What Is the Future of Cell-Based Therapy for Acute Myocardial Infarction
2017; Lippincott Williams & Wilkins; Volume: 120; Issue: 2 Linguagem: Inglês
10.1161/circresaha.116.310340
ISSN1524-4571
AutoresBryon A. Tompkins, Makoto Natsumeda, Wayne Balkan, Joshua M. Hare,
Tópico(s)Cardiac Fibrosis and Remodeling
ResumoHomeCirculation ResearchVol. 120, No. 2What Is the Future of Cell-Based Therapy for Acute Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWhat Is the Future of Cell-Based Therapy for Acute Myocardial Infarction Bryon A. Tompkins, Makoto Natsumeda, Wayne Balkan and Joshua M. Hare Bryon A. TompkinsBryon A. Tompkins From The Interdisciplinary Stem Cell Institute (B.A.T., M.N., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL. , Makoto NatsumedaMakoto Natsumeda From The Interdisciplinary Stem Cell Institute (B.A.T., M.N., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL. , Wayne BalkanWayne Balkan From The Interdisciplinary Stem Cell Institute (B.A.T., M.N., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL. and Joshua M. HareJoshua M. Hare From The Interdisciplinary Stem Cell Institute (B.A.T., M.N., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL. Originally published20 Jan 2017https://doi.org/10.1161/CIRCRESAHA.116.310340Circulation Research. 2017;120:252–255Although therapy for cardiovascular disease has led to consistent annual declines in mortality, myocardial infarction still represents an irreversible injury to the myocardium leading to the substrate for heart failure and sudden cardiac death.1 Indeed, the extent of scar resulting from myocardial infarction is an important predictor of mortality.2 Even with timely coronary intervention, infarct size is a significant problem likely exacerbated by ischemia/reperfusion injury.3 Supported by preclinical studies, cell-based therapy has emerged as an attractive treatment for minimizing/reversing the effects of myocardial infarction in patients.4,5Article, see p 324Stem Cell Therapy After Acute Myocardial InfarctionStem cell (SC) mobilization from the bone marrow to acutely injured tissue significantly enhancing wound healing was first observed in a mouse skin wound model.6 Large animal models demonstrated that SC therapy produces significant improvements in acute myocardial infarction (AMI),7,8 leading to clinical trials for SC therapy in patients with AMI and heart failure. Bone marrow–derived SC therapy for AMI is safe. Unfortunately, the hypoxic post-AMI environment is hostile to cardiomyocytes and migrating or introduced SCs, and this proapoptotic milieu may be the limiting factor clinically. However, a recent meta-analysis reported that patients with ischemic cardiomyopathy who received bone marrow–derived SCs exhibited improved left ventricular ejection fraction (LVEF) and reduced infarct size and remodeling (Table).9Table 1. Randomized Control Trials Evaluating CD34+ Bone Marrow–Derived Stem Cell Therapy for Acute Myocardial InfarctionSourceSample SizeCell TypeNo. of CellsRoute of InjectionResultsAMITendera et al16200CD34+NAICNo significant improvementQuyyumi et al1031CD34+5–15×106ICDose-dependent perfusion improvementQuyyumi et al11161CD34+8–43×106ICNo significant improvementICMPatel et al1720CD34+NRIMImproved EFRefractory anginaLosordo et al1824Peripheral CD34++G-CSFNRIMNo significant improvementLosordo et al12167Peripheral CD34++G-CSF1–5×105/kgIMImproved angina and exercise tolerance in low-dose groupHenry et al19112Peripheral CD34++G-CSF1–100×105/kgIMEarly termination of study, Reduced angina frequencyNIDCMVrtovec et al20110Peripheral CD34++G-CSF1.13±0.26×108ICImproved EF, 6MWD, Decreased NT-pro-BNP, Lower morality for stem cell treatmentVrtovec et al2145Peripheral CD34++G-CSF1.27–2.16×108IMNo response in diabetics, Increased EF and decreased NT-pro-BNP in nondiabetics6MWD indicates 6-minute walk distance; AMI, acute myocardial infarction; EF, ejection fraction; G-CSF, granulocyte colony-stimulating factor; IC, intracoronary; ICM, ischemic cardiomyopathy; IM, intramuscular; NA, not available; NT-pro-BNP, N-terminal pro B-type natriuretic peptide; NIDCM, nonischemic dilated cardiomyopathy; NR, not reported; and RCT, randomized controlled trial.CD34+ Cells in Clinical SettingsEndothelial progenitor cells (EPCs) are bone marrow–derived mononuclear cells expressing both hematopoietic SC and endothelial cell markers. The prototypical EPC, selected on the basis of CD34 expression (CD34+), promotes neovascularization and regeneration.13 The neovascular effects were demonstrated in a Phase I/II trial, where CD34+ EPCs administered to patients with refractory angina pectoris, decreased the frequency of events, and increased exercise tolerance as compared to placebo-treated patients.12 Furthermore, CD34+ EPCs mobilize from the bone marrow post-AMI and enter the peripheral circulation; this degree of mobilization is directly correlated with improved outcomes.11 However, large ischemic insults and adverse remodeling remain an extensive burden, even for efficient mobilizers. The extensive preclinical data supporting ischemic tissue repair by CD34+ cells prompted Quyyumi et al10 