Relationship between lifestyle habits and cardiovascular risk factors in familial hypercholesterolemia.

BACKGROUND AND AIM: Little is known about the cardioprotective potential of a healthy lifestyle in familial hypercholesterolemia (FH). The objective of this study was to evaluate the relationship between lifestyle and cardiovascular risk factors in adults with FH. METHODS AND RESULTS: This cross-sectional study leveraged data from the CARTaGENE Quebec population-based cohort (Canada). Participants with FH were identified using the validated Simplified Canadian Definition for FH. A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity); 3) eating a healthy diet (Alternate Healthy Eating Index ≥50%); 4) having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day); and 5) sleeping 7-8 h/day. Among the 122 included individuals (women, n = 78; men, n = 44; mean age ± SD: 57.3 ± 6.7 years), 92 (75.4%) had a HLS ≤3/5, while only 5 (4.1%) had a HLS of 5/5. After adjustments for sex, age, body mass index, and lipid-lowering medication use, we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (ß = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels (ß = -0.07, 95% CI = -0.13, -0.01%; P = 0.02), and statistical trends suggested favorable associations with HDL-cholesterol (ß = 0.06, 95% CI = -0.02, 0.14 mmol/L; P = 0.06) and waist circumference (ß = -2.22, 95% CI = -4.62, 0.17 cm; P = 0.07). CONCLUSION: This study suggests that a healthy lifestyle is favorably associated with CVD risk factors in adults with FH.

Associations between insulin-like growth factor binding protein-2 and lipoprotein kinetics in men.

Low circulating concentrations of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with dyslipidemia, notably with high triglyceride (TG) levels. However, the determinants by which IGFBP-2 influences lipoprotein metabolism, especially that of TG-rich lipoproteins (TRLs), are poorly understood. Here, we aimed to assess the relationships between IGFBP-2 levels and lipoprotein production and catabolism in human subjects. Fasting IGFBP-2 concentrations were measured in the plasma of 219 men pooled from previous lipoprotein kinetics studies. We analyzed production rate and fractional catabolic rates of TRLapoB-48, and LDL-, IDL-, and VLDLapoB-100 by multicompartmental modeling of l-[5,5,5-D3] leucine enrichment data after a 12 h primed constant infusion in individuals kept in a constant nutritional steady state. Subjects had an average BMI of 30 kg/m2, plasma IGFBP-2 levels of 157 ng/ml, and TG of 2.2 mmol/l. After adjustments for age and BMI, IGFBP-2 levels were negatively associated with plasma TG (r = -0.29; P < 0.0001) and positively associated with HDL-cholesterol (r = 0.26; P < 0.0001). In addition, IGFBP-2 levels were positively associated with the fractional catabolic rate of VLDLapoB-100 (r = 0.20; P < 0.01) and IDLapoB-100 (r = 0.19; P < 0.05) and inversely with the production rate of TRLapoB-48 (r = -0.28; P < 0.001). These correlations remained statistically significant after adjustments for age, BMI, and the amount of fat given during the tracer infusion. These findings show that the association between low plasma IGFBP-2 and high TG concentrations could be due to both an impaired clearance of apoB-100-containing VLDL and IDL particles and an increased production of apoB-48-containing chylomicrons. Additional studies are necessary to investigate whether and how IGFBP-2 directly impacts the kinetics of TRL.

Polymorphisms in the stearoyl-CoA desaturase gene modify blood glucose response to dietary oils varying in MUFA content in adults with obesity.

Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.

Diets Enriched with Conventional or High-Oleic Acid Canola Oils Lower Atherogenic Lipids and Lipoproteins Compared to a Diet with a Western Fatty Acid Profile in Adults with Central Adiposity.

BACKGROUND: Novel oils high in monounsaturated fatty acids (MUFAs) and low in saturated fatty acids (SFAs) are an alternative to partially hydrogenated oils high in trans-unsaturated fatty acids. There is widespread use of high-MUFA oils across the food industry; however, limited knowledge of their cardiovascular impact exists. OBJECTIVES: We investigated the effects of diets containing canola oil, high-oleic acid canola oil (HOCO), and a control oil blend (diet formulated to emulate a Western fat profile) on lipids, lipoproteins, and apolipoproteins (apos), as secondary outcomes of the trial. METHODS: In a multi-center, double-blind, randomized, 3-period crossover, controlled feeding trial, men (n = 44) and women (n = 75) with a mean age of 44 y, mean body mass index (BMI; in kg/m2) of 31.7, and an increased waist circumference plus ≥1 metabolic syndrome criteria consumed prepared, weight-maintenance diets containing canola oil [17.5% MUFAs, 9.2% polyunsaturated fatty acids (PUFAs), 6.6% SFAs], HOCO (19.1% MUFAs, 7.0% PUFAs, 6.4% SFAs), or control oil (10.5% MUFAs, 10.0% PUFAs, 12.3% SFAs) for 6 wk with ≥4-wk washouts. Fasting serum lipids were assessed at baseline and 6 wk. Diet effects were examined using a repeated measures mixed model. RESULTS: Compared with the control, canola and HOCO diets resulted in lower endpoint total cholesterol (TC; -4.2% and -3.4%; P < 0.0001), LDL cholesterol (-6.6% and -5.6%; P < 0.0001), apoB (-3.7% and -3.4%; P = 0.002), and non-HDL cholesterol (-4.5% and -4.0%; P = 0.001), with no differences between canola diets. The TC:HDL cholesterol and apoB:apoA1 ratios were lower after the HOCO diet than after the control diet (-3.7% and -3.4%, respectively). There were no diet effects on triglyceride, HDL cholesterol, or apoA1 concentrations. CONCLUSIONS: HOCO, with increased MUFAs at the expense of decreased PUFAs, elicited beneficial effects on lipids and lipoproteins comparable to conventional canola oil and consistent with reduced cardiovascular disease risk in adults with central adiposity. This trial was registered at www.clinicaltrials.gov as NCT02029833.

Common Variants in Lipid Metabolism-Related Genes Associate with Fat Mass Changes in Response to Dietary Monounsaturated Fatty Acids in Adults with Abdominal Obesity.

BACKGROUND: Different fatty acids (FAs) can vary in their obesogenic effect, and genetic makeup can contribute to fat deposition in response to dietary FA composition. However, the antiobesogenic effects of the interactions between dietary MUFAs and genetics have scarcely been tested in intervention studies. OBJECTIVE: We evaluated the overall (primary outcome) and genetically modulated (secondary outcome) response in body weight and fat mass to different levels of MUFA consumption. METHODS: In the Canola Oil Multicenter Intervention Trial II, a randomized, crossover, isocaloric, controlled-feeding multicenter trial, 44 men and 71 women with a mean age of 44 y and an increased waist circumference (men ∼108 cm and women ∼102 cm) consumed each of 3 oils for 6 wk, separated by four 12-wk washout periods. Oils included 2 high-MUFA oils-conventional canola and high-oleic canola (<7% SFAs, >65% MUFAs)-and 1 low-MUFA/high-SFA oil blend (40.2% SFAs, 22.0% MUFAs). Body fat was measured using DXA. Five candidate single-nucleotide polymorphisms (SNPs) were genotyped using qualitative PCR. Data were analyzed using a repeated measures mixed model. RESULTS: No significant differences were observed in adiposity measures following the consumption of either high-MUFA diet compared with the low-MUFA/high-SFA treatment. However, when stratified by genotype, 3 SNPs within lipoprotein lipase (LPL), adiponectin, and apoE genes influenced, separately, fat mass changes in response to treatment (n = 101). Mainly, the LPL rs13702-CC genotype was associated with lower visceral fat (high-MUFA: -216.2 ± 58.6 g; low-MUFA: 17.2 ± 81.1 g; P = 0.017) and android fat mass (high-MUFA: -267.3 ± 76.4 g; low-MUFA: -21.7 ± 102.2 g; P = 0.037) following average consumption of the 2 high-MUFA diets. CONCLUSIONS: Common variants in LPL, adiponectin, and apoE genes modulated body fat mass response to dietary MUFAs in an isocaloric diet in adults with abdominal obesity. These findings might eventually help in developing personalized dietary recommendations for weight control. The trial was registered at clinicaltrials.gov as NCT02029833 (https://www.clinicaltrials.gov/ct2/show/NCT02029833?cond=NCT02029833&rank=1).

