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In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.

Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q

Cardiovascular diseases are responsible for approximately one-third of deaths around the world. Among cardiovascular diseases, the largest single cause of death is ischemic heart disease. Ischemic heart disease typically manifests as progressive constriction of the coronary arteries, which obstructs blood flow to the heart and can ultimately lead to myocardial infarction. This adversely affects the structure and function of the heart. Conventional treatments lack the ability to treat the myocardium lost during an acute myocardial infarction. Stem cell therapy offers an excellent solution for myocardial regeneration. Stem cell sources such as adult stem cells, embryonic and induced pluripotent stem cells have been the focal point of research in cardiac tissue engineering. However, cell survival and engraftment post-transplantation are major limitations that must be addressed prior to widespread use of this technology. Recently, biomaterials have been introduced as 3D vehicles to facilitate stem cell transplantation into infarct sites. This has shown significant promise with improved cell survival after transplantation. In this review, we discuss the various injectable hydrogels that have been tried in cardiac tissue engineering. Exploring and optimizing these cell-material interactions will guide cardiac tissue engineering towards developing stem cell based functional 3D constructs for cardiac regeneration. [ABSTRACT FROM AUTHOR]

A 3-dimensional, robust, and sustained myocardial restoration by means of tissue engineering remains an experimental approach. Prolific protocols have been developed and tested in small and large animals, but, as clinical cardiac surgeons, we have not arrived at the privilege of utilizing any of them in our clinical practice. The question arises as to why this is. The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support in its viability and function. Currently, available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed, and heart transplantation is an ultima ratio treatment option. Owing to the equivocal results of cell-based therapies, several strategies have been pursued to overcome the limitations of the current treatment options. Preclinical data, as well as first-in-human studies, conducted to-date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In light of the available data, injectable biomaterials suitable for transcatheter delivery appear to have the highest translational potential. This article presents a current state-of-the-literature review in the field of hydrogel-based myocardial restoration therapy.

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.

Cardiac injury due to any cause leads to cardiac cell damage and thereby to ventricular dysfunction. Unlike current medical therapy, cardiac regeneration by stem cell therapy is a promising approach which has a potential to reverse left ventricular dysfunction. It is conceived to complement and potentially transform available therapeutic armamentarium. Early experience in clinical studies support the safety and feasibility of cell therapy and as adjuvants to established practice. This review discusses type of stem cells used, its therapeutic indications, and its current status.

Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.

Cardiac stem cell therapy holds great potential to prompt myocardial regeneration in patients with ischemic heart disease. The selection of the most suitable cell type is pivotal for its successful application. Various cell types, including crude bone marrow mononuclear cells, skeletal myoblast, and hematopoietic and endothelial progenitors, have already advanced into the clinical arena based on promising results from different experimental and preclinical studies. However, most of these so-called first-generation cell types have failed to fully emulate the promising preclinical data in clinical trials, resulting in heterogeneous outcomes and a critical lack of translation. Therefore, different next-generation cell types are currently under investigation for the treatment of the diseased myocardium. This review article provides an overview of current stem cell therapy concepts, including the application of cardiac stem (CSCs) and progenitor cells (CPCs) and lineage commitment via guided cardiopoiesis from multipotent cells such as mesenchymal stem cells (MSCs) or pluripotent cells such as embryonic and induced pluripotent stem cells. Furthermore, it introduces new strategies combining complementary cell types, such as MSCs and CSCs/CPCs, which can yield synergistic effects to boost cardiac regeneration. [ABSTRACT FROM AUTHOR]

Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction Noninvasive radionuclide imaging of cells using technetium99m-hexamethylpropyleneamine oxime ( 99m Tc-HMPAO) is a potential diagnostic tool for several applications. Herein we aimed to evaluate the labeling efficiency and cellular toxicity of 99m Tc-HMPAO with Stromal Vascular Fraction (SVF) of adipose tissue to develop a process tool for theranostic purposes, in particular imaging cardiac stem cell therapy. Methods Ten million cells of SVF were labeled with 99m Tc-HMPAO complex and excess radiolabel was cleared off through washing in PBS. The labeling efficiency of 99m Tc-HMPAO was detected in labeled cells and their subsequent supernatant wash using isotope dose calibrator and gamma camera. The cytotoxicity was assessed for the comparative reactive oxygen species (ROS) by H 2 DCFDDA, apoptotic events by annexin-V and TUNEL assay and mitochondrial potential by JC-1. Results An encouraging labeling efficiency of 33% was observed with 99m Tc-HMPAO complex. The radionuclide labeling of SVF demonstrated significant safety profile as evaluated by apoptotic assays. Conclusion 99m Tc-HMPAO labeling efficiency of 33% of total SV fraction would produce sufficient radioactive signals that would enable for in vivo tracking of cells by SPECT-CT. The radionuclide did not demonstrate any significant impact on the structural or functional organization of the labeled cells. Our study indicates that SVF can be safely labeled with 99m Tc-HMPAO without adverse cytotoxic events and for its potential role in imaging cardiac stem cell therapy. [ABSTRACT FROM AUTHOR]

