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Reduction of Circulating Endothelial Progenitor Cell Level Is Associated with Contrast-Induced Nephropathy in Patients Undergoing Percutaneous Coronary and Peripheral Interventions  [PDF]
Chia-Hung Chiang, Po-Hsun Huang, Chun-Chih Chiu, Chien-Yi Hsu, Hsin-Bang Leu, Chin-Chou Huang, Jaw-Wen Chen, Shing-Jong Lin
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089942
Abstract: Objectives Reduced number and impaired function of circulating endothelial progenitor cells (EPCs) in patients with chronic kidney disease have been reported. However, there is little data about the association between circulating EPC levels and risk of contrast-induced nephropathy (CIN). The aim of this study was to investigate the relationship between circulating EPCs and CIN in patients after angiography. Methods and Results A total of 77 consecutive patients undergoing elective percutaneous coronary intervention (PCI) and percutaneous transluminal angioplasty (PTA) were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess EPC number before the procedure. CIN was defined as an absolute increase ≧0.5 mg/dl or a relative increase ≧25% in the serum creatinine level at 48 hours after the procedure. Eighteen (24%) of the study subjects developed CIN. Circulating EPC levels were significantly lower in patients who developed CIN than in those without CIN (CD34+KDR+, 4.11±2.59 vs. 9.25±6.30 cells/105 events, P<0.001). The incidence of CIN was significantly greater in patients in the lowest EPC tertile (CD34+KDR+; from lowest to highest, 52%, 15%, and 4%, P<0.001). Using univariate logistic regression, circulating EPC number (CD34+KDR+) was a significant negative predictor for development of CIN (odds ratio 0.69, 95% CI 0.54–0.87, P = 0.002). Over a two-year follow-up, patients with CIN had a higher incidence of major adverse cardiovascular events including myocardial infarction, stroke, revascularization of treated vessels, and death (66.7% vs. 25.4%, P = 0.004) than did patients without CIN. Conclusions Decreased EPC level is associated with a greater risk of CIN, which may explain part of the pathophysiology of CIN and the poor prognosis in CIN patients.
Procalcific Phenotypic Drift of Circulating Progenitor Cells in Type 2 Diabetes with Coronary Artery Disease
Gian Paolo Fadini,Mattia Albiero,Lisa Menegazzo,Elisa Boscaro,Carlo Agostini,Saula Vigili de Kreutzenberg,Marcello Rattazzi,Angelo Avogaro
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/921685
Abstract: Diabetes mellitus (DM) alters circulating progenitor cells relevant for the pathophysiology of coronary artery disease (CAD). While endothelial progenitor cells (EPCs) are reduced, there is no data on procalcific polarization of circulating progenitors, which may contribute to vascular calcification in these patients. In a cohort of 107 subjects with and without DM and CAD, we analyzed the pro-calcific versus endothelial differentiation status of circulating CD34
Decreased Circulating Endothelial Progenitor Cell Levels and Function in Patients with Nonalcoholic Fatty Liver Disease  [PDF]
Chia-Hung Chiang, Po-Hsun Huang, Fa-Po Chung, Zu-Yin Chen, Hsin-Bang Leu, Chin-Chou Huang, Tao-Cheng Wu, Jaw-Wen Chen, Shing-Jong Lin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031799
