Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy])

Jorge Bartolucci, Fernando J Verdugo, Paz L González, Ricardo E Larrea, Ema Abarzua, Carlos Goset, Pamela Rojo, Ivan Palma, Ruben Lamich, Pablo A Pedreros, Gloria Valdivia, Valentina M Lopez, Carolina Nazzal, Francisca Alcayaga-Miranda, Jimena Cuenca, Matthew J Brobeck, Amit N Patel, Fernando E Figueroa, Maroun Khoury, Jorge Bartolucci, Fernando J Verdugo, Paz L González, Ricardo E Larrea, Ema Abarzua, Carlos Goset, Pamela Rojo, Ivan Palma, Ruben Lamich, Pablo A Pedreros, Gloria Valdivia, Valentina M Lopez, Carolina Nazzal, Francisca Alcayaga-Miranda, Jimena Cuenca, Matthew J Brobeck, Amit N Patel, Fernando E Figueroa, Maroun Khoury

Abstract

Rationale: Umbilical cord-derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. Although bone marrow-derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients.

Objective: Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction.

Methods and results: Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×106 cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow-derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, known to be involved in myogenesis, cell migration, and immunoregulation. UC-MSC-treated patients presented no adverse events related to the cell infusion, and none of the patients tested at 0, 15, and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC-treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6, and 12 months of follow-up assessed both through transthoracic echocardiography (P=0.0167 versus baseline) and cardiac MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy.

Conclusions: Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs.

Clinical trial registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777.

Keywords: cardiomyopathies; clinical trial; heart failure; mesenchymal stromal cells; umbilical cord.

© 2017 The Authors.

Figures

Figure 1.
Figure 1.
Umbilical cord–derived mesenchymal stem cells (UC-MSCs) and marrow–derived mesenchymal stem cells (BM-MSCs) displayed different cardiac differentiation potential and paracrine factors profile. Cardiac differentiation was induced in UC-MSCs and BM-MSCs by cultured with 5-azacytidine (5-AZA) 10 µmol/L during 25 d. Cardiac differentiation potential was evaluated through mRNA relative expression of cardiac gene (NCx2.5, GATA-4, MEF2C, MYH7B, GJA1, and TNNT2) by real time polymerase chain reaction (RT-PCR) with B2M as a housekeeping gene (A) and by detection of cardiac proteins using indirect immunofluorescence staining troponin and connexin-43 (B), the respective graphs show the quantification of positive cells in the each staining. TGFβ3 expression was quantitated by quantitative RT-PCR (C). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels were evaluated by ELISA assay (C). Data shown in the graphs are the mean±SEM of at least 3 individual experiments. *P<0.05, ***P<0.001, UC-MSCs compared with BM-MSCs. +P<0.05, ++P<0.001 UC-MSC-4 compared with UC-MSCs-1, 2, and 3.
Figure 2.
Figure 2.
Umbilical cord–derived mesenchymal stem cells (UC-MSCs) and marrow–derived mesenchymal stem cells (BM-MSCs) display the same suppressive capacities to inhibit proinflammatory T-cells. PHA-activated peripheral blood mononuclear cells (PBMC) obtained from dilated cardiomyopathy patients with heart failure and reduced ejection fraction (HFrEF) labeled with 5(6)-carboxyfluorescein diacetate N-succinimidyl (CFSE) were coculture with or without mesenchymal stem cells (MSCs) at a 1:10 ratio (MSCs:PBMC). A, T-cell proliferation was evaluated by the reduction in CFSE intensity at 72 h after culture, the graphs in the left is a representative CFSE proliferation panel (light color histogram represents activated PBMCs and dark color histogram to activated PBMC cocultured with MSCs). B, Th1, Th2, CD8, and regulatory T cells subsets analysis from coculture of PBMC and MSCs. Results are represented as mean±SEM of at least 3 independent experiments using at least 3 different donors for PBMC (healthy donor and HF patient), UC-MSCs, and BM-MSCs. ***P<0.001 UC-MSCs or BM-MSCs with respect to PHA.
Figure 3.
Figure 3.
Umbilical cord–derived mesenchymal stem cells (UC-MSCs) possess a superior migration capacity compared with marrow–derived mesenchymal stem cells (BM-MSCs). Migration capacity of MSCs was evaluated by transwell assay in response to serum from patients with heart failure and reduced ejection fraction after 16 h. The pictures show the representative staining with violet crystal and the left graph the quantification of % of migrated cells under the different conditions. Data shown in the graphs are the mean±SEM of at least 3 serum donors, UC-MSCs, and BM-MSCs. *P<0.05 UC-MSCs vs BM-MSCs.
Figure 4.
Figure 4.
Study flow chart. UC-MSC indicates umbilical cord–derived mesenchymal stem cell.
Figure 5.
Figure 5.
Changes in CMRmeasurements from baseline to 12-mopost-treatment in studied groups.A, Left ventricular ejection fraction (LVEF). B, Left ventricular end-diastolic volume (LVEDV). C, Left ventricular end-systolic volume (LVESV). Continuous line represents umbilical cord–derived mesenchymal stem cell group (n=14 per protocol). Dashed line represents placebo group (n=13 per protocol; withdrawal of consent from 1 patient). Statistical analysis is based on mixed effect maximum likelihood regression between baseline and follow-up measures for each group and variability between groups.

