Myocardial infarction (MI) presents an evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia and remains a major cause of morbidity and mortality.
Universal Definition of Myocardial Infarction, 2007
Pathology of Acute Myocardial Infarction, Medscape Reference
Unfortunately, myocardial necrosis starts rapidly before reperfusion can be achieved in most of the patients, leaving an infarct zone that contains nonfunctional myocytes that are remodeled into the scar tissues surrounded by region of ischemia. This loss of viable myocardium initiates a process of adverse ventricular remodeling and a downward spiral leading to congestive heart failure. Evidence such as fraction of cardiomyocytes may be able to reenter the cell cycle and that limited regeneration can occur through recruitment of resident and circulating stem cells were presented, but it was also realized that these endogenous repair mechanisms are overwhelmed by the substantial damage to the myocardium from the injury that it faces during MI.
However, the existence of these endogenous repair mechanisms as well as the concept of adult stem cell plasticity suggested that cardiac repair may be achieved therapeutically in these clinical settings and gave a way for preclinical trials. Subsequent promising reports of these same trials prompted rapid initiation of human clinical trials.
Mobilized bone marrow cells repair the infarcted heart, improving function and survival 2001 Aug
Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium 2004 Mar 21
Haematopoietic stem cells and repair of the ischaemic heart 2005 Dec
Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells 2001 Jun
Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function 2001 Apr
Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans 2002 Oct
Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion. NOGA-guided subanalysis of the MYSTAR prospective randomised study 2010 Mar
Methods of stem cell delivery in cardiac diseases 2006 Mar
One-Year Safety Analysis of the COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133 Bone Marrow Stem Cells to Placebo in Patients after Acute Myocardial Infarction and Left Ventricular Dysfunction 2011 Feb
Stem cells are primitive, undifferentiated, undefined pluripotent multilineage cells that retain the ability to renew themselves through mitotic cell division and can divide and create a cell more differentiated than itself.
Stem Cell Information)
(Stem Cells MedlinePlus)
Every single cell in the body originates from this type of cell. Stem cells are cells with the potential to develop into many different types of cells in the body. They serve as a repair system for the body. There are two main types of stem cells: embryonic stem cells and adult stem cells. Adult stem cells are defined as undifferentiated progenitor cells from an individual after embryonic development. Multiple tissues have been shown to contain organ-specific progenitor cells. However, adult stem cells have less potential to differentiate without assistance. Stem cells are usually classified according to the following criteria: origin, type of organ or tissue from which the cells are derived, surface markers, and final differentiation fate.
(Table 1)
Major cell types with potentials for cardiac cell therapy.
Stem cells types used in heart repair.
Mechanism of myocardial repair
There is still controversy as to whether actual differentiation occurs versus large cell fusion with resident myocytes. This is because on one hand the myocyte deficit in infarction-induced heart failure is on the order of one billion cardiomyocytes and on the other hand the documentation of Left Ventricular Functional (LVF) improvement within 72 hours is far earlier than would be expected for cell regeneration of any meaningful extent (Regeneration gaps: observations on stem cells and cardiac repair 2006 May).
The fact that after transplantation of hundreds of millions of cells, less than 2% of the cells are actually still present in the tissue within 2 weeks of implant; the prevailing concept of stem cell efficacy has shifted toward the cytokineparacrine hypothesis (Cell-based cardiac repair: reflections at the 10-year point 2005 Nov).
It has also been proposed that through paracrine mechanisms stem cells release angiogenic ligands, protect cardiomyocytes from apoptotic cell death, induce proliferation of endogenous cardiomyocytes, and may recruit resident CSCs (Figure 1).
Mechanism of action of stem cells for cardiac functional improvement.
Indeed, various studies showed that progenitor cells secrete survival factors such as endothelial growth factor, stromal-derived factor (SDF- 1), angiopoietin 1, hepatocyte growth factor, insulin-like growth factor 1, and periostin
Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines 2001 Avg
Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms 2004 Mar
Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair 2007 Avg
Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling 2006 Jun
Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells 2005 Nov
In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function 2007 Feb
thymosin b4 which promotes wound healing or the Wnt antagonist secreted frizzled-related protein 2 (SFRP-2) which protects cardiomyocytes from hypoxia-induced apoptosis and thus stimulate tissue recovery after ischemic injury and minimize the infarct size. Regardless of the mechanisms, there appears to be general agreement that stem cell therapy has the potential to improve perfusion and contractile performance of the injured heart.
Which Cell Populations Should Be Delivered?
While the ideal cell type for stem cell therapies remains to be determined to date, bone marrow-derived stem cells, isolated from whole bone marrow aspirate, remain the most commonly used cell type for human studies. Unfractionated bone marrow cells gained advantage over above cells due to many reasons. It has the feasibility of procuring, no requirement of in vitro expansion and above all the availability of mixed population of cells with characteristic for differentiating into various populations of cells. And of course it has no ethical issues. However, importantly MSCs have also emerged as most promising cell population with their inherent property of transdifferentiating into cardiomyocytes and to be tolerated by the immune system giving us the most convenient “off-the-shelf” reagent.
What Number of Cells Should Be Given?
Myocardium contains approximately 20 million cardiomyocytes per g of tissue. The average left ventricle approximately weighs 200g and therefore contains approximately 4 billion cardiomyocytes. To cause a heart failure, an infarct needs to kill approximately 25% of the ventricle (for comparison, infarcting 40% of the ventricle results in acute cardiogenic shock). Therefore, the myocyte deficit in infarction-induced heart failure is in the order of one billion cardiomyocytes. True cardiac regeneration would therefore require restoring approximately one billion cardiomyocytes and ensuring their synchronous contraction via electromechanical junctions with host myocardium.
