according to a world health organization ( who ) report , cardiovascular diseases ( cvds ) are the number one cause of death globally . it was estimated that 17.3 million people died from cvds in 2008 , representing 30% of all global deaths .
in addition , it is predicted that almost 23.6 million people will die from cvds by 2030 ( who , 2011 ) .
the most important risk factors of cvds are unhealthy diet , physical inactivity , smoking , and harmful use of alcohol .
the effects of unhealthy diet and physical inactivity may show up in individuals as raised blood pressure , raised blood glucose , raised blood lipids , and overweight and obesity .
rapid reperfusion of the culprit vessel for salvaging ischemic myocardium and optimal medications reduce complications and improve survival rate .
although many drugs and medical devices have been developed , the incidence of cvds remains high .
more efficacious therapeutic modalities need to be explored by medical researchers . since the discovery of stem cells , a significant amount of research and development has emerged to be clinically applied for various incurable diseases including cvds .
traditionally , the myocardium has been considered as terminally differentiated ; however , there is growing evidence that cardiomyocytes are able to become proliferative when they face substantial damage such as myocardial infarction or heart failure.1)2 ) in addition to intrinsic repair mechanisms , progenitor / stem cell plasticity has emerged as one of the ways to be regenerated.3 ) stem cells are undifferentiated pluripotent multilineage cells with the ability to renew themselves .
the sources of stem cells include the embryo , fetus , and various parts of adult tissues .
many clinical trials showed excellent safety and feasibility of adult stem cells , but the efficacy of stem cell therapy is not satisfactory to improve cardiac function substantially .
the basic mechanisms of stem cell action on the injured myocardium will not be discussed here .
we will focus instead on the current status of preclinical / clinical studies regarding therapeutic opportunities . in this review ,
we summarize recent results of preclinical / clinical trials that have evaluated the safety , feasibility , and efficacy of cell therapy in heart disease .
direct or indirect transplantation of adult stem cells to damaged hearts is emerging as an innovative strategy to ameliorate cardiac remodeling and dysfunction after acute myocardial infarction ( ami ) .
potential sources of functional cardiomyocytes has been explored and utilized for cell therapy to replace injured cardiomyocytes .
stem cells are characterized by their ability to self - renew , clone , and differentiate into multiple tissues .
adult stem cells are isolated and characterized from various sources ; peripheral blood,4 ) bone marrow ( bm),5 ) adipose tissue,6 ) umbilical cord blood,7 ) amniotic membrane,8 ) and dental pulp.9 ) a large number of animal studies have demonstrated that stem cells could be engrafted and differentiated within the heart.3)10 - 12 ) in preclinical studies , several large - animal species , including swine , sheep , and dogs , have been used to investigate the effects of stem cell therapy in cvds models .
stem cells can be delivered to the heart by intravenous infusion , direct surgical injection , or catheter - based intracoronary infusion .
orlic and colleagues first reported the repair of infarct myocardium through transplantation of bone marrow cells ( bmcs ) in mice.3 ) progenitors or stem cells with cardiomyogenic potential were studied both in vitro and in vivo .
experimental data showed the expression of cardiac markers such as cardiac contractile proteins in stem cells in transplanted myocardium .
one of the popular strategies to increase the cardiomyogenesis of stem cells is the stimulation of stem cells with an anticancer drug , 5-azacytidine , which is a nonspecific deoxyribonucleic acid methylation inhibitor .
transient stimulation with 5-azacyticine for one day substantially increased cardiac protein expression in bm - derived mesenchymal stem cells ( mscs ) and sca-1-positive adult cardiac stem cells with spontaneous beating on culture system.13 ) to prove functional stem cell therapy , a small animal model has widely been used .
myocardial infarction was experimentally induced by surgical ligation of the coronary artery such as left anterior descending artery in mice or rats , sometimes with reperfusion .
various stem cell types , transplantation route , cell number , and transplantation timing have been studied in these small animal models .
many studies are reported that stem cell therapy is safe , feasible , and promising for the cure of mi .
histological data has revealed that the injected stem cells can survive in ischemic myocardium that participated in neovascularization and cardiomyogenesis .
scar size , cardiac remodeling , fibrosis , and inflammation were much more effectively improved .
based on these fantastic results of animal studies , many clinical studies were designed and initiated to transfer stem cell therapy to the bedside all over the world .
various stem cells or progenitor cells have been introduced for cardiac repair in the last few years , although many past and ongoing clinical trials use predominantly adult autologous bm - derived cells .
the use of bmcs in cvds has the advantage that bm can be easily accessed , and isolated cells can be expanded for autologous application .
