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Item does not contain fulltext AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104 682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be approximately 1 : 300 000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 +/- 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.

Item does not contain fulltext PURPOSE OF REVIEW: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). RECENT FINDINGS: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. SUMMARY: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.

AIMS: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).METHODS AND RESULTS: Of the theoretical estimated prevalence of 1/500 for heterozygous FH, CONCLUSION: Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

Item does not contain fulltext BACKGROUND: IL-32 has been previously shown to promote inflammation in rheumatoid arthritis patients and to contribute to IL-1beta-induced ICAM-1 as well as other proinflammatory cytokines synthesis in human umbilical endothelial cells (HUVECs). Given the high rate of atherosclerosis in RA, these observations suggest that IL-32 may be involved in the inflammatory pathways of atherosclerosis. METHODS: mRNA and protein levels of IL-32 were determined in human atherosclerotic arterial vessel wall tissue by quantitative real-time PCR and immunohistochemistry. HUVEC and M1/M2 macrophages were stimulated with proinflammatory cytokines and TLR ligands to assess IL-32 mRNA induction. Human THP1 macrophages were transduced with AdIL-32gamma, to investigate induction of several proatherosclerotic mediators. Finally, aortas from IL-32gamma transgenic mice were studied and compared with aortas from age-matched wild-type mice. RESULTS: IL-32 expression was detectable in human atherosclerotic arterial vessel wall, with the expression of IL-32beta and IL-32gamma mRNA significantly enhanced. TLR3-ligand Poly I:C in combination with IFNgamma were the most potent inducers of IL-32 mRNA expression in both HUVEC and M1/M2 macrophages. Adenoviral overexpression of IL-32gamma in human THP1 macrophages resulted in increased production of CCL2, sVCAM-1, MMP1, MMP9, and MMP13. The IL-32gamma transgenic mice chow a normal fat diet exhibited vascular abnormalities resembling atherosclerosis. CONCLUSIONS: IL-32 acts as a proinflammatory factor and may be implicated in the inflammatory cascade contributing to atherosclerosis. By promoting the synthesis of matrix metalloproteinases, it may further contribute to plaque instability. Further studies are warranted to investigate whether IL-32 may serve as a potential therapeutic target in fighting atherosclerosis.

Anemia is present in more than 40% of the patients with chronic heart failure (CHF), especially in those with reduced ejection fraction. The etiology is not yet understood. Hematocrit is a major determinant of whole blood viscosity, which is an important factor of the total peripheral resistance for the heart. Therefore, lowering blood viscosity may reduce after-load for the failing heart. Patients with homozygous familial hypercholesterolemia (HFH) are characterized by markedly elevated low-density lipoprotein (LDL) cholesterol levels and premature ischemic heart disease. Selective LDL-cholesterol apheresis in HFH patients to remove LDL from the circulation is the recommended treatment of this condition and has been shown to reduce whole blood viscosity. The level of B-type Natriuretic Peptide (BNP) is a parameter of filling conditions in the heart and is predominantly induced by cardiac after-load. BNP was measured in 4 consecutive HFH patients before and after treatment with selective LDL-apheresis. We observed that 20% reduction of blood viscosity by LDL-apheresis in these patients resulted in 40% lower levels of BNP. In chronic heart failure patients, anemia might be a compensatory mechanism of the organism in order to reduce after-load for the failing heart by lowering blood viscosity.

Item does not contain fulltext Dyslipidemia, especially elevated serum levels of cholesterol, is causally related to cardiovascular disease. The specific role of triglycerides has long been controversial. In this article we discuss the role of serum triglycerides in relation to the risk of cardiovascular disease. First, the (patho)physiology of triglycerides is described, including the definition and a short summary of the primary and secondary causes of hypertriglyceridemia. Furthermore, we will give an overview of the published epidemiological studies concerning hypertriglyceridemia and cardiovascular disease to support the view that triglyceride-rich lipoproteins are an independently associated risk factor. Finally, treatment strategies and treatment targets are discussed. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. 01 mei 2012

Contains fulltext : 97193.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL. METHODS AND RESULTS: Surprisingly, anti-inflammatory M2 macrophages but not pro-inflammatory M1 macrophages rapidly accumulated oxidized LDL. Simultaneously, expression of Kruppel-like factor 2, a nuclear transcription factor known to suppress inflammation in endothelial cells and monocytes, decreased and the functional phenotype of M2 macrophages shifted towards a pro-inflammatory profile, characterized by higher production of IL-6, IL-8 and MCP-1 and lower expression of IL-10 upon stimulation with LPS. In contrast, Kruppel-like factor 2 expression and the phenotype of M1 macrophages remained largely unchanged upon oxidized LDL exposure. Downregulation of Kruppel-like factor 2 expression of M2 macrophages using siRNA technology led to a significant increase of LPS-induced MCP-1 secretion. CONCLUSIONS: We show that (1) anti-inflammatory M2 macrophages are more susceptible to foam cell formation than pro-inflammatory M1 macrophages, (2) exposure to oxidized LDL renders M2 macrophages pro-inflammatory, and (3) Kruppel-like factor 2 is involved in the enhanced secretion of MCP-1 by M2 macrophages loaded with oxidized LDL. The phenotype switch of M2 macrophages from an anti- to a pro-inflammatory profile may play an important role in pathogenesis of atherosclerosis, and could represent a novel therapeutic target.

BACKGROUND: To compare apolipoprotein B (apoB), non-high-density lipoprotein-cholesterol (non-HDL-c) and low-density lipoprotein-cholesterol (LDL-c) for identifying individuals with a deteriorated cardiovascular (CV) risk profile, including a panel of subclinical atherosclerosis measurements and prevalent cardiovascular disease (CVD) in a Dutch population-based cohort. METHODS: Clinical and biochemical measurements and a panel of noninvasive parameters of subclinical atherosclerosis were determined in 1517 individuals, aged 50-70 years. RESULTS: Both men and women with increasing levels of apoB and non-HDL-c were more obese, had higher blood pressure and fasting glucose levels, and a more atherogenic lipid profile. Furthermore, compared to the reference group (composed of those with apoB, non-HDL-c and LDL-c levels in the bottom quartiles), participants with high apoB and high non-HDL-c levels had a lower ankle-brachial index at rest (-3.5% and -3.1%, respectively) and after exercise (-6.3% and -4.7%, respectively), a thicker near wall (+4.8% and +4.2%, respectively), far wall (both +6.2%), and mean intima-media thickness (+5.7% and +5.3%, respectively) and more plaques (+54.2% and +54.3%, respectively). In addition, they also showed increased stiffness parameters (e.g. pulse wave velocity both +3.6%). Less clear differences in CV risk profile and subclinical atherosclerosis parameters were observed when participants were stratified by LDL-c level. Furthermore, apoB but not LDL-c detected prevalent CVD, and non-HDL-c only detected prevalent CVD in men. The discriminatory power for prevalent CVD expressed as area under the receiver operating characteristic curve was 0.60 (P < 0.001) for apoB, 0.57 (P = 0.001) for non-HDL-c and 0.54 (P = 0.108) for LDL-c. CONCLUSION: Our data support the use of first apoB and secondly non-HDL-c above LDL-c for identifying individuals from the general population with a compromised CV phenotype.