Abstract: Objectives Nonalcoholic fatty liver disease (NAFLD) is associated with advanced atherosclerosis and a higher risk of cardiovascular disease. Increasing evidence suggests that injured endothelial monolayer is regenerated by circulating bone marrow derived-endothelial progenitor cells (EPCs), and levels of circulating EPCs reflect vascular repair capacity. However, the relation between NAFLD and EPC remains unclear. Here, we tested the hypothesis that patients with nonalcoholic fatty liver disease (NAFLD) might have decreased endothelial progenitor cell (EPC) levels and attenuated EPC function. Methods and Results A total of 312 consecutive patients undergoing elective coronary angiography because of suspected coronary artery disease were screened and received examinations of abdominal ultrasonography between July 2009 and November 2010. Finally, 34 patients with an ultrasonographic diagnosis of NAFLD, and 68 age- and sex-matched controls without NAFLD were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess circulating EPC numbers. The adhesive function, and migration, and tube formation capacities of EPCs were also determined in NAFLD patients and controls. Patients with NAFLD had a significantly higher incidence of metabolic syndrome, previous myocardial infarction, hyperuricemia, and higher waist circumference, body mass index, fasting glucose and triglyceride levels. In addition, patients with NAFLD had significantly decreased circulating EPC levels (all P<0.05), attenuated EPC functions, and enhanced systemic inflammation compared to controls. Multivariate logistic regression analysis showed that circulating EPC level (CD34+KDR+ [cells/105 events]) was an independent reverse predictor of NAFLD (Odds ratio: 0.78; 95% confidence interval: 0.69–0.89, P<0.001). Conclusions NAFLD patients have decreased circulating EPC numbers and functions than those without NAFLD, which may be one of the mechanisms to explain atherosclerotic disease progression and enhanced cardiovascular risk in patients with NAFLD.
Circulating Endothelial Progenitor Cells in Kidney Transplant Patients  [PDF]
Giovana S. Di Marco, Peter Rustemeyer, Marcus Brand, Raphael Koch, Dominik Kentrup, Alexander Grabner, Burkhard Greve, Werner Wittkowski, Hermann Pavenst?dt, Martin Hausberg, Stefan Reuter, Detlef Lang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024046
Abstract: Background Kidney transplantation (RTx) leads to amelioration of endothelial function in patients with advanced renal failure. Endothelial progenitor cells (EPCs) may play a key role in this repair process. The aim of this study was to determine the impact of RTx and immunosuppressive therapy on the number of circulating EPCs. Methods We analyzed 52 RTx patients (58±13 years; 33 males, mean ± SD) and 16 age- and gender-matched subjects with normal kidney function (57±17; 10 males). RTx patients received a calcineurin inhibitor (CNI)-based (65%) or a CNI-free therapy (35%) and steroids. EPC number was determined by double positive staining for CD133/VEGFR2 and CD34/VEGFR2 by flow cytometry. Stromal cell-derived factor 1 alpha (SDF-1) levels were assessed by ELISA. Experimentally, to dissociate the impact of RTx from the impact of immunosuppressants, we used the 5/6 nephrectomy model. The animals were treated with a CNI-based or a CNI-free therapy, and EPCs (Sca+cKit+) and CD26+ cells were determined by flow cytometry. Results Compared to controls, circulating number of CD34+/VEGFR2+ and CD133+/VEGFR2+ EPCs increased in RTx patients. There were no correlations between EPC levels and statin, erythropoietin or use of renin angiotensin system blockers in our study. Indeed, multivariate analysis showed that SDF-1 – a cytokine responsible for EPC mobilization – is independently associated with the EPC number. 5/6 rats presented decreased EPC counts in comparison to control animals. Immunosuppressive therapy was able to restore normal EPC values in 5/6 rats. These effects on EPC number were associated with reduced number of CD26+ cells, which might be related to consequent accumulation of SDF-1. Conclusions We conclude that kidney transplantation and its associated use of immunosuppressive drugs increases the number of circulating EPCs via the manipulation of the CD26/SDF-1 axis. Increased EPC count may be associated to endothelial repair and function in these patients.