Correlates of the difference in plasma carotenoid concentrations between men and women.

Health professionals consider the evaluation of eating habits to be challenging, given the potential biases of dietary questionnaires based on self-reported data. Circulating carotenoid concentrations are reliable biomarkers of dietary carotenoid intake and could be useful in the validation of dietary assessment tools. However, there is a sex difference in circulating carotenoids, with women displaying higher concentrations compared with men independent of intake. The aim of the present study was to identify the correlates of plasma carotenoid concentrations among men (n 155) and women (n 110) enrolled in six fully controlled dietary interventions with varying dietary carotenoid intakes. We looked at the associations of post-intervention fasting plasma carotenoid concentrations (α-carotene, ß-carotene, ß-cryptoxanthin, lutein, lycopene and zeaxanthin) with physical and metabolic characteristics. We found that increased body weight (r -0·47, P<0·0001) and waist circumference (r -0·46, P<0·0001) were associated with lower plasma total carotenoid concentrations, while elevated plasma LDL-cholesterol (r 0·49, P<0·0001) and HDL-cholesterol (r 0·50, P<0·0001) concentrations were correlated with higher total carotenoids in plasma. Women had significantly higher plasma total carotenoid concentrations compared with men, despite significantly lower dietary carotenoid intake. Adjustment of circulating carotenoid concentrations for plasma HDL-cholesterol eliminated sex difference in plasma carotenoid concentrations. Our results suggest that physical characteristics as well as plasma lipids are associated with circulating carotenoid concentrations and that these variables should be taken into account when using plasma carotenoids as biomarkers for food intake in men and women.

Comparing the serum TAG response to high-dose supplementation of either DHA or EPA among individuals with increased cardiovascular risk: the ComparED study.

Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar.

Plasma PCSK9 correlates with apoB-48-containing triglyceride-rich lipoprotein production in men with insulin resistance.

Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important in the pathogenesis of atherosclerosis in insulin resistance (IR). We investigated the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations with apoB-48-containing TRL metabolism in 148 men displaying various degrees of IR by measuring in vivo kinetics of TRL apoB-48 during a constant-fed state after a primed-constant infusion of L-[5,5,5-D3]leucine. Plasma PCSK9 concentrations positively correlated with TRL apoB-48 pool size (r = 0.31, P = 0.0002) and production rate (r = 0.24, P = 0.008) but not the fractional catabolic rate (r = -0.04, P = 0.6). Backward stepwise multiple linear regression analysis identified PCSK9 concentrations as a positive predictor of TRL apoB-48 production rate (standard ß = +0.20, P = 0.007) independent of BMI, age, T2D/metformin use, dietary fat intake during the kinetic study, and fasting concentrations of TGs, insulin, glucose, LDL cholesterol, or C-reactive protein. We also assessed intestinal expression of key genes involved in chylomicron processing from duodenal samples of 71 men. Expression of PCSK9 and HMG-CoAR genes was positively associated (r = 0.43, P = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR.

Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding.

Triglycerides are the conventional tool to measure VLDLs, whereas LDL cholesterol (LDL-C) is the conventional tool to measure LDLs. Multiple epidemiological studies, including a series of genetically based analyses, have demonstrated that cardiovascular risk is related to triglycerides independently of LDL-C, and this has led to a series of new therapeutic agents designed specifically to reduce plasma triglycerides. The triglyceride hypothesis posits that increased levels of triglycerides increase cardiovascular risk and decreasing plasma triglycerides decreases cardiovascular risk. In this work, we will examine the validity of the triglyceride hypothesis by detailing the biological complexities associated with hypertriglyceridemia, the genetic epidemiological evidence in favor of hypertriglyceridemia, the evidence from the fibrate randomized clinical trials relating triglycerides and clinical outcomes, and the completeness of the evidence from the initial studies of novel mutations and the therapeutic agents based on these mutations that lower triglycerides. Because of the multiple metabolic links between VLDL and LDL, we will try to demonstrate that measuring triglycerides and LDL-C alone are inadequate to document the lipoprotein profile. We will try to demonstrate that apoB must be measured, as well as triglycerides and cholesterol, to have an accurate estimate of lipoprotein status.

Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism.

The mechanisms underlying the oversecretion of apolipoprotein (apo)B-48-containing triglyceride-rich lipoproteins (TRL) in insulin-resistance (IR) states in humans remain to be fully understood. The objective of this study was to evaluate the association between the plasma levels of insulin and glucose and the intestinal expression of key genes involved in chylomicron metabolism in a large sample of nondiabetic men displaying various degrees of IR. Duodenal biopsies were obtained by gastroduodenoscopy in 127 men free of intestinal disease. Gene expression was measured using quantitative PCR in duodenal samples. Plasma insulin and glucose concentrations were measured in the fasting state. Postprandial TRL apoB-48 kinetics were measured using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in a subgroup of 75 subjects maintained in a constant fed state. Plasma insulin levels were negatively associated with intestinal expression of ACS1 (standard ß = -0.20, P = 0.007), DGAT1 (ß = -0.18, P = 0.001), DGAT2 (ß = -0.20, P = 0.02), and MTP (ß = -0.27, P = 0.0005), whereas glucose levels were positively associated with MTP expression (ß = 0.15, P = 0.04) independent of age, BMI, waist circumference, dietary intake, and duodenal expression of SREBP1c. Insulin levels, but not glucose concentrations, were positively correlated with postprandial TRL apoB-48 production rate ( r = 0.24, P = 0.04) and pool size ( r = 0.27, P = 0.03). In conclusion, plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism. These results suggest that alterations in intestinal lipoprotein metabolism associated with IR may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency. NEW & NOTEWORTHY We demonstrate that plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism in men. For instance, intestinal expression of MTP is negatively associated with plasma insulin concentrations and positively associated with plasma glucose concentrations. Alterations in intestinal lipoprotein metabolism associated with insulin resistance may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency.

Imputation of Baseline LDL Cholesterol Concentration in Patients with Familial Hypercholesterolemia on Statins or Ezetimibe.

BACKGROUND: Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy. METHODS: To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions. RESULTS: After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe. CONCLUSIONS: We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.

Supplementation with Resveratrol and Curcumin Does Not Affect the Inflammatory Response to a High-Fat Meal in Older Adults with Abdominal Obesity: A Randomized, Placebo-Controlled Crossover Trial.

Background: High-fat meals induce postprandial inflammation. Resveratrol is a polyphenol known to prevent comorbidities associated with cardiovascular disease and exerts an anti-inflammatory action. There is also an increasing body of evidence supporting the role of curcumin, a polyphenol from the curcuminoid family, as a modulator of proinflammatory processes. Objective: The objectives of this study were to investigate the following: 1) the bioavailability of resveratrol consumed in combination with curcumin after consumption of a high-fat meal; and 2) the acute combined effects of this combination on the postprandial inflammatory response of subjects with abdominal obesity. Methods: In a double blind, crossover, randomized, placebo-controlled study, 11 men and 11 postmenopausal women [mean ± SD age: 62 ± 5 y; mean ± SD body mass index (in kg/m2): 29 ± 3] underwent a 6-h oral fat tolerance test on 2 occasions separated by 1-2 wk: once after consumption of a dietary supplement (200 mg resveratrol and 100 mg curcumin, Res/Cur) and once after consumption of a placebo (cellulose). Plasma concentrations of total resveratrol and its major metabolites as well as inflammatory markers, adhesion molecules, and whole blood NFκB1 and PPARA gene expression were measured during both fat tolerance tests. Results: Kinetics of resveratrol and identified metabolites revealed rapid absorption patterns but also relatively limited bioavailability based on free resveratrol concentrations. Supplementation with Res/Cur did not modify postprandial variations in circulating inflammatory markers (C-reactive protein, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesion molecules [soluble E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1] compared to placebo (PTreatment×Time > 0.05). However, Res/Cur significantly decreased the cumulative postprandial response of sVCAM-1, compared to placebo (incremental area under the curve -4643%, P = 0.01). Postprandial variations of whole-blood PPARA and NFKB1 gene expression were not different between Res/Cur and placebo treatments. Conclusions: Acute supplementation with Res/Cur has no impact on the postprandial inflammation response to a high-fat meal in abdominally obese older adults. Further studies are warranted to examine how resveratrol and curcumin may alter the vascular response to a high-fat meal. This trial was registered at clinicaltrials.gov as NCT01964846.

