REVIEW ARTICLE Adult Bone Marrow–Derived Cells for Cardiac Repair A Systematic Review and Meta-analysis Ahmed Abdel-Latif, MD; Roberto Bolli, MD; Imad M. Tleyjeh, MD, MSc; Victor M. Montori, MD, MSc; Emerson C. Perin, MD; Carlton A. Hornung, PhD, MPH; Ewa K. Zuba-Surma, PhD; Mouaz Al-Mallah, MD; Buddhadeb Dawn, MD Background: The results from small clinical studies sug- gest that therapy with adult bone marrow (BM)– derived cells (BMCs) reduces infarct size and improves left ventricular function and perfusion. However, the effects of BMC transplantation in patients with ischemic heart disease remains unclear. ing progenitor cells. Compared with controls, BMC transplantation improved left ventricular ejection fraction (pooled difference, 3.66%; 95% confidence interval [CI], 1.93% to 5.40%; P⬍.001); reduced infarct scar size (−5.49%; 95% CI, −9.10% to −1.88%; P= .003); and reduced left ventricular end-systolic volume (−4.80 mL; 95% CI, −8.20 to −1.41 mL; P= .006). Methods: We searched MEDLINE, EMBASE, Science Citation Index, CINAHL (Cumulative Index to Nursing and Allied Health), and the Cochrane Central Register of Controlled Trials (CENTRAL) (through July 2006) for randomized controlled trials and cohort studies of BMC transplantation to treat ischemic heart disease. We conducted a random-effects meta-analysis across eligible studies measuring the same outcomes. Results: Eighteen studies (N = 999 patients) were eligible. The adult BMCs included BM mononuclear cells, BM mesenchymal stem cells, and BM-derived circulat- Author Affiliations: Division of Cardiology and the Institute of Molecular Cardiology (Drs Abdel-Latif, Bolli, Zuba-Surma, and Dawn) and Department of Epidemiology and Population Health, School of Public Health and Information Sciences (Dr Hornung), University of Louisville, Louisville, Ky; Knowledge and Encounter Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minn (Drs Tleyjeh and Montori); King Fahd Medical City, Riyadh, Saudi Arabia (Dr Tleyjeh); Department of Cardiology, University of Texas, Houston (Dr Perin); and Division of Cardiovascular Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (Dr Al-Mallah). I Conclusions: The available evidence suggests that BMC transplantation is associated with modest improvements in physiologic and anatomic parameters in patients with both acute myocardial infarction and chronic ischemic heart disease, above and beyond conventional therapy. Therapy with BMCs seems safe. These results support conducting large randomized trials to evaluate the impact of BMC therapy vs the standard of care on patient-important outcomes. Arch Intern Med. 2007;167:989-997 SCHEMIC HEART DISEASE (IHD) IS a major cause of mortality and morbidity worldwide and accounts for approximately 20% of all deaths in the United States.1-3 Despite significant advances in medical therapy and interventional strategy, the prognosis of millions of patients with acute myocardial infarction (MI) and ischemic cardiomyopathy remains dismal.4,5 Although the underlying mechanism remains controversial, numerous studies in animals have documented that transplantation of bone marrow (BM)–derived cells (BMCs) following acute MI and in ischemic cardiomyopathy is associated with a reduction in infarct scar size and improvements in left ventricular (LV) function and perfusion.6 In humans, transplantation of BMCs and BM-derived circulating progenitor cells (CPCs) in patients with acute MI as well as chronic IHD has yielded similar encouraging results.7,8 However, these studies in humans are heterogeneous in their methods and have (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 989 yielded disparate results. These studies have each enrolled a small number of patients and have fallen short of providing conclusive results. Thus, the extent to which BMC transplantation can improve outcomes in patients with IHD remains unclear. To our knowledge, there are no comprehensive syntheses of these data. Therefore, we performed a systematic review of the literature and meta-analysis to critically evaluate and summarize the potential therapeutic benefits of BMC transplantation for cardiac repair in patients with IHD. METHODS REVIEW QUESTION AND STUDY PROTOCOL The review question was to what extent does BMC transplantation affect cardiovascular outcomes in patients with IHD? We report this protocol-driven systematic review according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE)9 and Quality of Re- WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. plete search strategy is available on request from the authors. 213 Reports Identified by Initial Search DATA ABSTRACTION 81 Reports Excluded (Review Articles and Editorials) 132 Reports Reviewed 95 Reports Excluded (Animal Studies) 37 Reports Examined in Detail 19 Reports Excluded 6 BMCs Were Mobilized by Cytokines 6 Lack of a Control Group 7 BMCs Were Studied In Vitro or Not Transplanted 12 RCTs and 6 Cohort Studies Included in the Meta-analysis Figure 1. Flow diagram of eligible studies of bone marrow–derived cells (BMCs) transplantation in patients with acute myocardial infarction and chronic ischemic heart disease. RCTs indicates randomized controlled trials. porting of Meta-analysis (QUOROM)10 statements. ELIGIBILITY CRITERIA Two reviewers (A.A.