Cardiac Function Improvement and Bone Marrow Response –

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 stu...

Full description

Bibliographic Details
Main Authors: Gustav Steinhoff, Julia Nesteruk, Markus Wolfien, Günther Kundt, 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
Format: Article
Language:English
Published: Elsevier 2017-08-01
Series:EBioMedicine
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396417302967
id doaj-506c8e7e8ae54a5c92e1b4df2aea82a0
record_format Article
collection DOAJ
language English
format Article
sources DOAJ
author Gustav Steinhoff
Julia Nesteruk
Markus Wolfien
Günther Kundt
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
spellingShingle Gustav Steinhoff
Julia Nesteruk
Markus Wolfien
Günther Kundt
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
Cardiac Function Improvement and Bone Marrow Response –
EBioMedicine
Randomised double-blinded phase III multicentre trial
CD133+
CD34+
Endothelial progenitor cell (EPC)
SH2B3
Lnk adaptor
Cardiac repair
Cardiac stem cell therapy
Angiogenesis
author_facet Gustav Steinhoff
Julia Nesteruk
Markus Wolfien
Günther Kundt
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
author_sort Gustav Steinhoff
title Cardiac Function Improvement and Bone Marrow Response –
title_short Cardiac Function Improvement and Bone Marrow Response –
title_full Cardiac Function Improvement and Bone Marrow Response –
title_fullStr Cardiac Function Improvement and Bone Marrow Response –
title_full_unstemmed Cardiac Function Improvement and Bone Marrow Response –
title_sort cardiac function improvement and bone marrow response –
publisher Elsevier
series EBioMedicine
issn 2352-3964
publishDate 2017-08-01
description 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 5 ml placebo or a suspension of 0.5–5 × 106 CD133+. Outcome: Primary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI. Findings (prespecified): Safety (n = 77): 180 d 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 180 d, 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 180 d 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 ± 3.32 months (R) vs. +72.3 ± 5.0 months (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.gov NCT00950274.
topic Randomised double-blinded phase III multicentre trial
CD133+
CD34+
Endothelial progenitor cell (EPC)
SH2B3
Lnk adaptor
Cardiac repair
Cardiac stem cell therapy
Angiogenesis
url http://www.sciencedirect.com/science/article/pii/S2352396417302967
work_keys_str_mv AT gustavsteinhoff cardiacfunctionimprovementandbonemarrowresponse
AT julianesteruk cardiacfunctionimprovementandbonemarrowresponse
AT markuswolfien cardiacfunctionimprovementandbonemarrowresponse
AT guntherkundt cardiacfunctionimprovementandbonemarrowresponse
AT jochenborgermann cardiacfunctionimprovementandbonemarrowresponse
AT robertdavid cardiacfunctionimprovementandbonemarrowresponse
AT jensgarbade cardiacfunctionimprovementandbonemarrowresponse
AT janagroße cardiacfunctionimprovementandbonemarrowresponse
AT axelhaverich cardiacfunctionimprovementandbonemarrowresponse
AT holgerhennig cardiacfunctionimprovementandbonemarrowresponse
AT alexanderkaminski cardiacfunctionimprovementandbonemarrowresponse
AT joachimlotz cardiacfunctionimprovementandbonemarrowresponse
AT friedrichwilhelmmohr cardiacfunctionimprovementandbonemarrowresponse
AT paulamuller cardiacfunctionimprovementandbonemarrowresponse
AT robertoostendorp cardiacfunctionimprovementandbonemarrowresponse
AT ulrikeruch cardiacfunctionimprovementandbonemarrowresponse
AT samirsarikouch cardiacfunctionimprovementandbonemarrowresponse
AT annaskorska cardiacfunctionimprovementandbonemarrowresponse
AT christofstamm cardiacfunctionimprovementandbonemarrowresponse
AT gudruntiedemann cardiacfunctionimprovementandbonemarrowresponse
AT florianmathiaswagner cardiacfunctionimprovementandbonemarrowresponse
AT olafwolkenhauer cardiacfunctionimprovementandbonemarrowresponse
_version_ 1725171999731351552
spelling doaj-506c8e7e8ae54a5c92e1b4df2aea82a02020-11-25T01:11:15ZengElsevierEBioMedicine2352-39642017-08-0122C20822410.1016/j.ebiom.2017.07.022Cardiac Function Improvement and Bone Marrow Response –Gustav Steinhoff0Julia Nesteruk1Markus Wolfien2Günther Kundt3Jochen Börgermann4Robert David5Jens Garbade6Jana Große7Axel Haverich8Holger Hennig9Alexander Kaminski10Joachim Lotz11Friedrich-Wilhelm Mohr12Paula Müller13Robert Oostendorp14Ulrike Ruch15Samir Sarikouch16Anna Skorska17Christof Stamm18Gudrun Tiedemann19Florian Mathias Wagner20Olaf Wolkenhauer21Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyUniversity Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, GermanyUniversity Medicine Rostock, Department of Medical Informatics and Biostatistics, Ernst-Heydemann-Straße 8, 18055 Rostock, GermanyHeart and Diabetes Center North Rhine Westfalia, University Hospital of the Ruhr, University Bochum, Georgstraße 11, 32545 Bad Oeynhausen, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyMedical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, GermanyUniversity Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyUniversity Medicine Goettingen, Department of Diagnostic Radiology, Robert-Koch-Straße 40, 37075 Göttingen, GermanyDepartment of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Medicine III, Technical University Munich, Klinikum rechts der Isar, Ismaninger Straße 22, 81675 München, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyMedical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyGerman Heart Center Berlin, Department of Heart-, Thoracic-, and Vascular Surgery, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Cardiac and Vascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, GermanyUniversity Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, GermanyObjective: 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 5 ml placebo or a suspension of 0.5–5 × 106 CD133+. Outcome: Primary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI. Findings (prespecified): Safety (n = 77): 180 d 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 180 d, 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 180 d 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 ± 3.32 months (R) vs. +72.3 ± 5.0 months (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.gov NCT00950274.http://www.sciencedirect.com/science/article/pii/S2352396417302967Randomised double-blinded phase III multicentre trialCD133+CD34+Endothelial progenitor cell (EPC)SH2B3Lnk adaptorCardiac repairCardiac stem cell therapyAngiogenesis