Circulating endothelial and progenitor cells: Evidence from acute and long-term exercise effects  [cached]
Matina Koutroumpi,Stavros Dimopoulos,Katherini Psarra,Theodoros Kyprianou
World Journal of Cardiology , 2012, DOI: 10.4330/wjc.v4.i12.312
Abstract: Circulating bone-marrow-derived cells, named endothelial progenitor cells (EPCs), are capable of maintaining, generating, and replacing terminally differentiated cells within their own specific tissue as a consequence of physiological cell turnover or tissue damage due to injury. Endothelium maintenance and restoration of normal endothelial cell function is guaranteed by a complex physiological procedure in which EPCs play a significant role. Decreased number of peripheral blood EPCs has been associated with endothelial dysfunction and high cardiovascular risk. In this review, we initially report current knowledge with regard to the role of EPCs in healthy subjects and the clinical value of EPCs in different disease populations such as arterial hypertension, obstructive sleep-apnea syndrome, obesity, diabetes mellitus, peripheral arterial disease, coronary artery disease, pulmonary hypertension, and heart failure. Recent studies have introduced the novel concept that physical activity, either performed as a single exercise session or performed as part of an exercise training program, results in a significant increase of circulating EPCs. In the second part of this review we provide preliminary evidence from recent studies investigating the effects of acute and long-term exercise in healthy subjects and athletes as well as in disease populations.
Quantification of Circulating Endothelial Progenitor Cells Using the Modified ISHAGE Protocol  [PDF]
Caroline Schmidt-Lucke,Stephan Fichtlscherer,Alexandra Aicher,Carsten Tsch?pe,Heinz-Peter Schultheiss,Andreas M. Zeiher,Stefanie Dimmeler
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013790
Abstract: Circulating endothelial progenitor cells (EPC), involved in endothelial regeneration, neovascularisation, and determination of prognosis in cardiovascular disease can be characterised with functional assays or using immunofluorescence and flow cytometry. Combinations of markers, including CD34+KDR+ or CD133+KDR+, are used. This approach, however may not consider all characteristics of EPC. The lack of a standardised protocol with regards to reagents and gating strategies may account for the widespread inter-laboratory variations in quantification of EPC. We, therefore developed a novel protocol adapted from the standardised so-called ISHAGE protocol for enumeration of haematopoietic stem cells to enable comparison of clinical and laboratory data.
The Relationship between Endothelial Progenitor Cell Populations and Epicardial and Microvascular Coronary Disease—A Cellular, Angiographic and Physiologic Study  [PDF]
Kim H. Chan, Philippa J. L. Simpson, Andy S. Yong, Louise L. Dunn, Chirapan Chawantanpipat, Chijen Hsu, Young Yu, Anthony C. Keech, David S. Celermajer, Martin K. C. Ng
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093980
Abstract: Background Endothelial progenitor cells (EPCs) are implicated in protection against vascular disease. However, studies using angiography alone have reported conflicting results when relating EPCs to epicardial coronary artery disease (CAD) severity. Moreover, the relationship between different EPC types and the coronary microcirculation is unknown. We therefore investigated the relationship between EPC populations and coronary epicardial and microvascular disease. Methods Thirty-three patients with a spectrum of isolated left anterior descending artery disease were studied. The coronary epicardial and microcirculation were physiologically interrogated by measurement of fractional flow reserve (FFR), index of microvascular resistance (IMR) and coronary flow reserve (CFR). Two distinct EPC populations (early EPC and late outgrowth endothelial cells [OECs]) were isolated from these patients and studied ex vivo. Results There was a significant inverse relationship between circulating OEC levels and epicardial CAD severity, as assessed by FFR and angiography (r = 0.371, p = 0.04; r = -0.358, p = 0.04; respectively). More severe epicardial CAD was associated with impaired OEC migration and tubulogenesis (r = 0.59, p = 0.005; r = 0.589, p = 0.004; respectively). Patients with significant epicardial CAD (FFR<0.75) had lower OEC levels and function compared to those without hemodynamically significant stenoses (p<0.05). In contrast, no such relationship was seen for early EPC number and function, nor was there a relationship between IMR and EPCs. There was a significant relationship between CFR and OEC function. Conclusions EPC populations differ in regards to their associations with CAD severity. The number and function of OECs, but not early EPCs, correlated significantly with epicardial CAD severity. There was no relationship between EPCs and severity of coronary microvascular disease.
