Evaluation Of Dilated Cardiomyopathy By Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation In Rabbits And Humans

Bone marrow-derived cells with the self-renewal ability and multipotency of differentiation have shown the capacity of regenerating damaged myocadial tissue. Bone marrow mononuclear cells(BMMNCs)contain a group of multipotent adult stem cells have been explored as vehicles for cell therapy replacing damaged myocardium of dilated cardiomyopathy(DCM), it may be a new therapeutic method for end stage cardiovascular diseases. In the experimental study, we establish adriamycin-induced dilated cardiomyopathic model through ear-border vein in New Zealand rabbit, and autologous BMMNCs separated from bone marrow by density gradient centrifugation were infused into left coronary artery by cardiac catheterization which is similar to intracoronary BMMNCs transplantation in clinical trials, then we evalute the cardiac function and myocardial matrix remodeling after the cell transplantation. We evalute the efficacy and safety of dilated cardiomyopathy by autologous intracoronary BMMNCs transplantation, then preliminarily explore the inner mechanism of the marked therapeutic effect in our prospective randomized controlled clinical trial.Partâ… Evaluation of dilated cardiomyopathy by autologous intracoronary mononuclear bone marrow cell transplantation in rabbitsObjective To establish dilated cardiomyopathic model in New Zealand rabbit. We evaluted the animal model by light microscopy, electron microscopy, myocardial perfusion imaging and indexes of hemodynamics. Autologous BMMNCs separated from bone marrow by density gradient centrifugation were infused into left coronary artery by cardiac catheterization which is similar to intracoronary BMMNCs transplantation in clinical trials, then we evaluted the cardiac function and myocardial matrix remodeling after the cell transplantation.Methods Adriamycin was injected to produce New Zealand rabbit DCM model through ear-border vein. Indexes of hemodynamics and serum BNP were measured as baseline characteristics, ^99mTc-MIBI myocardial perfusion imaging showed the difference between DCM group and normal group. Histomorphological changes were evaluted by light microscopy and ultrastructure characteristics were investigated by transmission electron microscopy. Twenty survived DCM rabbits were randomly divided into intracoronary transplant group and control group equally. Autolougous BMMNCs were labeled with DAPI and infused into left coronary artery in cell transplant group through plastic 4F catheter. Four weeks after transplantation, the differentiation and attribution of BMMNCs were evaluted, indexes of hemodynamics and serum BNP were measured to evalute the cardiac function again. The collagen volume fraction(CVF), MMP-2 and MMP-3 in the left ventricular myocardium were semi-quantitative determined to evalute the cardiac matrix remodeling after intracoronary BMMNCs transplantation.Results ^99mTc-MIBI myocardial perfusion imaging indicated low infusion in cardiac apex, ventricular cavity became enlarged and the wall was thin in DCM group, the histomorphological and ultrastructure changes of myocardium coincide with the characteristics of DCM. After 4 weeks of intracoronary transplantation, indexes of hemodynamics examination indicated there was statistical significance compared with control group. Serum BNP was decreased significantly in intracoronary transplant group (P=0.012), the expression of MMP-2 and MMP-3 in the myocardium were also lower than control group, whereas the CVF was increased little, there was statistical significance compared with control group. The contribution of DAPI labeling BMMNCs was observed damaged myocadial tissue by fluorescent microscope, while no evidence indicated the existing of transplant cells by transmission electron microscopy.Conclusions The adriamycin-induced cardiomyopathic rabbit model was similar to the pathophysiological changes of DCM in humans, it may be used for stem cell basic research in cardiology. Autologous intracoronary transplantation in DCM rabbits significantly improved the cardiac function by enrichiment of BMMNCs in myocardium and delayed the progress of collagen metabolism in cardiac matrix remodeling. The beneficial effects might be mediated by their ability to decrease the stress expression of MMPs.Partâ…¡Evaluation of dilated cardiomyopathy by autologous intracoronary mononuclear bone marrow cell transplantation in humansObjective To evalute dilated cardiomyopathy by autologous intracoronary mononuclear bone marrow cells transplantation in our prospective randomized controlled clinical trial and explore the inner mechanism of the marked therapeutic effect preliminarily.Methods Twenty-eight patients with dilated cardiomyopathy were included. After standard therepy for chronic heart failure, 16 patients were transplanted with autolougous BMMNCs via coronary artery. Another 12 patients were treated by standard therepy alone. During 6 months of follow-up, cardiac examinations(echocardiography, ¹³N-NH3 myocardial perfusion and ¹⁸F-FDG metabolism imaging, ^99mTc-MIBI myocardial perfusion imaging, serum NT-proBNP, 6 min walking test and Minnesota living with heart failure questionnaire) were performed to evalute the efficacy of autologous intracoronary BMMNCs transplantation.Results After 3 months of follow-up, LVEF had increased significantly within the cell therapy group [from(28.31±4.52)ï¼…to(31.17±4.61)ï¼…, P=0.003], while there was no statistical significance compared with control group(P=0.126). After 6 months of follow-up, LVEF increased considerably, while there was no statistical significance compared with 3 months. PET/CT was performed and showed significant improvement in ¹³N-NH3 myocardial perfusion and ¹⁸F-FDG metabolism imaging. ^99mTc-MIBI myocardial perfusion imaging indicated significant improvement in cell transplantation group. Further cardiac examinations(NT-proBNP, 6 min walking test and Minnesota living with heart failure questionnaire) indicated significantly different from the baseline.Conclusions Autologous intracoronary BMMNCs transplantation for dilated cardiomyopathy is safe and effective under clinical conditions. The marked therapeutic effect may be contributed by stem-associated myocardial regeneration and neovascularization.