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FOCUS ISSUE: CARDIAC REGENERATION

Safety and Efficacy of Subcutaneous-Only Granulocyte-Macrophage Colony-Stimulating Factor for Collateral Growth Promotion in Patients With Coronary Artery Disease

Department of Cardiology, University Hospital, Bern, Switzerland

Manuscript received October 20, 2004; revised manuscript received January 19, 2005, accepted January 25, 2005.

^_* Reprint requests and correspondence: Dr. Christian Seiler, Professor and Co-Chairman of Cardiology, University Hospital, CH-3010 Bern, Switzerland. (Email: christian.seiler.cardio{at}insel.ch).

OBJECTIVES: This study was designed to investigate the safety and efficacy of a short-term subcutaneous-only granulocyte-macrophage colony-stimulating factor (GM-CSF) protocol for coronary collateral growth promotion.

BACKGROUND: The safety and efficacy of an exclusively systemic application of GM-CSF in patients with coronary artery disease (CAD) and collateral artery promotion has not been studied so far.

METHODS: In 14 men (age 61 ± 11 years) with chronic stable CAD, the effect of GM-CSF (molgramostim) on quantitatively assessed collateral flow was tested in a randomized, double-blind, placebo-controlled fashion. The study protocol consisted of an invasive collateral flow index (CFI) measurement in a stenotic as well as a normal coronary artery before and after a two-week period with subcutaneous GM-CSF (10 µg/kg; n = 7) or placebo (n = 7). Collateral flow index was determined by simultaneous measurement of mean aortic, distal coronary occlusive, and central venous pressure.

RESULTS: Collateral flow index in all vessels changed from 0.116 ± 0.05 to 0.159 ± 0.07 in the GM-CSF group (p = 0.028) and from 0.166 ± 0.06 to 0.166 ± 0.04 in the placebo group (p = NS). The treatment-induced difference in CFI was +0.042 ± 0.05 in the GM-CSF group and –0.001 ± 0.04 in the placebo group (p = 0.035). Among 11 determined cytokines, chemokines, and their monocytic receptor concentrations, the treatment-induced change in CFI was predicted by the respective change in tumor necrosis factor-alpha concentration. Two of seven patients in the GM-CSF group and none in the placebo group suffered an acute coronary syndrome during the treatment period.

CONCLUSIONS: A subcutaneous-only, short-term protocol of GM-CSF is effective in promoting coronary collateral artery growth among patients with CAD. However, the drug’s safety regarding the occurrence of acute coronary syndrome is questionable.

Abbreviations and Acronyms   CAD = coronary artery disease   CFI = collateral flow index   CVP = central venous pressure   ECG = electrocardiogram   GM-CSF = granulocyte-macrophage colony-stimulating factor   Pao = mean aortic pressure   Poccl = mean coronary artery occlusive pressure   PCI = percutaneous coronary intervention   TNF = tumor necrosis factor

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