References

    1. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109:923–940. doi: 10.1161/CIRCRESAHA.111.243147.
    1. 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.
    1. 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.
    1. Kandala J, Upadhyay GA, Pokushalov E, Wu S, Drachman DE, Singh JP. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy. Am J Cardiol. 2013;112:217–225. doi: 10.1016/j.amjcard.2013.03.021.
    1. Gho JM, Kummeling GJ, Koudstaal S, Jansen Of Lorkeers SJ, Doevendans PA, Asselbergs FW, Chamuleau SA. Cell therapy, a novel remedy for dilated cardiomyopathy? A systematic review. J Card Fail. 2013;19:494–502. doi: 10.1016/j.cardfail.2013.05.006.
    1. Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circ Res. 2015;116:1361–1377. doi: 10.1161/CIRCRESAHA.116.304386.
    1. Gaebel R, Furlani D, Sorg H, Polchow B, Frank J, Bieback K, Wang W, Klopsch C, Ong LL, Li W, Ma N, Steinhoff G. Cell origin of human mesenchymal stem cells determines a different healing performance in cardiac regeneration. PLoS One. 2011;6:e15652. doi: 10.1371/journal.pone.0015652.
    1. 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.
    1. Nishiyama N, Miyoshi S, Hida N, Uyama T, Okamoto K, Ikegami Y, Miyado K, Segawa K, Terai M, Sakamoto M, Ogawa S, Umezawa A. The significant cardiomyogenic potential of human umbilical cord blood-derived mesenchymal stem cells in vitro. Stem Cells. 2007;25:2017–2024. doi: 10.1634/stemcells.2006-0662.
    1. Ramkisoensing AA, Pijnappels DA, Askar SF, Passier R, Swildens J, Goumans MJ, Schutte CI, de Vries AA, Scherjon S, Mummery CL, Schalij MJ, Atsma DE. Human embryonic and fetal mesenchymal stem cells differentiate toward three different cardiac lineages in contrast to their adult counterparts. PLoS One. 2011;6:e24164. doi: 10.1371/journal.pone.0024164.
    1. Santos Nascimento D, Mosqueira D, Sousa LM, Teixeira M, Filipe M, Resende TP, Araújo AF, Valente M, Almeida J, Martins JP, Santos JM, Bárcia RN, Cruz P, Cruz H, Pinto-do-Ó P. Human umbilical cord tissue-derived mesenchymal stromal cells attenuate remodeling after myocardial infarction by proangiogenic, antiapoptotic, and endogenous cell-activation mechanisms. Stem Cell Res Ther. 2014;5:5. doi: 10.1186/scrt394.
    1. González PL, Carvajal C, Cuenca J, Alcayaga-Miranda F, Figueroa FE, Bartolucci J, Salazar-Aravena L, Khoury M. Chorion mesenchymal stem cells show superior differentiation, immunosuppressive, and angiogenic potentials in comparison with haploidentical maternal placental cells. Stem Cells Transl Med. 2015;4:1109–1121. doi: 10.5966/sctm.2015-0022.
    1. Gong X, Wang P, Wu Q, Wang S, Yu L, Wang G. Human umbilical cord blood derived mesenchymal stem cells improve cardiac function in cTnT(R141W) transgenic mouse of dilated cardiomyopathy. Eur J Cell Biol. 2016;95:57–67. doi: 10.1016/j.ejcb.2015.11.003.
    1. Liu CB, Huang H, Sun P, Ma SZ, Liu AH, Xue J, Fu JH, Liang YQ, Liu B, Wu DY, Lü SH, Zhang XZ. Human umbilical cord-derived mesenchymal stromal cells improve left ventricular function, perfusion, and remodeling in a porcine model of chronic myocardial ischemia. Stem Cells Transl Med. 2016;5:1004–1013. doi: 10.5966/sctm.2015-0298.
