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PURPOSE OF REVIEW Patients with familial hypercholesterolemia, familial combined hyperlipidemia and hyperlipoprotein(a) are at high cardiovascular risk. Increasing evidence suggest that lifestyle-related risk factors such as physical inactivity, and poor diet quality could influence cardiovascular risk in these patients. Our objective is to review the evidence that supports the role of lifestyle-related factors in the prediction of cardiovascular risk in patients with inherited lipid disorders. RECENT FINDINGS Recent studies have shown that smoking, a poor diet quality, physical inactivity, fitness levels, abdominal obesity, insulin resistance, and type 2 diabetes were associated with the presence of atherosclerosis and long-term cardiovascular outcomes in patients with familial hypercholesterolemia. Recent evidence also suggest that managing other cardiovascular risk factors such as cholesterol levels, obesity, glycemic control, blood pressure, smoking, physical inactivity, and diet quality could reduce long-term cardiovascular risk associated with hyperlipoprotein(a). Whether targeting these risk factors could ultimately decrease cardiovascular risk in these patients remains unknown. SUMMARY Although reducing the number of atherogenic apolipoprotein-B containing particle with lipid-lowering therapy represents the cornerstone of treatment of patients with inherited lipid disorders, lifestyle-related risk factors such as physical inactivity and poor diet quality need to be targeted for the optimal management of these high-risk patients.

Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and dyslipidemia constitutes a major risk factor for CVD and premature atherosclerosis. Therapies to reduce the plasma levels of atherogenic lipoproteins are well established interventions that decrease CVD risk. However, treatment of dyslipidemia with the most widely used lipid-lowering drugs (ie, statins and ezetimibe) often fails to protect a significant proportion of patients from cardiovascular risk. The development of several novel therapies to treat lipid-related disorders and their associated risks is ongoing and includes the following: (1) reducing plasma levels of atherogenic lipoproteins using proprotein convertase subtilisin/kexin type 9 inhibitors, antisense inhibitors of Apolipoprotein (Apo)(a), microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides of ApoB for inhibiting very low-density lipoprotein production, and inhibitors of angiopoietin-like protein 3 or ApoC-III for triglyceride-rich lipoprotein management upstream of low-density lipoprotein production as well as gene replacement therapy to improve low-density lipoprotein and triglyceride-rich lipoprotein clearance; and (2) emerging therapies that target high-density lipoprotein (HDL) and reverse cholesterol transport using cholesteryl ester transfer protein inhibitors, HDL peptide mimetics, and autologous infusion of pre-β HDLs. Clinical trials of several of these emerging therapies are currently being conducted. Despite the potential efficacy of these new therapies in CVD prevention, their costs might limit their use because of limited reimbursement funds. Therefore, the real challenge facing the next generation of lipid-lowering agents will most likely be accessibility, reflecting a new paradigm that applies to almost all emerging therapies for any disease in the era of precision medicine.

High fruit and vegetable (FAV) intake is associated with a lower prevalence of chronic diseases. Identifying the ideal number of FAV servings needed to reduce chronic disease risk is, however, difficult because of biases inherent to common self-report dietary assessment tools. The aim of our study was to examine the associations between daily FAV intake and plasma carotenoid concentrations in men and women enrolled in a series of fully controlled dietary interventions. We compiled and analysed data from a group of 155 men and 109 women who participated in six fully controlled dietary interventions and compared post-intervention fasting plasma carotenoid (α-carotene,β-carotene,β-cryptoxanthin, lutein, lycopene, zeaxanthin) concentrations with regard to the daily FAV servings consumed by the participants. We found that plasmaβ-cryptoxanthin, lutein and zeaxanthin concentrations were positively associated with daily FAV servings (P≤0·005). However, daily FAV intake was negatively associated with plasmaα-carotene (PPβ-carotene. When men and women were analysed separately, we found that for any given number of FAV servings consumed women had higher circulating lutein concentrations compared with men (PPβ-cryptoxanthin (Pβ-cryptoxanthin concentrations in women than in men for a given FAV consumption. Results from these fully controlled dietary feeding studies indicate that plasmaβ-cryptoxanthin and lutein concentrations can be used as robust biomarkers of FAV consumption. They also suggest the existence of sex differences influencing circulatingβ-cryptoxanthin and lutein concentrations following FAV consumption.

Background and aims Our aim was to gain insight into the role that lipoprotein lipase (LPL) and hepatic lipase (HL) plays in HDL metabolism and to better understand LPL- and HL-deficiency states. Methods We examined the apolipoprotein (apo) A-I-, A-II-, A-IV-, C-I-, C-III-, and E-containing HDL subpopulation profiles, assessed by native 2-dimensional gel-electrophoresis and immunoblotting, in 6 homozygous and 11 heterozygous LPL-deficient, 6 homozygous and 4 heterozygous HL-deficient, and 50 control subjects. Results LPL-deficient homozygotes had marked hypertriglyceridemia and significant decreases in LDL-C, HDL-C, and apoA-I. Their apoA-I-containing HDL subpopulation profile was shifted toward small HDL particles compared to controls. HL-deficient homozygotes had moderate hypertriglyceridemia, modest increases in LDL-C and HDL-C level, but normal apoA-I concentration. HL-deficient homozygotes had a unique distribution of apoA-I-containing HDL particles. The normally apoA-I:A-II, intermediate-size (α-2 and α-3) particles were significantly decreased, while the normally apoA-I only (very large α-1, small α-4, and very small preβ-1) particles were significantly elevated. In contrast to control subjects, the very large α-1 particles of HL-deficient homozygotes were enriched in apoA-II. Homozygous LPL- and HL-deficient subjects also had abnormal distributions of apo C-I, C-III, and E in HDL particles. Values for all measured parameters in LPL- and HL-deficient heterozygotes were closer to values measured in controls than in homozygotes. Conclusions Our data are consistent with the concept that LPL is important for the maturation of small discoidal HDL particles into large spherical HDL particles, while HL is important for HDL remodeling of very large HDL particles into intermediate-size HDL particles.

Dietary n-3 polyunsaturated fatty acids (PUFAs) have been proposed to modulate plasma lipids, lipoprotein metabolism, and inflammatory state and to reduce triglyceride (TG) concentrations. The present double-blind, randomized, placebo-controlled, crossover study investigated the effects of n-3 PUFA supplementation at 3 g/d for 8 weeks on the intravascular kinetics of intestinally derived apolipoprotein (apo) B-48-containing lipoproteins in 10 men with type 2 diabetes.In vivokinetics of the TG-rich lipoprotein (TRL) apoB-48 and VLDL apoB-100 were assessed using a primed-constant infusion of L-[5,5,5-D3] leucine for 12 hours in a fed state. Compared with the placebo, n-3 PUFA supplementation significantly reduced fasting TG concentrations by −9.7% (P=0.05) but also significantly increased plasma levels of cholesterol (C) (+6.0%,P=0.05), LDL-C (+12.2%,P=0.04), and HDL-C (+8.4,P=0.007). n-3 PUFA supplementation had no significant impact on postprandial TRL apoB-48 and VLDL apoB-100 levels or on the production or catabolic rates of these lipoproteins. These data indicate that 8-week supplementation with n-3 PUFAs in men with type 2 diabetes has no beneficial effect on TRL apoB-48 and VLDL apoB-100 levels or kinetics.

Studies have demonstrated large within-population heterogeneity in plasma triacylglycerol (TG) response to n-3 PUFA supplementation. The objective of the study was to compare metabolomic and transcriptomic profiles of responders and non-responders of an n-3 PUFA supplementation. Thirty subjects completed a 2-week run-in period followed by a 6-week supplementation with n-3 PUFA (3 g/d). Six subjects did not lower their plasma TG (+9 %) levels (non-responders) and were matched to 6 subjects who lowered TG (-41 %) concentrations (responders) after the n-3 PUFA supplementation. Pre-n-3 PUFA supplementation characteristics did not differ between the non-responders and responders except for plasma glucose concentrations. In responders, changes were observed for plasma hexose concentrations, docosahexaenoic acid, stearoyl-CoA-desaturase-18 ratio, and the extent of saturation of glycerophosphatidylcholine after n-3 PUFA supplementation; however, no change in these parameters was observed in non-responders. Transcriptomic profiles after n-3 PUFA supplementation indicate changes in glycerophospholipid metabolism in both subgroups and sphingolipid metabolism in non-responders. Six key genes in lipid metabolism: fatty acid desaturase 2, phospholipase A2 group IVA, arachidonate 15-lipoxygenase, phosphatidylethanolamine N-methyltransferase, monoglyceride lipase, and glycerol-3-phosphate acyltransferase, were expressed in opposing direction between subgroups. In sum, results highlight key differences in lipid metabolism of non-responders compared to responders after an n-3 PUFA supplementation, which may explain the inter-individual variability in plasma TG response.

Background. The shift away from traditional lifestyle in the Inuit population over the past few decades has been associated with an increased prevalence of coronary heart disease (CHD) risk factors such as obesity, high blood pressure (BP) and diabetes. However, the impact of this transition on the pro-inflammatory marker high-sensitivity C-reactive protein (hs-CRP) has not been documented. Objectives. To examine the prevalence of elevated plasma hs-CRP concentrations in Inuit from Nunavik in the province of Quebec (Canada) and identify anthropometric, biochemical and lifestyle risk factors associated with elevated hs-CRP. Design. A population-representative sample of 801 Inuit residents from 14 villages of Nunavik, aged between 18 and 74 years, was included in the analyses. Subjects participated in a clinical session and completed questionnaires on lifestyle. Multivariate logistic regression was used to determine risk factors for elevated hs-CRP. Results. Elevated plasma hs-CRP concentrations (]2 mg/L) were present in 32.7% (95% confidence interval (CI) 29.535.8) of the Inuit adult population and were more prevalent among women than among men (36.7% vs. 29.0%, p0.007). Multivariate logistic regression analysis indicated that every 1 mmHg increase in systolic BP was associated with a 3% increase in the odds of having hs-CRP concentrations ]2 mg/L in the Inuit population (95% CI 1.011.04). The combination of older age (]50 vs. B30 years) and elevated waist circumference (gender-specific cut-off values) in a multivariate logistic model was also associated with a 13.3-fold increase in the odds of having plasma hs-CRP concentrations ]2 mg/L (95% CI 5.830.9). Conclusions. These data indicate that elevated hs-CRP is relatively prevalent among Inuit with values that are similar to those seen in Canadian Caucasian populations. Sex, age, waist circumference and systolic BP are major factors that increase the risk of this inflammatory phenotype among Inuit from Nunavik, despite their different lifestyle background compared with Caucasians. Keywords: Nunavik; risk factors; waist circumference; aging; sex; systolic blood pressure; Inuit; C-reactive protein; prevalence (Published: 17 October 2012) Citation: Int J Circumpolar Health 2012, 71 : 19066 - http://dx.doi.org/10.3402/ijch.v71i0.19066 To access the supplementary material to this article, please see Supplementary files under Article Tools.

Familial partial lipodystrophy (FPLD) is characterized by abnormal fat distribution and a metabolic syndrome with hypertriglyceridemia. We identified a family with a severe form of FPLD3 with never-reported clinical features and a novel mutation affecting the DNA binding domain of PPARγ (E157D). Apart from the lipodystrophy and severe metabolic syndrome, individuals presented musculoskeletal and hematological issues. E157D heterozygotes had a muscular habitus yet displayed muscle weakness and myopathy. Also, E157D heterozygotes presented multiple cytopenias and a susceptibility to autoimmune disease. In vitro studies showed that the E157D mutation does not decrease the receptor's affinity to classical PPAR response elements or its responsiveness to a PPARγ agonist, yet it severely reduces its target gene transcription. Microarray experiments demonstrated a decreased activation of a wide array of genes, including genes involved in the PPAR response, the immune response, hematopoiesis, and metabolism in muscle. In addition, a subset of genes with cryptic PPAR response elements was activated. In summary, we describe a large family with a novel PPARγ mutation, which extends the clinical phenotype of FPLD3 to include muscular, immune, and hematological features. Together, our results support the role of PPARγ in controlling homeostasis of multiple systems beyond lipid metabolism.

