Number and Function of Bone-Marrow Derived Angiogenic Cells and Coronary Flow Reserve in Women without Obstructive Coronary Artery Disease: A Substudy of the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) (original) (raw)
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Background: Endothelial progenitor cells (EPCs) are a diverse population of mononuclear cells derived from bone marrow that are mobilized in response to vascular injury, circulate in peripheral blood and contribute to vascular repair. We evaluated circulating EPCs in women with coronary microvascular dysfunction (CMD) compared to matched controls. Methods: Twenty-nine symptomatic women with no obstructive coronary atherosclerosis (<50% epicardial coronary ste-nosis), and diagnosed with CMD invasively, and eleven reference control women were included. EPCs were defined as cells either expressing cell surface markers CD34+/CD133+ or CD34+/VEGFR2+. Results: Mean and median levels of CD34+/CD133+ and CD34+/VEGFR2+ in the CMD group trended lower than the reference control group, although this was not statistically significant. There was a significant positive correlation between CD34+/CD133+ subsets and LDL levels which was not found with CD34+/VEGFR2+. Conclusions: These pilot data in women with CMD demonstrate no difference in EPCs between CMD women compared to reference control subjects. Our study combined with prior publications in similarly characterized and larger populations suggests that absolute EPC levels (BMDAC), but not EPCs alone, may be adequately sensitive for providing a complete depiction of endothelial injury or function in this population.
Circulating CD34+ cell subsets in patients with coronary endothelial dysfunction
Nature Clinical Practice Cardiovascular Medicine, 2008
Introduction-Circulating cells that express CD34 including hematopoietic progenitors and endothelial progenitor cells may have a role in the development and progression of atherosclerosis. Endothelial dysfunction is an early manifestation of atherosclerotic disease. The aim of this study was to evaluate the association between coronary endothelial dysfunction (CED) and circulating CD34+ subsets.
Circulation, 2004
Background-Cell therapy with bone marrow-derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow-derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclear. Methods and Results-BM-MNCs were isolated from bone marrow aspirates in 18 patients with ICMP (ejection fraction, 38Ϯ11%) and 8 healthy control subjects (controls). The number of hematopoietic stem/progenitor cells (CD34 ϩ / CD133 ϩ ), CD49d ϩ (VLA-4) cells, and CXCR4 ϩ cells did not differ between the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with ICMP was significantly lower compared with BM-MNCs from healthy controls 37.3Ϯ25.0 versus 113.8Ϯ70.4 granulocyte-macrophage colony-forming units; Pϭ0.009). Likewise, the migratory response to stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF-1, 46.3Ϯ26.2 versus 108.6Ϯ40.4 cells/microscopic field, PϽ0.001; VEGF, 34Ϯ24.2 versus 54.8Ϯ29.3 cells/ microscopic field, Pϭ0.027). To assess the in vivo relevance of these findings, we tested the functional activity of BM-MNCs to improve neovascularization in a hindlimb animal model using nude mice. Two weeks after ligation of the femoral artery and intravenous injection of 5ϫ10 5 BM-MNCs, laser Doppler-derived relative limb blood flow in mice treated with BM-MNCs from patients with ICMP was significantly lower compared with mice treated with BM-MNCs from healthy controls (0.45Ϯ0.14 versus 0.68Ϯ0.15; PϽ0.001). The in vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro assessment of SDF-1-induced migration (rϭ0.78; PϽ0.001) and colony-forming capacity (rϭ0.74; PϽ0.001). Conclusions-BM-MNCs isolated from patients with ICMP have a significantly reduced migratory and colony-forming activity in vitro and a reduced neovascularization capacity in vivo despite similar content of hematopoietic stem cells. This functional impairment of BM-MNCs from patients with ICMP may limit their therapeutic potential for clinical cell therapy. (Circulation. 2004;109:1615-1622.)
