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Stem Cells in the Treatmentof Heart Disease

Stefan Janssens

Division of Cardiology and Vesalius Research Center, VIB, Gasthuisberg University Hospital, University of Leuven, B-3000 Leuven, Belgium;email: [email protected]

Annu. Rev. Med. 2010. 61:287–300

The Annual Review of Medicine is online atmed.annualreviews.org

This article’s doi:10.1146/annurev.med.051508.215152

Copyright c 2010 by Annual Reviews. All rights reserved

0066-4219/10/0218-0287$20.00

Key Wordscardiac stem cells, neovascularization, cardiomyogenesis, regenerativemedicine (myocardial repair), transdifferentiation

Abstract

Progenitor cells residing in bone marrow, adipose tissue, and skeleta

muscle or circulating in the blood are capable of improving myocardiafunction in preclinical models. In contrast, early clinical studies usin

bone marrow cells have shown mixed results and reflect our incompletunderstanding of underlying mechanisms. Recent identification of var

ious cardiac precursor cells has suggested an endogenous reservoir fo

cell-based repair. However, confronted with massive cardiac cell lossinventive strategies and enabling technologies are required to mobilize or deliver functionally competent progenitor cells to sites of injury

or to effectively stimulate endogenous repair. We review our presenknowledge in this promising and rapidly evolving development in car

diovascular medicine and highlight obstacles as well as opportunities.

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AMI: acutemyocardial infarction

INTRODUCTION

Theuseofhumanstemcellsisbecomingpivotalfor the development of new therapeutic strate-

gies for many organ-specific diseases, which arecharacterized by abrupt or progressive loss of

function and for which existing therapies areinadequate. Many significant human diseases

with limited options for a definitive cure arecharacterized by the loss or malfunction of spe-cific cell types in the body. This is especially

true for diseases associated with aging, includ-ing Alzheimer’s and Parkinson’s disease, type II

diabetes, heart failure, osteoarthritis, and au-toimmune and hematopoietic disorders. The

potential use of stem cells is also attractive formedical conditions resulting from acute dam-

age to cells, e.g., infarction, trauma, and burns.In cardiology, the emerging field of treat-

ment called regenerative medicine or cell ther-apy has focused for many years on the develop-

ment of methods to either induce replacementof damaged cells with stem cells to replenish

the deficit or (at least) use stem cells to mediate

functional repair via paracrine, trophic effects(1). However, there is currently a growing un-

derstanding that in the course of evolution, theheart, like many adult solid organs, harbors a

population of endogenous progenitor cells, po-tentially capable of regenerating the parenchy-

mal cells of the tissue when properly activated(2). Importantly, for any cell therapy to be suc-

cessful, equal efforts are required (a) to developbiomaterials, (b) to study signaling cues that will

facilitate sustained cross-talk between cells andtheir specific microenvironment, and (c ) to de-

velop enabling technologies for successful clin-

ical applications.

THE UNMET CLINICAL NEEDIN HEART DISEASE

Despite state-of-the-art interventional andmedical therapy for myocardial infarction (MI)

andheart failure, clinical outcome remains poorin post-MI patients with reduced left ventricu-

lar (LV) function. The one-year mortality rateis 13%, and the incidence of the combined

endpoint of death, recurrent infarction, or

hospitalization for heart failure is 26%

These sobering results are based on caremonitoring of patients included in randomiz

controlled trials, where implantable automa

defibrillators, resynchronization devices, apharmacological treatment with beta blo

ers, angiotensin converting enzyme (ACinhibitors, or angiotensin receptor block

and spironolactone are optimally implement Most likely, clinical outcome in daily pract

outside the setting of randomized trials is evmore dismal.

Advanced heart disease results from abrupt or progressive loss of contractile m

ocytes, which in western societies is most ten caused by an acute or chronic reduction

coronary blood flow. Therefore, soon after

firstpromisingresultsfrommixedmononuclebone marrow cells or selected subpopulatio

in small-animal models of cardiac ischemic jury (4), translational studies in patients w

heart disease were initiated. In addition to thencouraging preclinical studies, the observ

chimerism in the human heart (5, 6) furthstimulated clinical researchers to explore aut

ogous mononuclear bone marrow cell transstrategies in ischemic heart disease.

