Supervised by: Amanda Liu, BEng, MSc. Amanda spent her undergraduate years studying Biochemical Engineering at UCL (University College London), where she was awarded First Class Honours. She then completed her Master’s degree in Clinical and Therapeutic Neuroscience at the University of Oxford. She is currently studying Medicine (Graduate Entry) at the University of Cambridge.
Cardiovascular disease (CVD) is the general term for diseases affecting the heart or blood vessels which usually presents itself with a build-up of fatty deposits in the arteries and increased risk of blood clots. Unfortunately, there is currently no cure for CVD, but patients are usually given prescriptions to help combat the disease as well as being given suggestions for lifestyle changes they can make. This disease limits patients’ abilities to live their lives to the fullest potential because of functional limitations of the heart and blood flow.
Despite this, there is currently no way of reversing the effects of CVD. However, researchers believe that there might soon be a solution with the aid of stem cell therapy. Many stem-cell-based therapies are currently underway, focusing on ways to regenerate the heart muscle and restore the structure and function of the heart. Stem cells could be the answer to cardiovascular disease, the leading cause of death globally, taking around 17.9 million lives per year.
The current paper discusses the benefit and impact of stem cells and their relationship with helping reserve cardiovascular disease.
Cardiovascular Disease; Embryonic Stem Cells; Mesenchymal Stem Cells; Heart Failure
Cardiovascular disease remains the number one non-communicable killer disease, which recorded a mortality rate of 17.5 million in 2012 and accounted for 46.2% of all reported deaths worldwide in 2014 (1). About 60% of CV disease is represented by ischemic heart disease responsible for structural cardiac abnormalities, finally leading to Heart Failure (HF) or/and death.
HF is a common, expensive, lethal, and disabling condition. Its prevalence in industrialized nations has reached epidemic proportions (e.g. >6.5 million in the USA) and continues to rise as the population ages (2). Despite significant advances over the last three decades, the prognosis of patients hospitalized with HF remains poor, and the 5-year mortality approaches 50% (3). Many patients with end-stage heart damage will require a heart transplant, yet there is a profound shortage of donors, illustrating the tremendous need for alternative/novel therapies (4). Therefore, HF constitutes a major public health problem worldwide, a leading cause of morbidity and mortality, and an increasing burden on healthcare systems around the globe.
Myocardial infarction (MI) is a common cause of heart failure (HF) due to a consequence of partial or complete occlusion of the coronary artery, which diminishes the delivery of oxygen and nutrient supply to the myocardium where the vessel serves (5). Approximately 25% of myocardial infarcted patients suffer from severe left ventricular dysfunction and are at risk of progressive heart remodeling (6).
Left ventricular (LV) remodeling describes the heart’s (mal)adaptation to mechanical, neurohormonal, and inherited changes by regulating ventricular size, shape, and function. While cardiomyocyte growth orchestrated by increased micro-circulatory blood supply (e.g. during pregnancy, growth, or athletic training) is considered physiological, and completely reversible, ‘adverse’ or ‘pathological’ remodeling following myocardial infarction (MI) confers disproportionate risk for heart failure (HF) and significantly decreases survival (7,8).
Post MI cardiac is characterized by a persistent inflammatory reaction after acute stress and during chronic pathologies, increased oxidative stress, myocyte apoptosis, imbalanced oxygen consumption, energy metabolism and extra-cellular matrix formation contributing to scar formation, endothelial dysfunction, 8 and decreased capillary density and neovascularization (8). Remodeling may occur inside the infarct zone and “at distance” from the infarct zone (remote remodeling) (9). The presence of the akinetic tissue restricts the overall cardiac performance, forcing the remaining myocytes to increase contractility to maintain adequate cardiac output. These events trigger abrupt alterations in the global cardiac architecture and cause cardiomyocyte hypertrophy, further myocyte loss, thinning of the ventricular wall, weakening of contractility, and an eventual cease in the function of the cardiomyocytes.
Although LV remodeling tries to compensate for the destruction of the cardiac cell, it is not a “metabolic efficient” process; cardiac blood flow and coronary network can not accommodate a progressive increase in the size of chambers, cardiac mass and hypertrophy of myocytes; very soon it becomes a deleterious process (8,9).
