Endothelial Progenitor Cells are Mobilized After Cardiac Surgery

doi:10.1016/j.athoracsur.2006.09.087

The Annals of Thoracic Surgery

Volume 83, Issue 2, February 2007, Pages 598-605

https://doi.org/10.1016/j.athoracsur.2006.09.087 Get rights and content

Background

There is evidence that endothelial progenitor cells (EPCs) are mobilized into the circulation after coronary artery bypass grafting (CABG) with cardiopulmonary bypass. However, there is little known about EPC mobilization after off-pump CABG or valve surgery. We aimed to establish the response of EPCs to various forms of cardiac surgery and examine the role of well-known mobilizing cytokines on EPC levels.

Methods

One hundred and ten patients were studied: 54 elective CABG (30 on-pump, 24 off-pump); 23 urgent CABG; and 33 non-CABG. The EPC functional status was assessed using the colony forming unit assay (EPC-CFU) and plasma levels of granulocyte colony-stimulating factor (G-CSF), stromal cell-derived factor 1-α, matrix metalloproteinase, and vascular endothelial growth factor were assessed by enzyme-linked immunosorbent assay. Samples were taken preoperatively and on days 1 and 5 after surgery.

Results

Patients requiring urgent CABG and non-CABG patients had significantly higher numbers of EPC-CFU prior to surgery than elective CABG patients. All elective patients showed a significant increase in postoperative EPC-CFU levels: on-pump CABG 10.4 ± 3.8 to 53.9 ± 11.9, p = 0.001; off-pump CABG 9.5 ± 3.5 to 65.7 ± 17.3, p = 0.006; non-CABG 23.5 ± 6.8 to 84.6 ± 27.2, p = 0.05. The postoperative EPC rise in elective patients correlated with plasma G-CSF levels (r = 0.387, p < 0.01). Urgent patients demonstrated a significant increase in G-CSF levels but this was not associated with an increase in EPC-CFU level.

Conclusions

Patients undergoing elective cardiac surgery demonstrated an increase in EPC-CFU postoperatively, which correlated with increased plasma G-CSF level. Urgent patients did not have an increase in EPC-CFU despite a plasma G-CSF rise. Endogenously mobilized EPCs present a potential therapeutic target.

Section snippets

Patient Population and Sample Collection

This study was approved by the local ethical committee of St George’s Hospital Medical School and signed informed consent was obtained from all participating patients. One hundred ten consecutive patients were included in the study, all operated on by a single surgeon between January and December 2005. Elective and urgent patients were recruited and analyzed as separate subgroups.

Urgent patients were defined as patients referred for CABG as inpatients that had suffered a troponin positive event

Study Population

Table 1 describes the demographic and operative characteristics of the study population. The non-CABG group comprised patients undergoing aortic valve replacements, 21; atrial septal defect closures, 2; and mitral valve repair, 3; or replacements, 7. There were no statistically significant differences between elective CABG patients in terms of euroSCORE, preoperative creatinine, and body mass index. However, off-pump patients were younger, had more cardiovascular risk factors, and had fewer

Comment

The aim of this study was to characterize cytokine and EPC response not only to elective CABG surgery with CPB but also off-pump CABG, valve surgery, and urgent CABG.

Our preoperative results agree with previous studies suggesting patients with coronary artery disease have reduced EPC function and that this correlates with the number of risk factors for cardiovascular disease [6, 7]. Specifically, EPC-CFU numbers in patients with low risk for cardiovascular disease or healthy volunteers were

