Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis

Manoj M Lalu, Sasha Mazzarello, Jennifer Zlepnig, Yuan Yi Ryan Dong, Joshua Montroy, Lauralyn McIntyre, P J Devereaux, Duncan J Stewart, C David Mazer, Carly C Barron, Daniel I McIsaac, Dean A Fergusson, Manoj M Lalu, Sasha Mazzarello, Jennifer Zlepnig, Yuan Yi Ryan Dong, Joshua Montroy, Lauralyn McIntyre, P J Devereaux, Duncan J Stewart, C David Mazer, Carly C Barron, Daniel I McIsaac, Dean A Fergusson

Abstract

Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating both acute myocardial infarction (AMI) and ischemic heart failure (IHF). However, the safety profile and efficacy of MSC therapy is not well-known. We conducted a systematic review of clinical trials that evaluated the safety or efficacy of MSCs for AMI or IHF. Embase, PubMed/Medline, and Cochrane Central Register of Controlled Trials were searched from inception to September 27, 2017. Studies that examined the use of MSCs administered to adults with AMI or IHF were eligible. The Cochrane risk of bias tool was used to assess bias of included studies. The primary outcome was safety assessed by adverse events and the secondary outcome was efficacy which was assessed by mortality and left ventricular ejection fraction (LVEF). A total of 668 citations were reviewed and 23 studies met eligibility criteria. Of these, 11 studies evaluated AMI and 12 studies evaluated IHF. There was no association between MSCs and acute adverse events. There was a significant improvement in overall LVEF in patients who received MSCs (SMD 0.73, 95% CI 0.24-1.21). No significant difference in mortality was noted (Peto OR 0.68, 95% CI 0.38-1.22). Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe. There is a need for a well-designed adequately powered randomized control trial (with rigorous adverse event reporting and evaluations of cardiac function) to further establish a clear risk-benefit profile of MSCs. Stem Cells Translational Medicine 2018;7:857-866.

Keywords: Myocardial infarction; Myocardial ischemia; Stem cells; Systematic review.

© 2018 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram of the study selection process.
Figure 2
Figure 2
Peto odds ratio (95% CI) and pooled estimates for mortality.
Figure 3
Figure 3
SMD (95% CI) and pooled estimates for left ventricular ejection fraction.
Figure 4
Figure 4
Risk of bias assessment.