However, cardiac remodeling represents the single mechanism of adaptation to the destruction of cardiac tissue since endogenous cardiac regeneration has a low magnitude. Evidence suggested that the mammalian heart is not a completely postmitotic organ, but the rate of renewal is very low (10,11). The annual rate of cardiomyocyte turnover ranges from cardiomyocyte turnover is currently estimated at 0.5% to 2% per year (10-12). Turnover rates are decreasing exponentially with age. At the age of 20, approximately 1-2% of cardiomyocytes turnover per year. By age 70, this rate decreases to approximately 0.3% (10, 11, 12).
The myocardium contains approximately 20 million cardiomyocytes per gram of tissue. The average left ventricle is approximately 200g and therefore contains approximately 4 billion cardiomyocytes. A severe MI can destroy one-quarter of the heart’s functional cardiomyocytes within a few hours (13). The staggeringly low turnover rate is not surprising and helps explain the poor prognosis of HF. Although cardiomyocytes appear to continue to renew throughout life, the quantitatively dominant mechanism of growth in the mammalian postnatal heart is an increase in cardiomyocyte size (14,15).
Basics of Cardiovascular disease
Cardiovascular disease refers to conditions that damage the heart or blood vessels. Usually, it manifests as a rise in the risk of blood clots and an accumulation of fatty deposits in the arteries. It can also be responsible for damage to arteries in organs such as the brain, heart, kidneys and eyes (16.) CVD does not only describe one type of heart disease but is more of a broader term that discusses four main cardiovascular system diseases.
One of which is coronary heart disease (CHD) which occurs when the flow of oxygenated blood is blocked or reduced to the heart. CHD puts unnecessary strain on the heart leaving patients more vulnerable to developing other conditions affecting their hearts. It could lead to angina, a heart attack, and possibly even heart failure. Coronary heart disease usually presents itself with symptoms: chest pain, shortness of breath, pain throughout the body, feeling faint, and nausea. As the disease progresses and the patient’s blood vessels fill with fatty acids, they develop atherosclerosis. Patients are more at risk of getting atherosclerosis if they have conditions like high cholesterol, high blood pressure, or diabetes (17).
The second cardiovascular system diseases are strokes and transient ischaemic attack (TIA), which is known as a small stroke. A stroke is when the blood supply to part of the brain is cut off, which can cause brain damage and possibly death. A transient ischaemic attack is similar, but the blood flow to the brain is only temporarily disrupted. The way both diseases present themselves is displayed in the face where it may have drooped on one side, the person may be unable to smile, or their mouth or eye may have dropped; in the arms when the person may not be able to lift both arms and keep them there because of arm weakness or numbness in one arm; and in speech, it may be slurred or garbled, they may not be able to talk at all, or they may not be able to understand what you are saying to them (16). Patients are more at risk of having a stroke if they already have high blood pressure, high cholesterol, irregular heartbeats, or diabetes (18). Patients are more at risk of having a TIA if they are smoking, have high blood pressure, are obese, have high cholesterol levels, are regularly drinking an excessive amount of alcohol, have an irregular heartbeat called atrial fibrillation, or have diabetes. Also, people over 55 years of age and people of Asian, African or Caribbean descent are also at a higher risk of having a TIA (19).
The third disease is peripheral arterial disease (PAD). It occurs when there’s a blockage in the arteries to the limbs, usually the legs. Peripheral arterial disease can cause dull or cramping, leg pain (which worsens while walking), hair loss on the legs and feet, numbness or weakness in the legs, or persistent ulcers on the feet and legs (16). There is no way to identify the disease, as it lacks unique symptoms. The pain in the legs has a wide range and will usually go away after a few minutes of resting one’s legs. PAD often develops slowly over time. If the pain develops quickly or gets suddenly worse, it could be a sign of a serious problem requiring immediate treatment (20).
Lastly, there is aortic disease which is a group of conditions affecting the aorta. It is the largest blood vessel in the body carrying blood from the heart to the rest of the body. The most common disease to affect the aorta is an aortic aneurysm (AA), where the aorta becomes weakened and bulges outwards (16). While it does not have symptoms, there is a chance it could burst and cause life-threatening bleeding. If it bursts, it can cause sudden, severe pain in the tummy or lower back, dizziness, sweating, paleness, clammy skin, a fast heartbeat, shortness of breath, fainting, or passing out. People at a higher risk of having an AA include all men aged 66 or over and women aged 70 or over who have one or more of the following risk factors: high blood pressure, chronic obstructive pulmonary disease, high blood cholesterol, a family history of AA, history of heart disease or stroke, or if they smoke or have previously smoked (21).