Item does not contain fulltext OBJECTIVE: To characterize the composition of very-low-density lipoprotein (VLDL) particles and the proportion of VLDL to total apolipoprotein B (apoB) particles in patients with hypertriglyceridemia caused by excess VLDL. METHODS: Subjects were selected from 2023 consecutive patients attending the Lipid Clinic at the Laval University Centre. Plasma lipids, apoB, and apoA-I were measured and chylomicron lipids and VLDL and LDL lipids and apoB determined after ultracentrifugation. Patients with hypertriglyceridemia caused by excess VLDL were divided into four groups on the basis of triglyceride and apoB. RESULTS: A total of 440 controls, 387 subjects with normotriglyceridemic hyperapoB, 38 with type III dysbetalipoproteinemia, 270 with mild hypertriglyceridemic normoapoB, 163 with moderate hypertriglyceridemic normoapoB, 458 with mild hypertriglyceridemic hyperapoB, and 295 subjects with moderate hypertriglyceridemic hyperapoB were compared. In patients with hypertriglyceridemia caused by excess VLDL, the VLDL particles were triglyceride and cholesterol-enriched. HyperapoB is associated with greater low-density lipoprotein (LDL) apoB than normoapoB, whereas greater triglycerides are associated with greater VLDL apoB. Thus, the ratio of VLDL apoB/total apoB was significantly less in those with mild hypertriglyceridemia compared with those with moderate hypertriglyceridemia, irrespective of the plasma apoB. CONCLUSIONS: The apoB phenotypes in hypertriglyceridemia caused by excess VLDL appear to be determined by the extent to which VLDL secretion increases, the extent to which VLDL particles can be converted to LDL particles, and the effects of core lipid exchange. More accurate characterization of hypertriglyceridemia caused by excess VLDL should lead to a better understanding of the determinants of VLDL clearance and conversion to LDL as well as of the atherogenic potential of VLDL.

Eicosapentaenoic and docosahexaenoic acids have been reported to have a variety of beneficial effects on cardiovascular disease risk factors. However, a large inter-individual variability in the plasma lipid response to an omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation is observed in different studies. Genetic variations may influence plasma lipid responsiveness. The aim of the present study was to examine the effects of a supplementation with n-3 PUFA on the plasma lipid profile in relation to the presence of single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster. A total of 208 subjects from Quebec City area were supplemented with 3 g/day of n-3 PUFA, during six weeks. In a statistical model including the effect of the genotype, the supplementation and the genotype by supplementation interaction, SNP rs174546 was significantly associated (p = 0.02) with plasma triglyceride (TG) levels, pre- and post-supplementation. The n-3 supplementation had an independent effect on plasma TG levels and no significant genotype by supplementation interaction effects were observed. In summary, our data support the notion that the FADS gene cluster is a major determinant of plasma TG levels. SNP rs174546 may be an important SNP associated with plasma TG levels and FADS1 gene expression independently of a nutritional intervention with n-3 PUFA.

Eicosapentaenoic and docosahexaenoic acids have been reported to have a variety of beneficial effects on cardiovascular disease risk factors. However, a large inter-individual variability in the plasma lipid response to an omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation is observed in different studies. Genetic variations may influence plasma lipid responsiveness. The aim of the present study was to examine the effects of a supplementation with n-3 PUFA on the plasma lipid profile in relation to the presence of single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster. A total of 208 subjects from Quebec City area were supplemented with 3 g/day of n-3 PUFA, during six weeks. In a statistical model including the effect of the genotype, the supplementation and the genotype by supplementation interaction, SNP rs174546 was significantly associated (p = 0.02) with plasma triglyceride (TG) levels, pre- and post-supplementation. The n-3 supplementation had an independent effect on plasma TG levels and no significant genotype by supplementation interaction effects were observed. In summary, our data support the notion that the FADS gene cluster is a major determinant of plasma TG levels. SNP rs174546 may be an important SNP associated with plasma TG levels and FADS1 gene expression independently of a nutritional intervention with n-3 PUFA.

Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta-analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty.

Background: Whereas the negative effect of consuming trans fatty acids found in partially hydrogenated vegetable oils on cardiovascular disease (CVD) risk is well established, the effect of trans fatty acids from ruminant sources (rTFAs) on CVD risk factors has not yet been established, particularly among women. Objective: We investigated the effects of a butter naturally enriched in rTFAs, of which vaccenic acid is the predominant isomer, on plasma lipid concentrations among healthy women. Design: In a double-blind, randomized, crossover controlled study, 61 healthy women aged 19–70 y were fed 2 isoenergetic diets lasting 4 wk each. The 2 diets were defined as moderately high in rTFAs (3.7 g/d, 1.5% of daily energy) and control (0.9 g/d, 0.3% of daily energy). Results: No significant effect of the rTFA diet was found on total plasma cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein A-I, and triglyceride concentrations compared with the control diet. There was a small yet statistically significant reduction in plasma HDL-cholesterol concentrations with the rTFA diet (22.8%; P = 0.004), which was significant (P for the BMI · treatment interaction = 0.006) among women with a BMI (in kg/m 2 ) 25 (25.2%; P = 0.004; n = 18) but not among women with a BMI ,25 (21.2%; P = 0.13; n = 43). Conclusions: These results suggest that an increase in dietary rTFAs equivalent to ;1% of daily energy has no significant effect on LDL but may be associated with a reduction in plasma HDLcholesterol concentrations, particularly in overweight women. This trial is registered at clinicaltrials.gov as NCT00930137. Am J Clin Nutr doi: 10.3945/ajcn.111.023408.

