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Granulocyte colony stimulating factor in chronic angina to stimulate neovascularisation: a placebo controlled
Sharon Chih1, Peter S Macdonald, Jane A McCrohon
1Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St, Darlinghurst, NSW 2010, Australia.
Insights
Granulocyte colony stimulating factor (G-CSF) mobilizes endothelial progenitor cells (EPCs) in patients with chronic ischaemic heart disease but does not improve myocardial perfusion or angina. G-CSF also increases adverse cardiac biomarkers.
Area of Science:
- Cardiology
- Regenerative Medicine
- Clinical Trials
Background:
- Experimental studies suggest granulocyte colony stimulating factor (G-CSF) promotes neovascularization and cardioprotection.
- Severe chronic ischaemic heart disease presents a significant clinical challenge.
- Endothelial progenitor cells (EPCs) play a role in vascular repair.
Purpose of the Study:
- To evaluate the efficacy of repeated low-dose G-CSF combined with exercise in patients with severe chronic ischaemic heart disease.
- To assess the impact of G-CSF on myocardial ischaemia, angina symptoms, and cardiac biomarkers.
- To investigate G-CSF's effect on endothelial progenitor cell mobilization.
Main Methods:
- A randomized, double-blind, crossover study involving 18 patients with Canadian Cardiovascular Society class III-IV angina.
- Patients received either dose-adjusted G-CSF or placebo, administered daily for 5 consecutive days at fortnightly intervals for three cycles.
- Exercise was initiated 6 weeks prior to treatment and continued throughout the study.
- Primary outcome: myocardial perfusion assessed by cardiac MRI. Secondary outcomes included angina symptoms (SAQ/UBQ-H), exercise stress tests (EST), EPC quantification, and angiogenic cytokine levels.
Main Results:
- G-CSF effectively mobilized EPCs (e.g., CD34+ cells increased 19-fold, p<0.05).
- No significant improvement in myocardial perfusion (cardiac MRI, EST) or angina symptoms (SAQ/UBQ-H) was observed with G-CSF compared to placebo.
- G-CSF treatment led to an increase in adverse prognostic cardiac biomarkers, including high-sensitivity C-reactive protein and N-terminal prohormone brain natriuretic peptide (both p<0.01 vs. placebo).
Conclusions:
- Repeated low-dose G-CSF with exercise does not improve myocardial perfusion or angina in patients with severe chronic ischaemic heart disease.
- While G-CSF successfully mobilizes EPCs, it is associated with increased levels of adverse cardiac biomarkers.
- The findings suggest that G-CSF may not be a beneficial therapeutic agent for this patient population.
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.
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