    1. 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.
    1. Banovic M, Loncar Z, Behfar A, Vanderheyden M, Beleslin B, Zeiher A, Metra M, Terzic A, Bartunek J. Endpoints in stem cell trials in ischemic heart failure. Stem Cell Res Ther. 2015;6:159. doi: 10.1186/s13287-015-0143-9.
    1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440–1463. doi: 10.1016/j.echo.2005.10.005.
    1. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr. 2011;24:277–313. doi: 10.1016/j.echo.2011.01.015.
    1. Heiberg E, Sjögren J, Ugander M, Carlsson M, Engblom H, Arheden H. Design and validation of Segment–freely available software for cardiovascular image analysis. BMC Med Imaging. 2010;10:1. doi: 10.1186/1471-2342-10-1.
    1. Garin O, Soriano N, Ribera A, Ferrer M, Pont A, Alonso J, Permanyer G Grupo IC-QoL. [Validation of the Spanish version of the Minnesota Living with Heart Failure Questionnaire]. Rev Esp Cardiol. 2008;61:251–259. doi: 10.1016/S1885-5857(08)60112-7.
    1. Comín-Colet J, Garin O, Lupón J, Manito N, Crespo-Leiro MG, Gómez-Bueno M, Ferrer M, Artigas R, Zapata A, Elosua R VALIC-KC Study Group. Validation of the Spanish version of the Kansas city Cardiomyopathy Questionnaire. Rev Esp Cardiol. 2011;64:51–58. doi: 10.1016/j.recesp.2010.10.003.
    1. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559. doi: 10.1371/journal.pone.0047559.
    1. 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.
    1. 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.
    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. doi: 10.1001/jama.2012.25321.
    1. Bartunek J, Behfar A, Dolatabadi D, et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol. 2013;61:2329–2338. doi: 10.1016/j.jacc.2013.02.071.
    1. 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.
    1. 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.
    1. Zhao XF, Xu Y, Zhu ZY, Gao CY, Shi YN. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genet Mol Res. 2015;14:3010–3017. doi: 10.4238/2015.April.10.11.
    1. 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.
    1. Patel AN, Henry TD, Quyyumi AA, Schaer GL, Anderson RD, Toma C, East C, Remmers AE, Goodrich J. 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.
    1. 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.
    1. 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.
    1. Kalogeropoulos AP, Fonarow GC, Georgiopoulou V, Burkman G, Siwamogsatham S, Patel A, Li S, Papadimitriou L, Butler J. Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction. JAMA Cardiol. 2016;1:510–518. doi: 10.1001/jamacardio.2016.1325.
    1. Rostagno C, Galanti G, Comeglio M, Boddi V, Olivo G, Gastone Neri Serneri G. Comparison of different methods of functional evaluation in patients with chronic heart failure. Eur J Heart Fail. 2000;2:273–280. doi: 10.1016/S1388-9842(00)00091-X.
    1. Sarullo FM, Fazio G, Brusca I, Fasullo S, Paterna S, Licata P, Novo G, Novo S, Di Pasquale P. Cardiopulmonary exercise testing in patients with chronic heart failure: prognostic comparison from peak VO2 and VE/VCO2 slope. Open Cardiovasc Med J. 2010;4:127–134. doi: 10.2174/1874192401004010127.
