Background-This study evaluated the hypothesis that transendocardial injections of autologous mononuclear bone marrow cells in patients with end-stage ischemic heart disease could safely promote neovascularization and improve perfusion and myocardial contractility. Methods and Results-Twenty-one patients were enrolled in this prospective, nonrandomized, open-label study (first 14 patients, treatment; last 7 patients, control). Baseline evaluations included complete clinical and laboratory evaluations, exercise stress (ramp treadmill), 2D Doppler echocardiogram, single-photon emission computed tomography perfusion scan, and 24-hour Holter monitoring. Bone marrow mononuclear cells were harvested, isolated, washed, and resuspended in saline for injection by NOGA catheter (15 injections of 0.2 cc). Electromechanical mapping was used to identify viable myocardium (unipolar voltage Ն6.9 mV) for treatment. Treated and control patients underwent 2-month noninvasive follow-up, and treated patients alone underwent a 4-month invasive follow-up according to standard protocols and with the same procedures used as at baseline. Patient population demographics and exercise test variables did not differ significantly between the treatment and control groups; only serum creatinine and brain natriuretic peptide levels varied in laboratory evaluations at follow-up, being relatively higher in control patients. At 2 months, there was a significant reduction in total reversible defect and improvement in global left ventricular function within the treatment group and between the treatment and control groups (Pϭ0.02) on quantitative single-photon emission computed tomography analysis. At 4 months, there was improvement in ejection fraction from a baseline of 20% to 29% (Pϭ0.003) and a reduction in end-systolic volume (Pϭ0.03) in the treated patients. Electromechanical mapping revealed significant mechanical improvement of the injected segments (PϽ0.0005) at 4 months after treatment. Conclusions-Thus, the present study demonstrates the relative safety of intramyocardial injections of bone marrowderived stem cells in humans with severe heart failure and the potential for improving myocardial blood flow with associated enhancement of regional and global left ventricular function. (Circulation. 2003;107:2294-2302.)

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 (100ϫ10 6 MSCs/10 mL saline) (nϭ6) or saline only (10 mL) (controls) (nϭ6). 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

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Context Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, since a substantial number of patients may not present for early cell delivery, we investigated the efficacy of autologous BMC delivery 2–3 weeks post-MI. Objective To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2–3 weeks following first MI. Design, Setting, and Patients LateTIME is a randomized, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute - sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of 87 patients with significant LV dysfunction (LVEF ≤ 45%) following successful primary percutaneous coronary intervention (PCI). Interventions Intracoronary infusion of 150 × 106 autologous BMCs (total nucleated cells) or placebo (2:1 BMC:placebo) was performed within 12 hours of bone marrow aspiration after local automated cell processing. Main Outcome Measures The primary endpoints were changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone from baseline to 6 months as measured by cardiac MRI at a core lab blinded to treatment assignment Secondary endpoints included changes in LV volumes and infarct size. Results 87 patients were randomized between July 2008 and February 2011: mean age = 57 ± 11 yrs, 83% male. Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible and safe. The change from baseline to six months in the BMC group, when compared to the placebo group, for LVEF (48.7 to 49.2% vs. 45.3 to 48.8%; Difference = −3.0, 95% CI −7.0 to 0.9), wall motion in the infarct zone (6.2 to 6.5 vs. 4.9 to 5.9 mm; Difference = −0.7, 95% CI −2.8 to 1.3), and wall motion in the border zone (16.0 to 16.6 mm vs. 16.1 to 19.3 mm; Difference = −2.6; 95% CI −6.0 to 0.8) were not statistically significant. There was no significant change in LV volumes and infarct volumes decreased by a similar amount in both groups at 6 months compared to baseline. Conclusions Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs compared to intracoronary placebo infusion, 2–3 weeks after PCI did not improve global or regional function at 6 months.