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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:112.)
© 2006 American Heart Association, Inc.

Vascular Biology

Circulating CD31⁺/Annexin V⁺ Apoptotic Microparticles Correlate With Coronary Endothelial Function in Patients With Coronary Artery Disease

Nikos Werner; Sven Wassmann; Patrick Ahlers; Sonja Kosiol; Georg Nickenig

From the Klinik für Innere Medizin II, Universitätsklinikum Bonn, Bonn, Germany.

Correspondence to Georg Nickenig, Klinik für Innere Medizin II, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany. E-mail georg.nickenig{at}ukb.uni-bonn.de

	Abstract

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Objective— Endothelial dysfunction predicts morbidity and mortality in patients at cardiovascular risk. Endothelial function may be decisively influenced by the degree of endothelial cell apoptosis.

Methods and Results— To test this hypothesis in humans, endothelial-dependent vasodilatation was invasively assessed in 50 patients with coronary artery disease (CAD) by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry was used to assess endothelial cell apoptosis by quantification of circulating CD31⁺/annexin V⁺ apoptotic microparticles in peripheral blood. Increased apoptotic microparticle counts positively correlated with impairment of coronary endothelial function. Multivariate analysis revealed that increased apoptotic microparticle counts predict severe endothelial dysfunction independent of classical risk factors, such as hypertension, hypercholesterolemia, smoking, diabetes, age, or sex.

Conclusions— In patients with CAD, endothelial-dependent vasodilatation closely relies on the degree of endothelial cell apoptosis, which is readily measurable by circulating CD31⁺/annexin V⁺ apoptotic microparticles. These findings possibly provide new options for risk assessment and may have implications for future treatment strategies of CAD.

Endothelial function may be influenced by the degree of endothelial cell apoptosis. Endothelial function and endothelial cell apoptosis was assessed in patients with coronary artery disease. Increased apoptotic microparticle counts correlated with impairment of invasively measured coronary endothelial function. Endothelial-dependent vasodilatation closely relies on the degree of endothelial cell apoptosis.

Key Words: apoptosis • apoptotic microparticles • endothelial dysfunction

	Introduction

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Coronary artery disease (CAD) is the main death cause in the industrialized world. The underlying disease, atherosclerosis, is initiated and propagated by a continuous damage of the vascular endothelium referred to as endothelial dysfunction.¹ The latter is not only a prerequisite of atherosclerosis but largely influences the outcome of patients at cardiovascular risk or with CAD.^2–4 On the molecular and cellular level, endothelial dysfunction is caused by reduced nitric oxide bioavailability, which is, in turn, regulated by genes, such as the nitric oxide synthase, phosphatidylinositol 3-kinase, and AKT.⁵ On the cellular level, endothelial dysfunction as well as atherogenesis, is based on a progressive loss of endothelial cells.⁶ The latter is determined by the degree of apoptosis of endothelial cells. Attempts to assess the degree of endothelial cell apoptosis in vivo have focused on the indirect measurement of soluble factors, for example, ICAM, vascular cell adhesion molecule, and E-selectins, with contradicting results.⁷ In contrast, endothelial cell-derived submicroscopic membranous vesicles are directly shed from mature endothelial cells on stimulation by activating agents, such as tumor necrosis factor , or during apoptosis.⁷ The so-called endothelial microparticles carry membrane proteins and phospholipids of the parent cell (eg, CD31 when derived from endothelial cells) and can be differentiated from microparticles derived from leukocytes, erythrocytes, or platelets.^7–9 Apoptotic microparticles have been shown to be elevated in conditions of endothelial cell damage, for example, in patients with lupus anticoagulant, thrombotic thrombocytopenic purpura, preeclampsia, paroxysmal nocturnal hemoglobinuria, and multiple sclerosis.^10–14 Recent evidence suggest an increase in endothelial microparticle levels in patients with cardiovascular disease, such as acute coronary syndromes, diabetes, arterial hypertension, and hypertriglyceridemia.^8,15–19 However, it is unknown whether the increased numbers of CD31⁺/annexin V⁺ microparticles in patients with cardiovascular risk factors correlate with coronary endothelial function, which would possibly establish a novel powerful marker of cardiovascular risk. To clarify these questions, we performed a clinical study in patients with established CAD in whom we invasively assessed coronary endothelial-dependent vasodilatation and the degree of endothelial cell apoptosis.

