Short-term exposure to exogenous lipids in premature infants and long-term changes in aortic and cardiac function.

OBJECTIVE: Intravenous lipid use is associated with an acute hyperlipidemia, but long-term consequences have not been studied. We investigated whether elevated lipids in humans during the critical period of preterm neonatal life have a long-term impact on aortic and myocardial function relevant to adult disease. METHODS AND RESULTS: We followed up 102 subjects born prematurely and now aged 23 to 28 years. Eighteen received intravenous lipids as neonates and were matched to controls with equivalent perinatal characteristics. Global and regional aortic stiffness and left ventricular function were assessed by cardiovascular magnetic resonance. Those who received intravenous lipids had greater aortic stiffness in early adulthood (P=0.0002), with greater stiffness in the abdominal aorta (P=0.012). The relationship was graded according to the elevation in neonatal cholesterol induced by intravenous lipids (P<0.0001) but not other metabolic parameters altered by the infusion. Peak systolic circumferential strain was also reduced in the lipid group (P=0.006), which, again, was proportional to neonatal cholesterol level (P<0.01). CONCLUSIONS: Aortic and myocardial function in young adulthood is associated with intralipid exposure during neonatal life for preterm infants, in a graded manner related to the rise in cholesterol. Circulating cholesterol during critical developmental periods may have long-term impacts on the human cardiovascular system.

Correlation of atherosclerosis between different topographic sites is highly dependent on the type of hyperlipidemia.

There is a surprising paucity of studies that provide quantitative correlative data on the extent of atherosclerosis between different topographic sites. The impact of cardiovascular risk factors is dependent on the vascular bed, which underlies site-selective effects on progression of atherosclerosis. Therefore, the intraindividual correlation of atherosclerosis between different topographic sites may be dependent on the specific cardiovascular risk profile. The focused objective of the current study is to evaluate whether the correlation of the extent of atherosclerosis between different topographic sites is dependent on the type of hyperlipidemia. Atherosclerosis was quantified at four different topographic locations in the aorta of rabbits with type II or type III hyperlipidemia. Correlation coefficients and semi-partial correlation coefficients adjusted for plasma lipoproteins and sex were determined to compare the degree of atherosclerosis at different topographic sites. Semi-partial correlations adjusted for total plasma cholesterol, plasma triglycerides, and sex of the intima/media ratio between different topographic sites were highly dependent on the type of hyperlipidemia. E.g., the semi-partial correlation coefficient between the intima/media ratio at the level of the ascending aorta and at the level of the descending thoracic aorta was 0.87 (p < 0.0001) in the model of type II hyperlipidemia and was only 0.10 (p = NS) in the model of type III hyperlipidemia. This divergent pattern was also observed for other intersite correlations. Semi-partial Pearson correlation coefficients were very similar to unadjusted Pearson correlation coefficients. Correlation of atherosclerosis between different topographic sites may vary importantly in relation to the type of hyperlipidemia.

[Cutting-edge research on the metabolism of remnant lipoproteins].

Lipoproteins in the plasma transport lipids to various tissues through the bloodstream. In an analysis based on specific gravity using ultracentrifugation, these can be divided into 4 main fractions: chylomicrons, VLDL, LDL, and HDL. Metabolism of the triglyceride-rich (TG-rich) lipoproteins, chylomicrons and VLDL, begins with the hydrolysis of TGs by lipoprotein lipase (LPL) and proceeds through intermediate metabolites (remnants). Those resulting from the former are referred to as chylomicron remnants, and those from the latter as VLDL remnants. Both types of remnant are enriched in cholesteryl esters and apolipoprotein E (apoE), and, moreover, they are referred to as atherogenic lipoproteins that readily accumulate in the arterial walls. At the research level, the analytical methods for remnants such as electrophoresis, ultracentrifugation, gel filtration, etc., are not necessarily simple. One of the methods used as a clinical laboratory test for the quantification of remnant lipoproteins is the remnant-like particle-cholesterol (RLP-C) assay. The significance of the assay as an evaluation for arteriosclerosis is well recognized internationally. Recently, a new method for measuring remnant lipoprotein cholesterol (RemL-C) has been developed that uses a reagent consisting of enzymes and a surfactant. With this method, measurements simply involve an automated analyzer in the same manner as for the homogeneous assay for HDL-C or LDL-C and have been shown to correlate well with values using conventional RLP-C reagents. Measurements can be made simply without the need for special equipment in a short period of time, about 10 minutes. Furthermore, this means that measurements can be made in this way with higher reproducibility and precision. Nevertheless, where the principles behind the two assays are different, discrepancies in the measured values can be identified in some cases. It is also important to understand the characteristics of both methods when using them. After detailing lipoprotein remnant measurement methods, we point out the significance of lipoprotein remnant measurements under conditions that have been the focus of recent particular attention, such as postprandial hyperlipidemia and metabolic syndrome.