High-fat, low-carbohydrate diets have been shown to raise plasma cholesterol levels, an effect associated with the formation of large low-density lipoprotein (LDL) particles. However, the impact of dietary intervention on time-course changes in LDL particle size has not been investigated. To test whether a short-term dietary intervention affects LDL particle size, we conducted a randomized, double-blind, crossover study using an intensive dietary modification in 12 nonobese healthy men with normal plasma lipid profile. Participants were subjected to 2 isocaloric 3-day diets: high-fat diet (37% energy from fat and 50% from carbohydrates) and low-fat diet (25% energy from fat and 62% from carbohydrates). Plasma lipid levels and LDL particle size were assessed on fasting blood samples after 3 days of feeding on each diet. The LDL particles were characterized by polyacrylamide gradient gel electrophoresis. Compared with the low-fat diet, plasma cholesterol, LDL cholesterol, and high-density lipoprotein cholesterol were significantly increased (4.45 vs 4.78 mmol/L, P = .04; 2.48 vs 2.90 mmol/L, P = .005; and 1.29 vs 1.41 mmol/L, P = .005, respectively) following the 3-day high-fat diet. Plasma triglycerides and fasting apolipoprotein B-48 levels were significantly decreased after the high-fat diet compared with the low-fat diet (1.48 vs 1.01 mmol/L, P = .0003 and 9.6 vs 5.5 mg/L, P = .008, respectively). The high-fat diet was also associated with a significant increase in LDL particle size (255.0 vs 255.9 A;P = .01) and a significant decrease in the proportion of small LDL particle (

Objective— SAR1b plays a significant role in the assembly, organization, and function of the coat protein complex II, a critical complex for the transport of proteins from the endoplasmic reticulum to the Golgi. Recently, mutations in SARA2 have been associated with lipid absorption disorders. However, functional studies on Sar1b-mediated lipid synthesis pathways and lipoprotein packaging have not been performed. Methods and Results— Sar1b was overexpressed in Caco-2/15 cells and resulted in significantly augmented triacylglycerol, cholesteryl ester, and phospholipid esterification and secretion and markedly enhanced chylomicron production. It also stimulated monoacylglycerol acyltransferase/diacylglycerol acyltransferase activity and enhanced apolipoprotein B-48 protein synthesis, as well as elevated microsomal triglyceride transfer protein activity. Along with the enhanced chylomicrons, microsomes were characterized by abundant Sec12, the guanine exchange factor that promotes the localization of Sar1b in the endoplasmic reticulum. Furthermore, coimmunoprecipitation experiments revealed high levels of the complex components Sec23/Sec24 and p125, the Sec23-interacting protein. Finally, a pronounced interaction of Sec23/Sec24 with sterol regulatory element binding protein (SREBP) cleavage-activating protein and SREBP-1c was noted, thereby permitting the transfer of the transcription factor SREBP-1c to the nucleus for the activation of genes involved in lipid metabolism. Conclusion— Our data suggest that Sar1b expression may promote intestinal lipid transport with the involvement of the coat protein complex II network and the processing of SREBP-1c.

No study has yet examined how weight loss modifies the impact of the Mediterranean diet (MedDiet) on cardiovascular risk factors in men with the metabolic syndrome (MetS). The objective of the study was to assess the efficacy of MedDiet, with and without weight loss, to modify the cardiometabolic risk profile of male patients with MetS.Twenty-six men aged between 24 and 62 years with the MetS consumed a North American control diet for 5 weeks followed by a 5-week MedDiet, both under weight-maintaining conditions. Participants then underwent a 20-week weight loss period, after which they consumed the MedDiet for five weeks under weight stable conditions. Body weight was reduced by 10.2% ± 2.9% after the weight loss period (p0.001). All foods were provided to participants during the weight stable phases of the study. The MedDiet in the absence of weight loss decreased total plasma cholesterol (C) (-7.1%), LDL-C (-9.3%) and the total/HDL-C ratio (-6.5%) compared to the control diet (all p0.04). The MedDiet combined with weight loss led to reductions in systolic blood pressure (-4.7%), diastolic blood pressure (-7.7%), triglycerides (-18.2%), ApoB (-10.7%), fasting glucose (-4.2%) and insulin (-29.9%) compared to the control diet (all p0.001).The MedDiet in the absence of weight loss leads to significant changes in plasma cholesterol concentrations but has little effects on other cardiometabolic risk factors associated with the MetS in men.

Lipid Research Centre, Service of Lipidology, Department of Medicine, Laval University, Centre Hospitalier Universitairede Quebec, Pavillon CHUL, Room S102, Quebec City, Quebec, Canada G1V 4G2 (Drs. Gangloff, Bergeron, Couture, andGagne); and Robarts Research Institute, University of Western Ontario, Ontario, Canada (Dr. Hegele; and R. Martins)Familial hypobetalipoproteinemia (FHBL) is character-ized by extremely low circulating levels of apolipoprotein(apo) B, the major protein constituent of chylomicrons,very-low-density lipoprotein (VLDL), and low densitylipoprotein (LDL) particles. Most cases of FHBL resultfrom nonsense mutations in the APOB gene that lead to apremature stop codon, which generate prematurely trun-cated apo B protein products.

Scope: Mechanisms by which trans fatty acids (TFA) from industrial (iTFA) and ruminant (rTFA) sources alter cholesterol homeostasis are virtually unknown. We compared the impact of dietary iTFA and rTFA on surrogate markers of cholesterol absorption (β-sitosterol and campesterol) and synthesis (lathosterol) in healthy men. Methods and results: In a randomized, controlled double-blind crossover study, 38 healthy men consumed three experimental isoenergetic diets for 4 wk each. The three diets were (i) high in iTFA (10.2 g/2500 kcal), (ii) high in rTFA (10.2 g/2500 kcal) and (iii) control diet low in TFA from any source (2.2 g/2500 kcal). The sum of plasma β-sitosterol and campesterol concentrations was significantly reduced after the iTFA diet compared with the control diet (−12%, p=0.050). The reduction in combined β-sitosterol and campesterol levels was larger in magnitude after the rTFA diet (−29% versus the control diet and −20% versus the iTFA diet, p

Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α.

No study has yet examined how weight loss specifically modifies the impact of the Mediterranean diet (MedDiet) on plasma cell adhesion molecules (CAM) in men with the metabolic syndrome (MetS). Therefore, this study examined the impact of the MedDiet consumed under controlled feeding conditions, with and without weight loss, on plasma CAM concentrations in men with the MetS. The diet of 26 men (age 24–62 years) with the MetS was first standardized to a North American control diet for 5 weeks followed by a 5-week MedDiet, both under weight-maintaining isocaloric feeding conditions. Participants then underwent a 20-week caloric restriction period that led to a 10.2 ± 2.9% reduction in body weight (p < 0.01), followed by the consumption of an isocaloric weight stable MedDiet for 5 weeks. All foods including red wine were provided during the isocaloric phases of the study. There was no change in the average concentrations of any of the CAM after the MedDiet without weight loss. The MedDiet combined with weight loss reduced plasma CAM concentrations by 10.9% (p < 0.01) compared with the control diet and by 6.8% (p = 0.068) compared with the MedDiet without weight loss. These data suggest that weight loss is required for the MedDiet to improve plasma CAM concentrations over a short period of time in men with the MetS. ClinicalTrial.gov registration number: NCT00988650.