CVD has quite a few risk factors. However, there are many ways to help patients from putting themselves at risk. Leading a healthy lifestyle significantly decreases a person’s chance of developing CVD. Things like eating a balanced diet, exercising regularly, quitting smoking, lessening one’s alcohol consumption, and maintaining a healthy weight are all ways to help prevent CVD without medical intervention. When discussing medical intervention, many doctors have different ways of going about managing the disease, either with medicine or surgery (16).
Basics of Stem Cells
Stem cells are special cells that have the capability to develop into different types of cells.
There are two main types of stem cells, embryonic stem cells (ESCs) and adult stem cells, also known as mesenchymal stem cells (MSCs).
Embryo-derived stem cells can be obtained during different stages of embryonic growth. Stem cells derived from the blastocyst are known as embryonic stem cells (EC), and cells derived at a later stage are known as embryonic germ cells (EG). These cells are pluripotent, which means that they have the capability to develop into any type of cell. They are influenced by their environment and self-renew rapidly in culture. They have the potential to differentiate into approximately 210 different cell types (22). This quality of embryonic stem cells allows them to repair damaged tissue, such as cardiac tissue.
There are two types of mesenchymal stem cells. One type can be extracted from fully developed tissues such as bone marrow, heart and skin tissues. However, the number of stem cells that can be obtained from these tissues is limited. In addition to this, stem cells that come from these tissues can only self-renew and divide to develop the same type of cells. Thus, most adult stem cells are classified as multipotent cells as they can only develop into specialized cell types present in a specific tissue or organ.
The other type of mesenchymal stem cells are known as induced pluripotent stem cells. These are adult stem cells that have been chemically modified to mimic the qualities of embryonic stem cells. Therefore induced pluripotent cells can develop into most other types of cells in the body. However, these stem cells pose a risk of teratoma formation.
Stem cell treatments are a desirable therapeutic option to regenerate the myocardium and improve cardiac function after myocardial infarction. They have the ability to renew damaged myocardium and restore the structure and pump function of the heart. However, these stem cells must be extracted, isolated and cultured in such a way that ensures safe and effective transplantation into humans. Research has shown that embryonic stem cells can differentiate into a wide range of cardiomyocyte cell types, including atrial, ventricular, sinus nodal and pacemaker-like cells (23). However, with the limited supply of donor human embryos and the various ethical and political issues surrounding the use of embryonic stem cells, it is very difficult to obtain an adequate amount of these stem cells. Thus, researchers have been primarily focused on the further development of stem cell therapy using adult stem cells.
Consequently, researchers have begun to focus on developing methods of using induced pluripotent cells in stem cell therapy for cardiovascular disease as they are more readily available. As of now, not much research has been carried out, but iPSCs have shown to closely resemble the qualities of embryonic stem cells in their application in treating heart disease. It is important to note that the plasticity of these iPSCs is more limited than embryonic stem cells. Their conversion into cardiomyocytes is unlikely and quantitatively very limited (24), and they often fail to integrate electromechanically with the recipient’s heart (25).
The use of mesenchymal stem cells is convenient as their immunomodulatory characteristics allow them to act as universal donors. These cells release angiogenic, apoptotic, mitogenic and homing factors that have cardio-protective actions (23). Various studies on animals have shown great success in the use of adipose tissue and bone marrow stem cells for cardiovascular disease. They are easy to isolate via liposuction and are a rich source of stem cells. MSCs can regulate the inflammatory response by suppressing white blood cells and triggering anti-inflammatory subsets in natural and adaptive immunit (26). Unfortunately, there are issues of low tissue retention and low survival rate after transplantation.
It was only recently discovered that cardiac stem cells are capable of regeneration. They can be extracted from adult human auricles. Studies show that cardiac somatic cells are more effective in differentiating than bone marrow or adipose tissue cells. Also, it is possible to cultivate a great number of these cardiac cells from a small biopsy. However, cardiac stem cells need to be expanded ex vivo before transplantation, making this process relatively expensive.