-L. and I.M.T.) judged eligibility of studies in duplicate and independently. Eligible studies were randomized controlled trials (RCTs) and cohort studies examining the effects of BMC transplantation on cardiovascular outcomes in patients with IHD. Because cytokines may exert cardiovascular effects, we excluded studies of cardiac repair solely via the mobilization of endogenous BMCs with systemic administration of cytokines. SEARCH STRATEGY We searched MEDLINE ( January 1980 to July 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) ( July 2006), EMBASE ( January 1980 to July 2006), CINAHL (Cumulative Index to Nursing and Allied Health) (January 1982 to July 2006), the US Food and Drug Administration Web site (http: //www.fda.gov), and BIOSIS Previews ( January 1980 to July 2006) using the following database-appropriate terms: coronary artery disease, myocardial infarction, stem cells, progenitor cells, bone marrow, circulating progenitor cells, myocardial regeneration, and cardiac repair. We sought additional studies by reviewing the reference lists of eligible studies and relevant review articles. The com- Two reviewers (A.A.-L. and I.M.T.) working in duplicate and independently used a standardized form to abstract the data from each study. The corresponding author (B.D.) solved disagreements that could not be solved by consensus. When necessary, LV end-diastolic volume was estimated from LV end-diastolic volume index, and infarct volume/mass was converted to infarct size expressed as a percentage of LV by calculating total LV myocardial volume from LV mass index. Data from echocardiography and cardiac magnetic resonance imaging were considered equivalent. When both echocardiographic and cardiac magnetic resonance imaging functional data were available, cardiac magnetic resonance imaging data were preferentially used. QUALITY ASSESSMENT We used the criteria by Jüni et al11 to ascertain the methodological quality of included randomized trials11 and a modified Newcastle-Ottawa scale12 to assess the quality of cohort studies. DATA ANALYSIS Meta-analyses The main outcomes of our review were change from baseline in mean LV ejection fraction, infarct scar size, LV endsystolic volume, and LV end-diastolic volume. We conducted random-effects meta-analyses to pool these outcomes across included studies, estimating weighted mean differences between BMC-treated patients and control patients and their associated 95% confidence intervals (CIs). We estimated the proportion of between-study inconsistency due to true differences between studies (rather than differences due to random error or chance) using the I2 statistic,13 with values of 25%, 50%, and 75% considered low, moderate, and high, respectively. Funnel plots graphically explored publication bias. We used RevMan version 4.2.7 (Cochrane Collaboration, 2004) for these analyses. Subgroup Analyses We conducted planned subgroup analyses and tested for treatment-subgroup interactions. Planned subgroups comprised the types of study design (RCTs vs cohort studies); the clinical scenario (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 990 in which BMCs were used (acute MI vs chronic IHD); timing of BMC transplantation after MI and/or percutaneous coronary intervention (⬍5 days vs within 5-30 days); the number of cells injected (above vs below the median of 80⫻106 BMCs used in the eligible studies); and the population of BMCs used (BM mononuclear cells vs nonmononuclear cells, including mesenchymal stem cells and BM-derived circulating progenitor cells). Because most of the included studies used the intracoronary route for BMC transplantation, the impact of the route of transplantation on outcomes could not be assessed. RESULTS SEARCH RESULTS Of 213 articles retrieved during the initial search (Figure 1), 81 were not reports of original investigations (review articles and editorials), 95 were conducted in animals, 6 used mobilization rather than transplantation of BMCs, 6 lacked control groups, and 7 were performed in vitro. Eighteen studies (12 RCTs and 6 cohort studies) with a total of 999 patients were eligible for review. The interreviewer agreement on study eligibility was 100%. STUDY CHARACTERISTICS Table 1 summarizes the character- istics of all studies included in our meta-analysis. Notably, the sample size in each study was relatively small (range, 20-204 patients; median, 36 patients), and the follow-up duration was relatively short (range, 3-18 months; median, 4 months). There was considerable heterogeneity in the timing of cell transplantation after MI or percutaneous coronary intervention (range, 1 day to 81 months; median, 9.8 days) and in the number of BMCs used (range, 2⫻106 to 60⫻109 cells [median, 80 ⫻106 BMCs]). STUDY QUALITY Table 2 describes the method- ological quality of the RCTs, and Table 3 describes the quality of the cohort studies. All cohort studies and at least 6 RCTs failed to blind participants and caregivers, WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. Table 1. Characteristics of Studies Included in the Meta-analysis Sample Size Mean Follow-up Duration, mo Assmus et al, 2006 92 3 RCT BMMNC and CPC Bartunek et al,15 2005 Chen et al,16 2004 Erbs et al,17 2005 Ge et al,18 2006 Hendrikx et al,19 2006 Janssens et al,20 2006 Kang et al,21 2006 35 69 26 20 20 67 82 4 6 3 6 4 4 6 Cohort RCT RCT RCT RCT RCT RCT Katritsis et al,22 2005 Lunde et al,23 2006 Meyer et al,24 2006 Mocini et al,25 2006 Perin et al,26 2004 Ruan et al,27 2005 Schächinger et al,28 2006 Strauer et al,29 2002 Strauer et al,30 2005 Li et al,31 2006 22 100 60 36 20 20 204 4 6 18 3 12 6 4 20 36 70 3 3 6 Source 14 Study Design Route of Injection IC ICM BMMNC (CD133⫹) MSC CPC BMMNC BMMNC BMMNC CPC 22 ± 11 ⫻ 106 (CPC), 205 ± 110 ⫻ 106 (BMMNC) 12.6 ± 2.2 ⫻ 106 48-60 ⫻ 109 69 ± 14 ⫻ 106 40 ⫻ 106 60.25 ± 31 ⫻ 106 172 ± 72 ⫻ 106 14 ± 5 ⫻ 108 IC IC IC IC IM IC IC AMI AMI ICM AMI ICM AMI AMI/ICM Cohort RCT RCT Cohort Cohort RCT RCT MSC and EPC BMMNC BMMNC BMMNC BMMNC BMC BMMNC 