Search

Background and Aims: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it., Methods: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis., Results: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m 2 , and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m 2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score., Conclusions: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance., Competing Interests: Declaration of competing interest HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer, SOBI and Kowa and research grants and donations from Akcea, Pfizer, MSD, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. ASW: Received grants from Akcea, Regeneron; Royalties from Elsevier and is a board member for familial hyperlipidaemia group, Europe. DD: Received honoraria for advisory boards from SOBI. NF: Received honoraria for presentations from SOBI. YT: Received speakers fee from Daiichi Sankyo and Amarin. PD: Received honoraria from SOBI, NOVARTIS, AMGEN and Daiichi Sankyo. PM: Participated on a Data Safety Monitoring Board and Advisory Board for Ionis, AKCEA, AMRYT, AMARIN, Ultragenix AG: received research grants from AMGEN, SANOFI, AMRYT, ULTRAGENYX, Consulting fee or honoraria from AMGEN, SANOFI, AMRYT, ULTRAGENYX, NOVARTIS, AKCEA, SERVIER. BB, SK, CD, AJ, FJ, MM, HD, PH, MM, AA, DO, PND: None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10 -4 ). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10 -6 ). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: This study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH)., Background: Common cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD)., Methods: REFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death., Results: We included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%., Conclusions: CAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH., Competing Interests: Funding Support and Author Disclosures This work was supported by the Agence Nationale de la Recherche (ANR-16-RHUS-0007) within the French national project CHOPIN (Cholesterol Personalized Innovation), France. SAFEHEART was supported by Fundación Hipercolesterolemia Familiar, Instituto de Salud Carlos III (G03/181 and FIS PI12/01289), and Centro Nacional de Investigación Cardiovascular (grant 08-2008), Spain. Dr Gallo has received honoraria for public speaking or consultancy support from Akcea Therapeutics, Amgen, Mylan, Novartis, Sanofi and Regeneron, Unilever, and Merck Sharpe & Dohme. Dr Perez de Isla has received honoraria for public speaking or consultancy support from Amgen, Sanofi, Merck Sharpe & Dohme, Mylan, Novartis, and Ferrer. Dr Charrière has received honoraria for board, conferences, or congresses from Akcea, Amgen, AstraZeneca, Biomarin, Boehringer Ingelheim, Lilly, Merck, Merck Sharpe & Dohme, Novartis, and Novo Nordisk. Dr Bruckert has received honoraria from Aegerion, Danone, Genfit, Merck Sharpe & Dohme, Sanofi/Regeneron Pharmaceuticals, Inc, AstraZeneca, Servier, Amgen, Akcea, Mylan, Novartis, and Silence Therapeutics. He also reports grants for expert witness from Sanofi and Amgen. Dr Moulin has received honoraria for board, conferences, clinical trials or congresses from Amgen, Akcea, Boehringer, Ingelheim Novo Nordisk, Merck Sharp & Dohme, and Sanofi. Dr Mata has received research grants from Amgen and Sanofi. Dr Béliard has received honoraria for boards, conferences, clinical trials, or congresses from Aegerion, Akcea, Elivie, Sanofi, or Amgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3' UTR as targets for miR regulation of PCSK9 expression., Methods: Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3'UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs., Results: The c.*571C and c.*234T variants located in the PCSK9 3'UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3'UTR., Conclusions: This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Severe hypertriglyceridemia (HTG), characterized by triglycerides (TG) permanently over 10 mmol/L, may correspond to familial chylomicronemia syndrome (FCS), a rare disorder. However, hypertriglyceridemic patients more often present multifactorial chylomicronemia syndrome (MCS), characterized by highly variable TG. A few nonsense variants of LMF1 gene were reported in literature in FCS patients. In this study, we described a woman with an intermittent severe HTG. NGS analysis and the sequencing of a long range PCR product revealed a homozygous deletion of 6507 base pairs in LMF1 gene, c.730-1528&#95;898-3417del, removing exon 6, predicted to create an in-frame deletion of 56 amino acids, p.(Thr244&#95;Gln299del). Despite an exon 6 homozygous deletion of LMF1, the patient's highly variable lipid phenotype was suggestive of MCS diagnosis., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Abetalipoproteinemia (ABL) is a rare recessive monogenic disease due to MTTP (microsomal triglyceride transfer protein) mutations leading to the absence of plasma apoB-containing lipoproteins. Here we characterize a new ABL case with usual clinical phenotype, hypocholesterolemia, hypotriglyceridemia but normal serum apolipoprotein B48 (apoB48) and red blood cell vitamin E concentrations., Methods: Histology and MTP activity measurements were performed on intestinal biopsies. Mutations in MTTP were identified by Sanger sequencing, quantitative digital droplet and long-range PCR. Functional consequences of the variants were studied in vitro using a minigene splicing assay, measurement of MTP activity and apoB48 secretion., Results: Intestinal steatosis and the absence of measurable lipid transfer activity in intestinal protein extract supported the diagnosis of ABL. A novel MTTP c.1868G>T variant inherited from the patient's father was identified. This variant gives rise to three mRNA transcripts: one normally spliced, found at a low frequency in intestinal biopsy, carrying the p.(Arg623Leu) missense variant, producing in vitro 65% of normal MTP activity and apoB48 secretion, and two abnormally spliced transcripts resulting in a non-functional MTP protein. Digital droplet PCR and long-range sequencing revealed a previously described c.1067+1217&#95;1141del allele inherited from the mother, removing exon 10. Thus, the patient is compound heterozygous for two dysfunctional MTTP alleles. The p.(Arg623Leu) variant may maintain residual secretion of apoB48., Conclusions: Complex cases of primary dyslipidemia require the use of a cascade of different methodologies to establish the diagnosis in patients with non-classical biological phenotypes and provide better knowledge on the regulation of lipid metabolism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options., (Copyright © 2018 Cuerq et al.)

