Paracrine Effects of Direct Intramyocardial Implantation of Bone Marrow Derived Cells to Enhance Neovascularization in Chronic Ischaemic Myocardium

Abstract Objective To determine the optimal bone marrow (BM) cell types, and their potential mechanisms of action for neovascularization in chronic ischaemic myocardium. Methods and results The functional effects, angiogenic potential and cytokine expression of direct intramyocardial implantation of autologous BM CD31-positive endothelial progenitor cells (EPC, n=9), BM mononuclear cells (MNCs, n=9), and saline (n=9) were compared in a swine model of chronic ischaemic myocardium. Autologous BM cells were harvested and catheter-based electromechanical mapping-guided direct intramyocardial injection was performed to target ischaemic myocardium. After 12 weeks, injection of BM-MNC resulted in significant improvements in left ventricular dP/dt (+21±8%, P=0.032), left ventricular pressure (+17±4%, P=0.048) and regional microsphere myocardial perfusion over ischaemic endocardium (+74±28%, P<0.05) and epicardium (+73±29%, P<0.05). No significant effects were observed following injection of BM-EPC or saline. Capillary density (1132±69 versus 903±44 per mm2, P=0.047) and expression of mRNA of vascular endothelial growth factor (VEGF, 32.3±5.6 versus 13.1±3.7, P<0.05,) and angiopoietin-2 (23.9±3.6 versus 13.7±3.1, P<0.05) in ischaemic myocardium was significantly greater in the BM-MNC group than the saline group. The capillary density in ischaemic myocardium demonstrated a significant positive correlation with VEGF expression (r=0.61, P<0.001). Conclusion Catheter-based direct intramyocardial injection of BM-MNC enhanced angiogenesis more effectively than BM-EPC or saline, possibly via a paracrine effect, with increased expression of VEGF that subsequently improved cardiac performance of ischaemic myocardium.