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Background. Atherosclerotic cardiovascular disease (ASCVD) is a common complication of diabetes mellitus and impaired fasting glucose (IFG). We hypothesized that the relation of fasting glucose levels to ASCVD is linear, with the prevalence of clinical ASCVD beginning to increase even among individuals currently categorized as normoglycemic. Methods. Patient charts were retrospectively reviewed from our Dyslipidemic Preventive Cardiology Clinic. We evaluated the prevalence of ASCVD relative to fasting glucose levels in a cross-section of patients at high risk for ASCVD. Results. In 558 dyslipidemic patients, ASCVD prevalence increased with increasing fasting glucose levels. A significantly higher prevalence of ASCVD was observed among patients with fasting glucose levels between 90 and 99 mg/dL versus lower levels. As glucose levels increased from 90 to 125 mg/dL, the prevalence of ASCVD continued to rise in parallel. Logistic regression analysis with forward likelihood ratio stepwise selection indicated that individuals with fasting blood glucose of 90–99 mg/dL were 2.6 times more likely to have ASCVD than those with lower levels of fasting blood glucose. Conclusion. Our findings suggest that the current cutoff for impaired fasting glucose of 100 mg/dL may be somewhat conservative and that a level above 90 mg/dL may be more appropriate as an ASCVD risk factor, particularly in patients with a lipid disorder.

Cardiovascular disease is the leading cause of morbidity and mortality in the developed world. Epidemiologic data support a strong relationship of atherosclerotic cardiovascular disease (ASCVD) with both elevated low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDL-C). The study of the human genetics of plasma lipid traits, both rare Mendelian disorders as well as common variants, has illuminated multiple genes and pathways involved in the regulation of LDL-C and HDL-C levels. Mendelian disorders of extremes of LDL-C and Mendelian randomization studies of common gene variants associated with LDL-C strongly support a causal relationship between LDL-C and ASCVD, independent of mechanism. In contrast, Mendelian disorders of extremes of HDL-C and Mendelian randomization studies of common genetic variants for HDL-C are inconsistent in their support of a causal relationship between HDL-C and ASCVD. In contrast to LDL-C, a causal relationship between HDL-C and ASCVD may be dependent on the specific mechanism leading to variation in HDL-C levels.

Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain–interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.

Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 × 10−61) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 × 10−23). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 × 10−41 and rs649129, P = 1.22 × 10−15, respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

P-selectin is a leukocyte adhesion receptor present in endothelial cells and platelets. We examined the role of P-selectin in the autologous phase of an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis using P-selectin–deficient mice and chimeric mice expressing P-selectin only in platelets or endothelial cells. P-selectin–deficient mice exhibited more severe glomerular damage with increased interstitial mononuclear leukocytic infiltrates, and had significantly increased proteinuria and mortality when compared to wild-type mice. P-selectin on the endothelium was predominantly responsible for protection from the exacerbated disease, because chimeric mice with endothelial P-selectin, and not mice with platelet P-selectin, showed glomerular injury similar to that in wild-type animals. Levels of soluble circulating P-selectin were increased in nephritic wild-type mice and in chimeric mice with endothelial P-selectin, but not platelet P-selectin. Levels of soluble P-selectin, which has been shown to be anti-inflammatory in vitro, were inversely associated with the severity of disease. P-selectin was not expressed in the endothelium of the glomerulus or interstitium. Thus, the protective effect in wild-type mice may be accounted for, in part by soluble P-selectin shed by non-renal endothelial cells, although other endothelial P-selectin–dependent mechanisms cannot be ruled out.

J. Clin. Invest. 103:649–659 (1999)

Background

L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte-leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form. Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc). This preliminary study seeks to discern amongst these disparate results and to discover whether there is an association between L-selectin concentrations in plasma and skin damage in SSc patients.

Methodology and Principal Findings

Nineteen cases with limited systemic sclerosis (lSSc) and 11 cases with diffuse systemic sclerosis (dSSc) were compared on a pairwise basis to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to diagnose SSc. Skin involvement was assessed using the modified Rodnan skin score (mRSS). We find no association between mRSS and plasma L-selectin concentration in lSSc cases (p = 0.9944) but a statistically significant negative correlation in dSSc cases (R2 = 73.11 per cent, p = 0.0008). The interpretation of the slope for dSSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration, the mRSS drops 4.22 (95 per cent CI: 2.29, 6.16). There was also a highly statistically significant negative correlation between sL-selectin and disease activity (p = 0.0007) and severity (p = 0.0007) in dSSc cases but not in lSSc cases (p = 0.2596, p = 0.7575, respectively).

