Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes
Nikos Werner, M.D., Sonja Kosiol, M.D., Tobias Schiegl, M.D., Patrick Ahlers, M.D., Katrin Walenta, M.D., Andreas Link, M.D., Michael Böhm, M.D., and Georg Nickenig, M.D.
Background Endothelial progenitor cells derived from bone marroware believed to support the integrity of the vascular endothelium.The number and function of endothelial progenitor cells correlateinversely with cardiovascular risk factors, but the prognosticvalue associated with circulating endothelial progenitor cellshas not been defined.
Methods The number of endothelial progenitor cells positivefor CD34 and kinase insert domain receptor (KDR) was determinedwith the use of flow cytometry in 519 patients with coronaryartery disease as confirmed on angiography. After 12 months,we evaluated the association between baseline levels of endothelialprogenitor cells and death from cardiovascular causes, the occurrenceof a first major cardiovascular event (myocardial infarction,hospitalization, revascularization, or death from cardiovascularcauses), revascularization, hospitalization, and death fromall causes.
Results A total of 43 participants died, 23 from cardiovascularcauses. A first major cardiovascular event occurred in 214 patients.The cumulative event-free survival rate increased stepwise acrossthree increasing baseline levels of endothelial progenitor cellsin an analysis of death from cardiovascular causes, a firstmajor cardiovascular event, revascularization, and hospitalization.After adjustment for age, sex, vascular risk factors, and otherrelevant variables, increased levels of endothelial progenitorcells were associated with a reduced risk of death from cardiovascularcauses (hazard ratio, 0.31; 95 percent confidence interval,0.16 to 0.63; P=0.001), a first major cardiovascular event (hazardratio, 0.74; 95 percent confidence interval, 0.62 to 0.89; P=0.002),revascularization (hazard ratio, 0.77; 95 percent confidenceinterval, 0.62 to 0.95; P=0.02), and hospitalization (hazardratio, 0.76; 95 percent confidence interval, 0.63 to 0.94; P=0.01).Endothelial progenitor-cell levels were not predictive of myocardialinfarction or of death from all causes.
Conclusions The level of circulating CD34+KDR+ endothelial progenitorcells predicts the occurrence of cardiovascular events and deathfrom cardiovascular causes and may help to identify patientsat increased cardiovascular risk.
Coronary artery disease results from a chronic inflammatorydisease of the vascular wall and leads to vessel occlusion andorgan damage.1 Despite intense efforts to determine the pathogenesisof atherosclerosis, this process remains poorly understood.Reports suggest that risk factors and a genetic predispositiontogether induce inflammatory processes that lead to cell damageand impair regeneration within the vessel wall.2,3 Since residentendothelial cells infrequently proliferate,4 it has been postulatedthat there are other sources of vascular replenishment in responseto continuous damage.5 Endothelial progenitor cells derivedfrom bone marrow circulate in the peripheral blood and havebeen implicated in neoangiogenesis after tissue ischemia hasoccurred.6,7,8,9 Endothelial progenitor cells are capable ofproliferating and differentiating into endothelial cells andare therefore ideal candidates for vascular regeneration.10,11Experiments in animals show that the systemic application ormobilization of stem cells and progenitor cells beneficiallyinfluences the repair of endothelial cells after injury andthe progression of atherosclerosis.12,13,14,15,16,17,18 In humans,the role of endothelial progenitor cells is less clear. Intracoronaryinjection of endothelial progenitor cells may improve left ventricularfunction after acute myocardial infarction.19,20,21 In addition,the accumulation of cardiovascular risk factors or an increasedoverall risk is associated with dysfunction and decreased numbersof endothelial progenitor cells.22,23
Although these data suggest that there is a close interplaybetween endothelial progenitor cells and cardiovascular riskfactors, the exact role of these cells in the pathogenesis ofcoronary artery disease remains to be determined. It is unknownwhether the number of endothelial progenitor cells relates tooutcomes in patients with coronary artery disease. In orderto test this hypothesis, we assessed the number of endothelialprogenitor cells in patients with coronary artery disease andprospectively analyzed cardiovascular outcomes during a follow-upperiod of 12 months.
