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Gallego-Navarro C, Jaggers J, Burkhart HM, Carlo WF, Morales DL, Qureshi MY, Rossano JW, Hagen CE, Seisler DK, Peral SC, Nelson TJ. Autologous umbilical cord blood mononuclear cell therapy for hypoplastic left heart syndrome: a nonrandomized control trial of the efficacy and safety of intramyocardial injections. Stem Cell Res Ther 2025; 16:215. [PMID: 40312733 PMCID: PMC12044795 DOI: 10.1186/s13287-025-04316-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 04/07/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND Preliminary phase I clinical trial results revealed that autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) preserved right ventricular cardiac function. To establish the efficacy of intramyocardial injections of an autologous UCB-MNC product at the time of stage II palliation surgery in patients with hypoplastic left heart syndrome (HLHS). METHODS A phase IIb, multicenter, open-label, nonrandomized study was conducted. Ninety-five children (fifty treated and forty-five controls) with HLHS and its variants, a history of stage I palliation surgery, and planned stage II palliation surgery at less than thirteen months were enrolled. We assessed coprimary efficacy endpoints for changes in right ventricular cardiac function through fractional area changes and longitudinal and circumferential strain, both in the short term (three months) and long term (twelve months). Second, we assessed changes in biomarkers of cardiac injury. Safety endpoints included severe adverse events (SAEs), changes in overall health through vital signs, and cumulative hospitalization. RESULTS Assessment of our coprimary efficacy endpoints revealed an unfavorable change in longitudinal cardiac strain in the treatment group compared with an improvement in strain in the control group (unadjusted p =.032) in the short term. No differences were observed between the groups in terms of other coprimary efficacy endpoints in the short or long term. A secondary assessment of biomarkers of cardiac injury revealed higher troponin T levels in the treatment group at three and six hours postsurgery. Regarding safety, no deaths related to the administered product or delivery procedure were reported. The treatment group presented a greater incidence (20%) of at least one SAE than the control group at three months (p =.048). Additionally, no statistically significant differences were found for the other safety endpoints. CONCLUSION Intramyocardial injections of autologous UCB-MNC products into the right ventricular myocardium during stage II palliation surgery failed to enhance cardiac function in patients with hypoplastic left heart syndrome. REGISTERED ON CLINICALTRIALS.GOV: Registered on ClinicalTrials.gov (NCT03779711) on 12/04/2018; URL: https://clinicaltrials.gov/ct2/show/NCT0377971 .
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Affiliation(s)
- Carlos Gallego-Navarro
- Division of Cardiovascular Diseases, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
- Program for Hypoplastic Left Heart Syndrome, Mayo Clinic Rochester, Rochester, MN, USA
| | - James Jaggers
- Division of Congenital Heart Surgery, Heart Institute, Children's Hospital Colorado, University of Colorado Denver Anschutz Medical Campus, Denver, CO, USA
| | - Harold M Burkhart
- Division of Cardiac, Thoracic and Vascular Surgery, University of Oklahoma Health Sciences, Oklahoma, USA
| | - Waldemar F Carlo
- Division of Pediatric Cardiology, University of Alabama Birmingham, Birmingham, AL, USA
| | - David L Morales
- Division of Congenital Heart Surgery, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - M Yasir Qureshi
- Program for Hypoplastic Left Heart Syndrome, Mayo Clinic Rochester, Rochester, MN, USA
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Joseph W Rossano
- Department of Pediatrics, Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, USA
| | | | - Drew K Seisler
- Program for Hypoplastic Left Heart Syndrome, Mayo Clinic Rochester, Rochester, MN, USA
| | - Susana Cantero Peral
- Division of Cardiovascular Diseases, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
- Program for Hypoplastic Left Heart Syndrome, Mayo Clinic Rochester, Rochester, MN, USA
| | - Timothy J Nelson
- Division of Cardiovascular Diseases, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA.
- Program for Hypoplastic Left Heart Syndrome, Mayo Clinic Rochester, Rochester, MN, USA.
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
- HeartWorks Inc. Rochester, Rochester, MN, USA.
- General Internal Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA.
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Roncalli J, Roubille F, Meyer N, Pompilio G, Leroux L, Henon P, Trebuchet G, Criquet A, de Kalbermatten M, Saloux E, Manrique A, Marie P, Bhatt DL, Solomon SD, Montalescot G, Newby DE, Zannad F, the EXCELLENT Trial Investigators. Transendocardial injection of expanded autologous CD34+ cells after myocardial infarction: Design of the EXCELLENT trial. ESC Heart Fail 2025; 12:1455-1463. [PMID: 39676512 PMCID: PMC11911568 DOI: 10.1002/ehf2.15124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 12/17/2024] Open
Abstract
AIMS The extent of irreversible cardiomyocyte necrosis after acute myocardial infarction (AMI) is a major determinant of residual left ventricular (LV) function and clinical outcome. Cell therapy based on CD34+ cells has emerged as an option to help repair the myocardium and to improve outcomes. The dose of CD34+ cells and the route of administration are two important factors that will determine the clinical effectiveness of the approach, provided it is robust and feasible. Here, we describe the rationale and design of the multicentre open-label randomized controlled phase I/IIb trial evaluating the safety and the likelihood of efficacy of transendocardial expanded CD34+ cell administration in patients presenting with AMI and a reduced LV ejection fraction. METHODS Patients with a large AMI and LV ejection fraction <50% are randomized 3:1 to transendocardial expanded CD34+ cell injection plus standard of care or standard of care alone. Patients randomized to intervention are treated with lenograstim for 5 days before 220 ± 10 mL blood cell harvest from which autologous CD34+ cells are purified and expanded for 9 days using an automated good manufacturing practice compliant platform. The primary endpoint is the incidence of major adverse cardiac events over 6 months. The main secondary endpoints are LV end systolic volume index and the viability of the infarcted segments. CONCLUSIONS Autologous CD34+ cell therapy is currently limited by technological constraints. This is the first trial to evaluate the feasibility and potential effect of CD34+ cells after automated expansion and transendocardial administration in patients with large AMI.
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Affiliation(s)
- Jerome Roncalli
- Department of Cardiology, Institute Cardiomet, Centre d'Investigations Cliniques Biotherapies 1436, INSERM I2MC 1297Toulouse University HospitalToulouseFrance
| | - François Roubille
- Cardiology DepartmentMontpellier University HospitalMontpellierFrance
| | - Nicolas Meyer
- GMRC, Pôle de Santé Publique, CHU de StrasbourgStrasbourgFrance
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative MedicineCentro Cardiologico Monzino IRCCSMilanItaly
- Dipartimento di Scienze Biomediche, Chirurgiche ed OdontoiatricheUniversity of MilanoMilanItaly
| | - Lionel Leroux
- Department of Interventional Cardiology and Intensive CareHaut‐Leveque HospitalPessacFrance
| | | | | | | | | | - Eric Saloux
- Department of CardiologyCaen University HospitalCaenFrance
| | - Alain Manrique
- Department of Nuclear MedicineNormandie Univ, UNICAEN, CHU de Caen NormandieCaenFrance
| | - Pierre‐Yves Marie
- Nuclear Medicine & Nancyclotep Experimental Platform, CHRU‐NancyUniversité de LorraineNancyFrance
| | - Deepak L. Bhatt
- Mount Sinai Fuster Heart HospitalIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Scott D. Solomon
- Cardiovascular Division, Brigham and Women's HospitalHarvard Medical SchoolBostonMAUSA
| | | | - David E. Newby
- British Heart Foundation Centre of Research ExcellenceThe University of EdinburghEdinburghUK
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433Centre Hospitalier Régional Universitaire de NancyNancyFrance
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Lee H, Cho HJ, Han Y, Lee SH. Mid- to long-term efficacy and safety of stem cell therapy for acute myocardial infarction: a systematic review and meta-analysis. Stem Cell Res Ther 2024; 15:290. [PMID: 39256845 PMCID: PMC11389242 DOI: 10.1186/s13287-024-03891-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/21/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND This comprehensive systematic review and meta-analysis investigated the mid- to long-term efficacy and safety of stem cell therapy in patients with acute myocardial infarction (AMI). METHODS The study encompassed 79 randomized controlled trials with 7103 patients, rendering it the most up-to-date and extensive analysis in this field. This study specifically focused on the impact of stem cell therapy on left ventricular ejection fraction (LVEF), major adverse cardiac events (MACE), and infarct size. RESULTS Stem cell therapy significantly improved LVEF at 6, 12, 24, and 36 months post-transplantation compared to control values, indicating its potential for long-term cardiac function enhancement. A trend toward reduced MACE occurrence was observed in the intervention groups, suggesting the potential of stem cell therapy to lower the risk of cardiovascular death, reinfarction, and stroke. Significant LVEF improvements were associated with long cell culture durations exceeding 1 week, particularly when combined with high injected cell quantities (at least 108 cells). No significant reduction in infarct size was observed. CONCLUSIONS This review highlights the potential of stem cell therapy as a promising therapeutic approach for patients with AMI, offering sustained LVEF improvement and a potential reduction in MACE risk. However, further research is required to optimize cell culture techniques, determine the optimal timing and dosage, and investigate procedural variations to maximize the efficacy and safety of stem cell therapy in this context.
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Affiliation(s)
- Hyeongsuk Lee
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Yeonjung Han
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea
| | - Seon Heui Lee
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea.
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Hosseinpour A, Hosseinpour H, Attar A. Preventive Effect of Bone Marrow Mononuclear Cell Transplantation on Acute Myocardial Infarction-Induced Heart Failure: A Meta-analysis of Randomized Controlled Trials. Cardiovasc Drugs Ther 2023; 37:1143-1153. [PMID: 35876933 DOI: 10.1007/s10557-022-07359-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE Heart failure (HF) is a major complication of acute myocardial infarction (AMI). Transplantation of bone marrow mononuclear cells (BM-MNC) in the setting of AMI has been proposed as a means for myocardial tissue regeneration. Several trials have explored the outcomes of these cells on surrogate end points such as left ventricular ejection fraction (LVEF) in patients with AMI. However, the data regarding the clinical efficacy are infrequent. Here, we performed a meta-analysis investigating the effect of BM-MNCs injection on the rate of hospitalization for HF in the long-term follow-up period. METHODS PubMed, Scopus, and Cochrane databases were queried with various combinations of keywords through May 2, 2022. A random-effects meta-analysis was performed to calculate risk ratio (RR) and 95% confidence interval (CI) of hospitalization for HF, all-cause mortality, and stroke rate. Subgroup analyses for hospitalization based on time and cell dose were performed. RESULTS A total of 2150 patients with AMI across 22 trials were included for quantitative synthesis. At long-term follow-up, AMI patients treated with an intracoronary injection of BM-MNCs were less likely to be hospitalized for heart failure compared to the control group receiving standard treatment (RR = 0.54, 95% CI = [0.37; 0.78], p = 0.002). There was no association between BM-MNC therapy and all-cause mortality (RR = 0.69, 95% CI = [0.47; 1.01], p = 0.05) and stroke (RR = 1.12, 95% CI= [0.24; 5.21], p = 0.85). CONCLUSION Autologous injection of BM-MNC in the setting of AMI may be associated with decreased risk of hospitalization of heart failure in the long term. However, its effect on all-cause mortality and stroke rate is questionable.
