phytosterols and Coronary-Artery-Disease

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.

Topics: ABO Blood-Group System; Adult; Apolipoproteins E; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cholesterol; Coronary Artery Disease; Female; Gene Expression Regulation; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hydroxymethylglutaryl CoA Reductases; Lipase; Lipid Metabolism; Lipoproteins; Male; Membrane Transport Proteins; Mendelian Randomization Analysis; Multifactorial Inheritance; Phytosterols; Polymorphism, Single Nucleotide; Scavenger Receptors, Class B

Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such as sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Coronary Artery Disease; Heterozygote; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Mutation; Phenotype; Phytosterols; Polymorphism, Genetic; Proprotein Convertase 9; Sitosterols

Plant sterols and stanols are similar in chemical structure to cholesterol, differing in their side chain configuration. The mechanism by which they lower cholesterol is thought to involve inhibition of cholesterol absorption. A number of products containing plant sterols are now available. A limitation on the development of such products is the poor water solubility of plant sterols. The most common solution is to esterify plant stanols or sterols with fatty acids to enhance availability in food fats such as margarines and salad dressings. A number of studies have shown the efficacy of plant stanol- and sterol-enriched margarines for lowering cholesterol. However, there have been no studies demonstrating that consumption of these stanol ester-containing margarines influences the incidence of coronary heart disease.

Topics: Administration, Oral; Clinical Trials as Topic; Coronary Artery Disease; Diet Therapy; Dietary Supplements; Evidence-Based Medicine; Food, Formulated; Humans; Hyperlipidemias; Hypolipidemic Agents; Phytosterols; Phytotherapy; Plant Extracts; Sitosterols

Phytosterols are plant sterols, mainly campesterol and sitosterol, and their respective stanols (5alpha-saturated derivatives), which chemically resemble cholesterol. They are present in a normal diet and are absorbed proportionally to cholesterol, but to a much lesser extent, such that less than 0.1% of serum sterols are plant sterols. Phytosterols inhibit intestinal cholesterol absorption, and fat-soluble plant stanol esters were introduced as a functional food for lowering serum cholesterol in the early 1990s; plant sterol esters entered the market at the end of the 1990s. Inhibition of the intestinal absorption of cholesterol stimulates cholesterol synthesis, a factor which limits serum cholesterol lowering to about 10% with phytosterols. Enrichment of the diet with plant stanol esters reduces absorption and serum concentrations of both cholesterol and plant sterols, whereas enrichment of the diet with plant sterol esters, especially in combination with statins, lowers serum cholesterol but increases serum plant sterol levels. Recent studies have suggested that high-serum plant sterol levels may be associated with increased coincidence of coronary heart disease. Estimates of coronary heart disease reduction by 20--25% with plant sterols/stanols is based mainly on short-term studies. Long-term cholesterol lowering, needed for the prevention of coronary heart disease, may be successful with plant stanol esters, which lower serum cholesterol in both genders over at least a year.

Topics: Coronary Artery Disease; Diet; Food, Fortified; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipids; Phytosterols

Use of plant stanols/sterols in forms that are sufficiently bioavailable for therapeutic effect should be a key element of maximal dietary therapy. This principle was recognized by National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and has been amply confirmed by experimental studies in humans. Since the introduction of statins, dietary therapy for control of elevated low-density lipoprotein (LDL) cholesterol levels has received less attention. The time has come, however, to reassert the importance of maximal dietary therapy as a cost-effective means for treatment of elevated LDL concentrations and for lifetime prevention of coronary heart disease.

Topics: Cholesterol, LDL; Combined Modality Therapy; Coronary Artery Disease; Cost-Benefit Analysis; Humans; Hypercholesterolemia; Phytosterols; Sitosterols; Treatment Outcome