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We have shown a mild decline in CPCs with age that is accelerated in those aging with multiple risk factors or CVD [27]. Similarly, in patients with transient ischemia or infarction, there is mobilization of CPCs [50–55]. High-risk subjects within our cohort, particularly those who were older, female, diabetic and with greater severity of CAD and PAD had fewer CPCs than participants without these risk factors.
Low quantities of circulating progenitor cells (CPCs), specifically CD34+ populations, reflect impairment of intrinsic regenerative capacity. This study investigates the relationship between subsets of CPCs and adverse outcomes.
1366 individuals undergoing angiography for evaluation of coronary artery disease (CAD) were enrolled into the Emory Cardiovascular Biobank. Flow cytometry identified CPCs as CD45med blood mononuclear cells expressing the CD34 epitope, with further enumeration of hematopoietic CPCs as CD133+/CXCR4+ cells and endothelial CPCs as vascular endothelial growth factor receptor-2 (VEGFR2+) cells. Adjusted Cox or Fine and Gray's sub-distribution hazard regression models analyzed the relationship between CPCs and 1) all-cause death and 2) a composite of cardiovascular death and non-fatal myocardial infarction (MI).
Over a median 3.1-year follow-up period (IQR 1.3–4.9), there were 221 (16.6%) all-cause deaths and 172 (12.9%) cardiovascular deaths/MIs. Hematopoietic CPCs were highly correlated, and the CD34+/CXCR4+ subset was the best independent predictor. Lower counts (≤median) of CD34+/CXCR4+ and CD34+/VEGFR2+ cells independently predicted all-cause mortality (HR 1.46 [95% CI 1.06–2.01], p = 0.02 and 1.59 [95% CI 1.15–2.18], p = 0.004) and cardiovascular death/MI (HR 1.50 [95% CI 1.04–2.17], p = 0.03 and 1.47 [95% CI 1.01–2.03], p = 0.04). A combination of low CD34+/CXCR4+ and CD34+/VEGFR2+ CPCs predicted all-cause death (HR 2.1, 95% CI 1.4–3.0; p = 0.0002) and cardiovascular death/MI (HR 2.0, 95% CI 1.3–3.2; p = 0.002) compared to those with both lineages above the cut-offs.
Lower levels of hematopoietic and endothelial CPCs indicate diminished endogenous regenerative capacity and independently correlate with greater mortality and cardiovascular risk in patients with CAD.
VEGF attenuates lung injury by inducing homing of CD133 <sup>+</sup> progenitors via VEGFR1
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Some work has reported that VEGF promotes vascular permeability and results in edema, aggravating lung injury [17]. On the other hand, studies have also shown that VEGF promotes repair of endothelial and epithelial barriers, and inhibits neutrophil aggregation [18,19]. Here we analyzed whether and how VEGF may catalyze progenitor homing to damaged lung tissue using a mouse model of ECC-induced lung inflammation [20].
Although vascular endothelial growth factor (VEGF) promotes vascular permeability and results in edema, studies have suggested it may protect the lung from inflammatory injury via poorly understood mechanisms. Using a mouse model of extracorporeal circulation (ECC), we found that levels of intravenous VEGF increased in lung tissue and inhibited inflammation, thereby attenuating lung injury. These effects could be obtained by intravenous injection or inhalation of VEGF, and they were abolished by treatment with anti-VEGF antibody. Detailed analyses using immunofluorescence and flow cytometry showed that VEGF increased the homing of CD133⁺ VEGFR1⁺ progenitors to lung tissue, and this homing could be mimicked in a dose-dependent manner by treatment with VEGF receptor 1 (VEGFR1) agonist and blocked by treatment with anti-VEGFR1 antibody. Interestingly, we found that exposing pulmonary monocytes in vitro to VEGF did not inhibit ECC-induced inflammation. Our results suggest that VEGF enters lung tissues from the circulation and that it attenuates lung injury not by directly inhibiting release of pro-inflammatory factors but by binding to VEGFR1 to recruit CD133⁺ progenitors. These progenitors then inhibit local inflammation.
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Ischemia stimulates a reparative response resulting in mobilization of circulating progenitor cells (CPCs). We hypothesized that women with chronic myocardial ischemia from coronary microvascular disease (CMD) will mobilize CPCs.
In 123 women with ischemic symptoms and signs but no obstructive coronary artery disease (CAD) enrolled in the Women's Ischemia Syndrome Evaluation – Coronary Vascular Dysfunction Study (WISE-CVD), we measured coronary flow reserve (CFR) in response to intracoronary adenosine. Peripheral blood CPCs were measured using flow cytometry for expression of CD34, CD133, CXCR4, and VEGFR2.