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Affiliation(s)
- Alireza Hosseinpour
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran
| | | | - Armin Attar
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran.
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Attar A, Farjoud Kouhanjani M, Hessami K, Vosough M, Kojuri J, Ramzi M, Hosseini SA, Faghih M, Monabati A. Effect of once versus twice intracoronary injection of allogeneic-derived mesenchymal stromal cells after acute myocardial infarction: BOOSTER-TAHA7 randomized clinical trial. Stem Cell Res Ther 2023; 14:264. [PMID: 37740221 PMCID: PMC10517503 DOI: 10.1186/s13287-023-03495-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 09/12/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cell (MSC) transplantation can improve the left ventricular ejection fraction (LVEF) after an acute myocardial infarction (AMI). Transplanted MSCs exert a paracrine effect, which might be augmented if repeated doses are administered. This study aimed to compare the effects of single versus double transplantation of Wharton's jelly MSCs (WJ-MSCs) on LVEF post-AMI. METHODS We conducted a single-blind, randomized, multicenter trial. After 3-7 days of an AMI treated successfully by primary PCI, 70 patients younger than 65 with LVEF < 40% on baseline echocardiography were randomized to receive conventional care, a single intracoronary infusion of WJ-MSCs, or a repeated infusion 10 days later. The primary endpoint was the 6-month LVEF improvement as per cardiac magnetic resonance (CMR) imaging. RESULTS The mean baseline EF measured by CMR was similar (~ 40%) in all three groups. By the end of the trial, while all patients experienced a rise in EF, the most significant change was seen in the repeated intervention group. Compared to the control group (n = 25), single MSC transplantation (n = 20) improved the EF by 4.54 ± 2%, and repeated intervention (n = 20) did so by 7.45 ± 2% when measured by CMR imaging (P < 0.001); when evaluated by echocardiography, these values were 6.71 ± 2.4 and 10.71 ± 2.5%, respectively (P < 0.001). CONCLUSIONS Intracoronary transplantation of WJ-MSCs 3-7 days after AMI in selected patients significantly improves LVEF, with the infusion of a booster dose 10 days later augmenting this effect. TRIAL REGISTRATION Trial registration: Iranian Registry of Clinical Trials, IRCT20201116049408N1. Retrospectively Registered 20 Nov. 2020, https://en.irct.ir/trial/52357.
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Affiliation(s)
- Armin Attar
- Department of Cardiovascular Medicine, TAHA Clinical Trial Group, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, 71344-1864, Iran.
| | | | - Kamran Hessami
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Javad Kojuri
- Department of Cardiovascular Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mani Ramzi
- Hematopathology and Molecular Pathology Service, Department of Pathology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, 71344-1864, Iran
| | | | - Marjan Faghih
- Department of Biostatistics, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Ahmad Monabati
- Hematopathology and Molecular Pathology Service, Department of Pathology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, 71344-1864, Iran.
- Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran.
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Clavellina D, Balkan W, Hare JM. Stem cell therapy for acute myocardial infarction: Mesenchymal Stem Cells and induced Pluripotent Stem Cells. Expert Opin Biol Ther 2023; 23:951-967. [PMID: 37542462 PMCID: PMC10837765 DOI: 10.1080/14712598.2023.2245329] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/07/2023]
Abstract
INTRODUCTION Acute myocardial infarction (AMI) remains a leading cause of death in the United States. The limited capacity of cardiomyocytes to regenerate and the restricted contractility of scar tissue after AMI are not addressed by current pharmacologic interventions. Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach due to their low antigenicity, ease of harvesting, and efficacy and safety in preclinical and clinical studies, despite their low survival and engraftment rates. Other stem cell types, such as induced pluripotent stem cells (iPSCs) also show promise, and optimizing cardiac repair requires integrating emerging technologies and strategies. AREAS COVERED This review offers insights into advancing cell-based therapies for AMI, emphasizing meticulously planned trials with a standardized definition of AMI, for a bench-to-bedside approach. We critically evaluate fundamental studies and clinical trials to provide a comprehensive overview of the advances, limitations and prospects for cell-based therapy in AMI. EXPERT OPINION MSCs continue to show potential promise for treating AMI and its sequelae, but addressing their low survival and engraftment rates is crucial for clinical success. Integrating emerging technologies such as pluripotent stem cells and conducting well-designed trials will harness the full potential of cell-based therapy in AMI management. Collaborative efforts are vital to developing effective stem cell therapies for AMI patients.
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Affiliation(s)
- Diana Clavellina
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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Raposo L, Cerqueira RJ, Leite S, Moreira-Costa L, Laundos TL, Miranda JO, Mendes-Ferreira P, Coelho JA, Gomes RN, Pinto-do-Ó P, Nascimento DS, Lourenço AP, Cardim N, Leite-Moreira A. Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion. Front Cardiovasc Med 2023; 10:1186574. [PMID: 37342444 PMCID: PMC10277821 DOI: 10.3389/fcvm.2023.1186574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/09/2023] [Indexed: 06/22/2023] Open
Abstract
Background Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine. Methods In a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing. Results As compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = -2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC. Conclusion Intracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.
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Affiliation(s)
- Luís Raposo
- Cardiology Department, Hospital de Santa Cruz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal
- Centro Cardiovascular, Hospital da Luz – Lisboa, Luz Saúde, Lisbon, Portugal
- Nova Medical School, Lisbon, Portugal
| | - Rui J. Cerqueira
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Cardiothoracic Surgery, Hospital Universitário de São João, Porto, Portugal
| | - Sara Leite
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Anta Family Health Unit, Espinho/Gaia Healthcare Centre, Espinho, Portugal
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Liliana Moreira-Costa
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Tiago L. Laundos
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- I3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Joana O. Miranda
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Pedro Mendes-Ferreira
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, Paris, France
| | - João Almeida Coelho
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Rita N. Gomes
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- I3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Perpétua Pinto-do-Ó
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- I3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Diana S. Nascimento
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- I3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - André P. Lourenço
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Anesthesiology, Hospital Universitário de São João, Porto, Portugal
| | - Nuno Cardim
- Centro Cardiovascular, Hospital da Luz – Lisboa, Luz Saúde, Lisbon, Portugal
- Nova Medical School, Lisbon, Portugal
| | - Adelino Leite-Moreira
- Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Cardiothoracic Surgery, Hospital Universitário de São João, Porto, Portugal
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Bonavida V, Ghassemi K, Ung G, Inouye K, Thankam FG, Agrawal DK. Novel Approaches to Program Cells to Differentiate into Cardiomyocytes in Myocardial Regeneration. Rev Cardiovasc Med 2022; 23:392. [PMID: 39076655 PMCID: PMC11270456 DOI: 10.31083/j.rcm2312392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/17/2022] [Accepted: 10/31/2022] [Indexed: 07/31/2024] Open
Abstract
With heart failure (HF) being one of the leading causes of hospitalization and death worldwide, multiple stem cell therapies have been attempted to accelerate the regeneration of the infarct zone. Versatile strategies have emerged to establish the cell candidates of cardiomyocyte lineage for regenerative cardiology. This article illustrates critical insights into the emerging technologies, current approaches, and translational promises on the programming of diverse cell types for cardiac regeneration.
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Affiliation(s)
- Victor Bonavida
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Kaitlyn Ghassemi
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Gwendolyn Ung
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Keiko Inouye
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA
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Hsiao LC, Lin YN, Shyu WC, Ho M, Lu CR, Chang SS, Wang YC, Chen JY, Lu SY, Wu MY, Li KY, Lin YK, Tseng WYI, Su MY, Hsu CT, Tsai CK, Chiu LT, Chen CL, Lin CL, Hu KC, Cho DY, Tsai CH, Chang KC, Jeng LB. First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction. Front Cardiovasc Med 2022; 9:961920. [PMID: 36017096 PMCID: PMC9395611 DOI: 10.3389/fcvm.2022.961920] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/13/2022] [Indexed: 12/17/2022] Open
Abstract
BackgroundAcute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization.ObjectivesThis phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention.MethodsConsenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period.ResultsEight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline.ConclusionThis pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.
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Affiliation(s)
- Lien-Cheng Hsiao
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Yen-Nien Lin
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Woei-Cherng Shyu
- Department of Neurology and Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
- Ever Supreme Bio Technology Co., Ltd, Taichung, Taiwan
| | - Ming Ho
- Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
| | - Chiung-Ray Lu
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shih-Sheng Chang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Chen Wang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jan-Yow Chen
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Shang-Yeh Lu
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Mei-Yao Wu
- School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Keng-Yuan Li
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Kai Lin
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Yih I. Tseng
- Molecular Imaging Center, National Taiwan University, Taipei, Taiwan
| | - Mao-Yuan Su
- Molecular Imaging Center, National Taiwan University, Taipei, Taiwan
| | - Chin-Ting Hsu
- Ever Supreme Bio Technology Co., Ltd, Taichung, Taiwan
| | | | - Lu-Ting Chiu
- Ever Supreme Bio Technology Co., Ltd, Taichung, Taiwan
| | | | - Cheng-Li Lin
- School of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Kai-Chieh Hu
- School of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Der-Yang Cho
- School of Medicine, China Medical University, Taichung, Taiwan
- Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan
| | - Chang-Hai Tsai
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- *Correspondence: Kuan-Cheng Chang,
| | - Long-Bin Jeng
- School of Medicine, China Medical University, Taichung, Taiwan
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
- Long-Bin Jeng,
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10
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Attar A, Hosseinpour A, Hosseinpour H, Kazemi A. Major cardiovascular events after bone marrow mononuclear cell transplantation following acute myocardial infarction: an updated post-BAMI meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2022; 22:259. [PMID: 35681123 PMCID: PMC9185901 DOI: 10.1186/s12872-022-02701-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/03/2022] [Indexed: 11/23/2022] Open
Abstract
Background The effect of bone marrow-derived mononuclear cells (BM-MNCs) after acute myocardial infarction (AMI) on myocardial function indices such as left ventricular ejection fraction has been widely studied. However, the effect of this intervention on major adverse cardiovascular events (MACE) was not the principal purpose of most investigations and its role is unclear. The aim of this study was to investigate the possible long-term clinical efficacy of BM-MNCs on MACE after AMI. Methods A comprehensive search was conducted through electronic databases for potentially eligible randomized trials investigating the impact of BM-MNC therapy following acute MI on clinical outcomes. Risk of bias of the eligible studies was assessed using the Cochrane Collaboration’s tool. The effect of treatment was displayed by risk ratio (RR) and its 95% confidence interval (CI) using random-effects model. Results Initial database searching found 1540 records and 23 clinical trials with a total of 2286 participants eligible for meta-analysis. Injection of BM-MNCs was associated with lower risk of composite end points of hospitalization for congestive heart failure (CHF), re-infarction, and cardiac-related mortality (91/1191 vs. 111/812, RR = 0.643, 95% CI = 0.489 to 0.845, p = 0.002). This effect was derived from both reduction of CHF (47/1220 vs. 62/841, RR = 0.568, 95% CI = 0.382 to 0.844, p = 0.005) and re-infarction rate (23/1159 vs. 30/775, RR = 0.583, 95% CI = 0.343 to 0.991, p = 0.046), but not cardiac-related mortality (28/1290 vs. 31/871, RR = 0.722, 95% CI = 0.436 to 1.197, p = 0.207). Conclusion This is the first meta-analysis focused on the cardiovascular outcomes of stem cell therapy after AMI and it revealed that transplantation of BM-MNCs may reduce composite endpoint of hospitalization for CHF, re-infarction, and cardiac related mortality driven mainly by reducing reinfarction and hospitalization for heart failure rates but not cardiovascular mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02701-x.
