Intracoronary Transplantation of Non-Expanded Peripheral Blood-Derived Mononuclear Cells Promotes Improvement of Cardiac Function in Patients With Acute Myocardial Infarction

Abstract

ifferentiation of mesodermal cells to angioblasts and subsequent endothelial differentiation was believed to exclusively occur in embryonic development, 1 but this dogma was overturned when human adult peripheral blood mononuclear cells (PBMNCs) were demonstrated to differentiate into the endothelial lineage. 2 These cells named "endothelial progenitor cells" (EPCs) expressed endothelial markers, and were incorporated into Circulation Journal Vol.71, August 2007 the sites of ischemia. 3,4 We have recently demonstrated that bone marrow mononuclear cells (BMMNCs) contain EPCs in the CD34 + cell fraction and various proangiogenic factors, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and angiopoietin 1 in the CD34 -cell fraction, and that implantation of BMMNCs into the site of ischemia enhances angiogenesis via harmonic supply of EPCs and angiogenic factors. 5,6 This technique has been used clinically and developed as a useful therapeutic option for human critical limb ischemia. 7 The concept of the heart as an organ composed of terminally differentiated myocytes incapable of regeneration is also being challenged. [8][9][10] Although attempts to replace necrotic tissue by transplanting other cells (eg, fetal cardiac myocytes or skeletal myoblasts) succeeded in reconstituting heart muscle, these cells failed to completely integrate structurally and to display characteristic physiological function. [11][12][13] In contrast, bone marrow cells (BMCs) have the ability to differentiate into various tissue and are likely to Circ J 2007; 71: 1199 -1207 (Received January 17, 2007 revised manuscript received March 28, 2007; accepted April 24, 2007 Background Transplantation of non-expanded peripheral blood mononuclear cells (PBMNCs) enhances neovessel formation in ischemic myocardium and limbs by releasing angiogenic factors. This study was designed to examine whether intracoronary transplantation of PBMNCs improves cardiac function after acute myocardial infarction (AMI). Methods and ResultsAfter successful percutaneous coronary intervention (PCI) for a ST-elevation AMI with occlusion of proximal left anterior descending coronary artery within 24 h, patients were assigned to either a control group or the PBMNC group that received intracoronary infusion of PBMNCs within 5 days after PCI. PBMNCs were obtained from patients by COBE spectra-apheresis and concentrated to 10 ml, 3.3 ml of which was infused via over-the-wire catheter. The primary endpoint was the global left ventricular ejection fraction (LVEF) change from baseline to 6 months' follow-up. The data showed that the absolute increase in LVEF was 7.4% in the control group and 13.4% (p=0.037 vs control) in the PBMNC group. Cell therapy resulted in a greater tendency of ∆Regional ejection fraction (EF) or significant improvement in the wall motion score index and Tc-99m-tetrofosmin perfusion defect score associated with the infarct area, compared with controls. Moreover, intracoronary administration of PBMNCs did not ex...

SPECT and PET to optimize cardiac stem cell therapy

“…Experimental and clinical studies of stem cell transplantation in the heart reveal that stem cells can differentiate into cardiac myocytes, endothelial cells, and secrete paracrine factors that reduce myocyte death, improve the microcirculation, attenuate adverse remodeling, and boost the regenerative capacity of the heart postinfarct. Unfortunately, the functional benefit seen following transplantation is modest at best, 1,7,9,13,16,[19][20][21]29 irrespective of the cell type and mode of delivery, because of very low levels of engraftment stemming from cell egress from the heart immediately following intra-myocardial cell delivery (low acute retention 30 ) and continued cell loss due to anoikis/apoptosis and necrosis (low engraftment 31,32 ). Low levels of cell engraftment results in small numbers of cells being available for cardiac differentiation and for secretion of paracrine factors.…”

“…Hence, it is important to quantify engraftment in vivo and examine the influence of cell number on functional benefit and cardiac electrophysiology. PET and SPECT imaging have the potential to play a major role in pre-clinical and clinical studies of stem cell therapies because they provide information on myocardial viability, ejection fraction, infarct size, coronary flow reserve, and myocardial perfusion (which are important endpoints following stem cell transplantation) [1][2][3]6,7,9,[12][13][14]16,19,[21][22][23][24][27][28][29][35][36][37][38][39][40][41][42][43] in addition to permitting quantification of stem cell engraftment.…”

Enhanced mesenchymal cell engraftment by IGF-1 improves left ventricular function in rats undergoing myocardial infarction

“…Transplantation of bone marrow-derived cells has been shown to improve cardiac function in animal models of myocardial hibernation and myocardial infarction (MI) [1,2]. The cell therapy using bone marrow-derived stem cells was also found to be effective in patients with ischemic cardiomyopathy and acute myocardial infarction [3][4][5], although contradictory results have also been reported [6].…”

Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene

“…Recently, Tastumi et al [40] reported that intracoronary infusion of non-expanded peripheral blood MNCs (5 × 10 9 cells) improved cardiac function in patients with myocardial infarction. In addition, hematopoietic progenitor cells (5.5 ± 3.9 × 10 6 ) purified from peripheral blood MNCs in TOPCARE-AMI trial improved cardiac function.…”