cytellin and Coronary-Artery-Disease

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

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

Elevated plasma plant sterol concentrations, xanthomatosis, and accelerated-often fatal-atherosclerosis at young age are the major findings in patients with homozygous sitosterolemia. A defect in the ABCG5 or ABCG8 co-transporter gene locus (STSL) causes an increased intestinal absorption and a decreased biliary elimination of all sterols, plant sterols as well as cholesterol, leading to a 50 to 200-fold increase in plasma plant sterol concentrations. A few recent publications indicate that even moderately elevated plasma plant sterol levels might be associated with an increased risk of atherosclerosis. This raises the question whether plant sterols themselves might be atherogenic or whether elevated plasma levels are a marker for a decreased ABCG5/G8 transporter activity which itself causes an increased risk for atherosclerosis. However, current data are too few to conclude that elevated plant sterol concentrations in plasma are an additional risk factor for coronary heart disease. But especially young patients suffering from xanthomatosis and/or atherosclerotic diseases with only mildly or moderately elevated plasma cholesterol should be screened for sitosterolemia by measurement of plasma plant sterol levels.

Topics: Age Factors; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Cholesterol; Chromosome Aberrations; Coronary Artery Disease; Genes, Recessive; Homozygote; Humans; Intestinal Absorption; Lipoproteins; Risk Factors; Sitosterols; Xanthomatosis

Topics: Apolipoprotein B-100; Apolipoproteins B; Coronary Artery Disease; Genes, Dominant; Genes, Recessive; History, 20th Century; Humans; Hyperlipoproteinemia Type II; Lipoproteins, LDL; Sitosterols

Plant stanols have been shown to reduce serum levels of low-density lipoprotein (LDL) cholesterol, and they are an attractive adjunct in dietary therapy for elevated LDL cholesterol. This investigation addressed 3 questions through metabolic studies in human subjects: (1) whether plant stanol esters given at higher doses than the 2-g/day dose recommended by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) will provide additional LDL-lowering efficacy (study 1); (2) whether substantial reduction in LDL cholesterol can be obtained in postmenopausal women with hypercholesterolemia by addition of plant stanol esters to the diet (study 2); and (3) whether ATP III goals can be obtained by adding plant stanol esters to an LDL-lowering regimen in high-risk patients who retain LDL cholesterol levels in the above-optimal range (ie, 2.6 to 3.3 mmol/L [100 to 129 mg/dL]), despite ongoing statin therapy (study 3). Study 1 showed that maximal LDL lowering with plant stanols in the form of esters can be achieved at a dose of 2 g/day. Higher doses do not provide additional efficacy. Study 2 demonstrated that stanol esters can reduce LDL cholesterol levels in postmenopausal women by about 13%, which makes use of stanol esters attractive as a component of nondrug therapy in these women who generally are at relatively low risk for coronary heart disease. Finally, study 3 found that plant stanols provide additional lowering of LDL cholesterol when added to ongoing statin therapy. This makes plant stanols an attractive dietary component to help to achieve the goals of LDL-lowering therapy in patients requiring an LDL-lowering drug.

Topics: Cholesterol, LDL; Coronary Artery Disease; Dose-Response Relationship, Drug; Female; Humans; Lipoproteins; Male; Middle Aged; Phytotherapy; Risk Factors; Sitosterols

