Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease

Background - Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow–derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals. Methods and Results - Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an '1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to '3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor–positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity

Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation

AbstractOBJECTIVESThis study assessed the predictive value of preprocedural C-reactive protein (CRP) levels on six-month clinical and angiographic outcome in patients undergoing coronary stent implantation.BACKGROUNDRecent data indicate that low-grade inflammation as detected by elevated CRP serum levels predicts the risk of recurrent coronary events.METHODSWe prospectively investigated the predictive value of preprocedural CRP-levels on restenosis and six-month clinical outcome in 276 patients after coronary stent implantation. The primary combined end point was death due to cardiac causes, myocardial infarction related to the target vessel and repeat intervention of the stented vessel.RESULTSGrouping patients into tertiles according to preprocedural CRP-levels revealed that, despite identical angiographic and clinical characteristics at baseline and after stent implantation, a primary end point event occurred in 24 (26%) patients of the lowest tertile, in 42 (45.6%) of the middle tertile and in 38 (41.3%) of the highest CRP tertile, p = 0.01. On multivariate analysis, tertiles of CRP levels were independently associated with a higher risk of adverse coronary events (relative risk = 2.0 [1.1 to 3.5], tertile I vs. II and III, p = 0.01) in addition to the minimal lumen diameter after stent (p = 0.04). In addition, restenosis rates were significantly higher in the two upper tertiles compared with CRP levels in the lowest tertile (45.5% vs. 38.3% vs. 18.5%, respectively, p = 0.002).CONCLUSIONSLow-grade inflammation as evidenced by elevated preprocedural serum CRP-levels is an independent predictor of adverse outcome after coronary stent implantation, suggesting that a systemically detectable inflammatory activity is associated with proliferative responses within successfully implanted stents

Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes Comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis

ObjectivesThe goal of this study was to determine the predictive value of pregnancy-associated plasma protein-A (PAPP-A) in patients with acute coronary syndromes (ACS).BackgroundPregnancy-associated plasma protein-A is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization.MethodsIn 547 patients with angiographically validated ACS and in a heterogeneous emergency room population of 644 patients with acute chest pain, respectively, PAPP-A as well as markers of myocardial necrosis (troponin T [TnT]), ischemia (vascular endothelial growth factor [VEGF]), inflammation (high-sensitivity C-reactive protein [hsCRP]), anti-inflammatory activity (interleukin [IL]-10), and platelet activation (soluble CD40 ligand [sCD40L]) were determined. Patients were followed for the occurrence of death or myocardial infarction.ResultsIn patients with ACS, elevated PAPP-A levels (>12.6 mIU/l) indicated an increased risk (odds ratio 2.44 [95% confidence interval (CI) 1.43 to 4.15]; p = 0.001). When the analysis was restricted to TnT-negative patients, PAPP-A still identified a subgroup of high-risk patients (odds ratio [OR] 2.72 [95% confidence interval (CI) 1.25 to 5.89]; p = 0.009). In a multivariable model, PAPP-A (OR 2.01; p = 0.015), sCD40L (OR 2.37; p = 0.003), IL-10 (OR 0.43; p = 0.003), and VEGF (OR 2.19; p = 0.018) were independent predictors. Prospective validation in patients with chest pain confirmed that PAPP-A levels reliably identify high-risk patients (adjusted OR 2.32 [95% CI 1.32 to 4.26]; p = 0.008). Patients negative for all three markers (TnT, sCD40L, and PAPP-A) were at very low cardiac risk (30 days: 3.0% event rate; no death).ConclusionsThe PAPP-A level as a marker of plaque instability is a strong independent predictor of cardiovascular events in patients with ACS. Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS

Nutritional risk index is a better predictor of early mortality than conventional nutritional markers after transcatheter aortic valve replacement: A prospective cohort study