Contains fulltext : 88642.pdf (Publisher’s version ) (Closed access) BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels or=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c >or=2.5mmol/l and not using maximum therapy. CONCLUSION: Only a small proportion of patients with heFH reaches the LDL-c treatment target of

Contains fulltext : 89207.pdf (Publisher’s version ) (Closed access) BACKGROUND: Familial hypercholesterolemia (FH) has been associated with increased cardiovascular risk when untreated or when normal LDL-C concentrations are not reached. Some patients with FH do not reach LDL-C goals despite intensive combination therapy. OBJECTIVE: This study assessed the efficacy and tolerability of colesevelam added to maximally tolerated, stable-dose combination treatment with a statin + ezetimibe. METHODS: This Phase IV, multicenter, randomized, double-blind, placebo-controlled trial enrolled patients aged 18 to 75 years with FH and an LDL-C concentration >2.5 mmol/L who were receiving a maximally tolerated and stable regimen of a statin + ezetimibe. Patients were randomly assigned to receive colesevelam 3.75 g/d or placebo added to the statin + ezetimibe for 12 weeks. The primary efficacy outcome was the difference in LDL-C between the colesevelam and placebo groups after 6 weeks. Secondary efficacy outcomes were between-group differences in LDL-C, total cholesterol (TC), HDL-C, triglyceride (Tg), apolipoprotein (apo) B, and apoA-I concentrations, as well as apoB/apoA-I ratio after 12 weeks. Tolerability was assessed based on the prevalences of adverse events by organ system class in each treatment group. RESULTS: Eighty-six patients were randomized (45 colesevelam, 41 placebo), of whom 84 (44 colesevelam, 40 placebo) were included in the primary analysis. The mean (SD) age of the participants was 52.8 (10.8) years, and 51 (59%) were men. The difference (95% CI) in LDL-C between colesevelam and placebo after 6 weeks was -18.5% (-25.3 to -11.8). Between-group differences in LDL-C, TC, HDL-C, Tg, and apoB/apoA-I ratio after 12 weeks were -12.0% (-17.8 to -6.3), -7.3% (-12.0 to -2.6), +3.3% (-2.4 to +9.0), +2.8% (-10.4 to +15.9), and -12.2% (-20.2 to -4.2), respectively. Colesevelam was generally well tolerated, with gastrointestinal adverse events in 12 of 45 patients (27%) versus 7 of 40 (18%) in the placebo group (P = NS). CONCLUSION: In these patients with FH, colesevelam added to a combination of a statin + ezetimibe was associated with significantly improved LDL-C concentrations compared with placebo during the 12-week study period and was generally well tolerated. 01 april 2010

Item does not contain fulltext PURPOSE OF REVIEW: Despite the use of currently available lipid-lowering therapies, a significant proportion of patients with severe hypercholesterolaemia do not reach treatment goals and consequently remain at increased risk for cardiovascular disease (CVD). On the basis of clinical experience, these patients tend to have the most severe forms of familial hypercholesterolaemia or markedly elevated LDL cholesterol (LDL-C) levels but are unable to tolerate statin therapy. RECENT FINDINGS: LDL apheresis is currently the best treatment option (or treatment rescue) to bring these patients closer to therapeutic LDL objectives, and has been shown to reduce the risk of CVD along with LDL-C levels. However, criteria for LDL apheresis eligibility and the percentage of patients receiving treatment vary widely from country to country across Europe. Despite the proven benefits of LDL apheresis, access to this procedure remains limited because of its high cost and low availability, reflecting inherent limitations of this treatment modality. SUMMARY: There is a need to both better define the patient population eligible for LDL apheresis and to create unified European guidelines governing the use of apheresis. In addition to improving access to apheresis where appropriate, new therapies are needed to further decrease LDL-C and reduce the ongoing CVD risk in patients with severe hypercholesterolaemia. 01 december 2010

Chronic periaortitis is thought to result from an autoallergic reaction to oxidized low-density lipoprotein (OxLDL). No data exist on lipid profile and atherosclerotic biomarkers. We investigated circulating levels of OxLDL and of anti-OxLDL (aOxLDL) antibodies in patients with chronic periaortitis using the cross-sectional case-control study on 20 patients with chronic periaortitis. Patients were compared to 20 age- and sex-matched controls. aOxLDL antibodies were measured by ELISA and expressed as mean optical density values at 450 nm from duplicate measurements (OD(450)). aOxLDL antibody titers (median [interquartile range]) did not differ significantly between patients and controls (aOxLDL-IgM: 0.70 [0.24-1.08] vs. 0.54 [0.25-0.73] OD(450); aOxLDL-IgG: 0.59 [0.38-0.75] vs. 0.41[0.33-0.63]OD(450)). Female patients had higher aOxLDL-IgM levels than male patients (1.02 [0.46-1.38] vs. 0.29 [0.22-0.84] OD(450); P = 0.05). aOxLDL-IgM titers were lower in patients with cardiovascular disease (CVD) than in patients without CVD (0.22 [0.16-0.37] vs. 0.92 [0.70-1.30] OD(450); P = 0.003) and correlated positively with HDL-cholesterol (r = 0.47, 95% CI 0.02-0.69; P = 0.03) and inversely with diastolic blood pressure (r = -0.46, 95% CI -0.75 to -0.01; P = 0.03) and OxLDL/apoB ratio (r = -0.41, 95% CI -0.73 to 0.04; P = 0.06). No differences or associations were found between aOxLDL-IgG titers and other variables between or within patients and/or controls. In patients OxLDL levels correlated with smoking pack-years (r = 0.58, 95% CI 0.17-0.81; P = 0.007). Data suggest a differing innate immune response to OxLDL in patients with chronic periaortitis compared to controls. Whether this response is causally related to chronic periaortitis development remains to be clarified.

