Risk Marker For Coronary Artery Disease Research Articles

No relation between coronary artery disease or electrocardiographic markers of disease in middle age and prenatal exposure to the Dutch famine of 1944–5

Objective and SettingAssociations between prenatal famine and coronary artery disease (CAD) have been examined before with inconsistent results. For further evaluation, we examined multiple cardiac risk markers in adult men...

Exhaled nitric oxide and atherosclerosis

Fractional exhaled nitric oxide concentration (FENO) measurement has been proposed to be an important adjunct in the diagnosis and management of asthma, pulmonary hypertension and cystic fibrosis. But do we understand how other diseases influence the FENO values? In particular, atherosclerosis is one of the pathological conditions, in which nitric oxide (NO) production is inhibited and its degradation enhanced. Therefore, hypothesis of the current study was that FENO is inversely associated with risk markers of atherosclerosis and with diseases leading secondarily to the progression of atherosclerosis. A long-term FENO value (median of biweekly measurements over a 24-week period) of 53 patients with ischaemic heart disease (IHD) was compared with the results of clinical and biochemical analyses. Fractional exhaled NO was inversely associated with the plasma concentration of triglycerides (P = 0·01) and with the blood concentration of glycated haemoglobin A1c (P = 0·03). It also tended to be inversely associated with the plasma glucose concentration (P = 0·10). However, there were no statistically significant associations with inflammatory or other biochemical markers, health status, lifestyle or other personal determinants. In accordance with the hypothesis, FENO is inversely associated with some of risk markers of atherosclerosis in patients with stable IHD (triglycerides and haemoglobin A1c, a marker of hyperglycaemic metabolism). A potential explanation is that, at hyperglycaemia and with higher triglyceride concentrations, atherosclerosis leads to endothelial dysfunction and, subsequently, to decreased production and increased degradation of NO.

B-Cell Aortic Homing and Atheroprotection Depend on Id3

B cells are abundant in the adventitia of normal and diseased vessels. Yet, the molecular and cellular mechanisms mediating homing of B cells to the vessel wall and B-cell effects on atherosclerosis are poorly understood. Inhibitor of differentiation-3 (Id3) is important for atheroprotection in mice and polymorphism in the human ID3 gene has been implicated as a potential risk marker of atherosclerosis in humans. Yet, the role of Id3 in B-cell regulation of atherosclerosis is unknown. To determine if Id3 regulates B-cell homing to the aorta and atheroprotection and identify molecular and cellular mechanisms mediating this effect. Loss of Id3 in Apoe(-/-) mice resulted in early and increased atherosclerosis. Flow cytometry revealed a defect in Id3(-/-) Apoe(-/-) mice in the number of B cells in the aorta but not the spleen, lymph nodes, and circulation. Similarly, B cells transferred from Id3(-/-) Apoe(-/-) mice into B-cell-deficient mice reconstituted spleen, lymph node, and blood similarly to B cells from Id3(+/+) Apoe(-/-) mice, but aortic reconstitution and B-cell-mediated inhibition of diet-induced atherosclerosis was significantly impaired. In addition to retarding initiation of atherosclerosis, B cells homed to regions of existing atherosclerosis, reduced macrophage content in plaque, and attenuated progression of disease. The chemokine receptor CCR6 was identified as an important Id3 target mediating aortic homing and atheroprotection. Together, these results are the first to identify the Id3-CCR6 pathway in B cells and demonstrate its role in aortic B-cell homing and B-cell-mediated protection from early atherosclerosis.

Serum Amyloid A Directly Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Although serum amyloid A (SAA) is an excellent marker for coronary artery disease, its direct effect on atherogenesis in vivo is obscure. In this study we investigated the direct effect of SAA on promoting the formation of atherosclerosis in apolipoprotein E-deficient (ApoE⁻/⁻) mice. Murine SAA lentivirus was constructed and injected into ApoE⁻/⁻ mice intravenously. Then, experimental mice were fed a chow diet (5% fat and no added cholesterol) for 14 wks. The aortic atherosclerotic lesion area was larger with than without SAA treatment. With increased SAA levels, the plasma levels of interleukin-6 and tumor necrosis factor-α were significantly increased. Macrophage infiltration in atherosclerotic regions was enhanced with SAA treatment. A migration assay revealed prominent dose-dependent chemotaxis of SAA to macrophages. Furthermore, the expression of monocyte chemotactic protein-1 and vascular cell adhesion molecule-1 (VCAM-1) was upregulated significantly with SAA treatment. SAA-induced VCAM-1 production was detected in human aortic endothelial cells in vitro. Thus, an increase in plasma SAA directly accelerates the progression of atherosclerosis in ApoE⁻/⁻ mice. SAA is not only a risk marker for atherosclerosis but also an active participant in atherogenesis.