Consumption of food products enriched with plant sterols and the use of ezetimibe reduce cholesterol absorption in the intestine and effectively reduce low-density lipoprotein (LDL) plasma levels. We evaluated the therapeutic effect of the ezetimibe+plant sterol association in patients with coronary artery disease still not reaching recommended lipid levels despite the use of statins. We performed a prospective open-label study with 41 patients with stable coronary disease and LDL >70 mg/dL. Patients were randomized into four groups for a 6-week treatment: the control (CT) group remained on the same statin therapy, the ezetimibe (EZ) group received 10 mg/day of ezetimibe, the plant sterol (PS) group received spread enriched with 2 g of plant sterols, and the ezetimibe+PS (EZ+PS) group received 10 mg/day EZ +2 g PS. Initial mean LDL level was 97.4 ± 31.1 mg/dL in control group, 105.1 ± 23.1 mg/dL in EZ group, 95.4 ± 27.7 mg/dL in PS group, and 97.0 ± 8.3 mg/dL in EZ+PS group (P > .05). After 6 weeks of treatment, LDL of patients slightly increased in the control group (+8.9%; P > .05) and dropped in EZ group (-19.1%; P = .06), PS group (-16.6%; P = .01), and EZ+PS group (-27.3%; P < .01). Mean LDL levels after treatment were 70.5 ± 17.9 mg/dL in EZ+PS group, lower than the other groups (control was 106.1 ± 34.9 mg/dL, EZ group was 85.0 ± 35.6 mg/dL, and PS was 79.6 ± 29.7 mg/dL) (P = .05 variance analysis factor [ANOVA]). Body weight, body-mass index, and glucose plasma levels did not change significantly after intervention. The combination of PS+ezetimibe was associated with lower LDL levels and suggests beneficial therapeutic effect against major cardiovascular events.

Topics: Adult; Aged; Anticholesteremic Agents; Coronary Artery Disease; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; Male; Middle Aged; Phytosterols; Prospective Studies; Young Adult

Several studies have observed a hypocholesterolemic effect of plant sterols in hypercholesterolemic patients on a balanced diet. The aim of this study was to examine the effect of phytosterol supplementation on risk factors of coronary artery disease in metabolic syndrome patients on a Westernized type diet.. In a randomized placebo-controlled design 108 patients with metabolic syndrome were assigned to consume either 2 plant sterol-enriched yogurt mini drink which provided 4 g phytosterols per day, or a yogurt beverage without phytosterols (control). The duration of the study was 2 months and the patients in both groups followed their habitual westernized type diet and recording it on food diaries. Blood samples were drawn at baseline and after 2 months of intervention. After 2 months supplementation with phytosterols, a significant reduction in total cholesterol, LDL-cholesterol, small and dense LDL (sdLDL) levels, as well as, apoB and triglycerides concentrations were observed in the intervention group (P < 0.05) compared to the control group. In addition, phytosterol supplementation lowered serum total cholesterol by 15.9%, LDL-cholesterol by 20.3% and triglyceride levels by 19.1% (P = 0.02, P < 0.001 and P < 0.001, respectively), although the patients kept their habitual westernized type diet. No differences were observed in HDL cholesterol, apoA1, glucose, C-reactive protein, fibrinogen levels and blood pressure.. Phytosterol supplementation improves risk factors of coronary artery disease even if the diet is a westernized type.

Topics: Adult; Aged; Anticholesteremic Agents; Apolipoprotein A-I; Arterial Pressure; Blood Pressure; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diet; Diet Records; Dietary Supplements; Energy Intake; Female; Fibrinogen; Humans; Male; Metabolic Syndrome; Middle Aged; Phytosterols; Risk Factors; Single-Blind Method; Triglycerides; Yogurt

To assess the mechanism of long-term LDL-C-lowering effect of ezetimibe-plus-statin.. Coronary artery disease patients whose LDL-C ≥ 70 mg/dL after treatment with atorvastatin 10 mg/day or rosuvastatin 2.5 mg/day were randomly assigned to receive ezetimibe 10 mg/day + statin (n = 78) or double-dose statin (n = 72) for 52 weeks.. Greater LDL-C reduction was observed and maintained until 52 weeks in ezetimibe-plus-statin, while LDL-C levels re-increased after 12 weeks in double-dose statin. Although lathosterol/TC increased, campesterol/TC decreased more in ezetimibe-plus-statin. In contrast, lathosterol/TC unchanged and campesterol/TC increased, increasing campesterol/lathosterol ratio for 52 weeks in double-dose statin. Plasma PCSK9 levels were higher in double-dose statin than in ezetimibe-plus-statin at 12 weeks, but similar at 52 weeks.. Although the difference in PCSK9 between 2 groups was transient, that in both campesterol and lathosterol persisted until 52 weeks. These results demonstrated simultaneous inhibition of cholesterol absorption and synthesis provides stable and greater decrease in LDL-C levels.