2-4 ⫻ 106 87 ± 47.7 ⫻ 106 24.6 ± 9.4 ⫻ 108 292 ± 232 ⫻ 106 25.5 ± 6.3 ⫻ 106 NR 236 ± 174 ⫻ 106 IC IC IC IM IM IC IC AMI/ICM AMI AMI ICM ICM AMI AMI 2348 ± 2318 (CPC), 2470 ± 2196 (BMMNC) 11.6 ± 1.4 18.4 ± 0.5 225 ± 87 1 217 ± 162 1-2 (Range) 7 ± 1 (AMI), 517 ± 525 (OMI) 224 ± 470 6 ± 1.3 4.8 ± 1.3 NR NR 1 4.3 ± 1.3 Cohort Cohort RCT BMMNC BMMNC CPC (PBSC) 28 ± 22 ⫻ 106 90 ⫻ 106 72.5 ± 73.3 ⫻ 106 IC IC IC AMI ICM AMI 8±2 823.5 ± 945.5 7±5 Cell Type Clinical Scenario Time From PCI and/or MI to Transplantation, d* No. of Cells Transplanted Abbreviations: AMI, acute myocardial infarction; BMC, bone marrow cell; BMMNC, bone marrow mononuclear cell; CPC, circulating progenitor cell; EPC, endothelial progenitor cells; IC, intracoronary injection; ICM, ischemic cardiomyopathy; IM, intramyocardial injection using electromechanical mapping system; MI, myocardial infarction; MSC, mesenchymal stem cell; NR, not reported; OMI, old myocardial infarction; PBSC, peripheral blood stem cells; PCI, percutaneous coronary intervention; RCT, randomized controlled trial. *Values are given as mean ± SD unless otherwise specified. Table 2. Quality Assessment Scale for Randomized Controlled Trials Included in the Meta-analysis Selection Was Allocation Adequate?* Source of Bias Assmus et al,14 2006 Chen et al,16 2004 Erbs et al,17 2005 Ge et al,18 2006 Hendrikx et al,19 2006 Janssens et al,20 2006 Kang et al,21 2006 Lunde et al,23 2006 Meyer et al,24 2006 Ruan et al,27 2005 Schächinger et al,28 2006 Li et al,31 2006 Performance Detection Was an Adequate Were Groups Were the Was the Method of Similar at the Patients/Caregivers Outcome Randomization Start of the Blinded to the Ascertained Described? Study? Intervention? Blindly? Attrition What Percentage Was Lost to Follow-up? Were All Patients Analyzed in the Group to Which They Were Assigned (Intention-to-Treat Analysis)? Y Y Y Y Y Y N Y Y Y Y N N N Y Y Y Y Y Y N Y Y Y Y Y Y Y Y Y Y Y Y N Y Y N N Y N N Y Y Y Y Y Y Y Y Y N Y Y Y Y 4 0 0 0 0 0 0 0 0 0 0 Y Y Y Y Y Y Y Y Y Y Y Y N Y N N 17 Y *“Adequate” means the use of central site, numeric code, opaque envelopes, drugs prepared by pharmacy, and other appropriate procedures (adapted from Jüni et al11). and at least 2 RCTs and 3 cohort studies failed to blind outcome assessors. The follow-up was complete in all eligible studies. The interreviewer agreement on these quality domains was greater than 90%. META-ANALYSES AND EFFICACY Compared with control, BMC transplantation improved LV ejection fraction by 3.66% (95% CI, 1.93% to 5.40%; [I 2 = 71%; P⬍.001]; (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 991 Figure 2), reduced infarct scar size by 5.49% (95% CI, −9.10% to −1.88% [I2 =66%; P=.003]; Figure 3); reduced LV end-systolic volume by 4.80 mL (95% CI, −8.20 to −1.41 mL; [I2 =0%; P=.006]; Figure 4); and reduced LV end-diastolic volume by WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. Table 3. Modified Newcastle-Ottawa Quality Assessment Scale12 for Cohort Studies Included in the Meta-analysis Selection* Source Outcome‡ Representativeness of the Exposed Cohort Selection of the Nonexposed Cohort Ascertainment of Exposure Incident Disease Comparability† Assessment of Outcome Length of Follow-up Adequacy of Follow-up A A A A A B A A A A A A A A A A A A A A A A A A A NR A A A A A A A A A A B B A A A A A A A A A A Bartunek et al,15 2005 Katritsis et al,22 2005 Mocini et al,25 2006 Perin et al,26 2004 Strauer et al,29 2002 Strauer et al,30 2005 Abbreviation: NR, not reported. *Selection: (1) Representativeness of the exposed cohort: A, truly representative of the average patient with ischemic heart disease; B, somewhat representative of the average patient with ischemic heart disease; C, selected group; and D, no description of the derivation of the cohort. (2) Selection of the nonexposed cohort: A, drawn from the same community as the exposed cohort; B, drawn from a different source; and C, no description of the derivation of the nonexposed cohort. (3) Ascertainment of exposure: A, secure record (eg, surgical records); B, structured interview; C, written self-report; and D, no description. (4) Demonstration that outcome of interest was not present at start of study: A, yes; B, no. †Comparability: Comparability of cohorts on the basis of the design or analysis: A, study controls for comorbidities; B, study controls for additional risk factors (such as age and severity of illness); and C, not done. ‡Outcome: (1) Assessment of outcome: A, independent blind assessment; B, record linkage; C, self-report; and D, no description. (2) Was follow-up long enough for outcomes to occur: A, yes; B, no. (3) Adequacy of follow-up of cohorts: A, complete follow-up—all subjects accounted for; B, subjects lost to follow-up unlikely to introduce bias (small number lost), follow-up rate higher than 90%, or description provided of those lost; C, follow-up rate 90% or lower (select an adequate percentage) and no description of those lost; and D, no statement. Study or Subcategory RCTs Assmus et al,14 2006 (BMCs) Assmus et al,14 2006 (CPCs) Chen et al,16 2004 Erbs et al,17 2005 Ge et al,18 2006 Hendrikx et al,19 2006 Janssens et al,20 2006 Kang et al,21 2006 (AMI) Kang et al,21 2006 (OMI) Lunde et al,23 2006 Meyer et al,24 2006 Ruan et al,27 2005 Schächinger et al,28 2006 Li et al,31 2006 N Treatment, Mean (SD), % N Control Mean (SD), % 28 26 34 11 10 10 33 25 16 50 30 9 95 35 2.90 (3.60) –0.40 (2.20) 18.00 (6.71) 7.20 (11.47) 4.80 (9.56) 6.10 (8.60) 3.40 (6.90) 5.10 (9.32) 0.00 (12.80) 1.20 (7.50) 5.90 (8.90) 5.96 (11.10) 5.50 (7.30) 7.10 (8.00) 18 18 35 11 10 10 34 25 16 50 30 11 92 35 –1.20 (3.00) –1.20 (3.00) 6.00 (7.91) 0.00 (8.97) –1.90 (5.85) 3.60 (9.10) 2.20 (7.30) –0.10 (12.43) 0.20 (10.61) 4.30 (7.10) 3.10 (9.60) –3.21 (7.18) 3.00 (6.50) 1.60 (7.00) 412 Subtotal Favors Control Favors BMC Treatment 395 Weight, % WMD (Random), % (95% CI) 8.09 8.33 6.62 2.80 3.68 3.21 6.68 4.26 3.01 7.21 5.43 2.89 8.04 6.55 4.10 (2.18 to 6.02) 0.80 (–0.82 to 2.42) 12.00 (8.54 to 15.46) 7.20 (–1.40 to 15.80) 6.70 (–0.25 to 13.65) 2.50 (–5.26 to 10.26) 1.20 (–2.20 to 4.60) 5.20 (–0.89 to 11.29) –0.20 (–8.35 to 7.95) –3.10 (–5.96 to –0.24) 2.80 (–1.88 to 7.48) 9.17 (0.77 to 17.57) 2.50 (0.52 to 4.48) 5.50 (1.98 to 9.02) 76.79 3.64 (1.56 to 5.73) Test for Heterogeneity: χ 132 = 59.81 (P<.001), I 2 = 78.3% Test for Overall Effect: Z = 3.42 (P< .001) Cohort Studies Bartunek et al,15 2005 Katritsis et al,22 2005 Mocini et al,25 2006 Perin et al,26 2004 Strauer et al,29 2002 Strauer et al,30 2005 19 11 18 11 10 18 Subtotal 87 7.10 (13.26) 1.95 (7.19) 5.00 (7.65) 5.10 (6.47) 5.00 (9.06) 8.00 (8.06) 16 11 18 9 10 18 4.30 (13.44) 1.62 (6.93) 1.00 (8.51) –3.00 (10.12) 4.00 (7.00) 1.00 (10.00) 2.68 4.40 4.90 3.28 3.59 4.38 2.80 (–6.08 to 11.68) 0.33 (–5.57 to 6.23) 4.00 (–1.29 to 9.29) 8.10 (0.46 to 15.74) 1.00 (–6.10 to 8.10) 7.00 (1.07 to 12.93) 82 23.21 3.83 (1.18 to 6.48) 477 100 3.66 (1.93 to 5.40) Test for Heterogeneity: χ 52 = 4.32 (P = .51), I 2 = 0% Test for Overall Effect: Z = 2.83 (P = .005) Total 499 Test for Heterogeneity: χ 192 = 64.73 (P<.001), I 2 = 70.6% Test for Overall Effect: Z = 4.14 (P<.001) –10 –5 0 5 10 WMD Random (95% CI) Figure 2. Forest plot of unadjusted difference in mean (with 95% confidence intervals [CIs]) improvement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow–derived cells (BMCs) compared with controls. The figure shows the summary of cohort studies and randomized controlled trials (RCTs). Transplantation with BMCs resulted in a 3.66% (95% CI, 1.93% to 5.40%) increase in mean LVEF. The overall effect was statistically significant in favor of BMC therapy. AMI indicates acute myocardial infarction; CPCs, circulating progenitor cells; OMI, old myocardial infarction; and WMD, weighted mean difference. (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 992 WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. Study or Subcategory RCTs Chen et al,16 2004 Erbs et al,17 2005 Janssens et al,20 2006 Lunde et al,23 2006 Meyer et al,24 2006 Subtotal N Treatment, Mean (SD), % N Control Mean (SD), % 34 11 33 50 30 –19.00 (8.54) –1.77 (9.23) –8.91 (11.73) –11.00 (12.70) –7.00 (12.73) 35 11 34 50 30 –5.00 (10.00) –0.93 (9.00) –5.34 (11.71) –7.80 (8.70) –5.82 (10.51) 158 Weight, % WMD (Random), % (95% CI) 14.28 10.01 12.58 14.44 12.18 –14.00 (–18.38 to –9.62) –0.84 (–8.46 to 6.78) –3.57 (–9.18 to 2.04) –3.20 (–7.47 to 1.07) –1.18 (–7.09 to 4.73) 63.50 –4.84 (–10.13 to 0.44) 6.81 8.54 8.71 12.43 –3.10 (–14.02 to 7.82) –1.60 (–10.56 to 7.36) –13.00 (–21.80 to –4.20) –7.00 (–12.72 to –1.28) 53 36.50 –6.58 (–11.06 to –2.11) 213 100 Favors BMC Treatment Favors Control 160 Test for Heterogeneity: χ 42 = 19.45 (P <.001), I 2 = 79.4% Test for Overall Effect: Z = 1.80 (P = .07) Cohort Studies Bartunek et al,15 2005 Perin et al,26 2004 Strauer et al,29 2002 Strauer et al,30 2005 19 11 10 18 Subtotal 58 –5.50 (17.88) –4.40 (9.44) –18.00 (10.44) –8.00 (8.51) 16 9 10 18 –2.40 (15.07) –2.80 (10.74) –5.00 (9.62) –1.00 (9.00) Test for Heterogeneity: χ 32 = 3.64 (P = .30), I 2 = 17.6% Test for Overall Effect: Z = 2.88 (P = .004) Total 216 –5.49 (–9.10 to –1.88) Test for Heterogeneity: χ 82 = 23.23 (P = .003), I 2 = 65.6% Test for Overall Effect: Z = 2.98 (P = .003) –10 –5 0 5 10 WMD Random (95% CI) Figure 3. Forest plot of unadjusted difference in mean (with 95% confidence intervals [CIs]) change in infarct scar size in patients treated with bone marrow–derived cells (BMCs) compared with controls. The figure shows the summary of cohort studies and randomized controlled trials (RCTs). Transplantation with BMCs resulted in a 5.49% (95% CI, −9.10% to −1.88%) decrease in mean infarct scar size. The overall effect was statistically significant in favor of BMC therapy. WMD indicates weighted mean difference. Study or Subcategory RCTs Assmus et al,14 2006 (BMCs) Assmus et al,14 2006 (CPCs) Erbs et al,17 2005 Hendrikx et al,19 2006 Janssens et al,20 2006 Kang et al,21 2006 (AMI) Kang et al,21 2006 (OMI) Meyer et al,24 2006 Ruan et al,27 2005 Schächinger et al,28 2006 Li et al,31 2006 Subtotal N Treatment, Mean (SD), mL N Control Mean (SD), mL 28 26 11 10 33 25 16 30 9 95 35 –3.40 (8.50) –3.40 (22.10) –9.60 (29.85) –8.67 (29.24) –1.87 (19.04) –5.50 (20.91) 3.60 (45.00) –0.85 (28.05) –4.69 (21.88) –0.60 (19.00) –11.20 (22.72) 18 18 11 10 34 25 16 30 11 92 35 –1.70 (20.40) –1.70 (20.40) –4.20 (24.27) –2.21 (23.97) 1.02 (19.72) 6.50 (34.63) 1.40 (37.41) 0.68 (21.25) 19.10 (26.46) 5.60 (22.00) –6.80 (19.13) 318 Favors BMC Treatment Favors Control Weight, % 300 WMD (Random), mL (95% CI) 11.68 7.17 2.23 2.10 13.39 4.59 1.40 7.27 2.57 33.14 11.91 –1.70 (–11.64 to 8.24) –1.70 (–14.39 to 10.99) –5.40 (–28.13 to 17.33) –6.46 (–29.89 to 16.97) –2.89 (–12.17 to 6.39) –12.00 (–27.86 to 3.86) 2.20 (–26.47 to 30.87) –1.53 (–14.12 to 11.06) –23.79 (–44.98 to –2.60) –6.20 (–12.10 to –0.30) –4.40 (–14.24 to 5.44) 97.46 –4.91 (–8.35 to –1.47) Test for Heterogeneity: χ102 = 5.37 (P = .86), I 2 = 0% Test for Overall Effect: Z = 2.80 (P = .005) Cohort Katritsis et al,22 2006 11 2.54 –0.76 (–22.06 to 20.54) Subtotal 11 11 2.54 –0.76 (–22.06 to 20.54) 329 311 100 –4.80 (–8.20 to –1.41) –3.83 (25.28) 11 –3.07 (25.69) Test for Heterogeneity: Not Applicable Test for Overall Effect: Z = 0.07 (P = .94) Total Test for Heterogeneity: χ 112 = 5.52 (P = .90), I 2 = 0% Test for Overall Effect: Z = 2.77 (P = .006) –10 –5 0 5 10 WMD Random (95% CI) Figure 4. Forest plot of unadjusted difference in mean (with 95% confidence intervals [CIs]) change in left ventricular end-systolic volume (LVESV) in patients treated with bone marrow–derived cells (BMCs) compared with controls. The figure shows the summary of cohort studies and randomized controlled trials (RCTs). Transplantation of BMCs resulted in a 4.80-mL (95% CI, −8.20 to −1.41 mL) decrease in LVESV. The overall effect was statistically significant in favor of BMC therapy. AMI indicates acute myocardial infarction; CPCs, circulating progenitor cells; OMI, old myocardial infarction; and WMD, weighted mean difference. 