Autologous bone-marrow mononuclear cell transplantation after acute myocardial infarction: comparison of two delivery techniques.

The objective of this study was to investigate safety and feasibility of autologous bone marrow mononuclear cells (BMMNC) transplantation in ST elevation myocardial infarction (STEMI), comparing anterograde intracoronary artery (ICA) delivery with retrograde intracoronary vein (ICV) approach. An open labeled, randomized controlled trial of 30 patients admitted with STEMI was used. Patients were enrolled if they 1) were successfully reperfused within 24 h from symptoms onset and 2) had infarct size larger than 10% of the left ventricle (LV). One hundred million BMMNC were injected in the infarct-related artery (intra-arterial group) or vein (intravenous group), 1% of which was labeled with Tc(99m)-hexamethylpropylenamineoxime. Cell distribution was evaluated 4 and 24 h after injection. Baseline MRI was performed in order to evaluate microbstruction pattern. Baseline radionuclide ventriculography was performed before cell transfer and after 3 and 6 months. All the treated patients were submitted to repeat coronary angiography after 3 months. Thirty patients (57 +/- 11 years, 70% males) were randomly assigned to ICA (n = 14), ICV (n = 10), or control (n = 6) groups. No serious adverse events related to the procedure were observed. Early and late retention of radiolabeled cells was higher in the ICA than in the ICV group, independently of microcirculation obstruction. An increase of EF was observed in the ICA group (p = 0.02) compared to baseline. Injection procedures through anterograde and retrograde approaches seem to be feasible and safe. BMMNC retention by damaged heart tissue was apparently higher when the anterograde approach was used. Further studies are required to confirm these initial data.

Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model.

BACKGROUND: Bone marrow-derived stem cells are under investigation as a treatment for ischemic heart disease. Mesenchymal stem cells (MSCs) have been used preferentially in the acute ischemia model; data in the chronic ischemia model are lacking. METHODS AND RESULTS: Twelve dogs underwent ameroid constrictor placement. Thirty days later, they received intramyocardial injections of either MSCs (100x10(6) MSCs/10 mL saline) (n=6) or saline only (10 mL) (controls) (n=6). All were euthanized at 60 days. Resting and stress 2D echocardiography was performed at 30 and 60 days after ameroid placement. White blood cell count (WBC), C-reactive protein (CRP), creatine kinase MB (CK-MB), and troponin I levels were measured. Histopathological and immunohistochemical analyses were performed. Mean left ventricular ejection fraction was similar in both groups at baseline but significantly higher in treated dogs at 60 days. WBC and CRP levels were similar over time in both groups. CK-MB and troponin I increased from baseline to 48 hours, eventually returning to baseline. There was a trend toward reduced fibrosis and greater vascular density in the treated group. MSCs colocalized with endothelial and smooth muscle cells but not with myocytes. CONCLUSIONS: In a canine chronic ischemia model, MSCs differentiated into smooth muscle cells and endothelial cells, resulting in increased vascularity and improved cardiac function.

Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy.

BACKGROUND: We recently reported the safety and feasibility of autologous bone marrow mononuclear cell (ABMMNC) injection into areas of ischemic myocardium in patients with end-stage ischemic cardiomyopathy. The present study evaluated the safety and efficacy of this therapy at 6- and 12-month follow-up. METHODS AND RESULTS: Twenty patients with 6- and 12-month follow-up (11 treated subjects; 9 controls) were enrolled in this prospective, nonrandomized, open-label study. Complete clinical and laboratory evaluations as well as exercise stress (ramp treadmill), 2-dimensional Doppler echocardiography, single-photon emission computed tomography (SPECT) perfusion scanning, and 24-hour Holter monitoring were performed at baseline and follow-up. Transendocardial delivery of ABMMNCs was performed with the aid of electromechanical mapping to identify viable myocardium. Each patient received 15 ABMMNC injections of 0.2 mL each. At 6 and 12 months, total reversible defect, as measured by SPECT perfusion scanning, was significantly reduced in the treatment group as compared with the control group. At 12 months, exercise capacity was significantly improved in the treatment group. This improvement correlated well with monocyte, B-cell, hematopoietic progenitor cell, and early hemapoietic progenitor cell phenotypes. CONCLUSIONS: The 6- and 12-month follow-up data in this study suggest that transendocardial injection of ABMMNCs in patients with end-stage ischemic heart disease may produce a durable therapeutic effect and improve myocardial perfusion and exercise capacity.

Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction - MiHeart/AMI study.

BACKGROUND: Myocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls. METHODS: A sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 x 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum). IMPLICATIONS: Many phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required. TRIAL REGISTER: This trial is registered at the NIH registry under the number NCT00350766.