Background: The LMF1 (lipase maturation factor 1) gene encodes a protein involved in lipoprotein lipase and hepatic lipase maturation. Homozygous mutations in LMF1 leading to severe hypertriglyceridemia (SHTG) are rare in the literature. A few additional rare LMF1 variants have been described with poor functional studies., Objective: The aim of this study was to assess the frequency of LMF1 variants in a cohort of 385 patients with SHTG, without homozygous or compound heterozygous deleterious mutations identified in lipoprotein lipase (LPL), apolipoprotein A5 (APOA5), apolipoprotein C2 (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) genes, and to determine their functionality., Methods: LMF1 coding variants were screened using denaturing high-performance liquid chromatography followed by direct sequencing. In silico studies of LMF1 variants were performed, followed by in vitro functional studies using human embryonic kidney 293T (HEK-293T) cells cotransfected with vectors encoding human LPL and LMF1 cDNA. LPL activity was measured in cell culture medium after heparin addition using human VLDL-TG as substrate., Results: Nineteen nonsynonymous coding LMF1 variants were identified in 65 patients; 10 variants were newly described in SHTG. In vitro, p.Gly172Arg, p.Arg354Trp, p.Arg364Gln, and p.Arg537Trp LMF1 variants decreased LPL activity, and the p.Trp464Ter variant completely abolished LPL activity. We identified a young girl heterozygote for the p.Trp464Ter variant and a homozygote carrier of the p.Gly172Arg variant with a near 50% decreased LPL activity in vitro and in vivo., Conclusion: The study confirms the rarity of LMF1 variants in a large cohort of patients with SHTG. LMF1 variants are likely to be involved in multifactorial hyperchylomicronemia. Partial LMF1 defects could be associated with intermittent phenotype as described for p.Gly172Arg homozygous and p.Trp464Ter heterozygous carriers., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagnostic strategy surrounding FCS and proposed an algorithm-based diagnosis tool for identification of these patients, which can be readily translated into practice. Features included in this FCS score comprise: severe elevation of plasma TGs (fasting TG levels >10 mmol/L [885 mg/dL] on multiple occasions), refractory to standard TG-lowering therapies, a young age at onset, the lack of secondary factors (except for pregnancy and oral oestrogens) and a history of episodes of acute pancreatitis. Considering 53 FCS patients from three cohorts and 52 MCS patients from three cohorts, the overall sensitivity of the FCS score (≥10) was 88% (95% confidence interval [CI]: 0.76, 0.97) with an overall specificity of 85% (95% CI: 0.75, 0.94). Receiver operating characteristic curve area was 0.91. Pragmatic clinical scoring, by standardising diagnosis, may help differentiate FCS from MCS, may alleviate the need for systematic genotyping in patients with severe HTG and may help identify high-priority candidates for genotyping., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim of the Study: Evaluate the added value of screening anti-ZnT8 antibodies (ZnT8A) in addition to the classical anti-GAD (GADA) and anti-IA-2 (IA-2A) antibodies for the diagnosis of type-1 diabetes (T1D) within a large cohort of both children and adults., Materials and Methods: Retrospective 2-year study including 516 patients (215 children, 301 adults) who had blood tests at diabetes onset and/or for diabetes classification. ZnT8A, GADA, and IA-2A were analyzed in all samples., Results: Among those individuals included, 142 (28%) were ZnT8A-positive. A total of 228/516 suffered from T1D, of whom 110 (48%) were ZnT8A-positive and 166 (73%) GADA and/or IA-2A positive. When adding ZnT8A to GADA/IA-2A, 184 (81%) patients were positive for ≥1 Ab. Regarding the 122 patients at T1D onset, 75 (61%) were positive for ZnT8A and the proportion of patients with T1D with ≥1 Ab reached 89%. The highest prevalence of ZnT8A was observed in children aged 6-10years. Fourteen of the 124 patients positive for ZnT8A with a known clinical diagnosis suffered from a disease other than T1D., Conclusions: ZnT8A should be included in routine evaluation at diabetes onset and is a valuable biological marker to classify newly-diagnosed diabetics. The predictive value in our high-risk subjects has to be confirmed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: The heterogeneity and mechanisms of multifactorial chylomicronemia (MCM) remain poorly understood. To gain new insights, post heparin lipolysis measured at 60 min (PHLA60), in addition to the more commonly used 10 min (PHLA10), was assessed in patients with history of MCM., Methods: 62 consecutive MCM patients were studied. The evaluation included LPL, APOC2, APOA5, GPIHBP1, LMF1 and APOE gene sequencing, as well as pre- and post-heparin injection biochemical analysis, including lipid profiles, determination of apolipoprotein B, B-48, CII, CIII, lipoprotein lipase (LPL) concentrations (LPLC0, LPLC10 and LPLC60) and post-heparin LPL activity (PHLA10 and PHLA60)., Results: In controls, PHLA60 did not differ from PHLA10, while in MCM patients, PHLA60 was significantly lower than PHLA10 (p<0.001). PHLA60 showed a bimodal distribution in MCM patients (p=0.03). One subgroup exhibited PHLA60 similar to controls, with persistent lipoprotein remodeling and, paradoxically, the highest basal plasma TG concentration. APOE ε4 was over-represented compared to the European population (p<0.05) and Apo CIII/Apo B ratio was increased (p<0.01). The other subgroup exhibited low PHLA60 (p<0.001) compared to both controls and the other MCM subgroup with a lipoprotein profile consistent with fast and transient remodeling. LMF1 p. Arg364Gln was over-represented compared to the European population (p<0.05)., Conclusions: The study showed that PHLA60 identifies a subgroup of MCM with a defect in lipolysability and/or hepatic clearance of triglycerides-rich lipoproteins, and a larger one with a defect in LPL availability. These findings provide new insights into the heterogeneity of MCM and might contribute to adjust treatment targeting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A good understanding of the natural history of rare genetic lipid disorders is a pre-requisite for successful patient management. Disease registries have been helpful in this regard. Lipoprotein Lipase Deficiency (LPLD) is a rare, autosomal-recessive lipid disorder characterized by severe hypertriglyceridemia and a very high risk for recurrent acute pancreatitis, however, only limited data are available on its natural course. Alipogene tiparvovec (Glybera ® ) is the first gene therapy to receive Marketing Authorization in the European Union; GENIALL (GENetherapy In the MAnagement of Lipoprotein Lipase Deficiency), a 15-year registry focusing on LPLD was launched in 2014 as part of its Risk Management Plan. The aim of this publication is to introduce the GENIALL Registry within a structured literature review of registries in rare genetic lipid disorders. A total of 11 relevant initiatives/registries were identified (homozygous Familial Hypercholesterolemia (hoFH) [n = 5]; LPLD [n = 1]; Lysosomal Acid Lipase Deficiency [LALD, n = 1], detection of mutations in genetic lipid disorders [n = 4]). Besides one product registry in hoFH and the LALD registry, all other initiatives are local or country-specific. GENIALL is the first global prospective registry in LPLD that will collect physician and patient generated data on the natural course of LPLD, as well as long-term outcomes of gene therapy., Conclusion: There is a limited number of international initiatives focusing on the natural course of specific rare genetic lipid disorders. The GENIALL LPLD Registry could be the first step towards a future broader global initiative that collects data related to familial chylomicronemia syndrome and their underlying genetic causes., (Copyright © 2016. Published by Elsevier B.V.)