Impact of HDL oxidation by the myeloperoxidase system on sterol efflux by the ABCA1 pathway

Protein oxidation by phagocytic white blood cells is implicated in tissue injury during inflammation. One important target might be high-density lipoprotein (HDL), which protects against atherosclerosis by removing excess cholesterol from artery wall macrophages. In the human artery wall, cholesterol-laden macrophages are a rich source of myeloperoxidase (MPO), which uses hydrogen peroxide for oxidative reactions in the extracellular milieu. Levels of two characteristic products of MPO-chlorotyrosine and nitrotyrosine-are markedly elevated in HDL from human atherosclerotic lesions. Here, we describe how MPO-dependent chlorination impairs the ability of apolipoprotein A-I (apoA-I), HDL's major protein, to transport cholesterol by the ATP-binding cassette transporter A1 (ABCA1) pathway. Faulty interactions between apoA-I and ABCA1 are involved. Tandem mass spectrometry and investigations of mutated forms of apoA-I demonstrate that tyrosine residues in apoA-I are chlorinated in a site-specific manner by chloramine intermediates on suitably juxtaposed lysine residues. Plasma HDL isolated from subjects with coronary artery disease (CAD) also contains higher levels of chlorinated and nitrated tyrosine residues than HDL from healthy subjects. Thus, the presence of chlorinated HDL might serve as a marker of CAD risk. Because HDL damaged by MPO in vitro becomes dysfunctional, inhibiting MPO in vivo might be cardioprotective.

FOXP3 levels in T cells negatively correlate with cardiovascular risk factors in healthy controls and patients with SLE (115.27)

Abstract Autoimmune diseases such as SLE manifest with increased risk for atherosclerosis. The role of regulatory T cells (Tregs) in atherosclerosis associated with autoimmune diseases is not clear. Here, we correlated T cell FOXP3 mRNA levels with clinical and laboratory risk markers of atherosclerosis in 36 patients with SLE and 33 healthy control subjects enrolled in the UCLA Biomarkers of Atherosclerosis in SLE study. Subjects underwent a carotid ultrasound to assess plaque and an evaluation for SLE disease activity and Framingham cardiovascular risk factors. PBMCs were obtained by Ficoll gradient and the T-cell fraction was isolated using AutoMACS. RNA from T cells was isolated and used for estimating FOXP3 mRNA using real-time qPCR. We found that FOXP3 was lower in patients than in controls. Interestingly, FOXP3 levels correlated with total cholesterol (r=-0.49), LDL cholesterol (r=-0.42), and homocysteine (r=-0.37) in healthy subjects. In patients with SLE, FOXP3 levels correlated with HDL cholesterol (r=-0.42), apoJ (r=-0.45), and adiponectin (r=-0.49). Thus, FOXP3 correlates with molecules associated with atherosclerosis risk in healthy and SLE subjects. Ongoing studies will determine the significance of these correlations.

Correlation of Apo B-48 and Apo B-100 with Oxidized LDL in Men with Central Obesity

BACKGROUND: Obesity has a central role in the metabolic syndrome, which raises the risk for atherosclerotic cardiovascular disease (ASVCD). Apo B-48 and Apo B-100 are the necessary structural proteins required for the assembly and secretion of chylomicron and VLDL which have role in atherogenesis. The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Oxidation of LDL is a hallmark of atherosclerosis development. The aim of this study was to asses the association between Apo B-48 and Apo B-100 with Oxidized-LDL as marker of atherosclerosis risk in central obesity. We hope that the result of this study can help to make a new strategy for the prevention and treatment of vascular disease.RESULTS: There were 68 patients aged 39.6±7.3 years, Apo B-48 concentration was 7.47±5.36 μg/mL, Apo B-100 was 117.26±25.74 mg/dL, and ox-LDL was 137.05±18.88 U/L. This study showed a significant correlation between Apo B-100 and ox-LDL (r=0.608, p<0.05) and correlation between Apo B-48 and ox-LDL (r=0.171, p<0.05). The levels of Apo B-100 were significantly different between obese with Mets and obese without Mets individuals (p<0.05).CONCLUSIONS: This study suggested that Apo B-100 concentration increase in obese in Mets as compared with obese without Mets. Apo B-48 and Apo B-100 were correlated with Oxidized LDL, but correlation between Apo B-100 and ox-LDL more significant that Apo B-48and ox-LDL.KEYWORDS: obesity, atherogenesis, Apo B-48, Apo B-100, ox-LDL

Hyperhomocysteinemia is Associated with Aortic Atheroma Progression in Stroke/TIA Patients

Significance: Aortic arch (AA) atheroma and AA atheroma progression are independent risk factors for recurrent vascular events in stroke/transient ischemic attack (TIA) patients. Total homocysteine level (tHcy) is an independent risk marker for atherosclerosis including that found in AA. The purpose of this study was to prospectively test the association between AA atheroma progression and tHcy. Methods: This is a cohort study of 307 consecutive hospitalized stroke/TIA patients undergoing transesophageal echocardiogram (TEE) as a part of their clinical workup. Measurable AA atheroma was detected in 167 patients of whom 125 consented to a protocol-mandated follow-up TEE at 12 months. Patients had evaluation for vascular risk factors, dietary factors (folate, B12 and pyridoxine), and methylene tetrahydrofolate reductase (MTHFR) polymorphism. One hundred eighteen stroke/TIA patients had tHcy, acceptable paired AA images, and detailed plaque measurements. An increase by ≥1 grade of AA atheroma was defined as progression. Results: Of the 118 patients, 33 (28%) showed progression and 17 (14%) showed regression of their index arch lesion at 1 year. tHcy (≥14.0 μmol/l) was significantly associated with progression on both univariate (RR = 3.4, 95% CI 2.0–5.8) and multivariate analyses (adjusted RR = 3.6, 95% CI 2.2–4.6). The changes in AA plaque thickness (r2 = 0.11; p < 0.001) and AA plaque area (r2 = 0.08; p = 0.002) correlated with tHcy. tHcy was associated with change in plaque thickness over 12 months, independent of age, dietary factors, renal function and MTHFR polymorphism (Standardized β-coefficient 0.335, p = 0.02). Conclusions: Our results validate the association and a linear correlation between tHcy and progression of AA atheroma.

Association Between Plasma Monocyte Chemoattractant Protein-1 Concentration and Cardiovascular Disease Mortality in Middle-Aged Diabetic and Nondiabetic Individuals

OBJECTIVEMonocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes.RESEARCH DESIGN AND METHODSMCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 ± 12 years, BMI 30.1 ± 6.6 kg/m2, 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990–1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files.RESULTSAt baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality.CONCLUSIONSIn middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.

Periodontal treatment influences risk markers for atherosclerosis in patients with severe periodontitis

This study investigated the effect of mechanical infection control for periodontitis and periodontal surgery on the prevalence of well-established risk factors for atherosclerosis, and plasma levels of cytokines, antibodies against heat shock proteins and markers of systemic inflammation. Sixty-eight patients between 39 and 73 years of age with severe periodontitis who had been referred to four specialist periodontology clinics in Sweden were investigated. A fasting venous blood sample was taken at baseline and additional samples were collected after 3 and 12 months. A total of 54 patients underwent periodontal treatment. The periodontal treatment was successful, as pathogenic gingival pockets decreased significantly. Plasma glucose, lipids and markers of systemic inflammation were not significantly altered after 3 months. One year after the initial treatment, HDL-C concentrations were significantly increased (Δ0.08 mmol/L) whereas LDL-C concentrations decreased (Δ0.23 mmol/L). Haptoglobin concentrations were also lower. Interleukin-18 and interferon-γ levels were also lower after 12 months (60 ng/L (−23%) and 11 ng/L (−97%) respectively). Treatment had no effect on plasma levels of IgA, IgG1, IgG2 antibodies against heat shock proteins. In conclusion, this study indicates that standard treatment for periodontal disease induces systemic changes in several biochemical markers that reflect the risk for atherosclerosis.

Elevated plasma adiponectin and decreased plasma homocysteine and asymmetric dimethylarginine in children with type 1 diabetes

Objective. Type 1 diabetes has a bad prognosis concerning the pathogenesis of cardiovascular diseases (CVD). The purpose of this study was to evaluate different possible new risk indices for CVD in children with type 1 diabetes. Material and methods. The present study included 30 children with diabetes (mean HbA1C 9.8%), aged between 4.7 and 18.6 years and with no clinical evidence of vascular complications, and 30 healthy subjects matched by sex, age and body mass index. Blood pressure was measured and blood samples were obtained for lipid profile, creatinine, glucose, high sensitive C‐reactive protein (hsCRP), intercellular adhesion molecule‐1 (ICAM‐1), asymmetric dimethylarginine (ADMA), adiponectin and homocysteine. Results. Children with diabetes had significantly higher blood pressure, plasma hsCRP, ICAM‐1, adiponectin levels and lower homocysteine, ADMA concentrations than their control subjects. In multivariate regression analysis, the best predictors for systolic blood pressure were diabetes group, plasma homocysteine concentration and BMI (Adj R2 = 0.38, p<0.0001), and for diastolic blood pressure diabetes group and triglycerides level (Adj R2 = 0.27, p<0.0001). Conclusions. Children with diabetes, in view of their higher future risk of CVD, are characterized by a higher concentration of protective adiponectin and paradoxically lower blood concentrations of some other possible risk markers of atherosclerosis, i.e. ADMA and homocysteine compared to healthy children.

A Diet Rich in Conjugated Linoleic Acid and Butter Increases Lipid Peroxidation but Does Not Affect Atherosclerotic, Inflammatory, or Diabetic Risk Markers in Healthy Young Men

Intake of conjugated linoleic acid (CLA) has been demonstrated to beneficially affect risk markers of atherosclerosis and diabetes in rats. CLA is naturally found in milk fat, especially from cows fed a diet high in oleic acid, and increased CLA intake can occur concomitantly with increased milk fat intake. Our objective was to investigate the effect of CLA as part of a diet rich in butter as a source of milk fat on risk markers of atherosclerosis, inflammation, diabetes type II, and lipid peroxidation. A total of 38 healthy young men were given a diet with 115 g/d of CLA-rich fat (5.5 g/d CLA oil, a mixture of 39.4% cis9, trans11 and 38.5% trans10, cis12) or of control fat with a low content of CLA in a 5-wk double-blind, randomized, parallel intervention study. We collected blood and urine before and after the intervention. The fatty acid composition of plasma triacylglycerol, cholesterol esters, and phospholipids reflected that of the intervention diets. The CLA diet resulted in increased lipid peroxidation measured as an 83% higher 8-iso-prostaglandin F2α concentration compared with the control, P < 0.0001. We observed no other significant differences in the effect of the interventions diets. In conclusion, when given as part of a diet rich in butter, a mixture of CLA isomers increased lipid peroxidation but did not affect risk markers of cardiovascular disease, inflammation, or fasting insulin and glucose concentrations.

Soluble CD36 and Risk Markers of Insulin Resistance and Atherosclerosis Are Elevated in Polycystic Ovary Syndrome and Significantly Reduced During Pioglitazone Treatment