Relation between the frequency of CD34+ bone marrow derived circulating progenitor cells and the number of diseased coronary arteries in patients with myocardial ischemia and diabetes
Ilkay Bozdag-Turan, R Goekmen Turan, C Hakan Turan, Sophie Ludovicy, Ibrahim Akin, Stephan Kische, Nicole S Arsoy, Henrik Schneider, Jasmin Ortak, Tim Rehders, Tina Hermann, Liliya Paranskaya, Peter Kohlschein, Manuela Bastian, A Tulga Ulus, Kurtulus Sahin, Hueseyin Ince, Christoph A Nienaber
Cardiovascular Diabetology , 2011, DOI: 10.1186/1475-2840-10-107
Abstract: The frequency of CD34/45+ BM-CPCs was measured by flow cytometry in 120 patients with coronary 1 vessel (IHD1, n = 40), coronary 2 vessel (IHD2, n = 40), coronary 3 vessel disease (IHD3, n = 40) and in a control group of healthy subjects (n = 40). There was no significant difference of the total number of cardiovascular risk factors between IHD groups, beside diabetes mellitus (DM), which was significantly higher in IHD3 group compared to IHD2 and IHD1 groups.The frequency of CD34/45+ BM-CPCs was significantly reduced in patients with IHD compared to the control group (CD34/45+; p < 0.001). The frequency of BM-CPCs was impaired in patients with IHD3 compared to IHD1 (CD34/45+; p < 0.001) and to IHD2 (CD34/45+; p = 0.001). But there was no significant difference in frequency of BM-CPCs between the patients with IHD2 and IHD1 (CD34/45+; p = 0.28). In a subgroup we observed a significant negative correlation between levels of hemoglobin AIc (HbAIc) and the frequency of BM-CPCs (CD34/45+; p < 0.001, r = -0.8).The frequency of CD34/45+ BM-CPCs in PB is impaired in patients with IHD. This impairment may augment with an increased number of diseased coronary arteries. Moreover, the frequency of CD34/45+ BM-CPCs in ischemic tissue is further impaired by diabetes in patients with IHD.Circulating progenitor cells are primitive bone marrow (BM) cells that have the capacity to proliferate, migrate and differentiate into various mature cell types [1,2]. These bone marrow-derived circulating progenitor cells (BM-CPCs) express unique surface markers, such as CD34+ and the early hematopoietic cell marker CD133+ (AC133+). During ischaemia, populations of BM-CPCs are mobilized and recruited to ischaemic areas, accelerating the neovascularization process [3]. Previous studies demonstrate that cardiovascular risk factors (CVRFs) for coronary artery disease correlate with a reduced number and functional activity of circulating endothelial progenitor cells [4]. Moreover, diabetic patients
Endothelial progenitor cells (CD34+KDR+) and monocytes may provide the development of good coronary collaterals despite the vascular risk factors and extensive atherosclerosis  [cached]
Sinan Altan Kocaman,Mehmet R?dvan Yal??n,Münci Ya?c?,Asife ?ahinarslan
Anadolu Kardiyoloji Dergisi , 2011,
Abstract: Objective: Endothelial progenitor cells (EPC) have a regenerative role in the vascular system. In this study, we aimed to evaluate simultaneously the effects of EPC and inflammatory cells on the presence and the extent of coronary artery disease (CAD) and the grade of coronary collateral growth in patients with clinical suspicion of CAD. Methods: This study has a cross-sectional and observational design. We enrolled 112 eligible patients who underwent coronary angiography consecutively (mean age: 59±9 years). The association of circulating inflammatory cells and EPC (defined by CD34+KDR+ in the lymphocyte and monocyte gate) with the presence, severity and extent of CAD and the degree of collateral growth were investigated. Logistic regression analysis was used to define the predictors of collateral flow.Results: Of 112 patients 30 had normal coronary arteries (NCA, 27%, 55±9 years) and 82 had CAD (73%, 61±8 years). Among the patients with