Background: The childhood/adult-onset lysosomal acid lipase deficiency (LALD; late-onset LALD) is a rare genetic disease. Children present severe fatty liver disease with early cirrhosis. Before enzyme replacement therapy, statins were the standard treatment to improve the severe dyslipidemia. However, late-onset LALD should be considered as a systemic metabolic disease: chronic hyper-low-density lipoprotein and hypo-high-density lipoprotein cholesterolemia induces early atherosclerosis in addition to the liver morbidity., Objective: To assess 4 new pediatric cases of late-onset LALD with an evaluation of hepatic, metabolic, and vascular evolution under statin., Methods: Four patients were retrospectively described. Anthropometric data (weight, height, and body mass index) and laboratory data (LIPA mutations, acid lipase residual activity, liver and lipid profile, and homeostatic model assessment index) were collected. Liver histology was assessed by the noninvasive tests FibroScan and FibroTest and confirmed by liver biopsy. Vascular impact was followed up by carotid intima-media thickness (cIMT) assessment., Results: The 4 cases of late-onset LALD came from 2 families, each with a boy (aged 8.6 and 11 years at diagnosis) and a girl (aged 10.6 and 13 years at diagnosis). Treatment with statins was performed for 8 and 5 years, respectively, from diagnosis. Statins decreased the low-density lipoprotein cholesterol mean value of 40%. All children showed significant liver fibrosis (F3 [n = 3]; F2 [n = 1]). cIMT showed the following for all children: abnormal measures without improvement and atherosclerotic plaques. One child developed a deleterious metabolic phenotype with obesity and insulin resistance (homeostatic model assessment = 3.08) associated with higher mean hepatic transaminases (149 vs 98, 88, and 61 IU/L) and increased mean cIMT values (raising from 0.47 to 0.5 mm vs 0.43 and 0.43 mm)., Conclusion: Late-onset LALD is a rare metabolic disease with a larger impact than liver disease. Our work shows the importance of having a global metabolic view and to evaluate the cardiovascular impact of the new enzymatic treatment., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: APOC3 is a major regulator of triglycerides metabolism. Several APOC3 variants are associated with hypertriglyceridemia (HTG). Our aim was to establish the potential regulation of APOC3 3'UTR variants associated with HTG by liver or intestinal miRNAs., Methods: We sequenced APOC3 3'UTR in 100 type 2 diabetic (TD2) patients with severe HTG (TG > 15 mmol/L) (HTG group) compared to 100 normotriglyceridemic patients (NTG group). We performed in silico studies to identify potential loss of miRNA binding induced by APOC3 3'UTR variants. We also performed in vitro studies to test the functionality of miRNA/APOC3 variants interactions: APOC3 3'UTR plasmids coupled with a firefly luciferase reporter were transfected in HepG2, HuH-7 and Caco-2 cells., Results: We identified only two variants: SstI (rs5128) and BbvI (rs5225) in APOC3 3'UTR in the 2 groups of patients. Only the SstI-S2 rare allele was significantly associated with HTG (allele frequency 19,5% in HTG group vs. 9,5% in NTG group, p = 0.0045). In silico studies predicted a potential loss in the binding of 5 miRNAs induced by the S2 variant. These 5 miRNAs are all endogenously expressed in human liver and intestine, as well as in the cell models studied. However, in vitro, the S2 variant did not modulate APOC3 3'UTR reporter gene expression in HepG2, HuH-7 and Caco-2 cells., Conclusions: Our results do not confirm the hypothesis of a direct regulation of the APOC3 SstI variant by hepatic or intestinal miRNAs., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Heterozygous familial hypercholesterolemia (heFH) is a genetic disease causing high levels of low-density lipoprotein cholesterol (LDL-C). Although this population is at high cardiovascular (CV) risk, the risk is variable within patients depending on additional risk factors. CV disease risk groups have been defined by the Nouvelle Société Francophone d'Athérosclérose (NSFA) and by the National Lipid Association recommendations., Objectives: The study aimed to describe a sample of French heFH patients, comparing patients at very high risk (VHR) and patients at high risk in terms of demographic and clinical characteristics as well as biological measurements and disease management., Methods: Cross-sectional retrospective analysis on 734 patients hospitalized after 2005 in 5 academic centers., Results: When considering NSFA classification, 550 (74.9%) patients belonged to the VHR group. Most patients in the VHR group presented more than 1 risk factor, the most prevalent ones being Lp(a) > 50 mg/dL and smoking. Patients in the VHR group were older (50.6 vs 45.0 years old, P = .0002), and presented a higher body mass index (25.5 kg/m(2) vs 23.3 kg/m(2), P < .0001). The proportion of patients with carotid arterial plaque was higher in the VHR group (59.8% vs 48.6%, P = .06). Total cholesterol (2.41 g/L on average) and LDL-C (1.65 g/L on average) were not found to be significantly different. Maximum level of lipid-lowering treatments were used in 34% of cases in the VHR group, significantly higher than 16% in the high-risk group (P = .001). Very similar results were found when using the National Lipid Association recommendations., Conclusion: This study provides a detailed description of French heFH patients according to their CV risk. Patients with very high CV risk had usually more advanced carotid plaques and were treated with heavier lipid-lowering drugs although their LDL-C level remained similar. This highlights the significant burden of this population., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Lipoprotein lipase (LPL) is a key enzyme in triglyceride (TG) metabolism. LPL gene single nucleotide polymorphisms (SNPs) are associated with TG concentrations however the functionality of many of these SNPs remains poorly understood. MicroRNAs (miR) exert post-transcriptional down-regulation and their target sequence on the 3'UTR may be altered by SNPs. We therefore investigated whether LPL 3'UTR SNPs could modulate plasma TG concentration through the alteration of miR binding-sites., Methods and Results: We performed genetic association studies of LPL 3'UTR SNPs with TG concentrations in 271 type 2 diabetic patients and in general population samples (2997 individuals). A specific LPL haplotype (Hap4) was associated with lower plasma TG concentration (TG-0.18, IC95% [-0.30, -0.07] mmol/L or logTG-0.13, IC95% [-0.18, -0.08], p = 4.77·10(-8)) in the meta-analysis. Hap4 comprises seven 3'UTR SNP minor alleles and p.Ser474Ter (rs328) a well-documented nonsense mutation associated with low TG concentration although by an unknown mechanism so far. Bio-informatic studies identified several putative miRNA binding-sites on the wild-type Hap1 haplotype, lost on Hap4. Functional validation performed in HEK-293T cells using luciferase expression constructs with various LPL 3'UTR allele combinations demonstrated a binding of miR-29, miR-1277 and miR-410 on Hap1, lost on Hap4. This loss of specific miR binding-site in presence of Hap4 was independent of the allelic variation of p.Ser474Ter (rs328)., Conclusions: We report the regulation of LPL by the miR-29, miR-1277 and miR-410 that is lost in presence of Hap4, a specific LPL TG-lowering haplotype. Consequently p.Ser474Ter association with TG concentration could be at least partially explained by its strong linkage disequilibrium with these functional 3'UTR SNPs., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Macrophages are well recognized as key pathophysiologic agents in many chronic inflammatory diseases, especially atherosclerosis. During atherogenesis process, low density lipoproteins (LDL) undergo oxidation (oxLDL) and become highly atherogenic as they induce a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells, the major cellular component of fatty streaks. OxLDL are enriched in oxidation products of cholesterol called oxysterols involved in the regulation of cholesterol homeostasis, by their ability to induce cellular oxidative stress and cytotoxicity. Little is known about intracellular oxysterol production in macrophages. Using both radiochemical and mass analyzes, we showed that THP1 macrophages promote the intracellular oxidation of LDL derived-cholesterol as well as intracellular cholesterol, this later mechanism being enhanced by exposure with native or oxLDL. We demonstrated that in both THP1 and Raw 267.4 cells cholesterol oxidation occurs in the late endosomal compartment. Most oxysterols were produced by non-enzymatic routes (7-ketocholesterol and 7α/β-hydroxycholesterol) but enzymatically formed 7α-, 27-hydroxycholesterol were also quantified. Incubation of THP1 macrophages with nLDL or oxLDL, induced a 2- and 100-fold increase in oxysterol production, respectively. Both oxysterols derived from LDL cholesterol and cellular cholesterol were readily exported to HDL whereas apoA1 was inefficient, showing that HDL plays a major role in the removal of excess oxysterols in THP1 macrophages., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background & Aims: Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities., Methods: We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands., Results: ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations., Conclusions: Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We aim at investigating arterial diseases at early stage, by assessing the longitudinal (i.e. in the same direction as the blood flow) motion of the intima-media complex. This recently evidenced phenomenon has been shown to provide relevant and complementary information about vascular health. Our method assesses the longitudinal and radial motion from clinical in vivo B-mode ultrasound sequences. To estimate the trajectory of a selected point during the cardiac cycle, we introduce a block matching method that involves a temporal update of the reference block using a pixel-wise Kalman filter. The filter uses the initial gray-level of the pixel as control signal to avoid divergence due to cumulating errors. The block and search-window sizes are adapted to the tissue of interest. The method was evaluated on image sequences of the common carotid artery, acquired in 57 healthy volunteers and in 25 patients at high cardiovascular risk. Reference trajectories were generated for each sequence by averaging the tracings performed by three observers. Six different computerized techniques were also compared to our method. With a pixel size of 30 μm, the average absolute motion estimation errors were 84 ± 107 μm and 20 ± 19 μm for the longitudinal and radial directions, respectively. This accuracy was of the same order of magnitude as the inter- and intra-observers variability, and smaller than for the other methods. The estimated longitudinal motion amplitude was significantly reduced in at-risk patients compared with healthy volunteers (408 ± 281 μm vs. 643 ± 274 μm, p<0.0001). Our method can constitute a reliable and time-saving technique to investigate the arterial stiffness in clinical studies, in the objective to detect early-stage atherosclerosis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Carotid intima-media thickness is a well established non-invasive surrogate marker of cardiovascular disease, however there is evidence that structural modification of the arterial adventitia also accompanies cardiovascular risk factors and might be involved causally in atherosclerosis. We sought to determine the relative contributions of the intima-media and adventitia to variation in ultrasound and magnetic resonance derived measures of carotid wall thickness., Methods: Carotid ultrasound and magnetic resonance imaging were undertaken in 20 participants. Carotid intima-media thickness, carotid extra-media thickness (which incorporates the arterial adventitia) and total wall thickness (a combined near-wall intima-media thickness and carotid extra-media thickness) using high-resolution ultrasound, and wall thickness using magnetic resonance imaging, were obtained., Results: All ultrasound-derived measures of the arterial wall thickness were highly correlated with wall thickness by magnetic resonance imaging (all P<0.001); as expected the total wall thickness by ultrasound measure was most tightly correlated (correlation coefficient=0.814, P<0.0001). In multivariable models, there was evidence that both carotid intima-media thickness and carotid extra-media thickness contributed independently to the variance in wall thickness by magnetic resonance imaging, especially for the most severe focal thickening. Measures of carotid wall thickness that incorporated all three layers of the arterial wall were more closely correlated with the number of cardiovascular risk factors than carotid intima-media thickness alone., Conclusions: These results indicate that the arterial adventitia is an important contributor to the wall thickness measure derived by magnetic resonance imaging, and that carotid extra-media thickness likely provides additional information concerning arterial structure than that obtained from carotid intima-media thickness alone., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: The combination of both morphological and cellular markers of subclinical atherosclerosis, in addition to conventional risk factors, may help to improve cardiovascular prevention in type 2 diabetic patients. The aim of our cross-sectional study was to evidence a putative increase in endothelial (EMP) or platelet (PMP) microparticles, in type 2 diabetic patients with coronary noncalcified plaques detected by multidetector CT (MDCT)., Methods and Results: Microparticles and coronary MDCT were assessed in 56 type 2 diabetic patients with different cardiovascular risk levels. Both EMP (r=0.35, p=0.022) and PMP (rho=0.34, p=0.022) were correlated with hsCRP. EMP were elevated in patients with acute coronary syndromes (p=0.034). EMP count was significantly higher in the presence of noncalcified diseased segments (p=0.01). By contrast, there was no association between hsCRP and noncalcified atheroma. This increase in EMP in noncalcified diseased segment carriers remained borderline significant after adjustment for coronary heart disease and hsCRP. Conversely, there was no association of PMP count with noncalcified diseased segments and no difference in PMP count between patients with and without acute coronary syndrome. No significant association between either EMP and PMP counts and mixed or calcified diseased segments was observed., Conclusions: We report for the first time an association between plasma EMP-CD144+ and coronary noncalcified plaques assessed by MDCT in a population of type 2 diabetic patients. EMP might be used as a surrogate marker of unstable plaques, and might help to improve cardiovascular prediction in diabetic patients with intermediate risk.

Type 2 diabetes is a situation at high cardiovascular risk, characterized by platelet hyperactivation, oxidative stress, elevated very-low density lipoprotein (VLDL) and low high-density lipoprotein concentrations. In the present report, we describe the effects of these alterations on the transfers of phospholipids (PL) from VLDL to platelets in basal conditions or after thrombin (0.1U/mL) or lipoprotein lipase (LPL, 500ng/mL)-mediated platelet activation. In vitro transfer of radiolabelled PL from VLDL (200microM PL) to platelets (2x10(8)/mL) was measured after incubations of 1h at 37 degrees C in a series of recombination experiments using control or diabetic platelets and VLDL, as well as normal or oxidized PL. Basal- and thrombin-stimulated transfers from diabetic VLDL were similar to those from control VLDL. However, LPL-stimulated transfer was decreased when using diabetic VLDL. This was likely due to their lowered ability to be lipolyzed. When we compared the platelets from either diabetic patients or control subjects, we observed that the transfers of PL from control VLDL to diabetic platelets were 20-30% higher than those to control platelets, whether in basal conditions or under LPL or thrombin stimulations. Finally, we observed that, in all conditions tested, the rate of transfers of oxidized PL was two to three times more elevated than that of non oxidized PL. Collective consideration of these data suggests that the transfer of PL from VLDL to platelets might be elevated in type 2 diabetes, favoring oxidative stress-mediated platelet hyperactivation.