Methods
Study Population
Between March 2003 and January 2004, 587 patients who consecutivelyunderwent coronary angiography were screened for inclusion inthe Endothelial Progenitor Cells in Coronary Artery Diseasestudy. Forty-nine patients without signs of coronary arterydisease on angiography and 19 patients with malignant, inflammatorydiseases or severe acute ischemia other than myocardial ischemiawere excluded from the study. Informed consent was obtainedfrom all patients, and the study protocol was approved by theethics committee of the University of Saarland. The investigatorsinitiated the study, had full access to and analyzed the data,and wrote the manuscript. All authors vouch for the data andanalysis.
Angiography
Cardiac catheterization was performed according to the guidelinesfor coronary angiography of the American College of Cardiologyand the American Heart Association.24 Biplane ventriculographywas performed in standard projections. The ejection fractionwas calculated by dividing the end-diastolic and end-systolicleft ventricular areas with the use of an automated computersystem (Digital Cardiac Imaging software, Philips). The extentof coronary artery disease was scored, by at least two independentinterventional cardiologists, as 0 (stenosis <50 percent),1 (stenosis of any main coronary artery 50 percent), 2 (stenosisof two main coronary arteries 50 percent), and 3 (stenosis ofthree main coronary arteries 50 percent).
Previous Events, Follow-up, and Causes of Death
The classification of previous events and follow-up data wasmade on the basis of medical records and personal interviews.Causes of death were determined by examination of hospital records,autopsy reports, and medical files of the patients' generalpractitioners. Deaths due to cardiovascular causes includedsudden deaths and deaths from acute myocardial infarction, coronaryartery disease, or congestive heart failure.
Preparation of Blood Samples
Arterial blood was drawn from the femoral artery and bufferedwith 20 ml of sodium citrate before cardiac catheterization.Mononuclear cells were isolated with the use of a Ficoll densitygradient (Biocoll, Biochrom) according to standard protocols.Additional blood samples were obtained for routine analyses.
Flow Cytometry
For fluorescence-activated cell-sorting analysis, mononuclearcells were resuspended in 100 µl of a fluorescence-activatedcell-sorting buffer containing phosphate-buffered saline, 0.1percent bovine albumin, and aprotinin (20 µl per milliliter).Immunofluorescent cell staining was performed with the use ofthe fluorescent conjugated antibody CD34–fluorescein isothiocyanate(FITC) (10 µl; Becton Dickinson), KDR (kinase insert domainreceptor), and CD133–phycoerythrin (PE) (10 µl;Miltenyi). For the identification of KDR+ cells, indirect immunolabelingwas performed with the use of a biotinylated goat mononuclearantibody against the extracellular domain of human KDR (R&DSystems). IgG2a–FITC–PE antibody (Becton Dickinson)served as a negative control. For staining of KDR, extensiveblocking was required with the use of human immunoglobulin (polyglobulin,10 percent; Bayer) and goat serum (Sigma-Aldrich). Cell fluorescencewas measured immediately after staining, and data were analyzedwith the use of CellQuest software (FACSCalibur, Becton Dickinson).Units of all measured components are absolute cell counts obtainedafter the measurement of 10,000 events in the lymphocyte gate.To assess the reproducibility of the measurements, two separateblood samples were obtained, on days 0 and 7, from 10 subjects.The intraclass correlation between the two probes was 0.94.Probes were measured at the same time of day, with identicalinstrument settings, by two investigators. For each patient,a corresponding negative control with IgG2a–FITC–PEantibody was obtained.
Colony-Forming Units of Endothelial Cells
In an endothelial basal medium (CellSystems) with supplements,1x107 mononuclear cells were seeded on human fibronectin–coatedplates (Sigma-Aldrich). After 48 hours, 1x106 nonadherent cellswere transferred into new fibronectin-coated wells to avoidcontamination with mature endothelial cells and nonprogenitorcells.22 After seven days in vitro, endothelial colony-formingunits in at least three wells were counted by two independentinvestigators. Colony-forming units of endothelial cells areexpressed as absolute numbers of colonies per well.
