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Thus, the decrease in cardiovascular events seen with intensive blood pressure control is not associated with an increased rate of other causes of hospitalization. Registration- URL https//www.clinicaltrials.gov; Unique identifier NCT01206062.A key immunomodulatory cytokine, IL-10 (interleukin-10), has been shown to be dysregulated in preeclampsia, a pregnancy-specific hypertensive disorder, further characterized by multi-system involvement. However, studies have reported inconsistent findings about circulating IL-10 levels in preeclamptic versus normotensive pregnancies. The aim of the present systematic review and meta-analysis was to assess circulating IL-10 levels in preeclamptic and normotensive pregnancies at 2 time points before, and at the time of preeclampsia diagnosis. PubMED, EMBASE, and Web of Science databases were searched to include all published studies examining circulating IL-10 levels in preeclamptic and normotensive pregnancies. Differences in IL-10 levels were evaluated by standardized mean differences. Of 876 abstracts screened, 56 studies were included in the meta-analysis. Circulating IL-10 levels were not different before the time of active disease (standardized mean differences, -0.01 [95% CI, -0.11 to 0.08]; P=0.76). At the time of active disease, women with preeclampsia (n=1599) had significantly lower IL-10 levels compared with normotensive controls (n=1998; standardized mean differences, -0.79 [95% CI, -1.22 to -0.35]; P=0.0004). IL-10 levels were lower in both early/severe and late/mild forms of preeclampsia. Subgroup analysis revealed that IL-10 measurement methodology (ELISA or multiplex bead array) and the sample type (plasma or serum) significantly influenced the observed differences, with the use of sera paired with ELISA technology providing the best distinction in IL-10 levels between preeclamptic and normotensive pregnancies. These findings support the role of decreased IL-10 levels in the pathophysiology of preeclampsia. Future studies should address the therapeutic potential of IL-10 in preeclampsia.Being born extremely preterm (EP; less then 28 weeks’ gestation) or extremely low birthweight (ELBW; less then 1000 g birthweight) may predict increased cardiometabolic risk in adulthood, but other early life predictors are less well described. We aimed to (1) compare cardiovascular health profiles between 165 adults born EP/ELBW and 127 controls at age 25 years, drawn from a prospective longitudinal cohort study, recruited at birth in 1991 to 1992; and (2) in the EP/ELBW group, determine early life associations of cardiovascular health. Cardiovascular health profiles were calculated individually for measures of anthropometry, abdominal visceral fat, blood pressure, fasting plasma glucose, insulin, lipids, C-reactive protein, vascular indices, exercise tolerance and smoking status, and summed for an overall score. Cardiovascular health profiles were compared between groups; using logistic regression (individual scores) and the Mann-Whitney U test (cumulative score). Compared with controls, adults born EP/ELBW had less favorable cardiovascular health profiles; individually for abdominal visceral fat (odds ratio, 0.56 [95% CI, 0.33-0.96], P=0.03), blood pressure (odds ratio 0.38 [95% CI, 0.23-0.63], P less then 0.001), exercise capacity (odds ratio 0.37 [95% CI, 0.22-0.63], P less then 0.001), and fasting glucose (odds ratio 0.51 [95% CI, 0.31-0.84], P=0.01) and overall (median [interquartile range] 10 [7-11] versus 11 [9-12], P=0.007). Male sex predicted unfavorable abdominal visceral fat, blood pressure and fasting glucose, and favorable exercise capacity. selleck inhibitor Greater increases in weight Z scores between 2 and 8, and 8 and 18 years predicted less favorable profiles of exercise capacity and visceral fat. Longer-term follow-up is critical to determine the cardiovascular sequelae of adults born EP/ELBW.Loss of BMP (bone morphogenic protein) signaling induces a phenotype switch of pulmonary arterial smooth muscle cells (PASMCs), which is the pathological basis of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Here, we identified FGF12 (fibroblast growth factor 12) as a novel regulator of the BMP-induced phenotype change in PASMCs and elucidated its role in pulmonary vascular remodeling during PAH development. Using murine models of PAH and lung specimens of patients with PAH, we observed that FGF12 expression was significantly reduced in PASMCs. In human PASMCs, FGF12 expression was increased by canonical BMP signaling. FGF12 knockdown blocked the antiproliferative and prodifferentiation effect of BMP on human PASMCs, suggesting that FGF12 is required for the BMP-mediated acquisition of the quiescent and differentiated PASMC phenotype. Mechanistically, FGF12 regulated the BMP-induced phenotype change by inducing MEF2a (myocyte enhancer factor 2a) phosphorylation via p38MAPK signaling, thereby modulating the expression of MEF2a target genes involved in cell proliferation and differentiation. Furthermore, we observed that TG (transgenic) mice with smooth muscle cell-specific FGF12 overexpression were protected from chronic hypoxia-induced PAH development, pulmonary vascular remodeling, and right ventricular hypertrophy. Consistent with the in vitro data using human PASMCs, FGF12 TG mice showed increased MEF2a phosphorylation and a substantial change in MEF2a target gene expression, compared with the WT (wild type) controls. Overall, our findings demonstrate a novel BMP/FGF12/MEF2a pathway regulating the PASMC phenotype switch and suggest FGF12 as a potential target for the development of therapeutics for ameliorating pulmonary vascular remodeling in PAH.An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI] 6.