CAD, the percent degree of luminal stenosis was <50% in 12 patients; 50-90% in 35 patients; and ≥90% in the other 35 patients. Circulating inflammatory cells were higher (leukocytes, 7150±1599 vs 8163±1588mm-3, p=0.001; neutrophils, 4239±1280 vs 4827±1273mm-3, p=0.021; monocytes, 512±111 vs 636±192mm-3, p=0.001) and EPCs were lower (0.27±0.15% vs 0.17±0.14%, p<0.001; 21±15 vs 13±12mm-3, p=0.004) in CAD group than NCA group. When we investigated the collateral growth in patients having ≥90% stenosis in at least one major coronary artery, we found that the patients with good collateral growth had significantly higher EPC (0.22±0.17% vs 0.10±0.05%, p=0.009; 18±15 vs 7±3mm-3, p=0.003) in comparison to patients with poor collateral growth. Presence of EPC was associated with reduced risk for coronary artery disease (OR: 0.934, 95%CI: 0.883-0.998, p=0.018) and was an independent predictor for good collateral growth (OR: 1.295, 95%CI: 1.039-1.615, p=0.022). A sum of CD34+KDR-, CD34+KDR+ and CD34-KDR+ cells (192±98mm-3), and a CD34-KDR- cell subpopulation within monocyte gate (514±173mm-3) reached to highest counts in good collateral group among all study population.Conclusion: Endothelial progenitor cells can be mobilized from bone marrow to induce the coronary collateral growth in case of myocardial ischemia even in presence of the vascular risk factors and extensive atherosclerosis. This finding may be supportive to investigate the molecules, which can specifically mobilize EPC without inflammatory cells.
Quantity and clinical relevance of circulating endothelial progenitor cells in human ovarian cancer
Yajuan Su, Lei Zheng, Qian Wang, Weiqi Li, Zhen Cai, Shilong Xiong, Jie Bao
Journal of Experimental & Clinical Cancer Research , 2010, DOI: 10.1186/1756-9966-29-27
Abstract: The number of circulating EPCs in the peripheral blood in 25 healthy volunteers and 42 patients with ovarian cancer was determined by flow cytometry. EPCs were defined by co-expression of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2). In addition, we determined CD34 and VEGFR2 mRNA levels by real-time reverse transcription-polymerase chain reaction. Plasma levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were determined by enzyme-linked immunosorbent assay.Circulating levels of EPCs were significantly increased in ovarian cancer patients, correlating with tumor stage and residual tumor size. Higher levels of EPCs were detected in patients with stage III and IV ovarian cancer than in patients with stage I and II disease. After excision of the tumor, EPCs levels rapidly declined. Residual tumor size greater than 2 cm was associated with significantly higher levels of EPCs. In addition, high circulating EPCs correlated with poor overall survival. Pretreatment CD34 mRNA levels were not significantly increased in ovarian cancer patients compared with healthy controls; however, VEGFR2 expression was increased, and plasma levels of VEGF and MMP-9 were also elevated.Our results demonstrate the clinical relevance of circulating EPCs in ovarian cancer. EPCs may be a potential biomarker to monitor ovarian cancer progression and angiogenesis and treatment response.Ovarian cancer is one of the most aggressive gynecological malignancies, and its high mortality is most often a direct result of delayed diagnosis. Only 25% of ovarian cancers are diagnosed while the malignancy is still confined to the ovary, and the cure rate in these patients can reach 90%. The remaining 75% of ovarian tumors have spread beyond the ovary by the time of diagnosis, and the cure rate for these patients is lower than 20% [1].With the advent of molecular-targeted therapies, treatment for ovarian cancer is now moving beyond conventional chemother
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