1.92 mL (95% CI, −6.31 to 2.47 [I2 =0%; P=.39]; Figure 5). We drew funnel plots to seek evidence of pub- lication bias: where inconsistency was high, the funnel plots were not interpretable; where inconsistency was (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 993 low, the funnel plots were inconclusive (available at: www.louisville.edu /medschool/medicine/cardiology WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. Study or Subcategory RCTs Assmus et al,14 2006 (BMCs) Assmus et al,14 2006 (CPCs) Erbs et al,17 2005 Hendrikx et al,19 2006 Janssens et al,20 2006 Kang et al,21 2006 (AMI) Kang et al,21 2006 (OMI) Lunde et al,23 2006 Meyer et al,24 2006 Ruan et al,27 2005 Schächinger et al,28 2006 Li et al,31 2006 Subtotal N Treatment, Mean (SD), mL N Control Mean (SD), mL 28 26 11 10 33 25 16 50 30 9 95 35 0.00 (17.00) –5.10 (30.60) –0.20 (37.38) 0.34 (59.50) 4.76 (25.84) 3.40 (27.40) 5.20 (51.51) –6.90 (34.30) 10.37 (34.51) –2.03 (25.84) 12.00 (31.00) –15.00 (33.65) 18 18 11 10 34 25 16 50 30 11 92 35 –5.10 (28.90) –5.10 (28.90) –7.60 (29.52) 5.78 (47.94) 4.76 (25.50) 10.10 (36.11) 2.10 (51.31) –2.80 (20.00) 6.12 (25.67) 29.28 (42.16) 14.00 (33.00) –8.60 (30.22) 368 Favors BMC Treatment Favors Control 350 Weight, % WMD (Random), mL (95% CI) 8.83 6.08 2.43 0.86 12.73 6.10 1.52 15.89 8.13 2.13 22.83 8.57 5.10 (–9.66 to 19.86) 0.00 (–17.79 to 17.79) 7.40 (–20.75 to 35.55) –5.44 (–52.80 to 41.92) 0.00 (–12.30 to 12.30) –6.70 (–24.47 to 11.07) 3.10 (–32.52 to 38.72) –4.10 (–15.11 to 6.91) 4.25 (–11.14 to 19.64) –31.31 (–61.41 to –1.21) –2.00 (–11.18 to 7.18) –6.40 (–21.38 to 8.58) 96.09 –1.83 (–6.30 to 2.65) Test for Heterogeneity: χ 112 = 6.58 (P = .83), I 2 = 0% Test for Overall Effect: Z = 0.80 (P = .42) Cohort Studies Bartunek et al,15 2005 Katritsis et al,22 2005 19 11 Subtotal 30 13.60 (51.88) –8.55 (36.49) 16 11 20.40 (54.82) –5.88 (31.26) 1.52 2.39 –6.80 (–42.38 to 28.78) –2.67 (–31.06 to 25.72) 27 3.91 –4.28 (–26.47 to 17.92) 377 100 –1.92 (–6.31 to 2.47) Test for Heterogeneity: χ 12 = 0.03 (P = .86), I 2 = 0% Test for Overall Effect: Z = 0.38 (P = .71) Total 398 Test for Heterogeneity: χ 132 = 6.65 (P = .92), I 2 = 0% Test for Overall Effect: Z = 0.86 (P = .39) –10 –5 0 5 10 WMD Random (95% CI) Figure 5. Forest plot of unadjusted difference in mean (with 95% confidence intervals [CIs]) change in left ventricular end-diastolic volume (LVEDV) in patients treated with bone marrow–derived cells (BMCs) compared with controls. The figure shows the summary of cohort studies and randomized controlled trials (RCTs). BMC transplantation resulted in a 1.92 mL (95% CI, −6.31 to 2.47) decrease in mean LVEDV. The overall effect was in favor of BMC therapy (not statistically significant). AMI indicates acute myocardial infarction; CPCs, circulating progenitor cells; OMI, old myocardial infarction; and WMD, weighted mean difference. /Archinternmed_2007_supplemental _data.pdf). SUBGROUP ANALYSES AND SAFETY We did not find any treatmentsubgroup interaction through any of our planned subgroup analyses (Table 4). The injection of BMCs was found to be safe without significantly greater risk of major local or systemic complications. Except for Bartunek et al,15 who reported a higher incidence of in-stent restenosis in the BM mononuclear cell– treated group (9 of 19 patients vs 4 of 16 patients in the control group), the rate of restenosis was comparable among BMC-treated and control patients. The incidence of other complications, such as recurrent angina, MI, and sustained or nonsustained supraventricular or ventricular arrhythmias, was not significantly different between BMC-treated patients and controls. A supplemental table of reported incidence of complications in BMC-treated patients and controls is available at: www .Louisville.edu/medschool/medicine /cardiology/Archinternmed_2007 _supplemental_data.pdf. COMMENT This systematic review and metaanalysis, the first, to our knowledge, to comprehensively summarize the available evidence of BMC transplantation in patients with IHD, indicates that BMC transplantation in patients with IHD is apparently safe and leads to modest benefits beyond those achieved with revascularization and conventional pharmacotherapy. Our results indicate that BMC transplantation may improve LV ejection fraction, infarct scar size, and LV end-systolic volume. However, the mechanisms explaining these benefits remain unclear. Although the plasticity of adult stem cells remains debatable, extensive data from animal models indicate that BMCs are capable of differentiating into cells of cardiac and vascular lineages.32-38 Bone marrow– derived mesenchymal stem cells, mononuclear cells, and circulating (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 994 endothelial progenitor cells have all been shown to differentiate into cardiomyocytes both in vitro and in vivo.7 Nevertheless, tracking