Granulocyte colony stimulating factor in chronic angina to stimulate neovascularisation: a placebo controlled crossover trial

Abstract

BACKGROUND: Experimental studies demonstrate that granulocyte colony stimulating factor (G-CSF) promotes neovascularisation and confers cardioprotection. OBJECTIVE: To assess the efficacy of repeated low dose G-CSF plus exercise on myocardial ischaemia in patients with severe chronic ischaemic heart disease. METHODS: 18 patients with Canadian Cardiovascular Society class III-IV angina completed a randomised, double blind, crossover study of dose adjusted G-CSF versus placebo. Exercise was commenced 6 weeks prior and continued for the duration of the study. G-CSF or placebo was administered daily for 5 consecutive days at fortnightly intervals for three cycles, followed by crossover after 6 weeks. Primary outcome was myocardial perfusion by cardiac magnetic resonance imaging (MRI). Secondary outcomes were: Seattle Angina and Utility Based Quality of Life Heart Questionnaire (SAQ/UBQ-H), Exercise Stress Test (EST) and quantification of endothelial progenitor cells (EPC) by flow cytometry and angiogenic cytokines by immunoassay. RESULTS: Compared with placebo, G-CSF had no effect on myocardial ischaemia by cardiac MRI, EST or SAQ/UBQ-H, despite effective EPC mobilisation (peak fold increase: CD34+ =19, CD34+ CD133+ = 37, CD34+ vascular endothelial growth factor receptor 2 (VEGFR-2)+ = 5, CD34+ CD133+ VEGFR-2+ = 3; all p<0.05 vs. placebo). Plasma levels of stromal cell derived factor 1, angiopoietin 1, interleukin 8 and tumour necrosis factor α decreased after a symptom limited EST while vascular endothelial growth factor and platelet derived growth factor remained unchanged. All cytokines were unchanged following G-CSF. Seven troponin I positive events occurred with G-CSF compared with three with placebo (p=0.289). High sensitivity C reactive protein and N terminal prohormone brain natriuretic peptide increased with G-CSF (both p<0.01 vs. placebo). CONCLUSION: In patients with chronic ischaemic heart disease, G-CSF mobilises EPCs but does not improve myocardial perfusion or angina. G-CSF increases plasma levels of adverse prognostic cardiac biomarkers. Clinical trial registration information Australian New Zealand Clinical Trials Registry: http://www.anzctr.org.au. Unique identifier: ACTRN012607000354482.