Differential DNA methylation in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a monogenic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C). A FH causing genetic variant in LDLR, APOB, or PCSK9 is not identified in 12-60% of clinical FH patients (FH mutation-negative patients). We aimed to assess whether altered DNA methylation might be associated with FH in this latter group. METHODS: In this study we included 78 FH mutation-negative patients and 58 FH mutation-positive patients with a pathogenic LDLR variant. All patients were male, not using lipid lowering therapies and had LDL-C levels >6 mmol/L and triglyceride levels <3.5 mmol/L. DNA methylation was measured with the Infinium Methylation EPIC 850 K beadchip assay. Multiple linear regression analyses were used to explore DNA methylation differences between the two groups in genes related to lipid metabolism. A gradient boosting machine learning model was applied to investigate accumulated genome-wide differences between the two groups. FINDINGS: Candidate gene analysis revealed one significantly hypomethylated CpG site in CPT1A (cg00574958) in FH mutation-negative patients, while no differences in methylation in other lipid genes were observed. The machine learning model did distinguish the two groups with a mean Area Under the Curve (AUC)±SD of 0.80±0.17 and provided two CpG sites (cg26426080 and cg11478607) in genes with a possible link to lipid metabolism (PRDM16 and GSTT1). INTERPRETATION: FH mutation-negative patients are characterized by accumulated genome wide DNA methylation differences, but not by major DNA methylation alterations in known lipid genes compared to FH mutation-positive patients. FUNDING: ZonMW grant (VIDI no. 016.156.445).

Coronary artery disease in a child with homozygous familial hypercholesterolemia: Regression after liver transplantation.

Children with homozygous familial hypercholesterolemia are at risk for early cardiovascular events secondary to coronary artery disease. Current medical therapy does not ameliorate this risk. Liver transplantation offers the most effective option to reduce circulating levels of low-density lipoprotein cholesterol and thereby reduce risk of cardiovascular events. Angiographic evidence of regression of coronary artery disease is presented.

Evaluation of the role of STAP1 in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is characterised by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and a substantial risk for cardiovascular disease. The autosomal-dominant FH is mostly caused by mutations in LDLR (low density lipoprotein receptor), APOB (apolipoprotein B), and PCSK9 (proprotein convertase subtilisin/kexin). Recently, STAP1 has been suggested as a fourth causative gene. We analyzed STAP1 in 75 hypercholesterolemic patients from Berlin, Germany, who are negative for mutations in canonical FH genes. In 10 patients with negative family history, we additionally screened for disease causing variants in LDLRAP1 (low density lipoprotein receptor adaptor protein 1), associated with autosomal-recessive hypercholesterolemia. We identified one STAP1 variant predicted to be disease causing. To evaluate association of serum lipid levels and STAP1 carrier status, we analyzed 20 individuals from a population based cohort, the Cooperative Health Research in South Tyrol (CHRIS) study, carrying rare STAP1 variants. Out of the same cohort we randomly selected 100 non-carriers as control. In the Berlin FH cohort STAP1 variants were rare. In the CHRIS cohort, we obtained no statistically significant differences between carriers and non-carriers of STAP1 variants with respect to lipid traits. Until such an association has been verified in more individuals with genetic variants in STAP1, we cannot estimate whether STAP1 generally is a causative gene for FH.

Efficacy and Safety of Alirocumab in Japanese Patients with Diabetes Mellitus: Post-hoc Subanalysis of ODYSSEY Japan.

