Prevalence of subclinical atherosclerosis is increased in systemic sclerosis and is associated with serum proteins: a cross-sectional, controlled study of carotid ultrasound.

OBJECTIVES: SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS. METHODS: Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure. RESULTS: Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001). CONCLUSION: Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.

Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by calcification, vasculopathy, and endothelial wall damage, all of which can increase the risk of developing atherosclerosis and cardiovascular disease. The aim of this study was to perform a systematic review and meta-analysis to determine whether the risk of atherosclerosis is increased in SSc patients compared to healthy individuals. METHODS: A systematic search was performed to identify studies published in PubMed and the Cochrane database up to May 2010, and recently published abstracts were also reviewed. Two reviewers independently screened articles to identify studies comparing the rate of atherosclerosis in SSc patients to that in healthy controls. The studies utilized one of the following methods: angiography, Doppler ultrasound to assess plaque and carotid intima-media thickness (IMT), computed tomography, magnetic resonance imaging, flow-mediated vasodilation (assessed as the FMD%), the ankle-brachial index, or autopsy. For carotid IMT and FMD% values, we computed a pooled estimate of the summary mean difference and explored predictors of carotid IMT using random-effects meta-regression. RESULTS: Of the 3,156 articles initially identified, 31 were selected for systematic review. The meta-analysis included 14 studies assessing carotid IMT and 7 assessing brachial artery FMD%. Compared to healthy controls, SSc patients had a higher prevalence of coronary atherosclerosis, peripheral vascular disease, and cerebrovascular calcification. Meta-analysis showed that SSc patients had increased carotid IMT (summary mean difference 0.11 mm, 95% confidence interval [95% CI] 0.05 mm, 0.17 mm; P = 0.0006) and lower FMD% (summary mean difference -3.07%, 95% CI -5.44%, -0.69%; P = 0.01) compared to controls. There was marked heterogeneity between the studies, which was mainly attributable to variations in disease duration and differences in the mean/median age between SSc patients and controls. CONCLUSION: Patients with SSc have an increased risk of atherosclerosis compared to healthy subjects. Further studies should elucidate the mechanism of this increased risk.

The decrement in circulating endothelial progenitor cells (EPCs) in type 2 diabetes is independent of the severity of the hypoadiponectemia.

BACKGROUND: Type 2 diabetes mellitus (DM) is associated with a decreased level of circulating endothelial progenitor cells (EPCs) and adiponectin. Experimental studies suggest a potential link between hypoadiponectinaemia and the depletion of the EPC level. This study investigated the relationships between adiponectin level and EPC in patients with type 2 DM. METHODS: A total of 95 type 2 DM patients (58.5 ± 8.8 years, 42 men) and 95 age- and sex-matched healthy controls were recruited. Circulating EPC levels were determined by flow cytometry using CD133(+), CD34(+), CD133(+) /KDR(+) and CD34(+) /KDR(+) as surface markers. Plasma adiponectin levels were measured by enzyme-linked immunosorbent assay. EPC function was studied by in vitro tube formation and migration assay. RESULTS: The levels of CD133(+) (p < 0.001) and CD133(+) /KDR(+) (p < 0.001) EPCs were independently associated with the presence of type 2 DM. The levels of CD34(+) (p = 0.004) and CD34(+) /KDR(+) (p = 0.013) EPCs were independently associated with haemoglobin A(1c). Nevertheless, there was no relationship between the number of EPCs and adiponectin level. Tube formation assay showed impaired pro-angiogenic function of EPC in DM patients compared with controls (p = 0.007). Interestingly, adiponectin supplementation (5 µg/mL) increased tube formation by 17.6% in EPCs from DM patients (p = 0.002). It also significantly enhanced cell migration by 35.9% in EPCs from DM patients (p = 0.01). CONCLUSIONS: We detected no relationship between the reduction in the level of EPC and in the level of total adiponectin in blood from patients with type 2 diabetes. EPC from patients with diabetes were stimulated when exposed to adiponectin in the test tube, findings that warrant further study.

High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis.