to hypothesize that the effects of CD34+ cells were dependent on quantity and mobility after an ST-segment–elevation myocardial infarction (STEMI). They reported a positive dose-dependent improvement in cell mobility, cardiac perfusion, and scar size reduction after intracoronary infusion of CD34+ EPCs in subjects post-STEMI.10 Those encouraging results inspired the current phase II clinical trial (PreSERVE-AMI [a Randomized, Double-Blind, Placebo-Controlled Clinical Trial]) to further elucidate the safety and bioactivity of autologous CD34+ marrow cells in patients post-STEMI.11PreSERVE-AMI TrialPreSERVE-AMI trial of intracoronary administration of autologous CD34+ cells in patients with left ventricular dysfunction post-STEMI was novel and appropriately powered.11 Subjects with successful stenting status post-STEMI were randomized to receive autologous CD34+ cells (n=78) or placebo (n=81) through intracoronary infusion after bone marrow harvest.The primary safety end points were adverse events, serious adverse events, and major adverse cardiac "events." There were no differences between placebo and treated subjects in these categories. No differences were observed in survival or incidence of major adverse cardiac "event" in the treated group, regardless of dose (P≥0.05). Adverse events and serious adverse events incidences were similar between control and treated subjects at 12-month follow-up. The primary efficacy end point was improvement in resting myocardial perfusion over 6 months, which was not met, as there were no differences between groups. Furthermore, no changes in LVEF or scar size at 6 months were observed between groups. Despite primary end points not being met, post hoc analyses were significant for reductions in infarct size and changes in LVEF after adjusting for total ischemia time. Additional testing with a larger patient population with allogeneic CD34+ cells may clarify the positive effects noted on tertiary analyses.Impact of Negative Trials in Regenerative MedicineAlthough positive trials are enticing and provide a direction for the field of regenerative medicine, negative studies can be just as impactful. Negative studies move the field forward by avoiding repetition of ineffectual trials. Negative and positive trials save the field time and money, which in the end promotes higher quality study designs and conclusions.Although the PreSERVE-AMI trial primary end point was not met, this failure does not negate the potential of CD34+ SCs to be an effective candidate for heart regeneration. Indeed, there are other instances in which SC trials face similar dilemmas in illustrating cell efficacy. Understanding these issues is a key to interpreting the results of this study.Factors to Consider for Interpretation of the PreSERVE-AMI Trial ResultsCell Dose and Cell SourceIn the study, post hoc analysis favors a dose-dependent response for improved LVEF and decreased scar. Although general pharmacokinetics display a dose escalation response to a drug, such a response is not consistent for cell therapy. In fact, there are clinical trials that display higher response to lower cell doses,14 possibly due to the detrimental effects of cells (pathogenic angiogenesis and obstruction). These studies illustrate that the ideal dose for SCs has yet to be elucidated.The patient population demonstrated a wide range of harvested cells ( 60×106). Furthermore, autologous SCs may be encumbered with baseline comorbidities (diabetes mellitus and age-related deficiencies), and thereby are likely to possess lower potency as compared to allogeneic cells. The important advantage of allogeneic cells is highlighted by the fact that 16 (8%) patients from this study did not meet release criteria after bone marrow aspiration. Allogeneic cells can be produced in a quality-controlled and cost-effective manner and represent an off-the shelf option.7Timing of TreatmentThe time of cell infusion after stent placement was variable in this study, with a mean of 9.4±1.43 and 9.3±1.23 days for controls and treated patients, respectively. A meta-analysis of clinical trials utilizing adult bone marrow for the treatment of myocardial infarction showed contradictory results in LVEF improvement secondary to the timing of treatment, where later administration of cells proved more efficacious compared with early administration (<48 hours).9 Suppression of migration and proliferation in the SC niche is seen at times of excess inflammation (AMI). Cell therapy in the acute phase focuses on their anti-inflammatory and myocardial salvage traits; whereas chronic treatment focuses primarily on regeneration capacities and reduction of adverse remodeling. The ideal timing post-transplantation for maximizing these effects has yet to be determined.Route of AdministrationThe optimal route of cell administration remains an area of uncertainty. Several methods are under investigation: transcatheter endocardial, open epicardial, intracoronary, intravenous and retrograde intracoronary sinus. Despite these methods, the effects of SC treatment in AMI are limited. Without extracellular support (engineered