Saturated Fats from Butter but Not from Cheese Increase HDL-Mediated Cholesterol Efflux Capacity from J774 Macrophages in Men and Women with Abdominal Obesity.

Background: Recent evidence suggests that the association between dietary saturated fatty acids (SFAs) and coronary artery disease risk varies according to food sources. How SFAs from butter and cheese influence HDL-mediated cholesterol efflux capacity (CEC), a key process in reverse cholesterol transport, is currently unknown. Objective: In a predefined secondary analysis of a previously published trial, we have examined how diets rich in SFAs from either cheese or butter influence HDL-mediated CEC, compared with diets rich in either monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). Methods: In a randomized crossover controlled consumption trial, 46 men and women with abdominal obesity consumed 5 isocaloric diets, each for 4 wk. Two diets were rich in SFAs either from cheese (CHEESE) or butter (BUTTER) [12.4-12.6% of energy (%E) as SFAs, 32%E as fat, 52%E as carbohydrates]. In 2 other diets, SFAs (5.8%E) were replaced with either MUFAs from refined olive oil (MUFA) or PUFAs from corn oil (PUFA). Finally, a lower fat and carbohydrate diet was used as a control (5.8%E as SFAs, 25.0%E as fat, 59%E as carbohydrates; CHO). Post-diet HDL-mediated CEC was determined ex vivo using radiolabelled J774 macrophages incubated with apolipoprotein B-depleted serum from the participants. Results: Mean (±SD) age was 41.4 ± 14.2 y, and waist circumference was 107.6 ± 11.5 cm in men and 94.3 ± 12.4 cm in women. BUTTER and MUFA increased HDL-mediated CEC compared with CHEESE (+4.3%, P = 0.026 and +4.7%, P = 0.031, respectively). Exploring the significant diet × sex interaction (P = 0.044) revealed that the increase in HDL-mediated CEC after BUTTER compared with CHEESE was significant among men (+6.0%, P = 0.047) but not women (+2.9%, P = 0.19), whereas the increase after MUFA compared with CHEESE was significant among women (+9.1%, P = 0.008) but not men (-0.6%, P = 0.99). Conclusion: These results provide evidence of a food matrix effect modulating the impact of dairy SFAs on HDL-mediated CEC with potential sex-related differences that deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02106208.

Diets Low in Saturated Fat with Different Unsaturated Fatty Acid Profiles Similarly Increase Serum-Mediated Cholesterol Efflux from THP-1 Macrophages in a Population with or at Risk for Metabolic Syndrome: The Canola Oil Multicenter Intervention Trial.

Background: Cholesterol efflux plays an important role in preventing atherosclerosis progression. Vegetable oils with varying unsaturated fatty acid profiles favorably affect multiple cardiovascular disease risk factors; however, their effects on cholesterol efflux remain unclear. Objective: The objectives of this study were to examine the effects of diets low in saturated fatty acids (SFAs) with varying unsaturated fatty acid profiles on serum-mediated cholesterol efflux and its association with the plasma lipophilic index and central obesity. Methods: The present study is a randomized, crossover, controlled-feeding study. Participants [men: n = 50; women: n = 51; mean ± SE age: 49.5 ± 1.2 y; body mass index (in kg/m2): 29.4 ± 0.4] at risk for or with metabolic syndrome (MetS) were randomly assigned to 5 isocaloric diets containing the treatment oils: canola oil, high oleic acid-canola oil, DHA-enriched high oleic acid-canola oil, corn oil and safflower oil blend, and flax oil and safflower oil blend. These treatment oils were incorporated into smoothies that participants consumed 2 times/d. For a 3000-kcal diet, 60 g of treatment oil was required to provide 18% of total energy per day. Each diet period was 4 wk followed by a 2- to 4-wk washout period. We quantified cholesterol efflux capacity with a validated ex vivo high-throughput cholesterol efflux assay. Statistical analyses were performed with the use of the SAS mixed-model procedure. Results: The 5 diets increased serum-mediated cholesterol efflux capacity from THP-1 macrophages similarly by 39%, 34%, 55%, 49% and 51%, respectively, compared with baseline (P < 0.05 for all). Waist circumference and abdominal adiposity were negatively correlated with serum-mediated cholesterol efflux capacity (r = -0.25, P = 0.01, r = -0.33, P = 0.02, respectively). Conclusion: Diets low in SFAs with different monounsaturated fatty acid and polyunsaturated fatty acid profiles improved serum-mediated cholesterol efflux capacity in individuals with or at risk for MetS. This mechanism may account, in part, for the cardiovascular disease benefits of diets low in SFAs and high in unsaturated fatty acids. Importantly, central obesity is inversely associated with cholesterol efflux capacity. This trial was registered at www.clinicaltrials.gov as NCT01351012.