    1. Forman DE, Guazzi M, Myers J, Chase P, Bensimhon D, Cahalin LP, Peberdy MA, Ashley E, West E, Daniels KM, Arena R. Ventilatory power: a novel index that enhances prognostic assessment of patients with heart failure. Circ Heart Fail. 2012;5:621–626. doi: 10.1161/CIRCHEARTFAILURE.112.968529.
    1. Honold J, Fischer-Rasokat U, Seeger FH, Leistner D, Lotz S, Dimmeler S, Zeiher AM, Assmus B. Impact of intracoronary reinfusion of bone marrow-derived mononuclear progenitor cells on cardiopulmonary exercise capacity in patients with chronic postinfarction heart failure. Clin Res Cardiol. 2013;102:619–625. doi: 10.1007/s00392-013-0574-1.
    1. Huang J, Zhang Z, Guo J, Ni A, Deb A, Zhang L, Mirotsou M, Pratt RE, Dzau VJ. Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res. 2010;106:1753–1762. doi: 10.1161/CIRCRESAHA.109.196030.
    1. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002;105:93–98. doi: 10.1161/hc0102.101442.
    1. Ahmet I, Sawa Y, Iwata K, Matsuda H. Gene transfection of hepatocyte growth factor attenuates cardiac remodeling in the canine heart: a novel gene therapy for cardiomyopathy. J Thorac Cardiovasc Surg. 2002;124:957–963. doi: 10.1067/mtc.2002.126655.
    1. Ahmet I, Sawa Y, Yamaguchi T, Matsuda H. Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart. Ann Thorac Surg. 2003;75:1283–1287. doi: 10.1016/S0003-4975(02)04677-5.
    1. Jayasankar V, Woo YJ, Pirolli TJ, Bish LT, Berry MF, Burdick J, Gardner TJ, Sweeney HL. Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card Surg. 2005;20:93–101. doi: 10.1111/j.0886-0440.2005.200373.x.
    1. Yang ZJ, Chen B, Sheng Z, Zhang DG, Jia EZ, Wang W, Ma DC, Zhu TB, Wang LS, Li CJ, Wang H, Cao KJ, Ma WZ. Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium- and high-dose groups. Mol Biol Rep. 2010;37:2075–2081. doi: 10.1007/s11033-009-9665-5.
    1. Hu ZP, Bao Y, Chen DN, Cheng Y, Song B, Liu M, Li D, Wang BN. Effects of recombinant adenovirus hepatocyte growth factor gene on myocardial remodeling in spontaneously hypertensive rats. J Cardiovasc Pharmacol Ther. 2013;18:476–480. doi: 10.1177/1074248413490832.
    1. Kim SW, Jin HL, Kang SM, Kim S, Yoo KJ, Jang Y, Kim HO, Yoon YS. Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair. Int J Cardiol. 2016;203:498–507. doi: 10.1016/j.ijcard.2015.10.110.
    1. Chen J, Liu Z, Hong MM, Zhang H, Chen C, Xiao M, Wang J, Yao F, Ba M, Liu J, Guo ZK, Zhong J. Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells. PLoS One. 2014;9:e115316. doi: 10.1371/journal.pone.0115316.
    1. Premer C, Blum A, Bellio MA, Schulman IH, Hurwitz BE, Parker M, Dermarkarian CR, DiFede DL, Balkan W, Khan A, Hare JM. Allogeneic mesenchymal stem cells restore endothelial function in heart failure by stimulating endothelial progenitor cells. EBioMedicine. 2015;2:467–475. doi: 10.1016/j.ebiom.2015.03.020.
    1. Karantalis V, DiFede DL, 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. doi: 10.1161/CIRCRESAHA.114.303180.

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