tissue), evidence suggests that intramyocardial injection attains the highest number of retained cells, despite their relatively low engraftment rate after an AMI.15 As performed in this study, intracoronary injection is preferred after an AMI because it avoids direct contact with the irritable myocardium, thereby minimizing the risk of arrhythmia or perforation. The inherent disadvantage of intracoronary delivery is possible for further occlusion of previously occluded arteries.Trial SizeAlthough the study was properly designed to power the primary efficacy end point, it is difficult to detect between group differences with limited sample sizes of Phase II trials. Furthermore, exploratory subgroup analyses, in this case, a dose-dependent response of CD34+ cells, are likely underpowered and hypothesis generating. Utilizing LVEF as an end point may have also obscured between group differences. In the AMI setting, LVEF can be misleading, as the hypokinetic wall motion is a result of a heterogeneous mix of infarcted and stunned myocardium. The cell-treated group had a longer total ischemic time, which implies they had larger infarcts and potentially a harsher environment further depriving the tissue of potential endogenous or exogenous cell repair. These complex confounding factors cannot be simply corrected by multiple regression models. Scar size as measured by magnetic resonance imaging is a better end point; as mentioned above, the extent of the scar is an important predictor of mortality.2Nonetheless, the number of larger phase II and phase III cell-based therapy trials for the treatment of heart disease trials is increasing, from 0 in 2014 and 2 in 2015 to 4 (including PreSERVE-AMI) in 2016. The Phase II CONCERT-HF (Combination of Mesenchymal and C-kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure; NCT02501811), Phase III DREAM HF-1 (Efficacy and Safety of Allogeneic Mesenchymal Precursor Cells [Rexlemestrocel-L] for the Treatment of Heart Failure; NCT02032004), and BAMI (The Effect of Intracoronary Reinfusion of Bone Marrow-Derived Mononuclear Cells [BM-MNC] on All Cause Mortality in Acute Myocardial Infarction; NCT01569178) trials are multicenter randomized trials currently enrolling an estimated 144, 600, and 3000 patients, respectively.ConclusionsDespite the failure to meet its end points, the PreSERVE-AMI trial ultimately represents an important step in the field of cardiac regeneration, by elucidating issues faced in the design of AMI trials. The hostile myocardial environment after AMI is a difficult hurdle to overcome for all progenitor cell types. This particular trial may have been affected by several unforeseen variables, including the use of autologous cells, which while immunotolerant, exhibit a decline in function with age and associated comorbidities (Online Figure). Autologous cell harvesting is also confounded by variable dosing, which may yield inconsistent results. Furthermore, the delay associated with the patients getting to the hospital for stenting means that time is an inherent ever-changing variable in an acute setting.Despite the aforementioned variables, it is important to note that the use of CD34+ cells provide improvements in subjects when coronary oxygen demand exceeds its supply.12 More importantly, they proved to be safe in the current trial when compared with placebo. The safety of CD34+ cells will likely inspire further studies utilizing EPCs. The PreSERVE-AMI trial provides important insights about the dosing of autologous CD34+ cells, time-to-treatment in an AMI setting, and safety. Moreover, the positive post hoc analyses from this trial will undoubtedly lead to important new hypotheses to be tested in future trials.DisclosuresDr Hare discloses a relationship with Longeveron LLC (consulting) and Vestion Inc. (equity, board membership, and consulting). He is funded by the National Institutes of Health grants R01HL084275, R01HL107110, UM1HL113460, and R01HL110737 and grants from the Starr and Soffer Family Foundations. The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA.116.310340/-/DC1.Correspondence to Joshua M. Hare, MD, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Biomedical Research Bldg, 1501 NW 10th Ave, Room 908, PO Box 016960 (R125), Miami, FL 33101. 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From experiment to clinic, Kardiologiia, 10.18087/cardio.2668, 59:8S, (15-23) Patel B, Manne R, Patel D, Gorityala S, Palaniappan A and Kurakula M (2021) Chitosan as Functional Biomaterial for Designing Delivery Systems in Cardiac Therapies, Gels, 10.3390/gels7040253, 7:4, (253) January 20, 2017Vol 120, Issue 2 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.116.310340PMID: 28104761 Originally publishedJanuary 20, 2017 Keywordsstem cellsmyocardial infarctionEditorialsclinical trialendothelial progenitor cellsdeath, sudden, cardiacPDF download Advertisement SubjectsAngiogenesisCell TherapyClinical StudiesContractile FunctionFibrosisHeart FailureIschemiaMyocardial InfarctionMyocardial RegenerationStem CellsTranslational Studies
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