1 DepartmentofGeneralInternalMedicine; 2 DepartmentofEpidemiologyandBiostatistics; 3 DepartmentofEndocrinology;and 4 DepartmentofClinicalChemistry,RadboudUniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands Abstract. Holewijn S, den Heijer M, van Tits LJ, Swin- kels DW, Stalenhoef AFH, de Graaf J (Radboud Uni- versity Nijmegen Medical Centre, Nijmegen, The Netherlands). Impact of waist circumference versus adiponectin level on subclinical atherosclerosis. A cross-sectional analysisina samplefrom the general population.JInternMed2010;267:588-598. Objective. Waist circumference is a clinical marker of obesity and an established risk factor for cardiovas- cular (CV) disease. Adiponectin, an adipocyte-de- rived hormone andnew biomarker ofobesity,was re- cently proposed as the missing link between obesity and increased cardiovascular risk. We evaluated waist and adiponectin in a middle-aged population- based cohort to compare the impact of both obesity- markers on subclinical atherosclerosis, in relation to otherCVriskfactors. Design, setting & subjects. Seven noninvasive measure- ments of atherosclerosis (NIMA), as surrogate mark- ers of (subclinical) atherosclerosis, were determined in 1517 participants of the Nijmegen Biomedical Study, aged 50-70 years, who were drawn from the Dutchcommunity.

Contains fulltext : 80105.pdf (Publisher’s version ) (Closed access) OBJECTIVE: High-density lipoprotein (HDL) antiatherogenic functions seem to be diminished during inflammatory conditions such as rheumatoid arthritis (RA). The aim of this study was to investigate the effects of tumour necrosis factor (TNF) inhibition on the antioxidative capacity of HDL in RA. METHODS: Plasma lipids and paraoxonase (PON-1) activity were investigated in 45 RA patients, before and during 6 months of anti-TNF therapy. In addition, HDL was isolated and tested for its ability to inhibit copper-induced oxidation of low-density lipoprotein in vitro. RESULTS: Plasma HDL concentrations did not change considerably after 6 months of therapy. However, stable increases of PON-1 activities were observed throughout the same period (p

Item does not contain fulltext OBJECTIVE: To compare incidences of cardiovascular disease (CVD) in general and myocardial infarction (MI) specifically between new users of different statins in daily practice. DESIGN AND METHODOLOGY: Retrospective observational cohort study. Data were obtained from the PHARMO Record Linkage System; the PHARMO database contains pharmacy dispensing records of 3 million patients in the Netherlands registered with community pharmacies, linked to hospitalisation records. The participants were new statin users in the period 2000-2005, excluding patients hospitalised for CVD events in the year prior to start of statin use. MAIN OUTCOME MEASURES: Adjusted hazard ratios of hospitalisations for CVD (including any type of ischemic heart disease, stroke, or revascularisation procedure) in general, or MI in particular, occurring during use of the initial statin within two years of start of therapy, comparing users of different statins. RESULTS: The mean follow-up duration of 76,147 new statin users (14,530 pravastatin, 27,752 simvastatin, 25,777 atorvastatin, 8088 rosuvastatin) was 55 weeks. Incidence rates of CVD and MI per 100 person years ranged from 0.75 and 0.15 for rosuvastatin to 1.72 and 0.29 for pravastatin. Rosuvastatin users had a lower incidence rate of CVD compared to other statin users in general (28% lower), and simvastatin (29% lower) and pravastatin users (40% lower) in particular. The difference with atorvastatin was not statistically significant. Since this was not a prospective randomised study, there is the potential for unobserved risk factors to be responsible for some of the differences observed. CONCLUSION: Compared to other statin users without recent prior cardiovascular events, the incidence of fatal and non-fatal CVD in this retrospective observational cohort study was 28% lower among rosuvastatin users.

Contains fulltext : 81899.pdf (Publisher’s version ) (Closed access) PURPOSE OF REVIEW: The present review aims to highlight the consequences for mother and child of profound hypercholesterolemia during pregnancy of women with familial hypercholesterolemia. RECENT FINDINGS: Familial hypercholesterolemia is increasingly diagnosed in younger patients due to the existence of screening programs and more widespread cholesterol testing. Increasing numbers of young female patients with familial hypercholesterolemia raise the issue of pregnancy and its consequences for the familial hypercholesterolemia patient herself but also for her offspring. When pregnancy is considered, lipid-lowering drugs are often discontinued because of the fear for teratogenic effects. The evidence for teratogenesis associated with statin use is scant and conflicting. On the other hand, several studies do suggest that pronounced hypercholesterolemia during pregnancy has adverse effects on both fetus and mother. In fact, human and animal studies reveal an enhanced tendency toward atherosclerosis in the offspring of women who suffer from hypercholesterolemia during pregnancy. In animal studies, some evidence exists that this can be reversed by treatment with lipid-lowering and antioxidative agents. Until today, however, no human studies exist that have evaluated efficacy or safety of lipid-lowering interventions in pregnant women with familial hypercholesterolemia. SUMMARY: Altogether, the suggested relationship between severe hypercholesterolemia and enhanced atherosclerosis in offspring and possibly the mother warrants further confirmation and, consequently, studies that focus on therapeutic strategies that can safely lower cholesterol levels during pregnancy in these women.