OBJECTIVE: To determine the relationship of disease activity to infections in patients with rheumatoid arthritis (RA). METHODS: From the CORRONA database, the incidence of physician-reported infections in RA patients on stable disease-modifying antirheumatic drug, biological, and corticosteroid therapy for at least 6 months was ascertained. Two composite measures of disease activity were defined: clinical disease activity index (CDAI) and disease activity score 28 (DAS28). Incident rate ratios (IRR) were calculated using generalised estimating equation Poisson regression models adjusted for demographics, medications and clinical factors. RESULTS: Of 1 6242 RA patients, 6242 were on stable therapy for at least 6 months and were eligible for analysis. 2282 infections were reported in the cohort, followed over 7290 patient-years. After controlling for possible confounders, disease activity was associated with an increased rate of infections. Each 0.6 unit increase in DAS28 score corresponded to a 4% increased rate of outpatient infections (IRR 1.04, p=0.01) and a 25% increased rate of infections requiring hospitalisation (IRR 1.25, p=0.03). There was a dichotomy in the relationship between infections and CDAI scores. For CDAI <10 (mild disease activity) patients had a 12% increased rate of outpatient infections with each 5 unit increase in CDAI score (IRR 1.12, p=0.003). At CDAI scores ≥10, there was no further increase in the rate of outpatient infections associated with higher disease activity. The relationship of CDAI to hospitalised infections showed similar trends to outpatient data but did not reach statistical significance after multivariate analysis (CDAI <10: IRR 1.56, p=0.08). CONCLUSIONS: In this large cohort of RA patients, higher disease activity was associated with a higher probability of developing infections.

The involvement of N-G,N-G-dimethyarginine dimethylhydrolase 1 in the proliferative effect of Astragali radix on cardiac cells.

AIM OF THE STUDY: Astragali radix (AR) is a widely used traditional medicine in oriental countries for treating various diseases including cardiovascular disease (CVD). We investigated the effects of AR extracts on rat cardiomyocytes and H9C2 cardiac cells as well as identified many target genes that mediate the effect of AR. MATERIALS AND METHODS: The effect of AR extracts on cell proliferation was assessed and cDNA microarray technique was used to analyse the differential gene expressions upon AR treatment in cardiac cells. One of the selected target genes was over-expressed to elucidate its role in cell proliferation. RESULTS: AR was shown to promote the proliferation of neonatal rat cardiomyocytes and H9C2 cells. Results of cDNA microarray hybridization showed that N-G,N-G-dimethylarginine dimethylaminohydrolase 1 (DDAH1) gene was up-regulated in AR-treated H9C2 cells and the results were further confirmed by reverse transcription polymerase chain reaction. Over-expression of DDAH1 gene in H9C2 cells significantly enhances the cell proliferation. Moreover, a drastic drop of DDAH1 expression in rat ventricular myocardium was observed from day 3 to day 5 after birth, which is the critical transition of cardiomyocytes from hyperplastic to hypertrophic growth. CONCLUSIONS: AR promotes cardiac cell proliferation and up-regulates the DDAH1, an enzyme that metabolized the endogenous nitric oxide (NO) synthase inhibitor. The effect of AR on the metabolism of NO deserves future investigation.

Course of dermal ulcers and musculoskeletal involvement in systemic sclerosis patients in the scleroderma lung study.

OBJECTIVE: To evaluate changes in vascular and musculoskeletal involvement in subjects in the Scleroderma Lung Study, a multicenter, double-blind, randomized, controlled trial comparing placebo treatment with oral cyclophosphamide (CYC) for 1 year in systemic sclerosis patients with interstitial lung disease. Subjects were then followed off the study agent for an additional 12 months. METHODS: The following parameters were noted at baseline and every 6 months for each patient: digital tip ulcers, other dermal ulcers, joint swelling, joint tenderness, large joint contractures, muscle tenderness, muscle weakness, oral aperture, hand extension, and fist closure. RESULTS: A total of 158 patients were enrolled from 13 centers in the US; 79 were randomized to the CYC group and 79 to the placebo group. There were no differences in dermal ulcer and musculoskeletal measures between the CYC and placebo groups at baseline and 12 and 24 months. Improvement in percent predicted forced vital capacity was associated with improvement in the Rodnan skin thickness score (P<0.05) at 12 and 24 months, and with increased mean oral aperture at 24 months (P=0.005). CONCLUSION: These data document the frequency and course of these vascular and musculoskeletal features over time, therefore providing essential information for sample size calculations and magnitude of effect in future clinical trials. There was no treatment effect of CYC on the vascular and musculoskeletal features described.