cellular differentiation after transplantation in humans remains particularly difficult. Another potential mechanism is that transplanted BMCs may secrete a variety of growth factors and cytokines,39 thereby enhancing myocyte survival following ischemic injury and facilitating the migration of resident cardiac stem cells40 to the site of injury and their reparative activity. The finding of infarct scar size reduction with BMC therapy may signify new myocyte formation, superior preservation of existing myocytes, or both following BMC transplantation. Beyond these mechanistic considerations, some technical issues remain unclear, such as the optimal number of BMCs, the optimal timing and route of transplantation, and the most effective type of BMC. Since only a small fraction of BMCs are retained in the myocardium following injection, 41 we analyzed the pooled data based on the number of cells transplanted. There were no sig- WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. nificant differences in outcomes between the groups that received less or more than the median number of cells. Although somewhat surprising, these findings perhaps underscore the importance of selective injection of the most efficacious cell subpopulation. Furthermore, the impact of cell number may be affected by the timing42 and route41 of transplantation, both of which may influence cell retention. The retention of injected endothelial progenitor cells was much lower in sham-operated nude rats compared with nude rats 24 hours after acute MI.42 Furthermore, the benefits of BMC injection in the first few days after acute MI may be jeopardized by the local inflammation that renders the myocardium a hostile environment for the injected cells. In the Reinfusion of Enriched Progenitor Cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial, the authors stratified data according to the time of BMC injection after acute MI.28 While there was no correlation between the timing of the procedure and LV contractile recovery in the placebo group, a significant correlation was observed in the BMC-treated group. Transplantation of BMCs was more beneficial when performed 5 days or later after acute MI.28 In our meta-analysis, injection of BMCs in the 5- to 30-day window resulted in a more than 3-fold greater reduction in infarct size and greater improvement in LV end-systolic volume compared with injection in the first 5 days after acute MI and/or percutaneous coronary intervention. Because the overall change in LV end-diastolic volume was not different between BMC-treated and control groups, a change in LV end-systolic volume may represent an improvement in global LV function. However, none of these interactions reached statistical significance, and the importance of these findings remains uncertain at this time. This lack of subgroup-treatment interaction may have resulted from a small number of studies with a small number of patients. Future meta-analyses with larger patient numbers or large randomized trials may identify potential interactions between treatment Table 4. Subgroup Analysis Examining the Impact of Study Design, Underlying Type of Cardiomyopathy, Timing of Transplantation, Number of BMCs Transplanted, and Type of BMCs Transplanted on Outcome Variables Outcome Difference in Mean (95% Confidence Interval) P Value for Interaction LVEF Infarct scar size LVESV LVEDV RCTs 3.64 (1.56 to 5.73) −6.49 (−10.23 to −2.75) −4.91 (−8.35 to −1.47) −1.83 (−6.30 to 2.65) Cohort Studies 3.83 (1.18 to 6.48) −6.31 (−10.27 to −2.35) −0.76 (−22.06 to 20.54) −4.28 (−26.47 to 17.92) .92 .94 .71 .83 LVEF Infarct scar size LVESV LVEDV Acute MI 3.95 (1.07 to 6.82) −6.45 (−11.55 to −1.36) −5.82 (−9.80 to −1.84) −3.20 (−8.17 to 1.78) Chronic IHD 3.45 (1.36 to 5.54) −4.12 (−8.20 to −0.05) −2.22 (−9.07 to 4.63) 0.72 (−8.18 to 9.62) .78 .48 .37 .45 LVEF Infarct scar size LVESV LVEDV BMCs Injected ⬍5 d After Acute MI and/or PCI 2.76 (1.05 to 4.47) −2.44 (−6.51 to 1.63) −5.64 (−11.00 to −0.29) −2.14 (−10.61 to 6.32) BMCs Injected 5-30 d After Acute MI and/or PCI 4.00 (−1.58 to 9.57) −8.80 (−15.20 to −2.40) −6.51 (−14.87 to 1.85) −5.34 (−13.08 to 2.41) .68 .10 .86 .58 LVEF Infarct scar size LVESV LVEDV No. of BMCs ⬍80 ⴛ 106 3.17 (1.01 to 5.33) −4.58 (−10.32 to 1.17) −3.55 (−10.22 to 3.12) −2.67 (−12.05 to 6.72) No. of BMCs ⱖ80 ⴛ 106 3.53 (0.90 to 6.16) −5.93 (−10.73 to −1.13) −4.58 (−8.59 to −0.56) −0.89 (−5.92 to 4.15) .84 .72 .79 .74 LVEF Infarct scar size LVESV LVEDV BMMNCs 2.69 (0.87 to 4.51) −4.37 (−7.01 to −1.73) −4.27 (−8.40 to −0.14) −0.65 (−5.87 to 4.56) MSCs and CPCs 4.89 (1.17 to 8.78) −7.80 (−20.68 to 5.07) −5.91 (−11.88 to 0.05) −5.00 (−13.11 to 3.12) .29 .61 .66 .38 Abbreviations: BMCs, bone marrow–derived cells; BMMNCs, bone marrow mononuclear cells; CPCs, circulating progenitor cells; IHD, ischemic heart disease; MI, myocardial infarction; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MSC, mesenchymal stem cell; PCI, percutaneous coronary intervention; RCT, randomized controlled trial. effects and the timing of BMC injection. It is important to note that the majority of studies included in our review used unfractionated BM mononuclear cells18,20,23-26,28-30 and that BMC transplantation was reportedly safe in these studies. Although intracoronary injection of CD133⫹ BM mononuclear cells was associated with an increased incidence of in-stent restenosis,15 no other major adverse effects were noted in studies using different BMC populations. This safety profile of BMC transplantation as reported in these studies with follow-up durations of up to 18 months supports conducting further investigation of