	Methods

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Study Subjects
All of the subjects enrolled in the study signed an informed consent document approved by the ethical committee of the University of Saarland. All of the patients received a coronary angiography because of suspected stenosis of their coronary arteries. Patients with angiographic signs of atherosclerosis were eligible for the study. Subjects with indication for bypass surgery or chronic occlusion of 2 vessels were not suitable for the study for safety reasons. Patients with no signs of atherosclerosis, malignant or inflammatory diseases, or conditions of acute myocardial ischemia were not included in the study. All of the patients were fasting for 12 hours before coronary angiography. All of the baseline blood samples were drawn before cardiac catheterization. Fifty patients were eligible for the study. Patient characteristics are displayed in Table 1. Medical history, including cardiovascular risk factors, previous and present cardiovascular events, current drug treatment, and vital signs, was obtained during a personal interview and from medical files.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of Study Subjects*

Study Protocol
Coronary endothelial-dependent vasodilatation was measured as described previously.²⁰ Heparin (10 000 IU) and acetylsalicylic acid (500 mg) were given intravenously, and a 7-French guiding catheter (Medtronic) was introduced into the left or right coronary artery. An over-the-wire balloon catheter (Maverick, Boston Scientific Scimed; 1.5 mm balloon) was advanced over a 0.014-inch guide wire into a nonbranching region of the target vessel. The inner lumen of the over-the-wire catheter was used for intracoronary drug infusion. This procedure allowed selective infusion into a single coronary artery and enabled contrast medium application without discontinuation of infusion.

Drug Administration
After a 15-minute equilibration period, resting measurements were performed. Drug administration was started when stable measurements under resting conditions were achieved. Saline (NaCl 0.9%), acetylcholine chloride (Miochol-E, Novartis Ophthalmics), adenosine (Adrekar, Sanofi-Synthelabo), and nitroglycerin (Trinitrosan, Merck) were administered through the inner lumen of the over-the-wire catheter with an infusion pump (Perfusor secura, Braun) at a flow rate of 1 mL/min over 3 minutes. After infusion of saline and baseline measurements, acetylcholine was infused with a starting dose of 1.8 µg/min (0.1 µmol/L estimated final intracoronary concentration), which was increased to a final dose of 18 µg/min (1 µmol/L estimated final intracoronary concentration). At the end of each infusion period of acetylcholine, coronary angiography was performed to assess the coronary luminal diameter. Each interval of drug administration was followed by a washout phase with normal saline infusion for 3 minutes before drug administration was continued. Adenosine was infused at a concentration of 15 µg/min (1 µmol/L estimated final intracoronary concentration) followed by coronary angiography. Finally, after another interval of saline infusion, nitroglycerin was infused at a concentration of 200 µg/min (15 µmol/L estimated final intracoronary concentration), and coronary angiography was performed.

Quantitative Coronary Angiography
Serial coronary angiograms were performed using identical projections, tube and table height, and magnification. The nonionic contrast medium iopromide (Ultravist 370, Schering) was used for angiography and was injected manually through the guiding catheter at low pressure. Biplane cineangiograms were recorded with the target vessel positioned near the isocenter. Overlapping of coronary segments was avoided. The film sequences were stored digitally for subsequent computer analysis. The coronary luminal diameter was analyzed by the use of an automated edge-detection software system (CAAS II, Pie Medical). The analysis was performed by a trained investigator who was blinded regarding the investigated subject and the drug administered for intracoronary infusion. The mean luminal diameter of the target vessel was measured at a segment proximal to the infusion catheter (control segment: 20 mm proximal from the point of infusion), and in 3 subsequent vessel segments distal of the over-the-wire balloon before and after drug application. For the comparison of the coronary response to acetylcholine, the combined response of all 3 of the analyzed vessel segments was used. The response of the vessel segment was calculated as the percentage of change in mean luminal diameter compared with the baseline measurement. Negative values indicate decreases in luminal diameter.

Blood Sample Preparation
Arterial blood was drawn under sterile conditions from the femoral artery before cardiac catheterization and was buffered using sodium citrate. Additional blood samples for routine analyses were obtained.

CD31⁺/Annexin V⁺ Microparticles
Plasma derived from 10-mL citrate-buffered blood was immediately centrifuged at 13 000 g for 2 minutes to generate platelet-poor plasma. Fifty µL of platelet-poor plasma were incubated with 4 µL of PE-conjugated monoclonal antibody against CD31 (Becton Dickinson) followed by incubation with fluorescein isothiocyanate-conjugated annexin V according to the manufacturer’s instructions. IgG 2_a-fluorescein isothiocyanate (Pharmingen) served as negative control. FACS analysis was performed immediately after staining using a FACSCalibur instrument (Becton Dickinson). CD31⁺/annexin V⁺ microparticles were defined as particles positively labeled for CD31 and annexin V (CD31⁺/annexin V⁺). To reduce the number of microparticles derived from nonendothelial cells, which may occasionally show low expression of CD31, only CD31^bright microparticles were selected. Figure 1 shows a representative FACS analysis for CD31⁺/annexin V⁺ microparticles. Data were analyzed using Cellquest software (Becton Dickinson).