Impact of lipoprotein apheresis with dextran-sulfate adsorption on the expression of genes involved in cardiovascular health in the blood of patients with homozygous familial hypercholesterolemia.

Lipoprotein apheresis (LA) with dextran sulfate adsorption (DSA) is a reliable method to decrease LDL-cholesterol (C) concentrations in patients with homozygous familial hypercholesterolemia (HoFH). The objective of the present study was to investigate the impact of LA with DSA on the mRNA expression of genes associated with cardiovascular health in the whole blood of HoFH patients. Blood samples were collected before and after LA treatment with DSA in 9 HoFH patients. Microarray analyses were performed to measure the whole blood expression of >30 000 annotated genes pre- and post-LA. Concomitant reductions in LDL-C (median -73.8%, range: -55.9 to -82.0, P = .0001) and lipoprotein (a) concentrations (median -74.1%, range -65.6 to -84.1, P = .003) were induced with LA treatment. LA with DSA did not impact the whole blood mRNA expression of most key genes involved in cardiovascular health, including those associated with cholesterol, fatty acid and lipoprotein metabolism. However, LA with DSA significantly upregulated the whole blood expression of early growth response protein (EGR)1 (1.94-fold, P = .02), EGR3 (1.56-fold, P = .0008) and B-cell lymphoma 3-encoded protein (BCL3; 1.25-fold, P = .03). In conclusion, this study demonstrated that a single LA treatment with DSA has very limited impact on the whole blood expression of a broad spectrum of genes associated with cardiovascular health. Our results suggest that contact between blood cells and the primary membrane or extracorporeal circulation could upregulate the expression of EGR1, EGR3, BCL3, and MMP9 in blood cells.

Does lifestyle contribute to disease severity in patients with inherited lipid disorders?

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.

LDL particle number and size and cardiovascular risk: anything new under the sun?

PURPOSE OF REVIEW: We provide here an up-to-date perspective on the potential use of LDL particle number and size as complementary risk factors to predict and manage cardiovascular disease (CVD) risk in the clinical realm. RECENT FINDINGS: Studies show that a significant proportion of the population has discordant LDL particle number and cholesterol indices [non-HDL cholesterol (HDL-C)]. Data also show that risk prediction may be improved when using information on LDL particle number in patients with discordant particle number and cholesterol data. Yet, most of the current CVD guidelines conclude that LDL particle number is not superior to cholesterol indices, including non-HDL-C concentrations, in predicting CVD risk. LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients' risk is not yet justified. SUMMARY: Additional studies are required to settle the debate on which of cholesterol indices and LDL particle number is the best predictor of CVD risk, and if such measures should be integrated in clinical practice.

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels.

BACKGROUND: Previous studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH). METHODS: A total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state. RESULTS: Plasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 ± 246.9 vs. HeFH: 324.9 ± 119.8 vs. CONTROLS: 194.5 ± 65.9 ng/mL, P < 0.0001; apoB-48: HoFH: 14.71 ± 4.36 vs. HeFH: 6.55 ± 4.24 vs. CONTROLS: 3.03 ± 2.07 µg/mL; P < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (ρ = 0.06, P = 0.5) and HeFH subjects (ρ = 0.07, P = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance (P < 0.0001). CONCLUSIONS: These data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels. TRIAL REGISTRATION: NCT02225340 .