Item does not contain fulltext Conventionally, atherogenic dyslipidemias have been defined by elevated levels of triglyceride and/or LDL cholesterol. However, cholesterol and triglycerides are not metabolically and physically independent entities. Rather, they are constituents of the atherogenic apolipoprotein B (apoB) particles, which differ in their origin and their metabolic function. Moreover, the risk of vascular disease is not related to the plasma concentration of cholesterol or triglyceride per se, but to the number, composition and size of the apoB particles, within which the cholesterol and triglycerides are contained. After all, the entire apoB particle--rather than individual cholesterol or triglyceride molecules--enters and is trapped within the arterial wall, and this particle initiates and sustains the process that results in atherosclerosis. Accordingly, we suggest a change of name and focus from dyslipidemias to dyslipoproteinemias. Virtually all the atherogenic apoB dyslipoproteinemias can be specifically identified on the basis of plasma levels of cholesterol, triglyceride and apoB. Not only does this enable an accurate diagnosis in the individual, but the major familial dyslipoproteinemias can be identified as well. Here, we review the diagnostic algorithm for apoB dyslipoproteinemias and provide, for the first time, a treatment plan on the basis of a reduction of atherogenic lipoprotein particles rather than plasma lipids. 01 juni 2010

Objectives: To assess the relationship between commonly used lipid indices and LDL peak particle diameter (LDL-PPD) in a large cohort of 1955 subjects. Design and methods: Four statistical methods were used for comparison: correlation, concordance analysis, kappa statistics and receiver operating characteristic curve (ROC) analysis. Results: Plasma triglyceride (TG) levels, TG/HDL-C, LDL-C/apoB, total cholesterol (TC)/TG, LDL-C/TG, and TG/apoB ratios were best correlated with LDL-PPD but none of these ratios accounted for more than 45% of the variation in LDL-PPD. Moreover, across the range of the lipid indices and LDL-PPD quintiles, just under 40% of the values were concordant, with kappas varying between 0.20 and 0.25. Finally, plasma TG levels and the lipid ratios yielded areas under the ROC curve between 0.78 and 0.80. Conclusions: The present study does not support the concept that plasma TG levels and the commonly used lipid indices may be considered as adequate surrogates for the small dense LDL phenotype. Our data also indicate that various lipid indices are not superior to plasma TG levels alone as a clinical tool for prediction of the small dense LDL phenotype.

Item does not contain fulltext The objectives of this analysis are to re-examine the foundational studies of the in vivo metabolism of plasma LDL (low-density lipoprotein) particles in humans and, based on them, to reconstruct our understanding of the governance of the concentration of plasma LDL and the maintenance of cholesterol homoeostasis in the hepatocyte. We believe that regulation of cholesterol homoeostasis within the hepatocyte is demonstrably more complex than envisioned by the LDL receptor paradigm, the conventional model to explain the regulation of plasma LDL and the fluxes of cholesterol into the liver, a model which was generated in the fibroblast but has never been fully validated in the hepatocyte. We suggest that the LDL receptor paradigm should be reconfigured as the apoB (apolipoprotein B) paradigm, which states that the rate at which LDL particles are produced is at least an important determinant of their concentration in plasma as the rate at which they are cleared from plasma and that secretion of cholesterol within VLDL (very-low-density lipoprotein) particles is an important mechanism of maintaining cholesterol homoeostasis within the hepatocyte. These two paradigms are not mutually exclusive. The LDL receptor paradigm, however, includes only one critical aspect of the regulation of plasma LDL, namely the rate at which LDL particles are cleared through the LDL receptor pathway, but ignores another - the rate at which LDL particles are added to the plasma compartment. The apoB paradigm includes both and points to a different model of how the hepatocyte achieves cholesterol homoeostasis in a complex metabolic environment. 01 maart 2010

Omega-3 fatty acids (FAs) may accelerate plasma triglyceride (TG) clearance by altering lipoprotein lipase (LPL) activity. Yet, the ability of n-3 FAs to increase LPL activity is dependent on transcription factors such as peroxisome proliferator-activated receptor alpha (PPARalpha). The objective was to examine the effects of n-3 FAs on LPL activity considering the occurrence of PPARalpha L162V polymorphism. First, 14 pairs of men either L162 homozygotes or carriers of the V162 allele were supplemented with n-3 FAs. Second, transient transfections in HepG2 cells, for the L162- and V162-PPARalpha variants with the peroxisome proliferator-response element from the human LPL gene, were transactivated with n-3 FAs. In vivo results demonstrate that the LPL activity increased non-significantly by 14.4% in L162 homozygotes compared with 6.6% in carriers of the PPARalpha-V162 allele, after n-3 FA supplementation. Additionally, the L162 homozygotes tended towards an inverse correlation between LPL activities and plasma TG levels. Conversely, carriers of the V162 allele showed no such relationship. In vitro data demonstrates that transcription rates of LPL tended to be higher for the L162-PPARalpha than V162-PPARalpha after n-3 FAs activation. Overall, these results indicate that n-3 FA supplementation increases the transcription rate of LPL to a greater extent in L162-PPARalpha than V162-PPARalpha.

Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (−43.0%), LDL-C (−53.6%), and triglycerides (−44.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (−48.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (−38.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r = 0.85; P < 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.

The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-α L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA+DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA+DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n14 per group). E4 status was determined afterwards. All subjects received an EPA+DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene × diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively.