Background: Nutritional risk index (NRI) has been shown to better predict survival than body mass index (BMI) or albumin after several cardiovascular interventions. Under assessment herein is whether NRI can have higher predictive value than conventional parameters for short-term survival after transcatheter aortic valve replacement (TAVR).Methods: A prospective cohort study was performed. In-hospital, 1-month and 3-month survival was evaluated. Since most patients undergoing TAVR are over 65, the NRI definition for a geriatric population (GNRI) was used. The impact of baseline BMI, albumin levels, and GNRI on in-hospital and short-term survival was assessed.Results: One hundred fifty two patients aged 82 ± 5.4 were included. In-hospital, 1-month, and 3-month mortality was 5.3%, 5.9%, and 9.2%, respectively. Mean GNRI was 112.7 ± 11.9, and was significantly lower in patients who died in-hospital (101.0 ± 8.8 vs. 113.3 ± 11.7), at 30 days (103.4 ± 10.9 vs. 113.3 ± 11.7), and at 90 days (104.0 ± 9.6 vs. 113.6 ± 11.8) than in survivors (all, p < 0.05). Three-month mortality in patients with no nutritional risk was 6.8% (9/132) vs. 25% (5/20) in patients with malnutrition (p = 0.022). In univariate analysis, GNRI predicted in-hospital, 30-day, and 90-day mortality (all, p < 0.05). Predictive value remained significant after adjusting for age, EuroSCORE II, and STS-Score (p < 0.05). Based on receiver operating curves, GNRI (AUC: 0.73) showed a betterdiscrimination for 3-month mortality than albumin (0.69), weight (0.67) or BMI (0.62). The optimal cut-off value was 109.8.Conclusions: The geriatric nutritional risk index predicts short-term mortality after TAVR and has a higher discriminating ability than other commonly used nutritional variables. It is a simple parameter that identifies those patients who could benefit from pre-procedural nutritional therapy

Endothelial dysfunction and inflammation in asymptomatic proteinuria

Background. Proteinuria is associated with vascular risk and a systemic increase in vascular permeability. Endothelial dysfunction occurs early in atherosclerosis and modulates vascular permeability. Vascular risk and chronic inflammation are associated. This study investigates whether the increased vascular permeability in proteinuria reflects systemic endothelial dysfunction and chronic inflammation. Methods. Twenty-one patients with asymptomatic proteinuria (1.29 g/24 h; range 0.18 to 3.17) and 21 matched controls were studied. Microvascular endothelial function was assessed using acetylcholine iontophoresis. Maximum microvascular hyperemia (MMH) was assessed by flux response to local skin heating. Macrovascular endothelial function was assessed by flow- associated dilation (FAD) in the brachial artery using ultrasound. von Willebrand factor (vWF) was measured as a marker of endothelial activation. Low-grade inflammation was assessed by measurement of circulating C-reactive protein (CRP) values using a high sensitivity assay. Results. FAD was impaired in proteinuric subjects (AP) compared to controls [1.8 (0.2 to 5.3) AP vs. 3.8 (1.5 to 6.2) C %; P = 0.014]. There was no significant difference between groups in MMH or in the response to acetylcholine iontophoresis. The AP group had a higher CRP [4.0 (0.5 to 39.0) AP vs. 0.2 (0.1 to 21.3) C mg/L; P lt 0.001] and tendency to higher vWF [101.5 (67.0 to 197.0) AP vs. 77.5 (45.0 to 185.0) C IU/dL; P = 0.046] compared to controls. In the AP, but not control, group there was an inverse correlation between CRP and microvascular function as determined by acetylcholine iontophoresis (r = -0.509; P = 0.018). Conclusions. In AP subjects there is evidence of macrovascular endothelial dysfunction remote from the kidney and of low-grade inflammation that is associated with microvascular endothelial dysfunction

MicroRNA regulation of endothelial homeostasis and commitment—implications for vascular regeneration strategies using stem cell therapies

Human embryonic (hESC) and induced pluripotent (hiPSC) stem cells have broad therapeutic potential in the treatment of a range of diseases, including those of the vascular system. Both hESCs and hiPSCs have the capacity for indefinite self-renewal, in addition to their ability to differentiate into any adult cell type. These cells could provide a potentially unlimited source of cells for transplantation and, therefore, provide novel treatments, e.g. in the production of endothelial cells for vascular regeneration. MicroRNAs are short, noncoding RNAs that act posttranscriptionally to control gene expression and thereby exert influence over a wide range of cellular processes, including maintenance of pluripotency and differentiation. Expression patterns of these small RNAs are tissue specific, and changes in microRNA levels have often been associated with disease states in humans, including vascular pathologies. Here, we review the roles of microRNAs in endothelial cell function and vascular disease, as well as their role in the differentiation of pluripotent stem cells to the vascular endothelial lineage. Furthermore, we discuss the therapeutic potential of stem cells and how knowledge and manipulation of microRNAs in stem cells may enhance their capacity for vascular regeneration

A Useful Predictor of Early Atherosclerosis in Obese Children: Serum High-sensitivity C-reactive Protein