Introduction Cardiovascular disease is a major cause of death worldwide. Different medical and surgical therapeutic options are well established, but a significant number of patients are not amenable to standard therapeutic options. Cell-based therapies after clinical application have shown different results in recent years. Here, we are giving a comprehensive overview on major available clinical data regarding cell therapy. Background Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. Different adult cardiac stem cells and progenitor cells, including mesenchymal, CD34+ and CD133+ autologous human bone marrow-derived stem cells ( BMCs), human myoblasts, and peripheral blood-derived stem and progenitor cells ( PBSCs) have been used for the therapy for end-stage heart failure. Future experiments will show the importance of novel cell populations and clarify the mechanism causing cell therapy-mediated observed effects. Conclusion Several clinical trials have reported on sole therapy, as well as combined application of autologous adult stem cells with conventional revascularization. The reported promising findings encourage further research in the field of the translational research. [ABSTRACT FROM AUTHOR]

End-stage heart failure is the final common pathway of an irreversible process associated with loss of myocardial cells. In this process, the capacity for renewal and repair of myocardial tissue is inadequate and ultimately leads to ventricular remodeling. Novel therapeutic strategies have been developed to prevent it, one being cell therapy, which has emerged as a potential approach to directly repopulate and repair the damaged heart. Here, we review the use of regenerative cell therapy for different cardiac diseases and discuss the positive effect of cell therapy mediated by paracrine factors instead of turning directly into cardiomyocytes. [ABSTRACT FROM AUTHOR]

Cardiac stem cell therapy has been proposed as a therapy option to treat the diseased myocardium. However, the low retention rate of transplanted single-cell suspensions remains a major issue of current therapy strategies. Therefore, the concept of scaffold-free cellular self-assembly into three-dimensional microtissues (3D-MTs) prior to transplantation may be beneficial to enhance retention and survival. We compared clinically relevant, human stem cell sources for their ability to generate 3D-MTs with particular regards to formation characteristics, proliferation-activity, viability and extracellular-matrix production. Single-cell suspensions of human bone marrow- and adipose tissue-derived mesenchymal stem cells (hBMMSCs and hATMSCs), Isl1+ cardiac progenitors derived from human embryonic stem cells (hESC-Isl1+ cells), and undifferentiated human induced pluripotent cells (hiPSCs) were characterized before to generate 3D-MTs using a hanging-drop culture. Besides the principal feasibility of cell-specific 3D-MT formation, a detailed head-to-head comparison between cell sources was performed using histology, immunocyto- and histo-chemistry as well as flow cytometry. Round-oval shaped and uniform 3D-MTs could be successfully generated from all cell types starting with a loose formation within the first 24 h that fully stabilized after 3 days and resulting in a mean 3D-MT diameter of 194.56 ± 18.01 μm (hBMMSCs), 194.56 ± 16.30 μm (hATMSCs), 159.73 ± 19.20 μm (hESC-Isl1+ cells) and 120.95 ± 7.97 μm (hiPSCs). While all 3D-MTs showed a homogenous cell distribution, hiPSC-derived 3D-MTs displayed a compact cell formation primarily located at the outer margin. hESC-Isl1+ and hiPSC-derived 3D-MTs maintained their proliferation-activity which was rather limited in the MSC-based 3D-MTs. All four 3D-MT types revealed a comparable viability in excess of 70% and showed a cell-specific expression profile being comparable to their single-cell counterparts. Extracellular matrix (ECM) production during 3D-MT formation was observed for all cell-specific 3D-MTs, with hiPSC-derived 3D-MTs being the fastest one. Interestingly, ECM distribution was homogenous for hATMSC- and hiPSC-based 3D-MTs, while it appeared to be primarily concentrated within in the center of hESC-Isl1+ and hBMMSC-based 3D-MTs. The results of this head-to-head comparative study indicated that 3D-MTs can be successfully generated from hESC-derived Isl1+ cells, hiPSCs and MSC lines upon hanging drop culture. Cell-specific 3D-MTs displayed sufficient viability and instant ECM formation. The concept of 3D-MT in vitro generation prior to cell transplantation may represent a promising delivery format for future strategies to enhance cellular engraftment and survival. [ABSTRACT FROM AUTHOR]