Statistical Analysis
The association between baseline levels of endothelial progenitorcells and the following prespecified end points was evaluatedafter 12 months: death from cardiovascular causes, the occurrenceof a first major cardiovascular event (acute myocardial infarction,hospitalization due to cardiovascular events, revascularization,or death from cardiovascular causes), the need for revascularization,hospitalization due to cardiovascular events, and death fromany cause. Levels of endothelial progenitor cells were analyzedas categorical variables after log transformation (on a base10 scale) to normalize distribution. In categorical analyses,we used prespecified thresholds corresponding to patients' endothelialprogenitor-cell counts (low, medium, and high) at the time ofenrollment. Continuous variables were tested for normal distributionwith the use of the Kolmogorov–Smirnov test. Means betweentwo categories were compared with the use of a two-tailed, unpairedStudent's t-test. The one-way analysis-of-variance test wasused for comparisons of categorical variables. For post hocanalysis, the Bonferroni correction was applied. A multivariateproportional-hazards regression analysis was performed to determinethe association between endothelial progenitor-cell counts andeach outcome. Analyses were adjusted for age; sex; smoking status;the presence of hypertension, diabetes, or hyperlipidemia; leftventricular ejection fraction; percutanous coronary intervention;a diagnosis of an acute coronary syndrome at the time of enrollment;the severity of coronary artery disease; and treatment withangiotensin-converting–enzyme (ACE) inhibitors, beta-blockers,3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins),and platelet inhibitors. The hazard ratio represents the predictedchange in the hazard for a unit increase in the predictor (e.g.,an increase from low to medium or from medium to high in thenumber of endothelial progenitor cells). Survival was determinedwith the use of the Kaplan–Meier method and the Cox regressionanalysis. The log-rank test was used to determine statisticaldifferences in terms of survival. Statistical significance wasassumed when a null hypothesis could be rejected at P<0.05.Statistical analysis was performed with the use of SPSS software,version 11.5, for Windows.
All data analyses and event classifications were performed byinvestigators blinded to the endothelial progenitor-cell statusof the patients.
Results
Baseline Characteristics
A total of 519 patients with coronary artery disease as diagnosedon angiography were enrolled. Of these, 12 patients (2.3 percent)were lost to follow-up. The mean (±SD) age of the remaining507 patients was 66.6±10.8 years (range, 30 to 87). Detailedcharacteristics of the patients are listed in Table 1.
Table 1. Baseline Characteristics of the Patients.
Endothelial Progenitor-Cell Counts and Baseline Clinical Variables
The number of endothelial progenitor cells ranged from 12 to1039 CD34+KDR+ cells, with a mean of 86.3±71.9. Afterlogarithmic transformation (base 10), endothelial progenitor-cellcounts were categorized into three groups according to the cellcount at the time of enrollment (Table 1). Group 1 representspatients with log numbers of endothelial progenitor cells of1.71 or less, group 2 patients with log numbers between 1.72and 1.96, and group 3 patients with log numbers between 1.97and 3.02.
In univariate analyses, smoking, diuretic therapy, and statintherapy were associated with high baseline levels of CD34+KDR+endothelial progenitor cells (P=0.02, P=0.007, and P=0.05, respectively),whereas low levels were associated with a high left ventricularejection fraction and treatment with angiotensin-receptor blockers(P=0.008 and P=0.03, respectively) (Table 1). In addition toCD34+KDR+ endothelial progenitor cells, we measured CD133+ cells,which resemble a subfraction of immature endothelial progenitorcells. Therapy with statins and ACE inhibitors was associatedwith high baseline levels of CD133+ cells (P=0.01 and P=0.03,respectively), whereas low levels were associated with increasedlow-density lipoprotein (LDL) cholesterol levels, advanced age,and high systolic blood pressure (P=0.01, P<0.001, and P=0.008,respectively).
In order to determine the functional capacity of circulatingendothelial progenitor cells, we measured the number of colony-formingunits of endothelial cells in a subgroup of 203 patients. Therapywith statins and ACE inhibitors was associated with increasednumbers of colony-forming units of endothelial cells (P=0.001and P=0.03, respectively), whereas reduced numbers of colony-formingunits of endothelial cells were associated with increased LDLcholesterol levels, advanced age, diabetes, smoking, and a familyhistory of premature coronary artery disease (P=0.01, P=0.002,P=0.01, P=0.002, and P=0.004, respectively).
