Safety and Efficacy of Bone Marrow Derived Progenitor Cells in Patients with Chronic Ischaemic Heart Failure

Abstract

Bone marrow stem/progenitor cell (BMSC) therapy for cardiac repair in humans is yet to fulfil the exciting potential demonstrated in preclinical experiments. This thesis presents three clinical studies addressing some of the unresolved issues regarding the ideal delivery method, the effect of patient-related factors on progenitor cell concentration/function and the possible biological mechanism(s) of action. The first study describes the intramyocardial arm of the REGENERATE-IHD trial- a randomised controlled trial assessing the efficacy of mobilised BMSCs in patients with ischaemic heart failure. In summary, 30 patients were randomised 1:1 to receive injection of BMSCs suspended in autologous serum or serum alone (control group). All patients received a 5-day course of G-CSF prior to bone marrow harvest and intramyocardial injection. At 1-year, there was a significant increase in ejection fraction, the primary end-point, in patients treated with BMSCs. There were also significant improvements in the secondary end-points of NT-proBNP and symptoms. In the second study, progenitor cell concentration and function were assessed in patients with ischaemic heart failure (IHD), dilated cardiomyopathy (DCM) and acute myocardial infarction (AMI). Findings include ageing having an inverse association with circulating CD34+ cell concentration as well as blunting the effects of G-CSF on BMSC mobilisation. DCM patients had 2 3 significantly higher baseline circulating progenitor cell concentrations compared to IHD/AMI. The final study presents preliminary data regarding a novel imaging technique to detect angiogenesis which is recognised as a potential therapeutic effect of BMSCs. Nine patients with heart failure underwent nuclear imaging using a radio-tracer peptide with a high affinity for v 3, an angiogenesis-related integrin, before and after intracoronary infusion of BMSCs/serum. Preliminary results showed detectable baseline uptake of the radio-tracer suggesting a novel finding of persistent angiogenesis following remote myocardial infarction and also hint at a tantalising possibility that BMSC infusion may lead to therapeutic angiogenesis.