Cardiac Function Improvement and Bone Marrow Response –
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
Affiliations
Gustav Steinhoff
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Julia Nesteruk
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Markus Wolfien
University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany
Günther Kundt
University Medicine Rostock, Department of Medical Informatics and Biostatistics, Ernst-Heydemann-Straße 8, 18055 Rostock, Germany
Jochen Börgermann
Heart and Diabetes Center North Rhine Westfalia, University Hospital of the Ruhr, University Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany
Robert David
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Jens Garbade
Department of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany
Jana Große
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Axel Haverich
Medical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, Germany
Holger Hennig
University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany
Alexander Kaminski
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Joachim Lotz
University Medicine Goettingen, Department of Diagnostic Radiology, Robert-Koch-Straße 40, 37075 Göttingen, Germany
Friedrich-Wilhelm Mohr
Department of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany
Paula Müller
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Robert Oostendorp
Department of Medicine III, Technical University Munich, Klinikum rechts der Isar, Ismaninger Straße 22, 81675 München, Germany
Ulrike Ruch
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Samir Sarikouch
Medical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, Germany
Anna Skorska
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Christof Stamm
German Heart Center Berlin, Department of Heart-, Thoracic-, and Vascular Surgery, Augustenburger Platz 1, 13353 Berlin, Germany
Gudrun Tiedemann
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Florian Mathias Wagner
Department of Cardiac and Vascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany
Olaf Wolkenhauer
University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany
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.