Contains fulltext : 81259.pdf (Publisher’s version ) (Closed access) CONTEXT AND OBJECTIVE: The metabolic syndrome (MetS) indicates an increased cardiovascular risk. The objective of the present study was to determine the impact of the MetS and its individual traits on subclinical atherosclerosis, as measured with six noninvasive measurements of atherosclerosis (NIMA) in a 50- to 70-yr-old Dutch population-based cohort. Furthermore, we determined the impact of three different definitions of the MetS. DESIGN: We performed NIMA in 1517 participants of the Nijmegen Biomedical Study. The MetS was defined by definitions of the National Cholesterol Education Program, International Diabetes Federation, and the World Health Organization. RESULTS: Participants with the MetS (National Cholesterol Education Program) were characterized by increased subclinical atherosclerosis compared with participants without any trait of the MetS, as reflected by lower ankle-brachial index at rest [percent change (95% confidence interval), M: -5.2% (-9; -1), F: -3.1% (-6; -1)] and after exercise [M: -7.7% (-17;+2), F: -6.6% (-11; -2)], higher augmentation index [M: +4.8% (+3; +7), F: +1.9% (+4; +18)], increased pulse wave velocity [M: +22.8% (+15;+32), F: +20.5% (+14; +28)], increased intima-media thickness [M: +9.3% (+5; +13), F: +6.9% (+3; +11)], and thicker plaques [M: +17.6% (-2; +41), F: +26.6% (+5; +53)]. Most intriguingly, the number of traits was strongly associated with the severity of subclinical atherosclerosis because all NIMA gradually deteriorated with increasing number of traits present; NIMA were already deteriorated when one or two traits were present and further deteriorated when four or five traits of the MetS were present. Similar result were found when International Diabetes Federation and World Health Organization definitions of the MetS were used. CONCLUSIONS: For cardiovascular risk prediction, it is more important to take into account the presence of each individual trait and the number of traits of the MetS than to diagnose the presence of the MetS.

Background— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P =0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

Contains fulltext : 69561tits.pdf (Publisher’s version ) (Closed access) Adiponectin is secreted from adipocytes in different multimers, of which the high molecular weight (HMW) form is supposed to mediate favorable metabolic and anti-atherogenic effects. We determined adiponectin multimers in 29 female and 22 male patients with familial combined hyperlipidemia (FCH) and 51 age-, gender-, and BMI-matched controls in relation to cardiovascular disease (CVD). We observed a clear sexual dimorphism of total adiponectin and its multimers. Female, but not male, FCH patients had significant lower total adiponectin and both HMW and low molecular weight (LMW) adiponectin than controls. The adiponectin sensitivity index (ASI), reflected by HMW/total adiponectin, and the LMW/HMW adiponectin ratio did not differ significantly between FCH females and control females. However, FCH females with CVD exhibited significantly lower ASI (34.2+/-10.1% vs 46.0+/-7.1%) and higher LMW/HMW ratio (1.5+/-0.8 vs 0.7+/-0.3) compared to FCH females without CVD, reflecting a more atherogenic adiponectin multimer distribution.

We have used a common TaqI restriction fragment length polymorphism (RFLP) near the human apolipoprotein C-II (apoC-II) gene to study linkage with apolipoprotein E (apoE). The inheritance of the apoC-II RFLP was followed in seven families that were segregating for apoE protein variants. No recombinants were observed in 20 informative meioses, giving an overall lod score of > 4.0 at recombination fraction 0. We have also observed apparent linkage disequilibrium between apoE and the apoC-II RFLP. Taken together these results demonstrate that these two apolipoprotein genes are closely linked and confirm that the gene for apoC-II is on human chromosome 19.

Contains fulltext : 71032.pdf ( ) (Closed access) BACKGROUND: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. METHODS: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. RESULTS: The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P

Contains fulltext : 71029.pdf ( ) (Closed access) In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3'-splice donor site in exon 4 and R385R was associated with a new 5'-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay.

INTRODUCTION: Familial combined hyperlipidemia (FCH) is characterized by several phenotypes, including an atherogenic lipoprotein profile, low grade inflammation, visceral obesity, insulin resistance, and hypertension. In this study, we investigated which of the clinical and biochemical characteristics of FCH patients contributes most to their increased risk of cardiovascular disease, by determining the association of a broad variety cardiovascular risk factors with the intima media thickness (IMT) of the common carotid artery (CCA) in 94 FCH patients and 216 non-affected relatives.METHODS: All subjects filled out a questionnaire about their smoking and drinking habits, medical history and medication use, and venous blood was drawn in the fasting state after discontinuation of lipid lowering medication (if used). IMT of the far wall and near wall of both CCAs was measured by high-resolution B-mode ultrasonography.RESULTS: The mean IMT in FCH patients (adjusted for age and gender) was 33 microm thicker when compared to their non-affected relatives (p=0.006). In multivariate analysis, the waist-to-hip ratio, the apoB concentration and the pulse pressure were significant and independent predictors of IMT in both FCH patients and their normolipidemic relatives. The most important independent predictor of IMT in FCH patients however, was the VLDL-c/TG ratio, explaining 32.8% of the variation in age- and gender-adjusted IMT, whereas this ratio was not an independent predictor of IMT at all in their unaffected relatives.CONCLUSION: Abdominal obesity, a higher blood pressure and dyslipidemia characterised by both an increased number of atherogenic particles and the presence of highly atherogenic remnant lipoproteins play an important role in the development of cardiovascular disease in FCH-patients.

Contains fulltext : 52459.pdf (Publisher’s version ) (Open Access) Recently, the upstream stimulatory factor 1 gene (USF1) was proposed as a candidate gene for familial combined hyperlipidemia (FCH). In this study, we examined the previously identified risk haplotype of USF1 with respect to FCH and its related phenotypes in 36 Dutch FCH families. The diagnosis of FCH was based on both the traditional diagnostic criteria and a nomogram. The two polymorphisms, USF1s1 and USF1s2, were in complete linkage disequilibrium. No association was found for the individual single nucleotide polymorphisms (SNPs) with FCH defined by the nomogram (USF1s1, P = 0.53; USF1s2, P = 0.53), whereas suggestive associations were found when using the traditional diagnostic criteria for FCH (USF1s1, P = 0.08; USF1s2, P = 0.07). USF1 was associated with total cholesterol (USF1s1, P = 0.05; USF1s2, P = 0.04) and apolipoprotein B (USF1s1, P = 0.06; USF1s2, P = 0.04). Small dense LDL showed a suggestive association (USF1s1, P = 0.10; USF1s2, P = 0.09). The results from the haplotype analyses supported the results obtained for the individual SNPs. In conclusion, the previously identified risk haplotype of USF1 showed a suggestive association with FCH and contributed to the related lipid traits in our Dutch FCH families.

