ABSTRACT
Endothelial progenitor cells (EPC) predict morbidity and mortality in patients at cardiovascular risk.Patients with low EPC counts and impaired endothelial colony forming activity have a higher incidence for cardiovascular events compared to patients with high EPC counts and favorable colony forming activity. The pathophysiological basis for this finding may be an insufficient endothelial cell repair by EPC.We postulate that EPC influence coronary endothelial function which itself is relevant for the outcome of patients at cardiovascular risk. To test this hypothesis in humans, endothelial function was invasively assessed in 90 patients with coronary heart disease by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry of mononuclear cells isolated from peripheral blood was performed to assess CD133(+) or CD34(+)/KDR(+) EPC. EPC function was assessed ex vivo by determination of endothelial colony forming units. Low EPC number as well as impaired endothelial colony forming activity correlated with severely impaired coronary endothelial function in univariate analysis. Multivariate analysis revealed that only the number of EPC predicts severe endothelial dysfunction independent of classical cardiovascular risk factors. Endothelial function closely correlates with the number of circulating EPC providing new mechanistic insights and options for risk assessment in patients with coronary heart disease.
Subject(s)
Coronary Artery Disease/pathology , Coronary Artery Disease/physiopathology , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Mesenchymal Stem Cells/pathology , AC133 Antigen , Aged , Antigens, CD/metabolism , Antigens, CD34/metabolism , Coronary Angiography , Endothelium, Vascular/metabolism , Female , Glycoproteins/metabolism , Humans , Linear Models , Male , Mesenchymal Stem Cells/metabolism , Middle Aged , Multivariate Analysis , Peptides/metabolism , Prospective Studies , Risk AssessmentABSTRACT
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.
Subject(s)
Annexin A5/metabolism , Apoptosis/physiology , Coronary Artery Disease/pathology , Endothelial Cells/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Acetylcholine/administration & dosage , Aged , Biomarkers/blood , Coronary Angiography , Coronary Artery Disease/blood , Coronary Artery Disease/epidemiology , Coronary Circulation/drug effects , Endothelial Cells/metabolism , Endothelial Cells/ultrastructure , Female , Humans , Male , Middle Aged , Risk Factors , Vasodilation/drug effects , Vasodilator Agents/administration & dosageABSTRACT
BACKGROUND: Endothelial progenitor cells derived from bone marrow are believed to support the integrity of the vascular endothelium. The number and function of endothelial progenitor cells correlate inversely with cardiovascular risk factors, but the prognostic value associated with circulating endothelial progenitor cells has not been defined. METHODS: The number of endothelial progenitor cells positive for CD34 and kinase insert domain receptor (KDR) was determined with the use of flow cytometry in 519 patients with coronary artery disease as confirmed on angiography. After 12 months, we evaluated the association between baseline levels of endothelial progenitor cells and death from cardiovascular causes, the occurrence of a first major cardiovascular event (myocardial infarction, hospitalization, revascularization, or death from cardiovascular causes), revascularization, hospitalization, and death from all causes. RESULTS: A total of 43 participants died, 23 from cardiovascular causes. A first major cardiovascular event occurred in 214 patients. The cumulative event-free survival rate increased stepwise across three increasing baseline levels of endothelial progenitor cells in an analysis of death from cardiovascular causes, a first major cardiovascular event, revascularization, and hospitalization. After adjustment for age, sex, vascular risk factors, and other relevant variables, increased levels of endothelial progenitor cells were associated with a reduced risk of death from cardiovascular causes (hazard ratio, 0.31; 95 percent confidence interval, 0.16 to 0.63; P=0.001), a first major cardiovascular event (hazard ratio, 0.74; 95 percent confidence interval, 0.62 to 0.89; P=0.002), revascularization (hazard ratio, 0.77; 95 percent confidence interval, 0.62 to 0.95; P=0.02), and hospitalization (hazard ratio, 0.76; 95 percent confidence interval, 0.63 to 0.94; P=0.01). Endothelial progenitor-cell levels were not predictive of myocardial infarction or of death from all causes. CONCLUSIONS: The level of circulating CD34+KDR+ endothelial progenitor cells predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients at increased cardiovascular risk.