We investigated the relation between soluble CD36 (sCD36), risk markers of atherosclerosis and body composition, and glucose and lipid metabolism in polycystic ovary syndrome (PCOS). Thirty PCOS patients were randomized to 30 mg/day pioglitazone or placebo for 16 weeks. Fourteen weight-matched healthy female subjects were included as control subjects. sCD36, oxidized LDL (oxLDL), high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, euglycemic-hyperinsulinemic clamps, and whole-body dual-energy X-ray absorptiometry scans were performed. sCD36 (2.87 relative units [0.88-9.36] vs. 1.67 relative units [0.72-3.89]), oxLDL (44.9 units/l [26.9-75.1] vs. 36.1 units/l [23.4-55.5]), and hsCRP (0.26 mg/dl [0.03-2.41] vs. 0.12 mg/dl [0.02-0.81]) were significantly increased in PCOS patients versus control subjects (geometric mean +/- 2 SD). In PCOS, positive correlations were found between central fat mass and sCD36 (r = 0.43), hsCRP (r = 0.43), and IL-6 (r = 0.42) (all P < 0.05). After adjusting for fat mass, sCD36 and oxLDL correlated inversely with measures of insulin-stimulated glucose metabolism and positively with lipid oxidation during insulin stimulation in PCOS patients and control subjects (n = 44). sCD36 and oxLDL were significant independent predictors of glucose and lipid metabolism, whereas hsCRP and IL-6 showed no significant contribution. Following pioglitazone treatment, insulin sensitivity increased, whereas sCD36 (3.21 relative units [0.76-13.6] vs. 2.33 relative units [0.84-6.46]) and hsCRP decreased (P < 0.05). No significant changes were measured in body composition. sCD36 and oxLDL correlated with measures of insulin sensitivity independent of central fat mass. Pioglitazone treatment reduced sCD36 while improving insulin-stimulated glucose metabolism, further supporting the association between sCD36 and insulin resistance in PCOS.

Measuring subclinical atherosclerosis: is homocysteine relevant?

We systematically reviewed published studies looking at the relationship between total serum homocysteine (tHcy) and subclinical markers of atherosclerosis, such as carotid intimal-medial thickness (C-IMT), coronary artery calcium (CAC) and ankle-brachial index (ABI) in asymptomatic individuals. We analyzed these studies to examine this relationship as well as to guide future avenues of investigation by identifying studies that will help in the inclusion of tHcy levels in current guidelines on atherosclerotic disease management. tHcy has been known to be associated with clinically evident atherosclerotic disease. However, tHcy is not incorporated in current guidelines for diagnosis of subclinical disease in high-risk asymptomatic individuals. We searched online databases (e.g., PUBMED, MEDLINE) for published articles assessing the relationship between tHcy and C-IMT, CAC and ABI. We limited the studies to asymptomatic populations, and excluded any study including symptomatic patients or individuals with a history of coronary, peripheral or cerebrovascular disease. A systemic review of 19 articles revealed a significant association between elevated levels of tHcy and subclinical markers of atherosclerosis in asymptomatic individuals in most studies. Mean tHcy levels were consistently found to be higher in men compared to women. A total of 12 studies showed a significant association between tHcy and other risk markers of atherosclerosis, even after adjusting for age, sex and conventional risk factors. There were seven studies in unique populations that showed no significant relationship. We also observed that studies lowering baseline tHcy levels did not lead to an improvement in C-IMT, CAC or ABI scores. This might indicate that tHcy has a stronger role as a marker of atherosclerotic disease than as a risk factor for the same. Based on our review, we conclude that there is a significant association between the subclinical atherosclerotic process and tHcy, and it shows potential as a cheap marker for risk stratification of asymptomatic patients. However, future studies further elucidating this association and elaborating the exact role of tHcy in the atherosclerotic disease process are required. The results of these studies suggest the incorporation of plasma tHcy levels in future risk reduction protocols for identification of individuals at higher risk of atherosclerotic events, and thus to categorize them for more aggressive treatment with established preventive and therapeutic measures.