Stem Cells in Heart Failure
a. Stem cells hypothesis
Despite guideline medical therapies that may improve prognosis, HF is a progressive condition, and many patients evolve to advanced stages of disease when available options remain only replacing the entire heart (heart transplant) or supporting the entire pump function (artificial heart). Progression is intrinsically related to the continuous process of adverse remodeling and myocyte loss. Because recent evidence suggests that the rate of myocyte loss is not possible to be compensated by myocyte’s renewal, which is very low (10-13), medical research has begun to search for other therapeutic pathways.
Because recent evidence suggests that endogenous stem cells minimally contribute to new cardiomyocyte formation, research has begun to search for endogenous pathways that play a role in stimulating existing cardiomyocyte proliferation. One such approach is a stem cell or cell-based therapy, a relatively new frontier in biomedical research that has sparked much debate and controversy in cardiovascular medicine. Stem cells are a unique cell type characterized by two important qualities: the ability to self-renew and the potential to differentiate into various cell types (27). Stem cells and other cell-based therapies hold promise to counteract the negative effects of tissue loss and subsequent adverse cardiac remodeling and promote cardiac repair.
b. Mechanism of cardiac reparation
When cell therapy emerged as a novel approach to heart disease almost two decades ago, the hope was that it would enable one, for the first time, to regenerate cardiac muscle after myocardial infarction (MI), replacing dead tissue with new contracting myocytes (28).
In the ensuing years, various types of adult cells (obtained from bone marrow, heart, adipose tissue, or other tissues) were found to be effective in improving left ventricular (LV) function in animal models of ischaemic cardiomyopathy. Still, none has been shown to regenerate new myocytes due to the failure of the cells to engraft and their inability to differentiate into mature cardiomyocytes (29, 30, 31).
Despite two decades of intense investigation, the mechanism(s) whereby transplantation of cells improves the function and structure of the diseased heart remains elusive. A debate currently exists as to whether cell engraftment and differentiation are a requirement for a therapeutic response. Over the past 10 years, a series of 12 pre-clinical studies have demonstrated that although cell therapy consistently improves function in the infarcted heart, the transplanted cells do not engraft in the myocardium and do not become cardiomyocytes; instead, they disappear almost completely within a few weeks of transplantation (32, 33, 34). The dissociation between functional improvement and cell engraftment was consistent and independent of the cell type studied (31, 32, 33, 34).
Notably, the formation of new contractile cardiomyocytes need not be the only mechanism whereby the function of a diseased heart can improve. In principle, other mechanisms unrelated to myogenesis could result in functional improvement, including angiogenesis, a reduction in apoptosis, modulation of the extracellular matrix (e.g. reduction in fibrosis), or a change in the contractile properties of native cardiomyocytes (35, 36). Most of the implanted cells were lost due to washing out from the injected area and cell death from ischemia and inflammation. It is thought that very few stem cells might be able to directly contribute to vascular structures, and there is no clinical evidence that transplanted stem/progenitor cells differentiate into new mature myocardials so far (37). Consequently, attention to transplanted stem cells has shifted from the capacity of myogenesis (in situ differentiation toward cardiomyocytes) to their capacity for secreting factors that affect the surrounding myocardium in a paracrine manner (37). Direct cardiomyocyte regeneration has a low magnitude. Currently, the primary mechanisms by which cell therapy exerts beneficial effects are now believed to include paracrine effects, immune regulation, neoangiogenesis, and microenvironment improvement. The transplanted stem cells released a large variety of cytokines, chemokines and growth factors that inhibit apoptosis and fibrosis, enhancing contractility (38). Stem cells can also secrete anti-inflammatory factors, such as IL-10, which can regulate myocardial inflammation after myocardial infarction and improve the microenvironment (39). Additionally, stem cells can secrete exosomes, which play important roles in cytoprotection, and stimulation of angiogenesis (40, 41). Another important benefit is an improvement of the infarct’s passive mechanical properties and subsequent amelioration of ventricular remodeling (42, 43). Improved passive mechanics may result in part from a mechanical buttressing of the infarcted wall by the transplanted cells.