Topics: Aged; Anticholesteremic Agents; Atorvastatin; Azetidines; Biomarkers; Cholesterol; Cholesterol, LDL; Coronary Artery Disease; Drug Administration Schedule; Drug Therapy, Combination; Ezetimibe; Female; Fluorobenzenes; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Middle Aged; Phytosterols; Proprotein Convertase 9; Proprotein Convertases; Prospective Studies; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Serine Endopeptidases; Sulfonamides; Time Factors; Treatment Outcome

Serum levels of cholesterol absorption and synthesis markers have been associated with cardiovascular risk in the United States and European countries. In this study, we examined the relevance of these biomarkers and the presence of cardiovascular disease (CVD) in Japanese individuals.. The CACHE consortium, comprising of 13 research groups in Japan possessing data on campesterol, an absorption marker, and lathosterol, a synthesis marker measured by gas chromatography, compiled the clinical data using the REDCap system.. Among the 2,944 individuals in the CACHE population, those with missing campesterol or lathosterol data were excluded. This cross-sectional study was able to analyze data from 2,895 individuals, including 339 coronary artery disease (CAD) patients, 108 cerebrovascular disease (CeVD) patients, and 88 peripheral artery disease (PAD) patients. The median age was 57 years, 43% were female, and the median low-density lipoprotein cholesterol and triglyceride levels were 118 mg/dL and 98 mg/dL, respectively. We assessed the associations of campesterol, lathosterol, and the ratio of campesterol to lathosterol (Campe/Latho ratio) with the odds of CVD using multivariable-adjusted nonlinear regression models. The prevalence of CVD, especially CAD, showed positive, inverse, and positive associations with campesterol, lathosterol, and the Campe/Latho ratio, respectively. These associations remained significant even after excluding individuals using statins and/or ezetimibe. The associations of the cholesterol biomarkers with PAD were determined weaker than those with CAD. Contrarily, no significant association was noted between cholesterol metabolism biomarkers and CeVD.. This study showed that both high cholesterol absorption and low cholesterol synthesis biomarker levels were associated with high odds of CVD, especially CAD.

Topics: Biomarkers; Cardiovascular Diseases; Cholesterol; Coronary Artery Disease; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Phytosterols

Short-term clinical trials have shown the cholesterol-lowering potentials of phytosterols, but their impacts on cardiovascular disease (CVD) remain controversial. This study used the Mendelian randomization (MR) to investigate the relationships between genetic predisposition to blood sitosterol concentration and 11 CVD endpoints, along with the potential mediating effects of blood lipids and hematological traits.. Random-effect inverse-variance weighted method was used as the main analysis of MR. Genetic instruments of sitosterol (seven SNPs, F = 253, and R. Genetically predicted one unit increment in log-transformed blood total sitosterol was significantly associated with a higher risk of coronary atherosclerosis (OR: 1.52; 95 % CI: 1.41, 1.65; n = 667,551), myocardial infarction (OR: 1.40; 95 % CI: 1.25, 1.56; n = 596,436), all coronary heart disease (OR: 1.33; 95 % CI: 1.22, 1.46; n = 766,053), intracerebral hemorrhage (OR: 1.68; 95 % CI: 1.24, 2.27; n = 659,181), heart failure (OR: 1.16; 95 % CI: 1.08, 1.25; n = 1,195,531), and aortic aneurysm (OR: 1.74; 95 % CI: 1.42, 2.13; n = 665,714). Suggestive associations were observed for an increased risk of ischemic stroke (OR: 1.06; 95 % CI: 1.01, 1.12; n = 2,021,995) and peripheral artery disease (OR: 1.20; 95 % CI: 1.05, 1.37; n = 660,791). Notably, blood non-high-density lipoprotein cholesterol (nonHDL-C) and apolipoprotein B mediated about 38-47 %, 46-60 %, and 43-58 % of the associations between sitosterol and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively. However, the associations between sitosterol and CVDs were less likely to depend on hematological traits.. The study suggests that genetic predisposition to higher blood total sitosterol is linked to a greater risk of major CVDs. Moreover, blood nonHDL-C and apolipoprotein B might mediate a significant proportion of the associations between sitosterol and coronary diseases.