AIM: To examine the efficacy and safety of alirocumab in Japanese patients with dyslipidemia with or without diabetes mellitus (DM). METHODS: Patients (n=216) with heterozygous familial hypercholesterolemia (heFH), non-FH at high cardiovascular risk with coronary artery disease (CAD), or category III (primary prevention) were enrolled; 148 (68.5%) patients had a diagnosis of DM at baseline. Patients were randomized (2:1), with stratification factor (heFH, non-FH), to alirocumab (75 mg every 2 weeks [Q2W] with increase to 150 mg if week 8 LDL-C was above predefined limits) or placebo subcutaneously for 52 weeks on top of stable statin therapy. RESULTS: At Week 24, least square (LS) mean±standard error changes in low-density lipoprotein cholesterol (LDL-C) concentration from baseline in alirocumab-treated patients were －63.1±1.6% and －60.8±2.7% in those with and without DM. These LDL-C reductions were maintained to Week 52: －63.0±1.6% (LS mean difference vs placebo －62.4±3.0%; P＜0.0001) with DM and －61.3±2.8% (LS mean difference vs placebo －53.4±4.0%; P＜0.0001) without DM. The most common adverse events in the alirocumab group were nasopharyngitis, back pain, injection site reaction, and fall. No particular safety signals or concerns were noted between DM and non-DM groups at 52 weeks. A dose-increase in alirocumab from 75 to 150 mg Q2W was necessary in two heFH patients, neither of whom had DM. CONCLUSIONS: In high-cardiovascular-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab produced substantial and sustained LDL-C reductions throughout the 52-week study regardless of DM status at baseline, with a similar safety profile to placebo.

Oral Fat Tolerance Test for Sitosterolemia and Familial Hypercholesterolemia: A Study Protocol.

AIM: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plasma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH). METHODS: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading. RESULTS: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients. CONCLUSION: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).

Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress.

BACKGROUND: Atherosclerotic lesions are predominantly observed in curved arteries and near side branches, where low or oscillatory shear stress patterns occur, suggesting a causal connection. However, the effect of shear stress on plaque vulnerability is unknown because the lack of an appropriate in vivo model precludes cause-effect studies. METHODS AND RESULTS: We developed a perivascular shear stress modifier that induces regions of lowered, increased, and lowered/oscillatory (ie, with vortices) shear stresses in mouse carotid arteries and studied plaque formation and composition. Atherosclerotic lesions developed invariably in the regions with lowered shear stress or vortices, whereas the regions of increased shear stress were protected. Lowered shear stress lesions were larger (intima/media, 1.38+/-0.68 versus 0.22+/-0.04); contained fewer smooth muscle cells (1.9+/-1.6% versus 26.3+/-9.7%), less collagen (15.3+/-1.0% versus 22.2+/-1.0%), and more lipids (15.8+/-0.9% versus 10.2+/-0.5%); and showed more outward vascular remodeling (214+/-19% versus 117+/-9%) than did oscillatory shear stress lesions. Expression of proatherogenic inflammatory mediators and matrix metalloproteinase activity was higher in the lowered shear stress regions. Spontaneous and angiotensin II-induced intraplaque hemorrhages occurred in the lowered shear stress regions only. CONCLUSIONS: Lowered shear stress and oscillatory shear stress are both essential conditions in plaque formation. Lowered shear stress induces larger lesions with a vulnerable plaque phenotype, whereas vortices with oscillatory shear stress induce stable lesions.

Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.

Familial hypercholesterolemia (FH), an autosomal dominant disease caused by mutations in the LDL receptor gene, is five times more frequent in the Afrikaner population of South Africa than it is in the population of the United States and Europe. It has been proposed that the high frequency is due to a founder effect. In this paper, we characterized 24 mutant LDL receptor alleles from 12 Afrikaner individuals homozygous for FH. We identified two mutations that together makeup greater than 95% of the mutant LDL receptor genes represented in our sample. Both mutations were basepair substitutions that result in single-amino acid changes. Each mutation can be detected readily with the polymerase chain reaction and restriction analysis. The finding of two common LDL receptor mutations in the Afrikaner FH homozygotes predicts that these mutations will predominate in the Afrikaner population and that the high frequency of FH is due to a founder effect. The increased incidence of ischemic heart disease in the Afrikaner population may in part be due to the high frequency of these two mutations in the LDL receptor gene.

The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland.

A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH.

Common low-density lipoprotein receptor mutations in the French Canadian population.