Source of Stem Cells and Cell Type
At time of writing, there is no consensus on the best cell source and type suitable for cardiac regeneration. An ideal stem cell would have contractile and electrophysiological properties, would have the potential to proliferate, engraft and survive in an ischemic area and have the ability to induce a paracrine effect to stimulate endogenous cardiac regeneration. However, no type of stem cell has met all of these expectations in clinical trials (44).
a.Pluripotent stem cells
Embryonic Stem Cells
For more than a decade, experimental work on embryonic stem cells (ESC) for myocyte reproduction has steadily progressed. There is evidence that the host myocardium can control the specific cardiomyocyte differentiation of a limited number of implanted ESC. Still, once a threshold is exceeded, uncontrolled proliferation and differentiation with teratoma formation occur (45). Researchers and industry have therefore focused on pre-differentiated cardiomyocytes from ESC, which can theoretically be produced in large quantities in vitro prior to implantation into the diseased heart (45, 46, 47). Clinical translation of this technology, however, is still hampered by several fundamental biologic and biotechnological problems: (I) theoretically, even a single naïve embryonic stem cell can give rise to a teratoma in the heart – therefore, ESC-derived myocytes or myocyte progenitor cell products must have 100% purity, requiring complex and reliable cell processing techniques; (II) the immunogenicity of embryonic stem cells and their in vitro progeny is incompletely understood, and it is unlikely that ESC-derived cell products can be transplanted in allogeneic fashion; (III) the ethical debate surrounding ESC procurement from viable human embryos continues to hamper the development of human ESC technology.
Induced pluripotent stem cells (iPS)
ESC-like cells can also be produced without the need to destroy an embryo by therapeutic cloning or reprogramming of somatic cells. iPS cells are taken from any tissue (usually skin or blood) and are genetically modified to behave like an embryonic stem cell. They are pluripotent, which means that they have the ability to form all adult cell types. iPS cloning requires virus-mediated transfection of cells with several genes, which can be mutagenic (48).
The therapeutic potential of hiPSCs is considerable, as they are patient-specific stem cells that do not face the immunologic barrier, in contrast to embryonic stem cells (49).
However, clinical applications of iPS cells face several major hurdles, such as low cellular reprogramming efficiency, oncogenic risks, low efficiency of cardiomyogenesis, and cell line-to-line variations (50, 51).
One of the major barriers that occurred during preclinical trials is that cardiomyocytes derived from PSCs (ESCs or iPSCs) have an immature phenotype compared to human adult cardiomyocytes (44). Moreover, human PSC-derived cardiomyocytes are functionally immature in terms of sarcomere organization, calcium handling properties, and metabolism compared to adult cardiomyocytes (52). This hinders their ability to integrate efficiently with host cardiomyocytes and is believed to be the reason that ventricular arrhythmias can arise (53).
Multipotent/unipotent stem cells
Bone-Marrow-Derived Stem Cells (Autologous): Bone marrow stem cells (BMSCs) are among the best described multipotent stem cells for transplantation because they are easily accessible, readily propagated in culture, and do not require adjunctive immunosuppressive therapy.
Mesenchymal Stem Cells (Autologous): Mesenchymal stem cells (MSCs) are another well-described group of cells used for cardiac transplantation. These cells can be derived from a variety of different tissues like cord blood, BM, and adipose tissue. MSCs can differentiate into various mesenchymal lineages such as skeletal myoblasts, chondrocytes, adipose tissue, and cardiomyocytes in vitro [71–79]. The major advantages of MSC-based cell therapy for cardiac repair lie in its ability to promote the growth, survival, or differentiation of other cells (54).
Skeletal Myoblasts (Autologous): Unipotent skeletal myoblasts are precursor cells of human skeletal muscle. These cells normally lie in a quiescent state but can reenter the cell cycle to proliferate and differentiate into functional skeletal muscle in response to injury (55). The unique features that make skeletal myoblasts suitable for cardiac repair are their autologous origin, high proliferative potential, resistance to ischemia, and low risk of tumorigenesis.
Resident Cardiac Stem Cells: Although this cell type has shown to improve some aspects of cardiac function in HF patients, isolation of autologous SCs is invasive, culture takes time (56).
