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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 3  |  Issue : 2  |  Page : 74-78

Cardiac stem cell therapy: Current status


Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication20-Nov-2017

Correspondence Address:
Sridharan Umapathy
Department of Cardiology, AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_12_17

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  Abstract 


Cardiac injury due to any cause leads to cardiac cell damage and thereby to ventricular dysfunction. Unlike current medical therapy, cardiac regeneration by stem cell therapy is a promising approach which has a potential to reverse left ventricular dysfunction. It is conceived to complement and potentially transform available therapeutic armamentarium. Early experience in clinical studies support the safety and feasibility of cell therapy and as adjuvants to established practice. This review discusses type of stem cells used, its therapeutic indications, and its current status.

Keywords: Bone marrow stem cells, cardiac stem cell therapy, cardiopoiesis, mesenchymal stem cells, stem cell therapy


How to cite this article:
Umapathy S. Cardiac stem cell therapy: Current status. J Pract Cardiovasc Sci 2017;3:74-8

How to cite this URL:
Umapathy S. Cardiac stem cell therapy: Current status. J Pract Cardiovasc Sci [serial online] 2017 [cited 2017 Dec 11];3:74-8. Available from: http://www.j-pcs.org/text.asp?2017/3/2/74/218801




  Introduction Top


Cardiovascular diseases are one of the leading causes of morbidity and mortality worldwide. Their incidence is increasing as well. Cardiac damage due to any cause leads to irreversible loss of cardiomyocytes which in turn causes ventricular dysfunction. Ventricular dysfunction is a major determinant of prognosis on short-term and long-term follow-up. Current medical therapy focuses on stabilising ventricular dysfunction with drugs and devices (CRT-P/CRT-D), thereby providing mortality benefit.[1] Finally, patients undergo heart transplantation or have left ventricular (LV) assist devices in advanced stages of heart failure. However, these modalities of therapeutic approach fail to reverse the underlying LV dysfunction. In this context, cardiac regeneration by stem cell therapy is a promising approach which can reverse LV dysfunction.

Traditionally, heart was considered as terminally differentiated postmitotic organ. Current evidence had shown the presence of cardiac stem cells and usual cardiac cell turnover varies from 1%/year by age of 25 years to 0.45%/year by 75 years. This cardiac regeneration has limited endogenous potential. This can be aided by stem cell therapy.


  Heart Failure Paradox Top


Current therapy had reduced early mortality in patients with acute myocardial infarction (MI)[2] but 12% patients die within 6 months. Of these patients, 25% die of progressive pump failure due to adverse LV remodelling.[3] This is turn leads to emergence of heart failure epidemic [Figure 1] so-called paradox of medical success.[4] Hence, quest for therapy that limits myocardial injury by reversing adverse LV remodeling is of paramount importance. This can be fulfilled by usage of stem cell therapy.
Figure 1: Heart failure paradox.

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Various stem cell sources can be utilized for cardiac stem cell therapy [4] as depicted in [Figure 2]. Ideal stem cells should have following characteristics: Electrophysiological, structural, and contractile properties similar to cardiomyocytes, ability to integrate with host tissue structurally and functionally, ability to retain proliferative potential, ability to undergo genetic manipulation ex vivo to promote desirable characteristics, to have autologous origin, and should be available in large quantities.[5]
Figure 2: Stem cell resources for cardiac regeneration.

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  Mechanism of Cardiac Regeneration Top


Mechanisms proposed by which stem cells promote cardiac regeneration include transdifferentiation [6],[7] and fusion,[8],[9] paracrine effect by secretion of growth factors, thereby stimulating neo-angiogenesis.[8],[10] They usually act by paracrine effects. This in turn may lead to reduction in scar size, reverse remodeling, and improvement in perfusion, thereby improving ventricular function.[11] This may translate into clinical benefits by improving functional class, reducing morbidity and mortality and better quality of life [Figure 3].
Figure 3: Mechanisms of stem cell therapy.

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  Indications of Stem Cell Therapy Top


Stem cell therapy is currently studied in following cardiovascular conditions:

  1. Acute MI
  2. Previous MI with large scar
  3. Dilated cardiomyopathy (non-ischemic)
  4. Refractory angina
  5. Peripheral artery disease.