Topics: Apolipoproteins; Cardiovascular Diseases; Cholesterol; Coronary Artery Disease; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Lipids; Mendelian Randomization Analysis; Myocardial Infarction; Phytosterols; Polymorphism, Single Nucleotide; Risk Factors; Sitosterols

Blood cholesterol levels are regulated by competing mechanisms of cholesterol synthesis, absorption and excretion. Plant sterols are natural constituents of plants, are not synthesized in humans, and serve as markers for cholesterol absorption. Ezetimibe lowers the intestinal absorption of cholesterol and plant sterols. We analyzed the associations of differences in cholesterol metabolism, in particular increased cholesterol absorption, and the occurrence of in-stent restenosis (ISR) in patients with stable coronary artery disease.. Elective stent implantation of de novo stenosis was conducted in 59 patients (74.6 % males, 67.2 ± 9.6 years). Cholesterol and non-cholesterol sterols were quantified in serum samples by gas chromatography or mass spectrometry. ISR was assessed by optical coherence tomography (OCT) and quantitative angiography (QCA) after six months.. Markers for cholesterol absorption (e.g. campesterol-to-cholesterol) were positively associated with ISR measured by QCA (%diameter stenosis, late lumen loss) and OCT (proliferation volume, %area stenosis), whereas markers for cholesterol synthesis (e.g. lathosterol-to-cholesterol) were negatively associated with ISR (%area stenosis: r = -0.271, p = 0.043). There was no association between ISR and total cholesterol, LDL, HDL, triglycerides. Markers for cholesterol absorption (e.g. campesterol-to-cholesterol) were significantly lower in ezetimibe-treated patients compared to patients on a statin only (1.29 ± 0.69 vs. 2.22 ± 1.23; p = 0.007). Combined lipid-lowering with ezetimibe plus statin reduced ISR compared to statin only (13.7 ± 10.4 vs. 22.5 ± 12.1 %diameter stenosis, p = 0.015).. Differences in cholesterol metabolism, more specifically increased cholesterol absorption, are associated with ISR.

Topics: Cholesterol, LDL; Constriction, Pathologic; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Ezetimibe; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Phytosterols; Stents; Triglycerides

Topics: Cholesterol; Coronary Artery Disease; Humans; Hypercholesterolemia; Lipoproteins; Phytosterols

Topics: Cholesterol; Coronary Artery Disease; Humans; Phytosterols; Sterols

Atherosclerosis, an inflammatory disorder of the vasculature and the underlying cause of cardiovascular disease, is responsible for one in three global deaths. Consumption of active food ingredients such as omega-3 polyunsaturated fatty acids, flavanols and phytosterols has many beneficial effects on cardiovascular disease. However, their combined actions on the risk factors for atherosclerosis remains poorly understood. We have previously shown that a formulation containing each of these active components at physiologically relevant doses modulated several monocyte/macrophage processes associated with atherosclerosis in vitro, including inhibition of cytokine-induced pro-inflammatory gene expression, chemokine-driven monocyte migration, expression of M1 phenotype markers, and promotion of cholesterol efflux. The objectives of the present study were to investigate whether the protective actions of the formulation extended in vivo and to delineate the potential underlying mechanisms. The formulation produced several favourable changes, including higher plasma levels of HDL and reduced levels of macrophages and myeloid-derived suppressor cells in the bone marrow. The mRNA expression of liver-X-receptor-α, peroxisome proliferator-activated receptor-γ and superoxide dismutase-1 was induced in the liver and that of interferon-γ and the chemokine (C-X-C motif) ligand 1 decreased, thereby suggesting the potential mechanisms for many beneficial effects. Other changes were also observed such as increased plasma levels of triglycerides and lipid peroxidation that may reflect potential activation of brown fat. This study provides new insights into the protective actions and the potential underlying mechanisms of the formulation in vivo, particularly in relation to risk factors together with changes in systemic inflammation and hepatic lipid alterations associated with atherosclerosis and metabolic syndrome, and supports further assessments in human trials.