Familial hypercholesterolemia (FH) has a frequency of 0.2% in most populations of the world. In selected populations such as the Afrikaners in South Africa, the Christian Lebanese, and the French Canadians, the disease is more frequent due to the founder effect. Previous studies demonstrated that a single mutation at the LDL receptor locus, the so-called French Canadian deletion, makes up 60% of the mutant genes responsible for FH in the French Canadian population. In this study, efforts were directed to determine if there were other common LDL receptor mutations in this population. Three missense mutations were identified and each mutation was reproduced and expressed in vitro. Two of the three mutations result in the production of an LDL receptor protein that is not processed to its mature form at a normal rate. Molecular assays were developed to detect the mutations directly, and the LDL receptor genes of 130 French Canadian FH heterozygotes were screened for the presence of the three missense mutations as well as two deletions. LDL receptor mutations were detected in 76% of individuals and 14% had one of the three missense mutations.

In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia.

The causes of primary moderate hypercholesterolemia are not understood, but some patients have reduced fractional clearance rates (FCRs) for low density lipoproteins (LDL). This could be due to either decreased activity of LDL receptors or to a defect in structure (or composition) of LDL that reduces its affinity for receptors. To distinguish between these causes, simultaneous turnover rates of autologous and normal homologous LDL were determined in 15 patients with primary moderate hypercholesterolemia. In 10, turnover rates of both types of LDL were indistinguishable, which indicated that autologous LDL was cleared as efficiently as normal homologous LDL. In five others, FCRs for autologous LDL were significantly lower than for homologous LDL. Two of the latter five were treated with mevinolin, and although FCRs for both types of LDL rose during treatment, differences in FCRs between the two types of LDL persisted. In these five patients, autologous LDL appeared to be a poor ligand for LDL receptors.

Hepatic overexpression of bovine scavenger receptor type I in transgenic mice prevents diet-induced hyperbetalipoproteinemia.

Hepatic scavenger receptors (SR) may play a protective role by clearing modified lipoproteins before they target the artery wall. To gain insight into this hypothesized function, transgenic mice expressing hepatic bovine SR (TgSR) were created and studied when fed chow, and during diet-induced hyperlipidemia. SR overexpression resulted in extensive hepatic parenchymal cell uptake of fluorescently labeled acetylated human low density lipoprotein (DiI ac-hLDL) and a twofold increase in 125I-acetylated-LDL clearance. Food intake and cholesterol absorption was indistinguishable between control and TgSR mice. In chow-fed mice, lipoprotein cholesterol was similar in control and TgSR mice. However, on a 3-wk high fat/cholesterol (HFHC) diet, the rise in apoB containing lipoproteins was suppressed in TgSR+/- and TgSR+/+ mice. The rise in HDL was similar in control and TgSR+/- mice, but significantly elevated in the TgSR+/+ mice. Overall, on chow, the ratio of apo-B containing lipoprotein cholesterol to HDL cholesterol was similar for all groups (control = 0.33; TgSR+/- = 0.32; TgSR+/+ = 0.38). However, after 3 wk on the HFHC diet, this ratio was markedly higher in control (2.34 +/- 0.21) than in either TgSR+/- (1.00 +/- 0.24) or TgSR+/+ (1.00 +/- 0.19) mice. In TgSR+/- mice, hepatic cholesteryl esters were reduced by 59%, 7 alpha-hydroxylase mRNA levels were elevated twofold, and a significant increase in fecal bile acid flux was observed after the 3-wk HFHC diet. These results suggest SR may play a protective role in liver by preventing diet-induced increases in apoB containing lipoproteins.

High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.