Gastric bypass reduces biochemical cardiac risk factors

Background Coronary artery disease (CAD) is the leading cause of death in the United States, with obesity as a leading preventable risk factor for CAD. Certain biochemical markers have demonstrated strong prediction for cardiovascular events. We hypothesized that in addition to weight reduction, gastric bypass will also induce a salutary effect on the biochemical cardiac risk factors. Methods At a single academic institution, from 2003 to 2004, we measured the biochemical cardiac risk factors in gastric bypass patients preoperatively and at 3, 6, and 12 months postoperatively. These risk factors included total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, total cholesterol/HDL cholesterol ratio, triglyceride/HDL cholesterol ratio, triglycerides, lipoprotein A, high-sensitivity C-reactive protein, and homocysteine. The data were analyzed using the Wilcoxon signed rank test. Results The mean age of the 356 patients was 43 years; 84% were women; the mean body mass index was 47 kg/m 2; 33% were diabetic; 50% were hypertensive; 23% were taking lipid-lowering medications; and 2% had known CAD. Significant improvement occurred in the biochemical cardiac factors from preoperatively to 12 months. The beneficial changes were as follows: total cholesterol, 192 mg/dL preoperatively to 166 mg/dL at 12 months; HDL cholesterol, 46 mg/dL preoperatively to 54 mg/dL at 12 months; low-density lipoprotein, 125 mg/dL preoperatively to 88 mg/dL at 12 months; total cholesterol/HDL cholesterol ratio, 4 preoperatively to 3 at 12 months; triglyceride/HDL cholesterol ratio, 3 preoperatively to 2 at 12 months; triglycerides, 133 mg/dL preoperatively to 92 mg/dL at 12 months; lipoprotein A, 14 mg/dL preoperatively to 13 mg/dL at 12 months; high-sensitivity C-reactive protein, 8 mg/L preoperatively to 1 mg/L; and homocysteine, 10 μmol/L preoperatively to 8 μmol/L at 12 months. Conclusions The results of our study have shown that gastric bypass significantly improves all biochemical markers of CAD risk, particularly C-reactive protein, which had an 80% reduction. As a result, gastric bypass decreases the cardiac risk by both weight loss and advantageous alterations of biochemical cardiac risk factors.

The Cardiovascular Effects of Selective Estrogen Receptor Modulators

Coronary artery disease (CAD) is the main contributor of mortality among postmenopausal women. Menopause-associated estrogen deficiency has both metabolic and vascular consequences that increase the risk for CAD. Hormone therapy (HT) has been reported to have a beneficial effect on metabolic and vascular factors influencing the incidence of CAD. Although observational studies have reported that HT reduces significantly the risk for CAD, randomized clinical trials (WHI, HERS, ERA) have questioned the efficacy of HT in primary and secondary CAD prevention despite confirming the lipid-lowering effect of HT. In the aftermath of the WHI, increased interest has been given to the action of selective estrogen receptor modulators (SERMs) and their effect on the cardiovascular system. The chemical structure of SERMs, either triphenylethilyn (tamoxifen) or benzothiophene (raloxifene) derivatives, differs from that of estrogens. SERMs are nonsteroidal molecules that bind, with high affinity, to the ER. SERMs induce conformational changes to the ligand-binding domain of the ER that modulate the ability of the ER to interact with coregulator proteins. The relative balance of coregulators within a cell determines the transcriptional activity of the receptor-ligand complex. SERMs therefore may express an estrogen-agonist or estrogen-antagonist effect depending on the tissue targeted. SERMs express variable effects on the metabolic and vascular factors influencing the incidence of CAD. SERMs have been reported to modulate favorably the lipid-lipoprotein profile. Toremifene expresses the most beneficial effect followed by tamoxifene and raloxifene, while ospexifene and HMR-3339 have the least effect and may even increase triglycerides. Raloxifene and tamoxifene decrease serum homocysteine levels and C-reactive proteins (CRP), which are both markers of CAD risk. Raloxifene has been reported to increase the nitric oxide (NO)-endothelin (ET)-1 ratio and, thus, contribute to proper endothelial function and vasodilation. Toremifene has no effect on the NO-ET-1 ratio. Finally, raloxifene decreases the vascular cell adhesion molecules and the inflammatory cytokines TNF-alpha and IL-6. Of the SERMs, raloxifene has had the most extensive evaluation regarding the effect on the vascular wall of endothelium. Although not confirmed by large clinical trials, raloxifene has been reported to have an effect on the cohesion of the intercellular junction (VE-cadherin) and the synthesis-degradation of extracellular matrix (MMP-2). The Multiple Outcomes Raloxifene Evaluation (MORE) study has reported that raloxifene may have a cardioprotective effect when administered to postmenopausal women at high risk for CAD disease.