Conclusions and Significance

No effective treatments exist for skin damage in SSc patients. Nor is there a laboratory alternative to the modified Rodnan skin score as is the case for other organs within the body. Modulation of circulating L-selectin is a promising target for reducing skin damage in dSSc patients. Plasma levels of soluble L-selectin could serve as an outcome measure for dSSc patients in clinical trials.

Cholesterol is essential for the growth and function of all mammalian cells, but abnormally elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) are a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). For many years, statin drugs have been used to effectively lower LDL-C, but ASCVD still persists in most of the world. Hence, additional LDL-C lowering is now recommended, and the search for therapeutic strategies that work in synergy with statins has now begun. Intestinal absorption and biliary excretion of cholesterol represent two major pathways and continue to show promise as druggable processes. Importantly, both of these complex physiological pathways are tightly regulated by key proteins located at the apical surface of the small intestine and the liver. One of these proteins, the target of ezetimibe Niemann-Pick C1-Like 1 (NPC1L1), was recently identified to be essential for intestinal cholesterol absorption and protect against excessive biliary sterol loss. In direct opposition of NPC1L1, the heterodimer of ATP-binding cassette transporters G5 and G8 (ABCG5/ABCG8) has been shown to be critical for promoting biliary cholesterol secretion in the liver, and has also been proposed to play a direct role in intestinal disposal of sterols. The purpose of this review is to summarize the current state of knowledge regarding the function of these opposing apical cholesterol transporters, and provide a framework for future studies examining these proteins.

OBJECTIVE: To investigate the significance of circulating adhesion molecules associated with leucocyte-endothelial cell interactions in asthma, serum levels of soluble E (sE)-selectin, soluble P (sP)-selectin, soluble L (sL)-selectin, and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in mild, moderate and severe asthma. METHOD: Serum levels of sE-selectin, sP-selectin, sL-selectin, and sVCAM-1 were measured in 32 women with asthma and 30 healthy donors using an enzyme-linked immunosorbent assay method. Twenty patients were suffering from severe asthma, and 12 from mild/moderate asthma. RESULTS: Serum sE-selectin and sVCAM-1 levels from patients with asthma were significantly higher than those observed in healthy donors (p < 0.01). The levels of sP-selectin were the same as those of controls. The level of sE-selectin exhibited an important increase in the severe asthmatic patients compared with mild/moderate asthma (p < 0.01). The sVCAM-1 level was increased in severe asthma when compared with healthy controls. There was no correlation between the levels of soluble selectins and the age of the patients. A significant correlation was found between sE-selectin and sVCAM-1 levels. CONCLUSION: These data indicate that circulating soluble forms of the selectins may have different kinetics during the clinical course of asthma, suggesting that they may reflect different inflammatory pathways in severe asthma. Both sVCAM-1 and sE-selectin may be useful immunological markers for monitoring disease activity in asthma.

Aims

Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients.

Methods and results

This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95% CI 2.0–4.9), attenuating slightly in multivariate models (HR 2.4; 95% CI 1.5–3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected.

Conclusion

Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.

Background

Elevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.

Methodology/ Principal Findings

Data of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of −0.37 ng/ml (p = 1.87×10−103) in KORA and −0.35 ng/ml (p = 5.11×10−84) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.

Conclusions/ Significance

Our findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.

Background

Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients.

Methods and results

We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62).

Conclusions

The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.

Background: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality and is an independent risk factor for hypertension. Novel circulating cardiovascular risk markers enabling a more accurate prediction of cardiovascular risk have been identified. Examination of these markers may clarify the increased risk in OSA and contribute to an analysis of the benefits of treatment.

Methods: Plasma levels of total cholesterol and triglyceride and activated coagulation factors XIIa and VIIa, factors VII, VIII, XII, fibrinogen, thrombin-antithrombin (TAT), von Willebrand factor antigen (vWFAg), soluble P-selectin (sP-sel), and homocysteine were measured before and after treatment for 1 month with therapeutic or subtherapeutic (control) continuous positive airways pressure (CPAP) in 220 patients with OSA.

Results: Levels of activated coagulation factors XIIa, VIIa, TAT and sP-sel were higher in OSA patients at baseline than in unmatched controls, but did not fall with 1 month of therapeutic CPAP treatment. The raised sP-sel levels correlated only with body mass index (p = 0.002). There was a trend towards a significant fall in total cholesterol with therapeutic CPAP (p = 0.06) compared with the control group. In the therapeutic group there was a clinically significant mean fall in total cholesterol of 0.28 mmol/l (95% confidence interval 0.11 to 0.45, p = 0.001) which may reduce cardiovascular risk by about 15%.

Conclusion: A number of activated coagulation factors are increased in untreated OSA patients, potentially contributing to vascular risk, but they do not fall with 1 month of CPAP treatment. Nasal CPAP may produce a clinically relevant fall in total cholesterol level, potentially reducing cardiovascular risk, but this needs to be verified in a larger prospective study.

The arteriovenous fistula (AVF) is the recommended form of dialysis vascular access, however, limited studies suggest that AVF creation may result in increased cardiovascular stress and remodeling. To explore the contribution of vascular access type to cardiovascular-related (CV) mortality, we analyzed USRDS Clinical Performance Measures data comprising 4854 patients that initiated dialysis between October 1, 1999–December 31, 2004. CV mortality included death from acute myocardial infarction, atherosclerotic heart disease, cardiomyopathy, arrhythmia, cardiac arrest or stroke. Risk of cardiovascular mortality during a 4-year observation was analyzed by Cox-regression methods with adjustments for demographic and co-morbid conditions. AVF use was strongly associated with lower all-cause and CV mortality. After adjustment for covariates, AVF use 90 days after dialysis initiation remained significantly associated with lower cardiovascular mortality [hazard ratio (HR) 0.69, p = 0.0004] compared with catheter use. These findings suggest that vascular access type influences cause-specific mortality beyond that of infection, and support existing guidelines recommending the use of an AVF early in the course of chronic end-stage renal disease therapy.

Background:

Platelet-derived microparticles (PDMP), selectins, and adiponectin play an important role in the development of atherosclerosis in diabetes. Miglitol has been shown to have a beneficial effect on postprandial hyperglycemia in diabetic patients. However, its influence on platelet activation markers (PDMP and soluble CD40 ligand [sCD40L]), selectins, and adiponectin in these patients is poorly understood.

Aim:

We investigated the effect of miglitol on circulating levels of PDMP, sCD40L, selectins, and adiponectin in patients with type 2 diabetes.

Methods:

Miglitol (150 mg/day) was administered for 4 months. Levels of PDMP, sCD40L, soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble L-selectin (sL-selectin), and adiponectin were measured by enzyme-linked immunosorbent assay at baseline, and after 1 and 4 months of treatment.

Results:

The levels of PDMP, sCD40L, sP-selectin, sE-selectin, and sL-selectin were higher in diabetic patients than in hypertensive patients, while there were no significant differences between hypertensive and hyperlipidemic patients. Before miglitol treatment, the adiponectin level of diabetic patients was lower than that of hypertensive patients. Miglitol therapy significantly decreased the plasma PDMP and sCD40L levels relative to baseline. Miglitol also caused a significant decrease of sP-selectin, sE-selectin, and sL-selectin. On the other hand, miglitol therapy led to a significant increase in adiponectin after 4 months of administration compared with baseline. Furthermore, the reduction of platelet activation markers and selectins during miglitol therapy was significantly greater in the responder (adiponectin-improved) group than the nonresponder group of diabetic patients.

Conclusion:

Miglitol has an adiponectin-dependent anti-atherothrombotic effect that may be beneficial for primary prevention of atherothrombosis in patients with type 2 diabetes.

Dysregulation of cholesterol balance contributes significantly to atherosclerotic cardiovascular disease (ASCVD), the leading cause of death in the United States. The intestine has the unique capability to act as a gatekeeper for entry of cholesterol into the body, and inhibition of intestinal cholesterol absorption is now widely regarded as an attractive non-statin therapeutic strategy for ASCVD prevention. In this chapter we discuss the current state of knowledge regarding sterol transport across the intestinal brush border membrane. The purpose of this work is to summarize substantial progress made in the last decade in regards to protein-mediated sterol trafficking, and to discuss this in the context of human disease.