Topics: Animals; Cardiotonic Agents; Coronary Artery Disease; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Omega-3; Flavanones; Functional Food; Gene Expression; Male; Mice; Mice, Inbred C57BL; Phytosterols; Risk Factors

Phytosterol (PS) consumption is associated with lower total and LDL-cholesterol (LDL-c) concentrations, but its impact on cardiovascular risk is unclear. This study assessed the effect of usual intake of PS on markers of subclinical atherosclerosis in the Longitudinal Study of Adult Health (ELSA-Brasil).. This cross-sectional study included 2560 participants of ELSA-Brasil, aged 48 (43-54) years, with available food frequency questionnaires (FFQ), coronary artery calcium (CAC) scores, carotid intima media thickness (cIMT), and carotid-femoral pulse wave velocity (cf-PWV), at baseline. Several logistic and linear regression models were used, and significance level was set at a P < 0.05. Mean values (SD) for PS consumption were 256 (198) mg/day, CAC 22.78 (110.54) Agatston Units, cf-PWV 9.07 (1.60) m/s and cIMT 0.57 (0.12) mm. PS consumption in Q4 was associated with lower total- and LDL-c levels, and with higher percentiles of cf-PWV (P < 0.001). Proportion of subjects in Q4 of PS consumption was 1.5 times higher among individuals in cf-PWV Q4, than in Q1 (P = 0.002, for comparisons among quartiles). There was a trend (P = 0.003) for higher cf-PWV with higher PS intake. In crude logistic and linear regressions, PS intake was associated with cf-PWV. In the adjusted models, these associations disappeared. No associations were found between PS and cIMT or CAC.. In this large and apparently healthy cross-sectional sample from ELSA-Brasil, usual PS consumption was associated with lower total- and LDL-cholesterol, but not with markers of subclinical atherosclerosis.

Topics: Adult; Biomarkers; Brazil; Carotid Artery Diseases; Carotid Intima-Media Thickness; Carotid-Femoral Pulse Wave Velocity; Cholesterol, LDL; Coronary Angiography; Coronary Artery Disease; Cross-Sectional Studies; Diet; Feeding Behavior; Female; Humans; Male; Middle Aged; Phytosterols; Predictive Value of Tests; Risk Assessment; Risk Factors; Vascular Calcification; Vascular Stiffness

To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols.. We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4).. Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; Coronary Artery Disease; Humans; Iceland; Phytosterols; Sterols

The aim of the study was to evaluate the relationship between phytosterols, oxyphytosterols, and other markers of cholesterol metabolism and concomitant coronary artery disease (CAD) in patients with severe aortic stenosis who were scheduled for elective aortic valve replacement. Markers of cholesterol metabolism (plant sterols and cholestanol as markers of cholesterol absorption and lathosterol as an indicator of cholesterol synthesis) and oxyphytosterols were determined in plasma and aortic valve tissue from 104 consecutive patients with severe aortic stenosis (n=68 statin treatment; n=36 no statin treatment) using gas chromatography-flame ionization and mass spectrometry. The extent of CAD was determined by coronary angiography prior to aortic valve replacement. Patients treated with statins were characterized by lower plasma cholesterol, cholestanol, and lathosterol concentrations. However, statin treatment did not affect the sterol concentrations in cardiovascular tissue. The ratio of campesterol-to-cholesterol was increased by 0.46±0.34μg/mg (26.0%) in plasma of patients with CAD. The absolute values for the cholesterol absorption markers sitosterol and campesterol were increased by 18.18±11.59ng/mg (38.8%) and 11.40±8.69ng/mg (30.4%) in the tissues from patients with documented CAD compared to those without concomitant CAD. Campesterol oxides were increased by 0.06±0.02ng/mg (17.1%) in the aortic valve cusps and oxidized sitosterol-to-cholesterol ratios were up-regulated by 0.35±0.2ng/mg (22.7%) in the plasma of patients with CAD. Of note, neither cholestanol nor the ratio of cholestanol-to-cholesterol was associated with CAD. Patients with concomitant CAD are characterized by increased deposition of plant sterols, but not cholestanol in aortic valve tissue. Moreover, patients with concomitant CAD were characterized by increased oxyphytosterol concentrations in plasma and aortic valve cusps.

