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CLINICAL RESEARCH: HEART FAILURE

Selective Functional Exhaustion of Hematopoietic Progenitor Cells in the Bone Marrow of Patients With Postinfarction Heart Failure

Department of Cardiology, Johann Wolfgang Goethe–University Frankfurt, Frankfurt, Germany.

Manuscript received February 14, 2006; revised manuscript received January 11, 2007, accepted January 22, 2007.

^_* Reprint requests and correspondence: Dr. Andreas M. Zeiher, Department of Cardiology, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. (Email: zeiher{at}em.uni-frankfurt.de).

Objectives: This study investigated whether reduced levels of circulating endothelial progenitors cells (EPCs) in chronic heart failure (CHF) are secondary to an exhaustion of hematopoietic stem cells (HSCs) in the bone marrow or to reduced mobilization.

Background: Circulating EPCs presumably originate from bone marrow-derived HSC. Persistent mobilization of EPCs was shown to be associated with favorable left ventricular infarct remodeling processes.

Methods: We assessed the number and functional capacity of EPCs in 17 healthy controls, 25 patients with ischemic cardiomyopathy (ICM), and 20 patients with dilated cardiomyopathy (DCM). To document an impairment of HSC function in the bone marrow, the colony-forming unit capacity of bone marrow–derived mononuclear cells and the number of CD34⁺ HSCs were examined in 6 healthy volunteers, 94 ICM patients, and 25 DCM patients.

Results: The number of EPCs was reduced in CHF, irrespective of its etiology. In contrast, the migratory capacity was selectively impaired in EPCs of ICM patients (4.8 ± 4.0 migrated cells; DCM 9.7 ± 5.8; p = 0.02). On multivariate analysis, ICM, advanced New York Heart Association functional class, and CHF were independent predictors of functional EPC impairment. The number of bone marrow-derived CD34⁺ cells did not differ between the CHF populations. However, colony-forming units (CFUs) were selectively reduced in ICM patients (54.4 ± 24.6; DCM 68.1 ± 26.9; p < 0.02). Ischemic cardiomyopathy was the only independent predictor of impaired CFU capacity. Impaired CFU capacity was associated with reduced matrix metalloproteinase-9 activity in the bone marrow plasma.

Conclusions: Ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular (LV) remodeling process.

Abbreviations and Acronyms   BM-MNC = bone marrow–derived mononuclear cell   CAD = coronary artery disease   CFU-GM = colony-forming unit–granulocyte-macrophage   CHF = chronic heart failure   DCM = dilated cardiomyopathy   EPC = endothelial progenitor cell   EPO = erythropoietin   HSC = hematopoietic stem cell   hsCRP = high-sensitivity C-reactive protein   ICM = ischemic cardiomyopathy   LV = left ventricular   MI = myocardial infarction   MMP = matrix metalloproteinase   NT-proBNP = N-terminal pro-brain natriuretic peptide   NYHA = New York Heart Association   PlGF = placental growth factor   TNF = tumor necrosis factor   VEGF = vascular endothelial growth factor

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