An increasing death rate due to cardiovascular disease in patients with rheumatoid arthritis (RA) has been reported. Keishibukuryogan (KBG) is a traditional Chinese/Japanese (Kampo) formula that has been administered to patients with blood stagnation, e.g. thrombotic disease and atherosclerosis. The objective of this study was to evaluate the efficacy of KBG on disease activity and endothelial dysfunction in RA patients. Sixteen RA patients were enrolled and administered KBG (12 g per day) for 12 weeks in addition to continuing other drugs. The disease activity of RA was assessed by modified disease activity scores for 28 joints (DAS28). Plasma levels of adhesion molecules, soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were evaluated. C-reactive protein (CRP), inflammatory cytokines (IL-1β, IL-6 and TNF-α) and lipid peroxide (LPO) were also evaluated. Fourteen patients completed the study. The disease activity of RA, tender joint count, swollen joint count and DAS28 decreased significantly. Among adhesion molecules, only sVCAM-1 decreased significantly. LPO also decreased significantly, whereas CRP and inflammatory cytokines remained unchanged. These results suggest that KBG has insufficient anti-inflammatory or immunomodulating effect but does have a beneficial effect on articular symptoms and a protective effect against endothelial dysfunction in RA patients.

Background

Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble P-selectin (sP-selectin), and soluble E-selectin (sE-selectin) have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459.

Methods and Results

Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95%CI=3.4–5.8%, p=7.3×10−14) and 7.2% (95%CI=4.7–9.7%, p=1.5×10−8), respectively, lower sICAM-1 levels (n=33,671). An allele dose dependent association also was observed for sP-selectin (n=4,921), with heterozygotes and minor allele homozygotes having 11.5% (95%CI=7.2–15.8%, p=1.7×10−7) and 18.6% (95%CI=9.1–28.1%, p=1.2×10−4), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for sE-selectin (n=2,860) whose level was 25.6% (95%CI=19.0–32.2%, p=2.1×10−14) lower in heterozygotes and 43.3% (95%CI=36.9–49.3%, p=4.3×10−42) lower in minor allele homozygotes, than in major allele homozygotes.

Conclusions

The data support the association of variation at the ABO locus with sICAM-1, sP-selectin and sE-selectin levels.

Abstract

Objectives

Psoriasis (PsO) is a common chronic T cell-mediated inflammatory disorder traditionally thought to manifest in the skin and joints (psoriatic arthritis, PsA). Recently, it has been shown that these patients have an increased risk for myocardial infarction and this was greater with increasing severity of psoriasis. Patients with psoriasis have reported to have cardiometabolic disturbances including obesity, insulin resistance, and dyslipidemia. This constellation of risk factors, referred to as the metabolic syndrome, increases the risk for atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus. The aim of this study was to determine the prevalence of metabolic syndrome in PsA.

Methods

In our study, we examined the records of 105 patients with PsA to determine the prevalence of metabolic syndrome in PsA. This was a retrospective analysis of the Sacramento Veterans Affairs database.

Results

Our results demonstrated an increased prevalence of the metabolic syndrome in patients with PsA (61/105 patients or 58.1%) compared to the 35.2 % reported for the Third National Health and Nutrition Examination Survery (NHANES III) data.

Conclusions

Thus, patients with PsA have a very high prevalence of metabolic syndrome, which predisposes them to an increased risk of both diabetes and ASCVD.

Background: Soluble E-selectin (sE-selectin) is a marker of activation of vascular endothelium.

Objective: To examine serum levels of sE-selectin in a cohort of 85 patients with early rheumatoid arthritis (RA) followed up for five years.

