Despite substantial advances in treatment, ischemic cardiacinjury and the ventricular dysfunction it can provoke remainmajor causes of morbidity and mortality throughout the world.The endogenous regenerative capacity of the heart appears inadequateto repair injured myocardium, leading to the cumulative lossof cardiomyocytes over the lifetime of a patient. This may contributeto the prevalence of heart failure as a diagnosis at hospitaladmission — particularly among the elderly.
For these reasons, experiments in animals suggesting that thetransfer of cells derived from bone marrow (BMC) could dramaticallyimprove cardiac function after infarction through regenerationof the myocardium1 or neovascularization2 generated tremendousexcitement. In addition, they stimulated clinical studies suggestingthat this approach is feasible, safe, and potentially effectivein humans.3,4 In this issue of the Journal, Schächingeret al.,5 Assmus et al.,6 and Lunde et al.7 — followingauthors of other recent reports8,9 — provide a realisticperspective on this approach while leaving room for cautiousoptimism and underscoring the need for further study (Table 1).
Table 1. Randomized, Controlled Trials of BMC for Cardiac Disease.
In the largest study of cardiac cell therapy to date, Schächingeret al. report the results of the Reinfusion of Enriched ProgenitorCells and Infarct Remodeling in Acute Myocardial Infarction(REPAIR-AMI) trial, a multicenter trial of the intracoronaryinfusion of BMC after successful percutaneous coronary interventionfor acute myocardial infarction. At 4 months, the absolute improvementin left ventricular ejection fraction (LVEF), measured by angiography,was greater among patients treated with BMC than among thosegiven placebo (5.5% vs. 3.0%, P=0.01). Subgroup analysis suggestedthat the benefit was greatest in patients with the worst LVEFat baseline. This double-blind and fully controlled trial providesthe best evidence yet for beneficial effects of BMC after acutemyocardial infarction. Enthusiasm is tempered somewhat by themodest size of the effect and by a recent report from the BoneMarrow Transfer to Enhance ST-Elevation Infarct Regeneration(BOOST) trial that the relative improvement in LVEF after infusionof BMC at 6 months, as compared with no infusion, was no longersignificant at 18 months, suggesting that the main effect wasan acceleration of recovery.9
It may be challenging to achieve significant improvements inLVEF in small cohorts of patients who have relatively preservedventricular function and who are already receiving state-of-the-arttherapy. Even some early trials of reperfusion in patients withacute myocardial infarction demonstrated either no improvementin LVEF10 or a modest improvement.11 Ultimately, the validationof cardiac cell therapy will require demonstration of benefitwith regard to clinical outcomes — as was the case withreperfusion. Studies performed to date have not been designedor powered to evaluate clinical outcomes. Nevertheless, it isencouraging that the REPAIR-AMI investigators found the rateof adverse clinical events to be significantly lower at 1 yearamong patients receiving BMC than among those receiving placebo.Given the relatively small number of events, this result willrequire replication in larger cohorts. However, it reinforcesthe message that BMC infusion is not only feasible but alsosafe, and it raises the possibility that clinical benefits mayexceed the modest improvement seen in ventricular function.Data on ventricular function at 1 year are not available.
In contrast, in the smaller Autologous Stem-Cell Transplantationin Acute Myocardial Infarction (ASTAMI) trial involving threenoninvasive imaging methods, Lunde et al. did not find a significantimprovement in LVEF at 6 months in the mononuclear BMC group,as compared with the control group. The study was powered tohave an 80% chance of detecting a change of 5 percentage pointsin LVEF; thus, a smaller effect could have been missed. However,the change closest to achieving significance — the changein LVEF as measured by magnetic resonance imaging (P=0.054)— actually favors the control group, arguing against thisexplanation. Technical differences in the characteristics orhandling of the infused BMC might explain the different outcomes.Janssens et al. also did not detect an improvement in globalventricular function at 4 months in the BMC group as comparedwith the control group, although infarct size was reduced andregional wall motion was improved in the BMC group.8 The identificationof features of BMC preparations and of patients that are predictiveof a favorable response should help to resolve these discrepanciesand to focus future trials.
The Transplantation of Progenitor Cells and Recovery of LV Functionin Patients with Chronic Ischemic Heart Disease (TOPCARE-CHD)trial by Assmus et al. evaluated the effects of BMC or progenitorcells derived from circulating blood (CPC) in patients withchronic ventricular dysfunction. In this randomized, crossovertrial, the absolute change in LVEF was significantly greateramong patients receiving BMC than among those receiving CPC.The groups received the other type of cell in the next phaseof the trial, but the result was independent of the order inwhich the cells were given, suggesting that the BMC effect issomewhat specific. Which quantitative or qualitative differencesin the cell populations account for their different effectsis currently unknown. Although the benefit observed after BMCinfusion was modest (an increase in LVEF by 2.9 percentage points),it is remarkable that any benefit was seen in these patients,who were studied on average more than 6 years after infarctionand who were already receiving optimal medical care. The TOPCARE-CHDtrial suggests that BMC can have effects beyond simple accelerationof healing after infarction. Whether repeated infusions wouldyield additive benefits and whether these benefits would persistwill be important questions for future trials.
Although the prospect of regeneration of cardiac tissue providedan initial stimulus for cell-based therapies,1 subsequent workin animals has questioned the ability of BMC to effectivelygenerate cardiomyocytes,12,13 and clinical studies have suggestedthat only 1.3 to 2.6% of infused BMC are retained in the heart.14Functional benefits may also be mediated through paracrine secretionof growth factors or cytokines, which could indirectly promotesurvival of cardiomyocytes, mobilization of endogenous progenitorcells, or neovascularization.
Do these distinctions matter? As pointed out by others,15 patientsbenefited from many established therapies — includingaspirin — before we understood the underlying mechanisms.There is no doubt that the ultimate success or failure of celltherapy will rest on its ability to show clinical efficacy ratherthan on the imputed mechanism. However, the heterogeneous cellpopulations used make BMC infusion fundamentally different frommost medical treatments. This complexity may help explain whyapparently similar protocols can yield disparate results.5,7Identifying which — if any — of the cellular constituentsis necessary for beneficial effects, and whether these effectsare mediated directly by the transplanted cells or indirectlythrough involvement of other cells, would enable targeted deliveryof essential components and is likely to be a critical stepin the full realization of the potential of this therapeuticapproach. Even aspirin might not be as effective if it werestill being delivered as willow bark.
As articulated in the consensus statement of the task forceof the European Society of Cardiology, the clinical need, feasibility,and safety of the treatment,15 as well as the need to resolvediscrepant results, mandate additional clinical trials. However,as illustrated by recent randomized trials,4,5,6,7,8,9 we shouldproceed in a manner that maximizes both the information gainedand the safety of patients. Patients should be treated withcells only as part of randomized, controlled trials and onlyafter they understand that neither the efficacy nor the long-termrisks of this approach are established. Future trials shouldbe powered to examine clinical end points and patients shouldbe followed over the long term and for both beneficial and adverseeffects. Simultaneously, we must continue to support basic andtranslational research that can help guide clinical investigation.
The enrollment of patients with a poor prognosis (i.e., largeinfarcts, poor left ventricular function) makes sense. Theyhave the greatest need for therapeutic approaches and thus havethe most favorable risk–benefit ratio. Demonstration ofincremental benefit, as compared with conventional therapy,is easier in these populations, and subgroup analyses suggestthat they are the most likely to benefit.5 The enrollment ofpatients with heart failure who use left ventricular assistdevices as a bridge to transplantation would also provide aunique opportunity to examine cellular and molecular mechanismsthrough analyses of cardiac tissue acquired both before cellinfusion (at implantation) and after (at transplantation).
Recent randomized studies of cell therapy for heart disease4,5,6,7,8,9represent a milestone in this rapidly developing field whileserving as a cogent reminder that many important clinical andfundamental questions have yet to be addressed. We should guardagainst both premature declarations of victory and prematureabandonment of a promising therapeutic strategy. The ultimatesuccess of this strategy is likely to depend on continued andeffective coordination of rigorous basic and clinical investigations.
No potential conflict of interest relevant to this article wasreported.
Source Information
From the Cardiovascular Division, Beth Israel Deaconess Medical Center, and the Harvard Stem Cell Institute — both in Boston.
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