Contains fulltext : 53623.pdf (Publisher’s version ) (Closed access) BACKGROUND: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. MATERIALS AND METHODS: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (-1131T>C and S19W) were genotyped. RESULTS: Haplotype analysis of APOA5 showed an association with FCH (p=0.029), total cholesterol (p=0.031), triglycerides (p

Objective: Annexin A5 (ANXA5) has been suggested to possess antiatherogenic properties. We investigated whether ANXA5 genetic variations and plasma ANXA5 levels were associated with carotid atherosclerosis and contributed to cardiovascular disease (CVD) risk in patients with familial hypercholesterolemia (FH). Methods: We sequenced the promoter region and exon 2 of ANXA5 in 284 FH patients from the ASAP (Atorvastatin versus Simvastatin on Atherosclerosis Progression) trial. Common haplotypes (H) were constructed based on seven single nucleotide polymorphisms (SNPs). We studied whether plasma ANXA5 levels or ANXA5 haplotypes were associated with the extent of atherosclerosis (evaluated by carotid intima-media thickness (IMT). The association between ANXA5 haplotypes and the risk for CVD events was investigated in 1730 FH patients from the GIRaFH (Genetic Identification of Risk factors in Familial Hypercholesterolemia) study. Results: In ASAP, individuals carrying the ANXA5 haplotype H2 exhibited lower plasma ANXA5 levels, whereas H4 carriers had increased levels of circulating ANXA5 compared to non-carriers. Plasma ANXA5 levels were not associated with carotid IMT. None of the four ANXA5 haplotypes correlated with the age-related IMT progression (ASAP study) or contributed to CVD risk (GIRaFH cohort). Conclusions: Both ANXA5 haplotypes and plasma ANXA5 levels were not associated with carotid IMT progression or CVD risk in FH patients.

Filiació URV: SI Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results: Early diagnosis ofHoFHand prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH.We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensiveACVDevaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta

Contains fulltext : 51017.pdf (Publisher’s version ) (Closed access) Inherited High Cholesterol is treatable, but highly underdiagnosed. To detect undiagnosed blood relatives at a presymptomatic stage, in the Netherlands written information packages are available to facilitate family communication. To investigate the role of those packages in the detection of carriers, we conducted a qualitative evaluation (plus-minus method combined with semistructured interviews with index patients and relatives). Our data suggest that interviewees approved the family approach for finding carriers, although reluctantly. The packages aided family disclosure by reducing hesitation. However, index patients only informed first-degree relatives and generally communicated the risk only once. This may be due to the cultural context and a limited understanding of genetics. For relatives the packages served as a cue to action and as a legitimation to gain access to a diagnostic cholesterol test. Despite the value of these written materials, they should not be used as the only communication between index patient and relatives.

Contains fulltext : 50695.pdf (Publisher’s version ) (Closed access) There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B

Contains fulltext : 50254.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. DESIGN: Double blind, randomized, cross-over study. SUBJECTS: Seventeen FCH patients. INTERVENTIONS: Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. MAIN OUTCOME MEASUREMENTS: Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. RESULTS: Pioglitazone improved insulin sensitivity (M value 37.7 +/- 3.6 micromol min(-1) kg(-1) vs. 33.0 +/- 3.3 micromol min(-1) kg(-1) during placebo, P < 0.05) and LDL composition by increasing the K value (-0.11 +/- 0.06 vs. -0.20 +/- 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). CONCLUSION: Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL.

Contains fulltext : 49852.pdf (Publisher’s version ) (Closed access) Non-transferrin-bound iron (NTBI) is implicated in lipid peroxidation but the relation with oxidative modification of low-density lipoprotein (LDL) is not known. We assessed variables reflecting in vitro and in vivo LDL oxidation in two age- and sex-matched groups (n=23) of hereditary hemochromatosis heterozygotes (C282Y), characterized by a clear difference in mean serum NTBI (1.55+/-0.57 micromol/L vs 3.70+/-0.96 micromol/L). Plasma level of oxidized LDL (absolute and relative to plasma apolipoprotein B), and IgG and IgM antibodies to oxidized LDL, markers of in vivo LDL oxidation, did not differ between the groups with low and high serum NTBI. Mean lag-phase of in vitro LDL oxidation was also not significantly different between both study groups. Conclusion: these findings do not support the hypothesis that NTBI promotes oxidative modification of plasma LDL.

Contains fulltext : 48945.pdf (Publisher’s version ) (Closed access) AIMS: The efficacy and safety of rosuvastatin, atorvastatin, and placebo were compared in patients with the metabolic syndrome. METHODS AND RESULTS: Patients with the metabolic syndrome with low-density lipoprotein cholesterol (LDL-C) > or =3.36 mmol/L (130 mg/dL) and multiple risk factors conferring a 10-year coronary heart disease risk score of >10% were randomized (2:2:1) to receive rosuvastatin 10 mg, atorvastatin 10 mg, or placebo for 6 weeks. Subsequently, the rosuvastatin 10 mg and placebo groups received rosuvastatin 20 mg and the atorvastatin 10 mg group received atorvastatin 20 mg for 6 weeks. LDL-C was reduced significantly more in patients receiving rosuvastatin 10 mg when compared with those receiving atorvastatin 10 mg at 6 weeks [intention-to-treat (ITT) population by randomized treatment: 41.7 vs. 35.7%, P < 0.001; ITT population by as-allocated treatment: 42.7 vs. 36.6%, P < 0.001]. Significant LDL-C reductions were also observed in patients receiving rosuvastatin when compared with those receiving atorvastatin at 12 weeks (48.9 vs. 42.5%, P < 0.001). More patients achieved LDL-C goals with rosuvastatin when compared with atorvastatin. Rosuvastatin increased high-density lipoprotein cholesterol significantly more than atorvastatin. Treatments were well tolerated. CONCLUSION: At equivalent doses, rosuvastatin had a significantly greater effect than atorvastatin in lowering LDL-C and improving the lipid profile and was well tolerated in patients with the metabolic syndrome.