therapeutic efficacy. The possibility that reporting bias may be affecting the otherwise favorable safety picture emerging from our review, however, demands caution. (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 995 The duration of follow-up in the studies included in this metaanalysis was relatively short. Although the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial showed persistent benefits after 12 months of BMC and circulating progenitor cell therapy,43 a longer follow-up of 18 months failed to demonstrate statistically significant improvements with cell therapy in the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) study.24 Whether the benefits of BMC therapy are ephemeral remains to be assessed in larger trials with longer follow-up duration (eg, 5 years). Moreover, a single dose of BMCs may not be sufficient for myocardial repair, and repeated infusions may result in sustained benefits over a longer time WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. frame, but this remains speculative. Genetic modifications of BMCs prior to transplantation may also potentially improve their regenerative capability.44 These avenues may be explored in future trials. Overall, our findings support the recent consensus statement on the use of autologous adult stem cells for cardiac repair by the task force of the European Society of Cardiology that called for a pragmatic approach for demonstrating the efficacy of stem cell therapy in myocardial repair in humans.45 Limitations in study quality (namely, lack of blinding), unexplained between-study inconsistency, sparse evidence, and indirectness of the outcomes (ie, exclusive reliance on surrogate outcomes) weaken the inferences. The methods for evaluating LV function, the type of BMC used, and the interval between acute MI and/or percutaneous coronary intervention and BMC transplantation varied among the included studies (Table 1), all of which are potential sources of heterogeneity. However, the consistency of the beneficial effect of BMCs in most of the prespecified primary end points and subgroups suggests that the association is valid. The fact that the beneficial effect of BMCs persisted across different study designs, BMC lines, timings and routes of transplantation, and clinical scenarios suggest that the association can cautiously be generalized to different patient populations. We believe that combining data from RCTs and cohort studies was justified because for both designs patients were followed prospectively, accurate methods were used to assess the primary end points, and few patients if any were lost to follow-up. Importantly, the results were consistent even when the analysis was restricted to RCTs or cohort studies alone (Table 4 and Figures 2-5), strengthening the fact that the results of the meta-analysis are cautiously generalizable. In conclusion, the results of our systematic review and metaanalysis suggest that BMC transplantation in patients with acute MI as well as chronic IHD is reportedly safe and is associated with modest improvements in LV ejection frac- tion, infarct scar size, and LV endsystolic volume, beyond those achieved with state-of-the-art therapy; however, there was no significant effect on LV end-diastolic volume. Although the benefits are modest, our results support the organization, funding, and conduct of larger randomized trials of BMC therapy designed to critically evaluate the long-term impact of BMC therapy on patient-important outcomes in patients with IHD. Accepted for Publication: January 24, 2007. Correspondence: Buddhadeb Dawn, MD, Division of Cardiology, 550 S Jackson St, Ambulatory Care Building, Third Floor, Louisville, KY 40292 (buddha@louisville.edu). Author Contributions: Drs AbdelLatif and Dawn had full access to all of the data in this study and take responsibility for data integrity and the accuracy of data analysis. Study concept and design: Abdel-Latif, Dawn, Bolli, Tleyjeh, and Hornung. Acquisition of data: Abdel-Latif, Tleyjeh, Perin, Zuba-Surma, Bolli, and Dawn. Analysis and interpretation of data: Abdel-Latif, Tleyjeh, Montori, Hornung, Perin, Bolli, Dawn, and AlMallah. Drafting of the manuscript: Abdel-Latif, Dawn, Zuba-Surma, Tleyjeh, Montori, Bolli, and AlMallah. Critical revision of the manuscript for important intellectual content: Dawn, Bolli, Montori, AbdelLatif, Tleyjeh, Hornung, and Perin. Statistical analysis: Abdel-Latif, Montori, Tleyjeh, Hornung, and Dawn. Obtained funding: Bolli and Dawn. Administrative, technical, or material support: Bolli and Dawn. Study supervision: Dawn, Bolli, Hornung, and Perin. Financial Disclosure: None reported. Funding/Support: This metaanalysis and publication was supported in part by grants R01 HL72410, HL-55757, HL-68088, HL-70897, HL-76794, and HL78825 from the National Institutes of Health. Additional Information: A supplementary table (reported incidence of complications in BMC-treated patients and controls) and figure (funnel plot [according to outcomes] for studies included in the metaanalysis) are available at: www .louisville.edu/medschool/medicine (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 996 /cardiology/Archinternmed_2007 _supplemental_data.pdf. REFERENCES 1. Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mtc sestamibi imaging predicts subsequent mortality. Circulation. 1995;92:334-341. 2. Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol. 2001;12:369-381. 3. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990; 81:1161-1172. 4. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347:1397-1402. 5. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA. 2004;292: 344-350. 