Methods: sE-selectin levels were assessed annually using an enzyme linked immunosorbent assay (ELISA) and related to simultaneously obtained clinical and laboratory measures. Joint inflammation was evaluated by active joint count, functional status by Health Assessment Questionnaire (HAQ), and radiographic findings in hands and feet by the Larsen method. Laboratory tests included serum C reactive protein (CRP) level, erythrocyte sedimentation rate, blood haemoglobin level, white blood cell count (WBC), and platelet count. Area under the curve (AUC) was calculated for each variable, and Jonckheere's test for ordered alternatives was applied to assess significance of association between sE-selectin AUC tertiles and other variables. Baseline sE-selectin tertiles were related to change in Larsen score and HAQ score at five years. Odds ratios (OR) with 95% confidence interval (CI) were calculated using univariate and multivariate logistic regression.

Results: sE-selectin levels were associated with CRP level (p=0.012), WBC (p=0.037), active joint count (p=0.019), progression of joint destruction (p=0.038), and HAQ score at five years (p=0.021), but not with extra-articular symptoms or comorbidity. Baseline sE-selectin levels in the third tertile predicted the HAQ score at five years (OR 4.18, 95% CI 1.15 to 15.22). sE-selectin levels of patients did not differ significantly from those of healthy control subjects.

Conclusion: The degree of activation of vascular endothelium is associated with activity and outcome of early RA.

Summary

Microparticles (MP) are lipid vesicles from platelets, leukocytes and endothelial cells that are involved in early thrombogenesis. We evaluated a detailed time-course analysis of MPs on thrombogenesis and the associated tissue factor (TF) activity in wild-type, in gene-deleted for E- and P-selectins and with high levels of P-selectin expression after the initiation of venous thrombosis in mice. Inferior vena cava (IVC) ligation was performed on C57BL/6 mice (n =191, 59 = wild-type [WT], 55 = gene-deleted for E- and P – selectins [knock-outs, EPKO] and 77 = elevated levels of soluble P-selectin, named Delta Cytoplasmic Tail (ΔCT). Animals were euthanised at various time points to assess MP production, origin and thrombus weight. MPs were re-injected into separate mice at concentrations of 80,000 and 160,000 units, as well as from different ages. In addition, MPs from thrombosed animals were pooled and TF activity quantitated using a chromogenic assay. Thrombus weight correlated negatively with MPs derived from leukocytes, and positively with MPs derived from platelets for WT animals (p<0.05), while MPs from platelets presented a positive correlation to thrombus weight in the WT and EPKO groups (p<0.01). Total MPs correlated negatively with thrombus weight in the ΔCT group (p<0.05). MP re-injections led to greater thrombus weight, while older MP reinjections tended to form larger thrombus than younger. Finally, TF bearing MPs showed a significant correlation to MP concentrations (R=0.99). In conclusion, MPs appear to be an important element in venous thrombogenesis.

Objective

P-selectin (PSEL) and its ligand, P-selectin glycoprotein ligand-1 (PSGL-1), play key roles in both the inflammatory response and the atherosclerotic process, but there are conflicting results regarding the affect of PSEL and PSGL-1 gene variation on risk for cardiovascular and cerebrovascular disease. We tested the association of four PSEL and two PSGL-1 polymorphisms with incident coronary heart disease (CHD) and ischemic stroke among 13,875 participants in the prospective Atherosclerosis Risk in Communities (ARIC) study. We also tested common haplotypes in the PSEL and PSGL-1 genes to assess associations with incident CHD and ischemic stroke.

Methods and Results

Incident ischemic stroke and CHD were identified through annual telephone calls and hospital and death certificate surveillance. Five hundred twenty-five validated ischemic stroke and 1,654 CHD events were identified. Allele frequencies for all PSEL and PSGL-1 polymorphisms were markedly different between whites and African Americans; therefore, all analyses were performed race-specific. Independent analyses showed the PSEL 290NN genotype to be a significant predictor of CHD in whites (HRR 1.30, 95%CI 1.00-1.70, P=0.05). PSGL-1 genotypes carrying the 62I allele were significantly protective for incident CHD (HRR 0.53, 95%CI 0.31-0.92, P=0.02) and ischemic stroke (HRR 0.73, 95%CI 0.55-0.97, P=0.03) in African Americans. Haplotype analyses showed the PSEL NNVP haplotype to be a significant predictor of incident CHD in whites (HRR 2.09, 95%CI 1.23-3.55, P=0.006). No significant haplotype findings were observed in African-Americans.