Route of Delivery
Several factors contribute to the success of stem cell therapy. One of the most significant factors is the route of delivery, yet there is no consensus on the best route (32). Different cell delivery pathways have been used, such as direct injection into the myocardium, introduction through the epicardial and coronary arteries, and introduction via intravenous infusion. These routes have been studied in many clinical settings. There are four primary methods of administration that are clinically practical, and each has its own advantages and disadvantages. For instance, although intracoronary delivery may cause poor cell retention in the heart, it carries the benefit of minimal inflammation. Transendocardial stem cell injections (TESI) are a minimally invasive technique where stem cells are injected directly into the myocardium through the endocardium. This procedure carries a small risk of perforation and arrhythmias; however, the retention of the cells is higher compared to other methods and in certain pathologies has shown greater effectiveness. Intravenous delivery of stem cells is the least invasive route and takes advantage of physiological attraction signals which induce cellular homing to the site of injury (32, 57, 58). With intravenous administration, there are concerns of poor implantation and retention. Unfortunately, very few studies have directly compared the therapeutic difference between routes of delivery. A meta-analysis of preclinical studies in models of acute myocardial infarction (AMI) by Kanelidis et al. (57) concluded that TESI was associated with improved efficacy over intracoronary delivery.
Transplantation of viable cells into the harsh environment of necrotic myocardium remains a significant therapeutic challenge resulting in very poor cell retention (59, 60). To combat this problem, tissue engineering approaches have designed biomaterials as cell retention mediums. These injectable biomaterials must be biodegradable, biocompatible, provide mechanical support, be of appropriate dimension, allow for precise placement (59), improve cell survival, and promote tissue regeneration (61, 62). These polymers can either be synthetic or naturally derived, each having its own advantages and disadvantages. Some polymers can even be specifically tailored to optimize cardiac repair (61, 62), and 3D-printing has increased the available types of biomaterials, improving cell integration and vascularization (63).
Clinical and Biological Factors Associated to Sucesses of Stem Cell Therapy
In addition to the cell type and administration route, cell-based therapies may also be impacted by other factors. These mainly include the dose of cells being administered, the frequency of cell administration, the timing of administration in relation to the injury (chronic heart failure versus acute MI), the metabolic state of the transplanted cells (previously frozen and thawed cells versus new cells), and the simultaneous use of other drugs, initiation of revascularization and treatment with surgery (64, 65, 66).
The exact timing of the administration of cells has not been confirmed. It is hypothesized that the longer the time interval between myocardial injury and administration of stem cells, the less there is a probability of benefit. Cardiac parameters [LVEF, LVESV, and left ventricular end-diastolic volume (LVEDV)] were significantly improved when stem cells were transplanted between 7 and 10 days after AMI (32, 67).
Cell retention, engraftment, and rejection
In preclinical and clinical trials, cell retention in the heart 24h post-administration does not seem to exceed 10% (30, 32, 68). The low percentage of retention is due to the rapid washout of cells once injected and poor engraftment potential (69). The inflamed heart post-MI, phagocytosis of cellular debris and a lack of tolerance to high mechanical forces in donor cells all contribute to the magnitude of cell death during SC therapy (70).
Rejection of transplanted cells is another important component to consider, particularly when the source is allogeneic. This has led to a push in cells that require minimal or no immunosuppression, such as ESC-derived cells, MSCs and MPCs (32).
Studies show large variabilities of cell dosages, ranging from 1 × 106 to 2 × 108 cells administered to patients, which is much lower than the cells lost after myocardial injury (12). Cell engraftment and survival upon transplantation are quite low, suggesting a need for larger doses of cells to be administered if the goal is to regenerate injured myocardium.
Two clinical trials (MSC-HF and TRIDENT) have demonstrated the therapeutic superiority of higher doses (71, 72). However, large doses of cells may cause aggregates, increasing the risk of arrhythmias (72).
Clinical Trials (RCTS) with Stem Cells in Heart Failure
Due to the heterogeneity of patient populations, and delivery methods, it is difficult to perform direct comparisons of clinical studies. In addition, most clinical trials of cell-based therapies for heart disease have only assessed medical endpoints, such as mechanical or clinical improvements in measurements, for example, the ejection fraction on echocardiography or other imaging methods, without reporting the ultimate benefits of such therapies.
Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function. In contrast to acute myocardial infarction (where results have been consistently negative for more than a decade), in the setting of HF, the results of Phase I-II trials are encouraging, both in ischaemic and non-ischaemic cardiomyopathy. Several well-designed Phase II studies have met their primary endpoint and demonstrated an efficacy signal, which is remarkable considering that only one dose of cells was used (12, 32). That an efficacy signal was seen 6-12 months after a single treatment provides a rationale for larger, rigorous trials. Importantly, no safety concerns have emerged.