The HDL Atherosclerosis Treatment Study (HATS) demonstrated a clinical benefit in coronary artery disease patients with low HDL cholesterol (HDL-C) levels treated with simvastatin and niacin (S-N) or S-N plus antioxidants (S-N+A) compared with antioxidants alone or placebo. Angiographically documented stenosis regressed in the S-N group but progressed in all other groups. To assess the mechanism(s) responsible for these observations, surrogate markers of cholesterol absorption and synthesis were measured in a subset of 123 HATS participants at 24 months (on treatment) and at 38 months (off treatment). Treatment with S-N reduced desmosterol and lathosterol levels (cholesterol synthesis indicators) 46% and 36% (P < 0.05), respectively, and elevated campesterol and beta-sitosterol levels (cholesterol absorption indicators) 70% and 59% (P < 0.05), respectively, relative to placebo and antioxidant but not S-N+A. Treatment with antioxidants alone had no significant effect. Combining S-N with antioxidants reduced desmosterol and lathosterol by 37% and 31%, and elevated campesterol and beta-sitosterol levels by 54% and 46%, but differences did not attain significance. Mean change in percent stenosis was positively associated with a percent change in lathosterol (r = 0.26, P < 0.005) and negatively associated with a percent change in beta-sitosterol (r = -0.21, P < 0.01). These data suggest that changes in stenosis were attributable, in part, to changes in cholesterol metabolism.

Topics: Antioxidants; Cholesterol; Constriction, Pathologic; Coronary Artery Disease; Desmosterol; Drug Therapy, Combination; Female; Humans; Hypolipidemic Agents; Lipoproteins, HDL; Male; Middle Aged; Niacin; Simvastatin; Sitosterols

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

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

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

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

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

This is a case report of a 19-year-old man who presented with acute myocardial infarction with obstruction of one coronary artery and rapid progression to three vessels in 8 months. He was proved to have sitosterolemia, a rare hereditary disease with plant sterol storing, resulting in juvenile coronary artery disease. Atherosclerotic complications can be preventable by administration of bile acid-binding resin, after the correct diagnosis is made. We introduce this disease with a review of the literature.

Topics: Adult; Age Factors; Coronary Artery Disease; Disease Progression; Humans; Lipid Metabolism, Inborn Errors; Male; Myocardial Infarction; Sitosterols

Recent large-scale trials have consistently documented the fact that a 25-35% reduction in low-density lipoprotein cholesterol (LDL-C) can delay the progression of atherosclerosis. This raises the question as to how much it is possible to reduce serum cholesterol using feasible therapies. The aim of this study was to investigate the cholesterol-lowering efficacy of a triple therapy combining bile acid malabsorption with the inhibition of cholesterol synthesis and absorption.. Eleven consecutive hypercholesterolemic coronary patients from Lipid Clinics on a low-fat, low-cholesterol baseline diet added simvastatin (20 mg/day) for three months, and then dietary plant stanol ester margarine (2.25 g of stanols/day) for eight weeks; finally, cholestyramine 8 g/day was added for another eight weeks. This was a before-after trial, in which the results of each period were compared with baseline and those of the previous period. Serum lipids were quantitated using commercial kits, and serum sterols by means of gas-liquid chromatography. Simvastatin lowered LDL-C by 39% (p < 0.001), and additional stanol ester margarine by a further 13% (p < 0.05). The triple treatment led to 67% reduction from baseline (p < 0.001), with all LDL-C values being < 2.6 mmol/L, and increased high-density lipoprotein cholesterol (HDL-C) by 15% (p < 0.01). It also increased the serum lathosterol/cholesterol ratio (p < 0.01), thus indicating an upregulation of cholesterol synthesis, and increased the serum sitosterol ratio (p < 0.01) despite the simultaneous consumption of plant stanols.. The massive reduction in LDL and increase in HDL-C obtained using our triple therapy suggests that the combination of stanol ester with only moderate doses of statin and resin makes it possible to control LDL-C levels effectively in hypercholesterolemic subjects.

Topics: Aged; Anticholesteremic Agents; Bile Acids and Salts; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Cholestyramine Resin; Coronary Artery Disease; Diet, Fat-Restricted; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Intestinal Absorption; Male; Simvastatin; Sitosterols; Treatment Outcome

Topics: Cardiotonic Agents; Coronary Artery Disease; Coronary Disease; Humans; Lipids; Sitosterols; Sterols

Topics: Coronary Artery Disease; Coronary Disease; Heart; Humans; Lipids; Sitosterols; Steroids