Objectives: We sought to develop a noninvasive technique to quantify the thickness of a segment of the carotid artery wall that incorporates the adventitia and to identify whether differences in this measure are associated with cardiovascular risk factors., Background: There is increasing evidence that the arterial adventitia undergoes extensive structural alteration, including thickening, in response to arterial injury. However, there is currently no widely accepted noninvasive technique for studying the thickness of the arterial adventitia in humans., Methods: The carotid artery and jugular vein were imaged simultaneously in longitudinal section with the use of high-resolution ultrasound. The distance from the jugular intima-lumen interface to the carotid media-adventitia margin was denominated as the carotid extra-media thickness (EMT). This measure includes the arterial adventitia but not the arterial intima or media. We measured the carotid EMT and intima-media thickness (IMT) in 175 subjects, including 54 with diabetes, 43 with dyslipidemia, 26 with other cardiovascular risk factors, and 52 healthy control subjects., Results: When compared with control subjects, the EMT was increased in both the diabetes (p < 0.0001) and dyslipidemia (p = 0.04) groups. Multivariate linear regression analyses revealed that diabetes, high-density lipoprotein cholesterol (inverse association), and systolic blood pressure (J-shaped association) were the factors most strongly associated with EMT. These associations appear to be independent of carotid IMT., Conclusions: Carotid EMT can be assessed by ultrasonography. It is physically distinct from IMT and provides additional information concerning the vascular changes associated with cardiovascular risk factors. As such, the measurement of EMT, in addition to IMT, may provide a more complete indication of the structural modification of the vasculature associated with cardiovascular risk factors than that obtained by the measurement of carotid IMT alone.