Mounting evidence suggests that stem cell therapy can impart beneficial effects to HF patients without necessarily augmenting common indices of LV function. For example, among placebo-controlled, double-blind, randomized Phase II trials in ischaemic HF, some have reported an improvement in LV function with cell treatment (e.g. MSC) (73, 74). Still, others have not: patients receiving cell therapy exhibited improved functional capacity and quality of life in TAC-HF (75) improved quality of life in ATHENA (76), and CONCERT-HF (77) and reduced mortality and cardiovascular hospitalization in ixCELL-DCM (78) and CONCERT-HF (60) yet none of these studies detected a change in LV function. DREAM-HF (79), the largest study of cell therapy in HF, has also reported a reduction in MACE (vide supra).
To note, stem cell therapy could alleviate the outcome of HF via systemic actions that do not necessarily result in augmented LV function. Because of this, and because the clinical outcome is more relevant to patients than surrogate endpoints such as LVEF or LVESV, there has been a shift away from LV function as the primary endpoint for cell therapy trials in HF.
Ethical Debate on the Use of Embryonic Stem Cells
There is much discussion behind the use of whether or not embryonic stem cells should be used for research in curing other diseases. The issue at hand is regarding the onset of human personhood and human reproduction that could have come from the embryos that are taken for research. This process causes the destruction of human embryos and brings up the discussion of which life is worth saving more.
It is often a matter of religious belief that the embryo is a life of its own due to the idea that “life begins at conception.” What goes along with this view is that the embryo has as many rights as a living person and therefore brings up issues of taking away consent and rights. However, there are some who view embryos as clumps of cells, and there are those who are indifferent to the conversation as a whole. They view the discussion from both perspectives that the embryos deserve respect as potential human beings but that it is acceptable to use them for certain research provided there is good scientific justification, careful oversight, and informed consent from the woman or couple for donating the embryo for research.
With these topics comes informed consent, which is regarded as a basic requirement for research with human subjects. If there is no consent given, it takes away a person’s autonomy and is stripping away their rights. With this comes many other steps such as waiver of consent, consent from the gamete donor, and confidentiality of the donor’s information (80).
Ethical Debate on the Use of Mesenchymal Stem Cells
Adult stem cells are considerably more readily available than embryonic stem cells. They can be derived from almost anywhere in the body. But with this wider selection of stem cells comes issues of consent, control and justice. There are various concerns surrounding animal testing, the use of animal cells in humans and, of course, the application of human stem cells themselves. Primarily, it is important to recruit suitable patient subjects and ensure they make an informed decision and give consent. This avoids the risk of ‘therapeutic misconception’ later on during the process. Adult stem cells, in particular iPCS, pose a large risk of teratoma formation. Toxicity and the risk of tumorigenicity must be assessed for all stem cell-based products, especially when genetically modified, in order to minimize the risks of harm as far as feasible before moving to humans (16).
With ongoing debates, concerns about animal testing must be addressed. It is a known fact that animals are inadequate models to predict effects on humans. As a result, some may say that we are endangering animal lives for little to no purpose. However, it could be argued that by testing on animals, we are saving the lives of humans that could have been harmed during this testing process. Also, another issue that has raised a lot of controversies is the use of animal-derived pluripotent stem cells in humans. Some fear the creation of chimeras – mythical creatures that are half human and half animal. Others view such research as an inappropriate crossing of barriers between species. However, animal-animal hybrids of various sorts exist today, such as the mule. Furthermore, it is often the case that human cells are injected into animals rather than the opposite (17).
Justice is a necessary consideration in stem cell research and treatment. It is ideal for storing different lines of broad multipotent and pluripotent stem cells, suitable for use in regenerative medicine applications. In the case of stem cell therapy for heart disease, this process will aid scientists in finding a good match for any potential recipient’s heart.
Cardiovascular disease has become an epidemic that impacts and kills millions each year. Until the idea of using stem cells was first introduced, there has been no plausible way to reverse the effects. The large number of patients who lose their lives each year encourages doctors to continue to push the research of stem cell transplants. Research funding and informed consent of patients allow these studies to keep going to save the lives of those afflicted with Cardiovascular disease. The use of Mesenchymal stem cells has been the most promising because of their ability to not cause an immune response because they are genetically the same as the patients already present stem cells. While there are some issues that are still being sorted out, the use of stem cells to combat CVD could save millions.
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