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Affiliation(s)
- Armin Attar
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Alireza Hosseinpour
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Asma Kazemi
- Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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11
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Suhar RA, Doulames VM, Liu Y, Hefferon ME, Figueroa O, Buabbas H, Heilshorn SC. Hyaluronan and elastin-like protein (HELP) gels significantly improve microsphere retention in the myocardium. Biomater Sci 2022; 10:2590-2608. [PMID: 35411353 PMCID: PMC9123900 DOI: 10.1039/d1bm01890f] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023]
Abstract
Heart disease is the leading cause of death globally, and delivery of therapeutic cargo (e.g., particles loaded with proteins, drugs, or genes and cells) through direct injection into the myocardium is a promising clinical intervention. However, retention of deliverables to the contracting myocardium is low, with as much as 60-90% of payload being lost within 24 hr. Commercially-available injectable hydrogels, including Matrigel, have been hypothesized to increase payload retention but have not yielded significant improvements in quantified analyses. Here, we assess a recombinant hydrogel composed of chemically modified hyaluronan and elastin-like protein (HELP) as an alternative injectable carrier to increase cargo retention. HELP is crosslinked using dynamic covalent bonds, and tuning the hyaluronan chemistry significantly alters hydrogel mechanical properties including stiffness, stress relaxation rate, and ease of injectability through a needle or catheter. These materials can be injected even after complete crosslinking, extending the time window for surgical delivery. We show that HELP gels significantly improve in vivo retention of microsphere cargo compared to Matrigel, both 1 day and 7 days post-injection directly into the rat myocardium. These data suggest that HELP gels may assist with the clinical translation of therapeutic cargo designed for delivery into the contracting myocardium by preventing acute cargo loss.
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Affiliation(s)
- Riley A Suhar
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
| | - Vanessa M Doulames
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Yueming Liu
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
| | - Meghan E Hefferon
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA
| | | | - Hana Buabbas
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
- Department of Biology, Stanford University, Stanford, California, 94305, USA
| | - Sarah C Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
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12
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Uemura L, Baggio Simeoni R, Bispo Machado Júnior PA, Gavazzoni Blume G, Kremer Gamba L, Sgarbossa Tonial M, Baggio Simeoni PR, Stadler Tasca Ribeiro V, Silvestre R, de Carvalho KAT, Napimoga MH, Cesar Francisco J, Guarita-Souza LC. Autologous Bone Marrow Mononuclear Cells (BMMC)-Associated Anti-Inflammatory Nanoparticles for Cardiac Repair after Myocardial Infarction. J Funct Biomater 2022; 13:jfb13020059. [PMID: 35645267 PMCID: PMC9149818 DOI: 10.3390/jfb13020059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 12/10/2022] Open
Abstract
To investigate the effect of transplantation of stem cells from the bone marrow mononuclear cells (BMMC) associated with 15d-PGJ2-loaded nanoparticles in a rat model of chronic MI. Chronic myocardial infarction (MI) was induced by the ligation of the left anterior descending artery in 40 male Wistar rats. After surgery, we transplanted bone marrow associated with 15d-PGJ2-loaded nanoparticle by intramyocardial injection (106 cells/per injection) seven days post-MI. Myocardial infarction was confirmed by echocardiography, and histological analyses of infarct morphology, gap junctions, and angiogenesis were obtained. Our results from immunohistochemical analyses demonstrated the presence of angiogenesis identified in the transplanted region and that there was significant expression of connexin-43 gap junctions, showing a more effective electrical and mechanical integration of the host myocardium. This study suggests that the application of nanoparticle technology in the prevention and treatment of MI is an emerging field and can be a strategy for cardiac repair.
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Affiliation(s)
- Laercio Uemura
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Rossana Baggio Simeoni
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
- Correspondence: ; Tel.: +55-41-988213440
| | - Paulo André Bispo Machado Júnior
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Gustavo Gavazzoni Blume
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Luize Kremer Gamba
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Murilo Sgarbossa Tonial
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Paulo Ricardo Baggio Simeoni
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Victoria Stadler Tasca Ribeiro
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Rodrigo Silvestre
- Instituto de Radiologia (InRad), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-070, Brazil;
| | - Katherine Athayde Teixeira de Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research & Pequeno Príncipe Faculties, 1632 Silva Jardim Avenue, Curitiba 80240-020, Brazil;
| | - Marcelo Henrique Napimoga
- Institute and Research Center São Leopoldo Mandic, São Leopoldo Mandic, Faculty–SLMANDIC, Campinas, São Paulo 13045-775, Brazil;
| | - Júlio Cesar Francisco
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
| | - Luiz Cesar Guarita-Souza
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), 1555 Imaculada Conceição Street, Curitiba 80215-901, Brazil; (L.U.); (P.A.B.M.J.); (G.G.B.); (L.K.G.); (M.S.T.); (P.R.B.S.); (V.S.T.R.); (J.C.F.); (L.C.G.-S.)
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Mathur A, Sim DS, Choudry F, Veerapen J, Colicchia M, Turlejski T, Hussain M, Hamshere S, Locca D, Rakhit R, Crake T, Kastrup J, Agrawal S, Jones DA, Martin J. Five‐year follow‐up of intracoronary autologous cell therapy in acute myocardial infarction: the REGENERATE‐AMI trial. ESC Heart Fail 2022; 9:1152-1159. [PMID: 35043578 PMCID: PMC8934988 DOI: 10.1002/ehf2.13786] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/18/2021] [Accepted: 12/13/2021] [Indexed: 12/22/2022] Open
Abstract
Aims The long‐term outcomes of the intracoronary delivery of autologous bone marrow‐derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE‐AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo. Methods and results A 5 year follow‐up of major adverse cardiac events (defined as the composite of all‐cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC‐treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non‐cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group. Conclusion This 5 year follow‐up analysis of the REGENERATE‐AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index.
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Affiliation(s)
- Anthony Mathur
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Doo Sun Sim
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiovascular Medicine Chonnam National University Hospital, Chonnam National University School of Medicine Gwangju Korea
| | - Fizzah Choudry
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Jessry Veerapen
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Martina Colicchia
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Tymoteusz Turlejski
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Mohsin Hussain
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Stephen Hamshere
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Didier Locca
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- École Polytechnique Fédérale de Lausanne Lausanne Switzerland
| | - Roby Rakhit
- Department of Cardiology The Royal Free Hospital, Royal Free London Foundation Trust London UK
| | - Tom Crake
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Jens Kastrup
- Rigshospitalet and University of Copenhagen Copenhagen Denmark
| | - Samir Agrawal
- Haemato‐Oncology, Barts Health NHS Trust & Immunobiology, Blizard Institute Queen Mary University of London London UK
| | - Daniel A. Jones
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
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14
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Attar A, Bahmanzadegan Jahromi F, Kavousi S, Monabati A, Kazemi A. Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials. Stem Cell Res Ther 2021; 12:600. [PMID: 34876213 PMCID: PMC8650261 DOI: 10.1186/s13287-021-02667-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/18/2021] [Indexed: 12/17/2022] Open
Abstract
Background Trials investigating the role of mesenchymal stem cells (MSCs) in increasing ejection fraction (LVEF) after acute myocardial infarction (AMI) have raised some controversies. This study was conducted to find whether transplantation of MSCs after AMI can help improve myocardial performance indices or clinical outcomes. Methods Randomized trials which evaluated transplantation of MSCs after AMI were enrolled. The primary outcome was LVEF change. We also assessed the role of cell origin, cell number, transplantation time interval after AMI, and route of cell delivery on the primary outcome. Results Thirteen trials including 956 patients (468 and 488 in the intervention and control arms) were enrolled. After excluding the biased data, LVEF was significantly increased compared to the baseline among those who received MSC (WMD = 3.78%, 95% CI: 2.14 to 5.42, p < 0.001, I2 = 90.2%) with more pronounced effect if the transplantation occurred within the first week after AMI (MD = 5.74%, 95%CI: 4.297 to 7.183; I2 = 79.2% p < 0.001). The efficacy of trans-endocardial injection was similar to that of intracoronary infusion (4% [95%CI: 2.741 to 5.259, p < 0.001] vs. 3.565% [95%CI: 1.912 to 5.218, p < 0.001], respectively). MSC doses of lower and higher than 107 cells did not improve LVEF differently (5.24% [95%CI: 2.06 to 8.82, p = 0.001] vs. 3.19% [95%CI: 0.17 to 6.12, p = 0.04], respectively).
Conclusion Transplantation of MSCs after AMI significantly increases LVEF, showing a higher efficacy if done in the first week. Further clinical studies should be conducted to investigate long-term clinical outcomes such as heart failure and cardiovascular mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02667-1.
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Affiliation(s)
- Armin Attar
- Department of Cardiovascular Medicine, TAHA Clinical Trial Group, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran.
| | | | - Shahin Kavousi
- Students' Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Monabati
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Kazemi
- Nutrition Research Center, Shiraz University of Medical Sciences, PO Box 71645-111, Shiraz, Iran.
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Mei X, Zhu D, Li J, Huang K, Hu S, Li Z, López de Juan Abad B, Cheng K. A fluid-powered refillable origami heart pouch for minimally invasive delivery of cell therapies in rats and pigs. MED (NEW YORK, N.Y.) 2021; 2:1253-1268. [PMID: 34825239 PMCID: PMC8612456 DOI: 10.1016/j.medj.2021.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Cardiac repair after heart injury remains a big challenge and current drug delivery to the heart is suboptimal. Repeated dosing of therapeutics is difficult due to the invasive nature of such procedures. METHODS We developed a fluid-driven heart pouch with a memory-shaped microfabricated lattice structure inspired by origami. The origami structure allowed minimally invasive delivery of the pouch to the heart with two small incisions and can be refilled multiple times with the therapeutic of choice. FINDINGS We tested the pouch's ability to deliver mesenchymal stem cells (MSCs) in a rodent model of acute myocardial infarction and demonstrated the feasibility of minimally invasive delivery in a swine model. The pouch's semi-permeable membrane successfully protected delivered cells from their surroundings, maintaining their viability while releasing paracrine factors to the infarcted site for cardiac repair. CONCLUSIONS In summary, we developed a fluid-driven heart pouch with a memory-shaped microfabricated lattice structure inspired by origami. The origami structure allowed minimally invasive delivery of the pouch to the heart with two small incisions and can be refilled with the therapeutic of choice.
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Affiliation(s)
- Xuan Mei
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Dashuai Zhu
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Junlang Li
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ke Huang
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shiqi Hu
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Zhenhua Li
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Blanca López de Juan Abad
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA,Lead contact,Corresponding author.