BACKGROUND: The reason why lipoprotein(a) concentrations are raised in individuals with clinical familial hypercholesterolaemia is unclear. We tested the hypotheses that high lipoprotein(a) cholesterol and LPA risk genotypes are a possible cause of clinical familial hypercholesterolaemia, and that individuals with both high lipoprotein(a) concentrations and clinical familial hypercholesterolaemia have the highest risk of myocardial infarction. METHODS: We did a prospective cohort study that included data from 46 200 individuals from the Copenhagen General Population Study who had lipoprotein(a) measurements and were genotyped for common familial hypercholesterolaemia mutations. Individuals receiving cholesterol-lowering drugs had their concentrations of LDL and total cholesterol multiplied by 1·43, corresponding to an estimated 30% reduction in LDL cholesterol from the treatment. In lipoprotein(a) cholesterol-adjusted analyses, total cholesterol and LDL cholesterol were adjusted for the lipoprotein(a) cholesterol content by subtracting 30% of the individuals' lipoprotein(a) total mass before total and LDL cholesterol were used for diagnosis of clinical familial hypercholesterolaemia. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria to clinically diagnose familial hypercholesterolaemia. Cox proportional hazard regression calculated hazard ratios (95% CI) of myocardial infarction. FINDINGS: Using unadjusted LDL cholesterol, mean lipoprotein(a) concentrations were 23 mg/dL in individuals unlikely to have familial hypercholesterolaemia, 32 mg/dL in those with possible familial hypercholesterolaemia, and 35 mg/dL in those with probable or definite familial hypercholesterolaemia (ptrend<0·0001). However, when adjusting LDL cholesterol for lipoprotein(a) cholesterol content the corresponding values were 24 mg/dL for individuals unlikely to have familial hypercholesterolaemia, 22 mg/dL for those with possible familial hypercholesterolaemia, and 21 mg/dL for those with probable or definite familial hypercholesterolaemia (ptrend=0·46). High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia and LPA risk genotypes were more frequent in clinical familial hypercholesterolaemia, whereas lipoprotein(a) concentrations were similar in those with and without familial hypercholesterolaemia mutations. The hazard ratios (HRs) for myocardial infarction compared with individuals unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less were 1·4 (95% CI 1·1-1·7) in those unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentrations of more than 50 mg/dL, 3·2 (2·5-4·1) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less, and 5·3 (3·6-7·6) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of more than 50 mg/dL. In analyses using Simon Broome or MEDPED criteria, results were similar to those using DLCN criteria to diagnose clinical familial hypercholesterolaemia. INTERPRETATION: High lipoprotein(a) concentrations and corresponding LPA risk genotypes represent novel risk factors for clinical familial hypercholesterolaemia. Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction. FUNDING: Danish Heart Association and IMK General Fund, Denmark.

Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice.

BACKGROUND: The CC-chemokines (CKs) recruit monocytes/macrophages to sites of inflammation; several different CC-CKs play a role in the pathogenesis of atherosclerosis. The vaccinia virus expresses a 35-kDa soluble protein (35K) that binds to and inactivates nearly all of the CC-CKs, providing a potentially useful therapeutic strategy for broad-spectrum CC-CK inhibition in atherosclerosis. A recombinant adenovirus encoding soluble 35K (Ad35K) was generated to investigate the effect of 35K gene transfer on atherosclerosis in Western diet-fed apolipoprotein E-knockout (ApoE KO) mice. METHODS AND RESULTS: ApoE KO mice received tail-vein injections of phosphate-buffered saline, Ad35K, or control adenovirus AdGFP encoding green fluorescence protein. Two weeks after Ad35K gene transfer, atherosclerotic lesion area was significantly reduced in aortic roots by 55% compared with PBS or AdGFP control mice (P<0.05). Furthermore, 35K gene transfer strikingly reduced the macrophage content in aortic root lesions by 85% (P<0.01) and reduced lipid deposition in descending aortas by more than half (P<0.05). By an in vitro chemotaxis assay, plasma and aortic homogenates from 35K gene transfer mice promoted significantly less CC-CK-induced cell migration than did PBS or AdGFP controls. CONCLUSIONS: These findings show that a single intravenous injection of a recombinant adenovirus encoding the broad-spectrum CC-CK inhibitor 35K can reduce atherosclerosis by inhibiting CC-CK-induced macrophage recruitment in atherosclerotic ApoE KO mice. These experiments suggest that CC-CKs play an important role in atherogenesis and are a rational target for therapeutic intervention.

A critical evaluation of the putative role of C3adesArg (ASP) in lipid metabolism and hyperapobetalipoproteinemia.

