Improvement of Collateral Perfusion and Regional Function by Implantation of Peripheral Blood Mononuclear Cells Into Ischemic Hibernating Myocardium

Abstract

Objective-This study was performed to evaluate the angiogenic effect of implantation of peripheral blood mononuclear cells (PB-MNCs) compared with bone marrow mononuclear cells (BM-MNCs) into ischemic hibernating myocardium. Methods and Results-A NOGA electromechanical system was used to map the hibernating region and to inject cells.PB-MNCs and BM-MNCs contained similar levels of vascular endothelial growth factor and basic fibroblast growth factor, whereas contents of angiogenic cytokines (interleukin-1␤ and tumor necrosis factor-␣) were larger in PB-MNCs. Numbers of endothelial progenitors were Ϸ500-fold higher in BM-MNCs. In BM-MNC-implanted myocardia of pigs, an increase in systolic function (ejection fraction from 33% to 52%) and regional blood flow (2.1-fold) and a reduction of the ischemic area (from 29% to 8%) were observed. PB-MNC implantation reduced the ischemic area (from 31% to 17%), the extent of which was less than that seen with BM-MNCs. In saline-implanted myocardium, the ischemic area expanded (from 28% to 38%), and systolic function deteriorated. Angiography revealed an increase in collateral vessel formation by PB-MNC or BM-MNC implantation. Capillary numbers were increased 2.6-and 1.7-fold by BM-MNC and PB-MNC implantation, respectively. BM-MNCs but not PB-MNCs were incorporated into neocapillaries. Conclusions-Catheter-based implantation of PB-MNCs can effectively improve collateral perfusion and regional function in hibernating ischemic myocardium by its ability to mainly supply angiogenic factors and cytokines. T herapeutic angiogenesis is a new and promising strategy to revascularize ischemic myocardium by stimulation of the growth of new blood vessels or maturation of preexisting collaterals. 1 Angiogenesis is induced by surgical or catheterbased delivery of angiogenic molecules, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). 2,3 Double-blind placebo-controlled clinical studies have indicated that intracoronary infusion of VEGF 4 or FGF2 5 does not improve myocardial perfusion, whereas catheter-based gene transfer of VEGF produces an increase in regional perfusion in patients with ischemic myocardium. 6 Myogenic cell grafting into the damaged myocardium is a promising approach for the treatment of heart failure. We and others have shown previously that intramyocardial transplantation of bone marrow (BM) mononuclear cells (MNCs) improves regional perfusion and systolic function in animal models of ischemic heart failure. [7][8][9][10] Marked increase in cardiac function after BM-MNC implantation may be due not only to neovascularization but also to cardiomyogenesis derived from marrow hematopoietic cells (see review 11 ) and/or marrow mesenchymal cells. 12 Hamano et al 13 reported the clinical efficacy and safety of BM-MNC implantation in 5 patients with ischemic heart disease in combination with bypass surgery. Thus, BM-MNC implantation may be feasible to salvage myocardial ischemia, although this procedure requires a minithoracotomy to exp...

Angiotensin II promotes NO production, inhibits apoptosis and enhances adhesion potential of bone marrow-derived endothelial progenitor cells

“…PB-MNCs effectively improve collateral perfusion primarily through their ability to supply angiogenic factors and cytokines. The implanted PB-MNCs were not incorporated into neocapillaries, whereas the implanted BM-MNCs were shown to differentiate into vascular ECs [18,19]. In addition, it has been shown that re-endothelialization at sites of vascular damage is also modulated by the mobilization and incorporation of BM-derived EPCs [20].…”

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

“…86 Others showed that transendocardial delivery of unfractionated autologous BM-MNCs induced collateral formation and rescued ventricular function in hibernating porcine myocardium. [87][88][89][90] Orlic et al reported that implantation of bone marrow-derived Lin Ϫ /c-kit ϩ cells, a subpopulation of BM-MNCs, into the infarct border enhanced new vessel formation. 91 In rats with limb ischemia, local intramuscular delivery of autologous BM-MNCs restored blood flow and exercise in association with enhanced neovascularization of the ischemic muscle.…”

Bone marrow cell therapy after acute myocardial infarction: the HEBE trial in perspective, first results

“…This hypothesis was strengthened by Kamihata et al's group showing an increased number of arterioles in response to peripheral blood mononuclear cells (PBMCs) and BMMC injection in the ischaemic myocardium of a pig model of AMI. 9 After the first clinical trials of intracoronary infusion of BMMCs after AMI in patients showed the method to be safe and feasible, 10,11 large-scale randomised trials were initiated to further evaluate the therapeutic effects of BMMC therapy. In the largest study so far, the REPAIR-AMI trial, 204 patients with AMI were randomly assigned to treatment with intracoronary infusion of BMMCs or placebo.…”

“…17 Based on the study by Kamihata et al, the beneficial effects of the BMMCs can be attributed to the paracrine effects of all mononuclear cell subsets, rather than the progenitor subpopulation. 18 For that reason, a patient group receiving intracoronary autologous PBMCs was included in the trial. A total of 200 patients with AMI treated with primary PCI with stent placement underwent magnetic resonance imaging (MRI) followed by intracoronary infusion of autologous BMMCs, intracoronary infusion of autologous PBMCs, or standard therapy (randomly assigned to a 1:1:1 ratio).…”