Incidence of Death and Cardiovascular Events
Table 2 shows the incidence of outcomes during the 12 monthsof follow-up. A total of 43 patients (8.5 percent) died, 23from cardiovascular causes (4.5 percent); other causes includedsepsis (9 patients), chronic renal insufficiency (3), pneumonia(4), and cerebral bleeding (3). In one patient, the cause ofdeath remained unclassified. Thirty-four patients (6.7 percent)had acute myocardial infarction, 163 (32.1 percent) requiredrevascularization, and 186 (36.7 percent) were admitted to ahospital owing to cardiovascular events.
Table 2. Number of Events at 12 Months of Follow-up.
In univariate analyses, the incidence of death from cardiovascularcauses was significantly influenced by advanced age (hazardratio, 1.07; 95 percent confidence interval, 1.01 to 1.12; P=0.01),low left ventricular ejection fraction (hazard ratio, 0.96;95 percent confidence interval, 0.94 to 0.99; P=0.004), concomitanttreatment with beta-blockers (hazard ratio, 3.38; 95 percentconfidence interval, 1.01 to 11.43; P=0.05), and a low levelof circulating endothelial progenitor cells (hazard ratio, 0.45;95 percent confidence interval, 0.25 to 0.81; P=0.007).
A multivariate regression analysis identified advanced age,low left ventricular ejection fraction, and a low level of circulatingendothelial progenitor cells as the only independent predictorsof death from cardiovascular causes. The occurrence of a firstmajor cardiovascular event was significantly influenced by agreater severity of coronary artery disease (hazard ratio, 1.52;95 percent confidence interval, 1.31 to 1.76; P<0.001), coronaryintervention (hazard ratio, 1.57; 95 percent confidence interval,1.20 to 2.06; P=0.001), a diagnosis of an acute coronary syndrome(hazard ratio, 1.51; 95 percent confidence interval, 1.13 to2.02; P=0.006) or subacute myocardial infarction (hazard ratio,1.57; 95 percent confidence interval, 1.03 to 2.40; P=0.04)at the time of enrollment, and a low level of circulating endothelialprogenitor cells (hazard ratio, 0.72; 95 percent confidenceinterval, 0.61 to 0.86; P<0.001). In a multivariate analysis,the degree of coronary artery disease and the level of circulatingendothelial progenitor cells were mutually independent predictorsof the occurrence of a first major cardiovascular event.
Endothelial Progenitor-Cell Levels and Clinical Outcomes
Cumulative event-free survival increased in a stepwise fashionacross increasing levels of baseline endothelial progenitorcells in analyses of death from cardiovascular causes (P=0.01)and a first major cardiovascular event (P<0.001) (Figure 1and Figure 2). Revascularization (P<0.001) and hospitalization(P=0.001) were significantly more frequent among patients withlower levels of endothelial progenitor cells than among thosewith higher levels.
Figure 1. Cumulative Event-free Survival in an Analysis of Death from Cardiovascular Causes at 12 Months, According to Levels of Circulating CD34+KDR+ Endothelial Progenitor Cells at the Time of Enrollment.
Figure 2. Cumulative Event-free Survival in Analysis of a First Major Cardiovascular Event (Myocardial Infarction, Hospitalization, Revascularization, or Cardiovascular Death) at 12 Months, According to Levels of Circulating CD34+KDR+ Endothelial Progenitor Cells at the Time of Enrollment.
