Clinical studies of cell therapy in cardiovascular medicine recent developments and future directions

Circulation Research

Volumn 123, Issue 2, 2018, Pages 266-287

  Banerjee, Monisha N ^a   Bolli, Roberto ^b   Hare, Joshua M ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^b University of Louisville School of Medicine   (United States)

Author keywords

Cell and tissue based therapy; Clinical trial; Heart diseases; Heart failure

Indexed keywords

ACUTE HEART INFARCTION; ADIPOSE DERIVED STEM CELL; ARTICLE; BONE MARROW DERIVED MONONUCLEAR CELL; CARDIAC STEM CELL; CARDIOPOIETIC STEM CELL; CARDIOSPHERE STEM CELL; CARDIOVASCULAR DISEASE; CARDIOVASCULAR MORTALITY; CELL THERAPY; CLINICAL EFFECTIVENESS; CLINICAL STUDY; CLINICAL TRIAL (TOPIC); HUMAN; ISCHEMIC CARDIOMYOPATHY; MESENCHYMAL STEM CELL; NONHUMAN; NONISCHEMIC CARDIOMYOPATHY; PRIORITY JOURNAL; QUALITY OF LIFE; REFRACTORY ANGINA; REGENERATIVE MEDICINE; STEM CELL; THERAPY EFFECT; TREATMENT OUTCOME; ADVERSE EVENT; PROCEDURES; STEM CELL TRANSPLANTATION;

CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; HUMANS; REGENERATIVE MEDICINE; STEM CELL TRANSPLANTATION;

EID: 85053162188     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.118.311217     Document Type: Article

References (162)

1. Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2016;12:CD007888. doi: 10.1002/14651858.CD007888.pub3.
2. Fisher SA, Zhang H, Doree C, Mathur A, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2015:CD006536.
3. Khan AR, Farid TA, Pathan A, Tripathi A, Ghafghazi S, Wysoczynski M, Bolli R. Impact of cell therapy on myocardial perfusion and cardiovascular outcomes in patients with angina refractory to medical therapy: a systematic review and meta-analysis. Circ Res. 2016;118:984–993. doi: 10.1161/CIRCRESAHA.115.308056.
4. Menasché P, Hagège AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K, Vilquin JT, Marolleau JP. Myoblast transplantation for heart failure. Lancet. 2001;357:279–280. doi: 10.1016/S0140-6736(00)03617-5.
5. Mathur A, Arnold R, Assmus B, et al. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial. Eur J Heart Fail. 2017;19:1545–1550. doi: 10.1002/ejhf.829.
6. Bartunek J, Terzic A, Davison BA, et al; CHART Program. 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. doi: 10.1093/eurheartj/ehw543.
7. Perin EC, Willerson JT, Pepine CJ, et al; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012;307:1717–1726. doi: 10.1001/jama.2012.418.
8. Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, Mente A, Yusuf S. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–694. doi: 10.1161/CIRCRESAHA.117.308903.
9. Mozaffarian D, Benjamin EJ, Go AS, et al; Writing Group Members; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38–e360. doi: 10.1161/CIR.0000000000000350.
10. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544. doi: 10.1016/S0140-6736(16)31012-1.
11. Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, McAlister FA. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol. 2009;53:13–20. doi: 10.1016/j.jacc.2008.08.067.
12. Benjamin EJ, Blaha MJ, Chiuve SE, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–e603. doi: 10.1161/CIR.0000000000000485.
13. Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, Ikonomidis JS, Khavjou O, Konstam MA, Maddox TM, Nichol G, Pham M, Piña IL, Trogdon JG; American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606–619. doi: 10.1161/HHF.0b013e318291329a.
14. Barker WH, Mullooly JP, Getchell W. Changing incidence and survival for heart failure in a well-defined older population, 1970-1974 and 1990-1994. Circulation. 2006;113:799–805. doi: 10.1161/CIRCULATIONAHA.104.492033.
15. Szummer K, Wallentin L, Lindhagen L, Alfredsson J, Erlinge D, Held C, James S, Kellerth T, Lindahl B, Ravn-Fischer A, Rydberg E, Yndigegn T, Jernberg T. Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995–2014. Eur Heart J. 2017;8:3056–3065. doi: 10.1093/eurheartj/ehx515.
16. Gheorghiade M, Larson CJ, Shah SJ, et al. Developing new treatments for heart failure: focus on the heart. Circ Heart Fail. 2016;9:e002727.
17. Stehlik J, Stevenson LW, Edwards LB, Crespo-Leiro MG, Delgado JF, Dorent R, Frigerio M, Macdonald P, MacGowan GA, Nanni Costa A, Rogers JG, Shah AS, Taylor R, Venkateswaran RV, Mehra MR. Organ allocation around the world: insights from the ISHLT International Registry for Heart and Lung Transplantation. J Heart Lung Transplant. 2014;33:975–984. doi: 10.1016/j.healun.2014.08.001.
18. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763–776.
19. Bergmann O, Zdunek S, Felker A, et al. Dynamics of cell generation and turnover in the human heart. Cell. 2015;161:1566–1575. doi: 10.1016/j.cell.2015.05.026.