  Modes of Cell Delivery Top


Stem cells can be delivered to heart either by intravenous, intracoronary, transendocardial, or by epicardial route. Intravenous route is least preferred due to reduced cell homing to infract region secondary to prolonged circulation time and first pass effect. Intracoronary route is usually preferred because of safety profile and lesser first pass effect.[12] After intracoronary route, cell retention within 24 h is <10%, 90% cells die within a week, and only <1% transplanted cells identifiable after 1 month. Techniques such as ischemic preconditioning [13] and retrograde coronary sinus occlusion [14] have been tried to improve cell retention. Transendocardial stem cell delivery can be done with special catheter systems (NogaStar catheter) under electromechanical guidance and cells can be delivered in peri-infarct regions.[15] NOGA system incorporates spatial, electrophysiological, and mechanical information in real time to reconstruct the heart's endocardial surface in 3D. For stem cell therapy, these components are complemented by the 8-Fr MyoStar™ delivery catheter with sensing properties and an injection component comprising a retractable, straight, 27-gauge nitinol needle.[16] Disadvantages of transendocardial route being cell wash-out into ventricles, arrhythmic risk, and cardiac tamponade. Epicardial stem cell delivery usually done along with coronary artery bypass surgery (CABG) by direct infiltration into peri-infarct area under vision.[17]


  Bone Marrow Cells Top


Bone marrow cells can be easily obtained by bone marrow aspiration from posterior iliac crest and most commonly used cell type till date. They act predominantly by paracrine effects as explained earlier and promote cardiac progenitor activity as well. After aspiration, they are segregated into total nucleated cells,[18] mononuclear cells,[19] and CD133/CD34 positive cells.[20] To render them resistant to hostile environment, stem cells can be preconditioned by transfection with human endothelial nitric oxide synthase,[21] by utilizing growth factors [22] and microRNA-based therapy.[23] Based on preclinical studies, at least 1010–1011 stem cells may be needed for cell therapy due to poor cell survival after current modes of cell delivery. Recent meta-analysis involving 48 randomized trials had shown that minimum 50 million cells will be needed for cell efficacy.[24]


  Acute Myocardial Infarction Top


Acute MI leads to irreversible cardiac muscle damage leading to ventricular dysfunction. Major goal of cell therapy is to reverse adverse remodeling by enhancing cardiac myocyte regeneration and neoangiogenesis. Most of the cell therapy trials used intracoronary route after successful stenting of infarct-related artery. Efficacy of cell therapy was assessed by improvement in LV ejection fraction (LVEF), reduction in scar size, and cardiac volumes.

REPAIR-AMI trial involving 204 patients with acute MI showed improvement in LVEF by 2.5% at 4 months follow-up and reduction in mortality and ischemic end points.[25] Similar results were shown by FINCELL trial (5% LVEF improvement).[26] In a Phase III randomized controlled trial (RCT) involving a similar cohort with bone marrow cells between 7 and 21 days post-MI did not show any difference in primary outcome of LVEF improvement. Subgroup analysis of patients who received >5 × 108 cells showed 3% absolute improvement in LVEF with similar efficacy up to 3 weeks post-MI.[27]

ASTAMI,[28] HEBE,[29] TIME,[30] LATE TIME,[31] SWISS AMI [32] were acute MI trials that showed neutral results with cell therapy. These mixed results can be explained by usage of different cell isolation procedures, nonstandardized mode of cell delivery, mixed population of cells used, and inherent impairment of autologous cells due to associated comorbidities. In a meta-analysis involving 2037 patients with a median follow-up duration of 6 months, intracoronary infusion of bone marrow cells improved LVEF by 2.1% with no reduction in clinical outcomes.[33]


  Chronic Ischemic Heart Failure Top


In chronic ischemic heart failure, bone marrow cells were commonly used and showed feasibility and excellent safety profile. In a trial involving 391 patients with ischemic heart failure (LVEF <35%) belonging to New York Heart Association Class III over 5-year follow-up, cell therapy with bone marrow cells showed improvement in LV function, quality of life, and improved survival on long term.[34] In a meta-analysis of 48 RCTs involving 2602 patients, bone marrow stem cells showed improvement of LVEF by 2.9% predominantly by reduction in end systolic volume (by 6.37 ml) and reduction of scar size by 2.25% translating into improved clinical outcomes.[24]


  Nonischemic Cardiomyopathy Top


In a study from our center involving 81 patients with dilated cardiomyopathy (41 patients and 40 controls), intracoronary stem cell therapy showed improvement in LV function (5.9%), functional class, and quality of life on long-term follow-up of 3 years.[35]


  Skeletal Myoblasts Top


They are the first cells to be used for cardiac cell therapy. They have favorable characteristics such as easy accessibility, low risk of tumorigenesis, and increased resistance to ischemia. However, larger trial like MAGIC [36] has shown neutral results with increased risk of ventricular arrhythmia on follow-up.


  Mesenchymal Stem Cells Top


Mesenchymal stem cells (MSCs) are a subpopulation of bone marrow cells comprising 0.001%–0.01% of cells.[37] They act by paracrine effect by secreting growth factors,[38] promoting endogenous repair by direct cell-to-cell interaction,[39] and produce a immunosuppressive milieu.[40] Due to lack of major histocompatibility complex Class II antigens, even allogeneic MSCs can be utilized for cell therapy. In POSEIDON trial which included 31 patients with ischemic heart failure, there were no significant differences between autologous and allogeneic MSCs in terms of efficacy or adverse events. Both of them reduced infarct size by 33% with no significant improvement in LV function on 13-month follow-up.[41] In POSEIDON-DCM study involving 37 patients, allogeneic MSCs are better than autologous cells in improving LV function, 6 min walk distance and quality of life with lesser adverse effects and MACE.[41]


  Adipose Tissue-Derived Stem Cells Top


Human adipose tissue contains large amount of multipotent cells with properties similar to bone marrow MSCs.[42] They are easily accessible by liposuction and can be harvested in large quantities.[43] In Phase I study, 14 STEMI patients showed no improvement in LV function.[44] Larger ADVANCE trial involving 375 STEMI patients is underway. In a study of 21 patients with refractory angina, adipose-derived cells by transendocardial route showed modest improvement in scar size, myocardial perfusion with no change in LV function on 18-month follow-up. Patients showed modest improvement in functional class and functional capacity.[45]


  Cardiac Progenitor Cells Top


They are isolated from myocardium obtained by endomyocardial biopsy and from excised right atrium appendage during CABG. They include cells positive for c-kit, Sca-1, side population cells, epicardial progenitors, and cardiospheres. In a Phase I study involving ischemic heart failure (EF <40%) patients, c-kit positive cells were injected into graft supplying infarct territory 4 months after CABG.[46] At 12 month follow-up, cardiac MRI showed improved LV function by 13 units, 30% reduction in scar size and increase in viable mass.[47] Cardiosphere-derived cells are mixed population cells comprising primitive and early committed cells. A Phase 1 study of 17 patients with ischemic heart failure showed scar reduction with no improvement in LV function.[48]


  Cardiopoiesis Top


Cardiopoiesis is a lineage specifying program which converts nonreparative cell type to reparative type.[48] In C-CURE trial (Phase II) involving 21 patients with ischemic heart failure (EF ≤40%), pretreated autologous MSCs (cardiopoietic cells) through transendocardial route, showed improved LV function by 7% with reduction in end-systolic volume. No adverse effects occurred at 2-year follow-up.[49] Phase III CHART trial is underway.


  Limitations of Cell Therapy Top


There is still limited knowledge on the role of number and function of cells needed for optimal cell repair. Low cell dosages may limit the efficacy of cell therapy whereas high cell dosages require rapid ex vivo progenitor cell expansion. Rates of cell engraftment are low despite advancement in cell delivery techniques. Autologous stem cells have impaired capacity in patients with cardiovascular risk factors further limiting cell therapy efficacy.


  Novel Concepts Related to Cell Therapy Top


Embryonic stem cells

Human embryonic stem cells (ESCs) obtained from inner cell layer of blastocyst are undifferentiated cells with pluripotency and infinite self-renewal capacity. Disadvantages being immunogenicity, teratogenicity, and ethical concerns surrounding them.[50] Human ESC-derived cardiac progenitor cells showed good results in preclinical studies.[51] They are produced by forming embryoid bodies, coculturing with visceral endoderm cells, and by directed differentiation with growth inducers.[5] A Phase I clinical study with human ESC-derived cardiac progenitor cells involving six patients of ischemic heart failure is underway. Authors have reported symptomatic improvement of a single patient by 3 months involved in this study who had epicardial implantation of these cells during CABG along with immunosuppression.[52]

Induced pluripotent stem cells

Sir John B Gurdon and Dr. Shinya Yamanaka were awarded Nobel prize in 2012 for their discovery of induced pluripotent stem cells. They are manmade dedifferentiated cells reprogrammed from human fibroblasts which share similar properties with ESCs.[53],[54] As they can be directed to differentiate toward cardiomyocytes, iPSCs represent a potential resource of personalized heart tissue replacement and a valuable tool to further understand potential pathways in cardiac regeneration. However, they do carry the risk of teratogenicity, immunogenicity, and mutations.[55] Hence, their usage is challenging and not yet feasible for clinical applications.


  Conclusion Top


Cardiac regenerative therapy is conceived to complement and potentially transform available therapeutic armamentarium. Early experience in clinical studies supports the safety and feasibility of cell therapy and as adjuvants to established practice. However, lack of therapeutic inconsistency of patient derived stem cells still remains a hurdle to its central adoption. We still have limited knowledge on optimal cell dose, best cell to use, optimal timing, and mode of cell delivery required for optimal cardiac repair. Approaches such as the use of cardiac stem cells, allogeneic stem cells, ex vivo preconditioning of autologous stem cells, and cardiopoiesis appear promising.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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  In this article
   Abstract
  Introduction
   Heart Failure Pa...
   Mechanism of Car...
   Indications of S...
   Modes of Cell De...
  Bone Marrow Cells
   Acute Myocardial...
   Chronic Ischemic...
   Nonischemic Card...
  Skeletal Myoblasts
   Mesenchymal Stem...
   Adipose Tissue-D...
   Cardiac Progenit...
  Cardiopoiesis
   Limitations of C...
   Novel Concepts R...
  Conclusion
   References
   Article Figures

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