Conclusions

PSEL S290N, in single polymorphism analysis and in the haplotypic background with T715P, was associated with increased risk of incident CHD in whites. The PSGL-1 M62I polymorphism was associated with decreased risk of both incident CHD and stroke in African Americans. These findings illustrate the complex relationship between genetic variation and disease in different racial groups.

Background

HIV infection is associated with premature development of cardiovascular disease (CVD). Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce CVD risk.

Methods

A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy (SMART) study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40L and P-selectin levels.

Results

At study entry, median (IQR) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n=114), participants randomized to immediate ART (n=134) had 10.3% lower ADMA levels (p=0.003) at 12 months; treatment differences in sCD40L (95% CI:-17 to 44%; p=0.53) and P-selectin (95% CI:-10 to 10%; p=0.95) were not significant. The difference in ADMA for those assigned immediate ART compared to those assigned ART deferral was greater among younger patients and those with higher levels of hsCRP and D-dimer (p≤0.05 for interaction for both), but not HIV RNA level at baseline (p=0.51).

Discussion

ART initiation leads to declines in ADMA levels, a marker of nitric-oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that up-regulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.

Background

The Metabolic Syndrome (MS) confers an increased risk for diabetes and cardiovascular disease. We previously showed that simvastatin has concomitant benefits in reducing low-density lipoprotein (LDL)–cholesterol and inflammation in MS subjects. The levels of plasminogen activator inhibitor 1(PAI-1), soluble P-selectin (sP-selectin), and soluble CD40 ligand (sCD40L) play an important role in the development and progression of atherosclerosis. Their levels are increased in the MS. The current study was to investigate the effects of simvastatin on PAI-1, sP-selectin, and sCD40 ligand.

Methods

Fifty subjects with MS were randomized into either placebo or simvastatin (40 mg/day) group for 8 weeks. Blood samples were obtained at baseline and at the end of the study. PAI-1 activity and sP-selectin and sCD40L levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results

There was no baseline difference in any of the parameters studied. Compared to baseline, simvastatin significantly reduced (P < 0.05) the circulating PAI-1 activity (24.3 ± 5.2 IU/mL at baseline vs. 21.4 ± 3.9 IU/mL after 8 weeks of treatment). Simvastatin did not alter (P < 0.05) the levels of sP-selectin (111.4 ± 35.9 ng/mL at baseline vs. 118.5 ± 71.2 ng/mL after 8 weeks) or sCD40L (2.0 ± 1.6 ng/mL at baseline vs. 1.5 ± 1.0 ng/mL after 8 weeks).

Conclusion

Our data indicate that simvastatin therapy has significant effects on the fibrinolytic system in MS subjects as evidenced in a reduction in PAI-1 activity.

Abstract

Background

The Metabolic Syndrome (MS) confers an increased risk for diabetes and cardiovascular disease. We previously showed that simvastatin has concomitant benefits in reducing low-density lipoprotein (LDL)–cholesterol and inflammation in MS subjects. The levels of plasminogen activator inhibitor 1(PAI-1), soluble P-selectin (sP-selectin), and soluble CD40 ligand (sCD40L) play an important role in the development and progression of atherosclerosis. Their levels are increased in the MS. The current study was to investigate the effects of simvastatin on PAI-1, sP-selectin, and sCD40 ligand.

Methods

Fifty subjects with MS were randomized into either placebo or simvastatin (40 mg/day) group for 8 weeks. Blood samples were obtained at baseline and at the end of the study. PAI-1 activity and sP-selectin and sCD40L levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results

There was no baseline difference in any of the parameters studied. Compared to baseline, simvastatin significantly reduced (P < 0.05) the circulating PAI-1 activity (24.3 ± 5.2 IU/mL at baseline vs. 21.4 ± 3.9 IU/mL after 8 weeks of treatment). Simvastatin did not alter (P < 0.05) the levels of sP-selectin (111.4 ± 35.9 ng/mL at baseline vs. 118.5 ± 71.2 ng/mL after 8 weeks) or sCD40L (2.0 ± 1.6 ng/mL at baseline vs. 1.5 ± 1.0 ng/mL after 8 weeks).

Conclusion

Our data indicate that simvastatin therapy has significant effects on the fibrinolytic system in MS subjects as evidenced in a reduction in PAI-1 activity.