Background: Two minor apolipoprotein A5 (APOA5) gene haplotypes, represented by -1131T>C and S19W polymorphisms, are strong determinants of plasma triglyceride (TG) concentration variability across human populations. Hypertriglyceridemia is frequent in type 2 diabetes (T2D) and hyperchylomicronemia is not uncommon., Methods: We investigated the association of -1131T>C and S19W polymorphisms with diabetic dyslipidemia in 400 Caucasian T2D patients divided in 2 groups: group N with 130 normotriglyceridemics (TG<90th percentile) and group M with 270 moderately hypertriglyceridemics. A third group of 51 diabetic patients (group H) with history of hyperchylomicronemia (TG>15 mM) was also studied., Results: The -1131C allele was more frequent in both mild and severe hypertriglyceridemia (20.6% vs 9.8% vs 5.0%, group H vs M vs N, p<0.001). The 19W allele was more frequent only in patients with hyperchylomicronemia (14.0% vs 6.5% vs 6.1%, group H vs M vs N, p=0.001). In group N+M, the -1131C allele was associated with higher TG (+13%, p=0.034) and lower HDLc (-10%, p=0.004). The 19W allele was only associated with lower HDLc (-9%, p=0.022)., Conclusion: These results suggest that in T2D APOA5 polymorphisms contribute to modulate dyslipidemia. Both -1131T>C and S19W polymorphisms are associated with hyperchylomicronemia and only -1131T>C polymorphism with mild hypertriglyceridemia.

Background: LDL-cholesterol therapeutic objectives attainment under lipid lowering therapy remains inadequate. The correlates of LDL-cholesterol therapeutic objective attainment have not been thoroughly explored in an observational setting., Methods: Patients under lipid lowering therapy and managed by general practitioners were included. LDL-cholesterol therapeutic objective was defined according to the number of cardiovascular risk factors associated with dyslipidemia (AFSSAPS-2005 guidelines)., Results: Most of the 2727 patients (mean age: 64.7+/-11.0) received a statin (70.0%) or a fibrate (24.3%) in monotherapy. 58.5% of patients at high cardiovascular risk did not reach therapeutic objective. Compared to simvastatin, patients receiving fibrates were less likely to be at therapeutic objective (OR=0.38, 95% CI=[0.26-0.54]). So were patients receiving fluvastatin (OR=0.41, IC95%=[0.26-0.64]) or pravastatin (OR=0.49, IC95%=[0.35-0.70]) at the dosages used by GPs. No significant difference appeared with atorvastatin (OR=0.99, 95% CI=[0.71-1.39]) or rosuvastatin (OR=1.25, CI95%=[0.77-2.02]). Patients with LDL-cholesterol levels<0.7 g/L tended to be prescribed high doses of lipid lowering therapy., Conclusions: In real conditions of lipid lowering therapy use, LDL-cholesterol therapeutic objective attainment was inadequate in high-risk patients, and TO differences were observed between drugs at prescribed doses.