References

    1. Fihn SD, Blankenship JC, Alexander KP et al. ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation 2014;2014:2018.
    1. dos Santos CC, Murthy S, Hu P et al. Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis. Am J Pathol 2012;181:1681–1692.
    1. Mei SH, Haitsma JJ, Dos Santos CC et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010;182:1047–1057.
    1. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 2011;109:923–940.
    1. Jackson MV, Morrison TJ, Doherty DF et al. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells 2016;34:2210–2223.
    1. Islam MN, Das SR, Emin MT et al. Mitochondrial transfer from bone‐marrow‐derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012;18:759–765.
    1. Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol 2009;217:318–324.
    1. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res 2015;116:1413–1430.
    1. Fisher SA, Zhang H, Doree C et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2015;9:CD006536.
    1. Fisher SA, Doree C, Mathur A et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure.Cochrane Database Syst Rev 2016;12:CD007888.
    1. van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P et al. Human relevance of pre‐clinical studies in stem cell therapy: systematic review and meta‐analysis of large animal models of ischaemic heart disease. Cardiovasc Res 2011;91:649–658.
    1. Chen S, Liu Z, Tian N et al. Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J Invasive Cardiol 2006;18:552–556.
    1. Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. BMJ 2009;339:b2535.
    1. McGowan J, Sampson M, Salzwedel DM et al. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol 2016;75:40–46.
    1. Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–317.
    1. Higgins JP, Altman DG, Gotzsche PC et al. Cochrane Bias Methods G and Cochrane Statistical Methods G. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
    1. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2009.
    1. Brockhaus AC, Grouven U, Bender R. Performance of the Peto odds ratio compared to the usual odds ratio estimator in the case of rare events. Biom J 2016;58:1428–1444.
    1. Chen SL, Fang WW, Qian J et al. Improvement of cardiac function after transplantation of autologous bone marrow mesenchymal stem cells in patients with acute myocardial infarction. Chin Med J (Engl) 2004;117:1443–1448.
    1. Chullikana A, Majumdar AS, Gottipamula S et al. Randomized, double‐blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy 2015;17:250–261.
    1. Gao LR, Pei XT, Ding QA et al. A critical challenge: dosage‐related efficacy and acute complication intracoronary injection of autologous bone marrow mesenchymal stem cells in acute myocardial infarction. Int J Cardiol 2013;168:3191–3099.
    1. Gao LR, Chen Y, Zhang NK et al. Intracoronary infusion of Wharton's jelly‐derived mesenchymal stem cells in acute myocardial infarction: double‐blind, randomized controlled trial. BMC Med 2015;13:162.
    1. Hare JM, Traverse JH, Henry TD et al. A randomized, double‐blind, placebo‐controlled, dose‐escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277–2286.
    1. Lee JW, Lee SH, Youn YJ et al. A randomized, open‐label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction. J Korean Med Sci 2014;29:23–31.
    1. Musialek P, Mazurek A, Jarocha D et al. Myocardial regeneration strategy using Wharton's jelly mesenchymal stem cells as an off‐the‐shelf 'unlimited' therapeutic agent: results from the Acute Myocardial Infarction First‐in‐Man Study. Postepy Kardiol Inter 2015;11:100–107.
    1. Rodrigo SF, van Ramshorst J, Hoogslag GE et al. Intramyocardial injection of autologous bone marrow‐derived ex vivo expanded mesenchymal stem cells in acute myocardial infarction patients is feasible and safe up to 5 years of follow‐up. J Cardiovasc Transl Res 2013;6:816–825.
    1. Wang X, Xi WC, Wang F. The beneficial effects of intracoronary autologous bone marrow stem cell transfer as an adjunct to percutaneous coronary intervention in patients with acute myocardial infarction. Biotechnol Lett 2014;36:2163–2168.
    1. Yang Z, Zhang F, Ma W et al. A novel approach to transplanting bone marrow stem cells to repair human myocardial infarction: delivery via a noninfarct‐relative artery. Cardiovasc Ther 2010;28:380–385.
    1. Houtgraaf JH, den Dekker WK, van Dalen BM et al. First experience in humans using adipose tissue‐derived regenerative cells in the treatment of patients with ST‐segment elevation myocardial infarction. J Am Coll Cardiol 2012;59:539–540.
    1. Bartunek J, Terzic A, Davison BA et al. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham‐controlled CHART‐1 clinical trial. Eur Heart J 2017;38:648–660.
    1. Guijarro D, Lebrin M, Lairez O et al. Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: results of the MESAMI 1 pilot trial. Int J Cardiol 2016;209:258–265.
    1. Hare JM, Fishman JE, Gerstenblith G et al. Comparison of allogeneic vs autologous bone marrow‐derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 2012;308:2369–2379.
    1. Heldman AW, DL DF, Fishman JE et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC‐HFT randomized trial. JAMA 2014;311:62–73.
    1. Karantalis V, DL DF, Gerstenblith G et al. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial. Circ Res 2014;114:1302–1310.
    1. Li X, Hu YD, Guo Y et al. Safety and efficacy of intracoronary human umbilical cord‐derived mesenchymal stem cell treatment for very old patients with coronary chronic total occlusion. Curr Pharm Des 2015;21:1426–1432.
    1. Mathiasen AB, Haack‐Sorensen M, Jorgensen E et al. Autotransplantation of mesenchymal stromal cells from bone‐marrow to heart in patients with severe stable coronary artery disease and refractory angina‐‐final 3‐year follow‐up. Int J Cardiol 2013;170:246–251.
    1. Mathiasen AB, Qayyum AA, Jorgensen E et al. Bone marrow‐derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo‐controlled trial (MSC‐HF trial). Eur Heart J 2015;36:1744–1753.
    1. Viswanathan C, Davidson Y, Cooper K et al. Tansplantation of autologous bone marrow derived mesenchymal stem cells trans‐epicardially in patients undergoing coronary bypass surgery. Indian Heart J 2010;62:43–48.
    1. Wang JA, Xie XJ, He H et al. A prospective, randomized, controlled trial of autologous mesenchymal stem cells transplantation for dilated cardiomyopathy. Zhonghua Xin Xue Guan Bing Za Zhi 2006;34:107–110.
    1. Zhao XF, Xu Y, Zhu ZY et al. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genet Mol Res 2015;14:3010–3017.
    1. Ausset S, Auroy Y, Lambert E et al. Cardiac troponin I release after hip surgery correlates with poor long‐term cardiac outcome. Eur J Anaesthesiol 2008;25:158–164.
    1. Nagpal A, Choy FC, Howell S et al. Safety and effectiveness of stem cell therapies in early‐phase clinical trials in stroke: a systematic review and meta‐analysis. Stem Cell Res Ther 2017;8:191.
    1. Ioannidis JP, Evans SJ, Gotzsche PC et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004;141:781–788.
    1. Wu HDD, Cao H et al. Efficacy and safety of mesenchymal stromal cells on left ventricular function after acute myocardial infarction: a meta‐analysis of randomized controlled trials. Int J Clin Exp Med 2017;10:5871–5882.
    1. Wang Z, Wang L, Su X et al. Rational transplant timing and dose of mesenchymal stromal cells in patients with acute myocardial infarction: a meta‐analysis of randomized controlled trials. Stem Cell Res Ther 2017;8:21.
    1. Chen X, Wang C, Yin J et al. Efficacy of mesenchymal stem cell therapy for steroid‐refractory acute graft‐versus‐host disease following allogeneic hematopoietic stem cell transplantation: a systematic review and meta‐analysis. PLoS One 2015;10:e0136991.

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