Cardiac regenerative therapy is still not used in daily clinical practice. A reason for this might be the modest effect on relevant global clinical endpoints [i.e. ejection fraction (EF)] in preclinical studies. To introduce proper improvement strategies, it is important to extend the focus from clinical endpoints to more detailed local measures of cardiac function. In this review, we discuss the measurement principles of all invasive and non-invasive techniques that are used to assess the local effects of cardiac regenerative therapy in order to improve feedback to researchers unravelling the dominant pathways that lead to effective cardiac regeneration. Generally adopted mechanisms of cardiac regenerative therapy are: (i) vasculogenesis, (ii) cardiomyogenesis, and (iii) matrix-assisted myocardium stabilization. Since direct in vivo measures of these mechanisms do not exist, we discuss the measurement techniques of local microvascular resistance, myocardial perfusion, viability, fibrosis, and deformation imaging. The ability of these techniques to reflect the mechanism of cardiac regenerative therapy, and the results of applications in stem cell studies are discussed, and critically commented upon. Special attention is given to applications of deformation imaging, since this has recently been suggested and used as a potential new technique to assess local changes of cardiac biomechanics, which requires special knowledge about cardiac physiology. We conclude that besides the clinically relevant EF measurements, detailed measures of local cardiac function provide information about the local changes induced by cardiac regenerative therapy. In particular, combination of deformation imaging, by ultrasound or magnetic resonance imaging, with simultaneously measured local geometry and pressure measurements is a promising approach to assess the effects of cardiac regenerative therapy on local cardiac biomechanics. This approach provides information about local tissue contractility, stiffness, and thereby remodelling. We recommend that researchers use this comprehensive approach in future studies. [ABSTRACT FROM PUBLISHER]

Intracoronary and intramyocardial stem cell therapy aim at the repair of compromised myocardium thereby—as a causal treatment—preventing ventricular remodeling and improving overall performance. Since the first-in-human use of bone marrow stem cells (BMCs) after acute myocardial infarction in 2001, a large number of clinical studies have demonstrated their clinical benefit: BMC therapy can be performed with usual cardiac catheterization techniques in the conscious patient as well as also easily during cardiosurgical interventions. New York Heart Association severity degree of patients as well as physical activity improve in addition to (“on top” of) all other therapeutic regimens. Stem cell therapy also represents an ultimate approach in advanced cardiac failure. For acute myocardial infarction and chronic ischemia, long-term mortality after 1 and 5 years, respectively, is significantly reduced. A few studies also indicate beneficial effects for chronic dilated cardiomyopathy. The clinical use of autologous BMC therapy implies no ethical problems, when unmodified primary cells are used. With the use of primary BMCs, there are no major stem cell-related side effects, especially no cardiac arrhythmias and inflammation. Various mechanisms of the stem cell action in the human heart are discussed, for example, cell transdifferentiation, cell fusion, activation of intrinsic cardiac stem cells, and cytokine-mediated effects. New techniques allow point-of-care cell preparations, for example, within the cardiac intervention or operation theater, thereby providing short preparation time, facilitated logistics of cell transport, and reasonable cost effectiveness of the whole procedure. The 3 main indications are acute infarction, chronic ischemic heart failure, and dilated cardiomyopathy. Future studies are desirable to further elucidate the mechanisms of stem cell action and to extend the current use of intracoronary and/or intramyocardial stem cell therapy by larger and presumably multicenter and randomized trials. [Copyright &y& Elsevier]

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A 3-dimensional, robust, and sustained myocardial restoration by means of tissue engineering remains an experimental approach. Prolific protocols have been developed and tested in small and large animals, but, as clinical cardiac surgeons, we have not arrived at the privilege of utilizing any of them in our clinical practice. The question arises as to why this is. The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support in its viability and function. Currently, available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed, and heart transplantation is an ultima ratio treatment option. Owing to the equivocal results of cell-based therapies, several strategies have been pursued to overcome the limitations of the current treatment options. Preclinical data, as well as first-in-human studies, conducted to-date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In light of the available data, injectable biomaterials suitable for transcatheter delivery appear to have the highest translational potential. This article presents a current state-of-the-literature review in the field of hydrogel-based myocardial restoration therapy. [ABSTRACT FROM AUTHOR]

In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy., (Copyright © 2020 Zhao, Ye, Su and Garg.)

Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG)., Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133 + bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions., Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical:SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK -/- mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3., Validation: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature., Interpretation: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response., Funding: German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 0.5-5×10 6 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., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The article offers updates on two cardiac stem cell studies conducted at Houston Methodist DeBakey Heart & Vascular Center. The first trial involved direct injection of the patient's own bone marrow-derived stem cells into the left ventricle during a surgical procedure. Meanwhile, a phase II multicenter trial involved direct injection of the patient's stem cells into the failing myocardium during coronary artery bypass surgery.