6. Dawn B, Bolli R. Adult bone marrow–derived cells: regenerative potential, plasticity, and tissue commitment. Basic Res Cardiol. 2005;100:494503. 7. Dawn B, Zuba-Surma E, Abdel-Latif A, Tiwari S, Bolli R. Cardiac stem cell therapy for myocardial regeneration: a clinical perspective. Minerva Cardioangiol. 2005;53:549-564. 8. Wollert KC, Drexler H. Clinical applications of stem cells for the heart. Circ Res. 2005;96:151-163. 9. Stroup DF, Berlin JA, Morton SC, et al; Metaanalysis of Observational Studies in Epidemiology (MOOSE) Group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283:2008-2012. 10. Moher D, Cook J, Eastwood S, Olkin I, Rennie D, Stroup D. Improving the quality of reports of metaanalyses of randomised controlled trials: the QUOROM statement. Lancet. 1999;354:18961900. 11. Jüni P, Altman D, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ. 2001;323:42-46. 12. Wells G, Shea B, O’Connell D, et al. The NewcastleOttawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis. Ottawa, Ontario: The Ottawa Health Research Institute. http://www.ohri.ca/programs/clinical _epidemiology/nosgen.doc. Accessed March 11, 2006. 13. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ. 2003;327:557-560. 14. Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006;355: 1222-1232. 15. Bartunek J, Vanderheyden M, Vandekerckhove B, et al. Intracoronary injection of CD133positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation. 2005;112(suppl):I178-I183. 16. Chen SL, Fang WW, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92-95. 17. Erbs S, Linke A, Adams V, et al. Transplantation of blood-derived progenitor cells after recanali- WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved. 18. 19. 20. 21. 22. 23. 24. 25. zation of chronic coronary artery occlusion: first randomized and placebo-controlled study. Circ Res. 2005;97:756-762. Ge J, Li Y, Qian J, et al. Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI) [published online ahead of print June 14, 2006]. Heart. 2006;92:1764-1767. Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006;114 (suppl):I101-I107. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow–derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006;367:113-121. Kang H, Lee H, Na S, et al. Differential effect of intracoronary infusion of mobilized peripheral blood stem cells by granulocyte colonystimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction: the MAGIC Cell-3-DES randomized, controlled trial. Circulation. 2006;114(suppl):I145-I151. Katritsis DG, Sotiropoulou PA, Karvouni E, et al. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv. 2005;65:321-329. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injections of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006; 355:1199-1209. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation. 2006;113:12871294. Mocini D, Staibano M, Mele L, et al. Autologous bone marrow mononuclear cell transplantation in 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. patients undergoing coronary artery bypass grafting. Am Heart J. 2006;151:192-197. Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation. 2004;110(suppl 1):II213-II218. Ruan W, Pan C, Huang G, Li Y, Ge J, Shu X. Assessment of left ventricular segmental function after autologous bone marrow stem cells transplantation in patients with acute myocardial infarction by tissue tracking and strain imaging. Chin Med J (Engl). 2005;118:1175-1181. Schächinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow–derived progenitor cells in acute myocardial in acute myocardial infarction. N Engl J Med. 2006;355:1210-1221. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913-1918. Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol. 2005;46:1651-1658. Li ZQ, Zhang M, Jing YZ, et al. The clinical study of autologous peripheral blood stem cell transplantation by intracoronory infusion in patients with acute myocardial infarction (AMI) [published online ahead of print July 5, 2006]. Int J Cardiol. 2007; 115:52-56. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest. 1999;103:697-705. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999;100(suppl):II247II256. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A. 2001;98:10344-10349. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler (REPRINTED) ARCH INTERN MED/ VOL 167, MAY 28, 2007 997 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002;105:93-98. Kawada H, Fujita J, Kinjo K, et al. Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood. 2004;104:3581-3587. Hattan N, Kawaguchi H, Ando K, et al. Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intracardiac grafts in mice. Cardiovasc Res. 2005;65:334-344. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701-705. Urbich C, Aicher A, Heeschen C, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005; 39:733-742. Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763-776. Hofmann M, Wollert KC, Meyer GP, et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005; 111:2198-2202. Aicher A, Brenner W, Zuhayra M, et al. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation. 2003;107:2134-2139. Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:30093017. Mangi AA, Noiseux N, Kong D, et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003;9:1195-1201. Bartunek J, Dimmeler S, Drexler H, et al. The consensus of the task force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for repair of the heart. Eur Heart J. 2006;27:13381340. WWW.ARCHINTERNMED.COM Downloaded from www.archinternmed.com on September 18, 2008 ©2007 American Medical Association. All rights reserved.