EARLY CLINICAL EXPERIENCE

Initial trials of autologous bone marrow cedocumented safety and feasibility both in

tients with acute myocardial infarction (AMand in those with chronic ischemia and

ported a modest, beneficial effect on recupation of LV function (7, 8, 9). By virtue

their exploratory design andemphasis on safethese studies were not randomized, and th

lacked a control population undergoing bomarrow aspiration followed by intracoron

infusion of vehicle or infusion of an irre

vant cell type. Again, the encouraging resuof this first clinical experience have accel

ated subsequent introduction of larger randoized controlled trials. By 2006, four indepe

dent randomizedstudiesusing autologous bomarrow–derived progenitor cells had be

reported in AMI patients ( Table 1). T

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PCI: percutaneouscoronary intervention

LVEF: left ventricularejection fraction

common objective was to investigate whether

or not intracoronary infusion of autologous

bone marrow cells conferred incremental ben-efit beyond state-of-the-art reperfusion ther-

apy and postinfarction pharmacological ther-apy. Inherent to the early stage of development,

the studies differed in design, patient numbers,cell preparation methods, timing of cell trans-

fer after percutaneous coronary intervention(PCI), and imaging modalities.

The BOOST study was the first random-ized controlled study to report a significant

improvement in global LV function recovery after six months, expressed as a 6% incremen-

tal increase in LV ejection fraction (LVEF)

evaluated using magnetic resonance imaging(MRI) in patients who had received intracoro-

nary cell infusion after a median of 4.8 daysfollowing index PCI (10). The authors at-

tributed the transient cell-mediated benefit toenhanced regional contraction in the infarct

border zones. The study was, however, notplacebo-controlled; the control group did not

undergo bone marrow aspiration, nor a sec-ond coronary intervention with repeated stop

flow conditions. Moreover, functional recovery at six months was confined to the cell trans-

fer group and—somewhat unexpectedly—not

observed in control patients. Of note, one andfive years later, global LV function in patients

who had received cell transfer was the same asthat in patients who had received state-of-the-

art treatment (11). The relatively small numberof patients, the absence of a control group un-

dergoing repeat coronary infusions, andthe rel-atively mild reduction in LV function after the

index infarction need to be considered when in-terpreting these results.

Two subsequent double-blind randomizedplacebo-controlled studies, conducted at the

universities of Leuven and Frankfurt (12, 13)in a similar AMI population, addressed some

of these confounding variables associated with

bone marrow aspiration and a second catheter-ization. The increase in global LV function

recovery in patients randomized to cell transferabove and beyond the increase in control

patients receiving state-of-the-art therapy

ranged from 1.2% to 2.5% supplemen

increase in LVEF. In addition, patients ceiving cell transfer had a significantly grea

reduction in infarct size for a similar arearisk, as assessed using repeated MRI, an

greater recovery of regional systolic functi

Importantly, these beneficial effects wsustained at one-year follow-up (14, 15).

Whereas bone marrow cell isolation, preration, and characterization protocols w

similar in the Leuven and Frankfurt stuies, this was not the case for the Norw

gian ASTAMI study ( Table 1). The latter walso not placebo-controlled and concluded

100 post-AMI patients that mononuclear bomarrow–derived cell transfer did not incre

global LV function recovery or reduce infasize at six months as evaluated by MRI (1

Although the reasons for these divergent fin

ings are still unclear, significant differencestrial design, isolation, and characterization

the stem cell preparation need to be conside(17). Indeed, a head-to-head comparison of

cell infusate in the Repair-AMI and the A TAMI studies revealed important difference

bone marrow cell functionality, depending laboratory procedures (17, 18).

The Frankfurt Repair-AMI trial was a mticenter study involving 18 different sites w

a central core laboratory for bone marrow cprocessing (13). Cell transfer was therefore n

always performed on the same day after the

dex PCI but ranged from three to seven da whereas patients in the Leuven study receiv

placebo or bone marrow cell infusion at 2after the first intervention. Interestingly, wh

data were stratified by time of cell transfer aby severity of LV dysfunction at baseline,

benefit was predominantly observed in patiereceiving delayed cell transfer and in patie

with a baseline LVEF below the median vaof 49%. The latter observation is in agr

ment with our own findings of significanenhanced metabolic recovery in AMI patie

with large infarctions receiving cell transfer.

though the studieswere not powered to primily evaluate the effects of MI size, there wa

significant interaction between infarct sever

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and subsequent benefit from cell transfer. The

best results were observed in patients suffer-

ing from large infarctions with more depressedglobal ejection fractions (incremental increase

in LVEF of 5%–6%). Because of the smallernumber of patients, we failed to detect a signif-

icant difference in global functional recovery but did observe significantly greater improve-

ment in regional contractile function in the in-farct core and border zones, using both MRI

and tissue Doppler analysis (19). Interestingly,strain rate and MRI-based wall-motion analysis

in all infarcted segments with a >50% trans-mural extent of myocardial necrosis confirmed

a significant benefit up to one year after cell

transfer (15). We cannot exclude that by givingthe cells sooner after the index infarction, we

may have missed a more favorable time pointfor cell transfer, especially in view of the high

incidence of microvascular obstruction that isobserved in the early phase of reperfusion and

that may limit homing, engraftment, and survival of infused cells.

As highlighted in editorial comments thataccompanied these pioneering studies, the best

focus for future cell therapy efforts, therefore, would be in patients with severe ischemic car-

diomyopathy (anterior infarctions and signif-

icant LV dysfunction) (20, 21). This focus isconsistent with the unmet clinical need in this

expanding population and represents the primetarget in second-generation clinical trials.

A major point of discussion, however, re-mains whether or not the absolute incremen-

tal increase in LVEF of 1.2% to 2.5% or thefavorable effect on coronary flow reserve (22),

infarct remodeling, and recovery of regionalLV function translate into a meaningful clini-

cal benefit at longer-term follow-up and justify the additional costs of cell-based interventions.

Although only adequately powered prospectiveclinical trials can provide the answers, the ques-

tion echoes earlier discussions on the benefit of

changes in LVEF of similar magnitudeobtained with beta blockers and ACE inhibitors in heart

failure (23).

STEMI: ST-segmeelevation myocardiainfarction

SECOND-GENERATION RANDOMIZED CLINICAL TRIALS

The common objective of the first four land-

mark trials was to investigate incremental ben-efit of autologous bone marrow cell transfer

on global LV function recovery beyond state-of-the-art therapy for ST-segment elevation

myocardial infarction (STEMI). In contrast,the most recent randomized studies also ad-dressed (a) cell transfer in AMI patients re-

ceiving thrombolysis (24), (b) the added valueof CD34+CxCR4-selected hematopoietic stem

cells(25),(c )selectionofalternativecontrolcellsandsurrogate primary end points (26), (d )more

restrictive inclusion criteria, and (e) differenttiming (early or late) and cell delivery routes

(combined intramyocardial and intracoronary injection) (27) ( Table 1).

The FINCELL study is a multicenter ran-domized placebo-controlled trial including 80

patients with STEMI treatedwith thrombolysis

followed by PCI and stenting 2–6 days after theacute coronary event (24). Patients were ran-

domly assigned to receive intracoronary mixedbone marrow cells or placebo solution infused

into the infarct-related coronary artery imme-diately after stenting. This study confirmed that

intracoronary administration of bone marrowcells is safe in STEMI patients treated with

thrombolytic therapy followed by PCI and isassociated with an incremental improvement of

global LVEF measured by LV angiography (7.1 vs 1.2%, p = 0.05) and 2D echocardiography

(4.0 vs −1.4%, p = 0.03). In this study, how-

ever, the biological significance of the observedchanges in LVEF remains unclear as baseline

values indicated virtually preserved global LV function before cell infusion.

The Polish REGENT trial, in contrast, wasa randomized but not placebo-controlled mul-

ticenter trial including 200 AMI patients withbaseline LVEF ≤40% undergoing primary

PCI (25). Patients were randomly assigned toselected CD34+CXCR4+ bone marrow cell

infusion, unselected mononuclear cell infusion,or control (ratio 2:2:1). The median time

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8/3/2019 Annu. Rev. Med. 2010, 61, 287–300


between PCI and cell infusion was seven days

(range 3–12 days), and the median number

of infused CD34+CXCR4+ cells was 1.9 ×

106 in the selected cell group versus 1.78 ×

106 in the unselected mononuclear cell group. At six months, the increase in LVEF observed in

the cell treatment groups was not significantly different from the increase in control patients.

Of note, and consistent with the Repair-AMIstudy, a post hoc analysis in patients whose

initial LVEF was below the median value of 37% indicated a more pronounced (∼5%)

increase in global function recovery followingcell transfer. Importantly, the design of the

study did not allow evaluation of potential

benefits of bone marrow cell enrichmentstrategies, because the number of injected

CD34+CxCR4+ cells did not differ betweenthe two cell arms of this study. Moreover,

the primary endpoint analysis using repeated MRI was performed in only ∼60% of included

patients (117 of 200 patients), which reducedthe power to detect cell-mediated differences

in global function recovery. The HEBE trial is also a multicenter

randomized but not placebo-controlled trialincluding 200 STEMI patients undergoing

primary PCI (26). Patients in eight medical

centers in the Netherlands were randomized tointracoronary bone marrow–derived mononu-

clear cell infusion, mononuclear peripheralblood cell infusion, or primary PCI alone

(ratio 1:1:1). Cell aspiration and intracoronary infusion were performed 3–8 days after primary

PCI. Despite promising results in the pilottrial (28, 29), intracoronary infusion of bone

marrow–derived cells failed to improve re-gional myocardial function recovery (primary

endpoint) and global LV function and LV remodeling (secondary endpoints) in first-time

large-STEMI patients undergoing PCI. The

reasons for these negative findings are unclear,and although we are still awaiting data on

infarct remodeling in this carefully executedstudy with serial MRI analysis in 189 of 200 pa-

tients, we can only speculate that the functionalcapacity of cells and/or their ability to home,

engraft, and survive in ischemic myocardium

is insufficient to mediate detectable biologi

effects. MYSTAR was a randomized multicen

open-label trial including 60 patients w

LVEF <45% after AMI (27). Bone marroderived mononuclear cells were delivered

combined intramyocardial injection and intcoronary infusion at either 3–6 weeks (ear

or 3−4 months (late) after AMI. This studemonstrated feasibility, safety, and efficacy

combined delivery of a large number of atologous bone marrow–derived mononucl

cells in patients after AMI with severely dpressed LV function. Early and late treatm

both resulted in an improvement in infarct sand global systolic function recovery, and

benefit was sustained at 9–12 months. Ho

ever, in the absence of a randomized contgroup, the biological significance is uncl

Prospective randomized controlled trials wbe required, including the ongoing multice

ter SWISS-AMI trial in 150 STEMI patiencomparing early, late, or no cell transfer af

PCI. Taken together, these recently reported

als, some of which are still ongoing, confithat treatment with bone marrow–derived c

is safe and feasible in AMI patients and in ptients with ischemic cardiomyopathy. Howev

the use of selected bone marrow stem cedid not show an additional benefit over mix

mononuclear bone marrow cells or state-

the-art reperfusion and pharmacological thapy, despite selection of patients with mo

pronounced LV dysfunction (REGENT aHEBEstudies).Itisdifficulttoreconcilethea

parently discrepant results in the above stud with the earlier-stated best window of opp

tunity for cell therapy, but limitations in studesign or conduct may account for some of

variability. Moreover, accumulating data poto reduced functionality of bone marrow c

in patients with severe and advanced ischemheart disease (30), and these recent obser

tions may well have affected the outcome

REGENT and HEBE, which specifically tgeted patients with large MIs and likely mo

advanced atherosclerotic disease.

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UNRESOLVED QUESTIONS ON MECHANISMS OF ACTION:CARDIOPROTECTION VERSUSCARDIOMYOGENESIS?

Until recently, the major premise in preclini-

cal tests was that circulating or bone marrow–derived progenitor cells could potentially re-

populate the injured myocardium and undergomilieu-dependent differentiation to form vas-cular cells and cells with a cardiomyocyte-like

phenotype (31). Improvements in cardiac func-tion following adult mononuclear stem or pro-

genitor cell injection in preclinical models wereinitially ascribed to cardiac and vascular regen-

eration via such autocrine transdifferentiationmechanisms (4). However, theplasticity of adult

stem cells remains debatable, with more recentdata questioning the validity of the cardiomyo-

genic potential of these cells (32). Based on ob-servations in genetically engineered mice al-

lowing unambiguous tracking of both donor

lineage and cardiac phenotype with a singlemolecular marker, the prevailing view among

stem cell scientists and developmental biolo-gists is that cardiac transdifferentiation after

direct injection of hematopoietic stem cells is very limited (33, 34). Moreover, limited reten-

tion, engraftment, and survival of transferredcells in clinical and preclinical studies alike fa-

vor paracrine effects via secreted trophic factorsthat may stimulate nutrient blood supply, re-

duce apoptotic cardiomyocyte death,or activateresidual cardiac resident stem cells (Figure 1)

(35, 36). Differentiation into cardiomyocyteshas only been clearly demonstrated in embry-

onic stem cells (37) and cardiac resident stem

cells (38, 39). More recent preclinical stud-ies in mice have likewise suggested that in-

tracardiac injection of in vitro expanded adultmesenchymal stem cells exerted a beneficial

effect on the infarcted myocardium by enhanc-ing neoangiogenesis rather than via true car-

diac regeneration (40). Thus, despite initialreports of cardiomyogenic potential, many sub-

sequent studies in mice, rats, and pigs have con-cludedthatbonemarrow–derived or circulating

CSC: cardiac stemcell

progenitor cells may improve cardiac function

indirectly via release of trophic factors that en-

hance angiogenesis and rescue cardiomyocytesat risk in the infarct border zone (35, 41, 42).

Similarly, the limited improvement in globalsystolic function recovery in clinical studies

with adult mononuclear bone marrow cells hastraditionally been ascribed to insufficient hom-

ing, engraftment, and survival of transplantedcells into the ischemic and hostile milieu. To

a certain extent, this may relate to faulty ex-trapolation of the data from small animals to

the human, failure to properly account forthe difference in size between rodent and hu-

man, and the unknown nature, functionality,

and number of true stem cells administered(43).

In addition, most of the cell transplantation–based therapeutic approaches used so far are

predicated on the concept that the adulthuman myocardium does not have intrinsic

regenerative capacity because the workingmyocytes are terminally differentiated cells

with no regenerative capacity. Recently, how-ever, the adult myocardium has been found

to harbor a population of resident pluripotentcells with the characteristics of true cardiac

stem cells, i.e., self-renewing, clonogenic,

and multipotent. Several groups have iden-tified cardiac stem cells possessing growth

factor–receptor systems and reported differentmembrane markers or transport proteins.

These endogenous cardiac stem cells (CSCs)are able to regenerate the contractile myocytes

and endothelial and smooth muscle cells of the microvasculature, but their numbers vary

substantially between species, and it is unclear whether they constitute phenotypic variations

of a unique cell type (38, 44). The very recentdemonstration that human ISL1 heart progen-

itors, isolated from second-heart-field-derivedstructures in embryonic life, are capable of self-

renewal, expansion, and differentiation into the

major cell types in the heart provides anotherimportant model system for ES-cell-derived

cardiomyogenesis (55). All these discoveries


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Functional repair

Stem cell transfer

Myocardial

injury/damagePCI (CABG-MedR/)

Trophiceffects

Cardiac regeneration

Stimulation/maturation of cardiac stem cells

Transdifferentiation?

Ischemia Necrosis Remodeling

Cardiac muscle Skeletal muscle Adipose tissueBone marrow

CardioprotectionCMC apoptosisCMC oxidative stressCMC metabolismNeovascularizationFibrosis/matrix remodeling

Figure 1

Cell-based myocardial functional repair. Abbreviations: PCI, percutaneous coronary intervention; CABGcoronary artery bypass grafting; CMC, cardiomyocyte.

have opened novel therapeutic avenues for

physiologically meaningful regeneration of the myocardium damaged by ischemic orinflammatory events or by congenital defects

(1, 45, 46). The problem is that these reservoirs of cells

are usually overridden in patients with AMI,

advanced coronary artery disease, and chronicheart failure. Despite this limited capacity for

regeneration of myocardium, the existence of these repair mechanisms suggests that cardiac

repair may be achieved therapeutically in these

clinical settings, given the appropriate stim-ulation (in situ activation, multiplication anddifferentiation of the eCSCs) and/or adoptive

transfer of (stem) cells involved in these pro-cesses (47, 48). Cardiac repair via endogenous

CSCs represents a major target for translationalresearch in the years to come.

THE QUEST FOR THE OPTIMA

CELL SOURCE: AUTOLOGOUS VERSUS ALLOGENEIC,EXOGENOUS VERSUSENDOGENOUS PROGENITOR CELLS?

Autologous cell therapies, even if their clical efficacy were markedly superior, suffer fr

relative complexity and face significant cconstraints posedby the need to make the tre

ment affordable to large numbers of candate patients. Moreover, the clinical requi

ment for a readily available (“off-the-shel

treatment that can be prepared and admintered in the majority of catheterization la

oratories during the acute phase of the dease remains a major challenge ( Table 2).

circumvent some of these obstacles, a ra

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Basic research:Stem/progenitor celldifferentiation andmaturation

Interaction:Cells, microenvironment,and biomaterials

Tissue generation: Tissue organization

Enablingtechnologies:• Biomarkers• Imaging technologies• High-throughput• technologies• Model systems• Bioreactors

Regenerative

therapies:• Clinical validation

Figure 2

Regenerative medicine: a stepwise investigational approach.

reduced functional capacity, along with absenceof cardiomyogenesis, limit bone marrow cell–

based cardiac repair (Figure 2). We also lack a proper understanding of the vital cues in the

microenvironment to which cells are exposedand of the more complex signals for tissue or-

ganization. Several potential priming strategiesof adult progenitor cells with PPAR-gamma

modulators, eNOS enhancers, integrin activa-

tors, and statins are being applied to improvehoming, engraftment, and other critical pro-

genitor cell functions (54). Some have already shown promising results in experimental mod-

els (30) and will undergo clinical testing. Mean- while, priming of the ischemic target milieu

with shockwave treatment and targeted inves-tigations to identify optimal cell dose, deliv-

ery methods, cell type, and timing of trans-fer are ongoing (54). Importantly, innovative

tissue engineering protocols that combine cells with artificial or natural scaffolds may further

enhance cell-mediated benefit. All of these con-

ditions need to be and will be tested in properly designed and focused preclinical large-animal

models and in properly sized mechanistic clical trials.

In contrast, it is not known whether in vicardiomyogenic differentiation enhances in

gration and coupling of transferred cells aaccelerates functional recovery, and these qu

tions represent a much greater challenge. O when successful cardiac prespecification pro

cols have been established in vitro will weable to test this treatment paradigm in expe

mental models.Rapidly growing insights in c

diopoietic programming from induced pluritent patient-specific cells or in stimulation a

amplification mechanismsof endogenousCSoffer significant potential for cardiomyogene

in the years to come without prohibitive ethior immunological obstacles.

Finally, we should realize that none the above obstacles will be overcome with

concomitant efforts to developcritically needenabling technologies. These include char

terization of biomarkers (monitoring bioloical activity and efficacy of implanted c

and biomaterials), validation of appropri

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imaging modalities (molecular imaging tools),

high-throughput techniques (screens of small

moleculescapable of specifying andguiding dif-ferentiation processes), model systems (mim-

icking interactions between stem cells and localenvironment), and bioreactors (cell amplifica-

tion procedures under GMP conditions).

CONCLUSIONS

Many of the cell-based treatment protocolshave proven modestly effective at best. Al-

though they are interesting from the point of view of advancing a new paradigm for the treat-

ment of ischemic heart disease and heart fail-

ure, none is poised to solve the severe pub-lic health problem of advanced cardiac disease

yet. So far, most bone marrow cell transfer issafe and might constitute a valuable treatment

option for patients with large MI and signifi-cantly impaired LV function. The absolute in-

cremental increase in global function recovery following cell transfer is modest, and at least

three randomized trials failed to show signif-

icant changes in surrogate endpoints. Underthese circumstances, judicious clinical devel-

opment of cell-based cardiac repair requires

stepwise investigations of the critical limita-tions to functional recovery, as we understand

it today. At an early stage, this will best beaccomplished through collaborative studies on

cell-enhancement strategies involving expertcenters andwill benefitfrom standardized oper-

ational procedures for progenitor cell procure-ment, processing, and functional evaluation. At

the same time, cross-talk between clinicians,basic scientists, and developmental stem cell

biologists will be indispensable in this rapidly progressing field of medicine. Preclinical stud-

ies in relevant large-animal models are needed

to define our best options. It is very likely that new and better progenitor cell populations

will be identified in the near future and thatcardiac prespecification or endogenous CSC

activation will become a realistic treatmentoption.

DISCLOSURE STATEMENT

Dr. Janssens is a group leader at VIB and holds a named chair financed by AstraZeneca at

KU-Leuven, Belgium.

ACKNOWLEDGMENTS

Dr. Janssens is supported by a research grant from the Flemish Institute for Scientific Research,

FWO and the University of Leuven, Belgium (GOA).

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Using Genetic Diagnosis to Determine Individual

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Emotion Recollected in Tranquility: Lessons Learned

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Tilo Grosser, Ying Yu, and Garret A. FitzGerald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p

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The Future of Antiplatelet Therapy in Cardiovascular Disease

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Pharmacogenetics of Warfarin

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Diagnosis and Treatment of Neuropsychiatric Disorders

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437

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Annu. Rev. Med. 2010, 61, 287–300