View larger version (42K): [in this window] [in a new window]   Figure 1. Representative FACS analysis of CD31+/annexin V+ apoptotic microparticles. The gate (top left) was set using sizing microparticles. Annexin V (top right), CD31 (bottom left), and CD31+/annexin V+ (bottom right) microparticles are shown.

Statistical Analysis
Data are expressed as mean±SEM. We used log-transformed values (log base, 10) of microparticles as continuous variables. Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov test. The means between 2 categories were compared with the use of a 2-tailed, unpaired Student t test. The 1-way ANOVA test was used for comparisons of categorical variables. For post-hoc analysis, the Bonferroni test was applied. Univariate and nonparametric bivariate correlations were performed using the Pearson correlation coefficient. Multiple linear regression analysis was performed where indicated to identify independent variables influencing the prediction of microparticle changes in peripheral blood. Statistical significance was assumed when a null hypothesis could be rejected at P<0.05. Statistical analysis was performed using SPSS 11.5 for Windows.

	Results

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Baseline Characteristics
Fifty consecutive patients with angiographically determined CAD were eligible for the study. The average age was 66.3±11.4 years, and there was a high prevalence of coronary risk factors, such as hypertension (88%), hypercholesterolemia (86%), diabetes (26%), and smoking (24%). More than half of the patients showed 1 or 2 vessel disease, whereas 26% displayed 3-vessel CAD. Detailed patients characteristics are depicted in Table 1.

Endothelial Function and Endothelial Apoptotic Microparticles
Coronary endothelial-dependent vasodilatation was assessed by quantitative coronary angiography during intracoronary acetylcholine infusion (1 µmol/L estimated final intracoronary concentration) and was correlated with the number of CD31⁺/annexin V⁺ circulating apoptotic microparticles from each patient as determined by flow cytometry. Univariate analysis identified a highly significant correlation between CD31⁺/annexin V⁺ apoptotic microparticle numbers in peripheral blood and an impaired coronary endothelial-dependent vasodilatation. Figure 2 shows that patients with high levels of endothelial apoptotic microparticles display a strong impairment of endothelial-dependent vasorelaxation, demonstrating a significant positive correlation of endothelial cell apoptosis and endothelial dysfunction of the coronary artery (r=–0.549; P<0.001). Furthermore, age, male gender, and low-density lipoprotein cholesterol negatively correlate with endothelial-dependent vasorelaxation (r=–0.309, P=0.005; P=0.015; r=–0.253, P=0.011, respectively), whereas diabetes, smoking, hypertension, and a positive family history of premature CAD were not associated with coronary endothelial dysfunction (Table 2). Multivariate analysis correcting for age, gender, diabetes, hypertension, hyperlipidemia, family history of premature CAD, smoking, and statin treatment identified CD31⁺/annexin V⁺ apoptotic microparticle numbers as the only independent predictor (P=0.003) for an impaired endothelial-dependent vasorelaxation after intracoronary infusion of acetylcholine (Table 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. The number of CD31+/annexin V+ apoptotic microparticles negatively correlates with endothelial-dependent vasodilatation after intracoronary infusion of acetylcholine. High numbers of apoptotic microparticles are a strong predictor for an impaired coronary endothelial vasomotion. Negative values of change in luminal diameter indicate vasoconstriction.

View this table: [in this window] [in a new window]   TABLE 2. Correlation of Endothelial Microparticles and Cardiovascular Risk Factors With Endothelial-Dependent Vasorelaxation After Intracoronary Infusion of Acetylcholine

Vasodilatation induced by either nitroglycerin or adenosine is mediated by endothelial-independent mechanisms. Neither nitroglycerin- nor adenosine-mediated vasodilatation showed a significant correlation with endothelial cell apoptosis (r=0.071, P=0.624 and r=–0.076, P=0.600, respectively; Figure 3A and B), and, therefore, additional statistical analysis on these results was not warranted.

View larger version (19K): [in this window] [in a new window]   Figure 3. The number of CD31+/annexin V+ apoptotic microparticles does not correlate with endothelial-independent vasorelaxation after intracoronary administration of nitroglycerin or adenosine.