Type 2 diabetes mellitus is associated with elevated plasma triglyceride levels, low high-density lipoprotein cholesterol, and a high incidence of cardiovascular disease. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and fibrates are frequently used in the treatment of diabetic dyslipidemia, but their specific impact on the inflammation processes involved in atherosclerosis remains to be fully characterized. The objective of this 2-group parallel study was to investigate the differential effects of a 6-week treatment with either atorvastatin 20 mg/d alone (n = 19) or micronized fenofibrate 200 mg/d alone (n = 19) on inflammation, cell adhesion, and oxidation markers in type 2 diabetes mellitus subjects with marked hypertriglyceridemia. In addition to the expected changes in lipid levels, atorvastatin decreased plasma levels of C-reactive protein (-26.9%, P = .004), soluble intercellular adhesion molecule 1 (-5.4%, P = .03), soluble vascular cell adhesion molecule 1 (-4.4%, P = .008), sE-selectin (-5.7%, P = .02), matrix metalloproteinase 9 (-39.6%, P = .04), secretory phospholipase A(2) (sPLA(2)) (-14.8%, P = .04), and oxidized low-density lipoprotein (-38.4%, P.0001). On the other hand, fenofibrate had no significant effect on C-reactive protein levels and was associated with reduced plasma levels of sE-selectin only (-6.0%, P = .04) and increased plasma levels of sPLA(2) (+22.5%, P = .004). These results suggest that atorvastatin was potent to reduce inflammation, oxidation, and monocyte adhesion in type 2 diabetes mellitus subjects with marked hypertriglyceridemia, whereas fenofibrate decreased sE-selectin levels only and was associated with an elevation of sPLA(2) levels.

The specific impact of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates on the in vivo metabolism of apolipoprotein (apo) B has not been systematically investigated in patients with type 2 diabetes mellitus with high plasma triglyceride (TG) levels. Therefore, the objective of this 2-group parallel study was to examine the differential effects of a 6-week treatment with atorvastatin or fenofibrate on in vivo kinetics of apo B-48 and B-100 in men with type 2 diabetes mellitus with marked hypertriglyceridemia. Apolipoprotein B kinetics were assessed at baseline and at the end of the intervention using a primed constant infusion of [5,5,5-D(3)]-l-leucine for 12 hours in the fed state. Fenofibrate significantly decreased plasma TG levels with no significant change in plasma low-density lipoprotein cholesterol (LDL-C) and apo B levels. On the other hand, atorvastatin significantly reduced plasma levels of TG, LDL-C, and apo B. After treatment with fenofibrate, very low-density lipoprotein (VLDL) apo B-100 pool size (PS) was decreased because of an increase in the fractional catabolic rate (FCR) of VLDL apo B-100. No significant change was observed in the kinetics of LDL apo B-100. Moreover, fenofibrate significantly decreased TG-rich lipoprotein (TRL) apo B-48 PS because of a significant increase in TRL apo B-48 FCR. After treatment with atorvastatin, VLDL and IDL apo B-100 PSs were significantly decreased because of significant elevations in the FCR of these subfractions. Low-density lipoprotein apo B-100 PS was significantly lowered because of a tendency toward decreased LDL apo B-100 production rate (PR). Finally, atorvastatin reduced TRL apo B-48 PS because of a significant decrease in the PR of this subfraction. These results indicate that fenofibrate increases TRL apo B-48 as well as VLDL apo B-100 clearance in men with type 2 diabetes mellitus with marked hypertriglyceridemia, whereas atorvastatin increases both VLDL and IDL apo B-100 clearance and decreases TRL apo B-48 and LDL apo B-100 PR.

Background: Dietary n–3 polyunsaturated fatty acids (PUFAs) decrease the risk of cardiovascular disease (CVD). Yet, genetic variations of the gene encoding the peroxisome proliferator-activated receptor-α (PPARα) can also modulate CVD risk factors. Since fatty acids, including n–3 PUFAs, are natural ligands of PPARα, a gene-diet interaction effect could be observed. Aims: To examine whether n–3 PUFA- induced changes in CVD risk factors are influenced by the PPARα L162V polymorphism. Methods: Fourteen men, carriers of the V162 allele and 14 L162 homozygotes, were matched according to age and body mass index. Subjects followed, for 8 weeks, a low-fat diet and then were supplemented daily with 5 g of fish oil for 6 weeks. Results: Baseline characteristics were similar for both genotype groups. Independently of the genotype, the supplementation was associated with a significant decrease in plasma triacylglycerol and fasting glucose concentrations, diastolic blood pressure, and with an increase in total apolipoprotein B concentrations. The extent of the decrease in plasma triacylglycerol concentrations was comparable for both genotype groups (p < 0.03). A significant genotype-by-diet interaction effect was observed for plasma C-reactive protein concentrations (p = 0.01). Conclusions: The PPARα L162V polymorphism may contribute to the interindividual variability in the CVD risk factor response to n–3 PUFAs.

Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n = 11) and nondiabetic controls (n = 13) using a primed-constant infusion of l-[5,5,5-D(3)]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these subfractions.

The objective of this study was to investigate the presence of Thy-1 in the myocardium and on cardiac fibroblasts and to determine whether or not cardiac fibroblasts form a heterogeneous population in term of Thy-1 expression. Thy-1 expression was examined by immunohistology of ventricular sections from normal and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Thy-1 immunostaining was detected in connective tissue on alpha8 integrin-positive and discoidin domain receptor 2 (DDR2)-positive fibroblasts. Enhanced Thy-1 staining was observed in the hearts of DOCA-salt rats particularly in areas of interstitial fibrosis. Cardiac mRNA analysis confirmed the increased Thy-1 expression. On cultured cardiac fibroblasts, flow cytofluorometry showed that cells, from primary culture to passage 4, were double positive for Thy-1 and for both alpha8 integrin and DDR2. Analysis of isolated lipid rafts by detergent-free sucrose gradient indicated that Thy-1 protein was probably located in these structures, but it may be located on a membrane microdomain slightly different from those of caveolin-1, as revealed by immunocytochemistry. Differentiation of fibroblasts into myofibroblasts being a characteristic of cardiac fibrosis and scarring, cardiac fibroblasts were stimulated in the presence of transforming growth factor-beta (TGF-beta) or connective tissue growth factor. While the expression of smooth muscle alpha-actin and alpha8 integrin doubled, Thy-1 level, measured by Western blotting and flow cytofluorometry, was not influenced by TGF-beta. These results demonstrate that cardiac fibroblasts express Thy-1 and form a homogeneous population. Thy-1 expression also appears to be independent of fibroblast differentiation. The dichotomy between the increased Tthy-1 expression in the fibrotic area and the lack of association with fibroblast differentiation suggests that Thy-1 may represent a marker of fibroblast proliferation in the myocardium.