Subjects were 53 ± 11 years, BMI 30 ± 8; 44% hypertensive, 11% diabetic, 23% hyperlipidemic and 7% smokers. Lower CFR correlated inversely with higher levels of hematopoietic-enriched CD34+ (r = −0.23, p = 0.011), CD34+/CD133+ (r = −0.24, p = 0.008), and CD34+/CXCR4+ (r = −0.19, p = 0.036) cells. In multivariable regression analyses, after adjusting for traditional cardiovascular risk factors, lower CFR remained significantly associated with elevated levels of CD34+ (β −0.18, p = 0.042), CD34+/CD133+ (β −0.24, p = 0.036), and CD34+/CXCR4+ (β −0.22, p = 0.050) cells. We found no association between CFR and CD34+/VEGFR2+ cells.
In women with non-obstructive CAD, impaired CFR is associated with higher levels of CPCs, suggesting that chronic myocardial ischemia from CMD stimulates CPC mobilization. The functional significance of elevated CPCs in these subjects requires further investigation as a potential biomarker and treatment target.
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Peripheral vascular disease is a highly prevalent disorder, but more importantly is associated with a high degree of morbidity and a high risk or mortality. Treatment options for this disorder are limited and novel approaches are severely needed. Cell therapy offers a novel approach to improving blood supply via vascular- and angio-genesis. Here we review the potential of mesenchymal stem cells for the treatment of this highly limiting and morbid disease.
Endothelial progenitor cells-potential new avenues to improve neoangiogenesis and reendothelialization
2013, International Review of Cell and Molecular Biology
The term endothelial progenitor cell (EPC) was established more than 10 years ago and is used to refer to a group of circulating cells that display endothelial lineage qualities and are able to home to areas of ischemia or vascular injury and to facilitate the repair of damaged blood vessels or develop new vessels as needed. This chapter reviews the current lineage relationships among all the cells called EPC and will clear the terminology used in EPC research. Furthermore, an overview of the clinical and in vitro research, as well as cytokine and drug interactions and potential EPC applications, is given.
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This study was designed to determine the levels of early endothelial progenitor cells (EPCs), apelin, vascular endothelial growth factor (VEGF) and stromal cell-derived growth factor-1 (SDF-1) after acute myocardial infarction (AMI), and to investigate the relationships between these cytokines and early EPCs. Early EPCs, defined as CD133⁺, KDR⁺, and CD34⁺ cells, were quantified by flow cytometry. The levels of early EPCs and those cytokines in AMI patients were significantly different from those with coronary artery disease or controls (P < 0.05). Plasma apelin levels were inversely correlated with Gensini score and early EPCs (both P < 0.01). Early EPCs, VEGF and SDF-1 showed different patterns of changes in AMI patients during the first 24 h. The trend in the change of early EPCs was proportionally correlated with that of VEGF (P < 0.05). AMI patients exhibited increased early EPCs with remarkably decreased apelin levels and enhanced VEGF levels.

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Original articleCardiovascularEndothelial Progenitor Cells are Mobilized After Cardiac Surgery

Background

Methods

Results

Conclusions

Section snippets

Patient Population and Sample Collection

Study Population

Comment

J Am Coll Cardiol

Lancet

J Am Coll Cardiol

J Thorac Cardiovasc Surg

Int J Cardiol

Blood

J Thorac Cardiovasc Surg

Isolation of putative progenitor endothelial cells for angiogenesis

Science

Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization

Circ Res

Endothelial progenitor cells characterization and role in vascular biology

Circ Res

The impact of progenitor cells in atherosclerosis

Nat Clin Pract Cardiovasc Med

Progenitor cells in vascular disease

J Cell Mol Med

Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease

Circ Res

Circulating endothelial progenitor cells, vascular function, and cardiovascular risk

N Engl J Med

Circulating endothelial progenitor cells and cardiovascular outcomes

N Engl J Med

Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair

Circulation

Original article
Cardiovascular
Endothelial Progenitor Cells are Mobilized After Cardiac Surgery