Serum amyloid A: The “other” inflammatory protein

Inflammation long has been recognized as a hallmark of atherosclerotic lesions, but more recently attention has focused on chronic low-level elevations of specific plasma inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A (SAA), which may not only represent markers of atherosclerosis risk but also participate directly in atherogenesis. This article briefly reviews evidence for and against potential roles of CRP as an atherosclerosis risk marker and in athero-genesis. The remainder of the article focuses on SAA, an inflammatory protein that is carried on, and may fundamentally alter the function of, high-density lipoprotein. Data are reviewed regarding the regulation of SAA by dietary cholesterol, obesity, and insulin resistance, and its potential role as an atherosclerosis mediator. Lying at the intersection of inflammation, dyslipidemia, obesity, and insulin resistance, SAA may play a key role in regulating the contributions of these processes to atherogenesis.

The 3′-UTR C > T polymorphism of the oxidized LDL-receptor 1 ( OLR1) gene does not associate with coronary artery disease in Italian CAD patients or with the severity of coronary disease

Background and aim Oxidized low-density lipoproteins (OxLDLs) play a critical role in endothelial dysfunction, which is implicated in the pathogenesis of atherosclerosis. Vascular endothelial cells internalize and degrade oxLDL through the endothelial lectin-like oxidized LDL receptor 1 ( OLR1). OLR1 is up-regulated in several pathological conditions, including hypertension, hyperlipidemia, diabetes, atherosclerosis and inflammation, and represents therefore a good candidate for coronary artery disease (CAD). Recently, a 3′-UTR (188 C > T) SNP in the OLR1 gene has been reported to be associated with coronary artery stenosis and myocardial infarction. In the present study we investigated whether the OLR1 gene 188 C > T SNP is a genetic risk marker for CAD in Italian patients with angiographically defined coronary atherosclerosis, and assessed its relation with clinical and metabolic abnormalities, including severity of disease (classified as restenosis, single- or multiple coronary vessels disease, and MI). Methods The 3′-UTR C > T SNP was detected in real-time PCR in 351 subjects with CAD and in 215 control subjects. Results The OLR1-T allele frequencies were 48.9% in the CAD subjects and 47.7% in controls, with no significant difference between the two groups. Also, the 3′-UTR C > T SNP did not associate with any of the parameters of severity of disease. Furthermore, none of the other clinical and metabolic parameters were associated with the OLR1 gene SNP. Conclusions Our observations suggest that, in our population, the 3′-UTR C > T polymorphism of the OLR1 gene is unlikely to play a role in the pathogenesis of coronary artery disease.

The Gene Encoding Fibrinogen-β Is a Target for Retinoic Acid Receptor-Related Orphan Receptor α

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (alpha, beta, gamma). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR)alpha is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified RORalpha as a regulator of fibrinogen-beta gene expression in human hepatoma cells and in mouse liver. A putative RORalpha response element (RORE) was identified in the human fibrinogen-beta promoter. EMSA showed that RORalpha binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers RORalpha-dependent transcriptional activation to both the human fibrinogen-beta and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of RORalpha specifically increases endogenous fibrinogen-beta mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-beta RORE is occupied by RORalpha in HepG2 cells. Thus, the human fibrinogen-beta gene is a direct target for RORalpha. Furthermore, fibrinogen-beta mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of RORalpha in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk.

Coronary Artery Disease Risk Factors In Fire Fighters

Several studies have examined the prevalence of high coronary artery disease (CAD) risks among fire fighters and the need for health and wellness promotion in this population. Few studies, however, have examined the effectiveness of health and wellness programming in reducing these risks in fire fighters. PURPOSE To determine the effectiveness of a voluntary health and wellness program in changing CAD risk factors in fire fighters. METHODS Sixty male fire fighters were introduced to a one year voluntary wellness program that included four separate lectures on exercise, health, & nutrition; availability of work time and equipment for exercise along with personalized exercise prescriptions; and two annual complete physical examinations. Physical exam included measures of systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG) and blood glucose (G). Student's t tests were used to check for significant difference in risk factors after the one year period with type I error rate set at 0.05. RESULTS No CAD risk markers showed significant improvement over the one year period. Some group averages for CAD risk markers exhibited positive trends. CONCLUSIONS These data suggest a voluntary wellness program may be ineffective at altering CAD risk factors in fire fighters over a one year period.Table