional study of 246 healthy individuals (mean age 59±6 years, 77% men) was conducted. Subjects underwent an echocardiographic assessment and extensive blood lipid measurements, including evaluation of TG-related indices, such as serum apolipoprotein (apo) CII and CIII levels, apo CIII levels in VLDL+LDL particles, and apo CIII ratio (CIII level in HDL/CIII level in VLDL+LDL). Results: Twenty-three patients (9.3%) were diagnosed as having AVS. On average, these patients were 5 years older and had higher levels of serum cholesterol, LDL-C and LP(a), compared with non-AVS subjects. In addition, the AVS patients exhibited higher concentrations of serum apo CII, serum apo CIII and apo CIII in VLDL+LDL, and a lower apo CIII ratio. Adjusting for age and gender, a 1 S.D. increment in apo CIII in VLDL+LDL was associated with odds ratio (OR) of 1.76 (95% CI: 1.17–2.65) for AVS. Further adjustment for atherosclerotic risk factors did not alter the association appreciably (OR=1.65, 95% CI: 1.06–2.58). Conclusion: TG-rich lipoproteins may be involved in the early development of AVS. Confirmation in prospective studies is required. [Copyright &y& Elsevier]

Aims: Apolipoprotein C-III (apoC-III) has been recognized as a useful marker of triglyceride-rich lipoproteins (TRLs) metabolism and proposed as an indicator of prognosis for coronary risk in healthy subjects. We studied cross-sectionally in a population having low cholesterol levels, but a high prevalence of the metabolic syndrome, whether serum levels of total apoC-III or its sub-fractions were independent markers of prevalent coronary heart disease (CHD) or were related to variables reflecting the metabolic syndrome. Methods and results: In 857 unselected participants of the representative population sample of the Turkish Adult Risk Factor Survey in 2001, apoC-III as well as other risk variables were evaluated, and CHD was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. The sample consisted of men and women, aged 33–82 years, having a mean waist circumference of 89.4 and 92.9 cm, respectively, 42% of whom had the metabolic syndrome identified by criteria of the ATP III. ApoC-III values were measured by turbidimetric immunoassay. Mean concentrations for non-high-density lipoprotein (nonHDL) apoC-III in men and women were 6.4 and 6.2 mg/dl, respectively, and for apoC-III in HDL were 6.2 and 6.3 mg/dl, respectively. NonHDL apoC-III was similar to, and apoC-III in HDL was higher than that in Western populations. Both fractions of apoC-III were significantly correlated with lipids, lipoproteins, apoB, anthropometric measures, and blood pressures in both genders. Correlations for both were high with serum triglycerides (rs=around 0.70) and apoB (rp=around 0.37). Total apoC-III as well as both fractions were significantly correlated in women also with levels of inflammatory risk markers: strongly (r=0.40–0.45, P<0.001) with complement C3, and weakly (rs=around 0.20, P<0.001) with C-reactive protein. A cutoff of >7.0 mg/dl as opposed to lower levels of nonHDL apoC-III indicated the presence of hypertriglyceridemic hyperapo B with an age-adjusted odds ratio (OR) of 13.8; it indicated the presence of metabolic syndrome with 4.66-fold likelihood. Total apoC-III and nonHDL apoC-III proved to be significantly (P-trend <0.05 and 0.002) and strongly associated with prevalent CHD in men even after adjustment for age, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C): OR gradients across upper and lower quartiles were 3.88-fold (CI: 1.3; 11.4) and 8.8-fold (CI: 2.6; 29.8), respectively. Conclusions: In a population among whom the metabolic syndrome prevails, total- and nonHDL apoC-III are each a determinant in both genders of the metabolic syndrome and of hypertriglyceridemic hyperapo B. Each is a powerful significant marker of prevalent CHD in men independent of LDL- and HDL-C levels. In women, despite being correlated with inflammatory risk markers, the significant association of elevated levels of apoC-III with CHD did not prove to be independent of age. [Copyright &y& Elsevier]