Increasing levels of CD34+KDR+ endothelial progenitor cellswere associated with a decreased risk of death from cardiovascularcauses (Table 3). The risk of death from cardiovascular causeswas increased by a factor of more than three among patientswith low endothelial progenitor-cell levels, as compared withpatients with high levels. After adjustment for age, sex, cardiovascularrisk factors, concomitant drug therapy, the severity of coronaryartery disease, left ventricular ejection fraction, percutaneouscoronary intervention, and a diagnosis of acute coronary syndrome,the association between increasing levels of endothelial progenitorsand a decreased risk of death from cardiovascular causes remainedsignificant (P=0.001) (Table 3). Decreasing endothelial progenitor-celllevels were associated with the development of a first majorcardiovascular event. A multivariate analysis with adjustmentfor covariates confirmed a significant association between CD34+KDR+endothelial progenitor-cell levels and the occurrence of a firstmajor cardiovascular event (hazard ratio, 0.74; 95 percent confidenceinterval, 0.62 to 0.89; P=0.002) (Table 3). In multivariateanalyses, the rates of revascularization and hospitalizationdue to cardiovascular causes were significantly decreased amongpatients with high levels of circulating endothelial progenitorcells (hazard ratio for revascularization, 0.77; 95 percentconfidence interval, 0.62 to 0.95; P=0.02; and hazard ratiofor hospitalization, 0.76; 95 percent confidence interval, 0.63to 0.94; P=0.01). No significant association was detected betweenendothelial progenitor-cell levels and acute myocardial infarctionand death from any cause.
Table 3. Multivariate Analysis of the Association between Increasing Levels of CD34+KDR+ Endothelial Progenitor Cells and Outcomes.
Cumulative event-free survival increased in stepwise fashionwith increasing baseline CD133+ endothelial progenitor-celllevels in an analysis of death from cardiovascular causes (P=0.03by the log-rank test), a first major cardiovascular event (P=0.04),and hospitalization (P=0.04) (Figure 1 of the Supplementary Appendix,available with the full text of this article at www.nejm.org).In a multivariate analysis, the association between increasingCD133+ endothelial progenitor-cell levels and reduced risksof a first major cardiovascular event (hazard ratio, 0.81; 95percent confidence interval, 0.66 to 0.98; P=0.03) and hospitalization(hazard ratio, 0.75; 95 percent confidence interval, 0.61 to0.93; P=0.007) remained significant.
Cumulative event-free survival increased in stepwise fashionwith increasing baseline levels of colony-forming units of endothelialcells in an analysis of a first major cardiovascular event (P=0.03),revascularization (P=0.01), and hospitalization (P=0.01) (Figure2 of the Supplementary Appendix). A multivariate analysis confirmeda significant association between increasing numbers of colony-formingunits and decreased risks of a first major cardiovascular event(hazard ratio, 0.68; 95 percent confidence interval, 0.49 to0.96; P=0.03), revascularization (hazard ratio, 0.58; 95 percentconfidence interval, 0.38 to 0.88; P=0.01), and hospitalization(hazard ratio, 0.59; 95 percent confidence interval, 0.41 to0.85; P=0.004).
Discussion
Experimental and clinical studies suggest that there is an evolvingrole for endothelial progenitor cells in neoangiogenesis andrejuvenation of the endothelial monolayer.6,12,17 The presenceof immature circulating cells in the peripheral blood has beenadvocated as a marker of an organism's regenerative capacity,25and current trials of therapy aim to increase the number ofprogenitor cells at the site of tissue damage.19,20,21 Despitenumerous studies, the role of endothelial progenitor cells asa prognostic marker is unclear. Various serum markers have beenidentified that predict mortality and morbidity due to cardiovascularcauses.26,27,28,29,30 In contrast to the measurement of a singleserum marker for the prediction of risk, use of a cellular markerof risk, such as the level of endothelial progenitor cells,unifies the complex interactions of multiple negative factorsand may yield a better picture of in vivo mechanisms. In thisprospective study, we demonstrated that a single measurementof CD34+KDR+ endothelial progenitor cells is a useful tool topredict cardiovascular outcomes in patients with coronary arterydisease. During the observational period of 12 months, a significantlyhigher incidence of death from cardiovascular causes was observedin patients with low baseline levels of endothelial progenitorcells. The association between these levels and death from cardiovascularcauses was independent of the severity of coronary artery disease,a diagnosis of an acute coronary syndrome at the time of enrollment,cardiovascular risk factors, and drug therapy known to influencecardiovascular outcomes.