Item does not contain fulltext OBJECTIVE: Although several studies have reported a positive effect of statins on endothelial vasoreactivity, most studies performed in subjects with type 2 diabetes mellitus report no effect at all. This lack of effect may be related to the existence of insulin resistance, or to insufficient lowering of atherogenic (apo)lipoproteins. Therefore, we tested in this study whether treatment of insulin resistant familial combined hyperlipidaemia (FCH) patients with a high dose (40 mg/day) of the potent rosuvastatin was able to improve endothelial function, without necessarily improving insulin sensitivity. RESEARCH DESIGN AND METHODS: In a double-blind randomised crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean [standard deviation] age 54 [7] years) underwent a 4-week run-in period after which they were randomised to treatment with placebo once daily for 12 weeks, followed by rosuvastatin 40 mg/day for 12 weeks or vice versa. Endothelial function was determined after 8 and 12 weeks of both treatment periods, respectively, by measurement of flow-mediated vasodilation (FMD) using high-resolution ultrasound and by measurement of vasodilator response to intrabrachial acetylcholine (Ach) by venous occlusion plethysmography (forearm blood flow [FBF]). RESULTS: Plasma levels of lipids, (apo)lipoproteins and high-sensitivity C-reactive protein (hsCRP) improved significantly after rosuvastatin therapy compared to placebo. However, rosuvastatin had no effect on homeostasis model assessment (HOMA)-indices or on vasodilator responses to intra-brachial acetylcholine-infusion (FBF-ratio increased from a mean of 1.28 [SD: 0.46] to 5.82 [3.44] after rosuvastatin and from 1.33 [0.67] to 5.99 [3.89] after placebo, p = 0.35). Endothelium-dependent FMD was also unchanged (1.6% [3.1%] vs. 3.2% [3.5]%, p = 0.56 rosuvastatin vs. placebo, respectively). CONCLUSION: In patients with FCH, a 12-week treatment of rosuvastatin 40 mg/day did not improve endothelial function (either in large conduit vessels or in resistance vessels), despite significant improvements in plasma lipids, (apo)lipoproteins. and low-grade inflammation.

Objective— To investigate binding of C-reactive protein (CRP) and annexin A5, 2 proteins with high affinity for negatively charged phospholipids, to oxidized low-density lipoprotein (LDL) and the consequences of these interactions for subsequent binding of oxidized LDL to monocyte/macrophage-like U937 cells. Methods and Results— We found that CRP and annexin A5 at physiological concentrations bind Ca ++ dependently to oxidized phosphatidylcholine present in oxidized LDL but not to native LDL. Binding of CRP to oxidized LDL did not interfere with binding of annexin A5, and vice versa. In the presence of 2 to 10 mg/L CRP, binding of 125 I-labeled oxidized LDL to undifferentiated U937 cells increased 50% to 100%. This effect was independent of the presence of complement and could be inhibited by irrelevant IgG and by antibodies to CD64 but not by annexin A5. Annexin A5 alone had no effect on binding of oxidized LDL to the cells. Conclusions— These findings suggest that: (1) CRP and annexin A5 at physiological concentrations bind to distinct sites of negatively charged phospholipids present in oxidized LDL; (2) CRP enhances binding of oxidized LDL to monocytic/macrophage-like cells via Fcγ receptors; and (3) annexin A5 does not antagonize the CRP-induced enhanced binding of oxidized LDL to U937 cells.

Objective— Insulin resistance is associated with increased triglyceride levels, low high-density lipoprotein cholesterol, small dense low-density lipoprotein (LDL), and increased apolipoprotein B (apoB) levels, all characteristics of familial combined hyperlipidemia (FCH). Therefore, we explored the role of insulin resistance in FCH lipid phenotype expression. Methods and Results— FCH was defined by traditional diagnostic criteria including plasma total cholesterol or triglyceride levels >90th percentile. Insulin resistance was assessed by the Homeostasis Model Assessment (HOMA) index. In total, 132 subjects with FCH, 350 normolipidemic relatives, and 81 spouses who referenced as controls were studied. FCH subjects were significantly more insulin resistant compared with controls and normolipidemic relatives (HOMA index 2.9 [95% CI, 2.6 to 3.2], 2.2 [95% CI, 2.0 to 2.5], and 2.0 [95% CI, 1.9 to 2.2], respectively), even after correction for sex, age, and body mass index (BMI). The degree of insulin resistance was associated with the lipid phenotype expression, and a change in insulin-resistant state was associated with a change in lipid phenotype expression over 5 years. For any level of insulin resistance and degree of obesity, FCH subjects had increased levels of apoB and more small dense LDL compared with controls. Conclusion— Insulin resistance is a characteristic feature of FCH, which is not fully explained by their increased BMI and is associated with (change in) lipid phenotype expression. Furthermore, our results support the concept of genetic origin of high apoB and small dense LDL in FCH, which is modulated by insulin resistance and obesity.

Contains fulltext : 49079.pdf (Publisher’s version ) (Closed access) Serum paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme that can inhibit low-density lipoprotein (LDL) oxidation in vitro. The role of PON1 in vivo still remains to be clarified. We investigated the effect of PON1 genotype (-107C > T and 192Q > R), concentration, paraoxonase activity, and arylesterase activity on the early phase of lipid peroxidation in plasma samples of 110 patients with heterozygous familial hypercholesterolemia. The degree of lipid oxidation was assessed by quantitation of oxidized-linoleic acid (the most abundant fatty acid present in LDL) using high performance liquid chromatography. We found a significant inverse correlation between paraoxonase activity and the oxidized-linoleic acid concentration (r = -0.22, P = 0.03), independent of baseline linoleic acid levels. These findings support an anti-oxidative role for PON1 in patients with FH, and thus may give insight into the functioning of PON1 in vivo.

Background/Aim: In patients with end-stage renal disease (ESRD), cardiovascular complications are the main cause of death. Increased oxidative stress is one of the risk factors for enhanced atherosclerosis in this population. Literature data vary partially dependent on differences in methodology. The present study compares three different methods: plasma lipid peroxides, the newly developed measurement of circulating oxidized LDL (Ox-LDL) particles and the frequently used copper-induced LDL oxidation lag time. Methods: We assessed plasma lipid peroxides, circulating Ox-LDL and in vitro copper-induced LDL oxidation lag time in 47 non-diabetic patients with ESRD, at the start of renal replacement therapy, and compared these with 41 age- and sex-matched controls. Results: In ESRD, total cholesterol (4.6 ± 1.1 vs. 5.6 ± 0.9 mmol/l; p < 0.001), LDL cholesterol (2.8 ± 0.8 vs. 3.5 ± 0.7 mmol/l; p < 0.001) and HDL cholesterol (1.0 ± 0.3 vs. 1.4 ± 0.4 mmol/l; p < 0.001) were lower compared to controls. Plasma lipid peroxides were higher (1.1 ± 0.5 vs. 0.8 ± 0.5 µmol/l; p = 0.003) in ESRD. No differences were observed in plasma Ox-LDL (63.1 ± 62.0 vs. 55.3 ± 48.0 mg/l). However, due to the lower plasma LDL cholesterol in ESRD, LDL oxidation level was increased in ESRD (7.1 ± 0.1 vs. 4.2 ± 0.3%; p = 0.03). LDL lag time was slightly longer (89 ± 11 vs. 84 ± 11 min; p = 0.04) in ESRD. There were no significant differences regarding the amount and rate of dienes produced. Conclusions: Elevated levels of lipid peroxides and higher LDL oxidation levels support the theory that ESRD is associated with increased oxidative stress, which may explain the accelerated atherosclerosis. The measured amount of oxidative stress is not reflected by in vitro oxidizability of LDL.

