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

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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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Supported by a grant from the Swiss National Science Foundation, #3200BO-100065/1. The first two authors contributed equally to this work.