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J Am Coll Cardiol, 2007; 49:2341-2349, doi:10.1016/j.jacc.2007.01.095 (Published online 1 June 2007).
© 2007 by the American College of Cardiology Foundation
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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

Christine K. Kissel, MD1, Ralf Lehmann, MD, Birgit Assmus, MD, Alexandra Aicher, MD, Jörg Honold, MD, Ulrich Fischer-Rasokat, MD, Christopher Heeschen, MD, Ioakim Spyridopoulos, MD, Stefanie Dimmeler, PhD and Andreas M. Zeiher, MD*

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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