20. Madonna R, Van Laake LW, Davidson SM, et al. Position paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J. 2016;37:1789–1798. doi: 10.1093/eurheartj/ehw113.
21. Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol Rev. 2016;96:1127–1168. doi: 10.1152/physrev.00019.2015.
22. van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA. 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. doi: 10.1093/cvr/cvr113.
23. Lu Y, Wang Y, Lin M, Zhou J, Wang Z, Jiang M, He B. A systematic review of randomised controlled trials examining the therapeutic effects of adult bone marrow-derived stem cells for non-ischaemic dilated cardiomyopathy. Stem Cell Res Ther. 2016;7:186. doi: 10.1186/s13287-016-0441-x.
24. Afzal MR, Samanta A, Shah ZI, Jeevanantham V, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy for ischemic heart disease: evidence and insights from randomized controlled trials. Circ Res. 2015;117:558–575. doi: 10.1161/CIRCRESAHA.114.304792.
25. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107:913–922. doi: 10.1161/CIRCRESAHA.110.222703.
26. Zhang S, Wang D, Estrov Z, Raj S, Willerson JT, Yeh ET. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo. Circulation. 2004;110:3803–3807. doi: 10.1161/01.CIR.0000150796.18473.8E.
27. Quevedo HC, Hatzistergos KE, Oskouei BN, Feigenbaum GS, Rodriguez JE, Valdes D, Pattany PM, Zambrano JP, Hu Q, McNiece I, Heldman AW, Hare JM. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci USA. 2009;106:14022–14027. doi: 10.1073/pnas.0903201106.
28. Wu T, Cieply K, Nalesnik MA, Randhawa PS, Sonzogni A, Bellamy C, Abu-Elmagd K, Michalopolous GK, Jaffe R, Kormos RL, Gridelli B, Fung JJ, Demetris AJ. Minimal evidence of transdifferentiation from recipient bone marrow to parenchymal cells in regenerating and long-surviving human allografts. Am J Transplant. 2003;3:1173–1181.
29. Tang XL, Li Q, Rokosh G, Sanganalmath SK, Chen N, Ou Q, Stowers H, Hunt G, Bolli R. Long-term outcome of administration of c-kit(POS) cardiac progenitor cells after acute myocardial infarction: transplanted cells do not become cardiomyocytes, but structural and functional improvement and proliferation of endogenous cells persist for at least one year. Circ Res. 2016;118:1091–1105. doi: 10.1161/CIRCRESAHA.115.307647.
30. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11:367–368. doi: 10.1038/nm0405-367.
31. Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, Marbán E. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res. 2010;106:971–980. doi: 10.1161/CIRCRESAHA.109.210682.
32. Paliwal S, Chaudhuri R, Agrawal A, Mohanty S. Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci. 2018;25:31. doi: 10.1186/s12929-018-0429-1.
33. Mayourian J, Cashman TJ, Ceholski DK, Johnson BV, Sachs D, Kaji DA, Sahoo S, Hare JM, Hajjar RJ, Sobie EA and Costa KD. Experimental and computational insight into human mesenchymal stem cell paracrine signaling and heterocellular coupling effects on cardiac contractility and arrhythmogenicity. Circ Res. 2017;121:411–423.
34. Kandalam V, Basu R, Moore L, Fan D, Wang X, Jaworski DM, Oudit GY, Kassiri Z. Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation. 2011;124:2094–2105. doi: 10.1161/CIRCULATIONAHA.111.030338.
35. Kalra DK, Zhu X, Ramchandani MK, Lawrie G, Reardon MJ, Lee-Jackson D, Winters WL, Sivasubramanian N, Mann DL, Zoghbi WA. Increased myocardial gene expression of tumor necrosis factor-alpha and nitric oxide synthase-2: a potential mechanism for depressed myocardial function in hibernating myocardium in humans. Circulation. 2002;105:1537–1540.
36. Page B, Young R, Iyer V, Suzuki G, Lis M, Korotchkina L, Patel MS, Blumenthal KM, Fallavollita JA, Canty JM Jr. Persistent regional down-regulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. Circ Res. 2008;102:103–112. doi: 10.1161/CIRCRESAHA.107.155895.
37. Lim H, Fallavollita JA, Hard R, Kerr CW, Canty JM Jr. Profound apoptosis-mediated regional myocyte loss and compensatory hypertrophy in pigs with hibernating myocardium. Circulation. 1999;100:2380–2386.
38. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991;84:1589–1596.
39. Roura S, Planas F, Prat-Vidal C, Leta R, Soler-Botija C, Carreras F, Llach A, Hove-Madsen L, Pons Lladó G, Farré J, Cinca J, Bayes-Genis A. Idiopathic dilated cardiomyopathy exhibits defective vascularization and vessel formation. Eur J Heart Fail. 2007;9:995–1002. doi: 10.1016/j.ejheart.2007.07.008.
40. Sanganalmath SK, Bolli R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res. 2013;113:810–834. doi: 10.1161/CIRCRESAHA.113.300219.