American Heart Journal, 2005
Background Coronary artery microvascular dysfunction is prevalent in women with chest pain in the absence of obstructive coronary artery disease (CAD) and is manifested by attenuated coronary flow reserve (CFR). Markers of inflammation and endothelial cell activation have been found to be elevated in patients with chest pain but without CAD. The relationship between inflammation, endothelial activation, and CFR is not known. Methods Ninety-four women with chest pain in the absence of obstructive angiographic CAD underwent catheterizationbased assessment of CFR and measurement of levels of inflammatory markers (n = 78) and endothelial cell activation in the NHLBI WISE study. Results Coronary flow reserve did not correlate with levels of C-reactive protein (high-sensitivity C-reactive protein) (r s = À0.07, P = .53), interleukin (IL)-6 (r s = À0.12, P = .31), IL-18 (r s = 0.14, P = .23), tumor necrosis factor a (r s = À0.09, P = .43), transforming growth factor h1 (r s = 0.02, P = .84), and soluble intracellular adhesion molecule-1 (r s = 0.04, P = .68). Median levels of markers of inflammation and endothelial cell activation did not differ between the 57 women with abnormal CFR (b2.5) and the 37 women with normal coronary microvascular function (high-sensitivity C-reactive protein 0.32 vs 0.25 mg/dL, P = .80; IL-6 2.89 vs 2.39 pg/mL, P = .63; IL-18 218 vs 227 pg/mL, P = .59; tumor necrosis factor a 2.7 vs 2.4 pg/mL, P = .43; transforming growth factor h1 9928 vs 12 436 pg/mL, P = .76; soluble intracellular adhesion molecule-1 286 vs 287 pg/mL, P = .95). Multivariable models demonstrated no evidence of associations between markers of inflammation and of endothelial cell activation and CFR.
International Journal of Cardiology, 2007
Background: Angiogenic growth factors and stem cell therapies have demonstrated varying results in patients with chronic coronary artery disease. A reason could be that these mechanisms are already up-regulated due to reduced blood supply to the myocardium. The objective of this study was to examine if plasma concentrations of circulating stem cells and angiogenic cytokines in patients with severe stable chronic coronary artery disease were correlated to the clinical severity of the disease. Methods: Fifty-four patients with severe coronary artery disease and reversible ischemia at stress myocardial perfusion scintigraphy were prospectively included. The severity of the disease was quantified by an exercise tolerance test, Canadian Cardiovascular Society angina classification, and Seattle Angina Pectoris Questionnaire. Fifteen persons without coronary artery disease served as control subjects. Results: Plasma concentration of VEGF-A, FGF-2, SDF-1, and circulating CD34+ and CD34−/CD45−cells were similar in the two groups, but early stem cell markers (CD105, CD73, CD166) and endothelial markers (CD31, CD144, VEGFR2) were significantly different between patients and control subjects (p b 0.005 − 0.001). Diabetic patients had higher concentration of SDF-1 (2528 vs. 2150 pg/ml, p = 0.004). We found significant correlations between both VEGF-A, FGF-2, and CD34+ to disease severity, including degree of reversible ischemia, angina stability score, and exertional dyspnoea. Conclusions: Plasma concentrations of circulating stem cells and angiogenic cytokines have large inter-individual variations, which probably exclude them from being useful as indicators of myocardial ischemic burden.
Cardiology Journal
Background: Circulating endothelial cells (CEC) may be used to find new strategies for the early diagnosis of cardiovascular diseases. The major objective of the project is to broaden knowledge of CEC biology by determining their phenotypic characteristics. The additional aim is to clarify whether on the basis of these information it is possible to identify the origin of CEC release (from various cardiovascular compartments). Methods: Circulating endothelial cells were collected from arterial blood prior to angiography, as well as from arterial and venous blood obtained after angiography/coronary angioplasty, from 18 patients with non-ST-segment elevation myocardial infarction (NSTEMI). CECs were quantified by flow cytometry and defined as Syto16 (dye) + , CD45dim/neg, CD31 + and CD146 +. The additional CD36 + was establish as a marker of endothelial cells released from small vessels of the microcirculation. Results: The total number of CECs increased significantly after the percutaneous transluminal coronary angioplasty (PTCA) in the arterial system. Number of CECs isolated at similar time points (after invasive procedure) did not differ significantly between arteries and veins, but the number of CD36 + CECs after coronary angioplasty was significantly higher in the venous system, than in the arterial system. Conclusions: The number of CD36 + in artery samples obtained after coronary angioplasty (PTCA) had tendency to be decreased (in comparison to the sample obtained before angiography). It was major difference between those who had PTCA performed vs. those who had not.