Contains fulltext : 57893.pdf (Publisher’s version ) (Closed access) Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome, a hereditary autoinflammatory syndrome, is characterized by lifelong recurrent episodes of fever and inflammation. No effective treatment is known. It is caused by a defect of mevalonate kinase, an enzyme that follows 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase in the isoprenoid pathway. We wanted to test the hypothesis that inhibition of HMG-CoA reductase would ameliorate the inflammatory attacks. Six patients with hyper-IgD syndrome and proven mevalonate kinase deficiency were followed up for 2 treatment periods with either simvastatin, 80 mg/d, or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a drop in urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No side effects were observed. These data offer preliminary evidence for the hypothesis that simvastatin may improve inflammatory attacks in the hyper-IgD syndrome. This highlights the anti-inflammatory properties of HMG-CoA reductase inhibition.

Contains fulltext : 57477.pdf (Publisher’s version ) (Open Access) Although the atheroprotective role of HDL cholesterol (HDL-c) is well documented, effective therapeutics to selectively increase plasma HDL-c levels are not yet available. Recent progress in unraveling human HDL metabolism has fuelled the development of strategies to decrease the incidence and progression of coronary artery disease (CAD) by raising HDL-c. In this quest for novel drugs, cholesteryl ester transfer protein (CETP) represents a pivotal target. The role of this plasma protein in HDL metabolism is highlighted by the discovery that genetic CETP deficiency is the main cause of high HDL-c levels in Asian populations. The use of CETP inhibitors to effectively increase HDL-c concentration in humans was recently published and data with regard to the effect on human atherosclerosis are expected shortly. This review discusses the potential of CETP inhibitors to protect against atherosclerosis in the context of the current knowledge of CETP function in both rodents and humans.

Item does not contain fulltext We investigated whether long-term alpha-tocopherol therapy in chronic smoking affects superoxide generating capacity of neutrophils ex vivo. To this purpose, we randomly assigned 128 male chronic smokers (37 +/- 21 pack years of smoking) to treatment with placebo (n = 64) or alpha-tocopherol (400 IU dL-a-tocopherol daily, n = 64). After two years of therapy, we measured phorbol 12-myristate 13-acetate-induced superoxide production of isolated neutrophils and of diluted whole blood by monitoring reduction of ferricytochrome c and luminol-enhanced peroxidase-catalyzed chemiluminescence. Plasma lipids and lipoproteins were not different between the two treatment groups. As expected, concentrations of alpha-tocopherol in plasma and in low-density lipoproteins were markedly elevated in the supplemented group compared to the placebo group (+ 120%, P < 0.0001 and + 83%, P < 0.0001, respectively). Consequently, resistance to in vitro oxidation of low-density lipoproteins (reflected by lag time of conjugated diene formation) was higher in the supplemented group than in the placebo group (+ 22%, P < 0.0001). Superoxide generating capacity of neutrophils and superoxide production in diluted whole blood did not differ between alpha-tocopherol and placebo group. It is concluded that in chronic smoking long-term supranormal alpha-tocopherol intake does not reduce neutrophil superoxide-anion generating capacity, despite large increases in the concentrations of alpha-tocopherol in plasma and in low-density lipoproteins.

BACKGROUND: Measurement of intima-media thickness (IMT) is a well established surrogate marker for cardiovascular endpoints. We studied the long-term effects of statins on femoral IMT and plaque scoring in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study. METHODS AND RESULTS: Three hundred and twenty-five patients with familial hypercholesterolaemia were randomized to either atorvastatin 80 mg/day or simvastatin 40 mg/day. IMT was measured at baseline and at 2 years. At baseline, femoral IMT was 1.69 mm in the atorvastatin group and 1.61 mm in the simvastatin group; at 2 years, IMT increased by 0.06 mm (P=0.24) and 0.15 mm (P=0.012), respectively. No significant differences were obvious between these two treatment arms (P=0.26). Femoral plaques were present in 64.7% in the atorvastatin group and 56.1% in the simvastatin group at baseline; after 2 years, these proportions rose to 66.0% (P=0.47) and 67.3% (P=0.02), respectively (P=0.87 between treatment arms). Carotid plaques were present in 6.3% versus 4.9%; after 2 years, these percentages were 5.0% (P=0.48) versus 5.5% (P=0.71), respectively (P=0.90 between treatment arms). CONCLUSION: Our study indicates increased efficacy of atorvastatin 80 mg in retarding progression of atherosclerosis in the femoral artery compared with simvastatin 40 mg. Interestingly, in the carotid arteries these statins influenced IMT to a greater extent, whereas in the femoral artery the effects were more pronounced on plaque frequency. These findings underscore the generalized effects of lipid lowering on atherosclerosis

Item does not contain fulltext Familial combined hyperlipidemia (FCH) is characterised by hypercholesterolemia and/or hypertriglyceridemia and associated with an increased risk of cardiovascular disease (CVD). The plasma lipid and lipoprotein levels in subjects with FCH are relatively moderately elevated and do not fully explain the increased risk of CVD. Hyperhomocysteinemia is a disorder of methionine metabolism and also a well-known independent risk factor for CVD. We investigated whether subjects with FCH have higher plasma homocysteine concentrations than controls, and whether homocysteine contributes to the increased risk of CVD in FCH. Furthermore we evaluated whether parameters of lipid and lipoprotein metabolism and/or insulin resistance are associated with the homocysteine level. In total 667 subjects, including 161 subjects with FCH, 109 spouses who referenced as control group and 397 normolipidemic relatives were studied. FCH was defined by the presence of plasma total cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. The mean homocysteine concentration of the FCH group did not significantly differ from the control group. The risk for CVD due to hyperhomocysteinemia in subjects with FCH was not higher than in subjects without FCH. No associations were observed between plasma homocysteine concentration and plasma lipid and lipoprotein levels, including small dense low density lipoprotein, nor between homocysteine concentration and insulin resistance.