Topics: Aged; Aortic Valve; Aortic Valve Stenosis; Blood Vessels; Cholestanol; Cholesterol; Coronary Artery Disease; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Oxidation-Reduction; Phytosterols; Sitosterols

To evaluate the association between very low density lipoprotein cholesterol (VLDL-C) and cholesterol absorption and synthesis markers in patients with moderate and high risk of coronary heart disease.. A total 363 statin-naïve patients with moderate and high risk of coronary heart disease were consecutively recruited from two hospitals in Shanxi and Henan provinces between October 2008 and June 2009. A standard questionnaire and physical examination were performed at baseline. Atorvastatin (20 mg/day) was administered to patients for 4 weeks. Venous blood samples after an overnight fast were collected before and after treatment for measuring VLDL-C and cholesterol absorption and synthesis markers. In qualitative analyses, the baseline level of cholesterol absorption and synthesis markers and their reduction after atorvastatin treatment were categorized into 3 tertile groups.. (1) Of 363 patients, 283 patients with mean age of (55.43±9.01)years old with complete data were finally analyzed. The median level of baseline VLDL-C was 1.06 (0.65, 1.86) mmol/L. The median level of baseline cholesterol absorption marker (Campesterol) and cholesterol synthesis marker (Lathosterol) was 6.01 (3.78, 9.45) mg/L and 13.46 (8.30, 21.07) mg/L, respectively. (2) Partial correlation analysis and multiple regression showed the baseline level of VLDL-C was positively correlated with Campesterol (r=0.153, P<0.05) but not with Lathosterol(r=0.182, P=0.173). Furthermore, baseline VLDL-C level significantly increased with tertile of the baseline level of Campesterol in the qualitative analyses(P for trend=0.035). (3) Mean reduction in VLDL-C levels was 38.0% after 4 weeks atorvastatin treatment. VLDL-C reduction was positively correlated with Campesterol reduction (r=0.331, P<0.001). VLDL-C reduction significantly increased with the tertile of Campesterol reduction (P for trend=0.032). But this trend was not observed between VLDL-C level and Lathosterol (P for trend=0.798).. The level of VLDL-C was closely related to cholesterol absorption marker, and further studies are needed to validate if inhibitor of cholesterol absorption (for example by Ezetimibe) could bring about more effective VLDL-C lowering effect in this patient cohort.

Topics: Atorvastatin; Biomarkers; Cholesterol; Cholesterol, LDL; Cholesterol, VLDL; Coronary Artery Disease; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phytosterols; Risk Factors

The aim of this study was to evaluate the relationship between cholesterol metabolism and coronary plaque vulnerability.. Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences the progression of coronary atherosclerosis.. Consecutive stable angina pectoris patients (N = 80) not receiving any lipid-lowering therapy were divided into 2 groups based on the presence of in vivo thin cap fibroatheroma (TCFA) in de novo target vessels assessed by the combined use of virtual histology intravascular ultrasound and optical coherence tomography.. Patients with in vivo TCFA (n = 42) showed a higher campesterol-to-lathosterol ratio (3.36 [interquartile range, 2.10 to 4.26] vs. 1.50 [1.20 to 2.50], p < 0.0001). The campesterol-to-lathosterol ratio, low-density lipoprotein (LDL) cholesterol, and high-sensitivity C-reactive protein (hsCRP) were positively correlated with the percentage of necrotic core volume (r = 0.520, p < 0.0001; r = 0.520, p < 0.0001; and r = 0.539, p < 0.0001, respectively) and negatively correlated with thinnest fibrous cap thickness (r = -0.566, p < 0.0001; r = -0.530, p < 0.0001; and r = -0.358, p = 0.007, respectively) . The independent predictors of the incidence of TCFA were the campesterol-to-lathosterol ratio (odds ratio: 3.989, 95% confidence interval: 1.688 to 9.428; p = 0.002), LDL cholesterol (odds ratio: 1.425, 95% confidence interval: 1.023 to 1.985; p = 0.03), hsCRP (odds ratio: 1.025, 95% confidence interval: 1.003 to 1.047; p = 0.02), and the percentage of necrotic core volume (odds ratio:1.084, 95% confidence interval: 1.012 to 1.161; p = 0.02).. Enhanced absorption and reduced synthesis of cholesterol may be related to coronary plaque vulnerability.