41. Heldman AW, DiFede DL, 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. doi: 10.1001/jama.2013.282909.
42. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–967.
43. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–317. doi: 10.1080/14653240600855905.
44. Golpanian S, Schulman IH, Ebert RF, Heldman AW, DiFede DL, Yang PC, Wu JC, Bolli R, Perin EC, Moyé L, Simari RD, Wolf A, Hare JM; Cardiovascular Cell Therapy Research Network. Concise review: review and perspective of cell dosage and routes of administration from preclinical and clinical studies of stem cell therapy for heart disease. Stem Cells Transl Med. 2016;5:186–191. doi: 10.5966/sctm.2015-0101.
45. Perin EC, Sanz-Ruiz R, Sanchez PL, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J. 2014;168:88–95 e2.
46. Henry TD, Pepine CJ, Lambert CR, Traverse JH, Schatz R, Costa M, Povsic TJ, David Anderson R, Willerson JT, Kesten S, Perin EC. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv. 2017;89:169–177. doi: 10.1002/ccd.26601.
47. Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells. Proc Natl Acad Sci USA. 2007;104:14068–14073. doi: 10.1073/pnas.0706760104.
48. Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MV, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95:911–921. doi: 10.1161/01.RES.0000147315.71699.51.
49. Li TS, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B, Matsushita N, Blusztajn A, Terrovitis J, Kusuoka H, Marbán L, Marbán E. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with car-diosphere-derived cells. J Am Coll Cardiol. 2012;59:942–953. doi: 10.1016/j.jacc.2011.11.029.
50. Heeschen C, Lehmann R, Honold J, Assmus B, Aicher A, Walter DH, Martin H, Zeiher AM, Dimmeler S. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation. 2004;109:1615–1622. doi: 10.1161/01.CIR.0000124476.32871.E3.
51. Kizilay Mancini Ö, Lora M, Shum-Tim D, Nadeau S, Rodier F, Colmegna I. A proinflammatory secretome mediates the ompaired immunopotency of human mesenchymal stromal cells in elderly patients with atherosclerosis. Stem Cells Transl Med. 2017;6:1132–1140. doi: 10.1002/sctm.16-0221.
52. Golpanian S, El-Khorazaty J, Mendizabal A, DiFede DL, Suncion VY, Karantalis V, Fishman JE, Ghersin E, Balkan W, Hare JM. Effect of aging on human mesenchymal stem cell therapy in ischemic cardiomyopathy patients. J Am Coll Cardiol. 2015;65:125–132. doi: 10.1016/j. jacc.2014.10.040.
53. Fernandez-Aviles F, Sanz-Ruiz R, Climent AM, et al. Global position paper on cardiovascular regenerative medicine. Eur Heart J. 2017;38:2532–2546.
54. Menasché P, Vanneaux V, Hagège A, et al. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J Am Coll Cardiol. 2018;71:429–438. doi: 10.1016/j.jacc.2017.11.047.
55. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95. doi: 10.1067/mcp.2001.113989.
56. Vlietstra RE, Assad-Morell JL, Frye RL, Elveback LR, Connolly DC, Ritman EL, Pluth JR, Barnhorst DA, Danielson GK, Wallace RB. Survival predictors in coronary artery disease. Medical and surgical comparisons. Mayo Clin Proc. 1977;52:85–90.
57. Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol. 2010;56:392–406. doi: 10.1016/j.jacc.2010.05.011.
58. Traverse JH, Henry TD, Moye’ LA. Is the measurement of left ventricular ejection fraction the proper end point for cell therapy trials? An analysis of the effect of bone marrow mononuclear stem cell administration on left ventricular ejection fraction after ST-segment elevation myocardial infarction when evaluated by cardiac magnetic resonance imaging. Am Heart J. 2011;162:671–677. doi: 10.1016/j.ahj.2011.06.019.
59. Wang N, Hung CL, Shin SH, Claggett B, Skali H, Thune JJ, Køber L, Shah A, McMurray JJ, Pfeffer MA, Solomon SD; VALIANT Investigators. Regional cardiac dysfunction and outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction. Eur Heart J. 2016;37:466–472. doi: 10.1093/eurheartj/ehv558.
60. Foley PW, Chalil S, Khadjooi K, Irwin N, Smith RE, Leyva F. Left ventricular reverse remodelling, long-term clinical outcome, and mode of death after cardiac resynchronization therapy. Eur J Heart Fail. 2011;13:43–51. doi: 10.1093/eurjhf/hfq182.
61. Bhatt AS, Ambrosy AP, Velazquez EJ. Adverse remodeling and reverse remodeling after myocardial infarction. Curr Cardiol Rep. 2017;19:71. doi: 10.1007/s11886-017-0876-4.
62. Wu E, Ortiz JT, Tejedor P, Lee DC, Bucciarelli-Ducci C, Kansal P, Carr JC, Holly TA, Lloyd-Jones D, Klocke FJ, Bonow RO. Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study. Heart. 2008;94:730–736. doi: 10.1136/hrt.2007.122622.
63. Florea V, Rieger AC, DiFede DL, et al. Dose comparison study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy (The TRIDENT study). Circ Res. 2017;121:1279–1290. doi: 10.1161/CIRCRESAHA.117.311827.
64. Malliaras K, Marbán E. Cardiac regeneration validated. Nat Biotechnol. 2015;33:587. doi: 10.1038/nbt.3254.
65. Amado LC, Schuleri KH, Saliaris AP, Boyle AJ, Helm R, Oskouei B, Centola M, Eneboe V, Young R, Lima JA, Lardo AC, Heldman AW, Hare JM. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol. 2006;48:2116–2124. doi: 10.1016/j.jacc.2006.06.073.
66. Malliaras K, Smith RR, Kanazawa H, et al. Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. Circulation. 2013;128:2764–2775. doi: 10.1161/CIRCULATIONAHA.113.002863.
67. Hamo CE, Gheorghiade M, Butler J. Novel endpoints for heart failure clinical trials. Curr Heart Fail Rep. 2017;14:210–216. doi: 10.1007/s11897-017-0334-z.
68. Wessler BS, Kramer DG, Kelly JL, Trikalinos TA, Kent DM, Konstam MA, Udelson JE. Drug and device effects on peak oxygen consumption, 6-minute walk distance, and natriuretic peptides as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction. Circ Heart Fail. 2011;4:578–588. doi: 10.1161/CIRCHEARTFAILURE.111.961573.
69. Hobbs FD, Kenkre JE, Roalfe AK, Davis RC, Hare R, Davies MK. Impact of heart failure and left ventricular systolic dysfunction on quality of life: a cross-sectional study comparing common chronic cardiac and medical disorders and a representative adult population. Eur Heart J. 2002;23:1867–1876.
70. Porapakkham P, Porapakkham P, Zimmet H, Billah B, Krum H. B-type natriuretic peptide-guided heart failure therapy: a meta-analysis. Arch Intern Med. 2010;170:507–514. doi: 10.1001/archinternmed.2010.35.
71. Chow SL, Maisel AS, Anand I, Bozkurt B, de Boer RA, Felker GM, Fonarow GC, Greenberg B, Januzzi JL Jr, Kiernan MS, Liu PP, Wang TJ, Yancy CW, Zile MR; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Basic Cardiovascular Sciences; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Epidemiology and Prevention; Council on Functional Genomics and Translational Biology; and Council on Quality of Care and Outcomes Research. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation. 2017;135:e1054–e1091. doi: 10.1161/CIR.0000000000000490.
72. Natsumeda M, Florea V, Rieger AC, et al. A combination of allogeneic stem cells promotes cardiac regeneration. J Am Coll Cardiol. 2017;70:2504–2515. doi: 10.1016/j.jacc.2017.09.036.
73. Gerczuk PZ, Kloner RA. An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. J Am Coll Cardiol. 2012;59:969–978. doi: 10.1016/j.jacc. 2011.07.054.
74. Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N, Grünwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:3009–3017.
75. Schächinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J Am Coll Cardiol. 2004;44:1690–1699. doi: 10.1016/j.jacc. 2004.08.014.
76. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364:141–148. doi: 10.1016/S0140-6736(04)16626-9.
77. 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. doi: 10.1016/S0140-6736(05)67861-0.
78. Huikuri HV, Kervinen K, Niemelä M, Ylitalo K, Säily M, Koistinen P, Savolainen ER, Ukkonen H, Pietilä M, Airaksinen JK, Knuuti J, Mäkikallio TH; FINCELL Investigators. Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction. Eur Heart J. 2008;29:2723–2732. doi: 10.1093/ eurheartj/ehn436.
79. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM; REPAIR-AMI Investigators. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355:1210–1221. doi: 10.1056/ NEJMoa060186.
80. Schächinger V, Erbs S, Elsässer A, et al; REPAIR-AMI Investigators. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006;27:2775–2783. doi: 10.1093/eurheartj/ehl388.
81. Assmus B, Leistner DM, Schächinger V, et al; REPAIR-AMI Study Group. Long-term clinical outcome after intracoronary application of bone marrow-derived mononuclear cells for acute myocardial infarction: migratory capacity of administered cells determines event-free survival. Eur Heart J. 2014;35:1275–1283. doi: 10.1093/eurheartj/ehu062.
82. Traverse JH, Henry TD, Pepine CJ, et al; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012;308:2380–2389. doi: 10.1001/jama.2012.28726.
83. Traverse JH, Henry TD, Ellis SG, et al; Cardiovascular Cell Therapy Research Network. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011;306:2110–2119. doi: 10.1001/jama.2011.1670.
84. Sürder D, Manka R, Moccetti T, et al. Effect of bone marrow-derived mononuclear cell treatment, early or late after acute myocardial infarction: twelve months CMR and long-term clinical results. Circ Res. 2016;119:481–490. doi: 10.1161/CIRCRESAHA.116.308639.
85. Wollert KC, Meyer GP, Müller-Ehmsen J, et al. Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST-2 randomised placebo-controlled clinical trial. Eur Heart J. 2017;38:2936–2943. doi: 10.1093/eurheartj/ehx188.
86. Quyyumi AA, Vasquez A, Kereiakes DJ, et al. PreSERVE-AMI: a randomized, double-blind, placebo-controlled clinical trial of intracoronary administration of autologous CD34+ cells in patients with left ventricular dysfunction post STEMI. Circ Res. 2017;120:324–331. doi: 10.1161/CIRCRESAHA.115.308165.
87. Traverse JH, Henry TD, Pepine CJ, et al. TIME trial: effect of timing of stem cell delivery following ST-elevation myocardial infarction on the recovery of global and regional left ventricular function: final 2-year analysis. Circ Res. 2018;122:479–488. doi: 10.1161/CIRCRESAHA.117.311466.
88. Nicolau JC, Furtado RHM, Silva SA, Rochitte CE, Rassi A Jr, Moraes JBMC Jr, Quintella E, Costantini CR, Korman APM, Mattos MA, Castello HJ Jr, Caixeta A, Dohmann HFR, de Carvalho ACC; MiHeart/ AMI Investigators. Stem-cell therapy in ST-segment elevation myocardial infarction with reduced ejection fraction: a multicenter, double-blind randomized trial. Clin Cardiol. 2018;41:392–399. doi: 10.1002/clc.22882.
89. Gyöngyösi M, Wojakowski W, Lemarchand P, et al; ACCRUE Investigators. Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. 2015;116:1346–1360. doi: 10.1161/CIRCRESAHA. 116.304346.
90. Chong MS, Ng WK, Chan JK. Concise review: endothelial progenitor cells in regenerative medicine: applications and challenges. Stem Cells Transl Med. 2016;5:530–538. doi: 10.5966/sctm.2015-0227.
91. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J. 2007;28:766–772. doi: 10.1093/eurheartj/ehl509.
92. Bellenger NG, Burgess MI, Ray SG, Lahiri A, Coats AJ, Cleland JG, Pennell DJ. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? Eur Heart J. 2000;21:1387–1396. doi: 10.1053/euhj.2000.2011.
93. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation. 2012;126:551–568. doi: 10.1161/CIRCULATIONAHA.111.086074.
94. Hirsch A, Nijveldt R, van der Vleuten PA, Tijssen JG, van der Giessen WJ, Tio RA, Waltenberger J, ten Berg JM, Doevendans PA, Aengevaeren WR, Zwaginga JJ, Biemond BJ, van Rossum AC, Piek JJ, Zijlstra F; HEBE Investigators. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J. 2011;32:1736–1747. doi: 10.1093/ eurheartj/ehq449.
95. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W. 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. doi: 10.1016/j.jacc.2009.06.055.
96. 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. doi: 10.1186/s12916-015-0399-z.
97. Sanz-Ruiz R, Casado Plasencia A, Borlado LR, et al. Rationale and design of a clinical trial to evaluate the safety and efficacy of intracoronary infusion of allogeneic human cardiac stem cells in patients with acute myocardial infarction and left ventricular dysfunction: the randomized multicenter double-blind controlled CAREMI trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction). Circ Res. 2017;121:71–80. doi: 10.1161/CIRCRESAHA.117.310651.
98. Povsic TJ, Henry TD, Traverse JH, et al; RENEW Investigators. The RENEW trial: efficacy and safety of intramyocardial autologous CD34(+) cell administration in patients with refractory angina. JACC Cardiovasc Interv. 2016;9:1576–1585. doi: 10.1016/j.jcin. 2016.05.003.
99. Losordo DW, Henry TD, Davidson C, et al; ACT34-CMI Investigators. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109:428–436. doi: 10.1161/CIRCRESAHA.111.245993.
100. Henry TD, Losordo DW, Traverse JH, et al. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. Eur Heart J. 2018;39:2208–2216. doi: 10.1093/eurheartj/ehx764.
101. Solomon SD, Skali H, Anavekar NS, Bourgoun M, Barvik S, Ghali JK, Warnica JW, Khrakovskaya M, Arnold JM, Schwartz Y, Velazquez EJ, Califf RM, McMurray JV, Pfeffer MA. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation. 2005;111:3411–3419. doi: 10.1161/CIRCULATIONAHA.104.508093.
102. Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107:2294–2302. doi: 10.1161/01.CIR. 0000070596.30552.8B.
103. 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:II213–II218. doi: 10.1161/01.CIR. 0000138398.77550.62.
104. Assmus B, Honold J, Schächinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006;355:1222–1232. doi: 10.1056/NEJMoa051779.
105. Mathiasen AB, Qayyum AA, Jørgensen E, Helqvist S, Fischer-Nielsen A, Kofoed KF, Haack-Sørensen M, Ekblond A, Kastrup J. 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. doi: 10.1093/eurheartj/ehv136.
106. Bolli R, Chugh AR, D’Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378:1847–1857. doi: 10.1016/ S0140-6736(11)61590-0.
107. 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. doi: 10.1001/jama.2012.25321.
108. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marbán L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, Lardo AC, Gerstenblith G, Marbán E. Intracoronary Cardiosphere-Derived Cells for Heart Regeneration After Myocardial Infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012;379:895–904. doi: 10.1016/S0140-6736(12)60195-0.
