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(Circulation. 2005;111:3391-3399.)
© 2005 American Heart Association, Inc.

Exercise Physiology

Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes

Results of 3 Randomized Studies

Marcus Sandri, BSc^*; Volker Adams, PhD^*; Stephan Gielen, MD; Axel Linke, MD; Karsten Lenk, MD; Nicolle Kränkel, PhD; Dominik Lenz, PhD; Sandra Erbs, MD; Dierk Scheinert, MD; Friedrich Wilhelm Mohr, MD; Gerhard Schuler, MD; Rainer Hambrecht, MD

From the Heart Center (M.S., V.A., S.G., A.L., K.L., N.K., S.E., D.S., G.S., R.H.), Department of Internal Medicine/Cardiology; the Department of Pediatric Cardiology (D.L.); and the Department of Cardiac Surgery (F.W.M.), University of Leipzig, Leipzig, Germany.

Correspondence to Rainer Hambrecht, MD, Professor of Medicine, Herzzentrum—Universität Leipzig, Department of Internal Medicine/Cardiology, Strümpellstraße 39, 04289 Leipzig, Germany. E-mail hamr{at}medizin.uni-leipzig.de

Received December 3, 2004; revision received February 28, 2005; accepted March 8, 2005.

Background— Exercise training (ET) has been shown to improve regional perfusion in ischemic syndromes. This might be partially related to a regeneration of diseased endothelium by circulating progenitor cells (CPCs) or CPC-derived vasculogenesis. The aim of the present study was to determine whether ischemic stimuli during ET are required to promote CPC mobilization in patients with cardiovascular diseases.

Methods and Results— Patients with peripheral arterial occlusive disease (PAOD) were randomized to 4 weeks of daily ischemic ET or control (group A). Successfully revascularized patients with PAOD were randomized to 4 weeks of daily nonischemic ET or control (group B). Patients with stable coronary artery disease were subjected to 4 weeks of subischemic ET or control (group C). At baseline and after 4 weeks, the number of KDR⁺/CD34⁺ CPCs was determined by fluorescence-activated cell sorting analysis. Levels of vascular endothelial growth factor (VEGF) were measured by ELISA. A Matrigel assay was used to quantify CPC integration into vascular structures. Expression of the homing factor CXCR4 was determined by reverse transcription-polymerase chain reaction. In group A only, ischemic ET increased VEGF levels by 310% (P<0.05 versus control) associated with an increase in CPCs by 440% (P<0.05 versus control), increased CXCR4 expression, and enhanced integration of CPCs into endothelial networks. In contrast, subischemic ET in groups B and C increased CXCR4 expression and CPC integration.

Conclusions— In training programs, symptomatic tissue ischemia seems to be a prerequisite for CPC mobilization. However, ischemic and subischemic ET programs affect CXCR4 expression of CPCs, which might lead to an improved CPC integration into endothelial networks.

Key Words: angiogenesis • exercise • stem cells

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