Bone marrow mobilization with granulocyte macrophage colony-stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease

• Published in: The American heart journal 2009-07, Vol.158 (1), p.53-60.e1
• Main Authors: Subramaniyam, Veerappan, MD, Waller, Edmund K., MD, PhD, Murrow, Jonathan R., MD, Manatunga, Amita, PhD, Lonial, Sagar, MD, Kasirajan, Karthikeswar, MD, Sutcliffe, Diane, BS, Harris, Wayne, BS, Taylor, W. Robert, MD, PhD, FACC, Alexander, R. Wayne, MD, PhD, FACC, Quyyumi, Arshed A., MD, FACC
• Format: Article
• Language: English
• Subjects: Acute coronary syndromes; Aged; Ankle Brachial Index; Arterial Occlusive Diseases - drug therapy; Atherosclerosis - drug therapy; Biological and medical sciences; Blood and lymphatic vessels; Bone marrow; Bone Marrow - drug effects; Cardiology. Vascular system; Cardiovascular; Colonies & territories; Colony-Forming Units Assay; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Exercise Test - drug effects; Female; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; Granulocyte-Macrophage Colony-Stimulating Factor - adverse effects; Hematopoietic Stem Cell Mobilization - methods; Humans; Leukocyte Count; Male; Medical sciences; Middle Aged; Vascular endothelial growth factor; Vasodilation; Walking
• ISSN: 0002-8703; 1097-6744
• DOI: 10.1016/j.ahj.2009.04.014

Background We hypothesized that granulocyte macrophage colony-stimulating factor (GM-CSF) administration will be safe and will improve endothelial dysfunction and exercise capacity by mobilizing progenitor cells in patients with peripheral arterial disease (PAD). Methods Forty-five patients with PAD received thrice-weekly injections for 2 weeks of 3, 6, or 10 μg/kg per day of GM-CSF or placebo in successive cohorts of 15 subjects randomized 2:1 to drug or placebo. CD34+ mononuclear cell subsets and colony formation assay, endothelial function, ankle-brachial index, and walking capacity were measured. Results Granulocyte macrophage colony-stimulating factor administration was safe. After pooling data from GM-CSF cohorts, at 2 weeks, there was a significant increase in total leukocytes (43%, P < .0001), CD34+ cells (46%, P = .035), and colony-forming units (31%, P = .026, week 1). At 12 weeks, endothelial function improved with GM-CSF (flow-mediated vasodilation increased by 59%, P < .01) as did pain-free treadmill walking time (38 seconds, P = .008) and total treadmill walking time (55 seconds, P = .016). Corresponding changes were not observed in the placebo group. Conclusions Granulocyte macrophage colony-stimulating factor therapy in patients with PAD was associated with mobilization of progenitor cells, improvement of endothelial dysfunction, and exercise capacity. The efficacy of strategies designed to mobilize bone marrow progenitors warrants further study in patients with PAD.