109. Bartolucci J, Verdugo FJ, González PL, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase ½ randomized controlled trial (RIMECARD trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circ Res. 2017;121:1192–1204. doi: 10.1161/CIRCRESAHA.117.310712.
110. Menasché P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, Vilquin JT, Marolleau JP, Seymour B, Larghero J, Lake S, Chatellier G, Solomon S, Desnos M, Hagège AA. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008;117:1189–1200. doi: 10.1161/CIRCULATIONAHA.107.734103.
111. Reinecke H, MacDonald GH, Hauschka SD, Murry CE. Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. J Cell Biol. 2000;149:731–740.
112. Xiao C, Zhou S, Liu Y, Hu H. Efficacy and safety of bone marrow cell transplantation for chronic ischemic heart disease: a meta-analysis. Med Sci Monit. 2014;20:1768–1777. doi: 10.12659/MSM.892047.
113. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–1219. doi: 10.1161/CIRCRESAHA.108.176826.
114. Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol. 2011;50:280–289. doi: 10.1016/j.yjmcc.2010.08.005.
115. See F, Seki T, Psaltis PJ, Sondermeijer HP, Gronthos S, Zannettino AC, Govaert KM, Schuster MD, Kurlansky PA, Kelly DJ, Krum H, Itescu S. Therapeutic effects of human STRO-3-selected mesenchymal precursor cells and their soluble factors in experimental myocardial ischemia. J Cell Mol Med. 2011;15:2117–2129. doi: 10.1111/j.1582-4934.2010.01241.x.
116. Psaltis PJ, Paton S, See F, Arthur A, Martin S, Itescu S, Worthley SG, Gronthos S, Zannettino AC. Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. J Cell Physiol. 2010;223:530–540. doi: 10.1002/jcp.22081.
117. Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy. Circ Res. 2008;102:1319–1330. doi: 10.1161/ CIRCRESAHA.108.175943.
118. Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, Kajstura J, Pappas P, Tatooles A, Stoddard MF, Lima JA, Slaughter MS, Anversa P, Bolli R. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation. 2012;126:S54–S64. doi: 10.1161/CIRCULATIONAHA.112.092627.
119. Bolli R, Hare JM, March KL, et al. Rationale and design of the CONCERT-HF (Combination of Mesenchymal and c-kit(+) Cardiac Stem Cells as Regenerative Therapy for Heart Failure) Trial. Circ Res. 2018;122:1703–1715.
120. Kapelios CJ, Nanas JN, Malliaras K. Allogeneic cardiosphere-derived cells for myocardial regeneration: current progress and recent results. Future Cardiol. 2016;12:87–100. doi: 10.2217/fca.15.72.
121. Behfar A, Yamada S, Crespo-Diaz R, Nesbitt JJ, Rowe LA, Perez-Terzic C, Gaussin V, Homsy C, Bartunek J, Terzic A. Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J Am Coll Cardiol. 2010;56:721–734. doi: 10.1016/j.jacc.2010.03.066.
122. Teerlink JR, Metra M, Filippatos GS, Davison BA, Bartunek J, Terzic A, Gersh BJ, Povsic TJ, Henry TD, Alexandre B, Homsy C, Edwards C, Seron A, Wijns W, Cotter G; CHART Investigators. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur J Heart Fail. 2017;19:1520–1529. doi: 10.1002/ejhf.898.
123. Karantalis V, Suncion-Loescher VY, Bagno L, et al. Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. J Am Coll Cardiol. 2015;66:1990–1999. doi: 10.1016/j.jacc.2015.08.879.
124. Patel AN, Henry TD, Quyyumi AA, Schaer GL, Anderson RD, Toma C, East C, Remmers AE, Goodrich J, Desai AS, Recker D, DeMaria A; ixCELL-DCM Investigators. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet. 2016;387:2412–2421. doi: 10.1016/S0140-6736(16)30137-4.
125. Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Chambers DC, Yusen RD, Stehlik J; International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report-2017; focus theme: al-lograft ischemic time. J Heart Lung Transplant. 2017;36:1037–1046. doi: 10.1016/j.healun.2017.07.019.
126. Bello D, Shah DJ, Farah GM, Di Luzio S, Parker M, Johnson MR, Cotts WG, Klocke FJ, Bonow RO, Judd RM, Gheorghiade M, Kim RJ. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation. 2003;108:1945–1953. doi: 10.1161/01.CIR.0000095029.57483.60.
127. Fischer-Rasokat U, Assmus B, Seeger FH, Honold J, Leistner D, Fichtlscherer S, Schächinger V, Tonn T, Martin H, Dimmeler S, Zeiher AM. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail. 2009;2:417–423. doi: 10.1161/CIRCHEARTFAILURE. 109.855023.
128. Seth S, Bhargava B, Narang R, Ray R, Mohanty S, Gulati G, Kumar L, Airan B, Venugopal P; AIIMS Stem Cell Study Group. The ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial a long-term follow-up study. J Am Coll Cardiol. 2010;55:1643–1644. doi: 10.1016/j.jacc.2009.11.070.