Item does not contain fulltext OBJECTIVES: In the present study, we investigated the effects of statins on serum levels of soluble CD40 ligand (sCD40L) in patients with familial hypercholesterolemia (FH). BACKGROUND: Atherosclerotic disease seems to involve inflammatory and immunologic mechanisms, and sCD40L has recently been identified as one of the key players in the atherosclerotic process. HMG-Co A reductase inhibitors, statins, have been recognized as immunomodulators and reduce cardiovascular events and mortality, but the effects of statins on sCD40L has not been clarified. METHODS: In a randomized, double-blind, clinical trial, as part of the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial, 110 patients with FH were given atorvastatin 80 mg/daily (n = 57) or simvastatin 40 mg/daily (n = 53) for two years. RESULTS: Our main findings were: 1) at baseline patients with FH had significantly higher (approximately 27-fold) serum levels of sCD40L than healthy controls; 2) statin therapy markedly decreased serum levels of sCD40L (approximately 40% reduction); 3) this decrease in sCD40L was found during both "aggressive" (i.e., atorvastatin) and "conventional" (i.e., simvastatin) statin therapy and was not correlated with the degree of reduction in cholesterol levels. CONCLUSIONS: Our findings may suggest enhanced CD40L-CD40 interaction in FH and that this inflammatory response may be downregulated by statins.

Item does not contain fulltext In a randomized, double-blind, placebo-controlled trial we evaluated the effect of dietary chocolates enriched with a wood-based phytosterol-phytostanol mixture, containing 18 % (w/w) sitostanol, compared with placebo dietary chocolates in seventy subjects with primary hypercholesterolaemia (total cholesterol levels below 8 mmol/l). For 4 weeks, participants consumed three servings of the phytosterol-enriched chocolate/d that provided 1.8 g unesterified phytosterols/d or a placebo chocolate in conjunction with a low-fat, low-cholesterol diet. Plasma total and LDL-cholesterol levels were statistically significantly reduced by 6.4 % (-0.44 mmol/l) and 10.3 % (-0.49 mmol/l), respectively, after 4 weeks of phytosterol-enriched-chocolate treatment. Plasma HDL-cholesterol and triacylglycerol levels were not affected. Consumption of phytosterol-enriched chocolates significantly increased plasma lathosterol concentration (+20.7 %), reflecting an increased endogenous cholesterol synthesis in response to phytosterol-induced decreased intestinal cholesterol absorption. Furthermore, the chocolates enriched with phytosterols significantly increased both plasma sitosterol (+95.8 %) and campesterol (+64.1 %) levels, compared with the placebo chocolate group. However, the absolute values of plasma sitosterol and campesterol remained within the normal range, that is, below 10 mg/l. The chocolates with phytosterols were palatable and induced no clinical or biochemical side effects. These findings indicate that dietary chocolate enriched with tall oil-derived phytosterols (1.8 g/d) is effective in lowering blood total and LDL-cholesterol levels in subjects with mild hypercholesterolaemia and thus may be helpful in reducing the risk of CHD in these individuals.

Objective: To describe the rationale, design and baseline data of a study conducted to determine the efficacy, safety and tolerability of simvastatin in children and adolescents with heterozygous familial hypercholesterolaemia (heFH). Methods: Patients were recruited from nine lipid clinics worldwide. After a 4-week diet/placebo run-in period, patients were randomised to receive either simvastatin or placebo. Simvastatin was started at 10 mg/day and titrated at 8-week intervals to 20 and then 40 mg/day. During a second 24-week extension period, patients continued to receive simvastatin 40mg or placebo daily according to the original allocation. Results: A total of 173 patients [98 boys (average age 13.2 years), 75 girls (average age 14.5 years)] were included in the study. Baseline total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) were severely elevated in heFH boys and girls compared with 69 healthy non-affected controls who were not part of the study. In heFH boys and the male siblings, respectively, mean total-C was 6.78 ± 1.03 vs 3.80 ± 0.11 mmol/L (p < 0.001), and mean LDL-C was 5.09 ± 0.97 vs 2.53 ± 0.69 mmol/L (p < 0.001). In heFH girls and the female siblings, respectively, mean total-C was 7.44 ± 1.35 vs 4.24 ± 0.47 mmol/L (p < 0.001), and mean LDL-C was 5.68 ± 1.28 vs 2.44 ± 0.50 mmol/L (p < 0.001). Conclusion: This is the first and largest randomised, controlled, long-term clinical study to test the efficacy, safety and tolerability of a statin in boys and girls with heFH. The baseline data suggest that the sample selected for this study is representative of patients with heFH.

Background — Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. Methods and Results — In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity ( P P P =0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL 2, HDL 3 , and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. Conclusions — We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects ( P =0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

Background: High sensitivity C-reactive protein (hs-CRP) has emerged as the best studied and most promising marker of inflammation in atherosclerotic vascular disease. Materials and methods: The ASAP (effects of Atorvastatin vs. Simvastatin on Atherosclerosis Progression) study was a 2-year randomised, double-blind trial with 325 familial hypercholesterolemia patients, treated with torvastatin 80 mg or imvastatin 40 mg. Intima media thickness (IMT) of carotid artery segments and hs-CRP levels were determined at baseline, 1 and 2 years. Results: Baseline median hs-CRP values were 2.1 mg/l (interquartile range (IQR) 0.9-5.2) and 2.0 mg/l (IQR 0.8-3.0) and after 2 years these levels decreased to 1.1 mg/l (IQR 0.6-2.4) and 1.5 mg/l (IQR 0.6-3.0) in the atorvastatin 80 mg and sinivastatin 40 mg group, respectively. These changes were significant within as well as between the two groups. No correlations were observed between change in hs-CRP after 2 years and change in lipids. A significant correlation was found in univariate analysis between the decrease of hs-CRP and the reduction of IMT. Conclusions: Our results show that atorvastatin 80 mg reduces hs-CRP levels to a greater extent than sinivastatin 40 mg. Furthermore, we show that the extent of hs-CRP reduction is associated with the progression rate of the atherosclerotic process as measured by IMT. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved