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Heart Failure and Stem Cells

In this short informational guide we will look at heart failure and how stem cells can help. This guide includes information about heart failure, the causes, symptoms and treatments, how stem cells can help, the directions in which research is going, expanding stem cells, the delivery of these cells, homing, detecting niches and clinical studies. This information is meant as an overview of the condition and the possible future treatments that will be available and should not replace medical advice.

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About Heart Failure

Heart failure or HF for short is a chronic cardiovascular syndrome whereby damage to the heart muscle prevents it from filling or pumping blood around the body normally. Although there are many root causes that can precipitate the syndrome, the outcome is ultimately the same: the body’s organs are deprived of the blood they need to function properly. The heart continues to work, but not as efficiently as it should, and the blood returning to the heart through the veins backs up causing congestion in the tissues and in the kidneys. The can lead to swelling (edema) throughout the body, most often seen in the legs and ankles.

As time passes, the heart will try to compensate by increasing in size. Like any other muscle under strain, the heart tries to thicken but progressive enlargement weakens it by further reducing the efficiency in which the blood is pumped around the body. Eventually the ability of the heart to circulate blood through the body is so compromised that blood pressure begins to drop and fluids back up in the lungs causing shortness of breath, especially when lying down.

Heart failure is a major problem in both developed and developing nations. The five year mortality rate for this is around fifty percent which is great than than of breast cancer or colon cancer. In 2010 a report from the American Heart Association stated that the number of people newly diagnosed with heart failure in the United States alone was estimated to be more than 500,000 per year. It is estimated that approximately 5.8 million people over the age of 20 suffer with this condition and these numbers are expected to rise as the population ages.

Causes of HF

There are a number of different conditions that can increase your risk of developing heart failure. The most common cause in the developed world is coronary artery disease (myocardial infarction and myocardial ischemia), which results from a narrowing or blockage of the arteries that supply blood to the heart. Major risk factors for congestive heart failure include coronary artery disease and high blood pressure. Coronary artery disease accounts for 60 to 75 percent of all cases and high blood pressure (hypertension) is a concern in the elderly. Other risk factors include diabetes mellitus, abnormal heart valves (related to rheumatic fever or congenital heart defects), inflammation of the heart, or infection of the heart valves (endocarditis) or muslce (myocarditis).

Symptoms and Treatment

The most common signs of heart failure are fatigue and shortness of breath (dyspnea). People who are living with this condition may also experience fluid retention which often shows as swollen legs or ankles, or a constant cough (from fluid in the lungs), as well as weight gain due to the build up of fluid in the abdomen. These symptoms can become worse if you diet is high in salt, you have excessive fluid intake, or take medications that cause water or salt retention. Colds and flu can also make symptoms worse.

There is no cure for heart failure but it can be controlled. This is done by treating the underlying conditions that cause it. The goals for treatment are three-pronged: to improve symptoms, to stop the heart failure from getting worse, and to prolong life.

The standard treatment for people with advanced symptoms of heart failure involves medications and lifestyle changes. Frontline medications include diuretics to reduce fluid retention, and angiotensin converting enzyme (ACE) inhibitors and beta blockers to prevent or slow the progressive heart enlargement. Aldosterone antagonists act on the kidney to increase urine output as well as to reduce scarring in the heart, while drugs such as digoxin help to regulate the heartbeat. Lifestyle changes are also important which includes more rest, reduced dietary salt intake and modifying daily activities.

There are some patients who may need any one of a number of common heart procedures and this will depend on the root cause of their heart failure. Some of the heart surgeries require stopping the patient’s heart and in these cases heart-lung machines substitute by pumping blood throughout the body. Other procedures are less invasive and can be accomplished with a catheter under local anesthetic. Example of heart surgeries include repairing faulty valves and implanting an artificial valve or mechanical pump. Blocked arteries can be bypassed with a piece of artery from the arm or chest, or a vein from the patient’s leg, or using a balloon catheter followed by implantation of a stent to keep the artery open.

In cases where the heart is so damaged that it cannot be repaired, a heart transplant may be the only option. Modern heart transplants have been successfully performed since 1980 and today around 85 percent of heart recipients will live at least an additional year, 75 percent live five more years and 36 percent live 20 years. Donor hearts are however in short supply and there is a long waiting list. In addition to this, to prevent the body from rejecting the donor heart, recipients must receive immunosuppressant therapy for the rest of their lives and this can leave them susceptible to a range of other diseases.

In addition to these existing therapies, researchers continue to investigate and test new ways to treat heart failure. This includes improved surgical methods and equipment and identifying genetic links or drugs that can help to regenerate heart muscle. Despite the range of treatments available for heart failure that slow the progression and alleviate the symptoms, none are able to regenerate heart tissue. Stem cells offer the promise of future therapies that may achieve the goal of obtaining a cure.

How Stem Cells Can Help ?