129. Martino H, Brofman P, Greco O, Bueno R, Bodanese L, Clausell N, Maldonado JA, Mill J, Braile D, Moraes J Jr, Silva S, Bozza A, Santos B, Campos de Carvalho A; Dilated Cardiomyopathy Arm of the MiHeart Study Investigators. Multicentre, randomized, double-blind trial of intracoronary autologous mononuclear bone marrow cell injection in non-ischaemic dilated cardiomyopathy (the dilated cardiomyopathy arm of the MiHeart study). Eur Heart J. 2015;36:2898–2904. doi: 10.1093/eurheartj/ehv477.
130. Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, Socan A, Schrepfer S, Torre-Amione G, Haddad F, Wu JC. Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res. 2013;112:165–173. doi: 10.1161/CIRCRESAHA.112.276519.
131. Vrtovec B, Poglajen G, Sever M, Lezaic L, Socan A, Haddad F, Wu JC. CD34+ stem cell therapy in nonischemic dilated cardiomyopathy patients. Clin Pharmacol Ther. 2013;94:452–458. doi: 10.1038/clpt.2013.134.
132. Hare JM, DiFede DL, Rieger AC, et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM Trial. J Am Coll Cardiol. 2017;69:526–537. doi: 10.1016/j.jacc.2016.11.009.
133. Butler J, Epstein SE, Greene SJ, Quyyumi AA, Sikora S, Kim RJ, Anderson AS, Wilcox JE, Tankovich NI, Lipinski MJ, Ko YA, Margulies KB, Cole RT, Skopicki HA, Gheorghiade M. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase II-A randomized trial. Circ Res. 2017;120:332–340. doi: 10.1161/CIRCRESAHA.116.309717.
134. Xiao W, Guo S, Gao C, Dai G, Gao Y, Li M, Wang X, Hu D. A randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy. Int Heart J. 2017;58:238–244. doi: 10.1536/ihj.16-328.
135. Vrtovec B, Poglajen G, Lezaic L, Sever M, Socan A, Domanovic D, Cernelc P, Torre-Amione G, Haddad F, Wu JC. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation. 2013;128:S42–S49. doi: 10.1161/CIRCULATIONAHA.112.000230.
136. Bocchi EA, Bacal F, Guimarães G, Mendroni A, Mocelin A, Filho AE, Dores da Cruz Fd, Resende MC, Chamone D. Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non ischemic refractory heart failure. Int J Cardiol. 2010;138:94–97. doi: 10.1016/j.ijcard.2008.06.002.
137. Kelkar AA, Butler J, Schelbert EB, Greene SJ, Quyyumi AA, Bonow RO, Cohen I, Gheorghiade M, Lipinski MJ, Sun W, Luger D, Epstein SE. Mechanisms contributing to the progression of ischemic and nonischemic dilated cardiomyopathy: possible modulating effects of paracrine activities of stem cells. J Am Coll Cardiol. 2015;66:2038–2047. doi: 10.1016/j.jacc.2015.09.010.
138. Kanelidis AJ, Premer C, Lopez J, Balkan W, Hare JM. Route of delivery modulates the efficacy of mesenchymal stem cell therapy for myocardial infarction: a meta-analysis of preclinical studies and clinical trials. Circ Res. 2017;120:1139–1150. doi: 10.1161/CIRCRESAHA.116.309819.
139. Block TJ, Marinkovic M, Tran ON, Gonzalez AO, Marshall A, Dean DD, Chen XD. Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies. Stem Cell Res Ther. 2017;8:239. doi: 10.1186/s13287-017-0688-x.
140. Perin EC, Borow KM, Silva GV, DeMaria AN, Marroquin OC, Huang PP, Traverse JH, Krum H, Skerrett D, Zheng Y, Willerson JT, Itescu S, Henry TD. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ Res. 2015;117:576–584. doi: 10.1161/CIRCRESAHA.115.306332.
141. Quyyumi AA, Waller EK, Murrow J, et al. CD34(+) cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent. Am Heart J. 2011;161:98–105. doi: 10.1016/j.ahj.2010.09.025.
142. Suncion VY, Ghersin E, Fishman JE, et al. Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res. 2014;114:1292–1301. doi: 10.1161/CIRCRESAHA.114.302854.
143. Dill T, Schächinger V, Rolf A, Möllmann S, Thiele H, Tillmanns H, Assmus B, Dimmeler S, Zeiher AM, Hamm C. Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J. 2009;157:541–547. doi: 10.1016/j.ahj.2008.11.011.
144. Vrtovec B, Sever M, Jensterle M, Poglajen G, Janez A, Kravos N, Zemljic G, Cukjati M, Cernelc P, Haddad F, Wu JC, Jorde UP. Efficacy of CD34+ stem cell therapy in nonischemic dilated cardiomyopathy is absent in patients with diabetes but preserved in patients with insulin resistance. Stem Cells Transl Med. 2016;5:632–638. doi: 10.5966/sctm.2015-0172.
145. Haddad F, Sever M, Poglajen G, Lezaic L, Yang P, Maecker H, Davis M, Kuznetsova T, Wu JC, Vrtovec B. Immunologic network and response to intramyocardial CD34+ stem cell therapy in patients with dilated cardiomyopathy. J Card Fail. 2015;21:572–582. doi: 10.1016/j.cardfail.2015.03.011.