experimental studies of cell priming revealed that it improved cell survival , retention , integration , and differentiation.12)14)15 ) in addition , genetic modification of stem cells before application with the prosurvival gene akt,16 ) vascular endothelial growth factor,17 ) or fibroblast growth factor 218 ) promoted therapeutic efficacy .
the anatomy and physiology of the porcine heart is well known to be similar to a human heart , and it is considered that the porcine mi model is the best model for cvds research .
cell number , delivery procedure , and surgical techniques in the porcine model are also similar to the clinical setting , and more realistic implications could be provided compared with a small animal model .
after successful percutaneous coronary intervention ( pci ) and coronary artery bypass graft surgery with optimal medications , cardiac function is restored only to a limited degree { 3 - 4% improvement in left ventricular ejection fraction ( lvef ) } which may result in cardiac remodeling in approximately 60% of the patients with myocardial infarction.19)20 ) many clinical studies have proceeded for proving their safety and efficacy to reach a final goal " new therapy " . regarding cell type
, most clinical trials have used unfractionated bmcs as the delivery product , postulating that stem / progenitor cells are the biologically applicable therapeutic agents .
the most widely applicable technique for stem cell delivery is intracoronary infusion from a clinical standpoint .
the first human clinical trial of stem cell trial was intracoronary infusion of autologous bm unfractionated mononuclear cells to ami patient.21 ) subsequent clinical studies of stem cells for ami were then initiated .
a variety of studies have demonstrated significant improvement of ventricular performance after stem cell therapy in ami , resulting in an increase in lvef and decrease in infarct size . in most cases ,
stem cell transplantation was performed in a time frame of 12 hours to several days after mi .
although there is large variability of hemodynamic data after cell therapy , there is moderate improvement of cardiac performance by stem cell therapy that is more quantitatively effective than therapeutic interventions and pharmacotherapy.22 ) thus , autologous stem cell therapy represents an innovative and effective procedure for regeneration of impaired hearts in the early phase after the infarct .
as seen in table 3 , most recent clinical trials utilized bm - derived mononuclear cells isolated from patients after pci .
bm has been considered the safest source for autologous transplantation of stem cells , usually mononuclear cells , in clinical trials . for
now the most widely used clinically approved source for stem cell therapy is autologous stem cells from bm ( www.clinicaltrials.gov ) .
in addition to bm - mononuclear cells , mscs are now actively under investigation for cardiac repair .
bm contains a population of hematopoietic stem cells and a rare population of plastic - adherent stromal cells ( 1 in 10000 nucleated cells in bm).23 ) these plastic adherent cells are mscs capable of forming singlecell colonies , expansion in culture , differentiation into osteoblasts , chondrocytes , and adipocytes.24)25 ) mscs were shown to be differentiated into a myogenic phenotype.13 ) animal studies demonstrated that human mscs could be transdifferentiated into endoderm - derived cells10 ) in injected myocardium , and coculture of msc with ventricular myocytes induced transdifferentiation into a cardiomyocyte phenotype in vitro.26 ) large - animal preclinical studies of mscs administration in post - mi heart demonstrated the ability of mscs to engraft , differentiate , and produce substantial functional recovery.12)16)27)28 ) the therapeutic effect of msc on ami has been reported in four clinical trials .
chen et al.29 ) infused autologous msc by intracoronary route and demonstrated regional wall motion and global lvef were improved after six months of cell therapy . at that time
, vulliet et al.30 ) reported that a microinfarction occurred after intracoronary infusion of mscs in a dog mi model .
a prochymal trial31 ) was designed to evaluate the safety of intravenous application of allogeneic bm - derived mscs to ami patients . according to animal studies
, a large proportion of infused cells were trapped in the lungs after administration , raising potential concerns regarding compromised pulmonary function.32 ) the results of the prochymal trial did not show any evidence of a pulmonary safety risk after infusion of allogeneic human ( h)bm - mscs .
instead , those data revealed improved pulmonary function in the msc - treated patients , compared with baseline status . the rate of arrhythmia event was 4-fold lower in the hmscs group than in the placebo group ( 8.8% vs. 36.8% , p=0.025 ) . in ischemic cardiomyopathy , transendocardial injection of autologous bm - derived progenitor cells including mononuclear cells or mscs produced functional recovery in scarred myocardium and reversed remodeling of the lv chamber.33 ) unfortunately
, however , they did not determine superiority between mononuclear cells and mscs . without the placebo control group ,
the transendocardial autologous cells in an ischemic heart failure trial ( tac - hft ) and percutaneous stem cell injection delivery effects on neomyogenesis ( poseidon ) trials34 ) are in progress to intensify those limitations ( www.clinicaltrials.gov ) .
tac - hft is designed for comparing bm - mscs versus mononuclear cells , and poseidon is comparing the effects of allogeneic versus autologous msc therapy in ischemic cardiomyopathy patients . the delivery of multistem , an allogeneic bm - derived stem cell produced by athersys , inc .
( cleveland , oh , usa ) , to ami patients has proved to be safe and well tolerated.35 ) they showed multistem delivered via transarterial adventitia using a microsyringe catheter was safe with improvement of cardiac function in a dose - dependent manner . although the exact mechanism of msc effects is still unresolved , accumulating results of large animal studies and clinical studies have shown that msc - based therapy for cardiac repair is safe and provides substantial improvement in cardiac structure and function .
the therapeutic effect of stem cell therapy on heart disease has been shown by experimental studies using small animal models .
results have been reported as extraordinarily promising with experimental results such as cardiomyogenesis , neovascularization , and paracrine effect on injured myocardium .
intracoronary transfer of autologous bmcs after optimum reperfusion therapy does not dramatically augment recovery of global lv function in patients , but could favorably affect cardiac remodeling after mi .
mixed results have been reported in clinical trials of stem cell administered patients after ami with minimal improvement of ejection fraction or only a transient clinical benefit .
the different outcomes were attributed to differences in cell preparations , timing and method of cell administration , choice of endpoints , and characteristics of patients .
some studies failed to determine persistent clinical benefits after stem cell application ( table 3 ) .
arrhythmias have been reported to be associated with intramyocardial rather than intracoronary injection of stem cells in the early clinical studies ; intramyocardial injection could be responsible for arrhythmogenesis .
in addition , local injection induces a highly uneven distribution of cells , at least early after injection , which increases electrophysiological heterogeneity .
although recent available results of clinical experience35)36 ) so far suggest that proarrhythmic effects may be transient , cardiac arrhythmia occurs unpredictably , and long - term follow - up studies would be essential to understand the arrhythmogenesis induced by stem cell transplantation .
the most effective and safe cell type for myocardial repair and the clinical significance of cell therapy - induced arrhythmias will be determined in future pre - clinical and clinical studies .
there was a case report about fatal events after autologous hematopoietic stem cell application in a lupus nephritis patient.37 ) after direct renal injection of stem cells isolated from peripheral blood , masses at the sites of injection were developed with hematuria .
pathologic analysis revealed the masses were angiomyeloproliferative lesions and suggested to be a possible complication of stem cell therapy .
there was no way to find out the detailed cause of death in those cases , but stem cell transplantation could be a causative event .
the ultimate goal of cell therapy is the regeneration of lost cardiac muscle along with the reversal of adverse remodeling . despite growing clinical experience ,
the absence of standardized clinical end point in human trials has left us with fundamental questions .
issues to be addressed in the future include determining the ideal cell type , the cell number to be delivered , optimal cell isolation method , efficient cell storage , and optimal time of administration to improve the efficacy of the therapy .
after that , more realistic and optimized conditions of stem cell therapy will be applied to patients suffered from cvds with guaranteed safety .
the risk of exposing patients to possible adverse outcomes of cell therapy must be seriously considered before clinical application .
the argument that clinical trials should be delayed till mechanisms are perfectly understood will deprive a large number of patients from therapeutic chances that may bring them clinical recovery . stem cell therapy is a novel and innovative approach to cardiac therapeutics which has been achieved by numerous preclinical and early clinical studies showing safety , feasibility , and early efficacy .
recent evidence from studies in animals and humans demonstrates the important roles of stem cells in cvds . in this review ,
reports of recent clinical trials of stem cell therapy for myocardial infarction are summarized and some important considerations are suggested for further application . for now , the challenge is to improveme the scientific concept to clinical setting with current treatment modalities .
 the contribution of stem cells to cure damaged hearts has finally been unraveled . 
 a large number of preclinical and clinical studies have showed beneficial outcomes after myocardial infarction . in this review , the current understanding of stem cell therapy in preclinical and clinical experiences is summarized . 
 stem cells from bone marrow have shown a potential to improve cardiac performance after myocardial infarction in animal and early clinical studies . 
 clinical trials from all over the world have provided safety assessments of stem cell therapy with marginal improvement of clinical outcomes . 
 thus , further investigations should be encouraged to resolve the discrepancies between studies , clinical issues , and unclear translational findings . 
 this review provides information and commentary on key trials for stem cell - based treat - ment of cardiovascular disease . 
Introduction
Walking With Animal Study
Running With Clinical Study
Looking Back With Consideration
Conclusion