When Dose Cells Should Be Transplanted?
In the first 48 hours of AMI attack, debridement and formation of a fibrin-based provisional matrix predominates before a healing phase ensues. At the initial 3-4 days after MI cell adhesion, molecule concentration which has not yet declined may promote the transplanted cells into inflammatory process than in the formation of functional myocardium. It is only by 7th day after MI that VEGF concentration peaks and cell adhesion molecule concentration declines.
By 2 weeks after scar formation, the benefits achieved due to cell transplantation are reduced. Therefore, the ideal time point of transplantation remains 7–14 days. This was very much evident in the REPAIR AMI trial wherein patients being treated up to 4 days after the MI showed no benefit, whereas later treatment (day 4 to 8) provided an enhanced improvement of EF during follow-up. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial 2006 Dec. This suggests that microenvironment after AMI changes during the first week after reperfusion, thereby modulating the homing or the subsequent functional activity of the infused cells and cell homing might be best after a few days rather than immediately after reperfusion. Further studies are warranted to prospectively address this question.
Cell Processing
Standardization of cell isolation protocols which have a major impact on the functional activity of bone marrow-derived progenitor cells is also a crucial issue. The comparison of the cell processing of ASTAMI and REPAIR trials highlighted a very crucial point that the assessment of cell number and viability may not entirely reflect the functional capacity of cells in vivo. Additional functional testing appears to be mandatory to assure proper cell function before embarking on clinical cell therapy trials. The recovery of total cell number, colony-forming units (CFU), the number of MSCs, and the capacity of the isolated BMSCs to migrate in response to SDF-1 was significantly reduced when using the ASTAMI Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction 2006 Sep protocol of Lymphoprep, storage in NaCl plus plasma compared with the REPAIR Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial 2006 Dec protocol of Ficoll, and storage in X-vivo 10 medium plus serum. Comparison of the individual steps identified the use of NaCl and plasma for cell storage as major factors for functional impairment of the BMSCs in ASTAMI trail.
Which Application Method Is the Most Efficient?
The most commonly utilized method of stem cell delivery is the transvascular approach. It is suited for the treatment of recently infarcted and reperfused myocardium which delivers maximum cells to the site of injury. Cells are delivered through the central lumen of an over-the-wire balloon catheter during transient balloon inflations to maximize the contact time of the cells with the microcirculation of the infarct-related artery. This stop-flow technique is relatively easy to perform within less than an hour and enhances cell retention within the infarcted area. Direct needle injection of the stem cells into the infarcted regions of the heart that requires an open-chest procedure may not be possible all the time for human patients.
The use of IV therapy could be more effective considering that the cells have the advantage of reaching the tissue and vessels surrounding the infarct region. When using direct infusion, the cells primarily reach the area that they are injected into, whereas IV administration is not necessarily limited to the immediate infarcted region. It is possible that the stem cells will also repair areas of the heart damaged during any previous injury and not detected by imaging, therefore preventing any future problems in that region. Since IV administration is safer for use on humans than catheterization, clinical trials utilizing IV therapy with humans would be a critical step for the standardization of stem cell treatment. Hare et al. had used intravenous approach to deliver the allogenic MSCs to the infarct region with positive outcome (A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction 2009 Dec).
Development of Safe and Effective Cell Tracking Modalities
Because the mechanism through which cell therapy acts is still being characterized, clinical trials that establish mechanistic correlates will be most helpful. For example,
studies using MRI in patients suggest that cell therapy might alter the rate of infarct repair or influence the amount of scar contraction. Positron emission tomography studies have demonstrated glucose uptake and enhanced myocardial blood flow in cell-engrafted regions which provide important information regarding effects on tissue metabolism and perfusion. Another very useful mechanistic end point for clinical trial is the ability to track the cells after they are implanted, for instance, through use of paramagnetic particles visible by MRI, positron emitting isotopes, or molecular tracers. Finally tissue-based analyses should be included in clinical trial design, either by evaluation of explanted hearts at the time of the transplantation or by autopsy of patients who die following cell therapy. The huge scope of the problem from the bench to the bedside and back again led to the establishment of consortia. The Cardiovascular Cell Therapy Research Network, which comprises 5 institutions and is sponsored by the National Heart, Lung, and Blood Institute, will address a specific series of questions over a 5-year period. Broadly speaking, the major objectives are to develop phase 1 and 2 clinical trials for cell delivery for left ventricular dysfunction (AMI and chronic heart failure) while defining parameters and models for successful translation of newer cell types (Cardiac cell therapy: bench or bedside? 2007 Nature).
Conclusion
There is a wealth of preclinical and early clinical data showing safety, feasibility, and early efficacy of adult cell based therapy. The apparent lack of immediate commercial or industrial interest should not discourage the scientific community from adopting a disciplined strategy in pursuing this field. Now only clinical trials can lead to optimization of it. Stem cell therapies should therefore precede randomized, placebo-controlled double-blind clinical trials. Another compelling argument for initiating clinical research is that the results of these investigations often provide pivotal insights that allow a new field to advance. For now, the main challenge is to improve the translation of cellular and molecular concepts into clinically relevant endpoints so that stem cell therapy in conjunction with current treatment modalities may help to further reduce the mortality and improve the quality of life in MI patients.