Background: There is limited evidence as to whether the metabolic syndrome (MetS) is associated with depression or anxiety and, if so, whether this association is gender-specific. This study investigated in each gender whether the MetS is associated with anxiety or depression and whether these relationships are independent of age, obesity, smoking status, socioeconomic factors, and lifestyle., Methods: Metabolic syndrome (American Heart Association/National Heart, Lung, and Blood Institute criteria), depression, and anxiety (Hospital Anxiety and Depression Scale) were assessed in 1598 subjects at risk of cardiovascular disease., Results: In both men and women, the MetS was associated with an increased prevalence of depression but not anxiety. The number of components of the MetS increased with increasing levels of depression but not anxiety. This association between the MetS and depressive symptoms was independent of age, smoking status, socioeconomic factors, and lifestyle. The relationship was observed across body mass index categories and was independent of anxiety., Conclusions: The MetS is associated with depression and depressive symptoms but not anxiety irrespective of gender and overweight/obesity status in subjects at risk of cardiovascular disease. These findings suggest a potential importance of screening for depression in patients with the MetS.

Background and Aims: The use of phytosterol-enriched margarines (PEM) in patients at cardiovascular risk has not been thoroughly explored. We determined the proportion of users of PEM in a population at high cardiovascular risk, and their characteristics. In addition, the correlates of using at least 25 g/d of PEM were identified., Methods and Results: Patients with at least two cardiovascular risk factors in addition to dyslipidemia (primary prevention) or with past cardiovascular disease (secondary prevention) were recruited by general practitioners (GPs). Baseline characteristics were collected from a computerized GP database linked to a survey. GPs recorded patterns of PEM use. First, users were compared with non-users. Then, analyses were conducted to identify characteristics of patients using PEM at a recommended dose (>or=25 g/d). Among 1631 patients with documented consumption, a minority used PEM (15.2%), and only 36.4% of consumers used it at recommended level. Overall, PEM users did not differ from non-users as to general characteristics, nor as to the level of cardiovascular risk in primary prevention. However, PEM users reported significantly more cardiovascular events among their parents (OR=1.4; 95% CI=[1.0-1.9]). Consumers who used at least 25 g/d of PEM were more likely to be men (OR=3.1; 95% CI=[1.6-5.8]), to be aged 60-74 (OR=3.0; 95% CI=[1.4-6.4]), or 75 or older (OR=4.0; 95% CI=[1.5-10.6]). Again, no difference was observed regarding the level of cardiovascular risk., Conclusions: The level of use of PEM was low in this population of high cardiovascular risk patients. In addition, only a third of users consumed margarine at the recommended level. Our data suggest that pattern of use of PEM is not related to the level of cardiovascular risk.

The metabolic syndrome is associated with increased risk of cardiovascular disease. However, the association between metabolic syndrome and atherosclerosis in hypercholesterolemic patients remains unknown. We examined the association between carotid atherosclerosis and metabolic syndrome definitions using the NCEP-ATPIII, International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) definitions in 1782 subjects at risk of cardiovascular disease including 926 with hypercholesterolemia (LDL cholesterol > or =160 mg/dL; mean=203 mg/dL). Irrespective of definition, carotid intima-media thickness was significantly higher in both men and women diagnosed with the MetS compared to those without MetS. This relationship persists in males with hypercholesterolemia, independently of LDL cholesterol level. Regression analyses, both unadjusted and adjusted for traditional risk factors, indicate that in males the AHA/NHLBI definition, and in females the IDF definition are the strongest predictors of carotid atherosclerosis. These results highlight important gender differences that exist in the current clinical definitions of the metabolic syndrome, with regards to predicting early atherosclerotic lesions. In addition, this study shows that in males with hypercholesterolemia, MetS is independently associated with increased atherosclerosis, supporting screening for MetS among people at risk of CVD.

Postprandial hypertriglyceridemia is considered as a risk factor for cardiovascular disease in Type 2 diabetes. However, little is known about the underlying mechanisms. Since the recently discovered apolipoprotein (apo) AV was identified as a modulator of triglyceride (TG) metabolism, the aim of the study was to determine the postprandial apoAV profile of Type 2 diabetic patients. We compared data from 11 patients with Type 2 diabetes mellitus to that of 12 non-diabetic normolipidemic subjects following the ingestion of a lipid-rich cream. Postprandial apoAV was elevated in diabetic patients but no correlation was observed either with plasma TG concentration or with the intensity of lipoprotein lipase-dependent lipolysis. These data obtained in human subjects suggest that plasma apoAV concentration does not play an acute or a direct role in the regulation of plasma TG in the postprandial state.