Background and aim Compared to a DASH-type diet, an intensively applied dietary portfolio reduced diastolic blood pressure at 24 weeks as a secondary outcome in a previous study. Due to the importance of strategies to reduce blood pressure, we performed an exploratory analysis pooling data from intensively and routinely applied portfolio treatments from the same study to assess the effect over time on systolic, diastolic and mean arterial pressure (MAP), and the relation to sodium (Na + ), potassium (K + ), and portfolio components. Methods and results 241 participants with hyperlipidemia, from four academic centers across Canada were randomized and completed either a DASH-type diet (control n = 82) or a dietary portfolio that included, soy protein, viscous fibers and nuts (n = 159) for 24 weeks. Fasting measures and 7-day food records were obtained at weeks 0, 12 and 24, with 24-h urines at weeks 0 and 24. The dietary portfolio reduced systolic, diastolic and mean arterial blood pressure compared to the control by 2.1 mm Hg (95% CI, 4.2 to −0.1 mm Hg) (p = 0.056), 1.8 mm Hg (CI, 3.2 to 0.4 mm Hg) (p = 0.013) and 1.9 mm Hg (CI, 3.4 to 0.4 mm Hg) (p = 0.015), respectively. Blood pressure reductions were small at 12 weeks and only reached significance at 24 weeks. Nuts, soy and viscous fiber all related negatively to change in mean arterial pressure (ρ = −0.15 to −0.17, p ≤ 0.016) as did urinary potassium (ρ = −0.25, p = 0.001), while the Na + /K + ratio was positively associated (ρ = 0.20, p = 0.010). Conclusions Consumption of a cholesterol-lowering dietary portfolio also decreased blood pressure by comparison with a healthy DASH-type diet. Clinical Trial Reg. No. NCT00438425, clinicaltrials.gov.

Substantial evidence exists indicating that elevated plasma levels of apolipoprotein (apo) B-48-containing lipoproteins are associated with increased cardiovascular disease risk. Overaccumulation of apoB-48-containing lipoproteins of intestinal origin observed in patients with insulin-resistance (IR) is thought to be attributable to both elevated intestinal production and reduced clearance of these lipoproteins. The objective of this study was to assess the relative contribution of IR, anthropometry, and dietary fat content on triglyceride (TG)-rich lipoprotein (TRL) apoB-48 kinetic. The in vivo kinetic of TRL apoB-48 was measured in 131 men with primed-constant infusion of L-[5,5,5-D3]leucine. TRL apoB-48 production rate (PR) and fractional catabolism rate (FCR) were determined by multi-compartmental modeling, while TRL apoB-48 pool size (PS) was measured by ELISA. IR was defined by TG levels > 1.5 mmol/L and Homeostasis Model Assessment of IR (HOMA-IR) > 2.5. Age was inversely associated with TRL apoB-48 FCR (ρ=-0.21; P=0.02), while BMI was positively correlated with TRL apoB-48 PR (ρ=0.33; P=0.0001) and PS (ρ=0.44; P

Background:Fish-oil derived fatty acids (FAs) of the n-3 family including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce inflammation through several underlying mechanisms including altered phospholipids FA composition. The L162V polymorphism of the PPAR-α gene is associated with a deteriorated metabolic profile and with obesity indices in numerous studies. Objective: To study whether the PPAR-α L162V polymorphism and changes in plasma phospholipid FA composition influence plasma C-reactive protein (CRP) levels in healthy adults following the n-3 FA supplementation.Method: 189 subjects were supplemented daily with 3g of n-3 FAs (1.9-2.2g EPA and 1.1g DHA) during six weeks. Changes in CRP levels are defined by Δ CRP and changes in plasma phospholipids n-3 (EPA+DHA) by Δ n-3. Results: In univariate analyses, Δ n-3 was negatively correlated with Δ CRP (r=-0.17 p=0.02). After stratification for sex, correlations were stronger in men (r=-0.24 p=0.02) and no longer significant in women (r=-0....

We evaluated the effects of 5 dietary oils on RHI: corn/safflower oil (69.3% LA, 17.6% MUFA), canola oil (62.8% MUFA, 29.3% PUFA: 19.5% LA, 10% ALA), high-oleic canola oil (72% MUFA, 17% PUFA: 15% LA, 2% ALA), high-oleic canola oil with DHA (63.8% MUFA, 13% LA, 6% DHA), and flax/safflower oil (69.4% PUFA: 37.5% LA, 32% ALA, 17.9% MUFA). We conducted a multi-center, randomized, 5-period crossover, controlled feeding study. RHI was measured after isocaloric, heart-healthy diets containing one of 5 oils for 4 weeks, followed by >2 week break. In adults at risk of MetS, there was no significant treatment effect for RHI, an index of endothelial function. There was a treatment x period interaction (p=0.03). Because of known menstrual changes in RHI, we made an a priori decision to separately analyze effects excluding premenopausal women. In this subsample (n = 85), there was a significant treatment effect (P=0.048). RHI on the corn/safflower diet was significantly greater than on the flax/safflower diet (mean R...