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Raposo L, Lourenço AP, Nascimento DS, Cerqueira R, Cardim N, Leite-Moreira A. Human umbilical cord tissue-derived mesenchymal stromal cells as adjuvant therapy for myocardial infarction: a review of current evidence focusing on pre-clinical large animal models and early human trials. Cytotherapy 2021; 23:974-979. [PMID: 34112613 DOI: 10.1016/j.jcyt.2021.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/25/2021] [Accepted: 05/06/2021] [Indexed: 12/28/2022]
Abstract
Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic "of-the-shelf" cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed.
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Affiliation(s)
- Luís Raposo
- Cardiology Department, Santa Cruz Hospital, West Lisbon Hospital Center, Lisbon, Portugal; Hospital da Luz Lisboa, Luz Saúde, Lisbon, Portugal; Nova Medical School, Lisbon, Portugal.
| | - André P Lourenço
- Department of Cardiac Surgery, University Hospital Centre São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Diana S Nascimento
- Institute for Research and Innovation in Health, University of Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal; Instituto Nacional de Engenharia Biomédica, University of Porto, Portugal
| | - Rui Cerqueira
- Department of Cardiac Surgery, University Hospital Centre São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Nuno Cardim
- Hospital da Luz Lisboa, Luz Saúde, Lisbon, Portugal; Nova Medical School, Lisbon, Portugal
| | - Adelino Leite-Moreira
- Department of Cardiac Surgery, University Hospital Centre São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
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Campos de Carvalho AC, Kasai-Brunswick TH, Bastos Carvalho A. Cell-Based Therapies for Heart Failure. Front Pharmacol 2021; 12:641116. [PMID: 33912054 PMCID: PMC8072383 DOI: 10.3389/fphar.2021.641116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/11/2021] [Indexed: 02/05/2023] Open
Abstract
Heart failure has reached epidemic proportions with the advances in cardiovascular therapies for ischemic heart diseases and the progressive aging of the world population. Efficient pharmacological therapies are available for treating heart failure, but unfortunately, even with optimized therapy, prognosis is often poor. Their last therapeutic option is, therefore, a heart transplantation with limited organ supply and complications related to immunosuppression. In this setting, cell therapies have emerged as an alternative. Many clinical trials have now been performed using different cell types and injection routes. In this perspective, we will analyze the results of such trials and discuss future perspectives for cell therapies as an efficacious treatment of heart failure.
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Affiliation(s)
- Antonio Carlos Campos de Carvalho
- Laboratory of Cellular and Molecular Cardiology, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Center of Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tais H. Kasai-Brunswick
- National Center of Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adriana Bastos Carvalho
- Laboratory of Cellular and Molecular Cardiology, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Berezin AE, Berezin AA. Stem-Cell-Based Cardiac Regeneration: Is There a Place For Optimism in the Future? Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
Stem cell therapy offers a breakthrough opportunity for the improvement of ischemic heart diseases. Numerous clinical trials and meta-analyses appear to confirm its positive but variable effects on heart function. Whereas these trials widely differed in design, cell type, source, and doses reinjected, cell injection route and timing, and type of cardiac disease, crucial key factors that may favour the success of cell therapy emerge from the review of their data. Various types of cell have been delivered. Injection of myoblasts does not improve heart function and is often responsible for severe ventricular arrythmia occurrence. Using bone marrow mononuclear cells is a misconception, as they are not stem cells but mainly a mix of various cells of hematopoietic lineages and stromal cells, only containing very low numbers of cells that have stem cell-like features; this likely explain the neutral results or at best the modest improvement in heart function reported after their injection. The true existence of cardiac stem cells now appears to be highly discredited, at least in adults. Mesenchymal stem cells do not repair the damaged myocardial tissue but attenuate post-infarction remodelling and contribute to revascularization of the hibernated zone surrounding the scar. CD34+ stem cells - likely issued from pluripotent very small embryonic-like (VSEL) stem cells - emerge as the most convincing cell type, inducing structural and functional repair of the ischemic myocardial area, providing they can be delivered in large amounts via intra-myocardial rather than intra-coronary injection, and preferentially after myocardial infarct rather than chronic heart failure.
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Affiliation(s)
- Philippe Hénon
- CellProthera SAS and Institut de Recherche en Hématologie et Transplantation, CellProthera SAS 12 rue du Parc, 68100, Mulhouse, France.
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20
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Yang YJ, Qian HY, Song L, Geng YJ, Gao RL, Li N, Wang H, Tian XQ, Huang J, Huang PS, Xu J, Shen R, Lu MJ, Zhao SH, Wu WC, Wu Y, Zhang J, Qian J, Xu JY, Xiong YY. Strengthening effects of bone marrow mononuclear cells with intensive atorvastatin in acute myocardial infarction. Open Heart 2020; 7:e001139. [PMID: 32393654 PMCID: PMC7223465 DOI: 10.1136/openhrt-2019-001139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 02/20/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE To test whether intensive atorvastatin (ATV) increases the efficacy of transplantation with autologous bone marrow mononuclear cells (MNCs) in patients suffering from anterior ST-elevated myocardial infarction (STEMI). METHODS This clinical trial was under a 2×2 factorial design, enrolling 100 STEMI patients, randomly into four groups of regular (RA) or intensive ATV (IA) with MNCs or placebo. The primary endpoint was the change of left ventricular ejection fraction (LVEF) at 1-year follow-up from baseline, primarily assessed by MRI. The secondary endpoints included other parameters of cardiac function, remodelling and regeneration determined by MRI, echocardiography, positron emission tomography (PET) and biomarkers. RESULTS All the STEMI patients with transplantation of MNCs showed significantly increased LVEF change values than those with placebo (p=0.01) with only in the IA+MNCs patients group demonstrating significantly elevation of LVEF than in the IA+placebo group (+12.6% (95%CI 10.4 to 19.3) vs +5.0% (95%CI 4.0 to 10.0), p=0.001), pointing to a better synergy between ATV and MNCs (p=0.019). PET analysis revealed significantly increased viable areas of myocardium (p=0.015), while the scar sizes (p=0.026) and blood aminoterminal pro-B-type natriuretic peptide (p<0.034) reduced. All these above benefits of MNCs were also attributed to IA+MNCs instead of RA+MNCs group of patients with STEMI. CONCLUSIONS Intensive ATV treatment augments the therapeutic efficacy of MNCs in patients with anterior STEMI at the convalescent stage. The treatment with the protocol of intensive ATV and MNC combination offers a clinically essential approach for myocardial infarction. TRIAL REGISTRATION NUMBER NCT00979758.
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Affiliation(s)
- Yue-Jin Yang
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hai-Yan Qian
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Song
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong-Jian Geng
- The Center for Cardiovascular Biology and Atherosclerosis, Department of Internal Medicine, University of Texas McGovern School of Medicine at Houston, Houston, Texas, USA
| | - Run-Lin Gao
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Na Li
- Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hong Wang
- Center for Cardiac Critical Care, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Xia-Qiu Tian
- Center for Cardiac Critical Care, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Ji Huang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Pei-Sen Huang
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Xu
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Shen
- Department of Nuclear Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min-Jie Lu
- Department of Magnetic Resonance Imaging, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shi-Hua Zhao
- Department of Magnetic Resonance Imaging, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei-Chun Wu
- Department of Echocardiography, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Wu
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Zhang
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Qian
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun-Yan Xu
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu-Yan Xiong
- Department of Cardiology, Center for Coronary Heart Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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The Effects of Granulocyte Colony-Stimulating Factor in Patients with a Large Anterior Wall Acute Myocardial Infarction to Prevent Left Ventricular Remodeling: A 10-Year Follow-Up of the RIGENERA Study. J Clin Med 2020; 9:jcm9041214. [PMID: 32340315 PMCID: PMC7230316 DOI: 10.3390/jcm9041214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
Background: the RIGENERA trial assessed the efficacy of granulocyte-colony stimulating factor (G-CSF) in the improvement of clinical outcomes in patients with severe acute myocardial infarction. However, there is no evidence available regarding the long-term safety and efficacy of this treatment. Methods: in order to evaluate the long-term effects on the incidence of major adverse events, on the symptom burden, on the quality of life and the mean life expectancy and on the left ventricular (LV) function, we performed a clinical and echocardiographic evaluation together with an assessment using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Seattle Heart Failure Model (SHFM) at 10-years follow-up, in the patients cohorts enrolled in the RIGENERA trial. Results: thirty-two patients were eligible for the prospective clinical and echocardiography analyses. A significant reduction in adverse LV remodeling was observed in G-CSF group compared to controls, 9% vs. 48% (p = 0.030). The New York Heart Association (NYHA) functional class was lower in G-CSF group vs. controls (p = 0.040), with lower burden of symptoms and higher quality of life (p = 0.049). The mean life expectancy was significantly higher in G-CSF group compared to controls (15 ± 4 years vs. 12 ± 4 years, p = 0.046. No difference was found in the incidence of major adverse events. Conclusions: this longest available follow-up on G-CSF treatment in patients with severe acute myocardial infarction (AMI) showed that this treatment was safe and associated with a reduction of adverse LV remodeling and higher quality of life, in comparison with standard-of-care treatment.
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22
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Liu Z, Mikrani R, Zubair HM, Taleb A, Naveed M, Baig MMFA, Zhang Q, Li C, Habib M, Cui X, Sembatya KR, Lei H, Zhou X. Systemic and local delivery of mesenchymal stem cells for heart renovation: Challenges and innovations. Eur J Pharmacol 2020; 876:173049. [PMID: 32142771 DOI: 10.1016/j.ejphar.2020.173049] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 02/20/2020] [Accepted: 02/27/2020] [Indexed: 02/07/2023]
Abstract
In the beginning stage of heart disease, the blockage of blood flow frequently occurs due to the persistent damage and even death of myocardium. Cicatricial tissue developed after the death of myocardium can affect heart function, which ultimately leads to heart failure. In recent years, several studies carried out about the use of stem cells such as embryonic, pluripotent, cardiac and bone marrow-derived stem cells as well as myoblasts to repair injured myocardium. Current studies focus more on finding appropriate measures to enhance cell homing and survival in order to increase paracrine function. Until now, there is no universal delivery route for mesenchymal stem cells (MSCs) for different diseases. In this review, we summarize the advantages and challenges of the systemic and local pathways of MSC delivery. In addition, we also describe some advanced measures of cell delivery to improve the efficiency of transplantation. The combination of cells and therapeutic substances could be the most reliable method, which allows donor cells to deliver sufficient amounts of paracrine factors and provide long-lasting effects. The cardiac support devices or tissue engineering techniques have the potential to facilitate the controlled release of stem cells on local tissue for a sustained period. A novel promising epicardial drug delivery system is highlighted here, which not only provides MSCs with a favorable environment to promote retention but also increases the contact area and a number of cells recruited in the heart muscle.
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Affiliation(s)
- Ziwei Liu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Reyaj Mikrani
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | | | - Abdoh Taleb
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, PR China
| | - Muhammad Naveed
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, PR China
| | - Mirza Muhammad Faran Asraf Baig
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210023, PR China
| | - Qin Zhang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Cuican Li
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Murad Habib
- Department of Surgery, Ayub Teaching Hospital, Abbottabad, Pakistan
| | - Xingxing Cui
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Kiganda Raymond Sembatya
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Han Lei
- Department of Pharmacy, Jiangsu Worker Medical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Xiaohui Zhou
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China; Department of Surgery, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, 210017, PR China; Department of Surgery, Nanjing Shuiximen Hospital, Nanjing, Jiangsu Province, 210017, PR China.