The occurrence of a first major cardiovascular event (acutemyocardial infarction, hospitalization, revascularization, ordeath from cardiovascular causes) was associated with reducedendothelial progenitor-cell levels. Analyses of the prespecifiedsingle end points revealed that hospitalization, the need forrevascularization, and to a lesser extent, the rate of deathfrom cardiovascular causes were the major factors for the predictionof end points.
Studies in animals suggest that enhancement of the number ofcirculating endothelial progenitor cells through exercise training,statin therapy, or estrogen therapy improves the replenishmentof the endothelial monolayer by endothelial progenitor cellsafter vascular injury and — due to enhanced restorationof the endothelial monolayer — diminishes neointima formation.14,16,31,32,33In humans, a small-scale study suggests that there is a higherincidence of restenosis in patients with reduced levels of circulatingendothelial progenitor cells than in patients with increasednumbers.34 In our study, we demonstrated that patients withhigh numbers of endothelial progenitor cells had a reduced riskof revascularization. These findings suggest that endothelialprogenitor cells contribute to the restoration of the endothelialmonolayer, as suggested by data from experimental studies.
Endothelial progenitor-cell levels were not predictive of deathfrom all causes, acute myocardial infarction, or stroke. Thisfinding may suggest that there was an excess of deaths fromnoncardiovascular causes among patients with increased endothelialprogenitor-cell levels. However, no excess of particular noncardiovascularcauses of death were identifiable (data not shown). Small-scalestudies suggest that after acute myocardial infarction, thenumbers of circulating CD34+ and CD133+KDR+ endothelial progenitorcells are up-regulated in response to tissue ischemia.3,35 Giventhe results of our study, we have to assume that the role ofendothelial progenitor cells in acute myocardial infarctionor stroke is more complex than was initially expected. In ourstudy, endothelial progenitor cells that were mobilized afteracute myocardial infarction were functionally impaired (datanot shown). This is in accordance with the finding that in patientswith congestive heart failure, there is impaired function ofprogenitor cells.36 At present, the pathophysiologic consequencesof this dysfunction are unknown. Further studies are neededto elucidate the exact role of endothelial progenitor cellsin acute myocardial infarction.
In addition to CD34+KDR+ endothelial progenitor cells, we measuredthe numbers of immature CD133+ cells, which also correlatedwith cardiovascular outcomes. In order to determine the functionalproperties of formerly circulating endothelial progenitor cells,we determined the number of endothelial colony-forming unitsin a subgroup of patients. We confirmed and extended the findingsof Hill et al.,22 demonstrating that functional properties ofendothelial progenitor cells influence cardiovascular outcomes.
Our results suggest that circulating endothelial progenitorcells in patients with coronary artery disease can be used toidentify patients at high risk for major adverse cardiac events.This finding supports the notion that immature cells play animportant part in the pathogenesis of atherosclerotic diseaseand that the measurement of endothelial progenitor cells mayimprove risk stratification. Further studies assessing the therapeutictargeting of circulating endothelial progenitor cells are warrantedto prove the underlying biologic concept that endothelial-cellregeneration through circulating endothelial progenitor cellsis necessary for vascular healing.
Supported by Deutsche Forschungsgemeinschaft and by a grant(LSHM-CT-2003-503254) from the European Vascular Genomics Networkof the European Commission.
We are indebted to Sybille Richter and Simone Jäger foroutstanding technical assistance and to Sven Wassmann for criticalreview of the manuscript.
Source Information
From the Division of Cardiology, Angiology, and Intensive Care Medicine, Department of Internal Medicine, University of Saarland, Homburg–Saar, Germany.
Address reprint requests to Dr. Nickenig at the Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, D-66421, Homburg–Saar, Germany, or at nickenig{at}med-in.uni-sb.de.
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Circulating Endothelial Progenitor Cells
Kim D. H., Leu H.-B., Chen J.-W., Lin S.-J., Ott H. C., Taylor D. A., Bertolini F., Mancuso P., Kerbel R. S., Boos C. J., Goon P. K.Y., Lip G. Y.H., Werner N., Nickenig G.
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353:2613-2616, Dec 15, 2005.
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50 percent), 2 (stenosis of two main coronary arteries 
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