146. Jokerst JV, Cauwenberghs N, Kuznetsova T, et al. Circulating biomarkers to identify responders in cardiac cell therapy. Sci Rep. 2017;7:4419. doi: 10.1038/s41598-017-04801-7.
147. Ménard C, Hagège AA, Agbulut O, Barro M, Morichetti MC, Brasselet C, Bel A, Messas E, Bissery A, Bruneval P, Desnos M, Pucéat M, Menasché P. Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study. Lancet. 2005;366:1005–1012. doi: 10.1016/S0140-6736(05)67380-1.
148. Zhu K, Wu Q, Ni C, et al. Lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells in infarcted nonhuman primates. Circ Res. 2018;122:958–969. doi: 10.1161/CIRCRESAHA.
149. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676. doi: 10.1016/j.cell.2006.07.024.
150. Kawamura M, Miyagawa S, Fukushima S, Saito A, Miki K, Ito E, Sougawa N, Kawamura T, Daimon T, Shimizu T, Okano T, Toda K, Sawa Y. Enhanced survival of transplanted human induced pluripotent stem cell-derived cardiomyocytes by the combination of cell sheets with the pedicled omental flap technique in a porcine heart. Circulation. 2013;128:S87–S94. doi: 10.1161/CIRCULATIONAHA.112.000366.
151. Yanamandala M, Zhu W, Garry DJ, Kamp TJ, Hare JM, Jun HW, Yoon YS, Bursac N, Prabhu SD, Dorn GW 2nd, Bolli R, Kitsis RN, Zhang J. Overcoming the roadblocks to cardiac cell therapy using tissue engineering. J Am Coll Cardiol. 2017;70:766–775. doi: 10.1016/j.jacc.2017.06.012.
152. Assmus B, Walter DH, Seeger FH, Leistner DM, Steiner J, Ziegler I, Lutz A, Khaled W, Klotsche J, Tonn T, Dimmeler S, Zeiher AM. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA. 2013;309:1622–1631. doi: 10.1001/jama.2013.3527.
153. Gwizdala A, Rozwadowska N, Kolanowski TJ, Malcher A, Cieplucha A, Perek B, Seniuk W, Straburzynska-Migaj E, Oko-Sarnowska Z, Cholewinski W, Michalak M, Grajek S, Kurpisz M. Safety, feasibility and effectiveness of first in-human administration of muscle-derived stem/progenitor cells modified with connexin-43 gene for treatment of advanced chronic heart failure. Eur J Heart Fail. 2017;19:148–157. doi: 10.1002/ejhf.700.
154. Taljaard M, Ward MR, Kutryk MJ, Courtman DW, Camack NJ, Goodman SG, Parker TG, Dick AJ, Galipeau J, Stewart DJ. Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): the first randomized placebo-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction. Am Heart J. 2010;159:354–360.
155. Lemcke H, Voronina N, Steinhoff G, David R. Recent progress in stem cell modification for cardiac regeneration. Stem Cells Int. 2018;2018:1909346. doi: 10.1155/2018/1909346.
156. Butler J, Epstein SE, Greene SJ, et al. Intravenous allogeneic mesenchymal stem cells for non-ischemic cardiomyopathy: safety and efficacy results of a phase II-A randomized trial. Circ Res. 2016;120:332–340. doi: 10.1161/CIRCRESAHA.116.309717.
157. Kishore R, Khan M. More than tiny sacks: stem cell exosomes as cell-free modality for cardiac repair. Circ Res. 2016;118:330–343. doi: 10.1161/CIRCRESAHA.115.307654.
158. Adamiak M, Cheng G, Bobis-Wozowicz S, et al. Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs. Circ Res. 2018;122:296–309. doi: 10.1161/CIRCRESAHA.117.311769.
159. Kervadec A, Bellamy V, El Harane N, et al. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J Heart Lung Transplant. 2016;35:795–807. doi: 10.1016/j.healun.2016. 01.013.
160. Tang J, Shen D, Caranasos TG, Wang Z, Vandergriff AC, Allen TA, Hensley MT, Dinh PU, Cores J, Li TS, Zhang J, Kan Q, Cheng K. Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome. Nat Commun. 2017;8:13724. doi: 10.1038/ncomms13724.
161. Tokita Y, Tang XL, Li Q, Wysoczynski M, Hong KU, Nakamura S, Wu WJ, Xie W, Li D, Hunt G, Ou Q, Stowers H, Bolli R. Repeated administrations of cardiac progenitor cells are markedly more effective than a single administration: a new paradigm in cell therapy. Circ Res. 2016;119:635–651. doi: 10.1161/CIRCRESAHA. 116.308937.
162. Guo Y, Wysoczynski M, Nong Y, Tomlin A, Zhu X, Gumpert AM, Nasr M, Muthusamy S, Li H, Book M, Khan A, Hong KU, Li Q, Bolli R. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol. 2017;112:18. doi: 10.1007/s00395-017-0606-5.