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23
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Xu J, Xiong Y, Li Q, Hu M, Huang P, Xu J, Tian X, Jin C, Liu J, Qian L, Yang Y. Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction. Stem Cells Transl Med 2019; 8:1068-1083. [PMID: 31245934 PMCID: PMC6766601 DOI: 10.1002/sctm.19-0013] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/25/2019] [Indexed: 12/14/2022] Open
Abstract
Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV-pretreated mesenchymal stem cells (MSCs) (ATV -MSCs) at 1 week post-acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV -MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell-derived factor-1 (SDF-1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV -MSCs at early (Early1, Early2, Early3), mid-term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF-1 expression 1.5∼2.6-fold in peri-infarcted region with inhibited inflammation. ATV -MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%∼24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%∼16.2%, and reduced infarct size in all groups 6 weeks post-AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV -MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV -MSCs were much more effective than single administration during early and mid-term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV -MSCs combined with intensive ATV administration at mid-term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019;8:1068-1083.
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Affiliation(s)
- Jun Xu
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Yu‐Yan Xiong
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Qing Li
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Meng‐Jin Hu
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Pei‐Sen Huang
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Jun‐Yan Xu
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Xia‐Qiu Tian
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Chen Jin
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Jian‐Dong Liu
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Li Qian
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Yue‐Jin Yang
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
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24
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Fernández-Avilés F, Sanz-Ruiz R, Bogaert J, Casado Plasencia A, Gilaberte I, Belmans A, Fernández-Santos ME, Charron D, Mulet M, Yotti R, Palacios I, Luque M, Sádaba R, San Román JA, Larman M, Sánchez PL, Sanchís J, Jiménez MF, Claus P, Al-Daccak R, Lombardo E, Abad JL, DelaRosa O, Corcóstegui L, Bermejo J, Janssens S. Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction. Circ Res 2019; 123:579-589. [PMID: 29921651 DOI: 10.1161/circresaha.118.312823] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
RATIONALE Allogeneic cardiac stem cells (AlloCSC-01) have shown protective, immunoregulatory, and regenerative properties with a robust safety profile in large animal models of heart disease. OBJECTIVE To investigate the safety and feasibility of early administration of AlloCSC-01 in patients with ST-segment-elevation myocardial infarction. METHODS AND RESULTS CAREMI (Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With STEMI and Left Ventricular Dysfunction) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial in patients with ST-segment-elevation myocardial infarction, left ventricular ejection fraction ≤45%, and infarct size ≥25% of left ventricular mass by cardiac magnetic resonance, who were randomized (2:1) to receive AlloCSC-01 or placebo through the intracoronary route at days 5 to 7. The primary end point was safety and included all-cause death and major adverse cardiac events at 30 days (all-cause death, reinfarction, hospitalization because of heart failure, sustained ventricular tachycardia, ventricular fibrillation, and stroke). Secondary safety end points included major adverse cardiac events at 6 and 12 months, adverse events, and immunologic surveillance. Secondary exploratory efficacy end points were changes in infarct size (percentage of left ventricular mass) and indices of ventricular remodeling by magnetic resonance at 12 months. Forty-nine patients were included (92% male, 55±11 years), 33 randomized to AlloCSC-01 and 16 to placebo. No deaths or major adverse cardiac events were reported at 12 months. One severe adverse events in each group was considered possibly related to study treatment (allergic dermatitis and rash). AlloCSC-01 elicited low levels of donor-specific antibodies in 2 patients. No immune-related adverse events were found, and no differences between groups were observed in magnetic resonance-based efficacy parameters at 12 months. The estimated treatment effect of AlloCSC-01 on the absolute change from baseline in infarct size was -2.3% (95% confidence interval, -6.5% to 1.9%). CONCLUSIONS AlloCSC-01 can be safely administered in ST-segment-elevation myocardial infarction patients with left ventricular dysfunction early after revascularization. Low immunogenicity and absence of immune-mediated events will facilitate adequately powered studies to demonstrate their clinical efficacy in this setting. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439398.
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Affiliation(s)
- Francisco Fernández-Avilés
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.)
| | - Ricardo Sanz-Ruiz
- From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense, Madrid, Spain (R.S.-R., A.C.P., M.E.F.-S., R.Y., J.B.).,CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.)
| | | | - Ana Casado Plasencia
- From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense, Madrid, Spain (R.S.-R., A.C.P., M.E.F.-S., R.Y., J.B.).,CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.)
| | - Inmaculada Gilaberte
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Ann Belmans
- Department of Cardiovascular Medicine, University Hospitals and KU Leuven, Belgium (J.B., A.B., P.C., S.J.)
| | - Maria Eugenia Fernández-Santos
- From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense, Madrid, Spain (R.S.-R., A.C.P., M.E.F.-S., R.Y., J.B.).,CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.)
| | - Dominique Charron
- HLA et Medicine (HLA-MED), Hôpital Saint-Louis, Paris, France (D.C., R.A.-D.)
| | - Miguel Mulet
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Raquel Yotti
- From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense, Madrid, Spain (R.S.-R., A.C.P., M.E.F.-S., R.Y., J.B.).,CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.)
| | - Itziar Palacios
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Manuel Luque
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Rafael Sádaba
- Department of Cardiac Surgery, Complejo Hospitalario de Navarra, Pamplona, Spain (R.S.)
| | - J Alberto San Román
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.).,Department of Cardiology, Instituto de Ciencias del Corazón (ICICOR), Valladolid, Spain (J.A.S.R.)
| | - Mariano Larman
- Department of Cardiology, Policlínia Guipuzcoa, San Sebastián, Spain (M.L.)
| | - Pedro L Sánchez
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.).,Department of Cardiology, Hospital Clínico Universitario, Salamanca, Spain (P.L.S.)
| | - Juan Sanchís
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.).,Department of Cardiology, Hospital Clínico Universitario, Valencia, Spain (J.S.)
| | - Manuel F Jiménez
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.).,Department of Cardiology, IBIMA, UMA, UGC Corazón Hospital Clínico Virgen de la Victoria, Málaga, Spain (M.F.J.)
| | - Piet Claus
- Department of Cardiovascular Medicine, University Hospitals and KU Leuven, Belgium (J.B., A.B., P.C., S.J.)
| | - Reem Al-Daccak
- HLA et Medicine (HLA-MED), Hôpital Saint-Louis, Paris, France (D.C., R.A.-D.)
| | - Eleuterio Lombardo
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - José Luis Abad
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Olga DelaRosa
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Lucia Corcóstegui
- Coretherapix S.L.U./Tigenix Group Madrid, Spain (I.G., M.M., I.P., M.L., E.L., J.L.A., O.D., L.C.)
| | - Javier Bermejo
- From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense, Madrid, Spain (R.S.-R., A.C.P., M.E.F.-S., R.Y., J.B.).,CIBERCV, Instituto de Salud Carlos III, Madrid, Spain (F.F.-A., R.S.-R., A.C.P., M.E.F.-S., R.Y., J.A.S.R., P.L.S., J.S., M.F.J., J.B.).,Department of Cardiovascular Medicine, University Hospitals and KU Leuven, Belgium (J.B., A.B., P.C., S.J.)
| | - Stefan Janssens
- Department of Cardiovascular Medicine, University Hospitals and KU Leuven, Belgium (J.B., A.B., P.C., S.J.)
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25
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Johnston PV, Hwang CW, Bogdan V, Mills KJ, Eggan ER, Leszczynska A, Wu KC, Herzka DA, Brinker JA, Schulman SP, Banerjee M, Florea V, Natsumeda M, Tompkins B, Balkan W, Hare JM, Tomaselli GF, Weiss RG, Gerstenblith G. Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction. J Am Heart Assoc 2019; 8:e012351. [PMID: 31340693 PMCID: PMC6761667 DOI: 10.1161/jaha.119.012351] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.
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Affiliation(s)
- Peter V Johnston
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Chao-Wei Hwang
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD.,Department of Biomedical Engineering Johns Hopkins University School of Medicine Baltimore MD
| | - Virginia Bogdan
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Kevin J Mills
- Department of Medicine Penn State Hershey Medical Center Hershey PA
| | - Elliott R Eggan
- Perelman School of Medicine University of Pennsylvania Philadelphia PA
| | - Aleksandra Leszczynska
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Katherine C Wu
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Daniel A Herzka
- Department of Biomedical Engineering Johns Hopkins University School of Medicine Baltimore MD
| | - Jeffrey A Brinker
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Steven P Schulman
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Monisha Banerjee
- Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Miami FL.,Department of Surgery University of Miami Miller School of Medicine Miami FL
| | - Victoria Florea
- Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Miami FL
| | - Makoto Natsumeda
- Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Miami FL
| | - Bryon Tompkins
- Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Miami FL.,Department of Surgery University of Miami Miller School of Medicine Miami FL
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Miami FL.,Department of Medicine University of Miami Miller School of Medicine Miami FL
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Miami FL.,Department of Medicine University of Miami Miller School of Medicine Miami FL
| | | | - Robert G Weiss
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
| | - Gary Gerstenblith
- Division of Cardiology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD
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26
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Low-energy cardiac shockwave therapy to suppress left ventricular remodeling in patients with acute myocardial infarction: a first-in-human study. Coron Artery Dis 2019; 29:294-300. [PMID: 29068804 DOI: 10.1097/mca.0000000000000577] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Although primary percutaneous coronary intervention (PCI) substantially reduces the mortality of patients with acute myocardial infarction (AMI), left ventricular (LV) remodeling after AMI still remains an important issue in cardiovascular medicine. We have previously demonstrated that low-energy cardiac shockwave (SW) therapy ameliorates LV remodeling after AMI in pigs. In this first-in-human study, we examined the feasibility and the effects of the SW therapy on LV remodeling after AMI in humans. PATIENTS AND METHODS Seventeen patients with AMI who successfully underwent primary PCI (peak-creatine kinase<4000 U/l) were treated with the SW therapy. Low-energy shock waves were applied to the ischemic border zone around the infarcted area at 2, 4, and 6 days since AMI. Next, we compared these patients with historical AMI controls by propensity score matching (N=25). RESULTS There were no procedure-related complications or adverse effects. At 6 and 12 months after AMI, LV function as assessed by MRI showed no signs of deleterious LV remodeling. When we compared the SW-treated group with the historical AMI controls at 6 months after AMI, LV ejection fraction was significantly higher in the SW-treated group (N=7) than in the historical control group (N=25) by echocardiography (66±7 vs. 58±12%, P<0.05). LV end-diastolic dimension also tended to be smaller in the SW than in the control group (47.5±4.6 vs. 50.0±5.9 mm, P=0.29). CONCLUSION These results suggest that low-energy extracorporeal cardiac SW therapy is feasible and may ameliorate postmyocardial infarction LV remodeling in patients with AMI as an adjunctive therapy to primary PCI.