Heart failure and stem cell therapy is an exciting prospect and researchers have already seen a number of experimental trials that are evaluating this approach. In theory, the ability of stem cells to grow into specific cell types and produce growth factors means that they could be a ready source of precursors to make heart cells (cardiomyocytes), blood vessel cells (endothelial cells), support cells and regulatory signals. In the case of heart failure, it is hoped that coaxing stem cells into action will contribute to a healthier heart microenvironment and promote the growth of heart tissue and blood vessels for the purpose of restoring at least some of the lost function of the heart.

There are a number of different types of stem cells being looked at for potential therapies for heart failure at the moment. Skeletal muscle stem cells (myoblasts) were the first to be tested in a clinical trial setting back in 2003. In the past 10 years tremendous gains have been made in preclinical research and now bone marrow stem cells, endothelial stem cells, mesenchymal stem cells, cardiac progenitor cells and fat-derived stem cells are all being explored as potential therapeutic sources. Some of these have even progressed to the clinical trial stage. Some stem cells, such as induced pluripotent stem cells and embryonic stem cells are still at the animal model testing stage. This is a crucial step towards vetting the potential and safety of using such cells in human studies.

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Research Directions

Research and clinical trials have yet to find a cure for heart failure. They have however helped to identify the many parameters that must be better understood before the full potential of stem cells can be applied to heart failure. Below you will find information on a few of the major challenges that researchers have to deal with in order to achieve their goal of a cure.

Expanding Stem Cells

Many transplanted stem cells never reach their target so it is vital to be able to transplant high numbers of stem cells in order to maximize the number of cells that are able to reach the damaged heart tissue. Researchers are looking at finding better method for isolation, identification and expansion of large numbers of stem cells in the laboratory and they have added some newer techniques to their arsenal as well.

Nanofibers are being saturated with growth factors that can boost stem cell numbers, and some types of stem cells such as HSCs are being seeded onto a bed of stromal cells that nurture the growth and expansion of HSCs. Also being tested is the delivery method for growth factor genes through genetic engineering either into a particular site in the body or into stem cells harvested from patients.

Delivery of stem cells

There are a number of different routes that are currently being used to deliver stem cells into patients with heart failure. The least invasive of these delivery methods is through the use of intravenous injection. This is where the stem cells are injected into the patient. Transepicardial injection is another delivery method and this is where the stem cells are injected into the heart from the outside. This requires surgery for direct visualization. This is the most invasive delivery method but it is also the most dependable. Transendocardial injection is less invasive and this is where the stem cells are injected through the inner wall using a catheter. This does however require sophisticated imaging or guidance systems to ensure delivery to the right areas. Intracoronary injection which is an injection directly into the arteries of the heart using a balloon-like catheter is the most common delivery method used following myocardial infarction. The main issue with this approach is in making sure that the injected stem cells do not plug up small vessels and reduce blood flow to the heart. This approach has been used in more than 2,000 patients in dozens of separate clinical trials and has be shown to have an excellent safety profile. Blockages or embolisms are the main concerns with the trans-venous coronary sinus injection delivery method too.

All the different delivery routes have similar problems and these include, retention of enough transplanted cells in the heart; cells becoming lodged in the lungs; or cells circulating to other organs in the body. In order to overcome some of these issues, researchers are developing new strategies such as tissue engineered biodegradable scaffolds or sheets loaded with stem cells. A recent trial has corroborated this approach, showing that transplantation of a bioengineered sheet loaded with cardiac progenitor cells was able to promote cardiogenesis and improve heart function in patients with myocardial infarction.

Homing

Endogenous stem cells live in many different parts of our bodies. Stimulating these into one action is challenging and getting them to travel to the desired site is another. Cells that are harvested from patients or donors and transplanted into the patient’s body also need cues to find their way to the desired location.

Researchers are trying to find the best way to encourage stem cells to home specifically to site where damage has been caused. In their search, they have identified a number of different intercellular messengers called cytokines which are releaed by damaged heart tissue. These can attract the stem cells. However, some of the factors such as SDF-1, are only found for a very short period of time after cardiac damage. One solution to this problem might be to deliver genetically engineered cells that express SDF-1 to cardiac tissue. In that way, the SDF-1 expressing cells will act like a beacon for stem cells to follow. Experimentation in animals has proven that this approach can be successful and that stem cells from bone marrow did actually home to damaged heart tissue expressing the SDF-1 beacon.

Detecting Stem Cell Niches

Finding new environments, or niches, within the body that harbor stem cells is an ongoing challenge for researchers. Not only is this important for identifying new stem cells sources, but also for understanding basic stem cell biology. The bone marrow is one such niche and this is where the self-renewal of hematopoietic stem cells is maintained. Other environments that contain stem cells include the heart, intestine, skin and neural tissue.

A new method for finding stem cells niches is called lineage mapping. This involves genetically tagging stem cell markers so that they can be tracked to their environment in the body. Japanese researchers have been using this technique and they showed that neural crest stem cells that were derived from an embryo and located in the heart could actually migrate and develop into cardiomyocytes following myocardial infarction.