	Discussion

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Vascular endothelium plays a pivotal role in the pathogenesis of numerous thrombotic and inflammatory disorders. The most prominent inflammatory disease of the vessel wall resembles atherosclerosis, which causes CAD, myocardial infarction, stroke, and peripheral artery disease.¹ Atherosclerosis is initiated and propagated by a continuous damage of the vascular endothelium leading to endothelial dysfunction, which influences the outcome of patients at cardiovascular risk or with established CAD. Endothelial dysfunction is characterized by reduced vasorelaxation of diseased vessels or abnormal vasoconstriction in response to acetylcholine, which is mediated by the endothelium. In contrast, nitroglycerin and adenosine application uniformly results in an endothelial-independent vasodilatation of diseased or unaffected vessels. Here we demonstrate that age, male gender, low-density lipoprotein cholesterol, and the number of circulating CD31⁺/annexin V⁺ apoptotic microparticles negatively correlate with acetylcholine-mediated endothelial-dependent vasorelaxation. Multivariate analysis correcting for cardiovascular risk factors and statin treatment identified circulating CD31⁺/annexin V⁺ apoptotic microparticle numbers as the only independent predictor for an impaired endothelial-dependent vasorelaxation in patients with manifest CAD. In contrast, nitroglycerin or adenosine-mediated vasomotion did not correlate with the degree of coronary endothelial-dependent vasodilatation indicating that CD31⁺/annexin V⁺ apoptotic microparticles specifically correlate with endothelial rather than smooth muscle cell function.

Our data suggest that, other than biochemical modulations in each endothelial cell, such as reduced nitric oxide production, the degree of endothelial cell loss mainly drives the progression of endothelial dysfunction. This is in agreement with reports showing that CD31⁺/annexin V⁺ microparticles are increased in conditions of systemic endothelial cell damage, such as in patients with thrombotic thrombocytopenic purpura, lupus anticoagulant, multiple sclerosis, and cardiovascular disease.^8,10–19 Interestingly, in patients with thrombotic thrombocytopenic purpura, microparticles are mainly increased because of an activation of endothelial cells, whereas in patients with cardiovascular risk factors (eg, increased oxidized low-density lipoprotein and/or elevated cholesterol), microparticles mainly derive from apoptotic endothelial cells.⁷ However, the discrimination between microparticles derived from apoptotic or activated cells remains difficult and is the subject of current research. In cardiovascular disease, Mallat et al¹⁷ demonstrated that in patients with acute coronary syndromes, microparticles were increased compared with a control group. These results were confirmed in patients with acute myocardial infarction.²¹ Interestingly, endothelial microparticles not only represent a marker of endothelial cell damage but have been shown to mediate functional properties. Microparticles display a significant procoagulatory activity,^17,22,23 and shedding of microparticles may be a way for the cell to eliminate noxious agents, indicating a functional role of endothelial microparticles in the organism. In this context, in vitro experiments demonstrated that isolated membrane particles impaired acetylcholine-induced vasorelaxation and nitric oxide production of rat aortic rings in a concentration-dependent manner.²⁴ Membrane particles derived from T lymphocytes impaired stress-induced dilatation of mouse small mesenteric arteries by affecting nitric oxide synthase.⁹ Boulanger et al²⁵ demonstrated that the total pool of circulating microparticles derived from patients with myocardial infarction affect endothelial-dependent vasodilatation of rat aortic rings. In contrast, statins, which are known for their vasculoprotective properties, have been shown to decrease endothelial microparticle release from human coronary artery endothelial cells in vitro.²⁶ In this line of evidence, our data underline the importance of pronounced endothelial cell apoptosis in vivo in the development of endothelial dysfunction in humans. Circulating CD31⁺/annexin V⁺ apoptotic microparticles highly significantly predict the degree of endothelial dysfunction in humans with CAD. At present, it remains unclear whether increased numbers of CD31⁺/annexin V⁺ apoptotic microparticles in patients with severe coronary endothelial dysfunction are increased because of a mechanical or (bio-)chemical injury or whether endothelial cells try to eliminate noxious agents, which themselves cause the dysfunction of the vascular endothelium.

Our findings suggest that endothelial cell apoptosis is independently involved in the pathogenesis of endothelial dysfunction. This enables novel insights into the cellular and molecular determinants of atherogenesis. Furthermore, circulating CD31⁺/annexin V⁺ apoptotic microparticles may serve as a novel marker of vascular dysfunction, which could possibly be instrumental for risk stratification, as well as monitoring of atheroprotective treatment regimens. Beyond that, novel treatment options that selectively influence endothelial cell apoptosis could possibly be derived from these results in the future.

	Acknowledgments

 
This work was supported by Deutsche Forschungsgemeinschaft and by the European Vascular Genomics Network, a Network of Excellence granted by the European Commission (Contract No. LSHM-CT-2003-503254). We thank the staff of the cardiac catheterization laboratory for excellent support. Sybille Richter and Simone Jäger provided outstanding technical assistance.

Received July 26, 2005; accepted October 5, 2005.

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