Anadolu Kardiyoloji Dergisi/The Anatolian Journal of Cardiology, 2011
Endothelial progenitor cells (CD34 + KDR + ) and monocytes may provide the development of good coronary collaterals despite the vascular risk factors and extensive atherosclerosis Endotelyal progenitor hücreler (CD34 + KDR + ) ve monositler vasküler risk faktörleri ve yaygın ateroskleroza rağmen iyi koroner kollateral gelişimini sağlayabilirler Original Investigation Özgün Araşt›rma ÖZET Amaç: Endoteliyal progenitör hücreler (EPH) vasküler sistemde onarıcı bir role sahiptir. Bu çalışmanın amacı kandaki enflamatuvar hücreler ve EPH'lerin, kardiyovasküler risk faktörleri ile birlikte ateroskleroz varlığı ve yaygınlığı ile ilişkisinin araştırılması ve koroner kollateral gelişim üzerine olan etkilerinin incelenmesidir. Yöntemler: Bu çalışma enine-kesitli ve gözlemsel bir modele sahiptir. Çalışmaya koroner anjiyografisi yapılan ardışık 112 hasta alındı (ortalama yaş: 59±9 yıl). Periferik kanda dolaşan enflamasyon hücreleri ve EPH (lenfositer ve monositer alanda CD34 + KDR + olarak tanımlanan) hücrelerin ateroskleroz varlığı, ciddiyeti, yaygınlığı ve kollateral gelişimi ile olan ilişkileri araştırıldı. Kollateral akım öngördürücülerinin belirlenmesinde lojistik regresyon analizi kullanıldı.
Cytotherapy, 2010
Background aims-The distinction between hematopoietic stem cells (HSC) and endothelial progenitor cells (EPC) is poorly defined. Co-expression of CD34 antigen with vascular endothelial growth factor (VEGF) receptor (VEGFR2) is currently used to define EPC (1). Methods-We evaluated the phenotypic and genomic characteristics of peripheral blood-derived CD34 + cells in 22 granulocyte-colony-stimulating factor (G-CSF)-mobilized patients with severe coronary artery disease and assessed the influence of cell selection and storage on CD34 + cell characteristics. Results-The median CD34 + cell contents in the products before and after enrichment with the Isolex 300i Magnetic Cell Selection System were 0.2% and 82.5%, respectively. Cell-cycle analysis showed that 80% of CD34 + cells were in G0 stage; 70% of the isolated CD34 + cells coexpressed CD133, a marker for more immature progenitors. However, less than 5% of the isolated CD34 + cells co-expressed the notch receptor Jagged-1 (CD339) and only 2% of the isolated CD34 + population were positive for VEGFR2 (CD309). Molecular assessment of the isolated CD34 + cells demonstrated extremely low expression of VEGFR2 and endothelial nitric oxide synthase (eNOS) and high expression of VEGF-A. Overnight storage at 4°C did not significantly affect CD34 + cell counts and viability. Storage in liquid nitrogen for 7 weeks did not affect the percentage of CD34 + cells but was associated with a 26% drop in cell viability. Conclusions-We have demonstrated that the majority of isolated CD34 + cells consist of immature and quiescent cells that lack prototypic markers of EPC. High VEGF-A gene expression might be one of the mechanisms for CD34 + cell-induced angiogenesis.
Circulating Apoptotic Progenitor Cells: A Novel Biomarker in Patients With Acute Coronary Syndromes
Arteriosclerosis, Thrombosis, and Vascular Biology, 2007
Background-Progenitor CD34 cells are capable of differentiating into endothelial cells and play a role in neoangiogenesis. Circulating CD34 ϩ cells and endothelial progenitor cells are increased in acute coronary syndrome (ACS) patients possibly because of peripheral mobilization. We tested the hypothesis that circulating apoptotic progenitors are detectable in healthy subjects and altered in ACS patients. Methods and Results-Peripheral blood mononuclear cells were isolated by Ficoll density gradient from 53 patients with ACS undergoing coronary angiography and 27 healthy subjects. Apoptosis in progenitor CD34 ϩ cells was assessed using the Annexin V-PE/7-AAD detection kit, and fluorescence-activated cell sorter analysis was performed with triple staining for CD34, annexin-V, and 7-AAD. The percentage of apoptotic CD34 ϩ progenitors was determined in the 2 subject groups and correlated with clinical characteristics. The percentage of apoptotic CD34 ϩ progenitor cells was significantly increased in patients with ACS as compared with healthy subjects and was associated with the extent of coronary stenosis by angiography. There was no significant correlation between apoptotic progenitor CD34 ϩ cells and the other parameters that we examined (age, smoking, hypertension, hyperlipidemia, diabetes mellitus, ejection fraction, creatinine levels, or taking any of the various medications, including beta blockers, thiazides, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium blockers, nitrates, or statins). Conclusion-We established for the first time to our knowledge an assay to detect circulating apoptotic progenitor cells using fluorescein isothiocyanate-anti-CD34 MAb, annexin V-PE, and 7-AAD and found that apoptotic CD34 ϩ cells are increased in ACS patients and in patients with more extensive coronary artery disease. This novel assay may shed new light on the factors governing the hemeostasis of progenitor CD34 ϩ cells. (Arterioscler Thromb Vasc Biol. 2007;27:e27-e31.