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27
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Andrié RP, Beiert T, Knappe V, Linhart M, Stöckigt F, Klein AM, Ghanem A, Lübkemeier I, Röll W, Nickenig G, Fleischmann BK, Schrickel JW. Treatment with mononuclear cell populations improves post-infarction cardiac function but does not reduce arrhythmia susceptibility. PLoS One 2019; 14:e0208301. [PMID: 30763348 PMCID: PMC6375577 DOI: 10.1371/journal.pone.0208301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 11/15/2018] [Indexed: 12/12/2022] Open
Abstract
Background Clinical and experimental data give evidence that transplantation of stem and progenitor cells in myocardial infarction could be beneficial, although the underlying mechanism has remained elusive. Ventricular tachyarrhythmia is the most frequent and potentially lethal complication of myocardial infarction, but the impact of mono nuclear cells on the incidence of ventricular arrhythmia is still not clear. Objective We aimed to characterize the influence of splenic mononuclear cell populations on ventricular arrhythmia after myocardial infarction. Methods We assessed electrical vulnerability in vivo in mice with left ventricular cryoinfarction 14 days after injury and intramyocardial injection of specific subpopulations of mononuclear cells (MNCs) (CD11b-positive cells, Sca-1-positive cells, early endothelial progenitor cells (eEPCs)). As positive control group we used embryonic cardiomyocytes (eCMs). Epicardial mapping was performed for analysing conduction velocities in the border zone. Left ventricular function was quantified by echocardiography and left heart catheterization. Results In vivo pacing protocols induced ventricular tachycardia (VT) in 30% of non-infarcted mice. In contrast, monomorphic or polymorphic VT could be evoked in 94% of infarcted and vehicle-injected mice (p<0.01). Only transplantation of eCMs prevented post-infarction VT and improved conduction velocities in the border zone in accordance to increased expression of connexin 43. Cryoinfarction resulted in a broad aggravation of left ventricular function. All transplanted cell types augmented left ventricular function to a similar extent. Conclusions Transplantation of different MNC populations after myocardial infarction improves left ventricular function similar to effects of eCMs. Prevention of inducible ventricular arrhythmia is only seen after transplantation of eCMs.
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Affiliation(s)
- René P. Andrié
- Department of Cardiology, University of Bonn, Bonn, Germany
- * E-mail:
| | - Thomas Beiert
- Department of Cardiology, University of Bonn, Bonn, Germany
| | - Vincent Knappe
- Department of Cardiology, University of Bonn, Bonn, Germany
| | - Markus Linhart
- Department of Cardiology, University of Bonn, Bonn, Germany
| | | | - Alexandra M. Klein
- Institute of Physiology I, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Alexander Ghanem
- Department of Cardiology, Asklepios Hospital Hamburg, Hamburg, Germany
| | - Indra Lübkemeier
- LIMES-Institute, Molecular Genetics, University of Bonn, Bonn, Germany
| | - Wilhelm Röll
- Department of Cardiovascular Surgery, University of Bonn, Bonn, Germany
| | - Georg Nickenig
- Department of Cardiology, University of Bonn, Bonn, Germany
| | - Bernd K. Fleischmann
- Institute of Physiology I, Life & Brain Center, University of Bonn, Bonn, Germany
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28
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Wang C, Liu Y, He D. Diverse effects of platelet-derived growth factor-BB on cell signaling pathways. Cytokine 2019; 113:13-20. [DOI: 10.1016/j.cyto.2018.10.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/17/2018] [Accepted: 10/19/2018] [Indexed: 12/12/2022]
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29
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Wang BH, Liew D, Huang KW, Huang L, Tang W, Kelly DJ, Reid C, Liu Z. The Challenges of Stem Cell Therapy in Myocardial Infarction and Heart Failure and the Potential Strategies to Improve the Outcomes. ACTA ACUST UNITED AC 2018. [DOI: 10.1142/s1793984418410088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cardiovascular disease remains the single highest global cause of death and a significant financial burden on the healthcare system. Despite the advances in medical treatments, the prevalence and mortality for heart failure remain unacceptably high. New approaches are urgently needed to reduce this burden and improve patient outcomes and quality of life. One such promising approach is stem cell therapy, including embryonic stem cells, bone marrow derived stem cells, induced pluripotent stem cells and mesenchymal stem cells. However, the cardiac microenvironment following myocardial infarction poses huge challenges with inflammation, adequate retention, engraftment and functional incorporation all crucial concerns. The lack of cardiac regeneration, cell viability and functional improvement has hindered the success of stem cell therapy in clinical settings. The use of biomaterial scaffolds in conjunction with stem cells has recently been shown to enhance the outcome of stem cell therapy for heart failure and myocardial infarction. This review outlines some of the current challenges in the treatment of heart failure and acute myocardial infarction through improving stem cell therapeutic strategies, as well as the prospect of suitable biomaterial scaffolds to enhance their efficacy and improve patient clinical outcomes.
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Affiliation(s)
- Bing Hui Wang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Danny Liew
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Kevin W. Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Li Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Wenjie Tang
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
| | - Darren J. Kelly
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy Victoria, Australia
| | - Christopher Reid
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Zhongmin Liu
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
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30
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Heinen A, Nederlof R, Panjwani P, Spychala A, Tschaidse T, Reffelt H, Boy J, Raupach A, Gödecke S, Petzsch P, Köhrer K, Grandoch M, Petz A, Fischer JW, Alter C, Vasilevska J, Lang P, Gödecke A. IGF1 Treatment Improves Cardiac Remodeling after Infarction by Targeting Myeloid Cells. Mol Ther 2018; 27:46-58. [PMID: 30528085 DOI: 10.1016/j.ymthe.2018.10.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 10/25/2018] [Accepted: 10/26/2018] [Indexed: 12/20/2022] Open
Abstract
Insulin-like growth factor 1 (IGF1) is an anabolic hormone that controls the growth and metabolism of many cell types. However, IGF1 also mediates cardio-protective effects after acute myocardial infarction (AMI), but the underlying mechanisms and cellular targets are not fully understood. Here we demonstrate that short-term IGF1 treatment for 3 days after AMI improved cardiac function after 1 and 4 weeks. Regional wall motion was improved in ischemic segments, scar size was reduced, and capillary density increased in the infarcted area and the border zone. Unexpectedly, inducible inactivation of the IGF1 receptor (IGF1R) in cardiomyocytes did not attenuate the protective effect of IGF1. Sequential cardiac transcriptomic analysis indicated an altered myeloid cell response in the acute phase after AMI, and, notably, myeloid-cell Igf1r-/- mice lost the protective IGF1 function after I/R. In addition, IGF1 induced an M2-like anti-inflammatory phenotype in bone marrow-derived macrophages and enhanced the number of anti-inflammatory macrophages in heart tissue on day 3 after AMI in vivo. In summary, modulation of the acute inflammatory phase after AMI by IGF1 represents an effective mechanism to preserve cardiac function after I/R.
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Affiliation(s)
- Andre Heinen
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Rianne Nederlof
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Priyadarshini Panjwani
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - André Spychala
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Tengis Tschaidse
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Heiko Reffelt
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Johannes Boy
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Annika Raupach
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Stefanie Gödecke
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Patrick Petzsch
- Biologisch-Medizinisches Forschungszentrum (BMFZ), Genomics and Transcriptomics Labor, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Karl Köhrer
- Biologisch-Medizinisches Forschungszentrum (BMFZ), Genomics and Transcriptomics Labor, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Maria Grandoch
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Anne Petz
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Jens W Fischer
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Christina Alter
- Institut für Molekulare Kardiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Jelena Vasilevska
- Institut für Molekulare Medizin II, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Philipp Lang
- Institut für Molekulare Medizin II, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Axel Gödecke
- Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
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31
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Nguyen PK, Rhee JW, Wu JC. Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review. JAMA Cardiol 2018; 1:831-841. [PMID: 27557438 DOI: 10.1001/jamacardio.2016.2225] [Citation(s) in RCA: 218] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Importance Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for more than 10% of deaths in the United States annually. Despite more than a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is an effective treatment strategy and can be routinely implemented in clinical practice. Objective To describe the progress in cardiac stem cell regenerative therapy using adult stem cells and to highlight the merits and limitations of clinical trials performed to date. Evidence Review Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 26, 2016. Twenty-nine randomized clinical trials and 7 systematic reviews and meta-analyses were included in this review. Findings Although adult stem cells were once believed to have the ability to create new heart tissue, preclinical studies suggest that these cells release cardioprotective paracrine factors that activate endogenous pathways, leading to myocardial repair. Subsequent randomized clinical trials, most of which used autologous bone marrow mononuclear cells, have found only a modest benefit in patients receiving stem cell therapy. The lack of a significant benefit may result from variations in trial methods, discrepancies in reporting, and an overreliance on surrogate end points. Conclusions and Relevance Although stem cell therapy for cardiovascular disease is not yet ready for routine clinical application, significant progress continues to be made. Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies.
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Affiliation(s)
- Patricia K Nguyen
- Stanford Cardiovascular Institute, Stanford University, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California3Veterans Affairs Palo Alto Health Care System, Stanford University, Stanford, California
| | - June-Wha Rhee
- Stanford Cardiovascular Institute, Stanford University, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California4Department of Radiology, Stanford University, Stanford, California
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32
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Nguyen PK, Neofytou E, Rhee JW, Wu JC. Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review. JAMA Cardiol 2018; 1:953-962. [PMID: 27579998 DOI: 10.1001/jamacardio.2016.2750] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Importance Although progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist. Objectives To summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them. Evidence Review Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 25, 2016. Ten randomized clinical trials and 8 systematic reviews were included. Findings One of the major clinical barriers facing the routine implementation of stem cell therapy in patients with cardiovascular disease is the limited and inconsistent benefit observed thus far. Reasons for this finding are unclear but may be owing to poor cell retention and survival, as suggested by numerous preclinical studies and a small number of human studies incorporating imaging to determine cell fate. Additional studies in humans using imaging to determine cell fate are needed to understand how these factors contribute to the limited efficacy of stem cell therapy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: coadministration of immunosuppressive and prosurvival agents, delivery of cardioprotective factors packaged in exosomes rather than the cells themselves, and use of tissue-engineering strategies to provide structural support for cells. If larger grafts are achieved using these strategies, it will be imperative to carefully monitor for the potential risks of tumorigenicity, immunogenicity, and arrhythmogenicity. Conclusions and Relevance Despite important achievements to date, stem cell therapy is not yet ready for routine clinical implementation. Significant research is still needed to address the clinical barriers outlined herein before the next wave of large clinical trials is under way.
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Affiliation(s)
- Patricia K Nguyen
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California3Veterans Affairs Palo Alto Health Care System, Palo Alto, California
| | - Evgenios Neofytou
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - June-Wha Rhee
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California4Department of Radiology, Stanford University School of Medicine, Stanford, California
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33
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Zwetsloot PP, Gremmels H, Assmus B, Koudstaal S, Sluijter JPG, Zeiher AM, Chamuleau SAJ. Responder Definition in Clinical Stem Cell Trials in Cardiology: Will the Real Responder Please Stand Up? Circ Res 2018; 119:514-8. [PMID: 27492842 DOI: 10.1161/circresaha.116.308733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Peter Paul Zwetsloot
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.).
| | - Hendrik Gremmels
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Birgit Assmus
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Stefan Koudstaal
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Joost P G Sluijter
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Andreas M Zeiher
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Steven A J Chamuleau
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
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Henry TD, Moyé L, Traverse JH. Consistently Inconsistent-Bone Marrow Mononuclear Stem Cell Therapy Following Acute Myocardial Infarction: A Decade Later. Circ Res 2018; 119:404-6. [PMID: 27458193 DOI: 10.1161/circresaha.116.309231] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Timothy D Henry
- From the Cedars-Sinai Heart Institute, Division of Cardiology, Los Angeles, CA (T.D.H.); University of Texas School of Public Health, Department of Biostatistics, Houston (L.M.); and Minneapolis Heart Institute Foundation, Division of Cardiology, MN (J.H.T.).
| | - Lem Moyé
- From the Cedars-Sinai Heart Institute, Division of Cardiology, Los Angeles, CA (T.D.H.); University of Texas School of Public Health, Department of Biostatistics, Houston (L.M.); and Minneapolis Heart Institute Foundation, Division of Cardiology, MN (J.H.T.)
| | - Jay H Traverse
- From the Cedars-Sinai Heart Institute, Division of Cardiology, Los Angeles, CA (T.D.H.); University of Texas School of Public Health, Department of Biostatistics, Houston (L.M.); and Minneapolis Heart Institute Foundation, Division of Cardiology, MN (J.H.T.)