Childhood obesity seems to contribute to the development of vascular inflammation and the progression of arterial wall changes. High-sensitivity C-reactive protein (hs-CRP) has recently emerged as a useful biomarker for vascular inflammation associated with atherosclerosis. The objectives of this study were to evaluate the association of the serum hs-CRP level with ultrasonic findings of early atherosclerosis, carotid intima-media wall thickness (IMT) and brachial flow-mediated dilation (FMD), in obese children. Thirty eight obese children and 45 sex/age-matched healthy control children were recruited. Serum CRP levels were measured by the high-sensitive latex turbidimetric immunoassay, and we measured carotid IMT and brachial FMD using high-resolution B-mode ultrasonography. Obese children had significantly higher hs-CRP levels (1.40±0.74 mg/L vs. 0.55±0.49 mg/L, p<0.01), as well as increased IMT (0.52±0.09 mm vs. 0.41±0.07 mm, p<0.01) and impaired FMD (7.35±7.78% vs. 20.34±16.81%, p<0.01) compared to healthy controls. Serum hs-CRP correlated positively with IMT (r=0.413, p<0.05) and inversely with FMD (r=-0.350, p<0.05) in the obesity group. Measurement of the serum hs-CRP level is a simple, cheap, and highly reproducible assay and correlates with IMT and FMD in obese children. Thus, it would be a useful marker for evaluating and estimating the degree of atherosclerosis in children

Microparticles: major transport vehicles for distinct microRNAs in circulation

AIMS: Circulating microRNAs (miRNAs) have attracted major interest as biomarkers for cardiovascular diseases. Since RNases are abundant in circulating blood, there needs to be a mechanism protecting miRNAs from degradation. We hypothesized that microparticles (MP) represent protective transport vehicles for miRNAs and that these are specifically packaged by their maternal cells. METHODS AND RESULTS: Conventional plasma preparations, such as the ones used for biomarker detection, are shown to contain substantial numbers of platelet-, leucocyte-, and endothelial cell-derived MP. To analyse the widest spectrum of miRNAs, Next Generation Sequencing was used to assess miRNA profiles of MP and their corresponding stimulated and non-stimulated cells of origin. THP-1 (monocytic origin) and human umbilical vein endothelial cell (HUVEC) MP were used for representing circulating MP at a high purity. miRNA profiles of MP differed significantly from those of stimulated and non-stimulated maternal THP-1 cells and HUVECs, respectively. Quantitative reverse transcription-polymerase chain reaction of miRNAs which have been associated with cardiovascular diseases also demonstrated significant differences in miRNA profiles between platelets and their MP. Notably, the main fraction of miRNA in plasma was localized in MP. Furthermore, miRNA profiles of MP differed significantly between patients with stable and unstable coronary artery disease. CONCLUSION: Circulating MP represent transport vehicles for large numbers of specific miRNAs, which have been associated with cardiovascular diseases. miRNA profiles of MP are significantly different from their maternal cells, indicating an active mechanism of selective 'packaging' from cells into MP. These findings describe an interesting mechanism for transferring gene-regulatory function from MP-releasing cells to target cells via MP circulating in blood

Rüstungskontrolle für die nächste Bundesregierung: Ein Empfehlungsbericht

Die nächste Bundesregierung wird in den kommenden Jahren vor drei schwierigen rüstungskontrollpolitischen Aufgaben stehen. Erstens muss sie an neuen Initiativen und Vertragswerken für bisher nicht regulierte, technologisch neue Waffengattungen arbeiten. Zweitens muss sie dabei helfen, die von akuten Krisen bedrohten, noch bestehenden Rüstungskontrollregime vor dem endgültigen Scheitern zu bewahren. Drittens muss sie ihren Teil dazu beitragen, die bewährten Mechanismen internationaler Rüstungskontrolle im Hinblick auf neue Herausforderungen weiterzuentwickeln. Keine dieser drei Aufgaben kann von den jeweils anderen losgelöst bearbeitet werden. Vielmehr wird die nächste Bundesregierung für das Gelingen einer solch ambitionierten Rüstungskontrollpolitik über eine Reihe von Zielkonflikten entscheiden müssen. Der vorliegende Bericht gliedert sich in neun Kapitel, die, jedes für sich, ein übergeordnetes Thema der Rüstungskontrolle behandeln und dabei konkrete Handlungsempfehlungen für die künftige Bundesregierung geben. Die Kapitel behandeln: die nukleare Rüstungskontrolle in Europa, den Atomwaffenverbotsvertrag, das Atomabkommen mit dem Iran, die nukleare Abrüstungsverifikation, das Chemiewaffenübereinkommen, die Cybersicherheit, die Regulierung vollautonomer letaler Waffensysteme, die deutsche Debatte um die Beschaffung bewaffneter Drohnen und die konventionelle Rüstungskontrolle in Europa