Topics: Aged; Angina, Stable; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Coronary Vessels; Disease Progression; Female; Fibrosis; Humans; Linear Models; Logistic Models; Male; Middle Aged; Multivariate Analysis; Necrosis; Odds Ratio; Phytosterols; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Risk Factors; Rupture, Spontaneous; Tomography, Optical Coherence; Ultrasonography, Interventional

Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).. A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)).. Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

Topics: ABO Blood-Group System; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Case-Control Studies; Coronary Artery Disease; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Lipoproteins; Male; Meta-Analysis as Topic; Metabolism; Phytosterols; Polymorphism, Single Nucleotide; Risk Factors; Validation Studies as Topic

Phytosterols have been proposed to be atherogenic. This research investigates whether plasma concentrations of phytosterols correlate with the manifestation of coronary heart disease.. The CORA study compares clinical, biochemical, and lifestyle factors in consecutive pre- and postmenopausal women with incident coronary heart disease to those in age-matched population-based controls. Controls (n=231) had significantly higher plasma concentrations of the major phytosterol species than cases (n=186) (4.649mg/l vs. 4.092mg/l; p<0.001). Cases had a higher dietary intake of phytosterols, but the ratio of lathosterol over sitosterol did not significantly differ. Phytosterols correlated with cholesterol concentrations of LDL and HDL, the phytosterol-carrying lipoproteins. The age-adjusted odds ratio for the association of total phytosterols and risk of coronary heart disease was 0.69 per 5mg/dl (95% CI 0.46-0.99). After adjustment for LDL- and HDL-cholesterol the odds ratio approached 1 (0.89; 95% CI 0.61-1.30), which was reached after additional adjustment for major risk factors, particularly those reflecting the metabolic syndrome (1.05; 95% CI 0.64-1.97).. Healthy controls had higher unadjusted concentrations of plasma phytosterols, but the adjusted odds ratio for coronary heart disease did not point to an impact of plasma phytosterols on coronary heart disease.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cholesterol; Coronary Artery Disease; Female; Humans; Metabolic Syndrome; Middle Aged; Odds Ratio; Phytosterols; Risk Factors; Sitosterols

Changes in the balance of cholesterol absorption and synthesis and moderately elevated plasma plant sterols have been suggested to be atherogenic. Measuring cholestanol, lathosterol, campesterol, and sitosterol, we investigated the relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease (CAD) in 2,440 participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. The coronary status was determined by angiography, and the severity of CAD was assessed by the Friesinger Score (FS). An increase in the ratio of cholestanol to cholesterol was associated with high FS (P = 0.006). In contrast, a high ratio of lathosterol to cholesterol went in parallel with low FS (P < 0.001). Whereas the campesterol to cholesterol ratio significantly correlated with the FS (P = 0.026), the relationship of the sitosterol to cholesterol ratio with the FS did not reach statistical significance in the whole group. Increased campesterol, sitosterol, and cholestanol to lathosterol ratios were associated high FS (P < 0.001). To conclude, there is a modest association of high cholesterol absorption and low cholesterol synthesis with an increased severity of CAD. An atherogenic role of plasma plant sterols themselves, however, seems unlikely in subjects without sitosterolaemia.

Topics: Aged; Cholestanol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Phytosterols; Radiography; Sitosterols

Data is limited on measures influencing cholesterol homeostasis in subjects at high risk of developing cardiovascular disease (CVD) relative to established risk factors. To address this, we quantified circulating indicators of cholesterol homeostasis (plasma phytosterols and cholesterol precursor concentrations as surrogate measures of cholesterol absorption and synthesis, respectively) in Framingham Offspring Study Cycle-6 participants diagnosed with established CVD and/or >or=50% carotid stenosis not taking lipid lowering medication (cases, N = 155) and matched controls (N = 414). Cases and controls had similar plasma LDL-cholesterol; HDL-cholesterol was significantly lower in males, while triglyceride concentrations were significantly higher in female cases relative to their respective controls. Cholesterol absorption markers were significantly higher (229 +/- 7 vs. 196 +/- 4, 169 +/- 6 vs. 149 +/- 3 and 144 +/- 5 vs. 135 +/- 3 for campesterol, sitosterol, and cholestanol, respectively), whereas cholesterol synthesis markers were significantly lower (116 +/- 4 vs. 138 +/- 3, 73 +/- 3 vs. 75 +/- 2 for lathosterol and desmosterol, respectively) in cases compared with controls, irrespective of sex. After controlling for standard risk factors, campesterol (2.47 [1.71-3.56]; P < 0.0001), sitosterol (1.86 [1.38-2.50]; P < 0.0001), cholestanol (1.57 [1.09-2.27]; P = 0.02), desmosterol (0.59 [0.42-0.84]; P = 0.003), and lathosterol (0.58 [0.43-0.77]; P = 0.0002) were significantly associated with CVD (odds ratio [95% confidence interval]). These data suggest that impaired cholesterol homeostasis, reflected by lower synthesis and higher absorption marker concentrations, are highly significant independent predictors of prevalent CVD in this study population.

