Revival of cytokine therapy in heart failure?

Dilated cardiomyopathy (DCM) and heart failure is a serious disease with a high morbidity and mortality rate in spite of optimal medical therapy. Although coronary artery disease is the main aetiology for the condition, a large group of patients have non-ischaemic DCM. Regenerative therapy with stem cells has been a focus to improve cardiac function, physical performance, and quality of life, and to reduce morbidity and mortality in these severely diseased patients. The focus was initially on cell sources from the bone marrow, but recent studies have extended interest to cells from many different tissues such as adipose tissue, heart, umbilical cord, etc., (Figure 1). Cytokine therapy with granulocyte colony-stimulating factor (G-CSF) has for many years been used in haematology to mobilize stem cells from the bone marrow into the blood for transplantation. The use of G-CSF for regenerative stem cell therapy in cardiac disease was intensively studied pre-clinically and clinically a decade ago (Figure 2). Several studies were conducted with subcutaneous injections of G-CSF for 5–7 days in patients with acute ST-segment elevation myocardial infarction (STEMI), heart failure, or refractory angina. – 4 The theory was that the mobilized stem cells from the bone marrow would pass via the blood through the cardiac circulation and be attracted to cardiac tissue areas with acute or chronic ischaemia or reduced myocyte function. The stem cells would then either differentiate into cardiac/endothelial cell or stimulate cardiac tissue to regenerate diseased tissue and improve cardiac pump function and perfusion. However, several well performed and controlled studies could not demonstrate any effect of G-CSF therapy alone on cardiac regeneration. 4 This rather disappointing result led to new theories for the use of G-CSF. The focus now shifted to some of the cell populations mobilized from the bone marrow. The CD34+, CD34+ CXCR4+ cells, and CD133+ mononuclear cells (MNCs) in particular were considered of importance for regenerative therapy. Therefore, studies were conducted with collection of these cell populations without or after subcutaneous G-CSF therapy. The isolated subpopulations were then injected via either the intracoronary or the transendocardial route into the myocardium in patients with STEMI, heart failure, or refractory angina. However, intracoronary infusion of MNCs or the CD34+ CXCR4+ subpopulation of cells isolated from bone marrow was without any effect in acute myocardial infarction. To increase the number of CD34+ cells for therapy, the cells were then isolated from the peripheral blood by apheresis after subcutaneous injections of G-CSF. A phase II study in patients with refractory angina with direct transendocardial myocardial injection of mobilized CD34+ demonstrated improvement in exercise capacity and symptoms. However, the confirmatory phase III trial was initiated but later stopped before completion probably due to the low rate of recruitment. In this issue of the journal, Dr Hamshere and colleagues present results from the REGENERATE-DCM trial in 60 patients with nonischaemic DCM. They introduce a new concept with a combination of subcutaneous G-CSF therapy for 5 days with mobilization of stem cells from the bone marrow followed by intracoronary infusion of bone marrow aspirated MNCs. In a rather complex randomized placebo-controlled trial design, the patients were divided into four groups: the ‘peripheral placebo group’ who received peripheral subcutaneous injected saline, the ‘peripheral G-CSF group’ who received subcutaneous G-CSF alone, the ‘intracoronary (IC) BMC group’ who underwent bone marrow harvest after G-CSF and received intracoronary infusion of autologous MNCs, and the ‘IC serum group’ who underwent bone marrow harvest after G-CSF but received intracoronary infusion of serum only. At 3 months follow-up, peripheral G-CSF combined with intracoronary MNC therapy was associated with a 5.37 percentage point increase in left ventricular ejection fraction (LVEF) (to 38.30+12.97% from 32.93+16.46%, P 1⁄4 0.0138), which was maintained for 1 year. There was also a decrease in New York Heart Association (NYHA) classification and N-terminal pro-brain natriuretic peptide (NT-proBNP), and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups.