Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: Safety and efficacy studies

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Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: Safety and efficacy studies Christof Stamm, MD, Hans-Dieter Kleine, MD, Yeong-Hoon Choi, MD, Simone Dunkelmann, MD, Jan-Arne Lauffs, Björn Lorenzen, MD, Arpad David, MD, Andreas Liebold, MD, Christoph Nienaber, MD, David Zurakowski, PhD, Mathias Freund, MD, Gustav Steinhoff, MD The Journal of Thoracic and Cardiovascular Surgery Volume 133, Issue 3, Pages 717-725.e5 (March 2007) DOI: 10.1016/j.jtcvs.2006.08.077 Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Consolidated Standards of Reporting Trials flowchart of trial history. CABG, coronary artery bypass grafting. The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Echocardiographic data of patients included in safety trial (n = 15). A, Relative to preoperative (preop) data, left ventricular ejection fraction (LVEF) increased significantly in response to coronary artery bypass grafting with CD133+ cell injection (F = 6.03, P = .012, repeated-measures analysis of variance). Left ventricular ejection fraction values were significantly higher than preoperative values at discharge and at 6 and 18 months (all P < .05). B, Trend toward sustained reduction in left ventricular end-diastolic volume (P = .06, preoperative vs discharge). Box plots indicate 25th and 75th percentiles (solid box), median (white bar), and minimum and maximum values of each data set (whiskers). Asterisk indicates P < .05 versus preoperative data. The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Representative single-photon emission computed tomographic scans of patient in safety trial who underwent bypass grafting to left anterior descending coronary artery and its branches, as well as injection of 5 × 106 CD133selected/CD34+ cells in posterior infarct area. At discharge (second panel), tracer activity in infarct area was still diminished, but at 6 months (third panel), perfusion had virtually returned to normal. The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Left ventricular ejection fraction (LVEF) before surgery (preoperative) and at 6 months’ follow-up (6 months) for individual patients. A, In patients undergoing coronary artery bypass grafting alone (n = 20), average LVEF (horizontal bar) rose from 37.9% ± 10.3% to 41.3% ± 9.1% (F = 7.72, P = .012, repeated-measures analysis of variance). B, In patients who underwent coronary artery bypass grafting with CD133+ bone marrow cell injection (n = 20), average left ventricular ejection fraction rose from 37.4% ± 8% to 47.1% ± 7% (F = 14.84, P < .0001, repeated-measures analysis of variance). Analysis of variance revealed significantly greater increase with coronary artery bypass grafting with CD133+ cell injection relative to coronary artery bypass grafting alone (P = .02). The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Mean left ventricular ejection fraction (LVEF) for coronary artery bypass grafting (CABG) and coronary artery bypass grafting with cellular therapy (CABG & cells) groups, indicating significant improvement for both groups between preoperative baseline and 6 months but with much larger improvement in patients treated with coronary artery bypass grafting with cells than with those treated with coronary artery bypass grafting alone (9.7% ± 8.8% vs 3.4% ± 5.5%, respectively). There was no significant mean difference in left ventricular ejection fraction between 2 weeks and 6 months in coronary artery bypass grafting alone group (P = .52), whereas significant increase was seen in coronary artery bypass grafting with cellular therapy group (F = 14.84, P < .001). Error bars represent SD. Asterisk denotes significant group difference at 6 months (mean difference 6.3%, 95% confidence interval 3%-11%, P < .01). The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure 6 Association between preoperative left ventricular ejection fraction (LVEF) and gain in left ventricular ejection fraction at 6-month follow-up. A, Linear regression indicated trend toward inverse correlation between preoperative left ventricular ejection fraction and postoperative change in left ventricular ejection fraction. B, All cell-treated patients (safety and efficacy trials combined) grouped according to preoperative left ventricular ejection fraction (<35% vs >35%). Patients with preoperative left ventricular ejection fraction less than 35% had increase in LVEF by average of 15.4%, whereas patients with baseline LVEF greater than 35% had increase by only 7.8% (F = 5.87, P = .02, 2-way analysis of variance). The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 Bland–Altman plot showing relationship between average left ventricular ejection fraction (LVEF) versus left ventricular ejection fraction difference between magnetic resonance imaging (MRI) and echocardiography and revealing in general that echocardiography provides slight linear underestimation of left ventricular ejection fraction relative to cardiac magnetic resonance imaging. Mean difference is 2.8% (solid line), and variability of difference is represented as 95% confidence interval or limits of agreement (±2 SD, dashed lines). Bland–Altman plot revealed significant underestimation of left ventricular ejection fraction with echocardiography relative to magnetic resonance imaging (P < .01, paired t test), although average difference was constant through range of left ventricular ejection fraction (slope not significantly different from 0, P = .16). The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure E2 Myocardial perfusion in ischemic myocardium of patients included in safety study. Activity in cell-treated area of interest was quantified by computerized colorimetric analysis and expressed asl ratio with respective preoperative (preop) value. Overall, there was sustained improvement of perfusion in target area (P < .01, Wilcoxon signed rank test). Box plots indicate 25th and 75th percentiles (solid box), median (white bar), and minimum and maximum values of each data set (whiskers). The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions

Figure E3 Myocardial perfusion in ischemic myocardium of patients included in efficacy study before operation (preop), at discharge, and at 6 months’ follow-up. Activity in cell-treated area of interest was quantified by computerized colorimetric analysis and expressed as ratio with respective preoperative value. Solid box represents patients undergoing coronary artery bypass grafting with CD133+ cell injection; open box represents patients undergoing coronary artery bypass grafting alone. Box plots indicate 25th and 75th percentiles (box), median (bar), and minimum and maximum values of each data set (whiskers). The Journal of Thoracic and Cardiovascular Surgery 2007 133, 717-725.e5DOI: (10.1016/j.jtcvs.2006.08.077) Copyright © 2007 The American Association for Thoracic Surgery Terms and Conditions