Objective: In order to determine the influence of the lipid status on the ability of cholesteryl ester transfer protein (CETP) to modify the plasma lipoprotein profile, the effect of hypercholesterolemia versus hypertriglyceridemia were compared in wild-type and CETP-transgenic (CETPTg) rats expressing CETP at a constant level., Methods and Results: Wild-type and CETPTg rats were fed either a chow diet, a high fat/high cholesterol (HF/HC) diet, or a sucrose diet. As compared to wild-type rats, CETPTg rats fed the standard chow exhibited lower high-density lipoproteins (HDL)-cholesterol concentration (-65%, p<0.01), but similar non-HDL-cholesterol concentrations. Both wild-type and CETPTg rats fed the HF/HC diet displayed pronounced increases in total and non-HDL-cholesterol levels, with no influence of CETP expression in this case. In contrast, the sucrose diet produced significant changes only in CETPTg rats which then exhibited a 82% increase in non-HDL-cholesterol in addition to a 80% reduction in HDL cholesterol when compared to sucrose-fed, wild-type rats (p<0.01 in both cases). The triglyceride to cholesterol ratio in very low-density lipoprotein (VLDL) was 10-fold lower in 'HF/HC' rats than in 'chow' and 'sucrose' rats (p<0.005 and p<0.01, respectively), and VLDL from 'HF/HC' animals were proven to constitute poor cholesteryl ester acceptors., Conclusions: CETP expression modified dramatically the lipoprotein phenotype in 'sucrose' rats but not in 'HF/HC' rats. These observations suggest that a CETP inhibitor treatment is susceptible to produce profound changes in hypertriglyceridemia or combined hyperlipidemia.

Adherence to lifestyle recommendations for prevention of cardiovascular disease remains a critical issue. We examined the association of anxiety and depression with healthy behaviors in a large population of subjects at risk of cardiovascular disease. We studied 1612 consecutive subjects referred for evaluation of cardiovascular risk factors. Separated scores reflecting unhealthy behaviors (physical inactivity, smoking and poor diet) were combined to produce a global unhealthy lifestyle score. The Hospital Anxiety and Depression scale (HAD) was used to assess both anxiety and depression. Both anxiety and depression were significantly associated with physical inactivity in both sexes and with an unhealthy diet in men but not in women. Anxiety and depression were both significantly correlated to smoking habits in men whereas only depression was related to smoking in women. In both sexes, the global score reflecting unhealthy lifestyles was positively associated with the degree of anxiety and depression. In multivariate analysis, both anxiety and depression appeared as independent determinant of unhealthy lifestyle in both sexes, with a stronger influence for depression. Depression and to a lesser extent anxiety are associated with a cluster of unhealthy behaviors in subjects at risk of cardiovascular disease, suggesting the difficulty of modifying lifestyle in patients with anxious-depressive disorders.

Aim: To evaluate in a prospective study the association of XbA1 apolipoprotein B (apoB) gene polymorphism with lipid parameters and cardiovascular (CV) events in a type 2 diabetic cohort., Methods and Results: A cohort of 212 type 2 diabetic patients, free of any cardiovascular complication, was studied. Cardiovascular events were registered for all the patients for 5 years. XbA1 apolipoprotein B gene polymorphism was analysed by PCR-RFLP method. A mild increase in HbA1c was found in X+X+ carriers (P = 0.014). Despite this lower glycemic control, there were no differences between genotype subgroups for lipid parameters except for apoB, significantly higher in X+X+ than in X-X- subjects. In univariate analysis, the cardiovascular events rate was higher in X-X- but did not reach statistical significance (P =0.07). In stepwise multivariate regression analysis, cardiovascular events risk was significantly higher in X- carriers (P = 0.014) and also in smokers, microalbuminuric and older patients., Conclusions: We report for the first time in a prospective study the association of XbA1 apolipoprotein B gene polymorphism and cardiovascular events in a diabetic population. The mechanism underlying the excess of cardiovascular risk in X- carriers, despite a better metabolic profile, is likely to involve a linkage disequilibrium between apolipoprotein B gene locus and another gene locus related to cardiovascular risk.

Postprandial lipid metabolism is largely dependent upon lipoprotein lipase (LPL), which hydrolyses triglycerides (TGs). The time course of LPL activity in the postprandial state following a single meal has never been studied, because its determination required heparin injection. Recently, we have shown that LPL activity could be accurately measured in nonheparinized VLDL using a new assay aiming to determine the LPL-dependent VLDL-TG hydrolysis. Based on the same principle, we used in this study TG-rich lipoprotein (TRL)-bound LPL-dependent TRL-TG hydrolysis (LTTH) to compare the time course of LPL activity of 10 type 2 diabetics to that of 10 controls, following the ingestion of a lipid-rich meal. The peak TG concentration, reached after 4 h, was 67% higher in diabetics than in controls (P < 0.005). Fasting LTTHs were 91.3 +/- 15.6 in controls versus 70.1 +/- 4.8 nmol NEFA/ml/h in diabetics (P < 0.001). LTTH was increased 2 h postprandially by 190% in controls and by only 89% in diabetics, resulting in a 35% lowering of the LTTH area under the curve in diabetics. Postprandial LTTH was inversely correlated with TG or remnant concentrations in controls but not in diabetics, and with insulin resistance in both groups. These data show that TRL-bound LPL activity increases in the postprandial state and is strongly reduced in type 2 diabetes, contributing to postprandial hypertriglyceridemia.

In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P < 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P < 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P < 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.