Current concepts in disease-modifying therapy for systemic sclerosis-associated interstitial lung disease: lessons from clinical trials.

Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc), which is also known as scleroderma. Two randomized clinical trials in patients with SSc-related ILD have shown that oral or intravenous cyclophosphamide is associated with modest but significant or near-significant improvements in lung function, dyspnea, and physical function. In addition, the Scleroderma Lung Study and an observational study showed that baseline forced vital capacity less than 70% and moderate fibrosis on thoracic high-resolution CT are predictors of response to cyclophosphamide therapy and/or survival, whereas active alveolitis on bronchoalveolar lavage is not. Newer therapies for SSc patients with ILD include mycophenolate mofetil, tyrosine kinase inhibitors (imatinib, dasatinib), and anti-interleukin-13 monoclonal antibody. Several uncontrolled trials have reported favorable results of mycophenolate mofetil in SSc-related ILD. A randomized double-blind controlled trial by the Scleroderma Lung Study Research Group is currently comparing the efficacy and safety of mycophenolate mofetil versus oral cyclophosphamide.

Platelet C4d is associated with acute ischemic stroke and stroke severity.

BACKGROUND AND PURPOSE: Platelets bearing complement C4d were recently reported to be 99% specific for a diagnosis of systemic lupus erythematosus (SLE) and associated with neuropsychiatric lupus. We compared the prevalence of platelet C4d and investigated the clinical associations of platelet C4d in patients with acute ischemic stroke. METHODS: We recruited 80 patients hospitalized for acute ischemic stroke. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIH-SS). Infarct volume was determined by MRI. Platelet C4d was measured by flow cytometry. RESULTS: Mean age was 57.9 years (range: 24.6 to 86.8 years), 58% were male, and 91% were white. Eight patients (10%) with acute ischemic stroke were platelet C4d-positive, which was significantly higher in prevalence compared to healthy controls (0%, P<0.0001) and non-SLE patients with immune/inflammatory disease (2%, P=0.004). The median NIH-SS score and infarct volume for acute stroke patients were 6 (interquartile range [IQR]: 2 to 13) and 3.4 cc (IQR: 1.1 to 16.6), respectively. Platelet C4d-positive patients were more likely to have a severe stroke compared to those with negative platelet C4d (NIH-SS median: 17.5 versus 5, P=0.003). Positive platelet C4d was independently associated with stroke severity (P=0.03) after controlling for age, anticardiolipin antibody (aCL) status, and total anterior circulation of stroke involvement, and also with infarct volume (P=0.005) after controlling for age, aCL status, and old stroke by MRI. CONCLUSIONS: Platelet C4d is associated with severe acute ischemic stroke. Platelet C4d may be a biomarker as well as pathogenic clue that links cerebrovascular inflammation and thrombosis.

Citrus polymethoxylated flavones improve lipid and glucose homeostasis and modulate adipocytokines in fructose-induced insulin resistant hamsters.

The present study was undertaken to determine whether supplementation with polymethoxylated flavones (PMFs) could ameliorate the fructose-induced hypertriglyceridemia and other metabolic abnormalities associated with insulin resistance (IR) in hamsters. Following feeding with the fructose diet, hamsters were supplemented orally with PMF-L or PMF-H (62.5 and 125 mg/kg/day) for 4 weeks. Both PMF-treated groups showed a statistically significant (p<0.05) decrease in serum triglyceride (TG) and cholesterol levels compared to the fructose-fed control group. The fructose control group at the end of the study showed elevated serum insulin and impaired insulin sensitivity (glucose intolerance). On the other hand, PMF-supplemented groups showed a reversal in these metabolic defects, including a decrease in insulin level and an improvement in glucose tolerance. PMF supplementation also reduced TG contents in the liver and heart and was able to regulate adipocytokines by significantly suppressing TNF-alpha, INF-gamma, IL-1beta and IL-6 expression and increasing adiponectin in IR hamsters. The mechanism of PMF on the activation of peroxisome proliferator-activated receptors (PPAR) was also explored. PMF-H supplementation significantly increased PPARalpha and PPARgamma protein expression in the liver. This is the first report of positive effects of PMF on adipocytokine production and on PPAR expression in IR hamsters. This study suggests that PMF can ameliorate hypertriglyceridemia and its anti-diabetic effects may occur as a consequence of adipocytokine regulation and PPARalpha and PPARgamma activation.