Topics: Absorption; Aged; Biomarkers; Carotid Stenosis; Case-Control Studies; Cholestanol; Cholesterol; Coronary Artery Disease; Diet; Family; Female; Homeostasis; Humans; Male; Massachusetts; Phytosterols

It has been suggested that plant sterol absorption is increased in type 1 diabetes mellitus (T1DM) and that this may relate to the increased cardiovascular risk seen in T1DM. The cardiovascular benefit of lowering low-density lipoprotein-cholesterol with statin medication has also been shown to be influenced by plant sterol absorption.. The relationship between sterol concentrations, coronary artery disease (CAD), and the use of statin medications in T1DM was compared between participants with CAD (Minnesota codes 1.1, 1.2, 1.3, 4.1-4.3, 5.1-5.3, and 7.1; n = 82), from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, and those without (n = 213). Serum sterol concentrations reflecting cholesterol absorption (β-sitosterol and campesterol) and synthesis (desmosterol and lathosterol) were assayed and analyzed by gas chromatography and were expressed as a ratio of total cholesterol (×10(3)).. No differences were observed in markers of cholesterol absorption between individuals with and without CAD. In patients with CAD, significantly lower levels were observed for both sterol markers reflecting cholesterol synthesis compared with individuals without CAD [desmosterol: 0.34 vs 0.42, respectively (P = 0.003); lathosterol 0.47 vs 0.54, respectively (P = 0.019)]. Further stratification by statin medication use revealed significantly lower levels of synthesis-reflecting sterols in individuals taking statin medication, particularly those with CAD.. Although previous reports suggest that higher levels of cholesterol absorption in T1DM potentially increase cardiovascular risk in this population, the present data suggest no differences in cholesterol absorption between T1DM individuals with and without CAD.

Topics: Adult; Cholesterol; Cholesterol, LDL; Coronary Artery Disease; Desmosterol; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Phytosterols; Sitosterols

Topics: Anticholesteremic Agents; Azetidines; Coronary Artery Disease; Drug Therapy, Combination; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phytosterols; Risk Factors

Statins do not always decrease coronary heart disease mortality, which was speculated based on increased serum plant sterols observed during statin treatment. To evaluate plant sterol atherogenicity, we fed low density lipoprotein-receptor deficient (LDLr(+/-)) mice for 35 weeks with Western diets (control) alone or enriched with atorvastatin or atorvastatin plus plant sterols or stanols. Atorvastatin decreased serum cholesterol by 22% and lesion area by 57%. Adding plant sterols or stanols to atorvastatin decreased serum cholesterol by 39% and 41%. Cholesterol-standardized serum plant sterol concentrations increased by 4- to 11-fold during sterol plus atorvastatin treatment versus stanol plus atorvastatin treatment. However, lesion size decreased similarly in the sterol plus atorvastatin (-99% vs. control) and the stanol plus atorvastatin (-98%) groups, with comparable serum cholesterol levels, suggesting that increased plant sterol concentrations are not atherogenic. Our second study confirms this conclusion. Compared with lesions after a 33 week atherogenic period, lesion size further increased in controls (+97%) during 12 more weeks on the diet, whereas 12 weeks with the addition of plant sterols or stanols decreased lesion size (66% and 64%). These findings indicate that in LDLr(+/-) mice 1) increased cholesterol-standardized serum plant sterol concentrations are not atherogenic, 2) adding plant sterols/stanols to atorvastatin further inhibits lesion formation, and 3) plant sterols/stanols inhibit the progression or even induce the regression of existing lesions.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Cholesterol; Coronary Artery Disease; Female; Heptanoic Acids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phytosterols; Pyrroles; Receptors, LDL; Sitosterols