The acylation stimulating protein, ASP is a small, basic serum protein capable of stimulating triglyceride synthesis in cultured fibroblasts and adipocytes. Sequence analysis of ASP has shown that ASP is identical to C3adesArg the inactive fragment of the complement anaphylatoxin peptide, C3a. It has been proposed that C3adesArg (ASP) can be generated by mature adipocytes secreting the three complement proteins: complement protein C3, factor B and factor D (adipsin). There have also been indications that adipocytes may express a specific C3adesArg (ASP)-receptor that is distinct from the recently cloned C3a-receptor. This suggests that C3adesArg (ASP) acts as an adipocyte autocrine and that it plays a central role in the metabolism of adipose tissue. Based on these observations a hypothesis for the etiology of hyperapobetalipoproteinemia (hyperapoB) has been proposed. Hyperapobetalipoproteinemia (hyperapoB), is a familial lipoprotein disorder characterized by increased hepatic secretion of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) particles. If C3adesArg (ASP) function in the adipose tissue is impaired, a reduced rate of triglyceride synthesis will follow, generating an increased flux of fatty acids to the liver. In response to an increased flow of fatty acids, the liver will increase its production of VLDL particles yielding the phenotype of hyperapoB. This review critically assesses this hypothesis and the potential role of C3adesArg (ASP) as a major determinant for triglyceride synthesis in the light of data collected in vitro and in vivo.

Hot Topics in Primary Care: Familial Hypercholesterolemia in Youth.

Worldwide, guidelines support early identification, aggressive lifestyle management, and pharmacologic lipid lowering therapies when appropriate in youth with FH. These guidelines are aimed at improving the unending cycle of premature CHD in families despite the vast body of knowledge regarding the natural history of undiagnosed and untreated FH. Although valid concerns have been raised about treating youth other than those with FH with lipid-lowering pharmaceuticals, we believe the preponderance of the evidence laid forth by multiple professional societies from the United States and abroad is clearly weighted in favor of early diagnosis and treatment with lifestyle modification, to prevent the acquisition of other risk factors, and habituation to lifelong low-fat diet and adequate physical activity. We can think of no other instance where providers in the field of family medicine could have such a profound impact on the current and future health of child and parent and even future generations.

The UMD-LDLR database: additions to the software and 490 new entries to the database.

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), one of the most frequent hereditary dominant disorders. The protein defect was identified in 1973, the gene was localized by in situ hybridization in 1985, and since, a growing number of mutations have been reported. The UMD-LDLR database is customized software that has been developed to list all mutations, and also to provide means to analyze them at the nucleotide and protein levels. The database has been recently modified to fulfill the recommendations of the Nomenclature Working Group for human gene mutations. However, in the current version, both the nomenclature and usual LDLR gene mutation names are reported since the latter are more commonly used. The software has also been modified to accommodate the splicing mutations and alleles that carry two nucleotide variations. The current version of UMD-LDLR contains 840 entries, of which 490 are new entries. Point mutations account for 90% of all mutations in the LDLR gene; the remaining are mostly major rearrangements, due to the presence of Alu sequences. Three new routines have been implemented in the software, thus giving users access to 13 sorting tools. In addition to the database, a Web site containing information about polymorphisms, major rearrangements, and promoter mutations is available. Both are accessible to the scientific community (www.umd.necker.fr) and should help groups working on LDLR to check their mutations and identify new ones, and greatly facilitate the understanding of functional classes/genotype relationships and of genotype/phenotype correlations.

A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.

BACKGROUND: Familial hypercholesterolaemia (FH) affects approximately 1 in 500 people (10 million world-wide) and the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years. Based on a systematic literature search, we review the natural history of FH, describe the diagnostic criteria, and consider the effectiveness of treatment. METHODS: A comprehensive review was conducted of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH, and the evidence on the effectiveness of treatment of FH in adults and children. Treatment options have changed since statin treatment became available, and we have not considered pre-statin therapy studies of treatment effectiveness. FINDINGS AND DISCUSSION: A clinical diagnosis of FH is widely used, but a definitive diagnosis can be made by genetic screening, although mutations are currently only detected in 30-50% of patients with a clinical diagnosis. Under-diagnosis of FH has been reported world-wide ranging from less than 1% to 44%. The relative risk of death of FH patients not treated with statins is between three and fourfold but treatment is effective, and delays or prevents the onset of coronary heart disease. Early detection and treatment is important. Aggressive LDL therapy is more effective in the regression of the carotid intima media thickness than conventional LDL therapy. Diagnosis at birth is problematic, and should be delayed until at least 2 years of age. Statins are not generally recommended for the treatment of children up to adolescence. Resins may be used but poor adherence is a problem. Technical advances in mutation detection, and the identification of other genes that cause FH, are likely to have important implications for the cost effectiveness of genetic diagnosis of FH.