Ongoing Clinical Studies

Skeletal Myoblasts

The first stem cells that were used in cardiac therapy were skeletal myoblasts isolated from muscle biopsies. This first trial took place in 2008 and since then a number of other trials using the same myoblasts have been initiated. Although some of these trials have been discontinued, two are still ongoing. These are PERCUTANEO, for patient that have suffered from myocardial infarction; and MARVEL, for patients with congestive heart failure. We are still waiting to see if these trials show sustained improvements in heart function and integration of skeletal stem cells into the damaged hearts of the participants.

Hematopoietic Progenitor/stem cells (HPSCs)

At present there are 30 plus NIH registered experimental trials evaluating stem cell therapy for heart disease. The majority of these trials are testing for the safety and efficacy of using hematopoietic progenitor/stem cells from bone marrow for treating various cardiovascular diseases. Over 1,000 patients have now been transplanted with various populations of bone marrow stem cells and the procedure has been shown to be safe and modestly beneficial. Although the transplanted bone marrow stem cells are not actually generating new heart cells, they appear to be providing some benefit by way of a mechanism that has yet to be determined. Further studies in this area may focus on using particular subsets of HPSCs in an effort to pinpoint the most efficacious cells.

Cardiac Stem Cells

It was always thought that the heart was incapable of repairing itself after an injury but in 2003 researchers were able to isolate cardiac stem cells from human heart tissue. Over the next 6 years, they characterized the cells and showed that cardiac stem cells do slowly renew a fraction of heart cells over the course of our lives. These results ignited the hope that it was possible to use cardiac stem cells to treat cardiovascular diseases. Over ten years of basic research has finally provided enough proof to warrant clinical trials in humans and there are currently four ongoing trials. These trials are testing autologous cardiac progenitor cells: ALCADIA for ischemic heart disease, CADUCUES for recent myocardial infarction, TICAP for heart failure and SCIPIO for heart failure due to myocardial infarction.

The interim results form the phase I SCIOIO trial show promise. Patients in the treatment process of the trial received their own cardiac stem cells which were isolated from heart biopsies and expanded in vitro. Up to 1 million cardiac stem cells were injected via balloon catheter into the coronary artery supplying the damaged heart tissue. Although the study was designed to test the safety and feasibility of the procedure, which it did, the post-study follow up has shown some increase in heart function and a decrease in infarct size up to one year after the treatment in 14 of the 16 patients. The next step in this trial will be to perform a larger phase 2 trial that will specifically test for the ability of cardiac stem cells to regenerate heart tissue that has died following myocardial infarction.

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Endothelial Progenitor Cells (EPCs)

Endothelial progenitor cells are thought to originate from stem cells in the bone marrow and are characterized by their ability to make the endothelial cells that line blood vessels throughout the body. The process of making new blood vessels, called neovascularization, is a crucial step towards promoting the regeneration of damaged heart tissue. Scientists are still debating on how to precisely characterize EPSs, but CD34 and CD133 have been suggested as important markers.

A handful of clinical trials are exploring the potential of these cells to contribute to the formation of new blood vessels in regions of cardiac damage found inpatients with cardiomyopathy, myocardial infarction, coronary artery disease and heart failure.

Mesenchymal Stem Cells

Mesenchymal stem cells can be found in a number of different tissues in our bodies. The most common source for these cells for use in clinical trials today is bone marrow or fat tissue. MSCs offer some advantages over HSCs in that they are extremely versatile and easily differentiated into a variety of cell types. These include fat cells, fibroblasts, bone and muscle cells. Another benefit to these cells is that they have a moderating effect on the immune system and because of this they can be transplanted from one individual to another without the same need for immunosuppressant drug therapy. This benefit will allow these cells to be manufactured in large batches in a more commercially viable way. Many of the clinical trials that are currently underway are looking at assessing the potential of MSCs to treat cardiovascular disease. These include APOLLO for the treatment of myocardial infarction, PPRECISE for nonvascularizable ischemic myocardium and PROCHYMAL for acute myocardial infarction.

PROCHYMAL was a phase I, randomized, double blind, placebo controlled, dose escalation study which demonstrated that allogeneic (not from the patient) human mesenchymal stem cells could be safely transplanted into patients after acute myocardial infarction. At six months after the procedure, patients in the treatment phase had improved cardiac function. These results have provided justification for further trials using MSCs.

Scientists know that it can take years to bring new therapies to patients and that fact that clinical trials using stem cells for heart failure are being actively pursued tells us about the massive achievements that have already been made in basic and clinical research. As these trial progress, their results should help to inform, refine and define future research questions. This in turn will provide a platform from which new trials will be able to launch. All in all, this will bring us even closer to being able to use stem cells as a front line treatment for heart failure and other cardiac diseases.

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