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Itier R, Roncalli J. New therapies for acute myocardial infarction: current state of research and future promise. Future Cardiol 2018; 14:329-342. [DOI: 10.2217/fca-2017-0047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Progress has been made into research on new therapies, mechanical and pharmacological approaches and repair/regenerative cellular therapy to treat irreversible cardiovascular pathologies, such as acute myocardial infarction. Research into cellular therapies is exploring the use of new cellular types. Although the therapeutic effects of cell therapy remain modest, results from clinical trials are encouraging. To expand this improvement, advances are being made that involve the paracrine function of stem cells, the use of growth factors, miRNA and new biomaterials. In the near future, these therapies should become part of routine clinical practice.
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Affiliation(s)
- Romain Itier
- Department of Cardiology A, Institute CARDIOMET, Clinical Center of Investigation for Biotherapies, CIC-BT 0511, INSERM 1048, University Hospital of Toulouse, Toulouse, France
| | - Jerome Roncalli
- Department of Cardiology A, Institute CARDIOMET, Clinical Center of Investigation for Biotherapies, CIC-BT 0511, INSERM 1048, University Hospital of Toulouse, Toulouse, France
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Mohl W, Henry TD, Milasinovic D, Nguemo F, Hescheler J, Perin EC. From state-of-the-art cell therapy to endogenous cardiac repair. EUROINTERVENTION 2018; 13:760-772. [PMID: 28844036 DOI: 10.4244/eij-d-17-00467] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Clinical heart failure prevention and contemporary therapy often involve breaking the vicious cycle of global haemodynamic consequences of myocardial decay. The lack of effective regenerative therapies results in a primary focus on preventing further deterioration of cardiac performance. The cellular transplantation hypothesis has been evaluated in many different preclinical models and a handful of important clinical trials. The primary expectation that cellular transplants will be embedded into failing myocardium and fuse with existing functioning cells appears unlikely. A multitude of cellular formulas, access routes and clinical surrogate endpoints for evaluation add to the complexity of cellular therapies. Several recent large clinical trials have provided insights into both the regenerative potential and clinical improvement from non-regenerative mechanisms. Initiating endogenous repair seems to be another meaningful alternative to recover structural integrity in myocardial injury. This option may be achieved using a transcoronary sinus catheter intervention, implying the understanding of basic principles in biology. With intermittent reduction of outflow in cardiac veins (PICSO), vascular cells appear to be activated and restart a programme similar to pathways in the developing heart. Structural regeneration may be possible without requiring exogenous agents, or a combination of both approaches may become clinical reality in the next decade.
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Affiliation(s)
- Werner Mohl
- Department of Cardiac Surgery (Emeritus), Medical University of Vienna, Vienna, Austria
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Madigan M, Atoui R. Therapeutic Use of Stem Cells for Myocardial Infarction. Bioengineering (Basel) 2018; 5:bioengineering5020028. [PMID: 29642402 PMCID: PMC6027340 DOI: 10.3390/bioengineering5020028] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/29/2018] [Accepted: 04/04/2018] [Indexed: 12/15/2022] Open
Abstract
Myocardial infarction is a leading cause of morbidity and mortality worldwide. Although medical and surgical treatments can significantly improve patient outcomes, no treatment currently available is able to generate new contractile tissue or reverse ischemic myocardium. Driven by the recent/novel understanding that regenerative processes do exist in the myocardium—tissue previously thought not to possess regenerative properties—the use of stem cells has emerged as a promising therapeutic approach with high expectations. The literature describes the use of cells from various sources, categorizing them as either embryonic, induced pluripotent, or adult/tissue stem cells (mesenchymal, hematopoietic, skeletal myoblasts, cardiac stem cells). Many publications show the successful use of these cells to regenerate damaged myocardium in both animal and human models; however, more studies are needed to directly compare cells of various origins in efforts to draw conclusions on the ideal source. Although numerous challenges exist in this developing area of research and clinical practice, prospects are encouraging. The following aims to provide a concise review outlining the different types of stem cells used in patients after myocardial infarction.
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Affiliation(s)
- Mariah Madigan
- Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
| | - Rony Atoui
- Health Sciences North, Sudbury, ON P3E 5J1, Canada.
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, ElSayed AS, Ashaal AE, Ali MM, El-Shal AS. Mechanistic effects of mesenchymal and hematopoietic stem cells: New therapeutic targets in myocardial infarction. J Cell Biochem 2018; 119:5274-5286. [PMID: 29266431 DOI: 10.1002/jcb.26637] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 12/19/2017] [Indexed: 12/16/2022]
Abstract
Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is of the most serious health threats today. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been explored as promising cell therapy in MI and regenerative therapy. Recently, reports investigated the potential therapeutic effects of MSCs or HSCs transplantation after MI in numerous experimental and clinical studies; however, their results are controversy and needs more explorations. The current review is an attempt to clarify the therapeutic potentials of MSCs and HSCs in MI therapy, as well as their possible effects; especially the paracrine one and the exosome-derived stem cell among animal models as well as clinical trials conducted within the last 10 years. In this context, various sources of MSCs and HSCs have been addressed in helping cardiac regeneration by either revitalizing the cardiac stem cells niche or revascularizing the arteries and veins of the heart. In addition, both MSCs and HSCs could produce paracrine mediators and growth factors which led to cardiomyocytes protection, angiogenesis, immunemodulation, antioxidants, anti-apoptotic, anti-inflammatory, antifibrotic, as well as increasing cardiac contractility. Recently, microRNAs (miRNAs), post-transcriptional regulators of gene expression, and long non-coding RNA (lncRNA), a miRNA sponge, are recent stem cell-derived mediators can be promising targets of MSCs and HSCs through their paracrine effects. Although MSCs and HSCs have achieved considerable achievements, however, some challenges still remain that need to be overcome in order to establish it as a successful technique. The present review clarified the mechanistic potentials of MSCs and HSCs especially paracrine effects involved in MI including human and animal studies and the challenges challenges regarding type, differentiation, route, and number of injections.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Mahmoud A Ali
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Hazem G Ghanem
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Ahmed I Shehata
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Hossam R Handal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Ahmed E Ashaal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Mazen M Ali
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Amal S El-Shal
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Abstract
Despite therapeutic advances that have prolonged life, myocardial infarction (MI) remains a leading cause of death worldwide and imparts a significant economic burden. The advancement of treatments to improve cardiac repair post-MI requires the discovery of new targeted treatment strategies. Recent studies have highlighted the importance of the epicardial covering of the heart in both cardiac development and lower vertebrate cardiac regeneration. The epicardium serves as a source of cardiac cells including smooth muscle cells, endothelial cells and cardiac fibroblasts. Mammalian adult epicardial cells are typically quiescent. However, the fetal genetic program is reactivated post-MI, and epicardial epithelial-to-mesenchymal transition (EMT) occurs as an inherent mechanism to support neovascularization and cardiac healing. Unfortunately, endogenous EMT is not enough to encourage sufficient repair. Recent developments in our understanding of the mechanisms supporting the EMT process has led to a number of studies directed at augmenting epicardial EMT post-MI. With a focus on the role of the primary cilium, this review outlines the newly demonstrated mechanisms supporting EMT, the role of epicardial EMT in cardiac development, and promising advances in augmenting epicardial EMT as potential therapeutics to support cardiac repair post-MI.
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Abstract
During the past decades, stem cell-based therapy has acquired a promising role in regenerative medicine. The application of novel cell therapeutics for the treatment of cardiovascular diseases could potentially achieve the ambitious aim of effective cardiac regeneration. Despite the highly positive results from preclinical studies, data from phase I/II clinical trials are inconsistent and the improvement of cardiac remodeling and heart performance was found to be quite limited. The major issues which cardiac stem cell therapy is facing include inefficient cell delivery to the site of injury, accompanied by low cell retention and weak effectiveness of remaining stem cells in tissue regeneration. According to preclinical and clinical studies, various stem cells (adult stem cells, embryonic stem cells, and induced pluripotent stem cells) represent the most promising cell types so far. Beside the selection of the appropriate cell type, researchers have developed several strategies to produce “second-generation” stem cell products with improved regenerative capacity. Genetic and nongenetic modifications, chemical and physical preconditioning, and the application of biomaterials were found to significantly enhance the regenerative capacity of transplanted stem cells. In this review, we will give an overview of the recent developments in stem cell engineering with the goal to facilitate stem cell delivery and to promote their cardiac regenerative activity.
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Wang D, Li LK, Dai T, Wang A, Li S. Adult Stem Cells in Vascular Remodeling. Am J Cancer Res 2018; 8:815-829. [PMID: 29344309 PMCID: PMC5771096 DOI: 10.7150/thno.19577] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 10/01/2017] [Indexed: 01/03/2023] Open
Abstract
Understanding the contribution of vascular cells to blood vessel remodeling is critical for the development of new therapeutic approaches to cure cardiovascular diseases (CVDs) and regenerate blood vessels. Recent findings suggest that neointimal formation and atherosclerotic lesions involve not only inflammatory cells, endothelial cells, and smooth muscle cells, but also several types of stem cells or progenitors in arterial walls and the circulation. Some of these stem cells also participate in the remodeling of vascular grafts, microvessel regeneration, and formation of fibrotic tissue around biomaterial implants. Here we review the recent findings on how adult stem cells participate in CVD development and regeneration as well as the current state of clinical trials in the field, which may lead to new approaches for cardiovascular therapies and tissue engineering.
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Dorobantu M, Popa-Fotea NM, Popa M, Rusu I, Micheu MM. Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease. World J Stem Cells 2017; 9:203-218. [PMID: 29321822 PMCID: PMC5746641 DOI: 10.4252/wjsc.v9.i12.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/08/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy (SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate end-points. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used - especially left ventricle ejection fraction (LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.
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Affiliation(s)
- Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania
| | | | - Mihaela Popa
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Iulia Rusu
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania.