A high fruit and vegetable (FAV) intake is associated with a lower prevalence of chronic diseases but identifying the optimal number of daily FAV servings (DFAVS) needed to reduce chronic disease risk is difficult due to the biases of common self-report dietary assessment tools. In this regard, plasma carotenoid levels have been suggested to be more accurate markers of FAV consumption than self-reported intakes. The aim of the present study was to examine the associations between DFAVS and plasma carotenoid levels in a group of 155 men and 110 women enrolled in 6 full-feeding dietary interventions we previously conducted. We measured and compared fasting plasma carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein, lycopene, zeaxanthin) and retinol levels with regards to the number of DFAVS provided and consumed by participants. Plasma β-cryptoxanthin, lutein and zeaxanthin levels were positively associated with consumed DFAVS (p

Autosomal dominant familial hypercholesterolemia (FH) is caused by genetic mutations in the LDL receptor (LDLR), its ligand apolipoprotein (apo) B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 levels have been shown to correlate with LDL-cholesterol (LDL-C) levels in FH, the extent to which PCSK9 levels modulate the phenotypic severity of this disease independent of LDLR genotype remains to be clarified.To assess the relationship between LDLR genotype and the plasma levels of PCSK9, LDL-C, and lipoprotein (a) (Lp(a)) in a large cohort of genetically defined FH heterozygotes (HeFH).A total of 292 HeFH carrying one of the nine French-Canadian mutations in the LDLR gene were recruited. The cohort included 226 carriers of a negative-receptor (NR) mutation and 66 carriers of a defective-receptor (DR) LDLR gene mutation. Fifty-six control subjects, who were matched with the HeFH subjects based on gender and body mass index, were also recruited.PCSK9 levels were higher in the HeFH group than in the control group (317.9±107.1 ng/mL vs. 203.3±59.8 ng/mL; P0.0001). The strength of the association between PCSK9 and LDL-C levels was similar among controls (r=0.37; P=0.005) and HeFH (r=0.31; P0.0001). Furthermore, a multiple linear regression analysis revealed that the positive correlation between PCSK9 and LDL-C levels remained significant after adjusting for LDLR genotype in the HeFH group.These results suggested that the contribution of PCSK9 levels to the phenotypic severity in FH heterozygotes is independent of LDLR genotype.

Low-density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL-C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin-induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (-63.3% vs. -59.9%; P = 0.05), LDL-C (-70.5% vs. -63.0%; P = 0.02), CRP (-75.3% vs. -48.8%; P 0.0001), and TNF-α (-23.7% vs. +14.7%; P = 0.003). Reductions in the plasma levels of PCSK9 (-45.3% vs. -63.4%; P = 0.31), lipoprotein (a) (-70.6% vs. -65.0%; P = 0.30), E-selectin (-16.6% vs. -18.3%; P = 0.65), ICAM-1 (-4.0 vs. 5.6%; P = 0.56), and VCAM-1 (8.3% vs. -1.8%; P = 0.08) were not different between the two systems. For the same volume of filtered plasma (3,000 mL), however, HELP led to greater reductions in plasma apoB (-63.1% vs. -58.3%; P = 0.04), HDL-C (-20.6% vs. -6.5%; P = 0.003), and PCSK9 (-63.4% vs. -28.5%; P = 0.02) levels. These results suggest that both LA systems are effective in reducing plasma lipids and inflammatory markers in HoFH. Compared with HELP, greater reductions in lipid levels and inflammatory markers were achieved with DS, most likely because this method allows for a larger plasma volume to be filtered. J. Clin. Apheresis 31:359-367, 2016. © 2015 Wiley Periodicals, Inc.

In this chapter, we will review the pathophysiology, clinical features, diagnostic criteria and treatment of the secondary apoB dyslipoproteinemias as classified by the apoB diagnostic algorithm.

Words matter. The words we choose to represent our beliefs govern how we act. Accordingly, the objective of this final chapter is to argue that we should change our language so that we will change our actions. The Risk Prediction Paradigm presently governs prevention of vascular disease. However, we believe prevention would be much more successful if we moved to the Causal Exposure Paradigm, which is simpler, more direct, and calls for earlier therapeutic intervention than the Risk Prediction Paradigm.231,248,249

In this chapter, we will review the pathophysiology, clinical features, diagnostic criteria and treatment of the primary apoB dyslipoproteinemias

LDL is the major proatherogenic apoB lipoprotein particle and statin therapy to lower LDL particle number in plasma substantially lowers the rates of cardiovascular events. Accordingly, every Guideline advocates statin therapy as fundamental to cardiovascular care. Nevertheless, notwithstanding that every guideline states they are evidence-based and all cite the same evidence, they do not agree on how to do it: that is, how much statin to give and what marker, if any, to assess the adequacy of therapy. The most recent European222 and Canadian guidelines195 recommend a target-based approach with LDL-C as the primary target and non-HDL-C and apoB as alternate targets. However, the Europeans have three targets and three intensities of therapy depending on the perceived level of risk whereas the Canadians have only one target level for each of the three markers and, therefore, only one intensity of therapy. On the other hand, the Joint British Societies196 and the National Lipid Association197 favor non-HDL-C as the best marker to judge the adequacy of LDL-lowering therapy (Table 6.1). Thus, as is obvious in Table 6.1, there is considerable variation in the targets for LDL-C, non- HDL-C and apoB amongst the different guidelines. Indeed for high-risk patients, the targets for LDL-C expressed in population percentiles differ between the 12th to 33rdpercentile whereas apoB percentile targets vary between the 35th and 67th percentile.

In this chapter we will review the data supporting the concept that the Mediterranean diet (MedDiet), even in the absence of clinically meaningful weight loss, represents a particular potent nutrition modality for the management of the atherogenic dyslipidemia associated with metabolic syndrome (MetS). MedDiet reduces the proinflammatory and pro-oxidative states associated with MetS in both men and women, independent of weight change. Data also emphasize that individuals with a deteriorated cardiometabolic profile are more likely to have several traditional and nontraditional cardiovascular risk factors respond favorably to MedDiet than those with a less deteriorated risk profile. In sum, our data and data from others indicate that MedDiet is highly effective in modulating several cardiometabolic risk factors in high-risk individuals, and in most instances, weight loss is not required for these beneficial effects to occur.

In 2001, Adult Treatment Panel II (ATPII) added non-HDL-C as an alternative to LDL-C to estimate risk and to guide therapy in hypertriglyceridemic patients.193 In 2012 and 2013, first the European lipid guidelines194 and then the Canadian Guidelines195 confirmed LDL-C as the prime measure for clinical care but stated that non-HDL-C or apoB could be alternative measures to drive clinical decisions. In 2013, the ACC/AHA guidelines stated therapy should be based on regimens, not lipid targets, whereas in 2014, the Joint British Societies Guidelines (JBS3)196 and the National Lipid Association197 selected non-HDL-C as the preferred target of therapy.