Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133+ Application After Myocardial Infarction
Gustav Steinhoff, Julia Nesteruk, Markus Wolfien, Günther Kundt, PERFECT Trial Investigators Group, Jochen Börgermann, Robert David, Jens Garbade, Jana Große, Axel Haverich, Holger Hennig, Alexander Kaminski, Joachim Lotz, Friedrich-Wilhelm Mohr, Paula Müller, Robert Oostendorp, Ulrike Ruch, Samir Sarikouch, Anna Skorska, Christof Stamm, Gudrun Tiedemann, Florian Mathias Wagner, Olaf Wolkenhauer, Gustav Steinhoff, Julia Nesteruk, Markus Wolfien, Günther Kundt, PERFECT Trial Investigators Group, Jochen Börgermann, Robert David, Jens Garbade, Jana Große, Axel Haverich, Holger Hennig, Alexander Kaminski, Joachim Lotz, Friedrich-Wilhelm Mohr, Paula Müller, Robert Oostendorp, Ulrike Ruch, Samir Sarikouch, Anna Skorska, Christof Stamm, Gudrun Tiedemann, Florian Mathias Wagner, Olaf Wolkenhauer
Abstract
Objective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair.
Design: Multicentre, double-blinded, randomised placebo controlled trial.
Setting: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.
Participants: Post-infarction patients with chronic ischemia and reduced LVEF (25-50%).
Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×106 CD133+.
Outcome: Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI.
Findings (prespecified): Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+. Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+vs placebo +2.6%, p=0.4).
Findings (post hoc): Responders (R) classified by ∆LVEF≥5% after 180d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.
Interpretation: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.
Trial registration: ClinicalTrials.govNCT00950274.
Keywords: Angiogenesis; CD133(+); CD34(+); Cardiac repair; Cardiac stem cell therapy; Endothelial progenitor cell (EPC); Lnk adaptor; Randomised double-blinded phase III multicentre trial; SH2B3.
Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
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References
- Auer P.L., Teumer A., Schick U. Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat. GenetNat. Genet. 2014;46(6):629–634. (Epub 2014 Apr 28)
- Bartunek J., Terzic A., Davison B.A. Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur. Heart J. 2016 Dec 23. pii: ehw543. (Epub ahead of print)
- Bartunek J., Terzic A., Davison B.A. 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(9):648–660.
- Bhatnagar A., Bolli R., Johnstone B.H. Cardiovascular cell therapy research network (CCTRN). Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-cardiovascular cell therapy research network (CCTRN) trial. Am. Heart J. 2016;179:142–150.
- Blatt A., Elbaz-Greener G.A., Tuby H., Maltz L. Low-level laser therapy to the bone marrow reduces scarring and improves heart function post-acute myocardial infarction in the pig. Photomed. Laser Surg. 2016;34(11):516–524.
- Cesari F., Caporale R., Marcucci R. NT-proBNP and the anti-inflammatory cytokines are correlated with endothelial progenitor cells' response to cardiac surgery. Atherosclerosis. 2008;199(1):138–146.
- Contreras A., Orozco A.F., Resende M. Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials. Basic Res. Cardiol. 2017;112(1):3.
- Donndorf P., Kaminski A., Tiedemann G., Kundt G., Steinhoff G. Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials. 2012;13:99.
- Fisher S.A., Mathur A., Taggart D.P., Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst. Rev. 2016;12
- Forman G., Cohen I. 2004. Learning From Little: Comparison of Classifiers Given Little Training.
- Fortney K., Dobriban E., Garagnani P. Genome-wide scan informed by age-related disease identifies loci for exceptional human longevity. PLoS Genet. 2015;11(12):e1005728.
- Henry Timothy D., Moyé Lem, Traverse Jay H. Consistently inconsistent—bone marrow mononuclear stem cell therapy following acute myocardial infarction - a decade later. Circ. Res. 2016;119:404–406.
- Hofmann W.K., de Vos S., Elashoff D. Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet. 2002;359(9305):481–486.