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, Talaat KA, Ashaal AE, El-Shal AS. Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction. J Gene Med 2017; 19. [PMID: 29044850 DOI: 10.1002/jgm.2995] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/07/2017] [Accepted: 10/07/2017] [Indexed: 12/12/2022] Open
Abstract
For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct-limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene-modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell-based therapy in MI.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud Ahmed Ali
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | | | | | | | | | | | | | - Amal S El-Shal
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Ghiroldi A, Piccoli M, Ciconte G, Pappone C, Anastasia L. Regenerating the human heart: direct reprogramming strategies and their current limitations. Basic Res Cardiol 2017; 112:68. [DOI: 10.1007/s00395-017-0655-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 10/12/2017] [Indexed: 12/15/2022]
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Mathur A, Fernández-Avilés F, Dimmeler S, Hauskeller C, Janssens S, Menasche P, Wojakowski W, Martin JF, Zeiher A, the BAMI Investigators. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update 2016. Eur Heart J 2017; 38:2930-2935. [PMID: 28204458 PMCID: PMC5837487 DOI: 10.1093/eurheartj/ehw640] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/27/2016] [Accepted: 12/19/2016] [Indexed: 12/11/2022] Open
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Jeyaraman MM, Rabbani R, Copstein L, Sulaiman W, Farshidfar F, Kashani HH, Qadar SMZ, Guan Q, Skidmore B, Kardami E, Ducas J, Mansour S, Zarychanski R, Abou-Setta AM. Autologous Bone Marrow Stem Cell Therapy in Patients With ST-Elevation Myocardial Infarction: A Systematic Review and Meta-analysis. Can J Cardiol 2017; 33:1611-1623. [PMID: 29173601 DOI: 10.1016/j.cjca.2017.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 10/02/2017] [Accepted: 10/02/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Randomized controlled trials (RCTs) on bone marrow stem cell (BMSC) therapy in ST-elevation myocardial infarction (STEMI) patients have reported conflicting results. Our main objective was to critically appraise and meta-analyze best-available evidence on efficacy and safety of intracoronary administration of autologous BMSC therapy in STEMI patients after primary percutaneous coronary intervention. METHODS We conducted a search of MEDLINE, PubMed, EMBASE, CENTRAL, Global Health, CINAHL, and conference proceedings in February 2017. Our primary outcome was all-cause mortality. Secondary and safety outcomes included cardiac death, heart failure, arrhythmias, repeat myocardial infarction, or target vessel revascularizations; or improved health-related quality of life, left ventricular ejection fraction, or infarct size. Summary relative and absolute risks were obtained using random effects models. We also evaluated the strength of evidence. RESULTS A comprehensive database search identified 42 RCTs (3365 STEMI patients). BMSC therapy did not significantly decrease mortality (risk ratio, 0.71; 95% confidence interval, 0.45-1.11; I2, 0%; absolute risk reduction, 0.1%; 95% confidence interval, -0.71 to 0.91; 40 trials; 3289 participants; I2, 0%; low strength of evidence). BMSC therapy had no effect on secondary or adverse outcomes. Trial sequential analysis for all-cause mortality showed no evidence of a clinically important difference, with a very low probability that future studies can change the current conclusion. CONCLUSIONS On the basis of evidence from 42 RCTs published in the past 15 years, we provide conclusive evidence for a lack of beneficial effect for autologous BMSC therapy in patients with STEMI.
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Affiliation(s)
- Maya M Jeyaraman
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
| | - Rasheda Rabbani
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Leslie Copstein
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Wasan Sulaiman
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Farnaz Farshidfar
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Hessam H Kashani
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Sheikh M Z Qadar
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Qingdong Guan
- Cellular Therapy Laboratory, CancerCare Manitoba, Winnipeg, Manitoba, Canada; Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, Manitoba, Canada
| | - Becky Skidmore
- Information Specialist Consultant, Ottawa, Ontario, Canada
| | - Elissavet Kardami
- Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - John Ducas
- Section of Cardiology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Samer Mansour
- Centre Hospitalier de l'Université de Montreal, Montreal, Quebec, Canada; Faculty of Medicine, Department of Medicine, Université de Montréal, Montreal, Quebec, Canada; Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Ryan Zarychanski
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Haematology and Medical Oncology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada
| | - Ahmed M Abou-Setta
- The George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
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Uitterdijk A, Groenendijk BCW, Gorsse-Bakker C, Panasewicz A, Sneep S, Tempel D, van de Kamp EH, Merkus D, van der Giessen WJ, Duncker DJ. Time course of VCAM-1 expression in reperfused myocardial infarction in swine and its relation to retention of intracoronary administered bone marrow-derived mononuclear cells. PLoS One 2017. [PMID: 28628621 PMCID: PMC5476248 DOI: 10.1371/journal.pone.0178779] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM-1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion. Methods and results VCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n≥6 swine per group). Since expression levels were significantly higher at 3 days (2.41±0.62%) than at 7 days (0.98±0.28%; p<0.05), we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43·106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group) and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72). This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group), as cell composition of the infused BMMNC fractions was similar. Conclusion These findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention.
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Affiliation(s)
- André Uitterdijk
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | | | | | - Anna Panasewicz
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | - Stefan Sneep
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | - Dennie Tempel
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | | | - Daphne Merkus
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | | | - Dirk J. Duncker
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
- * E-mail:
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48
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Mester A, Oltean-Péter B, Rodean I, Opincariu D, Stănescu A, Lázár E, Benedek I, Benedek I, Benedek I. Magnetic Resonance Imaging of Myocardial Function Following Intracoronary and Intramyocardial Stem Cell Injection. JOURNAL OF INTERDISCIPLINARY MEDICINE 2017. [DOI: 10.1515/jim-2017-0053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Abstract
Stem cell-based therapy is a new therapeutic option that can be used in patients with cardiac diseases caused by myocardial injury. Cardiac magnetic resonance imaging (MRI) is a new noninvasive imaging method with an increasingly widespread indication. The aim of this review was to evaluate the role of cardiac MRI in patients with myocardial infarction undergoing stem cell therapy. We studied the role of MRI in the assessment of myocardial viability, stem cell tracking, assessment of cell survival rate, and monitoring of the long-term effects of stem cell therapy. Based on the current knowledge in this field, this noninvasive, in vivo cardiac imaging technique has a large indication in this group of patients and plays an important role in all stages of stem cell therapy, from the indication to the long-term follow-up of patients.
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Affiliation(s)
- András Mester
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Center of Advanced Research in Multimodality Cardiac Imaging , Cardio Med Medical Center , Tîrgu Mureș , Romania
| | - Balázs Oltean-Péter
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Center of Advanced Research in Multimodality Cardiac Imaging , Cardio Med Medical Center , Tîrgu Mureș , Romania
| | - Ioana Rodean
- Center of Advanced Research in Multimodality Cardiac Imaging , Cardio Med Medical Center , Tîrgu Mureș , Romania
| | - Diana Opincariu
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Center of Advanced Research in Multimodality Cardiac Imaging , Cardio Med Medical Center , Tîrgu Mureș , Romania
| | - Alexandra Stănescu
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Center of Advanced Research in Multimodality Cardiac Imaging , Cardio Med Medical Center , Tîrgu Mureș , Romania
| | - Erzsébet Lázár
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
| | - István Benedek
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
| | - Imre Benedek
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Center of Advanced Research in Multimodality Cardiac Imaging , Cardio Med Medical Center , Tîrgu Mureș , Romania
| | - István Benedek
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
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49
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Shi X, Zhang W, Yin L, Chilian WM, Krieger J, Zhang P. Vascular precursor cells in tissue injury repair. Transl Res 2017; 184:77-100. [PMID: 28284670 PMCID: PMC5429880 DOI: 10.1016/j.trsl.2017.02.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 12/25/2016] [Accepted: 02/14/2017] [Indexed: 12/22/2022]
Abstract
Vascular precursor cells include stem cells and progenitor cells giving rise to all mature cell types in the wall of blood vessels. When tissue injury occurs, local hypoxia and inflammation result in the generation of vasculogenic mediators which orchestrate migration of vascular precursor cells from their niche environment to the site of tissue injury. The intricate crosstalk among signaling pathways coordinates vascular precursor cell proliferation and differentiation during neovascularization. Establishment of normal blood perfusion plays an essential role in the effective repair of the injured tissue. In recent years, studies on molecular mechanisms underlying the regulation of vascular precursor cell function have achieved substantial progress, which promotes exploration of vascular precursor cell-based approaches to treat chronic wounds and ischemic diseases in vital organ systems. Verification of safety and establishment of specific guidelines for the clinical application of vascular precursor cell-based therapy remain major challenges in the field.
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Affiliation(s)
- Xin Shi
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio
| | - Weihong Zhang
- Department of Basic Medicine, School of Nursing, Zhengzhou University, Zhengzhou, Henan Province, PR China
| | - Liya Yin
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio
| | - William M Chilian
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio
| | - Jessica Krieger
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio
| | - Ping Zhang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio.
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50
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Holst KA, Said SM, Nelson TJ, Cannon BC, Dearani JA. Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and Cardiac Arrhythmias. Circ Res 2017; 120:1027-1044. [PMID: 28302746 DOI: 10.1161/circresaha.117.309186] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 02/20/2017] [Accepted: 02/20/2017] [Indexed: 01/15/2023]
Abstract
Successful outcome in the care of patients with congenital heart disease depends on a comprehensive multidisciplinary team. Surgery is offered for almost every heart defect, despite complexity. Early mortality for cardiac surgery in the neonatal period is ≈10% and beyond infancy is <5%, with 90% to 95% of patients surviving with a good quality of life into the adult years. Advances in imaging have facilitated accurate diagnosis and planning of interventions and surgical procedures. Similarly, advances in the perioperative medical management of patients, particularly with intensive care, has also contributed to improving outcomes. Arrhythmias and heart failure are the most common late complications for the majority of defects, and reoperation for valvar problems is common. Lifelong surveillance for monitoring of recurrent or residual structural heart defects, as well as periodic assessment of cardiac function and arrhythmia monitoring, is essential for all patients. The field of congenital heart surgery is poised to incorporate new innovations such as bioengineered cells and scaffolds that will iteratively move toward bioengineered patches, conduits, valves, and even whole organs.
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Affiliation(s)
- Kimberly A Holst
- From the Department of Cardiovascular Surgery (K.A.H., S.M.S., J.A.D.), Departments of Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics (T.J.N., B.C.C.), and Division of Pediatric Cardiology (T.J.N., B.C.C.), Mayo Clinic, Rochester, MN
| | - Sameh M Said
- From the Department of Cardiovascular Surgery (K.A.H., S.M.S., J.A.D.), Departments of Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics (T.J.N., B.C.C.), and Division of Pediatric Cardiology (T.J.N., B.C.C.), Mayo Clinic, Rochester, MN
| | - Timothy J Nelson
- From the Department of Cardiovascular Surgery (K.A.H., S.M.S., J.A.D.), Departments of Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics (T.J.N., B.C.C.), and Division of Pediatric Cardiology (T.J.N., B.C.C.), Mayo Clinic, Rochester, MN
| | - Bryan C Cannon
- From the Department of Cardiovascular Surgery (K.A.H., S.M.S., J.A.D.), Departments of Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics (T.J.N., B.C.C.), and Division of Pediatric Cardiology (T.J.N., B.C.C.), Mayo Clinic, Rochester, MN
| | - Joseph A Dearani
- From the Department of Cardiovascular Surgery (K.A.H., S.M.S., J.A.D.), Departments of Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics (T.J.N., B.C.C.), and Division of Pediatric Cardiology (T.J.N., B.C.C.), Mayo Clinic, Rochester, MN.
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