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Stanford BIO 230 - Cardiac Cell Therapy

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editorialn engl j med 355;12 www.nejm.org september 21, 20061274The new england journal of medicineCardiac Cell Therapy — Mixed Results from Mixed CellsAnthony Rosenzweig, M.D.Despite substantial advances in treatment, ische-mic cardiac injury and the ventricular dysfunction it can provoke remain major causes of morbidity and mortality throughout the world. The endog-enous regenerative capacity of the heart appears inadequate to repair injured myocardium, leading to the cumulative loss of cardiomyocytes over the lifetime of a patient. This may contribute to the prevalence of heart failure as a diagnosis at hospi-tal admission — particularly among the elderly.For these reasons, experiments in animals suggesting that the transfer of cells derived from bone marrow (BMC) could dramatically improve cardiac function after infarction through regener-ation of the myocardium1 or neovascularization2 generated tremendous excitement. In addition, they stimulated clinical studies suggesting that this approach is feasible, safe, and potentially ef-fective in humans.3,4 In this issue of the Journal, Schächinger et al.,5 Assmus et al.,6 and Lunde et al.7 — following authors of other recent re-ports8,9 — provide a realistic perspective on this approach while leaving room for cautious opti-mism and underscoring the need for further study (Table 1).In the largest study of cardiac cell therapy to date, Schächinger et al. report the results of the Reinfusion of Enriched Progenitor Cells and In-farct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial, a multicenter trial of the in-tracoronary infusion of BMC after successful per-cutaneous coronary intervention for acute myo-cardial infarction. At 4 months, the absolute improvement in left ventricular ejection fraction (LVEF), measured by angiography, was greater among patients treated with BMC than among those given placebo (5.5% vs. 3.0%, P = 0.01). Sub-group analysis suggested that the benefit was greatest in patients with the worst LVEF at base-line. This double-blind and fully controlled trial provides the best evidence yet for beneficial ef-fects of BMC after acute myocardial infarction. Enthusiasm is tempered somewhat by the modest size of the effect and by a recent report from the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) trial that the rela-tive improvement in LVEF after infusion of BMC at 6 months, as compared with no infusion, was no longer significant at 18 months, suggesting that the main effect was an acceleration of re-covery.9It may be challenging to achieve significant improvements in LVEF in small cohorts of pa-tients who have relatively preserved ventricular function and who are already receiving state-of-the-art therapy. Even some early trials of reperfu-sion in patients with acute myocardial infarction demonstrated either no improvement in LVEF10 or a modest improvement.11 Ultimately, the vali-dation of cardiac cell therapy will require dem-onstration of benefit with regard to clinical out-comes — as was the case with reperfusion. Studies performed to date have not been designed or powered to evaluate clinical outcomes. Never-theless, it is encouraging that the REPAIR-AMI investigators found the rate of adverse clinical events to be significantly lower at 1 year among patients receiving BMC than among those receiv-ing placebo. Given the relatively small number of events, this result will require replication in larger cohorts. However, it reinforces the mes-sage that BMC infusion is not only feasible but also safe, and it raises the possibility that clini-cal benefits may exceed the modest improvement seen in ventricular function. Data on ventricular function at 1 year are not available.Copyright © 2006 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at LANE MEDICAL LIBRARY on November 17, 2008 .editor i aln engl j med 355;12 www.nejm.org september 21, 20061275In contrast, in the smaller Autologous Stem-Cell Transplantation in Acute Myocardial Infarc-tion (ASTAMI) trial involving three noninvasive imaging methods, Lunde et al. did not find a significant improvement in LVEF at 6 months in the mononuclear BMC group, as compared with the control group. The study was powered to have an 80% chance of detecting a change of 5 percentage points in LVEF; thus, a smaller effect could have been missed. However, the change closest to achieving significance — the change in LVEF as measured by magnetic resonance imag-ing (P = 0.054) — actually favors the control group, arguing against this explanation. Technical dif-ferences in the characteristics or handling of the infused BMC might explain the different out-comes. Janssens et al. also did not detect an improvement in global ventricular function at 4 months in the BMC group as compared with the control group, although infarct size was re-duced and regional wall motion was improved in the BMC group.8 The identification of features of BMC preparations and of patients that are predictive of a favorable response should help to resolve these discrepancies and to focus future trials.The Transplantation of Progenitor Cells and Recovery of LV Function in Patients with Chronic Ischemic Heart Disease (TOPCARE-CHD) trial by Assmus et al. evaluated the effects of BMC or progenitor cells derived from circulating blood (CPC) in patients with chronic ventricular dys-function. In this randomized, crossover trial, the absolute change in LVEF was significantly great-er among patients receiving BMC than among those receiving CPC. The groups received the other type of cell in the next phase of the trial, but the result was independent of the order in which the cells were given, suggesting that the BMC effect is somewhat specific. Which quanti-Table 1. Randomized, Controlled Trials of BMC for Cardiac Disease.*Trial orInvestigator Group Setting DesignNo. of Cells Administeredin Treatment Group ResultsBOOST4,9PCI after acute myo-cardial infarctionRandomized trial30 patients received BMC; 30 received no infusionLVEF assessed by MRIApproximately 2.5×109 unfractionated BMCAt 6 mo: LVEF 6% greater in BMC group than in control groupAt 18 mo: no significant difference in LVEF between the 2 groupsJanssens et al.8PCI after acute myo-cardial infarctionRandomized, double-blind trial33 patients received BMC; 34 received placebo infusionLVEF was assessed by MRIApproximately 3×108 Ficoll-separated BMCAt 4 mo: no significant difference


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Stanford BIO 230 - Cardiac Cell Therapy

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