Plasma Triglyceride Levels May Be Modulated by Gene Expression of IQCJ, NXPH1, PHF17 and MYB in Humans.

A genome-wide association study (GWAS) by our group identified loci associated with the plasma triglyceride (TG) response to ω-3 fatty acid (FA) supplementation in IQCJ, NXPH1, PHF17 and MYB. Our aim is to investigate potential mechanisms underlying the associations between single nucleotide polymorphisms (SNPs) in the four genes and TG levels following ω-3 FA supplementation. 208 subjects received 3 g/day of ω-3 FA (1.9-2.2 g of EPA and 1.1 g of docosahexaenoic acid (DHA)) for six weeks. Plasma TG were measured before and after the intervention. 67 SNPs were selected to increase the density of markers near GWAS hits. Genome-wide expression and methylation analyses were conducted on respectively 30 and 35 participants' blood sample together with in silico analyses. Two SNPs of IQCJ showed different affinities to splice sites depending on alleles. Expression levels were influenced by genotype for one SNP in NXPH1 and one in MYB. Associations between 12 tagged SNPs of IQCJ, 26 of NXPH1, seven of PHF17 and four of MYB and gene-specific CpG site methylation levels were found. The response of plasma TG to ω-3 FA supplementation may be modulated by the effect of DNA methylation on expression levels of genes revealed by GWAS.

Common Variants in Cholesterol Synthesis- and Transport-Related Genes Associate with Circulating Cholesterol Responses to Intakes of Conventional Dairy Products in Healthy Individuals.

BACKGROUND: Dairy intake has been associated with varying impacts on circulating cholesterol concentrations across nutritional epidemiology and intervention studies, with findings attributed mainly to differences in the nature of dairy products consumed or study designs. The contribution of the genomic architecture to such observations has yet to be revealed. OBJECTIVE: We assessed the impact of multiple common genetic variations in cholesterol-related genes on responses of serum cholesterol to the recommended amount of dairy product intake in Canada. METHODS: In a multicenter, randomized crossover design, 101 normolipidemic adults (n = 29 men and 72 women), with a mean ± SD age of 41.7 ± 16.7 y and a body mass index (BMI, in kg/m(2)) of 25.9 ± 4.3 consumed 3 servings/d of dairy [375 mL 1% milk-fat (MF) milk, 175 g 1.5% MF yogurt, and 30 g of 34% MF cheese] or energy-matched control products (juice, cashews, and cookies) provided within a prudent background diet for 4 wk each, separated by a 4- to 8-wk washout period. Serum lipid variables were determined by standard enzymatic methods by using an autoanalyzer. Candidate single nucleotide polymorphisms were assessed by TaqMan genotyping assay. RESULTS: The responsiveness of serum total cholesterol (TC) and LDL cholesterol to the dairy compared with the control diet was associated with individuals' genotypes. The cholesterol transport gene ATP-binding cassette subfamily G, member 5 (ABCG5) rs6720173-GG homozygotes had higher concentrations of TC (+0.18 mmol/L; P = 0.0118) and LDL cholesterol (+0.17 mmol/L; P = 0.0056) relative to C-allele carriers (-0.07 and -0.06 mmol/L, respectively). The bile acid synthesis gene cholesterol 7α-hydroxylase (CYP7A1) rs3808607-G-allele carriers had higher TC (+0.20 to +0.28 mmol/L; P = 0.0026) and LDL cholesterol (+0.19 mmol/L for GT genotype; P = 0.0260) relative to TT homozygotes (-0.11 and -0.03 mmol/L, respectively). In addition, the cholesterol synthesis gene 7-dehydrocholesterol reductase (DHCR7) rs760241-A-allele carriers had higher LDL cholesterol (+0.26 mmol/L; P = 0.0399) relative to GG homozygotes (+0.06 mmol/L). CONCLUSION: Genetic variations in ABCG5, CYP7A1, and DHCR7 may contribute to differing responses of serum cholesterol to dairy intake among healthy adults. This trial was registered at clinicaltrials.gov as NCT01444326.