- Ishige-Wada M., Kwon S.M., Eguchi M. Jagged-1 signaling in the bone marrow microenvironment promotes endothelial progenitor cell expansion and commitment of CD133 + human cord blood cells for postnatal Vasculogenesis. PLoS One. 2016;11(11):e0166660.
- Kuhn M. Building Predictive Models in R using the caret package. J. Stat. Softw. 2008;28(5):1–26.
- Kwon S.M., Suzuki T., Kawamoto A., Ii M., Eguchi M., Akimaru H., Wada M., Matsumoto T., Masuda H., Nakagawa Y., Nishimura H., Kawai K., Takaki S., Asahara T. Pivotal role of lnk adaptor protein in endothelial progenitor cell biology for vascular regeneration. Circ. Res. 2009;104(8):969–977.
- Lee Jun Hee, Ji Seung Taek, Kim Jaeho. Specific disruption of Lnk in murine endothelial progenitor cells promotes dermal wound healing via enhanced vasculogenesis, activation of myofibroblasts, and suppression of inflammatory cell recruitment. Stem Cell Res Ther. 2016;7(1):158.
- Maaten L.V.D., Hinton G. Visualizing data using t-SNE. J. Mach. Learn. Res. 2008;9:2579–2605.
- McPherson R., Tybjaerg-Hansen A. Genetics of coronary artery disease. Circ. Res. 2016;118(4):564–578. Feb 19.
- Nasseri B.A., Ebell W., Dandel M. Autologous CD133 + bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur. Heart J. 2014;35(19):1263–1274.
- O'Brien R.G., Muller K.E., Edward L.K., editors. Applied Analysis of Variance in Behavioral Science. Marcel Dekker; New York: 1993. Signified power analysis for t-tests through multivariate hypotheses.
- Rosenberger William F., Lachin John M. Wiley publ; 2003. Randomization in Clinical Trials: Theory and Practice; pp. 1–14.
- Saeb A.T., Al-Naqeb D. The impact of evolutionary driving forces on human complex diseases: a population genetics approach. Scientifica (Cairo) 2016;2016 (Epub 2016 May 30)
- Stamm C., Westphal B., Kleine H.D. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361(9351):45–46.
- Stamm C., Kleine H.D., Choi Y.H. Intramyocardial delivery of CD133 + bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J. Thorac. Cardiovasc. Surg. 2007;133(3):717–725.
- Strieter R.M., Kunkel S.L., Arenberg D.A., Burdick M.D., Polverini P.J. Interferon gamma-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis. Biochem. Biophys. Res. Commun. 1995;210(1):51–57.
- Takizawa H., Eto K., Yoshikawa A., Nakauchi H., Takatsu K., Takaki S. Growth and maturation of megakaryocytes is regulated by Lnk/Sh2b3 adaptor protein through crosstalk between cytokine- and integrin-mediated signals. Exp. Hematol. 2008 Jul;36(7):897–906.
- Taylor D.A., Perin E.C., Willerson J.T. Cardiovascular cell therapy research network (CCTRN). Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: an embedded cohort evaluation of the FOCUS-CCTRN trial. Cell Transplant. 2016;25(9):1675–1687.
- Tian T., Chen B., Xiao Y., Yang K., Zhou X., Zhou X. Intramyocardial autologous bone marrow cell transplantation for ischemic heart disease: a systematic review and meta-analysis of randomized controlled trials. Atherosclerosis. 2014;233(2):485–492.
- Tse H.F., Kwong Y.L., Chan J.K., Lo G., Ho C.L., Lau C.P. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003;361(9351):47–49.
- Vakil K., Florea V., Koene R. Effect of coronary artery bypass grafting on left ventricular ejection fraction in men eligible for implantable cardioverter-defibrillator. Am. J. Cardiol. 2016;117:957–960.
- Werner N., Kosiol S., Schiegl T. Circulating endothelial progenitor cells and cardiovascular outcomes. N. Engl. J. Med. 2005;353(10):999–1007.
Source: PubMed